In this study, a slow-release urea fertilizer hydrogel was synthesized from hydroxyl propyl methyl cellulose, polyvinyl alcohol and glycerol blends with paper (blended paper) as second layer. The fertilizer hydrogel was characterized by SEM, XRD and FTIR. Its retention in sandy soil, swelling behavior in distilled and tap water as well as slow-release behavior to urea were investigated. The results indicated that the fertilizer had good slow-release properties and ability to retain water in soil. However, the addition of blended paper as a second layer matrix was found to help improve the release properties of the fertilizer. The swelling kinetic of the hydrogel followed the Schott’s Second order model. The release kinetics of urea in water was best described by the Zero order model signifying that the release behavior was independent of fertilizer concentration

Telehealth is the delivery of many health care services and technologies to individuals at different geographical areas and is categorized as asynchronously or synchronously. The coronavirus disease 2019 (COVID-19) pandemic has caused major disruptions in health care delivery to breast cancer (BCa) patients and there is increasing demand for telehealth services. Globally, telehealth has become an essential means of communication between patient and health care provider. The application of telehealth to the treatment of BCa patients is evolving and increasingly research has demonstrated its feasibility and effectiveness in improving clinical, psychological and social outcomes. Two areas of telehealth that have significantly grown in the past decade and particularly since the beginning of the COVID-19 pandemic are telerehabilitation and teleoncology. There two technological systems provides opportunities at every stage of the cancer care continuum for BCa patients. We conducted a systematic literature review that examined the use of telehealth services via its various modes of delivery among BCa patients particularly in areas of screening, diagnosis, treatment modalities, as well as satisfaction among patients and health care professionals. The advantages of telehealth models of service and delivery challenges in delivery to patients in remote arears are discussed.

Nanostructured carriers have been widely used in pharmaceutical formulations for dermatological treatment. They offer targeted drug delivery, sustained release, improved biostability, and low toxicity, usually presenting advantages over conventional formulations. Due to its large surface area, small size and photothermal properties, graphene oxide (GO) has the potential to be used for such applications. Nanographene oxide (GOn) presented average sizes of 197.6 ± 11.8 nm, and a surface charge of -39.4 ± 1.8 mV, being stable in water for over 6 months. 55.5 % of the mass of GOn dispersion (at a concentration of 1 mg mL-1) permeated the skin after 6 h of exposure. GOn dispersions have been shown to absorb near-infrared radiation, reaching temperatures up to 45.7 °C, within mild photothermal therapy temperature range. Furthermore, GOn in amounts superior to those which could permeate the skin were shown not to affect human skin fibroblasts (HFF-1) morphology or viability, after 24 h of incubation. Due to its large size, no skin permeation was observed for graphite particles in aqueous dispersions stabilized with Pluronic P-123 (Gt-P-123). Altogether, for the first time, GOn potential as a topic administration agent and for delivery of photothermal therapy has been demonstrated.

Introduction: Despite more than one year passed since the first cases of SARS-CoV-2 were reported, there is still no consensus on the definition and clinical management of post-acute-COVID-19. The condition has heterogeneously been named as Chronic COVID syndrome, Post COVID-19 Syndrome, post-acute sequela of SARS-CoV-2 (PASC), and the more familiar long COVID. Method: In order to capture all relevant published studies, we undertook a multi-step search with no language restriction. The following four-step search strategy was utilized: First, a preliminary (limited) search was conducted on January 20, 2021, in Google Scholar and PubMed to identify the appropriate keywords. Then, on January 30, 2021, we adopted a search strategy of electronic databases from Cochrane Library, PsycINFO, PubMed, Embase, Scopus, and Web of sciences, using those keywords. Then, after duplicate removal, we screened all titles, abstracts, and full texts. This resulted in 66 eligible studies. Subsequently, after a forward and backward search of their references and citations an additional 54 publications were found, resulting in a total of 120 publications that formed the basis of the present analysis. The titles, abstracts, and full-texts of non-English articles were translated using Google Translate for further evaluation. We conducted our scoping review based on the PRISMA-ScR Checklist.Results: We found only one randomized clinical trial in our search. Of the 67 original studies, 22 were cohort and 28 were cross-sectional studies totaling 74.6% of the original studies. Of the total of 120 publications, 59 (49.1%) focused on signs and symptoms, 28 (23.3%) were focused on management, and 13 (10.8%) focused on pathophysiology. Ten (9%) publications focused on imaging studies. Ninety-one percent of the original investigations came from high and upper-middle-income countries, highlighting the scarcity of reports originating from low-income and lower-middle-income countries.Conclusion: The predominant symptoms among those with the so-called “Long COVID” were: fatigue, breathlessness, arthralgia, sleep difficulties, and chest pain. Recent reports also point to the risk of long-term sequela with cutaneous, respiratory, cardiovascular, musculoskeletal, mental health, neurologic, and renal involvement in those who survive the acute phase of the illness. The ambiguity and controversies in its definition have impaired proper recognition and management of those requiring additional support following the resolution of the acute phase of this infection. This has resulted in long-standing distress for the patients and their families. Our findings highlight the need for a multidisciplinary approach, support, and rehabilitation for these patients in terms of long-term mental and physical health.

The Mediterranean Sea is one of the most impacted basin in terms of microplastics pollution. Land-based activities are the major sources of plastic litter to the ocean, with harbors probably representing significant hotspots. In the framework of the SPlasH! project (Stop alle Plastiche in H2O, Interreg Marittimo project), microplastics were sampled in three north-western Mediterranean harbors during summer and winter. In this study, the areal concentrations of microplastics ranged from 5,576 to 379,965 items.km-2. A decreasing gradient was observed from the inner to the outer zones of the studied harbors, pointing out these enclosed systems as hotspots regarding microplastic pollution. During the summer, because of an enhancement of port activities, the areal concentrations of microplastics were higher than in winter. The investigation microplastics size classes distribution in the surface waters revealed that microplastic within a size range between 300 µm and 500 µm were depleted. During this study, we assessed trace metal partitioning (Pb, Fe, Cu, V, Cd and As) between the dissolved phase and biofilm, thus highlighting concentrations within the biofilm two and six orders higher than those in the dissolved phase. This result strongly suggest trace metal bioaccumulation within the biofilm. When trace metal concentrations are normalized over the corresponding surface of microplastics and microplastics, higher values were obtained for microplastics evidencing their enhanced capacities to bioaccumulate contaminants with respect to macroplastics.

Probiotics make up a large and growing segment of the commercial market of dietary supplements and are touted as offering a variety of human health benefits. Some of the purported positive impacts of probiotics include, but are not limited to, stabilization of the gut microbiota, prevention of gastrointestinal disorders and modulation of the host immune system. Current research suggests that the immunomodulatory effects of probiotics are strain specific and vary in mode of action. Here, we examined the immunomodulatory properties of Bacillus subtilis strain DE111 in a healthy human population. In a randomized, double blind, placebo-controlled four-week intervention, we examined peripheral blood mononuclear cells (PBMCs) at basal levels pre- and post-treatment as well as in response to stimulation with bacterial lipopolysaccharide (LPS). We observed an anti-inflammatory effect of B. subtilis, manifested as a decrease in immune cell populations within the basal state along with an increase in anti-inflammatory immune cells in response to LPS stimulation. Overall gastrointestinal health, microbiota, and circulating and fecal markers of inflammation and gut barrier function were largely unaffected by DE111 treatment. These data suggest that the novel probiotic B. subtilis DE111 may have clinical applications in modulating immune homeostasis via anti-inflammatory mechanisms.

Overweight and obesity adversely affect health-related quality of life (HRQOL) through day-to-day impairments of both mental and physical functioning. It is assumed that polyphenols within the Mediterranean diet may contribute to improve HRQOL. This investigation aimed at studying the effects of a polyphenol-rich ingredient on HRQOL in overweight and obese but otherwise healthy individuals. A randomized, double-blind, placebo-controlled study including 72 volunteers was conducted. Subjects were randomly assigned to receive for a 16-week period either 900 mg/day of the supplement or a placebo. Dietary recommendations were individually determined, and intakes were recorded; daily physical mobility was monitored. Improvement of HRQOL was set as the primary outcome and assessed at baseline and at the end of the investigation, using the Short-Form 36 (SF-36) Health survey. Body composition was analyzed using dual-energy X-ray absorptiometry (DXA). Physical activity level was calculated using International Physical Activity Questionnaire (IPAQ). After 16 weeks, despite there was no adherence to the Mediterranean Diet Serving Score (MDSS), supplemented individuals experienced significant HRQOL improvement (+5.3%; P=0.001), including enhanced perceived physical (+11.2%; P=0.002) and mental health (+4.1%; P=0.021) components; bodily pain, vitality, and general health, being the greatest contributors. Besides, body fat mass significantly decreased (-1.2 kg; P=0.033), mainly within trunk area (-1.0 kg; P=0.002). Engagement in physical activity significantly increased (+1308 Met-min/week; P=0.050). Hence, chronic supplementation with a nutritional diversity and dose of a Mediterranean diet-inspired polyphenol-rich ingredient resulted in a significant amelioration in both perceived physical and mental health, concomitant with the improvement of body composition, in healthy subjects with excessive adiposity.

Background: The Corona Virus Disease 2019 (COVID-19) is spreading globally now. However, the clinical presentation that predict prognosis of the patients are still largely unknow. Methods: We enrolled 393 patients infected with COVID-19 and 30 patients with common pulmonary bulla and reviewed their clinical features to evaluate the potential prognostic value of pulmonary vesicles, especially in the patients with severe symptoms. One COVID-19 patient with vesicles was treated by bullectomy for last resort, and its characteristics of the patient’s perioperative laboratory tests was analyzed. The pathological findings of bullectomy were described and compared with those of common bulla cases. Results: Patients infected with COVID-19 showed more dependence on ventilator, occurrence of super resistant bacteria, and prone to vesicle formation than common bulla (p<0.05). Disease severity is associated with age, sex, and usage of ventilator, ECMO and antibiotics, super resistance bacteria and vesicle formation (p<0.05). The average mortality rate of COVID-19 patients was 4.10% (25.4% in severe patients, 0.00% in mild patients). Interestingly, the mortality rate further increased in severe patients with pulmonary vesicles than those without pulmonary vesicles (35.7% vs 22.4%, p=0.0442). One COVID-19 patient with vesicles underwent bullectomy and had a poor prognosis, who showed diffuse alveolar damage and extensive necrosis in bullectomy specimen. Conclusions: Patients infected with COVID-19 are more prone to form pulmonary vesicles showed on chest CT scans, as an important poor prognosis factor, especially in the severe patients.

Malignant gliomas are heterogeneous neoplasms. Glioma stem-like cells (GSCs) are undifferentiated and self-renewing cells that develop and maintain these tumors. These cells are the main population that resist current therapies. Genomic and epigenomic analyses has identified various molecular subtypes. Bone morphogenetic protein 4 (BMP4) reduces the number of GSCs through differentiation and induction of apoptosis, thus increasing therapeutic sensitivity. However, the short half-life of BMP4 impedes its clinical application. We have previously reviewed BMP4 signaling in central nervous system development and glioma tumorigenesis and its’ potential as a treatment target in human gliomas. Recent advances in understanding both adult and pediatric malignant gliomas highlight critical roles of BMP4 signaling pathways in the regulation of tumor biology, and indicate its’ potential as a therapeutic molecule. Furthermore, significant progress has been made on synthesizing BMP4 biocompatible delivery materials, which can bind to and markedly extend BMP4 half-life. Here, we review current research associated with BMP4 in brain tumors, especially in pediatric malignant gliomas. We also summarize BMP4 delivery strategies, with a focus on biocompatible BMP4 binding peptide amphiphile nanostructures as promising novel delivery platforms for treatment of these devastating tumors.

We report an easy-to-implement device for SERS-based detection of various analytes dissolved in water droplets at trace concentrations. The device combines an analyte-enrichment system and SERS-active sensor site, both produced via inexpensive and high-performance direct fs-laser printing. Fabricated on a surface of water-repellent polytetrafluoroethylene substrate as an arrangement of micropillars, the analyte-enrichment system supports evaporating water droplet in the Cassie-Baxter superhydrophobic state, thus ensuring delivery of the dissolved analyte molecules towards the hydrophilic SERS-active site. The efficient pre-concentration of the analyte onto the sensor site based on densely-arranged spiky plasmonic nanotextures results in its subsequent label-free identification by means of SERS spectroscopy. Using the proposed device, we demonstrate reliable SERS-based fingerprinting of various analytes, including common organic dyes and medical drugs at ppb concentrations. The proposed device is believed to find applications in various areas, including label-free environmental monitoring, medical diagnostics, and forensics.

A large body of evidence has linked unhealthy eating patterns with an alarming increase in obesity and chronic disease worldwide. However, existing methods of assessing dietary intake in nutritional epidemiology rely on food frequency questionnaires or dietary records that are prone to bias and selective reporting. Herein, metabolic phenotyping was performed on 42 healthy participants from the Diet and Gene Intervention (DIGEST) pilot study, a parallel two-arm randomized clinical trial that provided complete diets to all participants. Matching urine and plasma specimens were collected at baseline and following 2 weeks of provision of either a Prudent or Western diet with a weight-maintaining menu plan designed by a dietician. Targeted and nontargeted metabolite profiling was conducted using three complementary analytical platforms, where 80 plasma metabolites and 84 creatinine-normalized urinary metabolites were reliably measured (CV < 30%) in the majority of participants (> 75%) after implementing a rigorous data workflow for metabolite authentication with stringent quality control. We classified a panel of metabolites with distinctive trajectories following 2 weeks of food provisions when using complementary univariate and multivariate statistical models. Unknown metabolites associated with contrasting dietary patterns were identified with high resolution MS/MS and/or co-elution after spiking with authentic standards. Overall, 3-methylhistidine and proline betaine concentrations increased consistently after participants were assigned a Prudent diet (q< 0.05) in both plasma and urine samples with a corresponding decrease in the Western diet group. Similarly, creatinine-normalized urinary imidazole propionate, hydroxypipecolic acid, dihydroxybenzoic acid, and enterolactone glucuronide, as well as plasma ketoleucine and ketovaline increased with a Prudent diet (p< 0.05) after adjustments for age, sex and BMI. In contrast, plasma myristic acid, linoelaidic acid, linoleic acid, a-linoleic acid, pentadecanoic acid, alanine, proline, carnitine and deoxycarnitine, as well as urinary acesulfame K increased among participants following a Western diet. Most metabolites were also correlated (r > ±0.30, p< 0.05) to changes in average intake of specific nutrients from self-reported diet records reflecting good adherence to assigned food provisions. Our study revealed robust biomarkers sensitive to short-term changes in habitual diet for accurate monitoring of healthy eating patterns in free-living populations, which is required for validating evidence-based public health policies for chronic disease prevention.

We compared the efficacy of a tailored and a targeted intervention designed to increase clinical breast exam (CBE), mammography, and genetic services/testing among young breast cancer survivors (YBCS) (diagnosed <45 years old) and their blood relatives. A two-arm cluster randomized trial recruited a random sample of YBCS from the Michigan cancer registry and up to two of their blood relatives. Participants were stratified according to race and randomly assigned as family units to the tailored (n=637) or the targeted (n=595) intervention. Approximately 40% of participants were Black; 12% YBCS and 27% relatives were living in more than 20 different U.S. States. Higher screening rates were reported by YBCS (CBE p=0.05; mammography p=0.04) and relatives (CBE p<0.01; mammography p=0.04) in the tailored arm, and by White/Other YBCS (CBE p=0.02) and relatives (CBE p<0.01; mammography p=0.03). YBCS genetic testing rates increased from 22% to 26% (p=0.11). Black YBCS and relatives reported higher self-efficacy and intention for genetic testing, and higher satisfaction and intervention acceptance. The tailored intervention improved CBE and mammography uptake - despite having minimal contact with participants. Professional referrals will improve genetic testing uptake. Intervention materials increased self-efficacy and satisfaction for Black women but could not overcome multiple access barriers.

