Triphenylphosphonium (TPP) derivatives of a decapeptide related to sequences of bactenecin 7 (Bac7) and oncocin (Onc112) were synthesized and studied as potential antimicrobial compounds using various biochemical and microbiological assays. It was shown that while the reduction of the Bac7 length to 10 a.a. residues dramatically decreases the affinity to bacterial ribosomes, the modification of peptide with alkyl-TPP moieties leads to an increase in the affinity. New analogs which structure combines a decapeptide related to Bac7 and Onc112 — Bac(1-10, R/Y) — and TPP, attached to the C-terminal amino acid residue through alkylamide linkers, inhibit translation in vitro and are found to be more selective inhibitors of bacterial translation as compared with eukaryotic translation, than Onc112 and Bac7. Triphenylphosphonium analogs of a decapeptide related to Bac7 and Onc112 suppress the growth of both gram-negative bacteria, similar to Onc112 and Bac7, and gram-positive ones as alkyl-TPP derivatives, and also act against some resistant laboratory strains. Bac(1-10, R/Y)-C2-TPP, containing a short alkylamide linker between the decapeptide and TPP, is transferred into the E. coli cells via the SbmA transporter protein. TPP derivatives of the decapeptide Bac(1-10, R/Y) containing either decylamide or ethylamide linker cause B. subtilis membrane depolarization, similar to alkyl-TPP. The Bac(1-10, R/Y)-C2-TPP analog is proved to be non-toxic for mammalian cells by MTT-test.

Several hypotheses have been presented on the origin of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from its identification as the agent causing the current coronavirus disease 19 (COVID-19) pandemic. So far, no hypothesis has managed to identify the origin, and the issue has resurfaced. Here we have unfolded a pattern of distribution of several mutations in the SARS-CoV-2 proteins across different continents comprising 24 geo-locations. The results showed an evenly uneven distribution of unique protein variants, distinct mutations, unique frequency of common conserved residues, and mutational residues across the 24 geo-locations. Furthermore, ample mutations were identified in the evolutionarily conserved invariant regions in the SARS-CoV-2 proteins across almost all geo-locations we have considered. This pattern of mutations potentially breaches the law of evolutionary conserved functional units of the beta-coronavirus genus. These mutations may lead to several novel SARS-CoV-2 variants with a high degree of transmissibility and virulence. A thorough investigation on the origin and characteristics of SARS-CoV-2 needs to be conducted in the interest of science and to be prepared to meet the challenges of potential future pandemics.

Results from the phase III Keynote-024 clinical trial have established Pembrolizumab monotherapy as the first-line standard of care for patients with metastatic NSCLC who have PD-L1 expression ≥ 50%, EGFR and ALK wild-type. However, given the differences between patients treated in routine clinical practice and within a clinical trial, real-world data are needed to confirm the treatment benefit in standard practice. Given the lack of data on large cohorts of patients with long follow-up, we designed a retrospective observational study of patients with NSCLC who were treated with Pembrolizumab, starting from its reimbursement eligibility until December 2020. The primary endpoints were to assess PFS and OS using the Kaplan-Meier method, treatment response and safety. We followed 880 patients (median follow-up: 35.1 months) until February 2022. Median PFS and OS were 8.6 months (95% CI: 7.6-10.0) and 25.5 months (95% CI: 21.8-31.6), respectively. We also found that ECOG PS, PD-L1 expression and smoking habit were prognostic factors for PFS, while age, sex, ECOG PS, smoking habit and histology had an impact on OS. Multivariable analysis confirms prognostic role of PD-L1 for PFS and ECOG for both PFS and OS. 39.9% of patients reported an adverse event, but only 6.3% of patients discontinued therapy due to toxicity. Our results suggest a long-term benefit of Pembrolizumab in the first-line setting as well as a safety profile consistent with the results of Keynote-042. Many collected variables appear to influence clinical outcome, but results from these exploratory unadjusted analyses should be interpreted with caution.

Background: COVID-19 represents a threat for frailty patients. Objective: Investigate efficacy, safety and economic value of treatment with Molnupiravir in a cohort of fragile patients affected by COVID-19. Methods: Observational, prospective study. The data collected allowed to assess efficacy and safety of Molnupiravir in real life, compare the results with a subgroup of patients treated with Nirmatrelvir-Ritonavir and to effect a cost-effectiveness analysis. Results: In January-December 2022, 435 patients (225 males, 220 females; median age 72 years), were enrolled; 24 patients were unvaccinated, 280 patients had ≥2 risk factors. Molnupiravir appeared to give better results than the SOC both clinically and economically. In these patients in comparison with literature data or SOC, hospitalization was 2.5% vs 6.8% (p<0.005), overall adverse effects 14,3% vs 30.4% (p<0.0001), severe adverse effects 2.6 vs 6.9% (p<0.001), thus involving a potential total savings of about € 92.954 per patient (8% of standard of care cost). Conclusions: early Molnupiravir treatment helped fragile patients who partially responded to vaccine, or with absolute contraindications to vaccination, to overcome COVID-19 without the need of hospitalization. Molnupiravir represents a clinical and economic effective treatment, avoiding disease progression in old patients suffering from multiple pathologies and taking several drugs.

Dyslipidemia is a disorder where abnormally lipid concentrations circulate in the bloodstream. The disorder is common in type 2 diabetics (T2D) and is linked with T2D comorbidities, particularly cardiovascular disease. Dyslipidemia in T2D is typically characterized by elevated plasma triglyceride and low high-density lipoprotein cholesterol (HDL-C) levels. There is a significant gap in the literature regarding dyslipidemia in rural parts of Africa, where lipid profiles may not be routinely captured through standard surveillance activities. This study aimed to characterize the prevalence and demographic profile of dyslipidemia in T2D patients in the rural community of Ganadougou, Mali. We performed a cross-sectional study of 104 subjects with T2D in Ganadougou between November 2021 and March 2022. Demographic and lipid profiles were collected through cross-sectional surveys and blood tests. The overall prevalence of dyslipidemia in T2D patients was 87.5% (91/104), which did not differ by sex (p = .368). High low-density lipoprotein cholesterol (LDL-C) was the most common lipid abnormality (78.9%, [82/104]). Dyslipidemia was associated with age and hypertension status (p = .013 and p = .036, respectively). High total and high LDL-C parameters were significantly associated with hypertension (p = .029 and p = .006, respectively). In low-resource settings such as rural Mali, there is a critical need to improve infrastructure for routine dyslipidemia screening to guide its prevention and intervention approaches. The high rates of dyslipidemia observed in Gandadougou, consistent with concomitant increases in cardiovascular diseases in Africa suggest that lipid profile assessments should be incorporated into routine medical care for T2D patients in African rural settings.

This work presents results of property researches of fabricated samples of silica few-mode optical fiber (FMF) with induced chirality under twisting 10 and 66 revolutions per meter, core diameter 11 µm, typical “telecommunication” cladding diameter 125 µm and improved height of quasi-step refractive index profile. Proposed FMF supports 4 guided modes over “C”-band. We represent results of computed characteristics, as well as experimentally measured spectral responses of laser-excited optical signals, including researches and analysis of few-mode effects, occurring after fiber Bragg grating writing.

Serum transferrin (sTf) plays a pivotal role in regulating iron biodistribution and homeostasis within the body. The molecular details of sTf Fe(III) binding, blood transport, and cellular delivery through transferrin receptor-mediated endocytosis are generally well-understood. Emerging interest exists in exploring sTf complexation of nonferric metals as it facilitates the therapeutic potential and toxicity of several of them. This review explores recent X-ray structural and physiologically relevant metal speciation studies to understand how sTf partakes in the bioactivity of key non-redox active hard Lewis acidic metals. It challenges preconceived notions of sTf structure function correlations that were based exclusively on the Fe(III) model by revealing distinct coordination modalities that nonferric metal ions can adopt and different modes of binding to metal-free and Fe(III)-bound sTf that can directly influence how they enter into cells and, ultimately, how they may impact human health. This knowledge informs on biomedical strategies to engineer sTf as a delivery vehicle for metal-based diagnostic and therapeutic agents in the cancer field. It is the intention of this work to open new avenues for characterizing the functionality and medical utility of nonferric-bound sTf and to expand the significance of this protein in the context of bioinorganic chemistry.

Congenital heart disease (CHD) is among the 4 more common causes of infant mortality in Latin America. Pulse oximetry screening (POS) is useful for early diagnosis and improved outcomes of critical CHD. We describe POS implementation efforts in Latin American countries guided and/or coordinated by the Ibero American Society of Neonatology (SIBEN) as well as the unique challenges that are faced for universal implementation. SIBEN collaborates to improve neonatal quality of care and outcomes. A few years ago, a Clinical Consensus on POS was finalized. Since then, we participated in 12 Latin American countries to educate neonatal nurses and neonatologists on POS and to help with its implementation. The findings reveal that despite wide disparities in care that exist between and within countries, and the difficulties and challenges for implementing POS, significant progress was made. We conclude that universal POS is not easy to implement in Latin America but, when executed, not only it has been of significant value for babies with CHD but also for many with other hypoxemic conditions. The successful and universal implementation of POS in the future is essential to reduce the mortality associated with CHD and other hypoxemic conditions and will ultimately lead to the survival of many more Latin American babies. POS saves newborns’ lives in Latin America.

Background: Obesity among pregnant women is common, and their offspring are predisposed to obesity, insulin resistance, and diabetes. Circulating metabolites that are related to insulin resistance and are associated with this decreased tissue-specific uptake are unknown. Here, we assessed metabolite profiles in elderly women and who were either female offspring from obese mothers (OOM) or offspring of lean mothers (OLM). Metabolic changes were tested for associations with metrics for insulin resistance. Methods: 37 elderly women were separated into an elderly offspring from obese mothers (OOM; n = 17) and elderly offspring from lean/normal weight mothers (OLM; n = 20) groups. We measured plasma metabolites using 1H-NMR and also insulin-dependent tissue specific glucose uptake in skeletal muscle were assessed. Associations were made between metabolites and glucose uptake. Results: Compared to the OLM group, we found that the 22:6 docosahexaenoic acid percentage of the total long chain n-3 fatty acids (DHA/FA) was significantly lower in OOM (P = 0.015). DHA/FA associated significantly to skeletal muscle GU (P = 0.031) and M-value in the OLM group only (P = 0.050). Conclusions: DHA/FA is associated with insulin-dependent skeletal muscle glucose uptake and that this association is significantly weakened in the offspring of obese mothers.

This study presents, for the first time, the development of fibers with favorable properties for biodegradable wound dressings made from the Ecovio® (EC) polymer blend, composed of poly(lactic acid) (PLA) and poly(butylene adipate-co-terephthalate) (PBAT), incorporated with tea tree essential oil (TTE). TTE presented antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus, achieving minimal inhibitory concentrations of 15 and 7.5 mg/mL, respectively. The TTE was mixed with EC in a binary chloroform and formic acid (85/15 v/v) mixture, leading to homogeneous and wettable fibers by electrospinning. The EC/TTE fibers were characterized confirming the TTE in the fibers. The tests showed that TTE (0.5, 1.0 or 1.5 mL) improved the polymer blend electrospinnability. TTE (1.5 mL or 75 w% concerning the EC) lead to homogeneous fibers with an average diameter of 278 nm. TTE (75 w%) increased the wettability of the EC fibers from 120±2° to 69±1°. Preliminary bacterial adhesion and proliferation assays demonstrated that the EC/TTE fibers have anti-adhesive activity e seems to be more toxic against P. aeruginosa compared to S. aureus after 24 hours of incubation. Compatibility tests with human blood indicated that the EC/TTE fibers accelerate blood coagulation. The EC/TTE fibers exhibit promising chemical and biological properties (in vitro) for the development of wound dressings.

The demand for a more sustainable agriculture, coupled with the need for optimized crop productivity, has driven the use of microorganisms for the biocontrol of diseases and pests, as well as for growth promotion. The use of plant growth-promoting rhizobacteria (PGPR) and plant growth-promoting fungi (PGPF) in Brazilian production systems has become increasingly common, with the number of microbial inoculant registrations in the country growing every year. PGPR and PGPF occupy various niches in the rhizosphere, playing a crucial role in soil nutrient cycling, as well as influencing various plant physiological processes. In this review, we address the main mechanisms used by these microbial agents in growth promotion and the use of strain co-inoculation as a strategy to enhance the efficacy of these products. Subsequently, we conduct an analysis of the available inoculants in Brazil, detailing the microorganisms available for the main Brazilian crops, and the prospects of this market regarding research and development of new products for the coming years based on the current challenges faced.

Herein we present the biocatalysed preparation of mono-N-carbamate-protected precursor of antitumoral Nutlin-3a, through enantioselective alkoxycarbonylation of meso-1,2-disubstituted-1,2-diaminoethane, using enzyme lipases and dialkyl carbonates as acylating agents. A series of supported or free lipase enzymes were screened in combination with commercially available diallyl-, diethyl and dimethyl- carbonate. The reactions were conducted at different temperatures, reaction times and with variable co-solvent systems to evaluate the effect on the enzyme catalytic activity. The best results in terms of conversion, enantiomeric excess and yield were obtained when lipase from Candida antarctica B (CAL-B) was used with diallyl carbonate (DAC) conducting the reaction solventless at 75 °C.

In these last years, self-healing polymers have emerged as a topic of considerable interest owing to their capability to partially restore material properties and thereby extend the product's lifespan. The main purpose of this study is to investigate the nano-indentation response in terms of hardness, reduced modulus, contact depth and coefficient of friction of a self-healing resin developed for use in aeronautical and aerospace contexts. To achieve this, the bifunctional epoxy precursor underwent tailored functionalization to improve its toughness, facilitating effective compatibilization with a rubber phase dispersed within the host epoxy resin. This approach aimed to highlight the significant impact of the quantity and distribution of rubber domains within the resin on enhancing its mechanical properties. The main results are that pure resin exhibits a higher hardness (about 36.7% more) and reduced modulus (about 7% more), consequently leading to a lower contact depth and coefficient of friction (11.4% less) compared to other formulations that, conversely, are well-suited for preserving damage from mechanical stresses due to their capabilities in absorbing mechanical energy. Furthermore, finite element method (FEM) simulations of the nanoindentation process were conducted. The numerical results were meticulously compared with experimental data, demonstrating a good agreement. This validation of the FEM model underscores its efficacy in predicting the mechanical behavior of nanocomposite materials under nanoindentation. The proposed investigation aims to contribute knowledge and optimization tips about self-healing resins.

