The root extracts of Symphytum officinale (comfrey) are commonly used in traditional medicine to treat muscle, joint, skin and bone disorders. However, little information is available on the biomedical functions of comfrey leaves. In this study, sequencing results of Internal Transcribed Spacer and trnL-trnF genes showed that plants purchased from the local market were comfrey and named as S. officinale WL (WL). The optimal extraction conditions of WL leave with the highest extract yield and contents of total phenols and flavonoids by microwave-assisted extraction were identified. The antioxidative and anti-inflammatory activities and possible molecular mechanism(s) of the WL leaf extract (WLE) were evaluated. Furthermore, the major component of WLE was identified as rosmarinic acid by HPLC. Results showed that the optimal extract condition was obtained with 750W microwave power, 50℃, 75% methanol, the solid-to-solvent ratio of 1:10, and 15 minutes. Results of all DPPH, ABTS and superoxide radical scavenging activities, reducing power, ferrous ion chelating activity, and ferric reducing antioxidant power showed high antioxidative capacities of WLE. Furthermore, WLE showed obvious DNA protecting activity. WLE attenuated lipopolysaccharides-stimulated inflammation by suppressing iNOS, COX-2, IL-1β, IL-6, and TNF-α expressions in RAW264.7 macrophages. These attenuations involved in inactivations of lipopolysaccharides-induced NF-κB and MAPK signaling pathways.

Understanding the dynamics of humoral immune responses throughout the COVID-19 pandemic is crucial for optimizing vaccine strategies. This study aimed to investigate the impact of infection and vaccine-induced immunity on the Albanian population from August 2021 to August 2022. Two independent samples from the Albanian general population were analyzed using an ELISA method to assess IgG class anti-Spike (S1) and anti-Nucleocapsid (N) SARS-CoV-2 antibodies. The results revealed a robust immune response among vaccinated individuals with prior COVID-19 infection who received only one vaccine dose. In the 2022 cohort, most individuals who received one vaccine dose achieved comparable seropositivity and antibody levels to those who received two doses. However, individuals aged 61 and over required two or three vaccine doses to reach the same level of immune response as the younger population. Notably, the time elapsed since infection or vaccination did not significantly impact the immune response. These findings highlight the importance of hybrid immunity and suggest that one vaccine dose may be sufficient for most individuals with prior COVID-19 infection. However, additional doses are necessary for optimal protection in older individuals. This study provides unique insights into humoral immune response dynamics that can be used to refine ongoing COVID-19 population vaccination strategies for middle-income countries with low vaccination coverage.

Bioactive fractions were isolated from the leaves extract of Kalanchoe pinnata and subjected to scrutiny for their prospective anti-obesity properties. An array of in vitro phytochemical, antioxidant, and enzyme inhibition assays were executed, which dis-cerned fractions F1 and F2 as the most effective fractions. These fractions were sub-sequently studied through in vivo experiments, affirming that F2 as the most potent fraction. Further characterization of F2 was conducted via HPTLC MS-MSn tech-niques. The outcomes demonstrated that F2 produced a notable anti-obesity effect in obese mice, reducing their body weight and lipid metrics, and leading to advanta-geous changes in their organs. An analytical examination of F2 revealed the existence of four principal compounds, which were subsequently subjected to in silco molecular docking and dynamic analysis, confirming their aptitude for binding to selected pro-teins. These findings imply that the utilization of Kalanchoe pinnata leaves could pro-vide a promising therapeutic strategy for the treatment of obesity.

This article describes the transition of an undirected active network, used for numerical and logical analysis, and made up of communicating operators and nodes, and being self-extensible, into a network of semantic structures, and the extensions necessary to handle language. The network, called Active Structure, was infused with knowledge in the form of tens of thousands of definitions taken from a human-readable dictionary. Where the dictionary fell short, from circularity, lack of a hierarchical form for its senses and sub senses, or inadequate detail around verbs, the entries were extensively curated. The result is a machine which has access to every meaning of every word in its vocabulary, and needs to manage the right meaning for every use of a word, a task that our unconscious minds now handle. To demonstrate that such a network can aspire to human-level tasks, we have begun loading an Anti-Money Laundering Act so that the machine can devise and test strategies against money launderers. There is a higher goal being aimed at, the breaking of the Four Pieces Limit. That is, the network is not intended to save money on human cognitive labor, but to raise an absurdly low limit on it.