Background: Zika virus (ZIKV) infection has significantly affected Latin America in 2015–2017. Most studies have been reported from Brazil and Colombia, and only a few from Central America. For these reasons we analyzed the incidence, incidence rates and evolution of cases in Honduras from 2016–2017. Methods: Using epidemiological weeks (EW) surveillance data on the ZIKV epidemics in Honduras, we estimated incidence rates (cases/100,000 population), and developed maps at national, departmental and municipal levels. Results: From 1 January 2016 to 31 December 2017, a total of 32,607 cases of ZIKV were reported (98.5% in 2016 for an incidence rate of 36.85 cases/100,000 pop; 1% confirmed by RT-PCR). The highest peak was reached on the EW 6°, 2016 (2,559 cases; 29.34 cases/100,000 pop). The department with the highest number of cases and incidence rate was Cortés (13,128 cases, 791.08 cases/100,000 pop in 2016). Discussion: The pattern and evolution of ZIKV infection in Honduras has been similar to that which occurred for chikungunya in 2015. As previously reported, infection with chikungunya involved predominantly the central and capital area of the country, reaching incidences there >750 cases/100,000 pop. Studies using geographical information systems linked with clinical disease characteristics are necessary to attain accurate epidemiological data for public health systems. Such information is also useful for assessment of risk for travelers who visit specific areas in a destination country.

As a universal pathogen leading to neonatal defects and transplant failure, Human cytomegalovirus (HCMV) has strict species specificity that the inability to using this virus in animals has hampered its pathogenesis study. However, the mechanism of cross-species barrier remains elusive that no non-human cell model has been established to fill this knowledge gap. We observed that primary dermis fibroblasts (TSDF) isolated from the Chinese tree shrew (Tupaia belangeri chinensis), a small laboratory animal with close affinity to primates, were permissive to HCMV replication. In TSDF infected with GFP-expressing HCMV, the green fluorescence and cytopathic effect were observed and the expression of 3 kinetic genes and replication of viral genome were detected. The cell-free viruses produced in TSDF reached 103 pfu/mL at 96 hpi, which were 10-fold lower than in primary human foreskin fibroblasts. Our results demonstrated that TSDF supported low level of lytic replication of HCMV. The TSDF model provides a useful platform for the mechanism study of species barrier of HCMV.

Heavy metals are compounds that can be hazardous and impair growth of living organisms. Bacteria have evolved the capability not only to cope with heavy metals but also to detoxify polluted environments. Three heavy metal-resistant strains of Mucilaginibacer rubeus and one of Mucilaginibacter kameinonensis were isolated from the gold/copper Zijin mining site, Longyan, Fujian, China. These strains were shown to exhibit high resistance to heavy metals with minimal inhibitory concentration reaching up to 3.5 mM Cu(II), 21 mM Zn(II), 1.2 mM Cd(II), and 10.0 mM As(III). Genomes of the four strains were sequenced by Illumina. Sequence analyses revealed the presence of a high abundance of heavy metal resistance (HMR) determinants. One of the strain, M. rubeus P2, carried genes encoding 6 putative P1B-1-ATPase, 5 putative P1B-3-ATPase and 4 putative Zn(II)/Cd(II) P1B-4 type ATPase, and 16 putative RND-type metal transporter systems. Moreover, the four genomes carry a high abundance of genes coding for putative metal binding chaperones. Analysis of the close vicinity of these HMR determinants uncovered the presence of clusters of genes potentially associated with mobile genetic elements. These loci include genes coding for tyrosine recombinases (integrases) and subunits of mating pore (type 4 secretion system) respectively allowing integration/excision and conjugative transfer of numerous genomic islands. Further in silico analyses revealed that their genetic organization and gene products resemble the Bacteroides integrative and conjugative element CTnDOT. These results highlight the pivotal role of genomic islands in the acquisition and dissemination of adaptive traits, allowing for rapid adaption of bacteria and colonization of hostile environments.

Huntington's disease (HD) is a progressive and fatal neurodegenerative disease caused by CAG repeat expansion in the coding region of huntingtin (HTT) protein. The accumulation of mutant HTT (mHTT) contributes to neurotoxicity by causing autophagy defects and oxidative stress that ultimately lead to neuronal death. Interestingly, epidemiologic studies have demonstrated that the prevalence of type-2 diabetes, a metabolic disease mainly caused by defective insulin signaling, is higher in patients with HD than in healthy controls. Although the precise mechanisms of mHTT-mediated toxicity remain unclear, the blockade of brain insulin signaling may initiate or exacerbate mHTT-induced neurodegeneration. In this study, we used an in vitro HD model to investigate whether neuronal insulin signaling is involved in mHTT-mediated neurotoxicity. Our results demonstrated that mHTT overexpression significantly impairs insulin signaling and causes apoptosis in neuronal cells. However, treatment with liraglutide, a GLP-1 analogue, markedly restores insulin sensitivity and enhances cell viability. This neuroprotective effect may be attributed to the contribution of the upregulated expression of genes associated with endogenous antioxidant pathways to oxidative stress reduction. In addition, liraglutide stimulates autophagy through AMPK activation, which attenuates the accumulation of HTT aggregates within neuronal cells. Our findings collectively suggest that liraglutide can rescue impaired insulin signaling caused by mHTT and that GLP-1 may potentially reduce mHTT-induced neurotoxicity in the pathogenesis of HD.

Transport of hydrophobic drugs in the human body exhibits complications due to the low solubility of these compounds. With the purpose of enhancing the bioavailability and biodistribution of such drugs, recent studies have reported the use of amphiphilic molecules, such as phospholipids, for synthesis of nanoparticles or nanocapsules. Given that phospholipids can self–assemble in liposomes or micellar structures, they are ideal candidates to function as vehicles of hydrophobic molecules. In this work, we report mesoscopic simulations of nanoliposomes, constituted by lecithin and coated with a shell of chitosan. The stability of such structure and the efficiency of encapsulation of capsaicin, as well as the internal and superficial distribution of capsaicin and chitosan inside the nanoliposome were analyzed. The characterization of the system was carried out through density maps and the potentials of mean force for the lecithin–capsaicin, lecithin–chitosan and capsaicin–chitosan interactions. The results of these simulations show that chitosan is deposited on the surface of the nanoliposome, as has been reported in some experimental works. It was also observed that a nanoliposome of approximately 18 nm in diameter is stable during the simulation. The deposition behavior was found to be influenced by pattern of N-acetylation of chitosan.

Pesticide exposure is a growing concern for public health. Although Brazil is the world's largest consumer of pesticides, few studies addressed the health effects among farmers. This study aimed to evaluate whether pesticide exposure is associated with respiratory outcomes among rural workers and relatives in Brazil during the crop and off-seasons. 82 family farmers were interviewed about occupational history and respiratory symptoms, and cholinesterase tests were conducted in the crop-season. Spirometry was performed during the crop and off-season. Respiratory outcomes were compared between seasons and multiple regressions were conducted to search for associations with exposure indicators. Participants were occupationally and environmentally exposed to multiple pesticides from an early age. During the crop and off-season, respectively, they presented a prevalence of 40% and 30.7% for cough, 30.7% and 24% for nasal allergies, and 24% and 17.3% for chest tightness. Significant relations between spirometry impairments and exposure indicators were found both during the crop and off-season. These findings provide complementary evidence about the association of pesticide exposure with adverse respiratory effects among family farmers in Brazil. This situation requires special attention as it may increase the risk of pulmonary dysfunctions, and the morbidity and mortality burden associated with these diseases.

To make low-cost catalytic materials that mimic the activity of tyrosinase enzymes (Catechol oxidase) is an exciting challenge of biochemical technology. Herein, we report the synthesis of a series of acylhydrazone-pyrazoles based biomolecule materials (L1-L7) with superior catecholase activity. These biomolecules were synthesized by a one pot chemical condensation between 5-methyl-1H-pyrazole-3-carbohydrazide and benzaldehyde derivatives. The X-ray single crystal diffraction (XRD) for two ligands L1 and L2 have been studied and the molecular structures were optimized and confirmed using the density functional theory (DFT/B3LYP) method. Copper (II) complexes of the biomolecules (L1-L7), generated in-situ, and were studied for their catalytic activities towards the oxidation reaction of catechol to ortho-quinone according to two parameters: the nature of the ligand and the nature of counter anion. The L7-CuSO4 was found to have an excellent catalytic activity (105.42 μmol·L−1·min−1) among the catalysts recently reported in the existing literature.

Historic expeditions are events that are flavored by exploratory, scientific, military or geographic characteristics. Such events are often documented in literature, journey notes or personal diaries. A typical historic expedition involves multiple site visits and their descriptions contain spatiotemporal and attributive contexts. Expeditions involve movements in space that can be represented by triplet features (location, time and description). However, such features are implicit and innate parts of textual documents. Extracting the geospatial information from these documents requires understanding the contextualized entities in the text. To this end, we developed a semi-automated framework that has multiple Information Retrieval and Natural Language Processing components to extract the spatiotemporal information from a two-volumes historic expedition gazetteer. Our framework has three basic components, namely, the Text Preprocessor, the Gazetteer Processing Machine and the JAPE (Java Annotation Pattern Engine) Transducer. We used the Brazilian Ornithological Gazetteer as an experimental dataset and extracted the spatial and temporal entities from entries that refer to three expeditioners’ site visits and mapped the trajectory of each expedition using the extracted information. Finally, one of the mapped trajectories was manually compared with a historical reference map of that expedition to assess the reliability of our framework. The reference map was manually prepared in previous research work by others.

Breast Cancer Associated Susceptibility Proteins Type 1/2 (BRCA1/2) promote cellular functioning by modulating NRF2-mediated antioxidant signaling. Redox failure in women with BRCA1/2 insufficiency increases the risk for breast/ovarian/uterine cancers. Risk‐reducing salpingo‐oophorectomy (RRSO) is a prophylactic surgery of the reproductive organs, which is frequently conducted by the age of 40 to lower the occurrence of cancer in women with BRCA1/2 mutations. However, abrupt estrogen decline following RRSO causes ovarian failure, which implicates various cellular physiological processes, resulting in increased release of free radicals and subsequent severe onset of menopausal symptoms. Comfort measures (e.g., hormonal replacement therapy (HRT) and mindfulness-based stress reduction (MBSR)) may improve chronological menopause-related quality of life, but their specific effects are not clear in women with gene mutations. Aiming to fill the gap, this study used path analysis to examine the effects of HRT and MBSR on menopausal symptoms among RRSO patients (N = 199, mean age = 50.5 ± 6.7 years). HRT alleviated menopausal symptoms in BRCA2 carriers and women who were physically active, premenopausal at the time of RRSO, had a high BMI, and had no history of breast cancer. It increased the severity of urogenital symptoms in those with a history of cancer. MBSR, on the other hand, was associated with increased intensity of most menopausal symptoms. The results suggest that young women undergoing recent RRSO may benefit from HRT at an individual level while their need for extensive measures to optimize their psychological wellbeing is ongoing. Adverse effects of MBSR, which are captured in the present study imply that MBSR may interfere with redox sensitivity associated with estradiol fluctuations in BRCA1/2 carriers. Investigations are needed to test this hypothesis and elaborate on the underlying mechanisms in those women.

Targeted image-guided oncologic surgery (IGOS) relies on the recognition of cell surface-associated proteins, which should be abundantly present on the tumor cells but preferably absent on cells in surrounding healthy tissue. The transmembrane receptor tyrosine kinase EphA2, a member of the A class of the Eph receptor family, has been reported to be highly overexpressed in several tumor types including breast, lung, brain, prostate, and colon cancer, and is considered amongst the most promising cell membrane-associated tumor antigens by the NIH. Another member of the Eph receptor family belonging to the B class, EphB4, has also been found to be up-regulated in multiple cancer types. In this study, EphaA2 and EphB4 are evaluated as target for IGOS of colorectal cancer by immunohistochemistry (IHC) using a tissue microarray (TMA) consisting of 168 pairs of tumor and normal tissue. The IHC sections were scored for staining intensity and percentage of cells stained. The results show a significantly enhanced staining intensity and more widespread distribution in tumor tissue compared with adjacent normal tissue for EphA2 as well as EphB4. Based on its more consistently higher score in colorectal tumor tissue compared to normal tissue, EphB4 appears to be an especially promising candidate for IGOS of colorectal cancer.

This study assessed the impact of inoculation with plant growth-promoting bacteria (PGPB) on stress-resistance and growth-promoting metabolites in Salicornia europaea L. across controlled and field conditions. Salicornia europaea seeds, inoculated with Brevibacterium casei EB3 and Pseudomonas oryzihabitans RL18, were grown in controlled laboratory experiments and in a nat-ural field setting. Metabolite composition was analyzed using GC-MS and UHPLC-MS. Under controlled conditions, PGPB inoculation significantly increased levels of unsaturated fatty acids, sugars, citric acid, acetic acid, chlorogenic acids, and quercetin. Inoculation under field condi-tions increased glucose, fructose, quercetin, and apigenin, alongside decreased unsaturated fatty acids and sterols, indicating a stress response shift in plant metabolism. Under controlled condi-tions, enhanced metabolite profiles induced by inoculation likely contributed to augmented bio-mass production and environmental stress resistance. Field plants revealed distinct phytochemi-cal profiles, suggesting higher stress levels. However, the accumulated metabolites from inocula-tion could enhance the plant's ability to cope with adverse conditions and improving stress tol-erance. This study unveils the intricate metabolic adaptations of Salicornia europaea under con-trolled and field stress conditions, highlighting PGPB's potential to enhance plant stress tolerance. Elevated stress-related metabolites may fortify plant defense mechanisms, laying the ground-work for stress-resistant crop development through PGPB-based inoculants, especially in saline agriculture.

The ribonuclease H (RNase H) active site of HIV-1 reverse transcriptase (RT) is the only viral enzyme not targeted by approved antiretroviral drugs. Using a fluorescence-based in vitro assay, we screened 65,239 compounds at a final concentration of 10 µM to identify inhibitors of RT RNase H activity. We identified 41 compounds that exhibited 50% inhibitory concentration (i.e., IC50) values &lt; 1.0 µM. Two of these compounds, 2-(4-methyl-3-(piperidin-1-ylsulfonyl)phenyl)benzo[d]isothiazol-3(2H)-one (1) and ethyl 2-(2-(3-oxobenzo[d]isothiazol-2(3H)-yl)thiazol-4-yl)acetate (2), which both share the same benzisothiazolone pharmacophore, demonstrate robust antiviral activity (50% effective concentrations of 1.68 ± 0.94 µM and 2.68 ± 0.54, respectively) in the absence of cellular toxicity. A limited structure-activity relationship analysis identified two additional benzisothiazolone analogs, 2-methylbenzo[d]isothiazol-3(2H)-one (3) and N,N-diethyl-3-(3-oxobenzo[d]isothiazol-2(3H)-yl)benzenesulfonamide (4), which also resulted in inhibition of RT RNase H activity and virus replication. Compounds 1, 2 and 4, but not 3, inhibited the DNA polymerase activity of RT (IC50 values ~ 1 to 6 µM). In conclusion, benzisothiazolone derivatives represent a new class of multifunctional RT inhibitors that warrants further assessment for the treatment of HIV-1 infection.