Previous studies show that women with a history of high-grade CIN have a greater risk of subsequent high-grade anogenital intraepithelial neoplasia or cancer, and the risk is greater for vaginal cancer than for anal and vulvar cancers. It is hypothesized that the laparoscopic hysterectomy procedure may cause a higher incidence of VaIN in hysterectomized women. There are few studies addressing this issue and they show mixed results. This study aimed to investigate the incidence of high-grade or worse VaIN in the population of women undergoing hysterectomy for CIN3 or benign uterine disease, illustrate treatment options and follow-up. Methods: This retrospective study was conducted on 170 women who underwent laparoscopic hysterectomy for high-grade cervical intraepithelial neoplasia (CIN3) or benign gynecological disease. The follow-up strategy included performing a cotest and colposcopy with biopsy if necessary. The median time between primary treatment and diagnosis of high-grade VaIN was 18 months. Results: High grade or worse VaIN was found in 8 patients after hysterectomy (4.7%). All cases of high-grade VaIN occurred in women with persistent HPV infection. The most frequent genotype was 16. Women hysterectomized for CIN3 showed an 8-fold greater risk than women hysterectomized for benign disease of developing high-grade VaIN. The risk of VaIN is low in women hysterectomized for benign disease. The risk of developing VaIN is greater in women with viral persistence Conclusion. All these elements suggest that it is the history of HPV-related disease of the lower genital tract and viral persistence, rather than hysterectomy itself, that should be considered a risk factor for the development of high-grade VaIN. After hysterectomy, patients with a history of CIN should undergo annual screening with vaginal dome cytology and HPV testing.

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: Boronic acids form di-ester bonds with cis-hydroxyl groups in carbohydrates. The formation of these adducts could impair the physical and chemical properties of the precursors, even their biological activity. Methods: Two carbohydrate-derivatives from D-fructose and D-arabinose and phenylboronic acid were synthesized in a straightforward one-step procedure and chemically characterized by spectroscopy and X-ray diffraction crystallography. Also, an acute toxicity test was performed to determine their Lethal Dose50 (LD50) by using the Lorke’s method. Results: Analytical chemistry assays confirmed adducts by the generation of the diester bonds with a β-D-pyranose of carbohydrates, including signals corresponding to the formation of new bonds, like the stretching of B-O bonds. The NMR spectra yielded information about the stereoselectivity in the synthesis reaction by the finding of just one signal in the range for the anomeric carbon in the 13C NMR spectra of both adducts. The acute toxicity tests showed that LD50 value for both compounds is 1265 mg/kg, while Effective Dose 50 for sedation is 531 mg/kg. However, differences were in the onset and lapse of sedation. Conclusions: These adducts are bioactive and highly safe agents. Further biological evaluation is desirable to explore medical purposes.

Uropathogenic E. coli (UPEC) is the main etiologic agent of urinary tract infections (UTI) and possesses virulence and resistance determinants commonly harbored in mobilizable genetic elements such as plasmids or pathogenicity islands (PAI). UPEC belongs to the group of Ex-traintestinal pathogenic E. coli, however the existence of hybrid strains has been described; these possess both diarrheagenic (DEC) and extraintestinal (ExPEC) E. coli traits and are considered as "hypervirulent strains," which represents a significant health problem. This study aimed to de-termine the prevalence of UPEC PAI, ExPEC sequence types (ST), DEC genes, carbapenemase and extended-spectrum β-lactamase (ESBL) phenotypes, fluoroquinolones/aminoglycosides resistance genotypes and the presence of plasmids in 40 clinical isolates previously characterized as UPEC. A 72.5% of the isolates presented PAI, mainly PAI IV536 (53%). Sixty-five percent of the β-lactam-resistant isolates were positive for ESBL phenotype, and 100% of the car-bapenem-resistant isolates were carbapenemase producers. The most prevalent ESBL-associated gene was blaCTX-M-2 (60%), while among isolates resistant to fluoroquinolones and aminoglycosides the most frequent resistance gene was aac(6')Ib (93%). Plasmid bands were present in 57% of the isolates. Seventy percent belonged to the ST131 clonal group. The presence of molecular markers associated with DEC pathotypes was detected in 20 isolates; 60% were classified as hybrid pathotypes. These data suggest, in addition to an important pathogenic potential, the existence of hybrid pathotypes in clinical isolates of E. coli causing UTI in the Mexican population.

Despite the recognized potential of nanoparticles, only a few formulations have progressed to clinical trials, and an even smaller number have been approved by the regulatory authorities and marketed. Virus-like particles (VLPs) have emerged as promising alternatives to most explored nanoparticles because of the absence of viral genetic material, their incapacity to replicate, mimicry of viral structure, and tropism conservation. Furthermore, VLPs can be surface functionalized with small molecules to improve circulation half-life and target specificity. Through the functionalization and coating of VLPs, it is possible to optimize the response properties to a given stimulus, such as heat, pH, an alternating magnetic field, or even enzymes. Surface functionalization can also modulate other properties, such as biocompatibility, stability, and specificity, deeming VLPs as potential vaccine candidates or delivery systems. In this review, we address the different types of functionalization of VLPs, their importance, and their consequent biomedical applications.

The study assessed the trapping efficacy of locally-modified 1) Gravid Aedes Trap(GAT) lined with insecticide-treated net (ITN) as a killing agent, 2) Autocidal Gravid Ovitrap(AGO) with sticky board in the semi-field system (SFS) and field setting. Fully-balanced Latin square experiments were conducted to compare GAT lined with ITN vs AGO, both with either yeast or grass infusion. Biogents-Sentinel (BGS) with BG-Lure and no CO2 was used as standard trap for Aedes mosquitoes. In the SFS, GAT outperformed AGO in collecting both nulliparous (65% vs 49%,OR=2.22,[95%CI:1.89-2.60],p

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.

Bactrocera dorsalis Hendel is a highly invasive horticultural pest of major economic importance worldwide. In Burkina Faso, it is one of the main insect pests constraining the mango production and export. Understanding the biology and the genetic dynamics of this insect pest provide cru-cial information for the development of effective control measures. The aim of this study was to understand the distribution, diversity and genetic structure of B. dorsalis in Burkina Faso. Male flies were collected transversally in Burkina Faso and analyzed by PCR using 10 microsatellite markers. The results showed an abundance of B. dorsalis varying from 87 to 2986 flies per trap per day in the different sampling sites. Genetic diversity was high in all sites with an average Shan-non's Information Index (I) of 0.72 per site. Gene flow was high between study populations and ranged from 10.62 to 27.53 number of migrants. Bayesian admixture analysis showed no evi-dence of structure while Discriminant Analysis of Principal Components identified three weakly separated clusters in the population of B. dorsalis in Burkina Faso. The results of this study could be used to optimize the effectiveness of current control interventions and to guide the imple-mentation of new, innovative and sustainable strategies.

Sepsis is a serious disease that can lead to mortality. The etiology of the disease is connected to how the body as a host reacts toward microbes such as bacteria, viruses, and fungi invasion. Current research shows that during sepsis, the reaction toward microbe attacks takes two main phases. The first is known as a cytokine storm, while the second is a vicious cycle of pro-inflammatory responses followed by a strict anti-inflammatory response led by CD4+ Tregs. Various immunomodulatory therapies have been proposed to break the cycle of pro- and anti-inflammatory reactions to sepsis. However, clinical trials did not show promising results, indicating further research into the mechanism that Treg uses to inhibit proinflammatory reactions. We used next-generation sequencing (NGS) analysis of bulk RNA-seq and single-cell RNA-seq data to examine the exact molecular pathways used by Treg to inhibit the immune response in sepsis. Our approach identified ACOD1 (Aconitate Decarboxylase 1) as a primary mediator of Treg suppression of immune cells. We identified and validated CD36 as a downstream target of ACOD1. CD36 is a known metabolite regulator in Tregs. Taken together, our results indicate that targeting ACOD1 could prove valuable in regulating Treg function during sepsis.

Outbreaks of Ebola ebolavirus (EBOV) have been associated with high morbidity and mortality. Milestones have been reached recently in the management of EBOV disease (EVD) with licensure of an EBOV vaccine and two monoclonal antibody therapies. However, neither vaccines nor therapies are available for other disease-causing filoviruses. In preparation for such outbreaks, and for more facile and cost-effective management of EVD, we seek a cocktail containing orally available and room temperature stable drugs with strong activity against multiple filoviruses. We previously showed that (bepridil + sertraline) and (sertraline + toremifene) synergistically suppress EBOV in cell cultures. Here we describe steps towards testing these combinations in a mouse model of EVD. We identified a vehicle suitable for oral delivery of the component drugs and determined that, thus formulated the drugs are equally active against EBOV as preparations in DMSO, and they maintain activity upon storage in solution for up to seven days. Pharmacokinetic (PK) studies indicated that the drugs in the oral delivery vehicle are well tolerated in mice at the highest doses tested. Collectively the data support advancement of these combinations to tests for synergy in a mouse model of EVD. Moreover, mathematical modeling based on human oral PK projects that the combinations would be more active in humans than their component single drugs.

We put forward a co-axial pump(optical)-probe(X-rays) experimental concept and show performance of the optical component. A Bessel beam generator with a central 100 micrometers-diameter hole (on the optical axis) was fabricated using femtosecond (fs) laser structuring inside a silica plate. This flat-axicon optical element produces a needle-like axial intensity distribution which can be used for the optical pump pulse. The fs-X-ray free electron laser (X-FEL) beam of sub-1 micrometer diameter can be introduced through the central hole along the optical axis onto a target as a probe. Different realisations of optical pump are discussed. Such optical elements facilitate alignment of ultra-short fs-pulses in space and time and can be used in light-matter interaction experiments at extreme energy densities on the surface and in the volume of targets. Full advantage of ultra-short 10 fs X-FEL probe pulses with fs-pump(optical) opens an unexplored temporal dimension of phase transitions and the fastest laser-induced rates of material heating and quenching. A wider field of applications of fs-laser-enabled structuring of materials and design of specific optical elements for astrophotonics is presented.

In an era of rapid global change, our ability to understand and predict Earth's natural systems is lagging behind our ability to monitor and measure changes in the biosphere. Bottlenecks in our ability to process information have reduced our capacity to fully exploit the growing volume and variety of data. Here, we take a critical look at the information infrastructure that connects modeling and measurement efforts, and propose a roadmap that accelerates production of new knowledge. We propose that community cyberinfrastructure tools can help mend the divisions between empirical research and modeling, and accelerate the pace of discovery. A new era of data-model integration requires investment in accessible, scalable, transparent tools that integrate the expertise of the whole community, not just a clique of ‘modelers’. This roadmap focuses on five key opportunities for community tools: the underlying backbone to community cyberinfrastructure; data ingest; calibration of models to data; model-data benchmarking; and data assimilation and ecological forecasting. This community-driven approach is key to meeting the pressing needs of science and society in the 21st century.

The chiral optical Tamm state (COTS) is a special localized state at the interface of a handedness-preserving mirror and a structurally chiral medium such as a cholesteric liquid crystal or a chiral sculptured thin film. The spectral behavior of COTS, observed as reflection resonances, is described by the temporal coupled-mode theory. Mode coupling is different for two circular light polarizations because COTS has a helix structure replicating that of the cholesteric. The mode coupling for co-handed circularly polarized light exponentially attenuates with the cholesteric layer thickness since the COTS frequency falls into the stop band. Cross-handed circularly polarized light freely goes through the cholesteric layer and can excite COTS when reflected from the handedness-preserving mirror. The coupling in this case is proportional to anisotropy of the cholesteric and theoretically it is only anisotropy of magnetic permittivity that can ultimately cancel this coupling. These two couplings being equal results in a polarization crossover (the Kopp--Genack effect) for which a linear polarization is optimal to excite COTS. The corresponding cholesteric thickness and scattering matrix for COTS are generally described by simple expressions.

Smoking has been established as a major risk factor for developing oral squamous cell carcinoma (OSCC), but less attention has been paid to the effects of smokeless tobacco products. Our objective is to identify potential biomarkers to distinguish the biological effects of combustible tobacco products from those of non-combustible using oral cell lines. Normal human gingival epithelial cells (HGEC), non-metastatic (101A) and metastatic (101B) OSCC cell lines were exposed to different tobacco product preparations (TPPs) including cigarette smoke total particulate matter (TPM), whole-smoke conditioned media (WS-CM), smokeless tobacco extract in complete artificial saliva (STE), or nicotine (NIC) alone. We performed microarray-based gene expression profiling and found 3456 probe sets from 101A, 1432 probe sets from 101B, and 2717 probe sets from HGEC to be differentially expressed. Gene Set Enrichment Analysis (GSEA) revealed xenobiotic metabolism and steroid biosynthesis were the top two pathways that were upregulated by combustible but not by non-combustible TPPs. Notably, aldo-keto reductase genes, AKR1C1 and AKR1C2, were the core genes in the top enriched pathways and were statistically upregulated more than 8 fold by combustible TPPs. Our qRT-PCR results statistically support AKR1C1 as a potential biomarker for differentiating the biological effects of combustible from non-combustible tobacco products.

In this article we present the design and development of T-Shirt prototypes that embed novel textile sensors for the capture of cardio and respiratory signals. The sensors are connected through textile interconnects to either an embedded custom designed data acquisition and transmission unit or to snap fastener terminals for connection to external monitoring devices. Prototypes with diverse approaches of integration are presented. The performance of the wearable systems is addressed in terms of signal-to-noise ratio amplitude and signal interference caused by baseline wander and motion artifacts, through laboratorial tests with subjects in standing and walking conditions. Performance tests were also conducted in Hospital environment using a T-Shirt prototype connected to a commercial 3-channel Holter monitoring device. The textile sensors and interconnects were realized with the assistance of an industrial 6-needle digital embroidery tool and their resistance to wear addressed with normalized tests of laundering and abrasion. The main aspects of the system´s design leading to major improvements and failure factors are discussed. Pathways and methods for the overall system´s optimization are highlighted.

Interferon-gamma (IFN-γ) is an important cytokine in host defense against tuberculosis infection. In some cases, administration of IFN-γ during tuberculosis infection can promote faster cure. In the present work, we have shown that in a mouse model, human interferon-gamma, exhibits some anti-tuberculosis activity, especially in combination with isoniazid.

Subacute rumen acidosis (SARA) is a prevalent issue in intensive livestock farming, particularly associated with high-concentrate diets. This study investigates the prevalence and impact of SARA in Greek dairy sheep farming and explores the use of computerized rumen colorimetry as a management and diagnostic tool for SARA in dairy sheep farms. Forty-two dairy sheep flocks were monitored regularly for rumen pH, milk composition, and milk yield over an approximately 9-month milking period. Computerized Rumen Mucosal Colorimetry was applied to 280 culled, aged ewes from these farms, with rumen wall samples taken for histological examination. SARA cases were identified in 19 farms (45%, n=48). Farms with SARA cases had lower milk fat levels, although milk yield was higher in these farms, while milk protein levels did not differ based on the SARA status of the farms. In culled ewes, rumen color was significantly associated with the farm's SARA status. Additionally, ewes from farms with more SARA cases exhibited increased thickness in the ruminal epithelium layers, particularly in the non-keratinized and total epithelium layers. In conclusion, SARA is a common disorder in the Greek dairy sheep industry, lowering the fat content of milk. The study suggests that computerized rumen epithelium colorimetry in aged culled ewes shows promise as a diagnostic tool for SARA in dairy sheep farms.

The critical systems, which the failure and malfunction may result in human, environment and financial severe damages, are essential components in various sectors and particularly in energy domains. Although unwished, integration error problems in supervision of critical systems occurs, incurring significant expenses because of operator’s subjective analysis and on hardware topology failures. In this work, a malleable model design approach is proposed to formulate and solve the integration error problem in the critical systems supervision in terms of reliability. A real Hybrid Power Plant (HPP) case is considered as a requirement for a study case with simulated data. A method framework with informal approach (C4 diagram) and formal approach (Hierarchical Coloured Petri Nets) in radial spectrum is applied to the HPP supervision design. Using formal methods, a formulation and solution to this problem through structured, scalable and compact mathematical representations are possible. This malleable model intends to guarantee functional correctness and then reliability of the plant supervision system based on system software architecture. Outcomes suggest corroboration that the malleable model is appropriate for energy domain, and can be used for other types of critical systems, bringing all the benefits of this methodology to the context in which it will be applied.

Climate change, increasing global food needs, and decreasing global resources brought a new era to human every-day live with a strong turn to circular economy and sustainability. Food packaging and preservation is an important global sector where enchanced research is carried out. New methods such as active packaging and chemical preservatives replacement are of major interest. Many researchers were published studies about active packaging films, replacement of chemical preservatives with natural originated extracts, and novel incorporation procedures. Sequentially to our and other scientists’ previous work, in this paper we present the results of the improvement which was achieved by incorporating the developed nanohybrid of natural-halloysite/carvacrol-extract, the pure natural carvacrol extract and the commonly used low-density-polyethylene. The well known corona-treatment procedure was employed to produced the optimum final film and the results shown that the low-density-polyethylene incorporated with natural-halloysite/carvacrol-extract nanohybrid and coated external with extra carvacrol extract exhibited aproximatelly 100% higher Young-Modulus values, slightly decreased ultimate strength by 20%, and almost stable elonation at break properties. The water-vapor and oxygen barrier increased by 40%. Finally, the antioxidant activity of the corrona-treated film increased by 28% compared to the similar but untreated product because of the lower release rate of the carvacrol.

The conformations of trifluoroacetyl triflate, CF3C(O)OSO2CF3, were investigated through vibrational experimental methods (gas-phase FTIR, liquid-phase Raman, and Ar-matrix FTIR spectroscopy) and Density Functional Theory (DFT) calculations. A potential energy surface was computed using the B3P86 /6-31+g(d) approximation as a function of the dihedral angles τ1 = CCOS and τ2 = COSC. The surface reveals three minima, which were further optimized using the B3LYP method with various basis sets (6-31++G(d), 6-311++G(d), tzvp and cc-pvtz). The global minimum corresponds to a syn-anti conformer (the CO double bound syn with respect the O−S single bond and the C−O single bond anti with respect to de S−C single bond). The other two minima represent enantiomeric syn-gauche forms. The Ar-matrix FTIR spectrum exhibited clear evidence of the presence of two conformers. Furthermore, the randomization process observed following broad-band UV-visible irradiation facilitated the identification of the IR absorption of each conformer. Based on the Ar-matrix FTIR experiments, the vapour phase of trifluoroacetyl triflate at room temperatures was composed of approximately 60-70% of the syn-anti conformer and 30-40% of the syn-gauche form.

Vaccination, particularly against pneumoccus and influenza, is a low-cost primary prevention, useful to avoid hard complications, particularly among frail older people. In this study, we aimed to assess the effect of a strategy for influenza and pneumococcal vaccination for outpatients, never practiced before, evaluating what could stimulate or demotivate vaccination among older people. This study was conducted during the 2023-2024 influenza season at the outpatient clinics of the Geriatrics section, University Hospital of Palermo (Italy). A total of 101 vaccinations were carried out. Half of the patients could be considered as pre-frail and about 20% frail, according to a comprehensive geriatric evaluation. Among participants, 46.3% received only vaccination against Pneumococcus and 26.8% only anti-influenza or the combination of anti-pneumococcus and anti-influenza. Compared with the previous seasons, a 19.5% increase of influenza and 90.2 % of pneumococcal vaccine uptake was observed. Side effects of vaccination were the main reason of the previous rejections, namely 74.8% for influenza and 29.5% for anti-pneumococcal vaccination. In conclusion, our study indicates how a new vaccination strategy in different settings is possible. Proposing influenza and pneumococcal vaccination for outpatients could be an effective instrument to improve immunization coverage that is still low among older people.

Background: The aim of this experimental work was to confirm the individual uniqueness of lip prints, to verify the presence of recurrent patterns according to the Suzuki and Tsuchihashi classification and to search for characteristics that can be used in establishing the sex of a subject. Methods: Lip prints were taken from a sample of 172 volunteers using liquid lipstick and transparent adhesive tape and were digitally analyzed. Results: 59 prints (35.3%) were not considered for Suzuki and Tsuchihashi classification due to quality errors and the impossibility of visualizing lip wrinkles in one or more sextants, all the digitized prints revealed themselves to be unique after having been analyzed using superimposition. Qualitatively valid prints indicated a prevalence of Type II in both male and female and the presence of sex-linked features. A major problem was that the analysis of the same print by different operators often resulted in a different attribution of a Type. Conclusions: The potential of cheiloscopy lies mainly in the matching of prints, given their uniqueness, and can be a valid tool in gender determination but the absence of a database greatly limits its use. It is necessary to establish an acquisition protocol for taking and analyzing prints that could reduce the errors committed by the operator.

Hydrogen has a leading role in accomplishing a net zero green-house gas emission future. Today’s challenge is producing green hydrogen to cover the fuel demand of transportation and industry, to gain independence from fossil fuels. This review’s goal is to demonstrate critically the existing methods of biomass treatment and assess their ability to scale up. Biomass is an excellent hydrogen carrier and biomass-derived processes are the main target for hydrogen production as it is an innovative pathway to green hydrogen production. Comparing the existing processes, thermochemical treatment is found to be far more evolved than biological or electrochemical treatment especially with regard to scaling prospects.

Atherosclerosis, a complex metabolic-immune disease characterized by a chronic inflammation driven by the buildup of lipid-rich plaques within arterial walls, has emerged as a pivotal factor in the intricate interplay between cancer and cardiovascular disease. This bidirectional relationship, marked by shared risk factors and pathophysiological mechanisms, underscores the need for a comprehensive understanding of how these two formidable health challenges intersect and influence each other. Cancer and its treatments can contribute to the progression of atherosclerosis while atherosclerosis with its inflammatory microenvironment can exert profound effects on cancer development and outcomes. Both cancer and cardiovascular disease involve intricate interactions between general and personal exposomes. In this review we want to summarize the state-of-the-art of translational data and try to show how oncologic studies on cardiotoxicity can broaden our knowledge of crucial pathways in cardiovascular biology with a positive impact on precision cardiology and cardioncology.

The most frequent cause of cardiac failure globally is ischemic heart disease, with chemothera-py-related cardiovascular side effects emerging as the second most frequent cause. Cancer therapy can result in acute cardiac events, such as coronary artery spasm, acute myocardial infarction, thromboembolism, myocarditis, bradycardia, tachyarrhythmias, atrio-ventricular blocks, QT pro-longation, torsades de pointes, pericardial effusion and hypotension, as well as chronic conditions, such as hypertension, systolic and diastolic left ventricular dysfunction presenting clinically as heart failure or cardiomyopathy. In cardio-oncology, when referring to cardiac toxicity and cardiovas-cular hypersensitivity, there is a great deal of misunderstanding. When a dose-related cardiovas-cular side effect continues even after the causative medication is stopped, it is referred to as cardi-otoxicity. A fibrotic response is the ultimate outcome of cardiac toxicity, which is defined as a dose-related cardiovascular adverse impact that lasts even after the causative treatment is stopped. Cardiotoxicity can occur after a single or brief exposure. On the other hand, the term cardiac or cardiovascular hypersensitivity describes an inflammatory reaction that is not dose-dependent, can occur at any point during therapy, even with very low medication dosages, and can show up as Kounis syndrome. It may also be accompanied by anti-drug antibodies and tryptase levels. In this comprehensive review, we present the current views on cardiac toxicity and cardiovascular hypersensitivity, together with the reviewed cardiac literature on the chemotherapeutic agents inducing hypersensitivity reactions. Cardiac hypersensitivity seems to be the pathophysiologic basis of coronary artery spasm, acute coronary syndromes such as Kounis syndrome and myocardi-tis caused by cancer therapy.

The study evaluated the impact of supplementing ZH in combination with D3 on growth performance, energy efficiency, carcass traits, and meat quality of feedlot lambs. Thirty-two Dorper x Katahdin cross lambs (37.3±5.72 kg) were utilized in a 29 d experiment in a complete randomized block design with a 2x2 factorial structure consisting of two levels of ZH for 26 d (0 and 0.20 mg /kg PV-1) and two levels of D3 for 7 d (0 and 1.5x106 IU/d-1). ZH improved (P≤0.05) average daily gain (ADG) and feed efficiency by 9.9% and 17.8%, respectively, as well as hot carcass weight (HCW) and dressing carcass by 4.3% and 2.6%, respectively. (p≤0.03). However, ZH increased (p<0.01) muscle pH and Warner-Bratzler shear force (WBSF) (2.5 and 23.0%, respectively). D3 supplementation negatively affected (P≤0.02) dry matter intake (DMI) (last 7 d) and ADG by 15.7% and 18.1%. On the other hand, D3 improved the pH of the longissimus muscle (LM) by 1.7% (p=0.03) without affecting WBSF. When D3 was supplemented in combination with ZH, it was observed that meat quality was improved by reducing muscle pH compared to lambs treated only with ZH. However, D3 did not improve meat tenderness produced by ZH supplementation.

Metabolic-associated fatty liver disease (MASLD) is not only associated with traditional cardiovascular risk factors such as T2DM and obesity, but it is also an independent risk factor for the development of cardiovascular disease. MASLD has been shown to be independently related to endothelial dysfunction and atherosclerosis. MASLD is characterized by a chronic proinflammatory response that, in turn, may induce a prothrombotic state. Several mechanisms such as endothelial and platelet dysfunction, changes in the coagulation cascade, decreased fibrinolytic activity can contribute to induce the prothrombotic state. Platelets are players and addresses of metabolic dysregulation; obesity and insulin resistance are related to platelet hyperactivation. Furthermore, platelets can exert a direct effect on liver cells, particularly through the release of mediators from granules. Growing data in literature support the use of antiplatelet agent as a treatment for MASLD. The use of antiplatelets drugs seems to have potential clinical implication for the prevention of HCC patients with MASLD, since platelets contribute to fibrosis progression and cancer development. This review aims to summarize the main data on the role of platelets in the pathogenesis of MAFLD and its main complications such as cardiovascular events and the development of liver fibrosis. Furthermore, we will examine the role of antiplatelet therapy not only in the prevention and treatment of cardiovascular events but also as a possible anti-fibrotic and anti-tumor agent.

Mucosal vaccination appears to be suitable to protect against SARS-CoV-2 infection. In this study, we tested an intranasal mucosal vaccine candidate to COVID-19 constituted of a cationic liposome containing a trimeric SARS-CoV-2 spike protein and CpG-ODNs, a Toll-like receptor 9 agonist, as adjuvant. In vitro and in vivo experiments indicated the absence of toxicity following the intranasal administration of this vaccine formulation. First, we found that subcutaneous or intranasal vaccination protected hACE-2 transgenic mice from infection with the wild-type (Wuhan) SARS-CoV-2 strain, as shown by weight lost and mortality indicators. However, when compared to the subcutaneous administration, the intranasal route was more effective in the pulmonary clearance of the virus and induced higher neutralizing antibodies and anti-S IgA titers. In addition, the intranasal vaccination afforded protection against gamma, delta and omicron virus variants of concern. Furthermore, the intranasal vaccine formulation was superior to intramuscular vaccination with a recombinant, replication-deficient chimpanzee adenovirus vector encoding the SARS-CoV-2 spike glycoprotein (Oxford/AstraZeneca) in terms of virus lung clearance and production of neutralizing antibodies in serum and bronchial alveolar lavage (BAL). Finally, the intranasal liposomal formulation boosted heterologous immunity induced by previous intramuscular vaccination with the Oxford/AstraZeneca vaccine that was more robust than homologous immunity.