Strain L. fermentum U-21 secretes chaperones into the medium and it is considered as the candidate for the development of drugs, so-called disaggregases, for Parkinson’s disease therapy. This study is devoted to characterization of secreted protein encoded by C0965_000195 locus. Analysis of sequence and predicted structure of the protein encoded by C0965_000195 allows us to attribute it to the ClpL, homologs of which are known to be chaperones. The chaperone activity of ClpL L. fermentum U-21 was evaluated in vivo by refolding of differing in thermostability luciferases from Aliivibrio fischeri and Photorhabdus luminescens in Escherichia coli cells. It was observed that clpL from L. fermentum U-21 can compensate for the deficiency in the clpB gene and enhance the ability to refold thermodenatured proteins in clpB- cells. In vitro experiments have demonstrated the ability of a spent culture medium containing proteins secreted by L. fermentum U-21 cells, including ClpL, to prevent thermodenaturation of luciferases partially.We suggest that the ClpL protein from L. fermentum U-21 strain, which exhibits disaggregase properties against aggregating proteins, may be one of the clue components that play a role in the pharmabiotic properties of this strain.

Background: Obesity is a global health crisis with a rapidly increasing prevalence among university students. Medical students are a unique population that may be at a higher risk of obesity due to the demanding nature of their studies and the associated stress. Objective: This study aimed to determine the prevalence of overweight, obesity, and the associated risk factors among medical students at Jazan University in Saudi Arabia. Methods: A cross-sectional study was conducted among 228 medical students from their 2nd to 6th academic years at the Faculty of Medicine, Jazan University. A self-administered questionnaire was used to collect data regarding sociodemographic characteristics, physical activity, dietary habits, comorbidities, medication use, family history, and lifestyle factors. Anthropometric measurements including height, weight, and waist circumference were recorded. Chi-square test and binary logistic regression were used to identify the risk factors associated with obesity. Results: The prevalence of overweight and obesity among the participants was 13.3% and 15% respectively. Hence, the combined prevalence of overweight and obesity is 28.3%. The mean weight was 63.39 ± 18.93 kilograms, and the mean height was 163.48 ± 9.78 centimeters. On the other hand, 17.3% of participants had underweight whereas 54.4% had normal BMI. Most of the participants (61%) did not engage in regular exercise. A high proportion consumed fruits (82.9%) and vegetables (58.8%) 3 or fewer days per week, and 84.2% consumed 3 or fewer meals per day. Fast food consumption more than 3 days per week was reported by 42.1% of participants. Obesity was not significantly associated with sociodemographic factors, physical activity, dietary habits, comorbidities, medication use, or family histories. However, those with a monthly family income of 15,000-24,999 riyals had significantly lower odds of obesity than those in the lowest income group (OR 0.230, p = 0.045). Conclusion: The prevalence of overweight and obesity among medical students at Jazan University is high. Although no significant associations were found between obesity and most risk factors, this study highlights the need for interventions that promote healthy lifestyles among medical students. Further research is needed to identify effective strategies for preventing and managing obesity in this population.

Polyphenols and fermentable fibers have shown favorable effects on gut microbiota composition and metabolic function. However, few studies have investigated whether combining multiple fermentable fibers or polyphenols may have additive beneficial effects on gut microbial states. Here, an in vitro fer-mentation model, seeded with human stool combined from 30 healthy volunteers, was supplemented with blends of polyphenols (PP), dietary fibers (FB) or their combination (PPFB) to determine influence on gut bacteria growth dynamics and select metabolite changes. PP and FB blends independently lead to significant increases in the absolute abundance of select beneficial taxa, namely Ruminococcus bromii, Bifidobacterium spp., Lactobacillus spp. and Dorea spp. Total short chain fatty acid concentrations, relative to non-supplemented control (F), increased significantly with PPFB and FB supplementation, but not PP. Indole and ammonia concentrations decreased with FB and PPFB supplementation, but not PP alone while increased antioxidant capacity was only evident with both PP and PPFB. These findings demonstrated that, while the independent blends displayed selective positive impacts on gut states, combination of both blends provided an additive effect. The work outlines the potential of mixed substrate blends to elicit a broader positive influence on gut microbial composition and function to build resiliency toward dysbiosis.

Angiogenesis is a critical physiological response to ischemia but becomes pathological when dysregulated and driven excessively by inflammation. We recently identified a novel angiogenic role for tripartite-motif-containing protein 2 (TRIM2) whereby lentiviral shRNA-mediated TRIM2 knockdown impaired endothelial angiogenic functions in vitro. This study sought to determine whether these effects could be translated in vivo and to determine the molecular mechanisms involved. CRISPR/Cas9-generated Trim2–/– mice that underwent a periarterial collar model of inflammation-induced angiogenesis exhibited significantly less adventitial macrophage infiltration relative to wildtype (WT) littermates, concomitant with decreased mRNA expression of macrophage marker Cd68 and reduced adventitial proliferating neovessels. Mechanistically, TRIM2 knockdown in endothelial cells in vitro attenuated inflammation-driven induction of critical angiogenic mediators, including nuclear HIF-1α, and curbed the phosphorylation of downstream effector eNOS. Conversely, in a hindlimb ischemia model of hypoxia-mediated angiogenesis, there were no differences in blood flow reperfusion to the ischemic hindlimbs of Trim2–/– and WT mice despite a decrease in proliferating neovessels and arterioles. TRIM2 knockdown in vitro attenuated hypoxia-driven induction of nuclear HIF-1α but had no further downstream effects on other angiogenic proteins. Our study has implications for understanding the role of TRIM2 in the regulation of angiogenesis in both pathophysiological contexts.

In recent years the number of available chemical pesticides has been significantly reduced and there have been an urgent need for discovery of alternative to chemical pesticides products, as among others the natural zeolites (zeolitic rocks). We determined the mineralogical and chemical composition of a specific and continuous layers of zeolitic rock sample (ZeotP) from Petrota, Ev-ros, Greece and evaluated its oviposition deterrent effect for the olive fruit fly Bactrocera oleae (Diptera: Terphritidae). The tested natural zeolite contained 70 wt. % Clinoptilolite, 18 wt. % Amorphous material, 7 wt. % Feldspars, 4 wt. % Cristobalite and 1 wt. % Quartz. We tested the oviposition deterrent effect of ZeotP mixed or not with an emulsifier adjuvant NU-FILM-P® in water and applied on the surface of olive fruits. The ZeotP oviposition deterrent effect for the ol-ive fly was very high under a series of tested temperatures (17°C, 20°C, 25°C and 30°C) and RHs (23%, 33%, 55%, 75%, 94%). In addition, the ZeotP residual deterrent effect after equable water spraying was high and similar to the respective effect of a pyrethroid insecticide (Decis®). Our results may contribute to an effective control of the olive fruit fly using an alternative to chemical pesticides natural zeolite (zeolitic rocks) product.

Antisense oligonucleotides (ASO), short single-stranded polymers based on DNA or RNA chemistries and synthesized in vitro, regulate gene expression by binding in a sequence-specific manner to an RNA target. The functional activity and selectivity in the action of ASOs largely depends on the combination of nitrogenous bases in a target sequence. This simple and natural property of nucleic acids provides an attractive route by which scientists can create different ASO-based techniques. Over the last 50 years, planned and realized applications in the field of antisense and nucleic acid nanotechnologies have produced astonishing results and posed new challenges for further developments, exemplifying the essence of the post-genomic era. Today the majority of ASOs are chemically modified and/or incorporated within nanoparticles to enhance their stability and cellular uptake. This review critically analyzes some successful cases using the antisense approach in medicine to address severe diseases, such as Duchenne muscular dystrophy and spinal muscular atrophy, and suggests some prospective directions for future research. We also examine in detail the elaboration of unmodified insect-specific DNA insecticides and RNA preparations in the areas of agriculture and forestry, a relatively new branch of ASO that allows circumvention of the use of non-selective chemical insecticides. When considering the variety of successful ASO modifications with an efficient signal-to-noise ratio of action, coupled with the affordability of in vitro oligonucleotide synthesis and post-synthesis procedures, we predict that the next half-century will produce a fruitful yield of tools created from effective ASO-based end products.

Marijuana is the most used illicit drug among youths in the United States. The objectives of the study were to identify the association between marijuana use and other risk behaviors including suicidality among high school students. The 2021 Mississippi Youth Risk Behavior Survey data sets were combined for this study. Crude odds ratio (OR) and adjusted odds ratio (AOR) with a 95% confidence interval were generated using the survey packages in R to account for weights and the complex sampling design of YRBS data. Tobacco products and alcohol use were significantly associated with marijuana use. Students who responded “Yes” to questions “currently used an electronic vapor product?”, “currently smoked cigarettes or cigars?” or “currently drank alcohol?” were more likely to use marijuana compared to students who responded “No”, after adjusting for other risk factors. Marijuana use is also significantly associated with students who had sex, compared to those who never had sex. The adjusted odds ratio is nearly doubled in those who had sex with the same sex or both sexes, compared to those who had heterosexual sex only. After adjusting for other health risk factors, the association between current marijuana use and attempted suicide was not statistically significant. The impact of students’ not sleeping in their parent's or guardian's home on current marijuana use was not significant after adjusting for other risk factors. Marijuana use is evenly burdened between males and females and between all race categories among Mississippi high school students. The identified associations seem to indicate that electronic vapor, tobacco products, and alcohol use could be the forerunners for drug use and should be treated accordingly in drug use prevention programs.

Introduction: During the COVID-19 pandemic, many countries implemented restrictions, social distancing measures, and lockdowns to limit the spread of the disease. The lockdowns have affected children’s screen time (ST), pain, and physical activity (PA) levels. The present study aimed to explore the relationships between several personal factors during the COVID-19 pandemic. Methods: The caregivers of 329 children (median age=8 years) filled out an online self-reported survey about the children’s PA, ST, and pain before, during, and after the COVID-19 curfew. Spearman’s rank correlation coefficient was used to explore the associations between these variables. Results: After the curfew, pain that existed before the pandemic had a weak negative relationship with PA intensity (-0.11, p=0.04) and a weak positive relationship with ST (r=+0.12, p=0.04). There was a strong positive relationship between ST in all time periods (p&gt;0.01). PA and ST had a weak negative relationship (p&gt;0.05) during the curfew and after the curfew but not before the COVID-19 pandemic. Age had a weak positive correlation with ST in all time periods (p&gt;0.01). In addition, ST was affected by the curfew. Conclusion: The study findings indicated that young children had longer ST during the curfew and after the curfew compared with before the curfew. Increasing PA could lessen children’s ST, which could, in turn, increase the probability that their general pain would decrease.

This study develops a hybrid machine learning (ML) algorithm integrated with IoT technology to improve the accuracy and efficiency of soil monitoring and tomato crop disease prediction in Anakapalle, a south Indian station. An IoT device collected one-minute and critical soil parameters—humidity, temperature, pH values, nitrogen (N), phosphorus (P), and potassium (K)—essential for assessing soil health and optimizing crop growth. Kendall's correlations were computed to rank these parameters for utilization in hybrid ML techniques. Various ML algorithms including K-Nearest Neighbors (KNN), Support Vector Machines (SVM), Decision Tree (DT), Random Forest (RF), and Logistic Regression (LR) were evaluated. A novel hybrid algorithm, 'Bayesian Optimization with KNN', was introduced to combine multiple ML techniques and enhance predictive performance. The hybrid algorithm demonstrated superior results with 95% accuracy, precision, and recall, and an F1 score of 94%, while individual ML algorithms achieved varying results: KNN (80% accuracy), SVM (82%), DT (77%), RF (80%), and LR (81%) with differing precision, recall, and F1 scores. This hybrid ML approach proved highly effective in predicting tomato crop diseases in natural environments, underscoring the synergistic benefits of IoT and advanced ML techniques in optimizing agricultural practices.

The objective of the described activity is to develop technologies or proposals that can be implemented within the cycle to enhance the relationship between climate change, water, energy, and food. The focus is on analyzing natural treatment systems for wastewater (NTSW) within the context of Macaronesia, considering factors such as life cycle assessment (LCA), carbon footprint, impacts, and mitigation capacity. The analysis of real case data from the Canary Islands and Cape Verde will inform the development of appropriate technologies tailored to different areas and scales within Macaronesia. This work includes a comprehensive life cycle analysis of the Santa Catarina (Cape Verde) NTSW. This analysis encompasses: a) Inventory analysis of the construction phase: This involves the assessment of inputs and outputs associated with the construction of the NTSW, including materials, energy consumption, transportation, and waste generation. The maintenance and operation phase is then evaluated, with a focus on the ongoing maintenance and operation activities required for the NTSW, including energy consumption, water usage, chemical inputs (if any), labour, and equipment maintenance. Finally, the impacts of the NTSW are evaluated. The environmental, social, and economic impacts generated by the NTSW are assessed. This includes an analysis of factors such as carbon emissions, water usage, land use, ecosystem impacts, human health effects, and economic costs. By conducting a comprehensive analysis of the Santa Catarina NTSW, the document aims to provide insights into the environmental performance and sustainability of the system. This information can then be used to identify areas for improvement, develop mitigation strategies, and inform decision-making processes regarding wastewater treatment technologies in Macaronesia. Furthermore, lessons learned from real case studies in the Canary Islands and Cape Verde can be applied to similar regions within the Macaronesia archipelago.

Although many physical activity (PA) interventions for older adults have proven ef-fective in controlled research settings, optimal implementation in real life remains challenging. This study identifies determinants perceived by stakeholders when im-plementing community-based PA interventions for older adults. We interviewed 31 stakeholders guided by the Consolidated Framework for Implementation Research (CFIR). Results showed that stakeholders are very specific about the role they can play in implementation making collaboration between stakeholders crucial. Barriers and motivators were identified in the CFIR intervention characteristics domain (relative advantage, complexity and costs, evidence quality and strength, and adaptability and trialability), in the outer setting domain (cosmopolitism, patient needs, and external policy and incentives), in the inner setting domain (implementation climate, relative priority, compatibility and organizational incentives and rewards) and in the individ-ual characteristics domain (knowledge and beliefs, and other personal attributes). An overarching theme was the stakeholders' emphasis on aiming for broad health goals in interventions, as they perceive PA as a means to reach these goals rather than an end in itself. Another overarching theme requiring attention in future implementation ef-forts is the need to tailor implementation efforts to the specific needs of older adults as the end users of the intervention.

Smart Transformer (ST)-based Meshed Hybrid AC/DC Microgrids (MHM) are a feasible alternative to increase the performance of conventional microgrids (MG) and to increase the penetration of Distributed Energy Resource (DER) at the same time, active and reactive power dispatch on the system. Despite this, MHMs present challenges in managing resources under uncertainties and controlling electronic converters associated with the ST and DER, making it complex to achieve optimal system performance. In this paper, a Data-Driven Distributionally Robust Optimization (DDDRO) for Day-Ahead Operation Planning of an ST-based MHM considering the reactive power dispatch of the DER that minimizes network losses, voltage deviations, and operation cost simultaneously, considering uncertainties of Photovoltaic Generators (PVG) and demand, is proposed. The Column and Constraint Generation (C&amp;CG) algorithm and Duality-Free Decomposition (DFD) method are adopted. Besides, the original mixed-integer non-linear planning problem is converted into a Mixed-Integer (MI) Second-Order Cone Programming (SOCP) problem through second-order cone relaxation and positive octagonal constraint method. Simulation experiments and results with a connected MHM system demonstrate the effectiveness and performance of the proposed model. Finally, we observe the effect of the meshed structure of MG and the positive impact of integrating the ST to form MHM, taking advantage of the degrees of freedom of this multi-stage converter for optimal energy management under uncertain conditions.