Background. The course of the COVID-19 epidemic process depends on population immunity which prevents pathogen spread among the population. Aim: to study the evolution of SARS-CoV-2 humoral immunity in the Belarusian population relative to COVID-19 pandemic dynamics. Materials and methods. The work was carried out according to a methodology for assessing population immunity developed by Rospotrebnadzor (Russia) and the Belarusian Ministry of Health with the participation of the St. Petersburg Pasteur Institute (SPPI), taking into account WHO recommendations. The study was approved by the Bioethics Committee of Belarus and the SPPI Bioethics Committee. Participant selection was carried out by questionnaire using a cloud (internet server) service. To monitor population immunity, a cohort of 4,661 people (participating in all stages of seromonitoring) was formed from the overall volunteer group. Volunteers were randomized by age group (1-17, 18-29, 30-39, 40-49, 50-59, 60-69, 70+ years), region, and professional group. For the detection of antibodies (Abs) to nucleocapsid (Nc) and S glycoprotein receptor-binding domain (RBD), corresponding assay systems were used following manufacturer instructions. The study was conducted in 4 stages according to a single scheme. Results. In the 1st stage (pandemic month 15), collective immunity was due mainly to Nc+RBD+ Ab status alone. By the 2nd stage (carried out after 4 months), their share decreased 1.2-fold, while the share of volunteers who had only RBD Abs increased 1.7-fold. In the 3rd and 4th stages (carried out after 9 and 19 months), the share of persons with RBD+Nc‒ compared to the 2nd stage decreased by 3.5%; the proportion of persons with Nc+RBD‒ Abs increased by 1.5-fold. The most important factor in population immunity was vaccination of the population, the coverage of which reached 70% by the 4th stage. Among vaccines, the Sputnik V and Sputnik Light vector designs were used most often. The whole-virion, inactivated BIBP-CorV vaccine was used less often. Conclusion. The evolution of collective SARS-CoV-2 humoral immunity included a set of changes in circulating Ab levels (Nc, RBD). The hybrid immunity formed helped to reduce the incidence to nearly zero.

Gastroenteropancreatic neuroendocrine neoplasms (GEP NENs) are rare cancers consisting of neuroendocrine carcinomas (NECs) and neuroendocrine tumors (NETs), which have been increasing in incidence in recent years. Few cell lines and pre-clinical models exist for the study of GEP NECs and NETs, limiting the ability to discover novel imaging and treatment modalities. To address this gap, we isolated tumor cells from cryopreserved patient GEP NECs and NETs and injected them into the flanks of immunocompromised mice to establish patient-derived xenograft (PDX) models. Two of 6 mice developed tumors (NEC913 and NEC1452). Over 90% of NEC913 and NEC1452 tumor cells stained positive for Ki67. NEC913 PDX tumors expressed neuroendocrine markers such as chromogranin A (CgA), synaptophysin (SYP), and somatostatin receptor-2 (SSTR2) whereas NEC1452 PDX tumors do not express SSTR2. Exome sequencing revealed loss of p53 and RB1 in both tumors. To demonstrate an application of these novel NEC PDX models for SSTR2-targeted peptide imaging, the NEC913 and NEC1452 cells were bilaterally injected into mice. Near infrared-labelled octreotide was administered and fluorescent signal was specifically observed for the NEC913 SSTR2 positive tumors. These 2 GEP NEC PDX models serve as valuable resource for GEP NEN therapy testing.

Hydrogenated amorphous silicon (a-Si:H) can be produced by plasma-enhanced chemical vapour deposition (PECVD) of SiH4 (Silane) mixed with Hydrogen. The resulting material shows outstanding radiation resistance properties and can be deposited on a wide variety of different substrates. These devices have been used to detect many different kinds of radiation namely: MIPs, x-rays, neutrons and ions as well as low energy protons and alphas. However, MIP detection using planar diodes has always been difficult due to the unsatisfactory S/N ratio arising from a combination of high leakage current, high capacitance and a limited charge collection efficiency (50% at best for a 30 µm planar diode). To overcome these limitations the 3D-SiAm collaboration proposes to use a 3D detector geometry. The use of vertical electrodes allows for a small collection distance to be maintained while conserving a large detector thickness for charge generation. The depletion voltage in this configuration can be kept below 400 V with consequent reduction in the leakage current. In this paper, following a detailed description of the fabrication process, the results of the tests performed on the planar p-i-n structures made with ion implantation of the dopants and with carrier selective contacts will be illustrated.

(1) We document the invertebrate fauna collected from 24 oak canopies in east and west Norway as a contribution to the Norwegian Biodiversity Information Centre’s “The Norwegian Taxonomy Initiative”. (2) A snap-shot inventory of the canopies was recorded by means of emitting a mist of synthetic pyrethroid into the canopies at night using a petrol-driven fogger, collecting the specimens in butterfly nets spread on the ground under the canopy. (3) Almost the entire catch of more than 6800 specimens was identified to 722 species. Out of 92 species new to the Norwegian fauna, 21 were new to science and additionally 15 were new to the Nordic fauna. Diptera alone constituted nearly half of the species represented with 61 new records (18 new species). Additionally, 24 Hymenoptera (one new species), six oribatid mites (two new species) and one Thysanoptera were new to the Norwegian fauna. (4) Our study emphasis the importance of oak tree as habitat both for a specific fauna and occasional visitors and it demonstrates that the canopy fogging technique is an efficient way to find the ‘hidden fauna’ of Norwegian forests. The low number of red listed species found reflects how poor the Norwegian insect fauna is still studied. Moreover, the implication of the IUCN red list criteria for new described or newly observed species is discussed.

Celtis iguanaea is popularly used in the treatment of diabetes mellitus. However, thorough chemical and pharmacological investigations regarding its activity are lacking. In this study, we investigated the effects of the hydroalcoholic extract from C. iguanaea (CI) on markers of cardiovascular diseases and the glucose metabolism in cholesterol-fed rats. Therefore, hypercholesterolemic rats (1% cholesterol) were orally treated with CI (150, 300, or 600 mg/kg) or simvastatin (4 mg/kg) (n = 6) once a day for 30 days along with a hypercholesterolemic diet. A control group (C) was given saline solution. CI showed significant decreases in serum levels of total cholesterol, LDL-cholesterol, HMG-CoA-reductase, IL-1, IL-6, TNF-α, and IFN-γ when compared to group C (p ˂ 0.05). Hypoglycemic effects were observed along with a decrease of the activity of sucrase (CI 600), maltase (CI 150, CI 300), and an increase in muscle glycogen levels (CI 300). Antioxidant effects were observed in plasma, and the histopathological analysis showed a significant decrease in the liver fat area for CI compared to group C (p < 0.001). Our results suggest that the biological effects of CI could be related to the presence of flavonoids that possibly exert antioxidant, enzymatic inhibitory, and insulin-mimetic effects.

Microneedle technology is a novel platform technology that revolutionizes ocular drug delivery and addresses critical challenges in the treatment of ocular diseases. Routine treatment methods, such as eye drops and intravitreal injections, suffer from low bioavailability and poor patient compliance. So, novel advanced platform technologies are required to overcome these challenges. Microneedle is a minimally invasive and promising alternative technique that helps precisely control drug delivery to targeted tissues and organs. This review investigates the potential impact of microneedle technology for eye care, underscoring recent advancements, underlying mechanisms, and emerging preclinical and clinical uses. Different types of microneedles, including solid, coated, dissolvable, and hollow, have demonstrated their potential and capability to bypass several barriers in the cornea and sclera. This ensures effective drug penetration and delivery. The current innovations in material science and fabrication methods have enhanced the safety and efficacy of microneedles, reducing discomfort and the chances of infections. These microneedle technologies offer sustained and controlled drug delivery, which could improve therapeutic outcomes for various disease conditions like age-related macular degeneration, glaucoma, diabetic neuropathy, etc. In the current review, recent preclinical and clinical studies emphasize microneedle-based ocular drug delivery's feasibility and potential benefits. These include improved pharmacokinetics, reduced dosing frequency, enhanced patient adherence, and, most importantly, microneedles offer versatile platforms for delivering a wide range of small and large molecules and gene therapies. Despite the exciting progress, obstacles such as regulatory barriers, scalability, and long-term biocompatibility persist. It will be essential to tackle these challenges through interdisciplinary research and partnerships to integrate microneedle technology into standard clinical use effectively. Ultimately, microneedle drug delivery offers a revolutionary method that has the potential to significantly enhance the treatment and results of ocular diseases, marking the dawn of a new era in eye care.

This article aims to determine the different factors that are associated with anxiety symptoms among Filipino farmers in Central Luzon. Eligible participants were screened for anxiety symptoms using the Generalized Anxiety Disorder-7 (GAD-7), while the Data Collection Tool for Factors Associated with Anxiety Symptoms (DCFAAS) was constructed and validated to determine the exposure of these factors. Among the 113 eligible farmers, only 19 (16.8%) experienced anxiety symptoms, with excessive worrying (39.8%) being the most frequent anxiety symptom. The mental health of Filipino farmers was significantly affected by the presence of physical illness (OR = 10.70 [1.367, 83.773]) and having relatives affecting work completion (OR = 6.45 [1.346, 30.896]). Therefore, policies must be focused on tackling these issues to address the mental health issues faced by farmers. The low prevalence of anxiety symptoms may stem from existing perceptions and barriers encountered in confiding psychological issues, and the Filipino’s religiosity and resiliency. Keywords: Farmers, Agriculture, Central Luzon, Generalized Anxiety Disorder, GAD-7

Purpose: The purpose of this study is to apply the Composite Radiographic Index modified (CRIm) in CBCT scans of patients with Medication related osteonecrosis of the jaws (MRONJ) in order to detect its validity, and corelate the radiologic findings with the clinical staging of the disease. Methods: This study included 43 patients with MRONJ diagnosis and CBCT scans performed in the School of Dentistry and approved by the Research Ethics Committee. Clinical staging for every patient (0-3) was provided according to AAOMS 2022 guidelines. In cases of patients with both jaws affected, each jaw was evaluated independently resulting to 52 CBCT scans. The 52 CBCT scans were assessed under standardized viewing conditions by 2 observers who evaluated independently the following 8 radiologic features: lytic changes, sclerosis, periosteal reaction, sequestration, non-healing extraction sockets and other findings (sinus implication, inferior alveolar canal involvement, jaw fracture). The CRIm index was constructed to assess the extent of osseous changes. The radiologic features were scored as absent (0), localized/single (1), extensive/multiple (2), yielding a theoretical range of 0–12. For statistical analysis Fisher’s exact test and Spearman’s correlation coefficient were performed. Results: A statistically significant association of clinical stage with lytic changes, sequestration and inferior alveolar canal involvement was found. Also, a statistically significant correlation of clinical stage with CRIm index classification was obtained. Conclusions: The CRIm index tends to increase as the clinical stages of MRONJ advance, suggesting a correlation between the clinical stage of MRONJ and the CRIm index.

The definition of patients with Special Needs (SN) is used in the literature to refer to individuals with mental and physical disorders for whom the usual perioperative pathways are not applicable due to lack of cooperation, regardless of age. Studies in the literature recognize the appropriateness of general anesthesia for performing day surgery dental care in this type of patient. The present retrospective, single-center, observational study involved 41 uncooperative patients aged between 3 and 17 undergoing dental surgery under general anesthesia. The main objective was to assess the possible incidence of difficult airway management, understood as difficulty ventilating and/or intubating the patient. A secondary objective was to highlight the influence of general anesthesia on patient outcomes by testing the incidence of perioperative complications. Tracheal intubation was successfully completed in all of the patients considered, and in no case did the patient have to be woken up because of difficulty in airway management. No perioperative complications attributable to anesthesia were found in any patients. From the present experience, it can be concluded that general anesthesia is a suitable option for performing dental care in pediatric subjects with special needs, and that although the peculiar peri-operative management of these patients might increase the risk of possible anesthesia-related side effects, no complications have been encountered in any case.

This work addresses the challenge of EEG visual multiclass classification into 40 classes for Brain-Computer interface applications, by using deep learning architectures. The visual multiclass classification approach offers BCI applications a significant advantage, since it allows the supervision of more than one BCI interaction, considering that each class label supervises a BCI task. However, because of the nonlinearity and nonstationarity of EEG signals, performing multiclassifiers based on EEG features remains a significant challenge for BCI systems. In the present work, mutual information-based discriminant channel selection and Minimum-Norm Estimate algorithms are implemented to select discriminant channels and enhance EEG data. Hence, deep EEGNet and Convolutional-recurrent neural networks are implemented separately to classify EEG data of image visualization into 40 labels. By using the k-fold cross-validation approach, average classification accuracies of 94.8% and 89.8% were obtained by implementing the aforementioned network architectures, respectively. Satisfactory results obtained with this method offer a new implementation opportunity for multi-task BCI applications by utilizing a reduced number of channels (&lt;50%), compared to those presented in the related literature where the whole set of channels is used.

Alzheimer´s disease (AD) is characterized by the brain deposition of senile plaques composed by amyloid-β peptides (Aβ) that increase inflammation. An endogenous peptide derived from the insulin-like growth factor (IGF)-I, glycine-proline-glutamate (GPE) has IGF-I-sensitizing and neuroprotective actions. Here, we examined the effects of GPE on Aβ levels and hippocampal inflammation generated by the intracerebroventricular infusion of Aβ25-35 during 2 weeks (300 pmol/day) in ovariectomized rats and the signaling-related pathways and levels of Aβ-degrading enzymes associated with these GPE-related effects. GPE prevented the Aβ-induced increase in the phosphorylation of p38 mitogen-activated protein kinase and the reduction in activation of signal transducer and activator of transcription 3, insulin receptor substrate-1 and Akt, as well as on interleukin (IL)-2 and IL-13 levels in the hippocampus. The functionality of somatostatin, measured as the percentage of inhibition of adenylate cyclase activity and the levels of insulin-degrading enzyme were also preserved by GPE co-treatment. These findings indicate that GPE co-administration may protect from Aβ insult by changing hippocampal cytokine content and somatostatin functionality through regulation of leptin- and IGF-I-signaling pathways that could influence the reduction in Aβ levels through modulation of levels and/or activity of Aβ proteases.

More than 20 years after the discovery of the first anelloviruses (AVs), they still remain a mysterious group of viruses. To date, there is no clear understanding of their impact on the host organism, although information is emerging about their participation in various pathologies. However, it is well known that AVs are an important component of the human virome. In the current study we assessed the abundance of AVs in viromes from four nasal and pharyngeal samples from children with respiratory symptoms using a metagenomic approach. It is worth noting that three patients had known respiratory viruses and one did not have any. Regarding AVs, they were detected in all samples, namely Torque teno mini virus (TTMV). The greatest abundance and diversity of AVs (Torque teno virus (TTV), TTMV and Torque teno midi virus (TTMDV)) were shown in a diseased patient with an absence of respiratory viruses, which may indicate the potential involvement of AVs in the maintenance of respiratory symptoms. An activated immune system to combat the main pathogens, against the background of which the number of AVs decreases, is discussed as a possible reason for the reduced diversity of anellome in other patients. We also compared the results of the metagenomic approach and qPCR for major respiratory viruses, which were in agreement. In addition, metagenomic sequencing made it possible to obtain additional data on viral genomes in order to establish their taxonomic identification and characterize individual viral profiles in patients from the Siberian part of Russia.

The concept of vulnerable carotid plaques is pivotal in understanding the pathophysiology of is-chemic stroke secondary to large-artery atherosclerosis. At the macroscopic evaluation, vulnera-ble plaques are characterized by one or more of the following features: microcalcification, neo-vascularization, lipid-rich necrotic core (LRNC), intraplaque hemorrhage (IPH), thin fibrous caps, plaque surface ulceration, huge dimension determining stenosis, and plaque rupture. Recognizing these macroscopic characteristics is crucial to estimating the risk of cerebrovascular events, also in case of non-significant (less than 50%) stenosis. Inflammatory biomarkers, such as cytokines and adhesion molecules, lipid-related markers like oxidized low-density lipoprotein (LDL), and proteolytic enzymes capable of degrading extracellular matrix components are among the key molecules that will be scrutinized for their associative roles in plaque instability. Through their quantification and evaluation, these biomarkers reveal intricate molecular cross-talking govern-ing plaque inflammation, rupture potential, and thrombogenicity. Current evidence demonstrates that plaque vulnerability phenotypes are multiple and heterogeneous and are associated with as many highly complex molecular pathways that determine the activation of an immune-mediated cascade that culminates in thromboinflammation. This narrative review provides a comprehen-sive analysis of current knowledge on molecular biomarkers expressed by symptomatic carotid plaques. It explores the association of these biomarkers with the structural and compositional at-tributes that characterize vulnerable plaques

The purpose of the present study was to investigate anti-staphylococcal activity of liposomal daptomycin, against four biofilm-producing S. aureus and S. epidermidis clinical strains, three of which are methicillin resistant. Neutral and negatively charged Daptomycin-loaded liposomes were prepared by three methods thin film hydration (TFH), DRV and microfluidic mixing (MM), and characterized for drug encapsulation (EE%), size distribution, zeta-potential, vesicle stability, drug release and drug integrity. Interestingly, whilst drug loading in THF and DRV nanosized (by extrusion) vesicles was around 30-35, very low loading (~4%) was possible in MM vesicles, requiring further explanatory investigations. Liposomal encapsulation protected daptomycin from degradation and preserve its bioactivity. Quantitative microtiter plate (crystal violet, CV), methylthiazoltetrazolium (MTT), and growth curve (GC) assays evaluated antimicrobial activity of neutral and negative charge daptomycin-liposomes towards planktonic bacteria and biofilms. Neutral liposomes exhibited dramatically enhanced inhibition of bacteria growth (compared to free drug) for all species studied, while negative charged liposomes were totally inactive. Biofilm prevention and treatment studies revealed high antibiofilm activity of liposomal daptomycin. Neutral liposomes were more active for prevention and negative charge ones for treating established biofilms. Planktonic bacteria as well as matured biofilms of low daptomycin susceptible MRSE and MRSA strains were almost completely eradicated by liposomal-daptomycin indicating the need for their further exploration as antimicrobial therapeutics.

The world faces two seemingly unrelated challenges—a shortfall in the STEM workforce and increasing antibiotic resistance among bacterial pathogens. We address these two challenges with Tiny Earth, an undergraduate research course that excites students about science and creates a pipeline for antibiotic discovery.

The development of new target stations for radioisotope production based on a dedicated 70~MeV commercial cyclotron is described. Currently known as the South African Isotope Facility (SAIF), this initiative will free the existing separated-sector cyclotron (SSC) at iThemba LABS (near Cape Town) to mainly pursue research activities in nuclear physics and radiobiology. It is foreseen that the completed SAIF facility will realize a three-fold increase in radioisotope production capacity compared to the current programme based on the SSC.

Metallic elements of higher economic value occurring in the mineralogy of Zimapán are Pb, Zn, Cu and Fe, said elements are sold as concentrates, which, even after processing, generally include significant concentrations of Mo, Cd, Sb, Ag and As that could recover through different leaching methods. In this work the influence of temperature was studied in the complexation of silver in the S₂O₃^2--O₂ system. Chemical and mineralogical characterization of concentrated Zn from the state of Hidalgo confirmed the presence of the silver contained in a sulfide of silver arsenic (AgAsS₂) through the techniques of Atomic Absorption Spectrophotometry (AAS), X-Ray Diffraction (XRD) and Scanning Electron Microscopy-Energy-Dispersive X-Ray Spectroscopy (SEM-EDS). The mineralogical species identified allowed the construction mineralogical species Pourbaix diagrams in the range of 298 K to 333 K, through which the Eh-pH conditions to obtain silver in solution were determined. The formation of Ag(S₂O₃)₂^3- complex was confirmed by characterizing liquors leached using the technique Infrared Spectroscopy Fourier Transform (FTIR).

Background: Leishmaniasis is a significant global public health issue that is caused by parasites from Leishmania genus. With limited treatment options and rising drug resistance, there is a pressing need for new therapeutic approaches. Molecular chaperones, particularly Hsp90, play a crucial role in parasite biology and are emerging as promising targets for drug development. Objective: This study evaluates the efficacy of 17-DMAG in treating BALB/c mice from cutane-ous leishmaniasis through in vitro and in vivo approaches. Materials and Methods: We assessed 17-DMAG cytotoxic effect on bone marrow-derived mac-rophages (BMMΦ) and its effects against L. braziliensis promastigotes and intracellular amastigotes. Additionally, we tested the compound's efficacy in BALB/c mice infected with L. braziliensis via intraperitoneal administration to evaluate the reduction of lesion size and de-crease of parasite load in the ears and lymph nodes of infected animals. Results: 17-DMAG showed selective toxicity [selective index=432) towards Leishmania amastigotes, causing minimal damage to host cells. The treatment significantly reduced lesion sizes in mice and results in parasite clearance from ears and lymph nodes. It also diminished in-flammatory responses and reduced the release of pro-inflammatory cytokines (IL-6, IFN-g, TNF) and the regulatory cytokine, IL-10, underscoring its dual leishmanicidal and anti-inflammatory properties. Conclusion: Our findings confirm the potential of 17-DMAG as a viable treatment for cutaneous leishmaniasis and support further research into its mechanisms and potential applications against other infectious diseases.

Abstract: Giant Cell Arteritis (GCA) is an autoimmune/autoinflammatory disease affecting large vessels in patients over 50 years old. The disease presents as an acute inflammatory response with two phenotypes, cranial-GCA and Large Vessel Vasculitis (LV)-GCA, involving the thoracic aor-ta and its branches. 18F-fluorodeoxyglucose positron emission tomography-computed tomogra-phy (18F-FDG PET-CT) is among the imaging techniques contributing to diagnosis of patients with systemic disease. However, its association with soluble inflammatory markers is still elu-sive. This proof-of-concept study aims to identify novel soluble serum biomarkers in PET/CT pos-itive patients with LV-GCA and associate them with active (0 months) and inactive disease (6 months following treatment), in sequential samples. The Most-Disease-Segment Target-to-Background Ratio (TBRMDS) was calculated for 9 LV-GCA patients, while 12 cranial-GCA and 7 Polymyalgia Rheumatica patients with negative initial PET/CT served as disease controls. Serum macrophage-related cytokines were evaluated by Cytometric Bead Array (CBA). Finally, previously published NMR-metabolomics data acquired at the same blood sampling were associated with PET/CT findings. TBRMDS was significantly increased in active versus inactive disease (3.45 vs. 2.55, p=0.008). The analysis identified 6 serum metabolites, as more sensitive to change from the active to inactive state. Among them, choline levels were exclusively altered in the LV-GCA group, but not the disease controls. Cytokine levels were not associated with PET/CT activity. Combining with CRP, ESR, and TBRMDS a composite index was generated to depict well the differences between active and inactive systemic LV-GCA (25.45 vs 11.45, p=0.0039). These preliminary results could pave the way for more extensive studies integrating serum metabolomic parameters with PET/CT imaging data to extract sensitive composite disease indexes useful for the everyday clinical practice.

Bioactive peptides are sequences of amino acids, cut from the parent protein with en-zymes or high pressure processing that can impart a tertiary health benefit to the con-sumer that goes beyond basic human nutrition. This study explores mesopelagic fish in-cluding Maurolicus muelleri and Benthosema glaciale as sources of peptides with an-ti-inflammatory, heart health beneficial, antioxidant and other bioactivities. Bioactive peptides were generated post-catch using different enzymatic hydrolysis processes ap-plied to mesopelagic species caught from experimental cruises targeting these fish. Maurolicus muelleri and Benthosema glaciale were the dominant species processed. Bi-oactive hydrolysates included a Maurolicus muelleri Alcalase hydrolysate and a Maurolicus muelleri autolysis. Hundreds of peptide sequences were identified using mass spectrome-try from active hydrolysates. In silico analysis was used to rank identified peptide se-quences in terms of overall bioactivity using Peptide Ranker, anti-inflammatory activity using PrepAIP, ability to impart Umami flavours with Umami-MRNN and dipeptidyl peptidase IV inhibitory potential using AntiDMPpred . Thirty peptides were selected fol-lowing in silico analysis. Several of the selected peptides had sequence homology with peptides derived from other fish proteins including Atlantic salmon (peptide QCPLHR-PWAL) and thin-lipped mullet (peptide FDAFLPM). Seven peptides predicted to have an-ti-inflammatory, anti-type 2 diabetes or Umami potential using in silico strategies were chemically synthesized and their anti-inflammatory activities confirmed using in vitro bioassays with COX-1 and COX-2 enzymes. The peptide QCPLHRPWAL inhibited COX-1 and COX-2 by 82.90% (+/-0.54) and 53.84% respectively and had a selectivity index greater than 10. This peptide warrant further research as a novel anti-inflammatory/pain relief peptide. Other bioactivities associated with DPP-IV inhibition and Umami flavours de-velopment are discussed. Identified peptides offer potential for use in functional foods or topical agents to prevent pain and inflammation associated with diseases like psoriasis, arthritis and inflammatory bowel disease, however further research in vivo is required.

Frequent and excessive consumption of alcohol, be it episodic or sustained misuse, ranks among the top causes of mortality globally. This comprehensive analysis seeks to elucidate how alcohol misuse precipitates death, with a particular focus on associated cardiac anomalies. Notably, the phenomenon of "Holiday Heart Syndrome," linked to binge drinking, is recognized for inducing potentially fatal cardiac arrhythmias. Moreover, persistent alcohol consumption is implicated in the development of alcoholic cardiomyopathy, a condition that underlies heart failure and arrhythmic disturbances of the heart. Additionally, individuals undergoing withdrawal from alcohol frequently exhibit disruptions in normal heart rhythm, posing a risk of death. This review further delves into additional alcohol-related mortality factors, including the heightened likelihood of hypertension, cerebrovascular accidents (strokes), and the connection between excessive alcohol use and Takotsubo syndrome.

Triple-negative breast cancer (TNBC) is an aggressive and highly metastatic type of tumor. TNBC is often enriched in tumor-infiltrating neutrophils (TINs), which support cancer growth in part by counteracting tumor-infiltrating lymphocytes (TILs). Prior studies identified the enhancer of zeste homolog 2 (EZH2) as a pro-tumor methyltransferase in primary and metastatic TNBC. We hypothesized that EZH2 inhibition in TNBC cells per se would exert anti-tumor activity by altering the tumor immune microenvironment. To test this hypothesis, we used CRISPR to generate EZH2-knockout (KO) and overexpressing lines from parent (wild-type -WT) 4T1 cells, an established murine TNBC model. In vitro, EZH2 KO and OE cells showed little change in replicative capacity and invasiveness, but marked changes in surface marker profile and cytokine/chemokine secretion compared to WT cells. On in vivo injection, EZH2 KO cells showed significantly reduced primary tumor growth and a 10-fold decrease in lung metastasis compared to WT cells, while EZH2 OE cells were unchanged. Compared to WT tumors, TIN:TIL ratios were greatly reduced in EZH2 KO tumors but unchanged in EZH2 OE tumors. Our findings show a tumor-intrinsic role of EZH2 in the 4T1 TNBC model in regulating TIN/TIL poise, primary tumor progression and lung metastasis in vivo.