The knowledge of the precise anatomy and dimensions of the pulp chamber in the different teeth allows the odontologist to perform correct diagnosis, as well as treatment planning and moni-toring. The clinical practice has introduced cone-beam computed tomography (CB-CT) as a method to evaluate the morphology and dimensions of the pulp chamber. Nevertheless, micro-computed tomography (micro-CT) is regarded as the gold standard in approaching those topics. Here we have designed an algorithm that takes as input DICOM images from in vivo CB-CT of permanent molars to determine the accuracy CB-CT for evaluation of pulp chamber volume. The values were compared with those from in vivo CB-CT (rough and expert manipulated) and ex vivo micro-CT. The relative errors obtained with the volume calculated by the algorithm vs. the volume measured by micro-CT do not exceed 5.7%; also, no significant differences were found between algorithm volumes vs. manipulated CB-CT volumes while all volumes were different from those obtained with automatic CB-CT software. These data demonstrate that volume algorithm CB-CT based may be a reliable technique for evaluation of the pulp chamber volume in permanent molars and can be useful in the diagnosis of pulp diseases, as well as in the planning and monitoring of their treatments.

Papain-like protease PLpro, a domain within a large polyfunctional protein nsp3, plays key roles in the life cycle of SARS-CoV-2, being responsible for the first events of cleavage of a polyprotein into individual proteins (nsp1-4) as well as for the suppression of cellular immunity. Here, we developed a new genetically encoded fluorescent sensor, named PLpro-ERNuc, for detection of PLpro activity in living cells using translocation-based readout. The sensor was designed as follows. A fragment of nsp3 protein was used to direct the sensor on the cytoplasmic surface of endoplasmic reticulum (ER) membrane, thus closely mimicking the natural target of PLpro. The fluorescent part included two bright fluorescent proteins - red mScarlet I and green mNeonGreen, separated by a linker with the PLpro cleavage site. Nuclear localization signal (NLS) was attached to ensure accumulation of mNeonGreen into the nucleus upon cleavage. We tested PLpro-ERNuc in the model of recombinant PLpro expressed in HeLa cells. The sensor demonstrated expected cytoplasmic reticular network in the red and green channels in the absence of protease, and efficient translocation of the green signal into nuclei in the PLpro-expressing cells (14-fold increase of the nucleus/cytoplasm ratio). Then, we used PLpro-ERNuc in the model of Huh7.5 cells infected with SARS-CoV-2 virus, where it showed robust ER-to-nucleus translocation of the green signal in the infected cells 24 h post infection. We believe that PLpro-ERNuc represents a useful tool for screening PLpro inhibitors as well as for monitoring virus spread in a culture.

The addition of 50% vitreous humor to the media bathing lens explants results in the induction of both fiber cell differentiation and a significant immune/inflammatory response. Although Fgfr loss blocks differentiation in lens epithelial explants, this loss is partially rescued by deleting Pten. To investigate the functions of the Fgfrs and Pten during lens fiber cell differentiation, we utilized a lens epithelial explant system and conducted RNA sequencing on vitreous humor-exposed explants lacking Fgfrs, or Pten or both Fgfrs and Pten. We found that Fgfr loss impairs both vitreous-induced differentiation and inflammation while the additional loss of Pten restores these responses. Furthermore, transcriptomic analysis suggested that PDGFR-signaling in FGFR-deficient explants is required to mediate the rescue of vitreous-induced fiber differentiation in explants lacking both Fgfrs and Pten. The blockage of β-crystallin induction in explants lacking both Fgfrs and Pten in the presence of a PDGFR-inhibitor supports this hypothesis. Our findings demonstrate that a wide array of genes associated with fiber cell differentiation are downstream of FGFR-signaling and that the vitreous-induced immune responses also depend on FGFR-signaling. Our data also demonstrates that many of the vitreous-induced gene expression changes Fgfr-deficient explants are rescued in explants lacking both Fgfrs and Pten.

This study aimed to determine whether the EQ-5D-5L tool captures the most common persistent symptoms, such as fatigue, memory/concentration problems and dyspnea in patients with post COVID-19 conditions, and if adding these symptoms improves the explained variance of the health-related quality of life (HRQoL). In this exploratory cross-sectional study, two cohorts of Swedish patients (n=177) with a history of COVID-19 infection answeared a questionnaire covering sociodemographic characteristics, clinical factors and HRQoL assessed using EQ-5D-5L with the Visual Analogue Scale (EQ-VAS). Spearman rank correlation and multiple regression analyses were employed to investigate the extent to which the most common persistent symptoms such as fatigue, memory/concentration problems and dyspnea were explained by the EQ-5D-5L. The explanatory power of EQ-5D-5L for EQ-VAS was also analysed, both with and without inclusion of symptom(s). We found that the EQ-5D-5L dimensions partly captured fatigue and memory/concentration problems but performed poorly in capturing dyspnea. Specifically, the EQ-5D-5L explained 55% of the variance in memory/concentration problems, 47% in fatigue and only 14% in dyspnea. Adding fatigue to the EQ-5D-5L increased the explained variance of the EQ-VAS by 5.7%, while the addition of memory/concentration problems and dyspnea had a comparatively smaller impact on the explained variance. Our study highlights the EQ-5D-5L’s strength in capturing fatigue and memory/concentration problems in post COVID-19 patients. However, it also underscores the challenges in assessing dyspnea in this group. Fatigue emerged as a notably influential symptom, significantly enhancing the EQ-5D-5L's predictive ability to for the EQ-VAS score in these patients.

The aim of our study was a comprehensive comparative assessment of the effect of consumption of 1 and 2% cholesterol as part of a standard diet with and without regular moderate physical activity on the main biomarkers of lipid and cholesterol metabolism, as well as the intestinal microbiota of male Wistar rats. The animals were randomly divided into 5 groups according to body weight and Open Field test results: Control (n=10), 1% Chol (n=10), 2% Chol (n=10), 1% Chol + RUN (n=10) and 2% Chol + RUN. The cholesterol was additionally added in the amount of 1g or 2g/100g, respectively, to the diet of animals. The rats of experimental groups 1% Chol + RUN and 2% Chol + RUN were subjected to regular (2 days a week) physical activity on a Treadmill. In rats of four experimental groups, when compared to the Control, a response of 39 indicators was revealed. The largest number of changes in biomarkers - 29 (statistically significant, p

Traumatic Brain Injury represents a significant public health concern due to its role in traumatic death and disability, often caused by head impacts or rapid accelerations. Despite advancements in Finite Element Head Models, existing models primarily represent adult males, neglecting anatomical and physiological differences between genders and age groups. Additionally, the mechanistic roles of specific intracranial tissues, such as the dura mater, have conventionally been overlooked. To better understand the mechanical behavior of the brain and its injured regions in the context of TBI, including the dura mater, this study proposes the development of a Female Finite Element Head Model. This model, representative of a middle-aged female subject, was developed using medical image-derived geometry and finite element modeling techniques. The validation results demonstrate a similarity between the numerical displacement curves and those obtained experimentally. In the model with dura mater, the numerical results show analogous behavior to the experimental results, despite minimal variations in the amplitude of the curves. These advancements highlight the significance of including the dura mater in biomechanical brain modeling. Incorporating the dura mater in Finite Element Head Models produces more realistic results than models without it. This emphasizes the importance of enhancing biomechanical models to better represent anatomical complexity.

Risk management for technological hazards mainly focuses on the consequences on human lives. Although technological risk analysis evaluates environmental vulnerability, it does not reflect the consequences on environmentally exposed elements, such as rivers, water springs, flora, and fauna. This paper's objective was to propose a conceptual framework and create a multidisciplinary evaluation model for environmental risk analysis in the oil and gas industry. Initially, the problem was approached from a global perspective to justify the necessity of a holistic environmental risk analysis methodology in the oil industry, using environmental risk factors as well as underlying factors, such as environmental fragility and lack of resilience. The holistic assessment was carried out based on probabilistic risk analysis methodologies to obtain a holistic environmental risk index, HERI. This methodology was applied to an oil and gas industry company in Colombia. This allowed greater disaggregation of the results to establish priorities for risk reduction actions and identify the company's weaknesses.

Several epidemiological studies have demonstrated that particulate matter (PM) in air pollution can be involved in the genesis or aggravation of different cardiovascular, respiratory, perinatal, and cancer diseases. This study assessed the in vitro effects of PM &lt;10 μm in aerodynamic diameter (PM10) on the secretion of cytokines by a human monocytic cell line (THP-1). We compared the chemotactic, pro-inflammatory, and anti-inflammatory cytokines induced by PM10 collected for two years during three different seasons in five different Mexico City locations. MIP-1α, IP-10, MCP-1, TNF-α, and VEGF were the main secretion products after stimulation with 80 μg/mL of PM10 for 24 hours. The THP-1 cells showed a differential response to PM10 obtained in the different sites of Mexico City. The PM10 from the north and the central city areas induced a higher pro-inflammatory cytokine response than those from the south. Seasonal pro-inflammatory cytokine secretion always exceeded the anti-inflammatory one. The rainy season-derived particles caused the lowest pro-inflammatory effects. We concluded that toxicological assessment of airborne particles provides evidence supporting their potential role in chronic exacerbation of local or systemic inflammatory responses that may worsen the evolution of some chronic diseases.

Background: To describe the effectiveness and safety of COVID-19 vaccine in a series of patients with rheumatoid arthritis (RA). Methods: Retrospective single-center study of RA patients, fulfilling the ACR 1987 or ACR/EULAR 2010 classification criteria, that received first COVID-19 vaccine between December 2020 and October 2021, had post-vaccination serology and subsequent follow-up of at least 6 months in a university hospital. Vaccine effectiveness was evaluated by the serological response and the incidence of post-vaccine COVID-19, and safety by the incidence of adverse events (AE) and RA flares. Adjusted logistic and linear multivariate regression analyses were carried out with Stata® to identify factors associated with vaccine response. Results: We included 118 patients with RA (87.2% women, age 65.4±11.6 years, evolution 12.0±9.6 years). 95.8% received complete vaccination schedule. Most patients (88.1%) developed adequate humoral immunogenicity, and the degree of serological response was significantly related to younger age and previous COVID-19 infection. After vaccination, 18.6% presented mild SARS-CoV-2 infection. Vaccine AE (19.5%) were mostly mild and inversely associated with age (OR 0.95). RA flares were anecdotal (1.7%) and inversely related to age (OR 0.95). Conclusion: Our results suggest that COVID-19 vaccine induces adequate humoral immunogenicity, with an acceptable safety profile in RA patients.

Due to combined climate and biodiversity crisis, the sustainable utilization of phytogenetic resources stands as one-way alternative while nutrient management strategies gain an increasing role in agriculture. Building on previous studies regarding the Endangered local endemic of Crete (Greece) Carlina diae (Asteraceae) with medicinal and ornamental value, this investigation focused on its pilot cultivation and fertilization (foliar or root application). Foliar application included chemical fertilizer (conventional) or integrated nutrient management (INM). Root application consisted of chemical fertilizer, biostimulant, or INM with biostimulant. Above-ground biomass content of nutrients, together with leaf chlorophyll fluorescence and colour parameters (SPAD meter, DA meter, Chroma Meter) were determined. The leaf content of chlorophyll, three key antioxidant compounds and minerals’ titers were also assessed. The fertilization scheme did not influence plant growth and visually perceived quality (leaf color and shape). Notably, foliar INM fertilization increased biomass partitioning to inflorescences (harvestable organ for either medicinal or ornamental purposes), and decreased tissue water content (facilitating processing). Considering all three antioxidants together, INM with biostimulant appeared the optimum scheme, being associated with the highest (carotenoids, phenolics) or the second highest (flavonoid) content. In C. diae, therefore, INM fertilization was optimal for upgrading yield (foliar) and herbal quality in terms of antioxidant profile (INM with biostimulant), which might be embraced as an eco-friendly approach for high quality yields.

High incidence of epithelial malignancies in HIV-1 infection is associated with co-infection with oncogenic viruses, such as high-risk human papillomaviruses (HR HPVs), most often HPV16. A collaboration between HIV-1 and HR HPVs in the malignant transformation of epithelial cells exposed to both viruses have long been anticipated. Here, we delineated the effects on in vitro and in vivo properties of HPV16-infected cervical cancer cells of HIV-1 reverse transcriptase. Epidermoid carcinoma Ca Ski cells were made to express RT of HIV-1 clade A (RT_A) or Green Fluorescence Protein (GFP) by lentiviral transduction, subclones with one or six copies of RT_A and six copies of GFP DNA were generated. Expression by subclones of GFP was assessed by flow cytometry, and of RT_A, by Western blotting. Cells were assessed for the levels of mRNA of the RT_A, E6 and its isoforms, and cellular factors characterizing oxidative stress, and EMT by the real-time PCR. Parameters of glycolysis and mitochondrial respiration were assessed by Seahorse technology. Subclones were surveyed for the changes in cell cycle, doubling time, migration capacity, clonogenic activity and for the capacity to form tumors in nude mice. Ca Ski RT_A produced 20-55 fg of RT_A per cell. Expression of RT_A caused a proportional increase in the expression of E6*I isoform. In Ca Ski, RT_A suppressed mitochondrial respiration and oxygen consumption, and increased glycolysis. Compared to parental cells and GFP control, transcription in Ca Ski RT_A of epithelial (E-CADHERIN) state marker was increased, and of mesenchymal (VIMENTIN) decreased, indicating acquisition by cells of the hybrid epithelial/mesenchymal (E/M) phenotype. While Ca Ski GFP and Ca Ski RT_A with one gene insert had reduced migration rate, decreased clonogenic activity in vitro, and diminished capacity to form tumors in nude mice, increase in RT_A copicity/expression mitigated these effects. Altogether, expression of HIV-1 RT_A gave Ca Ski cells the plasticity required to overcome negative effects of lentiviral transduction and potentially increased their tumorigenicity.

The twelve cranial nerves play a crucial role in nervous system, orchestrating a myriad of functions vital for our everyday life. These nerves are each specialized for particular tasks. Cranial Nerve I, known as the olfactory nerve, is responsible for our sense of smell, allowing us to perceive and distinguish various scents. Cranial Nerve II, or the optic nerve, is dedicated to vision, transmitting visual information from the eyes to the brain. Eye movements are governed by Cranial Nerves III, IV, and VI, ensuring our ability to track objects and focus. Cranial Nerve V controls facial sensation and jaw movement, while Cranial Nerve VII, the facial nerve, facilitates facial expressions and taste perception. Cranial Nerve VIII, or the vestibulocochlear nerve, plays a critical role in hearing and balance. Cranial Nerve IX, the glossopharyngeal nerve, affects throat sensation and taste perception. Cranial Nerve X, the vagus nerve, is a far-reaching nerve, influencing numerous internal organs such as the heart, lungs, and digestive system. Cranial Nerve XI, the accessory nerve, is responsible for neck muscle control, contributing to head movement. Finally, Cranial Nerve XII, the hypoglossal nerve, manages tongue movement, essential for speaking, swallowing, and breathing. Understanding these cranial nerves is fundamental in comprehending the intricate workings of our nervous system and the functions that sustain our daily lives.

The widespread use of the herbicide glyphosate has resulted in the global presence of its degra-dation product, aminomethylphosphonic acid (AMPA), in the global environment. AMPA is commonly found in water bodies, including freshwater systems. We investigated the effects of chronic and acute AMPA exposure on the survivorship, regenerative abilities, and locomotion of the brown planarian (Girardia tigrina), a water-dwelling flatworm commonly found in freshwa-ter ecosystems. We exposed planarians to two concentrations of AMPA, consistent with the high and low ranges of concentrations observed in US water systems. We measured endpoints includ-ing survivorship, regenerative abilities of head and tail segments, eyespot regeneration, and swimming speed. Compared to the control group, we found that planarians chronically exposed to AMPA exhibited (1) modestly reduced survivorship while regenerating and (2) slower regen-eration from the tail segment. No significant differences were observed in intact body growth during chronic exposure. Our findings highlight the potential ecological impacts of AMPA con-tamination on planarian populations. Understanding the effects of AMPA exposure on planarians contributes to our understanding of the ecological consequences of glyphosate use in freshwater ecosystems.