Urban sprawl is recognized as one of the most critical drivers disrupting the functional integrity of rural and natural landscapes. A systematic multiscale study has yet to be conducted to measure the Megalopolis of Mexico City's regional extent, comprising ca. 23 million inhabitants. This paper investigates land cover, land use, vegetation and soil changes at macro-regional, regional, local and site scales. Land cover/use data from the 1970s and 2018 were used as the primary input to analyze changes using remote sensing and geographical information systems. At the local scale, fieldwork data from the 1970s, 1990s, and 2020 served as the primary input and were subjected to multivariate analyses. At site scale, soils profiles and hydrological balance analyses at micro-basin level were conducted. Furthermore, social perception of changes was investigated among local residents/stakeholders using semi-structured interviews with four communities. Outcomes were validated to reach 85 percent accuracy in cartographic and 95 % statistical outputs. At the regional scale, land-use changes, especially human settlements, increased from about four to almost 40 % between 1970 and 2018 , with significant incursion into rural landscapes. At the local scale, analyses revealed significant decline in predominantly cold-humid vegetation types and conversion of agricultural fields into peri-urban landscapes. Site scale revealed the predominant importance of soils as the core landscape component for water infiltration and carbon sequestration. Nested multi-scale analyses revealed different disrupting processes which are hidden at one scale and evident at another. Poorly implemented, disconnected urban and environmental policies prevail as the main driving force, with implications for the weak local governance of rural communities. Regional integrated analyses are discussed in light of the relevance of urban resilience theory.

Cultures in Mediterranean climate zones (MCZs) around the world have long been reliant on groundwater and springs as freshwater sources. While their ecology and cultural sustainability are recognized as critically important, inter-relationships between springs and culture in MCZs has received little attention. Here we augmented a global literature review with case studies in MCZ cultural landscapes to examine the intensity of cultural and socio-economic impacts on springs ecohydrogeology. MCZs are often oriented on the west and southern coasts in tectonically active landscapes, which control aquifer structure, the prevalence of westerly winds, and aridity, and generally expose associated habitats to harsh, afternoon sunlight. Cultural appreciation and appropriation of springs ranges widely, from their use as subsitence supplies to profound traditions, such as Greco-Roman nymphs, and Asian and Abrahamic spiritual cleansing and baptism. Commoditization of water resources for agriculture, industry (e.g., mining, water bottling, geothermal resorts), and urban needs is placing ever-increasing, non-sustainable demands on aquifers and springs. When economic values approach or exceed cultural values, these irreplaceable aquatic resources are degraded and lost. Sustainable stewardship of springs and the aquifers that support them are a little-recognized, but central conservation challenge for modern society facing global climate changes.

Recent technical advances in the stem cell field have enabled the in vitro generation of complex structures resembling whole organs termed organoids. Most of these approaches employ culture systems that allow stem cell-derived or tissue progenitor cells to self-organize into three-dimensional (3D)-structures. Since organoids can be grown from various species, organs and from patient-derived induced pluripotent stem cells, they create significant prospects for modelling development and diseases, for toxicology and drug discovery studies, and in the field of regenerative medicine. Here, we report on intestinal stem cells, organoid culture, organoid disease modeling, transplantation, current and future uses of this exciting new insight model to veterinary medicine field.

The genome sequencing of Botrytis cinerea has supplied a general overview of the map of genes involved in secondary metabolite synthesis. B. cinerea genomic data have revealed that this phytopathogenic fungus has seven sesquiterpene cyclase (Bcstc) genes that encode proteins involved in the farnesyl diphosphate cyclization. Three sesquiterpene cyclases (BcStc1, BcStc5 and BcStc7) have been characterized, related to the biosynthesis of botrydial, abscisic acid and (+)-4-epi-eremophilenol, respectively. However, the role of the other four sesquiterpene cyclases (BcStc2, BcStc3, BcStc4 and BcStc6) remains unknown. BcStc3 is a well-conserved protein with homologues in many fungal species, and here, we have undertaken its functional characterization in the life cycle of the fungus. A null mutant ΔBcstc3 and an overexpressed–Bcstc3 transformant (OvBcstc3) were generated, and both strains show deregulation of those other sesquiterpene cyclase-encoding genes (Bcstc1, Bcstc5, Bcstc7). These results suggest a co-regulation of the expression of the sesquiterpene cyclase gene family in B. cinerea. Phenotypic characterization of both transformants revealed that BcStc3 is involved in oxidative stress tolerance, production of reactive oxygen species and virulence. The metabolomic analysis allowed the isolation of characteristic polyketides and eremophilenols from the secondary metabolism of B. cinerea, although no sesquiterpenes different from those already described were identified.

The CACCC-box motif emerges as a pivotal cis-regulatory element implicated in diverse developmental processes and diseases, particularly cardiovascular diseases (CVDs). This study centers on the intricate interplay between the CACCC-box and its binding proteins such as: the Krüppel-like family (KLF) of transcription factors as primary effectors in the context of CVDs. Our analysis was through a bioinformatics approach, which reveal significant transcriptional activity among KLF subgroup 2, exhibiting the highest number of interactions focusing on the established roles: pluripotency, cancer, and cardiovascular development and diseases. Our analysis reveals KLF's interactions with GATA4, MEF2C, NKX2.5 and other ~ 90 potential genes that participate in the regulation of the hypertrophic environment (or CVD's Environment). Also, the GO analysis showed genes containing the motif CACCC were enriched for multiple CVD’s, in combination with STRING analysis these results pointed to a link between KLFs and these diseases. The analysis further identifies other potential CACCC-box binding factors, such as SP family members, WT1, VEZF1, and -SALL4, which are implicated in cardiac contraction, remodeling, and inflammation processes.

Wearable Biosensor Technology (WBT) has emerged as a transformative tool in the educational system over the past decade. This systematic review encompasses a comprehensive analysis of WBT utilization in educational settings over a 10-year span (2012-2022), highlighting both the evolution of this field and its integration to address challenges in education by integrating technology to solve specific educational challenges, such as enhancing student engagement, monitoring stress and cognitive load, improving learning experiences, and providing real-time feedback for both students and educators. By exploring these aspects, the review sheds light on the potential implications of WBT for the future of learning. A rigorous and systematic search of major academic databases, including Google Scholar and Scopus, was conducted in accordance with PRISMA guidelines. Relevant studies were selected based on predefined inclusion and exclusion criteria. The articles selected were assessed for methodological quality and bias using established tools. The process of data extraction and synthesis followed a structured framework. Key findings include the shift from theoretical exploration to practical implementation with the EEG being the predominant measurement, aiming to explore mental states, physiological constructs, and teaching effectiveness. Wearable biosensors are significantly impacting the educational field, serving as an important resource for educators and a tool for students. Their application has the potential to transform and optimize academic practices through sensors that capture biometric data, enabling the implementation of metrics and models to understand the development and performance of students and professors in an academic environment, as well as to gain insights into the learning process.

The impact of systemic vascular resistance (SVR) in hypertrophic (HCM) and amyloid cardio-myopathies has been seldom investigated. We studied pressure-strain loop derived myocardial work (MW) indices and SVR in patients with either sarcomere HCM or wild type transthyretin cardiac amyloidosis (ATTR), presented with heart failure and preserved left ventricular ejection fraction (HFpEF) at the outpatient cardiology units at Messina and Catania University Hospitals (Italy). Patients were in sinus rhythm and needed to have good transthoracic ultrasound imaging quality to undergo transthoracic strain-echocardiography. Other than conventional parameters, SVR and GWI (global work index) were measured. Based on cross-tabulation (a way to assess the ventricular-arterial coupling), the patients were then classified in 4 classes according to the cut-off values suggested by previous studies of 1,440 dyne/s/cm-5 for SVR (Stefadouros et al., 1973) and 1576 mm Hg% for GWI (Olsen et al., 2022). Sixty patients, 30 in each group, aged 61±16 years, 78% males, were studied. HCM were younger than ATTR patients and in a better clinical status (23% HCM vs 77% ATTR were NYHA class 3, p<0.001). Overall, 51 patients (85%) showed high SVR, of whom 21 were HCM (70%) and 30 ATTR (100%) (p<0.005). Both, SVR and GWI were impaired (the poorest class C) in 43% HCM patients (with greater left ventricular concentric hypertrophy) vs 93% of ATTR patients (in advanced NYHA class) (p<0.001). In conclusion, assessing SVR and GWI in HFpEF patients with HCM or ATTR can help clinicians to interpret the pathophysiological and clinical features of such complex diseases.

The objective of this study was to evaluate the efficacy of one-step nucleic acid amplification (OSNA) for the detection of sentinel lymph node (SLN) metastasis compared to standard pathological ultrastaging in patients with early-stage endometrial cancer (EC). A total of 526 SLNs from 191 patients with EC were included in the study. 379 SLNs (147 patients) were evaluated by both methods, OSNA and standard pathological ultrastaging. The central 1-mm portion of each lymph node was subjected to semi-serial sectioning at 200-μm intervals and examined by hematoxylin-eosin and immunohistochemistry with CK19; the remaining tissue was analysed by OSNA for CK19 mRNA. The OSNA assay detected metastases in 19.7% of patients (14.9% micrometastasis and 4.8% macrometastasis), whereas pathological ultrastaging detected metastasis in 8.8% of patients (3.4% micrometastasis and 5.4% macrometastasis). Using the established cut-off value for detecting SLN metastasis by OSNA in EC (250 copies/μl), the sensitivity of the OSNA assay was 92%; specificity was 82%; diagnostic accuracy was 83%, and the negative predictive value was 99%. Discordant results between both methods were recorded in 20 patients (13.6%). OSNA resulted in an upstaging in 12 patients (8.2%). OSNA could aid in the identification of patients requiring adjuvant treatment at the time of diagnosis.

Arsenic, an element of environmental impact, can be incorporated into jarosite–type compounds and remain stabilised within the structure under a wide range of environmental conditions. In this study, a sample of ammonium–arsenic jarosite was synthesised by precipitation in sulphate medium at controlled pH of 1.2–1.8. The behaviour of arsenic during the thermal and chemical decomposition of jarosite was analysed; the degradation in alkaline medium of jarosite was also studied. According to the results, the synthesised jarosite is composed of joined rhombohedral crystals, forming tightly spherical shaped particles, 37–54 μm size. The ammonium jarosite produced possessed a high arsenic concentration; its calculated stoichiometry being (NH₄)Fe_2.45[(SO₄)_1.80(AsO₄)_0.20][(OH)_4.15(H₂0)_1.85]. It was found that arsenic is stabilised in the jarosite structure; upon heating, it remains in residual solids above 700°C, whilst in alkaline medium an incongruent dissolution takes place, with the arsenic retained in the solid phase along with iron. These solids, when exposed to high temperatures (1200°C), transform into a type of iron oxide known as hematite, so with arsenic it is retained an iron compound forming a stable compound which withstands high temperatures.

In the recent years, tubular nanostructures have been related with immense advances in various fields of science and technology. Considerable research efforts have been centered on the theoretical prediction and manufacturing of non-carbon nanotubes (NTs), which meet modern requirements for the developing of novel devices and systems. In this context, diatomic inorganic nanotubes formed by atoms of elements from the 13th group of the periodic table (B, Al, Ga, In, Tl) and nitrogen (N), have received much research attention. In the present work, the elastic properties of single-walled boron nitride, aluminium nitride, gallium nitride, indium nitride and thallium nitride nanotubes were numerically evaluated using the nanoscale continuum modelling approach (also called molecular structural mechanics). The elastic properties (rigidities, surface Young´s and shear moduli, and Poisson´s ratio) of nitride nanotubes are discussed with respect to the bond length of the corresponding diatomic hexagonal lattice. The results obtained contribute to a better understanding of the mechanical response of nitride compound-based nanotubes, covering a broad range from the well-studied boron nitride NTs to the hypothetical thallium nitride NTs.

Background: Features of post-traumatic stress disorder and anxiety may be present in Pulmonary Embolism (PE) patients along with impaired Quality of Life (QoL). We aim to evaluate health related QoL, anxiety and satisfaction with life, during the pandemic, in patients with a PE. Methods: Patients with PE were enrolled during their follow-up. All participants completed the Short Form 36 (SF-36) questionnaire, the State Trait Anxiety Inventory (STAI) X1 and X2 form, and the Satisfaction with Life Scale (SWLS). Results: 92 PE patients were included (mean age±SD=62.50±15.33 years, 56.5% males). Most of the mean values of the SF36 subscales were above the normative value except for “physical role functioning”) (45.92±42.41). “Emotional role functioning” (51.26±43.31) and “general health perceptions” (GH) (54.02±18.79) were slightly above the normative value of 50. Mean STAIX1 levels were 37.05±11.17 and mean STAIX2 levels were 39.80±10.47. Mean SWLS levels were 23.31±6.58. According to multiple linear regression analysis, mental healthscore (MH) and GH were predictive of SWLS(F (10,76) = 10.576, p

An observational cohort study of patients diagnosed with endometrial cancer (EC) stage IA G1, or atypical endometrial hyperplasia (AHE), undergoing organ-preserving treatment, was conducted. Objective of the study: to determine CDO1, PITX2, and CDH13 gene methylation levels in early endometrial cancer and atypical hyperplasia specimens obtained before organ-preserving treatment in the patients with adequate response and with insufficient response to hormonal treatment. Materials and methods: 41 endometrial specimens obtained during diagnostic uterine curettage in women with EC (n=28) and AEH (n=13), willing to preserve reproductive function, were studied; 18 specimens of endometrial cancer IA stage G1 from peri- and early postmenopausal women (comparison group) were included in the study. The control group included 18 endometrial specimens from healthy women obtained by diagnostic curettage for missed abortion and/or intrauterine adhesions. Methylation levels were analyzed using the modified MS-HRM method. Results: All 13 women with AEH had complete response (CR) to medical treatment. In the group undergoing organ-preserving treatment for uterine cancer IA stage G1 (n=28), 14 patients had complete response (EC CR group) and 14 had not (non-CR). It was found that all groups had statistically significant differences in CDO1 gene methylation levels with the control group (p&lt;0.001) except for the EC CR group (p=0.21). The p-value of difference between EC CR and EC non-CR groups was &lt;0.001. The differences in PITX2 gene methylation levels between the control and study groups were also significantly different (p&lt;0.001), except for AEH group (p=0.21). For the difference between EC CR and EC non-CR groups, the p-value was 0.43. For CDH13 gene methylation levels, statistically significant differences were found between the control and EC non-CR groups (p&lt;0.001), and the control and EC comparison groups (p=0.005). When comparing the EC CR group with EC non-CR group, the p-value for this gene was &lt;0.001. Simultaneous assessment of CDO1 and CDH13 genes methylation allowed to accurately distinguish between EC CR and EC non-CR groups (AUC=0.96). Conclusion: Assessment of CDO1 and CDH13 gene methylation in endometrial specimens from patients with endometrial cancer (IA stage G1), planned for medical treatment, can predict the treatment outcome.