X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy resulting from dysfunction of the protein myotubularin encoded by the MTM1 gene. XLMTM has a high neonatal and infantile mortality rate due to a severe myopathic phenotype and respiratory failure. However, in a minority of XLMTM cases, patients present with milder phenotypes and achieve ambulation and adulthood. Regarding wide phenotypic variability, we investigated the genotype-phenotype correlations in newly diagnosed XLMTM patients in a patients' cohort (previously published data plus three novel variants, n=414). We found a significant association between severe phenotype and truncating variants (p < 0.001), frameshift variants (p < 0.001), nonsense variants (p = 0.006), and in/del variants (p = 0.036). On the contrary, missense variants were significantly associated with the mild and moderate phenotype (p < 0.001). We found no significant association between phenotype and the MTM1-specific functional domain, contrasting with previously published data. Based on the significant facial gestalt difference between XLMTM patients and unaffected controls (p = 0.001), we consider the Face2Gene application as an effective diagnostic tool in XLMTM when using the correct algorithm. The Face2Gene application seems to be a practical, non-invasive diagnostic approach in XLMTM.

Haematopoietic stem cell transplantation (HSCT) is a curative approach for blood cancers, yet its efficacy is undermined by a range of acute and chronic complications. In light of mounting evidence to suggest that these complications are linked to a dysbiotic gut microbiome, we aimed to evaluate the feasibility of faecal microbiota transplantation (FMT) delivered during the acute phase after HSCT. Of note, this trial opted for FMT prepared using the individual’s own stool (autologous FMT) to mitigate risks of disease transmission from donor stool. Adults (>18 years) with multiple myeloma were recruited from a single centre. Stool was collected prior to starting first-line therapy. Patients that progressed to HSCT were offered FMT via 3 x re-tention enemas before day +5 (HSCT = day 0). Feasibility was determined by recruitment rate, number and volume of enemas administered, and retention time. Longitudinally collected stool samples were also col-lected to explore the influence of auto-FMT using 16S rRNA gene sequencing. N=4 (2F:2M) participants received auto-FMT in 12 months. Participants received an average of 2.25(1-3) enemas (43.67(25-50)mL total, retained for an average of 60.78(10-145)minutes). No AEs, attributed to the FMT, were identified. Although minimum requirements were met for the volume and retention of auto-FMT, recruitment was significantly impacted by the logistical challenges of pre-therapy stool collection. This ultimately under-mined the feasibility of this trial and suggests that third party (donor) FMT should be prioritised.

African indigenous herbs and medicinal plants are extensively reported for their protective and therapeutic potential against Diabetes. However, most of the constituent phytochemicals that may account for the therapeutic activity are largely uninvestigated. Exploring novel phytochemical–target interactions in silico could help to provide useful insights into the mechanism underpinning the biological activities of these plants and their constituent phytochemicals. The aim of this study was to explore the interactions of terpene struc-tures previously reported from selected African antidiabetic with two emerging drug targets in diabetes. Structure-based virtual screening was used to screen 107 terpene structures against DPP-4 and PTP1B enzymes. The MD simulation, MM-GBSA free energy calculation and DFT were used to clarify the inter-actions of the in silico hits with the target enzymes. Molecular docking, post-docking Prime MM-GBSA analysis revealed the top terpenes with high binding affinity with the active site regions of DPP-4 and PTP1B. Ensemble docking revealed three triterpenes viz: cucurbitacin B (T1), 6-Oxoisoiguesterin (T4) and 20-Epi-isoiguesterinol (T2) as in silico hits which exhibit strong interaction potential with critical residues that define the catalytic triad (Ser630 and His740); oxyanion cavity (Ser631); hydrophobic S1 pocket (Tyr662) and the charged S2 pocket (Arg125) in the active site region of DPP-4. The interactions of these compounds with DPP-4 exhibited structural stability and conformational flexibility during 100 ns full atomistic MD simulation as indicated by the structure dynamics parameters including RMSD, RoG, SASA and hydrogen bond number. The post-MD MM/GBSA calculations further revealed the stability of the triterpene-DPP-4 complexes. Furthermore, Frontier molecular orbital calculations showed that, the triterpenes possess high interaction potential with the enzyme. The triterpenes showed desirable ADMET properties and drug-likeness. Therefore, cucurbitacin B, 6-Oxoisoiguesterin and 20-Epi-isoiguesterinol are recommended for experimental validation.

Radiomics refers to the extraction and analysis of a wide range of medical imaging features in a non-invasive and cost-effective manner to comprehensively characterise tumours. In this study, machine learning models combining radiomics and clinical factors were developed to predict retroperitoneal lymph node metastasis in testicular germ cell tumours (TGCTs), with the aim of reducing unnecessary treatment in this group of young patients. Ninety-one patients with surgically proven testicular germ cell tumours and contrast-enhanced CT were included in this retrospective study. After segmenting 273 retroperitoneal lymph nodes using dedicated radiomics software, we developed machine-learning prediction models using Random Forest (RF), Light Gradient Boosting Machine (LGBM), Support Vector Machine Classifier (SVC), and K-Nearest Neighbours (KNN). For each classifier, we developed a radiomics-only, clinical-only, and combined radiomics-clinical prediction model. The models’ performances were evaluated using the area under the receiver operating characteristic curves (AUCs). The RF-based combined clinical and radiomic model showed the most robust performance in predicting LNM with an area under the curve (AUC) of 0.95 (±0.03; 95% CI), accuracy 87%, precision 89%, recall 86% and F1 score 87%, followed by the LGBM model with an area under the curve (AUC) of 0.93 (±0.05; 95% CI), accuracy 83%, precision 87%, recall 80% and F1 score 82%. Decision curve analysis demonstrated the clinical utility of our proposed RF-based combined clinical–radiomics model. Our study has identified reliable and predictive machine-learning techniques for predicting lymph node metastasis in early-stage testicular cancer. Identifying the most effective machine-learning approaches for predictive analysis based on radiomics integrating clinical risk factors can expand the applicability of radiomics in precision oncology and cancer treatment. Multi-centre validation is required to provide high-quality evidence for clinical application.

Rheumatoid arthritis (RA) is an autoimmune disease mainly characterized by joint inflammation. It presents extra-articular manifestations, with the lungs one of the affected areas. Among these, damage to the pulmonary interstitium (Interstitial Lung Disease -ILD) has been linked to proteins involved in the inflammatory process and related to extracellular matrix deposition and lung fibrosis establishment. Peptidyl arginine deiminase enzymes (PAD), which carry out protein citrullination, play a role in this context. A genetic association analysis was conducted on genes encoding two PAD isoforms, PAD2 and PAD4. This analysis also included ancestry informative markers and protein level determination in samples from patients with rheumatoid arthritis, RA-associated ILD, and clinically healthy controls. Significant single nucleotide variations (SNV) and a haplotype were identified as susceptibility factors for ILD-RA development. Elevated levels of PAD4 were found in ILD-RA cases, while PADI2 showed an association with RA susceptibility. This document presents the data obtained from the conducted research, which has been published.

Air pollution includes particle-bound Polycyclic Aromatic hydrocarbons (PAHs) which eventually reach the placenta triggering adverse perinatal outcomes by long-term exposure. Late-ly, air pollution has increased over the Metropolitan Area of Medellin-Colombia (MAMC) but its effects on pregnancy are still unknown. In this research, we made a real-time analysis of airborne total PAHs using a photoelectric sensor for residential places influenced by industrial and traffic sources contrasting southern and northern MAMC during the second peak of the bimodal ten-dency for PM2.5 emissions in this region. Additionally, we analyzed individual PAHs by GC/MS coupled to pressurized hot water extraction methodology. Data was applied in an Inhalation In-take Model to assess pregnancy exposure. The average concentration of PAHs over southern MAMC was three times higher than over northern MAMC where the abortion rate has been 1.4 times higher presented in database. Previous research found that PAHs act as an Endo-crine-Disrupting Chemical (EDC) during pregnancy and even heavy congeners could reside in umbilical cord blood. Finally, the annual series of abortion rates in the MAMC showed a signifi-cant correlation with the annual average levels of PM2.5 which are associate to PAHs. Although this significant correlation does not imply causality, our results suggest an important connection between both variables. This latter finding opens a gap in deeply understanding how regions with high PAHs-convergence influences abortion rates in MAMC.

Carbon (C) cycle n inland waters, including its concentrations and carbon dioxide (CO2) emis-sions from water surfaces are at the forefront of biogeochemical studies, especially in the re-gions, strongly impacted by on-going climate change. Towards better understanding of C stor-age, transport and emission in Central Asian mountain regions, extremely poorly studied until now, here we carried out systematic measurements of dissolved C and CO2 emissions in 15 riv-ers and 5 lakes located along a macro-transect of various natural landscapes in the Sayan-Altai mountain region, from high mountains of the Western Sayan in the northwest of Tyva to arid (dry) steppe and semi-deserts in intermountain basins of the southeast of Tyva, the border with Mongolia. New data on major hydrochemical parameters, CO2 fluxes by floating chambers, dis-solved organic and inorganic carbon concentrations collected over four main hydrological sea-sons allowed to assess the current C biogeochemical status of these water bodies in order to judge possible future changes under climate warming. We further tested the impact of perma-frost, river watershed size, lake area and climate parameters as well as ‘internal’ biogeochemical drivers (pH, mineralization, organic matter quality and bacterial population) on CO2 concentra-tion and emissions in lakes and rivers of this region, and compared them with available data on other subarctic and mountain settings.

Over the past decade, significant developments have occurred in treatment strategies for ovarian cancer, yet targeted therapy with few side effects is still a major issue. The cytochrome P450 (CYP) enzyme family plays a vital role in the tumorigenesis process and metabolism of drugs, with a negative impact on therapy outcomes. Gaining more insight into CYP expression is crucial for understanding the pathophysiology of ovarian cancer since many isoforms are essential for the metabolism of xenobiotics and steroid hormones, which drive the disease's development. The purpose of this review is to provide a clear understanding of differential CYP expression in ovarian cancer and its implications for the prognosis of ovarian cancer patients, together with their polymorphisms' effect on chemotherapy metabolism. Finally, we provide our thoughts on opportunities to exploit metabolic CYP expression for novel therapeutic development to treat ovarian cancer.

Low back pain (LBP) is a common musculoskeletal complaint that can impede physical function and mobility. Current management often involves pain medication, but there is a need for non-pharmacological and non-invasive interventions. Soft tissue manipulation (STM) such as massage has been shown to be effective in human subjects, but the molecular mechanisms underlying these findings are not well understood. In this paper, we evaluated potential changes in soft tissue levels of more than thirty pro- or anti-inflammatory cytokines following instrument-assisted STM (IASTM) in rats with chronic, induced LBP using Complete Freund’s Adjuvant. Our results indicate that IASTM is associated with reduced soft tissue levels of RANTES/CCL5 and increased soft tissue levels of IL-4, which are pro-inflammatory and anti-inflammatory factors, respectively, by 120 minutes post-treatment. IASTM was not associated with tissue-level changes in CXCL5/LIX (the murine homologue of IL-8), CXCL7, GM-CSF ICAM-1, IL1-ra, IL-6, IP-10/CXCL10, L-selectin, TNF-α, or VEGF at either 30- or 120 minutes post-treatment. Combined, our findings suggest that IASTM exerts tissue-level effects that are associated with improved clinical outcomes and potentially beneficial changes in pro/anti-inflammatory cytokines in circulation and at the tissue level.

The 2022-2023 Chilean summer showed increased temperatures and similar burned area, compared to the 2016-2017 season, where more than 500,000 hectares were compromised, mainly in the rural areas. After a brief review, it is revealed that the effects of forest fires on soil and hydrological properties are barely debated in Chile. Here, we showed a climatological analysis where temperature records in the 2016-2017 season were unusual, as well as another unexpected increase in the summer of 2022-2023, resulting in high-severity fires known as ‘mega-fires’ or “storm-fires”. Mega-fires affect forest plantations and native forests mainly from 33º S (Maule Region) to 39º S (Los Ríos Region) and they are expected to become frequent due to climate change, moving from the north to the south. We present an overview of the influence of wildfires on soil components in the most affected areas (inland, Coastal, and Andes ranges), their hydrological impacts, and potential erosion risk due to high winter precipitation. We propose several management practices that could help to prevent or mitigate these events, including pre-and post-fire interventions, such as afforestation and seeding, selective logging, mulching, erosion barriers, soil preparation, and dam monitoring. We argue that any effective plan in fire-prone and affected areas should include a combination of actions taken at the hillslope scale at integral ecosystem management, whose effectiveness should be monitored and verified regionally at the watershed scale.

The mitochondrial marker, cytochrome oxidase subunits II gene (mtDNA-COII) was employed to assess the genetic structure and diversity of Anopheles funestus, a very important malaria vector in Africa, that adapt and colonize different ecological niches in western Kenya. Mosquitoes were collected using mechanical aspirators in four sites (Bungoma, Port Victoria, Kombewa and Migori) in western Kenya. Following morphological identification, PCR was used to confirm species. The mtDNA-COII gene was amplified, sequenced and analyzed to determine genetic diversity and population structure. A total of 126 (Port Victoria-38, Migori-38, Bungoma-22 and Kombewa-28) sequences of mtDNA-COII were used for population genetic analysis. Anopheles funestus had high haplotype diversity (Hd= 0.97 to 0.98) but low nucleotide diversity (π =0.004 to 0.005). The neutrality test revealed significant (p<0.05) negative Tajima’s D and Fs values indicating population expansion with an excess of low-frequency variation due to evolutionary forces across all sites. No genetic differentiation or structure was observed across the sites (Fst = -0.01) and a high level of gene flow (Gamma St, Nm = 17.99 to 35.22) was observed among the populations. Population expansion suggests the high adaptability of this species to various ecological requirements hence sustaining its vectorial capacity and malaria transmission.

The cortical motor system can be reorganized following a stroke, with an increasing recruitment of the contralesional hemisphere. However, it is unknown whether a similar hemispheric shift occurs in the somatosensory system to adapt to this motor change, and whether this is related to movement impairments.  This proof-of-concept study assessed somatosensory evoked potentials (SEPs), P50 and N100, in hemiparetic stroke participants and age-matched controls using high-density electroencephalograph (EEG) recordings during tactile finger stimulation. The laterality index was calculated to determine hemispheric dominance of the SEP and re-confirmed with source localization.  The study found that latencies of P50 and N100 were significantly delayed in stroke brains when stimulating the paretic hand. The amplitude of P50 was negatively correlated with Fügl-Meyer Upper Extremity Motor Score in stroke. Bilateral cortical responses were detected in stroke, while only contralateral cortical responses were shown in controls, resulting in a significant difference in the laterality index.  These results suggested that somatosensory reorganization after stroke involves increased recruitment of ipsilateral cortical regions. This reorganization delays the latency of somatosensory processing after a stroke.  This research provided new insights related to the somatosensory reorganization after stroke, which could enrich future hypothesis-driven therapeutic rehabilitation strategies from a sensory or sensory-motor perspective.

Phase imaging of biochemical samples has been demonstrated for the first time at the Infrared Microspectroscopy (IRM) beamline of the Australian Synchrotron using the usually discarded Near-IR (NIR) region of the synchrotron-IR beam. The synchrotron-IR beam at the Australian Synchrotron IRM beamline has a unique fork shaped intensity distribution as a result of the gold coated extraction mirror shape, which includes a central slit for rejection of the intense X-ray beam. The resulting beam configuration makes any imaging task challenging. For intensity imaging, the fork shaped beam is usually tightly focused to a point on the sample plane followed by a pixel-by-pixel scanning approach to record the image. In this study, a pinhole was aligned with one of the lobes of the fork shaped beam and the Airy diffraction pattern was used to illuminate biochemical samples. The diffracted light from the samples was captured using a NIR sensitive lensless camera. A rapid phase-retrieval algorithm was applied to the recorded intensity distributions to reconstruct the phase information corresponding to different planes. The preliminary results are promising to develop multimodal imaging capabilities at the IRM beamline of the Australian Synchrotron.