Chagas disease is a Neglected Tropical Disease with limited and ineffective therapy. In a search for new antitrypanosomal compounds, we investigated the potential of metabolites from bacteria living in corals and sediments of the Southeastern Brazilian coast. Three corals Tubastraea coccinea, Mussismilia hispida, Madracis decactis and sediments yielded 11 bacterial strains, that were fully identified by MALDI-ToF/MS or gene sequencing, resulting in six genera - Vibrio, Shewanella, Mesoflavibacter, Halomonas, Bacillus and Alteromonas. To conduct this study, EtOAc extracts were prepared and tested against Trypanosoma cruzi. Crude extracts showed IC50 values ranging from 15 to 51 μg/mL against trypomastigotes. The bacterium Mesoflavibacter zeaxanthinifaciens was selected for fractionation, resulting in an active fraction (FII) with IC50 values of 17.7 μg/mL and 23.8 μg/mL against the trypomastigotes and amastigotes, respectively, with neither mammalian cytotoxicity nor hemolytic activity. Using NMR and ESI-HRMS analysis, FII revealed the presence of unsaturated iso-type fatty acids. Its lethal action was investigated, leading to a protein spectral profile of the parasite altered after treatment. FII also induced a rapid permeabilization of the plasma membrane of the parasite, leading to cell death. These findings demonstrate these unsaturated iso-type fatty acids as possible new hits against T. cruzi.

Contamination in coastal regions attributed to fluoride and nitrate cannot be disregarded, given the substantial environmental and public health issues they present worldwide. Maintaining water quality is crucial for environmental well-being. This comprehensive study was performed to assess the spatial as well as indexical water quality, identify contamination sources, and evaluate associated health risks pertaining to nitrate and flouride in AlHassa region, KSA. The physiochemical results revealed a pervasive pollution of the overall groundwater. The dominant water type was Na-Cl, indicating saltwater intrusion and reverse ion exchange impact. Spatiotemporal variations in physicochemical properties suggest diverse hydrochemical mechanisms, with geogenic factors primarily influencing groundwater chemistry. The groundwater pollution index varied between 0.8426 and 4.7172, classifying samples as moderately to very highly polluted. Similarly, the synthetic pollution index (in the range of 0.5021-4.0715) revealed that none of the samples had excellent water quality, with various degrees of pollution categories. Nitrate Health Quotient (HQ) values indicated chronic human health risks ranging from low to severe, with newborns being the most vulnerable. Household use of nitrate-rich groundwater for showering and cleaning did not pose significant health risks. Fluoride HQ decreased with age, and children faced the highest risk of fluorosis. The Hazard Index (HI) yielded moderate to high-risk values. Nitrate risks were 1.21 times higher than fluoride risks, as per average HI assessment. All samples fell into the vulnerable category based on the Total Hazard Index (THI), with 88.89% classified as very high risk. This research provides valuable insights into groundwater quality, guiding water authorities, inhabitants, and researchers in identifying safe water sources and vulnerable human populations. The results highlight the need for appropriate treatment techniques and long-term coastal groundwater management plans.

SARS-CoV-2 infection triggers distinct patterns of disease development, characterized by significant alterations in host regulatory responses. Severe cases exhibit profound lung inflammation and systemic repercussions. Remarkably, critically ill patients display a "lipid storm", influencing the inflammatory process and tissue damage. Sphingolipids (SL) play pivotal roles in various cellular and tissue processes, including inflammation, metabolic disorders, and cancer. In this study, we employed high-resolution mass spectrometry to investigate SL metabolism in plasma samples obtained from control subjects (n=55), COVID-19 patients (n=204), and convalescent individuals (n=77). These data were correlated with inflammatory parameters associated with the clinical severity of COVID-19. Additionally, we utilized RNAseq analysis to examine the gene expression of enzymes involved in the SL pathway. Our analysis revealed the presence of thirty-eight SL species from seven families in the plasma of study participants. The most profound alterations in the SL species profile were observed in patients with severe disease. Notably, the predominant sphingomyelin (SM d18:1) species emerged as a potential biomarker for COVID-19 severity, showing decreased levels in the plasma of convalescent individuals. Elevated SM levels were positively correlated with age, hospitalization duration, clinical score, neutrophil count, as well as the production of IL-6 and IL-8. Intriguingly, we identified a putative protective effect against disease severity mediated by SM (d18:1/24:0), while ceramide (Cer) d18:1/24:1 and d18:1/24:0 was associated with increased risk. Moreover, we observed enhanced expression of key enzymes involved in SL pathway, in blood cells from severe COVID-19 patients, suggesting a primary flow towards Cer generation in tandem with SM synthesis. These findings underscore the potential of SM as a prognostic biomarker for COVID-19 and highlight promising pharmacological targets. By targeting sphingolipid pathways, novel therapeutic strategies may emerge to mitigate the severity of COVID-19 and improve patient outcomes.

An analysis of 1300+ existing ACE mutations revealed that 400+ are damaging and led us to hy-pothesize that carriers of heterozygous loss-of-function (LoF) ACE mutations (which result in low ACE levels) could be at risk for the development of late-onset Alzheimer’s disease (AD) [Danilov, 2024]. Here we quantified blood ACE levels in EDTA-plasma from 41patients with 10 different heterozygous ACE mutations, as well as 33 controls, and estimated the effect of these mutations on ACE phenotype using a set of mAbs to ACE and two ACE substrates. We found that relatively frequent (~1%) AD-associated ACE mutations in the N domain of ACE, Y215C and G325R are truly damaging and, likely, transport-deficient, with ACE levels in plasma only ~50% of controls. Another AD-associated ACE mutation, R1250Q, in the cytoplasmic tail, did not cause a decrease in ACE and, likely, did not affect surface ACE expression. We have also developed a method to identify patients with anti-catalytic mutations in the N domain. These mutations may result in reduced degradation of amyloid beta peptide Aβ42, an important component for amyloid deposition. Consequently, these could pose a risk factor for the development of AD. Therefore, a systematic analysis of blood ACE levels in patients with all ACE mutations has potential to identify individuals at an increased risk of late-onset AD. These individuals may benefit from future preventive or therapeutic interventions involving a combination of chemical and pharmacological chaperones, as well as proteasome inhibitors, aiming to enhance ACE protein traffic. This approach has been previously demonstrated in a cell model of the transport-deficient ACE mutation, Q1069R [Danilov, 2010].

Background: Schistosome egg deposition in pregnant women may affect the placenta of infected mothers and cause Placental Schistosomiasis (PS). Histopathological examination of placental tissue is an inadequate detection method due to low sensitivity. So far, there has not been any sys-tematic review on PS. Methods: We conducted a systematic literature search on PubMed and in-cluded relevant secondary literature found in the citations of the primarily included publications. Results: We found a total of 8 publications describing PS with a total of 92 cases, describing egg deposition of dead and/or viable eggs and worms of S. haematobium and S. mansoni in placental tissue. One cross-sectional study investigating the prevalence of PS and its association to adverse birth outcomes, found 22% of placentas to be infested using a maceration technique but only < 1% using histologic examination. Additionally, no direct link to deleterious pregnancy outcomes could be shown. Conclusions: PS is a highly unattended and underdiagnosed condition in en-demic populations, due to a lack of awareness as well as low sensitivity of histopathological examinations. However, PS may play an important role in mediating or reinforcing adverse birth outcomes (ABO) such as fetal growth restriction (FGR) in maternal schistosomiasis, possibly by placental inflammation.

Indian tobacco farm laborers are primarily women and children working for very low wages. The aim of this study was to explore occupational and reproductive health challenges faced by women tobacco farm labors in Mysore District, India. We conducted interview and six focus group discussions among 41 women tobacco farm laborers. Codes and themes were generated based on deductive and inductive approaches using the socio-ecological model. Participants reported symptoms of green tobacco sickness including headaches, back pain, gastric problems, weakness, and allergies during menstruation, pre-natal, and post-natal periods. Participants had poor awareness about the health effects of tobacco farming and there were gender inequalities in wages and use of personal protective equipment. Participants received support from family and commu-nity health workers during their pregnancy and post-natal period. Women reported wanting ma-ternity benefits from the tobacco board, monetary support, and nutritional supplements. There is a need for health education about the environmental dangers of tobacco among farm laborers, and more supportive policies for women farmworkers during pregnancy and post-natal periods.

Previous studies showed that some lamellarin-resembling annelated azaheterocyclic carbaldehydes and related imino adducts, sharing the 1-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (1-Ph-DHPIQ) scaffold, are cytotoxic in tumor cells and may reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). Herein, we synthesized and evaluated for their antiproliferative activity in four tumor cell lines (RD, HCT116, HeLa, A549) and ability of inhibiting P-gp-mediated MDR some ten diversely substituted 1-Ph-DHPIQ derivatives bearing at position 2 carboxylate groups (COOH, COOEt), nitriles (CN) and Mannich bases (e.g., morpholinomethyl derivatives). Lipophilicity parametrization and molecular docking calculations improved the understanding of the structure-activity relationships in cytotoxicity and P-gp inhibition of the investigated 1-Ph-DHPIQs, which led us to disclose a novel Mannich base HCl salt (8b’), which proved to be cytotoxic to all the tested tumor cell lines in the low micromolar range (IC50 &lt; 20 M) and to inhibit in-vitro the efflux pumps P-gp and MRP1 responsible for MDR, with IC50s of 0.45 and 12.1 M, respectively.

: Background: Brain-derived neurotrophic factor (BDNF) is a crucial mediator of neuronal plasticity. Here, we investigated the effects of controlled normobaric hypoxia (NH) combined with physical inactivity on BDNF blood levels and executive functions. Methods: Twenty-five healthy adults (25.8±3.3 years, 15 female) were analyzed in a randomized, controlled cross-over study. Each intervention began with a 30 min resting phase under normoxia (NOR), followed by a 90 min continuation of NOR or NH (peripheral oxygen saturation [SpO₂] 85-80%). Serum and plasma samples were collected every 15 min. Heart rate and SpO₂ were continuously measured. Before and after each exposure, cognitive tests were performed and after 24 h another follow-up blood sample was taken. Results: NH decreased SpO₂ (p<.001, η_p²=.747) and increased heart rate (p=.006, η_p²=.116) significantly. The 30-min resting phase under NOR led to a significant BDNF reduction in serum (p <.001, η_p²=.581) and plasma (p <.001, η_p²=.362). Continuation of NOR further significantly reduced BDNF after another 45 min (p=.018) in serum and after 30 min (p=.040) and 90 min (p=.005) in plasma. There was no significant BDNF decline under NH. 24 h Follow-up examination showed a significant decline of serum BDNF, both after NH and NOR. Conclusion: Our results show that NH has the potential to counteract physical inactivity-induced BDNF decline. Therefore, our study emphasizes the need for a physically active lifestyle and its positive effects on BDNF. This study also demonstrates the need for a standardized protocol for future studies to determine BDNF in serum and plasma.

Zoo conditions are unique for reindeer, since even domestic reindeer are not kept in captive facilities like cattle. In the zoo, reindeer are usually surrounded by many different animals they would never encounter naturally. Thus they might pick up some new helminths. Numerous petting zoos raise an issue of safety of tactile communications for human visitors. Out study is the first large-scale one. Qualitative and quantitative fecal analysis was carried out for 233 reindeer distributed over 50 Russian zoos according to National Standard of the Russian Federation (GOST R 54627-2011) Ruminant animals—Methods of Laboratory Helminthological Diagnostics. Where possible, DNA analyses of helminths were performed targeting internal transcribed spacer region. In result, F. hepatica, Paramphistomum sp., Moniezia sp. (including M. expansa), gastrointestinal strongylids (including Nematodirus spp.), Dictyocaulus sp., E. rangiferi, Trichuris sp., and Capillaria sp. were found in 106 (45%) zoo reindeer. All these helminths were previously reported for reindeer and pose no direct danger for humans. Intensity of invasions was mostly low. Fecal examination might be considered as an indirect method for mange diagnostics, as Chorioptes and Demodex mites were found in reindeer fecal samples. The latter may represent a novel species of mite specific for reindeer.

Parkinson's disease (PD) is recognized as the second most prevalent primary chronic neurodegenerative disorder of the central nervous system. Clinically, PD is characterized as a movement disorder, exhibiting an incidence and mortality rate that is increasing faster than any other neurological condition. In recent years, there has been a growing interest concerning the role of the gut microbiome in the etiology and pathophysiology of PD. The establishment of a brain-gut microbiome axis is now real, with evidence denoting a bidirectional communication between the brain and the gut microbiota through metabolic, immune, neuronal, and endocrine mechanisms and pathways. Among these, the vagus nerve represents the most direct form of communication between the brain and the gut. Given the potential interactions between bacteria and drugs, it has been observed that the therapies for PD can have an impact on the composition of the microbiome. Therefore, in the scope of the present review, we will discuss the current understanding of gut microbiome on PD and whether this may be a new paradigm for treating this devastating disease.