Synechococcus sp. PCC 11901 reportedly demonstrates the highest, sustained growth of any known cyanobacterium under optimized conditions. Due to its recent discovery our knowledge of its biology, including the factors underlying sustained, fast growth, is limited. Furthermore, tools specific for genetic manipulation of PCC 11901 are not established. Here, we demonstrate that PCC 11901 shows faster growth than other model cyanobacteria, including the fast-growing species Synechococcus elongatus UTEX 2973, under optimal growth conditions for UTEX 2973. Comparative genomics between PCC 11901 and Synechocystis sp. PCC 6803 reveal conservation of most metabolic pathways but PCC 11901 has a simplified electron transport chain and reduced light-harvesting complex. This may underlie its superior light utilization, reduced photoinhibition and higher photosynthetic and respiratory rates. To aid biotechnology applications we developed a vitamin B12 auxotrophic mutant but were unable to generate unmarked knockouts using two negative selectable markers, suggesting that recombinase- or CRISPR-based approaches may be required for repeated genetic manipulation. Overall, this study establishes PCC 11901 as one of the most promising species currently available for cyanobacterial biotechnology and provides a useful set of bioinformatics tools and strains for advancing this field, in addition to insights into the factors underlying its fast growth phenotype.

Human Perrault syndrome (PRLTS) is defined by autosomal recessive inheritance with primary ovarian insufficiency and early hearing loss. Most PRLTS disease proteins modulate mitochondrial transcription or translation. Among the genetic causes are ClpP mutations, which trigger also complete azoospermia, whose cellular and molecular underpinnings are unknown. Here, the ClpP-null mouse model was studied by global transcriptomics, proteomics, RT-qPCR, immunoblots, tissue fractionation, testis histology, and was crossed with STING/IFNAR mutants. Spermatogenesis showed accumulated early spermatocytes, versus deficits of desynapsis and kinetochore factors; excess Dazl/Stra8 and acetylSMC3, versus deficient SHCBP1L, were molecular correlates. Spermiogenesis showed few round spermatids, tsHMG/TFAM in elongated spermatids was absent; transcripts for tail/acrosome factors were downregulated from start. Nuclear anomalies included a failed Rec8 induction, early BRDT deficiency, histone H3 cleavage, and cGAMP increase, among antiviral responses typical of ClpP-mutants. However, deletion of downstream innate immune signals STING/IFNAR failed to reestablish fertility. As mitochondrial triggers, we observed accumulation of ClpX, with PTCD1, POLDIP2, GRSF1, ALKBH7, DNAJA3, AURKAIP1, VWA8, and Perrault proteins ERAL1, PEO1, HARS2, partially showing nuclear redistribution. ClpP-depletion is known to cause extra-mitochondrial release of mispacked mtDNA/mtRNA/protein complexes. Now we define nuclear inflammatory responses and meiotic arrest as consequences, similar to observations in mito-mice and mutator-mice.

Human Perrault syndrome (PRLTS) is defined by autosomal recessive inheritance with primary ovarian insufficiency and early hearing loss. Most PRLTS disease proteins modulate mitochondrial transcription or translation. Among the genetic causes are ClpP mutations, which trigger also complete azoospermia, whose cellular and molecular underpinnings are unknown. Here, the ClpP-null mouse model was studied by global transcriptomics, proteomics, RT-qPCR, immunoblots, tissue fractionation, testis histology, and was crossed with STING/IFNAR mutants. Spermatogenesis showed accumulated early spermatocytes, versus deficits of desynapsis and kinetochore factors; excess Dazl/Stra8 and acetylSMC3, versus deficient SHCBP1L, were molecular correlates. Spermiogenesis showed few round spermatids, tsHMG/TFAM in elongated spermatids was absent; transcripts for tail/acrosome factors were downregulated from start. Nuclear anomalies included a failed Rec8 induction, early BRDT deficiency, histone H3 cleavage, and cGAMP increase, among antiviral responses typical of ClpP-mutants. However, deletion of downstream innate immune signals STING/IFNAR failed to reestablish fertility. As mitochondrial triggers, we observed accumulation of ClpX, with PTCD1, POLDIP2, GRSF1, ALKBH7, DNAJA3, AURKAIP1, VWA8, and Perrault proteins ERAL1, PEO1, HARS2, partially showing nuclear redistribution. ClpP-depletion is known to cause extra-mitochondrial release of mispacked mtDNA/mtRNA/protein complexes. Now we define nuclear inflammatory responses and meiotic arrest as consequences, similar to observations in mito-mice and mutator-mice.

Liquid biopsies are an integral part of the diagnosis of cancer. Here, we have extended previous validation studies of a new targeted NGS panel to include the detection of copy number amplifications (CNAs), fusions, and exon skipping variants. Detection of these gene classes included specimens from clinical and healthy donors and cell lines (fusions: ROS1, EML4-ALK, NTRK1), (exon skipping: MET exon 14), and (CNAs: HER2, CDK6, EGFR, MYC and MET). The limit of detection (LOD) for fusion/skipping was 42 copies (QC threshold = 3 copies) and was verified using 3 additional fusion/skipping variants. LOD for CNAs was 1.40-fold-change (QC threshold = 1.15-fold change) and was verified with 3 additional CNAs. In precision studies, all fusion/skipping variants were detected in all runs and all days of testing (n=18/18; 100%); average CV for repeatability was 20.5% (range 8.7% - 34.8%), and for reproducibility was 20.8% (range 15.7% - 30.5%). For CNAs, 28/29 (96.6%) copy gains were detected. For CNAs, average CV of 1.85% (range 0% to 5.49%) for repeatability and 6.59% (range 1.65% to 9.22%) for reproducibility. The test panel meets the criteria for being highly sensitive and specific and extends its utility for the detection of clinically relevant variants in cancer.

Somatic embryogenesis-mediated plant regeneration is essential for genetic manipulation of agronomically important traits in upland cotton. Genotype specific recalcitrance to regeneration is a primary challenge in deploying genome editing and incorporating useful transgenes into elite cotton germplasm. In this study, transcriptomes of a semi-recalcitrant cotton (Gossypium hirsutum L.) genotype ‘Coker312’ were analyzed at two critical stages of Somatic Embryogenesis that includes non-embryogenic callus (NEC) and embryogenic callus (EC) cells, and the results compared to a non-recalcitrant genotype ‘Jin668’. We discovered of 305 differentially expressed genes in Coker312, whereas, in Jin668, about 6-fold more genes (2,155) were differentially expressed. A total of 154 differentially expressed genes were common between the two genotypes. Gene enrichment analysis of upregulated genes identified functional categories such as lipid transport, embryo development, regulation of transcription, sugar transport, vitamin biosynthesis, among others. In Coker312 EC cells, five major transcription factors were highly upregulated: LEAFY COTYLEDON 1 (LEC1), WUS-related homeobox 5 (WOX5), ABSCISIC ACID INSENSITIVE3 (ABI3), FUSCA3 (FUS3), and WRKY2. In Jin668, LEC1, BABY BOOM (BBM), FUS3, and AGAMOUS-LIKE15 (AGL15) were highly expressed in EC cells. We also found that gene expression of these embryogenesis genes was typically higher in Jin668 when compared to Coker312. We conclude that significant differences in expression of the above genes between Coker312 and Jin668 may be a critical factor affecting the regenerative ability of these genotypes.

The present study was conducted the status of sea bass from Kokko and Kyuntone of The Gulf of Motttama Wetland (GoMW) area in Thanatpin Township in Bago Region Myanmar from September 2019 to August 2020. Fifty specimens were monthly collected, measured and weighed. Invoices of sea bass were collected for the depot and fish sellers by monthly. In Kokko, mean value of standard length and body weight were highest in March (32.70±1.58, 660.7±112.23). The mean value of standard length was peak in January (31.39±7.16) but peak of body weight was in March (963.24±280.86) in Kyuntone villages. The lowest mean value of standard length and body weight were found in June at both study areas. According to the invoice data revealed that monthly catch weight of sea bass is most abundance in October (829.92) kg in Kokko, (339.12) kg in Kyuntone. Based on price of relations to size group, small size C &lt; 300g (41%) was mostly abundance in Kokko and in Kyuntone small size C &lt; 300g (35%) was second abundance. Specimens were not landed in April and May. In June, young specimens were very rarely seen in both study sites. The important roles of wetland fishes, the economic valuation of GOMW in Myanmar and samples of fishing gear and value chain of sea bass in Myanmar was expressed in this study.

Transplant of human cancer cells into zebrafish larvae has emerged as a useful methodology in cancer research. Zebrafish have very low husbandry costs, are amenable to large-scale drug screening, and are unmatched for optical clarity in live animal imaging. However, there is currently no consensus on the ideal methods for xenograft of human cancer cells into zebrafish. Here, we have examined the effects of transplant site and housing temperature on both zebrafish larvae and human cancer cells using survival analyses, metabolomic approaches, and in vivo imaging. Our data show that while zebrafish larvae can adapt to the ideal conditions for mammalian cells, human cancer cells are highly sensitive to both temperature change and transplant site. Human cells housed in slightly cooler than physiologic temperatures had a significantly altered metabolism that resulted in changes in growth, survival, and response to chemotherapy. Cancer cells xenografted into the yolk of the larvae also had reduced proliferation and drug response compared to those xenografted into the soma, in part due to the differences in metabolites available at these sites. In total, temperature and transplant site can have profound effects on xenografted cells. Standardization of zebrafish xenograft methods will enhance data reproducibility between individual laboratories.

Tumor-associated macrophages are a key component in the tumor microenvironment, secreting extracellular vesicles (EVs) such as exosomes and other various factors for intercellular communication. However, macrophage-derived EVs heterogeneity and their cytotoxicity to cancer cells has not been well understood. Here, we aimed to separately isolate various types of macro-phage-EVs by size exclusion chromatography (SEC) method and investigate EV transmission and cytotoxicity to oral cancer cells. For fluorescence-labeling of cellular and EV membranes, palmitoylation signal-fused GFP and tdTomato were expressed in THP-1 monocytic cells and HSC-3 oral cancer cells, respectively. We found that fluorescence-labeled EVs secreted by macrophages were highly transmissive to oral cancer cells than those from parental monocytic cells. In a co-culture system and conditioned medium (CM), a macrophage-secreted unidentified factor was cytotoxic to oral cancer cells. We fractionated macrophage-derived EVs by the SEC method and performed western blotting to characterize various EV types. Three fractions were characterized: small exosomes (EXO-S: < 50 nm) fraction containing HSP90α, HSP90β, CD63 (EV marker) and β-actin; large exosomes (EXO-L: 50-200 nm) fraction containing CD9 (EV marker) and HSP90β; large EVs (100-500 nm) fraction. Notably, the macrophage-derived small exosomes fraction was cytotoxic to oral cancer cells, while large exosomes and large EVs were not. There-fore, it was implicated that macrophage-derived small exosomes are cytotoxic with high trans-mission potential to cancer cells.

Heat shock proteins (Hsps) are highly conserved molecules that are constitutively expressed and upregulated in response to physiological stress conditions. These immunogenic chaperones can have essential functions in fungi, particularly in dimorphic pathogens. Histoplasma capsulatum and Paracoccidioides species are dimorphic fungi that are the causative agents of histoplasmosis and paracoccidioidomycosis, respectively, which are systemic mycoses with significant rates of morbidity and mortality. Current treatment consists of long-term antifungal agents, and there is an urgent need for new therapeutic approaches with higher efficacy, lower toxicity, better biodistribution and improved selectivity. We engineered an immunoglobulin G1 (IgG1) isotype chimeric mouse-human monoclonal antibody, titled ch-MAb 4E12, from the parental IgG2a MAb 4E12, a monoclonal antibody to H. capsulatum Hsp60 that is protective in experimental histoplasmosis and paracoccidioidomycosis models elicited by H. capsulatum var. capsulatum and Paracoccidioides lutzii, respectively. The ch-MAb 4E12 increased phagolysosomal fusion and enhanced the yeasts uptake by PMA differentiated human THP1 macrophage cells in vitro. At low concentrations, the chimeric antibody significantly reduced the pulmonary and splenic fungal burden compared to an irrelevant antibody or no treatment. These results are the first to show that a chimeric mouse-human antibody can modify infection caused by dimorphic fungi.

Chikungunya virus is a re-emerging mosquito-borne alphavirus. Outbreaks are unpredictable and explosive in nature. Fever, arthralgia, and rash are common symptoms during the acute phase. Diagnostic tests are required to differentiate chikungunya virus from other co-circulating arboviruses, as symptoms can overlap, causing a dilemma for clinicians. Arthritis is observed during the sub-acute and chronic phases, which can flare up, resulting in increased morbidity that adversely affects activities of daily living. During the 2019 chikungunya epidemic in Thailand, cases surged in Bangkok in the last quarter of the year. Here, we demonstrate the chronic sequelae of post-chikungunya arthritis in one of our patients 1 year after the initial infection. An inflammatory process involving edema, erythema, and tenderness to palpation of her fingers' flexor surfaces was observed, with positive chikungunya IgG and negative IgM tests and antigen. The condition produced stiffness in the patient’s fingers and limited their range of motion, adversely affecting daily living activities. Resolution of symptoms was observed with a short course of an anti-inflammatory agent. More research is required to determine whether sanctuaries enable chikungunya virus to evade the host immune response and remain latent, flaring up months later and triggering an inflammatory response that causes post-chikungunya arthritis.

Phytophthora. infestans is a well known late blight causing oomycetes pathogen. It evolves and adapts to the host background and new fungicide molecules rapidly within a few years of their release, may be due to the predominance of transposable elements in its genome. Frequent and huge applications of fungicides cause environmental concerns. Here we developed target specific RNA interference based molecules, that are capable of effectively reducing the late blight infection. cDNA microarray expression data was used for the selection of genes involved in the early stage of infection process, sporulation etc. The in vitro synthesis of double stranded RNA molecule, targeting SDH, EF-1α, GPI-HAM344, PLD-3 and HSP-90 encoding genes revealed the reduction in growth, sporulation and symptom expression, which were subsequently assessed by culture bioassay, detached leaf assay and topical application methods. The multiple genes targeted dsRNA nano clay sprayed plants showed enhanced disease resistance (4% disease severity) and least sporulation (<1x103), compared to naked dsRNA spray. Use of nano clay was assumed to be involved in the effective delivery, protection and boosting the action of RNAi in potato plants. A significant difference in the growth, sporulation count, disease severity and reduced expression of the genes and confocal microscopy imaging authenticates the effects of SIGS on late blight disease progression. Our research demonstrated that topical dsRNA nano clay spray under the open-air environment could be an alternative to chemical fungicides and transgenic approaches as a novel plant protection strategy for late blight in an environmentally friendly manner.

Left Ventricular Outflow Tract (LVOT) obstruction occurs in approximately 70% of Hypertrophic Cardiomyopathy (HCM) patients and currently requires imaging or invasive testing for diagnosis, sometimes in conjunction with provocative physiological or pharmaceutical stimuli. To identify potential biomarkers of LVOT obstruction, we performed proteomics profiling of 1305 plasma proteins in 12 HCM patients with documented LVOT obstruction referred for surgical myectomy. Plasma was collected at the surgical preoperative visit approximately one month prior to surgery and then at the post surgical visit approximately 3 months later. Proteomic profiles were generated using the aptamer-based SOMAscan assay. Principal Component Analysis using the highest statistically significant proteins separated all preoperative samples from all postoperative samples. Further analysis revealed a set of 25 proteins that distinguished the preoperative and postoperative states with a paired t-test p value of <0.01. Ingenuity Pathway analysis facilitated the generation of protein interaction networks and the elucidation of key upstream regulators of the differentially expressed proteins such as interferon-, TGF-1 and TNF. Biological pathways affected by the surgery included organ inflammation, migration and motility of leukocytes, fibrosis, vasculogenesis, angiogenesis, acute coronary events, endothelial proliferation, eicosanoid metabolism, calcium flux, apoptosis and morphology of the cardiovascular system. Our results indicate that surgical relief of dynamic outflow tract obstruction in HCM patients is associated with unique alterations in plasma proteomic profiles that likely reflect improvement in organ inflammation and physiological function.

Chikungunya virus is an Alphavirus belonging to the family Togaviridae that is transmitted to humans by an infected Aedes mosquito. Patients develop fever, inflammatory arthritis, and rash during the acute stage of infection. Although the illness is self-limiting, atypical and severe cases are not uncommon, and 60% may develop chronic symptoms that persist for months or even for longer durations. Having a distinct periodical epidemiologic outbreak pattern, chikungunya virus reappeared in Thailand in December 2018. Here, we describe a cohort of acute chikungunya patients who had presented to the Bangkok Hospital for Tropical Diseases during October 2019. Infection was confirmed by real-time RT-PCR using serum collected at presentation to the Fever Clinic. Other possible acute febrile illnesses such as influenza, dengue, and malaria were excluded. We explored the sequence of clinical manifestations at presentation during the acute phase and associated the viral load with the clinical findings. Most of the patients were healthy individuals in their forties. Fever and arthralgia were the predominant clinical manifestations found in this patient cohort, with a small proportion of patients with systemic symptoms. Higher viral loads were associated with arthralgia, and arthralgia with the involvement of the large joints was more common in female patients

In this article we report the first investigation over time of the atmospheric conditions around TGFs occurrence, using GPS sensors in combination with geostationary satellite observations and ERA5 reanalyses data. The goal is to understand which characteristics are favourable to the development of these events and to investigate if any precursor signals can be expected. A total of 9 TGFs, occurred at a distance lower than 45 km from a GPS sensor, were analysed and two of them are shown here as an example analysis. Moreover, the lightning activity, collected by the World Wide Lightning Location Network (WWLLN) was used in order to identify any links and correlations with TGF occurrence and PWV trends. The combined use of GPS and the stroke rate trends identified, for all cases, a recurred pattern in which an increase of PWV is observed on a timescale of about two hours before the TGF occurrence that can be placed within the lightning peak. The temporal relation between the PWV trend and TGF occurrence is strictly related to the position of GPS sensors in relation to TGF coordinates. The life cycle of these storms observed by geostationary sensors, described TGFs producing clouds as intense with a wide range of extensions and, in all cases, the TGF is located at the edge of the convective cell. Furthermore, the satellite data give an added value in associating the GPS water vapor trend to the convective cell generating the TGF. The investigation with ERA5 reanalyses data showed that TGFs mainly occur in convective environment with not exceptional values with respect to the monthly average value of parameters measured in the same location. Moreover the analysis showed the strong potential of the use of GPS data for the troposphere characterization in areas with complex territorial morphology. This study provided indications on the dynamics of convective systems linked to TGFs and will certainly help refine our understanding on their production highlights a potential approach through the use of GPS data to explore the lightning activity trend and the TGFs occurrence.

Space missions have always assumed that the risk of spacecraft malfunction far outweighs the risk of human system failure. This assumption breaks down for longer duration exploration missions and exposes vulnerabilities in space medical system. Space agencies can no longer buy down the majority of human system risk through the crew member selection process and emergency re-supply or evacuation. No mature medical solutions exist to close the risk gap. With recent advances in biotechnology, there is promise in augmenting a space pharmacy with a biologically-based space foundry for on-demand manufacturing of high-value medical products. Here we review the challenges and opportunities of molecular pharming, the production of pharmaceuticals in plants, as the basis of a space medical foundry to close the risk gap in current space medical systems. Plants have long been considered an important life support object in space and can now also be viewed as programmable factories in space. Advances in molecular pharming-based space foundries will have widespread application in promoting simple and accessible pharmaceutical manufacturing on Earth.

(1) Background: It is unclear whether the reported presenting clinical features of coronavirus disease 2019 (COVID-19) are useful in identifying high-risk patients for early testing and isolation in the emergency department (ED). We aimed to compare the exposure history, clinical, laboratory, and radiographic features of ED patients who tested positive and negative for COVID-19; (2) Methods: We conducted a case-control study in seven EDs during the first five weeks of the COVID-19 outbreak in Hong Kong. Thirty-seven laboratory-confirmed COVID-19 patients were compared with 111 age- and gender-matched controls; (3) Results: There were no significant differences in patient characteristics and reported symptoms between the groups, except patient-reported fever. A positive travel history or contact history was the most significant predictor for COVID-19 infection. After adjustment for age and presumed location of acquiring the infection in Wuhan/Hubei, patient-reported fever (OR 2.6, 95% CI 1.1 to 6.3), delayed presentation (OR 5.0, 95% CI 2.0 to 12.5), having medical consultation before ED presentation (OR 7.4, 95% 2.9 to19.1), thrombocytopenia (OR 4.0, 95% CI 1.6 to 9.7), raised lactate dehydrogenase (OR 5.9, 95% CI 1.9 to 18.5), haziness, consolidation or ground-glass opacity on chest radiography (OR 5.6, 95% CI 2.0 to 16.0), and bilateral changes on chest radiography (OR 13.2, 95% CI 4.7 to 37.4) were associated with a higher odds of COVID-19 separately while neutrophilia was associated with a lower odds (OR 0.3, 95% CI 0.1-0.8); and (4) Conclusions: This study highlights several features that may be useful in identifying high-risk patients for early testing and isolation while waiting for test result. Further studies are warranted to verify the findings.

Coronavirus Disease 2019 (COVID-19), caused by a novel coronavirus named Severe Acute Respiratory Syndrome - Coronavirus-2 (SARS-CoV-2), emerged in early December 2019 in China and attained a pandemic situation worldwide by its rapid spread to nearly 167 countries with 287.239 confirmed cases and 11.921 human deaths with a case fatality rate (CFR) of around 4 per cent. Bats were considered as the reservoir host, and the search of a probable intermediate host is still going on. Animals have anticipated culprit of SARS-CoV-2 as of now. The disease is mainly manifested by pneumonia and related respiratory signs and symptoms, but the involvement of the gastrointestinal system and nervous system is also suggested. The severe form of the disease associated with death is mainly reported in older and immune-compromised patients with pre-existing disease history. Death in severe cases is attributed to respiratory failure associated with hyperinflammation. Cytokine storm syndrome associated with rampant inflammation in response to SARS-CoV-2 infection is considered as the leading killer of COVID-19 patients. COVID-19 patients were reported with higher levels of many pro-inflammatory cytokines and chemokines like IFN-g, IL-1b, IP-10, and MCP-1. Furthermore, severe cases of COVID-19 revealed higher levels of TNF-α, G-CSF, and MIP-1A. Blood profile of the COVID-19 patients exhibits lymphopenia, leucopenia, thrombocytopenia and RNAaemia along with increased levels of aspartate aminotransferase. SARS-CoV-2 infection in pregnant women does not lead to fetus mortalities unlike other zoonotic coronaviruses like SARS-CoV and MERS-CoV, with no evidence of intrauterine transmission to neonates. Rapid and confirmatory diagnostics have been developed, and high efforts are being made to develop effective vaccines and therapeutics. In the absence of any virus-specific therapeutic, internationally health care authorities are recommending adoption of effective prevention and control measures to counter and contain this pandemic virus. This paper is an overview of this virus and the disease with a particular focus on SARS-COV-2 / COVID-19 clinical pathology, pathogenesis and immunopathology along with a few recent research developments.

This study evaluated the impact of climate change on water resources in a large semi-arid urban watershed located in Niamey Republic of Niger, West Africa. The watershed was modeled using the fully integrated surface-subsurface HydroGeoSpheremodel at a high spatial resolution. Historical (1980-2005) and projected (2020-2050) climate scenario derived from the outputs of three Regional Climate Models (RCM) under the RCP 4.5 scenario were statistically downscaled using the multiscale quantile mapping bias correction method. Results show that the bias correction method is optimum at daily and monthly scales, and increased RCM resolution does not improve the performance of the model. The three RCMs predict increases of up to 1.6% in annual rainfall and of 1.58°C for mean annual temperatures between the historical and projected periods. The durations of the Minimum Environmental Flow (MEF) conditions, required to supply drinking and agriculture water, were found to be sensitive to changes in runoff resulting from climate change. MEF occurrences and durations are likely to be greater for (2020-2030), and then they will be reduced for (2030-2050). All three RCMs consistently project a rise in groundwater table of more than 10 meters in topographically high zones where the groundwater table is deep and an increase of 2 meters in the shallow groundwater table.

Schistosomiasis, a crippling ailment that afflicts over 220 million people worldwide. Yet or up till now, there is no vaccine for schistosomiasis, and chemotherapy relies heavily on a single drug, the praziquantel. The present study was undertaken to investigate the therapeutic effect of Monophosphoryl Lipid A (MPLA) as an adjuvant in soluble egg antigen (SEA) vaccinated mice against the deleterious pathological impacts induced in hepatic tissues of mice by Schistosoma mansoni infection. In addition, to study the associated parasitological, immunological and biochemical parameters. Parasitological parameters showed that intraperitoneal injection of MPLA into SEA-vaccinated and S. mansoni-infected mice was effective to a significant degree in reducing the worm and egg burden, granuloma count and diameter as well as the total area of infection in their livers versus SEA-untreated but infected ones. In addition, MPLA showed ameliorative action on the elevated liver oxidative stress marker, including malondialdehyde (MDA) and decrease in the level of the antioxidant enzymes, reduced glutathione (GSH) and catalase (CAT) which may have a role in the liver damage and fibrosis due to S. mansoni infection. In conclusion, treatment with MPLA has multi-functions in attenuating the deleterious impacts of S. mansoni infection in mice livers. Its effects are mediated through a reduction of ova count, worm burden, granuloma diameter and amelioration of antioxidant defense systems, and liver function biomarkers.

The effect of microstructure and chemistry of passive films on the kinetics of passive layer growth and passivity breakdown of some Ti-based alloys, namely Ti-6Al-4V, Ti-6Al-7Nb and TC21 alloys was studied. The rate of pitting corrosion was evaluated using cyclic polarization measurements. Chronoamperometry was applied to assess the passive layer growth kinetics and breakdown. Microstructure influence on the uniform corrosion rate of these alloys was also investigated employing Tafel extrapolation and dynamic electrochemical impedance spectroscopy. Corrosion studies were performed in 0.9% NaCl solution at 37 oC, and the obtained results were compared with ultrapure Ti (99.99%). The different phases of the microstructure were characterized by X-ray diffraction and scanning electron microscopy. Chemical composition and chemistry of the corroded surfaces were studied using X-ray photoelectron analysis. For all studied alloys, the microstructure consisted of α matrix, which was strengthened by β phase. The highest and the lowest values of the β phase’s volume fraction were recorded for TC21 and Ti-Al-Nb alloys, respectively. The uniform corrosion rate and pitting corrosion resistance (R_pit) of the studied alloys were enhanced following the sequence: Ti-6Al-7Nb < Ti-6Al-4V << TC21. The corrosion resistance of Ti-Al-Nb alloy approached that of pure Ti. The obvious changes in the microstructure of these alloys, together with XPS findings, were adopted to interpret the pronounced variation in their corrosion rates.

Yeasts belonging to the Metschnikowia genus are particularly interesting for the unusual formation of only two needle-shaped ascospores during their mating cycle. Presently, the meiotic process that can lead to only two spores from a diploid zygote is poorly understood. The expression of fluorescent nuclear proteins should allow the meiotic process to be visualized in vivo; however, no large-spored species of Metschnikowia has ever been transformed. Accordingly, we aimed to develop a transformation method for Metschnikowia borealis, a particularly large-spored species of Metschnikowia, with the goal of enabling the genetic manipulations required to study biological processes in detail. Genetic analyses confirmed that M. borealis, and many other Metchnikowiacea, are CUG-Ser yeasts. Codon-optimized selectable markers lacking CUG codons were used to successfully transform M. borealis by electroporation and lithium acetate, and transformants appeared to be the result of random integration. Mating experiments confirmed that transformed-strains were capable of generating large asci and undergoing recombination. Finally, random integration was used to transform an additional 18 yeast strains, and all attempts successfully generated transformants. The results provide a simple method to transform many yeasts from an array of different clades and can be used to study or develop many species for various applications.

As one of the most prominent seasonally recurring atmospheric circulation patterns, the Asian Summer Monsoon (ASM) plays a vital role for the life and livelihood of about a third of the global population. Changes in the strength and seasonality of the ASM significantly affect the region, yet the drivers of change and the varied regional responses of the ASM are not well understood. In the last two decades, there have been a number of studies reconstructing the ASM using stalagmite-based proxies such as oxygen isotopes (18O). Such reconstructions allow examination of the drivers and responses, increasing monsoon predictability. In this review paper, we focus on stalagmite 18O records from India at the proximal end of the ASM region. Indian stalagmite 18O records show well dated, high amplitude changes in response to the dominant drivers of the ASM on orbital to multi-centennial timescales and indicate the magnitude of monsoon variability in response to these drivers. We examine Indian stalagmite records collated in SISAL_v1 (version 1) database (http://researchdata.reading.ac.uk/139/) and support the database with a summary of record quality and regional climatic interpretations of the 18O record during different climate states. We highlight current debates and suggest the most useful time periods (climatic events) and locations for further work using tools such as data-model comparisons, spectral analysis methods, multi-proxy investigations and monitoring work

Background: First episode psychosis (FEP), schizophrenia and affective disorders are accompanied by activation of the immune inflammatory response system (IRS). The compensatory immune-regulatory reflex system (CIRS) is a regulatory immune response that is induced by the IRS but exerts negative feedback through, for example, increased levels of anti-inflammatory cytokines such as IL-4, IL-13 and IL-10. Different phenotypes of schizophrenia may exhibit distinct IRS and CIRS immune profiles.Aims: This study aims to examine the IRS and CIRS components, including macrophagic M1, T-helper (Th)-1, Th-2, Th-17 and T-regulatory (Treg) phenotypes, in antipsychotic-naïve FEP patients before and after risperidone treatment.Methods: We included 31 antipsychotic-naïve FEP patients who had measurements of IRS and CIRS biomarkers before and after treatment with risperidone for 10 weeks, and 22 healthy controls.Results: Antipsychotic-naive FEP patients showed interrelated increments in M1, Th-1, Th-2, Th-17 and Treg phenotypes and a relatively greater IRS response (especially granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6 and IL-12) as compared with the CIRS response (IL-4, IL-13, IL-5 and IL-10). Inflammatory markers, especially IL-6 and IL-8, were significantly correlated with negative, psychotic, affective and excitation symptom dimensions. Treatment with risperidone significantly suppressed the IRS and CIRS. Baseline levels of CIRS biomarkers, especially higher soluble tumor necrosis factor receptor-1 and IL-10 predicted clinical improvement during treatment.Discussion: Our findings indicate that FEP is characterized by robust IRS (M1 + Th-1 + Th-17) and CIRS responses, suggesting that monocytes, macrophages, Th-1, Th-2, Th-17 and Treg cells are activated. The findings indicate that a) FEP patients are prone to the detrimental effects of M1, Th-1, Th-17 and Th-2 cells, which may contribute to long-lasting abnormalities in brain circuitry; and b) in FEP, the CIRS may contribute to recovery from the acute phase of illness. Enhancing the CIRS is a new drug target to treat FEP.