Human immunodeficiency virus (HIV) and malaria, caused by infection with Plasmodium spp., are endemic in similar geographical locations. As a result, there is high potential for HIV/Plasmodium co-infection, which increases the pathology of both diseases. However, the immunological mechanisms underlying the exacerbated disease pathology observed in co-infected individuals are poorly understood. Here, we used the rhesus macaque (RM) model to characterize the immunopathogenic impact of Plasmodium fragile co-infection during antiretroviral therapy (ART)-treated simian immunodeficiency virus (SIV)-infection. We observed that P. fragile co-infection resulted in parasitemia and anemia, as well as persistently detectable viral loads (VL) and decreased absolute CD4+ T-cell counts despite daily ART treatment. Notably, P. fragile co-infection was associated with increased levels of inflammatory cytokines linked with neutrophil function, including monocyte chemoattractant protein 1 (MCP-1). P. fragile co-infection was associated with increased levels of neutrophil elastase, a plasma marker of neutrophil extracellular trap (NET) formation, but significant decreases in markers of neutrophil degranulation, potentially indicating a shift in neutrophil functionality during co-infection. Finally, we characterized levels of plasma markers of gastrointestinal (GI) barrier permeability and microbial translocation and observed significant correlations between indicators of GI dysfunction, clinical markers of SIV and Plasmodium infection, and neutrophil frequency and function. Taken together, these data indicate that neutrophil-driven inflammation and GI dysfunction may underlie heightened SIV/P. fragile co-infection pathogenesis.

The present exploratory study tested the hypothesis that computerized cognitive training (CCT) in home telemonitoring may beneficially affect eyes-closed resting-state electroencephalographic (rsEEG) rhythms in Parkinson's disease patients with cognitive deficits (PDCD). A Eurasian database provided clinical-demographic-rsEEG datasets in 40 PDCD patients, 29 PD patients without cognitive deficits (PDNCD), 40 Alzheimer’s disease patients with cognitive deficits (ADCD), and 40 cognitively normal older adults (Healthy). Sixteen of the 40 PDCD patients completed a cross-over unsupervised CCT program of simple, serious video games (versus a sham program) consisting of 14 daily sessions of approximately 20 minutes each in the patients' homes. Compared to the Healthy, PDNCD, and ADCD groups, the PDCD group was characterized by greater diffuse rsEEG delta (about 2-4 Hz) and theta (about 4-7 Hz) source activity. The PDCD patients who underwent the CCT program showed an improvement in video game performance and a reduction in these delta-theta source activities after this program compared to the control condition. In conclusion, these results suggest that the 2-week CCT program in home telemonitoring may mitigate the abnormal “slowing” of rsEEG rhythms in PDCD patients, possibly enhancing the regulation of brain arousal and quiet vigilance.

Background: Pancreatic neuroendocrine tumors (pNETs) represents a rare subset of pancreatic cancer. Functional tumors caused hormonal changes and clinical syndromes, while non-functional ones are often diagnosed late. Surgical management need a multidisciplinary planning, involving enucleation, distal pancreatectomy with or without spleen preserving, cen-tral pancreatectomy, pancreaticoduodectomy or total pancreatectomy. Minimally invasive ap-proach increased in the last decade compared to the open technique. The aim of this study is to analyze current diagnostic and surgical trends for pNETs, to identify better interventions and their outcomes. Methods: The study adhered to PRISMA guidelines, conducting a systematic review of literature from May 2008 to March 2022 across multiple databases. Several combinations of keywords was used ("NET", "pancreatic", "surgery", "laparoscopic", "minimally invasive", "robotic”, “enuclea-tion”,“parenchima sparing”) and relevant article references was manually checked. Manuscript quality was evaluated. Results: The study screened 3867 manuscripts, twelve studies were selected, primarily from Ita-ly, the United States, and China. A total of 7767 surgical treated patients was collected from 160 included centers. The mean age was 56,3 y.o. Enucleations (EN) and distal pancreatectomy (DP) was the most common performed surgery and represents 43.4% and 38.6% of the total interven-tions, respectively. Pancreatic fistula, post operative bleeding, re-operation and follow up was recorded and analyzed. Conclusions: Enucleation show better postoperative outcomes and lower mortality rates com-pared to pancreaticoduodenectomy (PD) or distal pancreatectomy (DP), despite similar risks of postoperative pancreatic fistula (POPF). DP was preferred over enucleation for pancreas body-tail, while laparoscopic enucleation is better for head pNETs.

Abstract: Breast cancer is one of the leading causes of death in the female population due to the re-sistance of cancer cells to many anticancer drugs used. Curcumin has cytotoxic activities against breast cancer cells, although it has limited use due to its poor bioavailability and rapid metabolic elimination. The synthesis of metal complexes of curcumin and curcuminoids is a relevant topic in the search for more active and selective derivatives of these molecular scaffolds. However, solubil-ity and bioavailability are concomitant disadvantages of these types of molecules. To overcome such drawbacks, the preparation of inclusion complexes offers a chemical and pharmacologically safe option for improving the aqueous solubility of organic molecules. Herein, we describe the preparation of the inclusion complex of dimethoxy curcumin magnesium complex with cyclodex-trin (DiMeOC-Mg-BCD, 5) in the stoichiometric relationship 1:1. This new inclusion complex's solubility in aqueous media (PBS) was improved by a factor of 6x over the free metal complex (DiMeOC-Mg). Furthermore, 5 affects cell metabolic rate, cell morphology, cell migration, induced apoptosis, and downregulation of the MMP-2 and MMP-9, IL-6, and STAT3 expression levels on MDA MB 231 cell lines. Results of an antitumor assay in an in-ovo model showed up to 30% inhi-bition of tumour growth for breast cancer (MDA-MB-231) when using 5 (0.650 mg/Kg dose), and 17.29 % inhibition with the free homoleptic metal complex (1.5 mg/Kg dose, DiMeOC-Mg). While the formulation of inclusion complexes from metal complexes of curcuminoids demonstrates its usefulness in improving the solubility and bioavailability of these metallodrugs, the new DiMeOC-Mg-BCD exhibits excellent potential for use as a therapeutic agent in the battle against breast cancer.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) continues to be a global threat due to its ability to evolve and generate new subvariants, leading to new waves of infection. Additionally, other coronaviruses like Middle East respiratory syndrome coronavirus (MERS-CoV, formerly known as hCoV-EMC) which first emerged in 2012, persists and continues to present a threat of severe illness to humans. The continued identification of novel coronaviruses, coupled with the potential for genetic recombination between different strains, raises the possibility of new coronavirus clades of global concern emerging. As a result, there is a pressing need for pan-CoV therapeutic drugs and vaccines. After extensive optimization of an HCV protease inhibitor screening hit, a novel 3CLPro inhibitor (MK-7845) was discovered and subsequently profiled. MK-7845 exhibited nanomolar in vitro potency with broad spectrum activity against a panel of clinical SARS-CoV-2 subvariants and MERS-CoV. Furthermore, when administered orally, MK-7845 demonstrated a notable reduction of viral burdens by &gt;6 log orders in the lungs of transgenic mice infected with SARS-CoV-2 (K18-hACE2 mice) and MERS-CoV (K18-hDDP4 mice).

Zika virus (ZIKV) is a notable arbovirus with maternal, sexual, and TORCH-related transmission capabilities. After 2015, Brazil had the highest number of ZIVK-infected pregnant women who lost their babies or delivered them with Congenital ZIKV Syndrome (CZS). ZIKV infection has been linked to variations in endogenous retroviruses (ERVs) and interleukins within the placenta. ERVs, remnants of ancient viral infections integrated into the genome, include syncytin receptors crucial for placental development. Interleukins, immune response regulators, aid immune tolerance and support syncytial structure development in the placenta, where syncytin receptors facilitate vital cell-to-cell fusion events. Since ZIKV can infect trophoblast cells, we investigated the relationship between ZIKV infections and ERV and interleukin modulations. Investigating the impact of ZIKV on trophoblast cells, we examined two cell types (BeWo and HTR8) infected with ZIKV-MR766 (African) and ZIKV-IEC-Paraíba (Asia-Brazilian) using Taqman and RT2 Profiler PCR Array assays. While early ZIKV infection (24-48 hours) did not induce differential ERV and interleukin expression, future studies involving additional trophoblastic cell lineages and extended infection timelines will illuminate the dynamic interplay between ZIKV, HERVs, interleukins, and cytokines essential for placental formation and function.

The present study aimed at investigating the in vitro and in vivo susceptibility of malaria parasites to crude extracts and fractions from Polyalthia suaveolens, Uvaria angolensis, and Monodora tenuifolia. The ethanolic extracts were prepared by maceration, and were further partitioned using water, dichloromethane, hexane, and methanol. The most promising fraction was subjected to column chromatography and the sub-fractions tested for activity in vitro. The antiplasmodial effect of extracts and fractions was tested against the Chloroquine resistant (PfK1) strain in 96 wells microtiter plate format using SYBR green florescence assay. The promising fraction was further assessed for cytotoxicity and acute toxicity in Swiss albino mice and subsequently against the rodent malaria parasite, P. berghei. Qualitative phytochemical screening was also performed on the promising fraction. The methanol fractions exerted the overall better effect with that of the twigs of P. suaveolens (PStw(Ace)) showing the highest potency with a IC50 value of 3.24 µg/mL followed by the fractions of leaf of M. tenuifolia (MoTel(Ace), IC50= 3.84 µg/ml) and stem bark of P. suaveolens (IC50= 4.90 µg/ml). The phytochemical screening showed the presence of alkaloids, lactones, and phenols in the more active fraction of P. suaveolens (PStw(Ace)). The chromatographic fractionation of this fraction led to 12 sub-fractions with PS8 sub-fraction being the most active (IC50= 4.42 µg/mL). In vivo, oral administration of 2000 mg/kg b.w of fraction PStw(Ace) in mice showed no signs of toxicity. Also, fraction PStw(Ace) at 400 mg/kg b.w exerted the highest suppressive effect against P. berghei strain B throughout the 4 days experiment (% parasitaemia below 5.2%). Overall, the results achieved supported the use of the three plants in the traditional treatment of malaria in Cameroon. More interestingly, the methanolic fraction of the twigs extract from P. suaveolens might be of interest in future development of an antimalarial phytodrug.

The enhancement of early diagnosis of lung cancer is mandatory to improve prognosis. We observed the increase cancer stem cells (CSC) and circulating tumor cells (CTC) in blood of mice on d3 after Lewis lung carcinoma (LLC) cell implantation before disease symptom. Besides we have developed an approach to reprogramming immune cells by inhibiting the MAPK/ERK pathway through MEKi and the PD-1/PD-L1 immune checkpoint signaling pathway. We hypothesized that reprogramming of spleen CD8+ T-cells could also create a population of immune cells with high antitumor activity. We reprogrammed CD8+ T-cells derived from the spleen of C57BL/6 mice (rsCD8+T-cells). The rsCD8+T-cells were able to migrate to lung and were more resistant after the exhaustion in vitro in comparison with naïve sCD8+T-cells. In the orthotopic LLC model, the rsCD8+T-cells therapy increased the amount of proliferating CD8+ and CD4+ T-cells in blood and lung from mice. The amount of CSC decreased in the blood and lung of mice treated with rsCD8+ T-cells. A morphological study revealed a decrease in the number of metastases in lung tissue. The antitumor effects of rsCD8+T-cells are based on the activation of the host immune response by increasing the populations of CD8+ and CD4+ T-cells and apoptosis of CSCs.

In current diagnostic systems, schizophrenia and bipolar disorder are still conceptualized as distinct categorical entities. Recently, both clinical and genetic evidence have challenged this Kraepelinian dichotomy. There are only few longitudinal studies addressing the potential overlaps between these conditions. Here, we present design and first results of the PsyCourse study, an ongoing transdiagnostic study of the affective-to-psychotic continuum that combines longitudinal deep phenotyping and dimensional assessment of psychopathology with an extensive collection of biomaterial. Within the DSM-IV framework, we compare two broad diagnostic groups: one consisting of predominantly affective and one of predominantly psychotic disorders. Depressive, manic, and psychotic symptoms as well as global functioning over time were analyzed. Furthermore, we explore the effects of polygenic risk scores for schizophrenia on diagnostic group membership and address their effects on non-participation in follow-up visits. While phenotypic results show differences in both current psychotic and manic symptoms, depressive symptoms did not vary between both groups. Polygenic risk scores for schizophrenia significantly explained part of the variability of the diagnostic group. Furthermore, there was a trend that a higher polygenic loading for schizophrenia was associated with attrition. Because of its unique properties, the PsyCourse study presents a prime resource for the interrogation of complex genotype-phenotype relationships.

The successful 2020 launch and 2021 landing of the National Aeronautics and Space Administration’s (NASA) Perseverance Mars rover initiated the first phase of the NASA and European Space Agency (ESA) Mars Sample Return (MSR) campaign. The goal of the MSR campaign is to collect scientifically interesting samples from the Martian surface and return them to Earth for further study in terrestrial laboratories. The MSR campaign consists of three major spacecraft components to accomplish this objective: the Perseverance Mars rover, the Sample Retrieval Lander (SRL) and the Earth Return Orbiter (ERO). Onboard the ERO spacecraft is the Capture, Containment and Return System (CCRS). CCRS will capture, process and return to Earth the samples that have been collected after they are launched into Mars orbit by the Mars Ascent Vehicle (MAV), which is delivered to Mars onboard the SRL. To facilitate the processing of the orbiting sample (OS) by CCRS we have designed and developed a vision system to determine the OS capture orientation. The vision system is comprised of two cameras sensitive to the visible portion of the electromagnetic spectrum and two illumination modules constructed from broadband light emitting diodes (LED). Vision system laboratory tests and physics-based optical simulations predict CCRS ground processing will be able to correctly identify the OS post-capture orientation using only a single vision system image that is transmitted to Earth from Mars orbit.

We analyse the light curve in the R-band gathered during the 2015/16 observing season of OJ287. We did a search for QPOs using several methods in wide time domain. No statistically significant periods were found in the high frequency domain both in the ground data and also in K2 observations. In the longer periods domain the Lomb-Scargle periodogram revealed several peaks above the 99\% significance level. The longest one, about 95-day, corresponds to the ISCO period of the more massive SMBH. The 43-day period could be an alias or can be attributed to accretion in the form of two armed spiral wave.