A new series of 1,3,4-oxadiazoles derivatives was synthesized, characterized and evaluated for their in vitro and in vivo anti-thrombotic activity. Compounds (3a-3i) exhibited significant clot lysis with respect to negative control and reference drug streptokinase (30,000 IU) while enhanced clotting time (CT) values were observed (130-342 sec) for these tested compounds than the standard drug heparin (110 sec.). High affinity towards 1NFY with greater docking score was observed for the compounds (3a, 3i, 3e, 3d and 3h) than the control ligand RPR200095. In addition, very good inhibitory potential against factor Xa (F-Xa) was observed with higher docking scores (5612-6270) with ACE values (–189.68 to –352.28 kcal/mol) than the control ligand RPR200095 (Docking score 5192; ACE –197.81 kcal/mol. In vitro, in vivo and in silico results proposed that these newly synthesized compounds can be used as anti-coagulant agents.

The purpose of this study was to report data analysis results from the International Health Regulations (2005) Ship Sanitation Certificates (SSC), recorded in the European Information System (EIS). International sea trade and population movements by ships can contribute to the global spread of diseases. SSC are issued to ensure the implementation of control measures if public health risk exists on board. EIS designed according to the World Health Organization (WHO) “Handbook for Inspection of Ships and Issuance of SSC”. Inspection data were recorded and SSC issued by inspectors working at European ports were analysed. From July 2011-February 2017, 107 inspectors working at 54 ports in 11 countries inspected 5579 ships. Of these, there were 29 types under 85 flags (including 19 EU flags). As per IHR (2005) 10,281 Ship Sanitation Control Exception Certificates (SSCEC) and 296 Ship Sanitation Control Certificates (SSCC) were issued, 74 extensions to existing SSC were given, 7565 inspection findings were recorded, and 47 inspections were recorded without issuing an SSC. The most frequent inspection findings were the lack of potable water quality monitoring reports (23%). Ships aged ≥12 years (Odds Ratio, OR = 1.77, 95%Confidence Intervals, CI = 1.37–2.29) with an absence of cargo at time of inspection (OR = 3.36, 95%CI = 2.51–4.50) had a higher probability of receiving an SSCC, while ships under the EU flag had a lower probability of having inspection findings (OR = 0.72, 95%CI = 0.66–0.79). Risk factors to prioritise the inspections according to IHR were identified by using the EIS. A global information system, or connection of national or regional information systems and data exchange, could help to better implement SSC using common standards and procedures.

Scrub typhus threatens one billion people in the Asia-Pacific area and cases have emerged outside this region. It is caused by infection with any of the multitude of strains of the bacterium, Orientia tsutsugamushi. A vaccine that affords heterologous protection and a commercially available molecular diagnostic assay are lacking. Herein, we determined that the nucleotide and translated amino acid sequences of outer membrane protein A (OmpA) are highly conserved among 51 O. tsutsugamushi isolates. Molecular modeling revealed the predicted tertiary structure of O. tsutsugamushi OmpA to be very similar to that of the phylogenetically related pathogen, Anaplasma phagocytophilum, including the location of a helix that contains residues functionally essential for A. phagocytophilum infection. PCR primers were developed that amplified ompA DNA from all O. tsutsugamushi strains, but not from negative control bacteria. Using these primers in quantitative real-time PCR enabled sensitive detection and quantitation of O. tsutsugamushi ompA DNA from organs of mice that had been experimentally infected with the Karp or Gilliam strains. The high degree of OmpA conservation among O. tsutsugamushi strains evidences its potential to serve as a molecular diagnostic target and justifies its consideration as a candidate for developing a broadly protective scrub typhus vaccine.

Since general relativity (GR) has already established that matter can simultaneously have two different values of mass depending on its context, we argue that the missing mass attributed to non-baryonic dark matter (DM) actually obtains because there are two different values of mass for the baryonic matter involved. The globally obtained "dynamical mass'' of baryonic matter can be understood as a small perturbation to a background spacetime metric even though it's much larger than the locally obtained "proper mass". Having successfully fit the SCP Union2.1 SN Ia data without accelerating expansion or a cosmological constant, we employ the same ansatz to compute dynamical mass from proper mass and explain galactic rotation curves (THINGS data), the mass profiles of X-ray clusters (ROSAT and ASCA data) and the angular power spectrum of the cosmic microwave background (Planck 2015 data) without DM. We compare our fits to modified Newtonian dynamics (MOND), metric skew-tensor gravity (MSTG) and scalar-tensor-vector gravity (STVG) for each data set, respectively, since these modified gravity programs are known to generate good fits to these data. Overall, we find our fits to be comparable to those of MOND, MSTG and STVG. While this favorable comparison does not establish the validity of our proposition, it does provide confidence in using the fits to pursue an underlying action. Indeed, the functional form of our ansatz reveals an interesting structure in these fits.

Tissue-like phantoms are widely used as a model for mimicking the optical properties of live tissue. This paper presents the results of a diffusion reflection method as well as fluorescence lifetime imaging microscopy measurements of fluorescein-conjugated gold nanorods in solution as well as inserted in solid tissue-imitating phantoms. A lack of consistency between the fluorescence lifetime results of the solutions and the phantoms raises a question about the ability of tissue-like phantoms to maintain the optical properties of inserted contrast agents.

In this paper, we study the problem of controllability of impulsive neutral evolution integrodifferential equations with state dependent delay in Banach spaces. The main results are completely new and are obtained by using Sadovskii's fixed point theorem, theory of resolvent operators, and an abstract phase space. An example is given to illustrate the theory.

Background: Molecular genetic events are among the numerous factors affecting the clinical course of papillary thyroid carcinoma (PTC). Recent studies have demonstrated that aberrant expression of miRNA, as well as different thyroid-related genes, correlate with the aggressive clinical course of PTC and unfavorable treatment outcome, which opens up new avenues for using them in personalization of the treatment strategy for patients with PTC. In the present work, our goal was to assess the applicability of molecular markers in preoperative diagnosis of aggressive variants of papillary thyroid cancer. Methods: The molecular genetic profile (expression levels of 34 different markers and BRAF mutation) was studied for 108 cytology specimens collected by fine-needle aspiration biopsy in patients with PTC having different clinical manifestations. Results: Statistically significant differences with adjustment for multiple comparisons (p &lt; 0.0015) for clinically aggressive variants of PTC were obtained for four markers: miRNA-146b, miRNA-221, FN1, and CDKN2A. Weak statistical correlation (0.0015&lt; р&lt;0.05) was observed for miRNA-31, -375, -551b, -148b, -125b, mtDNA, CITED1, TPO, HMGA2, CLU, NIS, SERPINA1, TFF3, and TMPRSS4. Conclusions: The recurrence risk of papillary thyroid carcinoma can be preoperatively predicted using miRNA-221, the fibronectin and cyclin-dependent kinase inhibitor 2A genes.

Metals play vital roles in biological systems, with iron/heme being essential for cellular and metabolic functions necessary for survival and/or virulence in many bacterial pathogens. Given the rise of bacterial resistance to current antibiotics, there is an urgent need for the development of non-toxic and novel antibiotics that do not contribute to resistance to other antibiotics. Gallium, which mimics iron, has emerged as a promising antimicrobial agent, offering a novel approach to combat bacterial infections. Gallium does not have any known functions in biological systems. Gallium exerts its effects primarily by replacing iron in redox enzymes, effectively inhibiting bacterial growth by targeting multiple iron/heme-dependent biological processes and suppressing the development of drug resistance. The aim of this review is to highlight recent findings on the mechanisms of action of gallium and provide further insights into the development of gallium-based compounds. Understanding the mechanisms underlying gallium’s biological activities will enhance its therapeutic application across various medical fields, offering promising avenues for the treatment of infectious diseases, cancer, and inflammatory conditions.

Tuberculosis (TB) is an infectious disease declared a global emergency by the World Health Organization and continues as one of the world’s top ten causes of death. TB diagnosis is more critical in developing countries where demanded infrastructure for detection, and treatment complicates the efforts against the disease. These aspects related to limited resources are significant, especially in areas away from the main cities, with few mechanisms to make a timely diagnosis that contributes to successfully addressing the possible patients. Artificial intelligence has begun to be essential in providing additional strategies in the diagnosis processes for health professionals’ support. This paper uses natural language processing (NLP) and machine learning (ML) techniques to create models that can supply TB diagnosis when the needed infrastructure is unavailable. Two different sources were explored: text extracted from electronic medical records (EMR) and patient clinical data (CD). Four proposals using five different machine learning models were implemented. The first two models employed ML and each data source independently. Then, two additional approaches developed a data fusion from both sources. This strategy’s employment was analyzed with physicians according to their pertinence in the process and understanding of the EMR. Finally, the results of the data fusion were compared to each source, obtaining better performance at using only the CD, where an area under the ROC curve of 69.9±2.3% was obtained. However, the advantage of analyzing physician’s reports is the availability of this information contrasted to clinical-specific data, which can be more useful in places far from the main cities without enough basic structure for its obtaining.

In this study is considered the design and implementation of pilots in desalination plants, in a systematic way, to evaluate energy improvements in water desalination processes. Pilot tests with the latest generation of reverse osmosis membranes in large desalination plants are becoming increasingly common, as small-scale experiments are carried out on the operation of new generation membranes with better salt rejection and lower energy consumption, to achieve the best water quality required for each case at the lowest possible cost. In this way, pilot tests are being carried out before the decision is made whether or not to change the reverse osmosis membranes, as this represents a significant investment and we minimize the risk of making a mistake in order to ensure the best results in terms of energy consumption, operating costs and reducing the environmental impact while complying with the required water quality. In this case, the Pareto analysis is used to highlight the 2 or 3 most significant causes whose treatment affects more than 80% of the possible energy improvement to be implemented. In this sense, figure 3 below shows the Pareto diagram for the energy improvement of N plants in a given territory. A series of factors that can affect this energy improvement have been numbered from 1 to 7, such as the seawater intake, the decision on the membranes, the energy recuperators, the high-pressure pump, the decisions on the pre-treatment, the feed pump or the post-treatment. The Pareto diagram has been studied at territorial level with a total of 180 seawater desalination plants. The novelty of this article is to apply Pareto diagram to a study of a total of 180 seawater desali-nation plants at territorial level in Canary Islands.

The electronic properties of calcium intercalated graphite (CaC6) as a function of pressure are revisited using density functional theory (DFT). The electronic band structures of CaC6, like many other layered superconducting materials, display cosine-shaped bands at or near the Fermi level (FL). Such bands encompass bonding/antibonding information with a strong connection to superconducting properties. Using an hexagonal cell representation for CaC6, construction of a double supercell in the c-direction effects six-folding in reciprocal space of the full cosine function, explicitly revealing the bonding/antibonding relationship divide at the cosine midpoint. Similarly, folding of the Fermi surface (FS) reveals physical phenomena relevant to electronic topological transitions (ETT) with application of pressure. For CaC6, the peak value for the superconducting transition temperature, Tc, occurs at about 7.5 GPa, near to the observed pressure of the calculated ETT. At this pressure, the radius of the nearly spherical Ca 4s-orbital FS coincides with three times the distance from the G centre point to the Brillouin zone (BZ) boundary of the 2c supercell (which is equal to half the identically defined distance for the primitive rhombohedral BZ). In addition, the ETT coincides with alignment of the non-bonding (inflection) point of the cosine band (the point at which the sign of the cosine amplitude modulation is reversed) with the FL. At other calculated pressure conditions, the Ca 4s-orbital FS undergoes topological changes that correspond and can be correlated to experimentally determined changes in Tc. The ETT is a key mechanism that circumscribes the known significant drop in Tc for CaC6 as a function of increasing pressure.

Background: Dietary quality and the consumption of antioxidant-rich foods has been shown to protect against memory decline. Therefore, this double-blind, randomized, placebo-controlled study aimed to investigate the effects of a nutritional supplement on changes in cognitive performance. Methods: In adults aged 40 to 70 years with subjective memory complaints, participants were randomly allocated to take a supplement containing vitamin E, astaxanthin, and grape juice extract daily for 12 weeks or a matching placebo. The primary outcomes comprised changes in cognitive tasks assessing episodic memory, working memory, and verbal memory. Secondary and exploratory measures included changes in the speed of information processing, attention, and self-report measures of memory, stress, and eye and skin health. Moreover, changes in plasma concentrations of brain-derived neurotrophic factor, malondialdehyde, tumor-necrosis factor-α, and interleukin-6 were measured, along with changes in skin carotenoid concentrations. Results: compared to the placebo, nutritional supplementation was associated with larger improvements in episodic memory, a self-report measure of everyday memory, increased plasma brain-derived neurotrophic factor, decreased plasma malondialdehyde, and increased skin carotenoid concentrations. However, there were no group differences in changes in the remaining outcome measures. Conclusions: Twelve weeks of supplementation with a nutritional supplement was associated with improvements in episodic memory and several biological markers associated with cognitive health. Future research will be essential to extend and validate the current findings.

It has been proven that in standard Einstein gravity, exotic matter (i.e. matter violating the point-wise and averaged weak and null energy conditions) is required to stabilize traversable wormholes. Quantum field theory permits these violations due to the quantum coherent effects found in any quantum field . Even reasonable classical scalar fields violate the energy conditions. In the case of the Casimir effect and squeezed vacuum states, these violations have been experimentally proven. It is advantageous to investigate methods of minimizing the use of exotic matter. One such area of interest is extended theories of Einstein gravity. It has been claimed that in some extended theories, stable traversable wormholes solutions can be found without the use of exotic matter. There are many extended theories of gravity and in this review paper we first explore f(R) theories and then explore some wormhole solutions in f(R) theories including Lovelock gravity.

An easy to implement and cost-effective Fiber Bragg Grating (FBG) sensor interrogation technique based on a ring Erbium-Doped Fiber Laser (EDFL) topology is proposed and experimentally assessed. The FBG sensor is part of the EDFL cavity and must have a central wavelength located within the linear region of the EDF’s amplified spontaneous emission (ASE) spectrum which occurs between 1530 and 1540nm. In this manner, the wavelength-encoded response of the FBG under strain is converted to a linear variation of the laser output power, removing the need for spectrum analysis as well as any limitations from the use of external edge-filtering components. In addition, the laser linewidth is significantly reduced with respect to the FBG bandwidth thus improving the resolution of the system, whereas its sensitivity can be controlled through the pumping power. The performance of the system has been characterized by modeling and experiments for EDF's with different lengths, doping concentrations and pumping power levels. The influence of mode-hopping in the laser cavity on the resolution and accuracy of the system has also been investigated.

Rett Syndrome (RTT) is a severe neurodevelopmental disorder predominately diagnosed in females and primarily caused by pathogenic variants in the X-linked gene Methyl-CpG Binding Protein 2 (MECP2). Most often, the disease causing MECP2 allele resides on the paternal X chromosome while a healthy copy is maintained on the maternal X chromosome with inactivation (XCI) resulting in mosaic expression of one allele in each cell. Preferential inactivation of the paternal X chromosome is theorized to result in reduced disease severity; however, establishing such a correlation is complicated by known MECP2 genotype effects and an age dependent increase in severity. To mitigate these confounding factors, we developed an age- and genotype-normalized measure of RTT severity by modeling longitudinal data collected in the US Rett Syndrome Natural History Study. This model accurately reflected individual increase in severity with age and preserved group-level genotype specific differences in severity allowing for the creation of a normalized clinical severity score. Applying this normalized score to a RTT XCI dataset revealed that XCI influence on disease severity depends on MECP2 genotype with a correlation between XCI and severity observed only in individuals with MECP2 variants associated with increased clinical severity. This normalized measure of RTT severity provides the opportunity for future discovery of additional factors contributing to disease severity that may be masked by age and genotype effects.