In the same way as the realization of some of the famous gedanken experiments imagined by the founding fathers of quantum mechanics has recently led to the current renewal of the interpretation of quantum physics, it seems that the most recent progresses of observational astrophysics can be interpreted as the realization of some cosmological gedanken experiments such as the removal from the universe of the whole visible matter or the cosmic time travel leading to a new cosmological standard model. This standard model involves two dark components of the universe, dark energy and dark matter. Whereas dark energy is usually associated with the cosmological constant, we propose to explain dark matter as a pure QCD effect, namely a gluonic Bose Einstein condensate, following the transition from the quark gluon plasma phase to the colorless hadronic phase. Our approach not only allows us to assume a ratio Dark/Visible equal to 11/2 but also provides gluons and (anti-)quarks with an extra mass of vibrational nature. Such an interpretation would comfort the idea that, apart from the violation of the matter/antimatter symmetry satisfying the Sakharov’s conditions, the reconciliation of particle physics and cosmology needs not the recourse to any ad hoc fields, particles or hidden variables.

There is an increasing interest in revisiting plants for drug discovery proving scientifically their role as remedies. Pistacia lentiscus (PL) is a wild-growing shrub rich in terpenoids, which are pharmacological appealing. The more recurrent components in the oil are represented by α-pinene, terpinene, caryophyllene, limonene, and myrcene. High concentration of polyphenols enriches the extracts. PL-extracts showed in vitro and in animal model strong anti-inflammatory and anti-oxidative activities. The anti-inflammatory activity mainly occurs due to inhibition of NF-kB pathway or directly toward the proinflammatory cytokines, or arachidonic acid cascade against COX-2 and LOX. The antimicrobial activity of PL essential oil and extracts includes among others Staphylococcus aureus, Escherichia coli, periodontal bacteria and Candida sp.. In conclusion, the biological properties, and particularly the anti-inflammatory and anti-microbial capacity, propose PL as a new safe pharmaceutical agent.

At a time when the world faces an emotional breakdown, crushing our dreams if not taking our lives, we realize that together we must fight the war against the COVID-19 outbreak even if almost the majority of the scientific community finds itself confined to home. Every day, like everyone else, we, scientists, listen to the latest news with its promises and announcements. Across the world, a surge of clinical trials trying to cure or slow down the coronavirus pandemic has been launched to bring hope instead of fear and despair. One first proposed clinical trial has drawn worldwide hype to the benefit of chloroquine (CQ), a well-known and broadly used anti-malarial drug, in the treatment of patients infected by the recently emerged deadly coronavirus (SARS-CoV-2). We should consider this information in the light of the long-standing anti-inflammatory and anti-viral properties of CQ-related drugs. Yet, none of the articles promoting the use of CQ in the current pandemic evoked a possible molecular or cellular mechanism of action that could account for any efficacy. Here, given the interaction of viruses with macroautophagy (hereafter referred to as autophagy), a CQ-sensitive anti-viral safeguard pathway, we would like to discuss the pros, but also the cons concerning the current therapeutic options targeting this process.

SARS-CoV-2 is a new coronavirus that has caused a worldwide pandemic. It produces severe acute respiratory disease (COVID-19), which is fatal in many cases, characterised by cytokine release syndrome (CRS). According to the World Health Organization (WHO), those who smoke are likely to be more vulnerable to infection. Here, in order to clarify the epidemiologic relationship between smoking and COVID-19, we present a systematic literature review until 28 April 2020 and a meta-analysis. It includes 18 recent COVID-19 clinical and epidemiological studies based on smoking patient status from 720 initial studies in China, USA, and Italy. The percentage of hospitalised current smokers was 7.7% (95%CI: 6.9-8.4) in China, 2.3% (95%CI: 1.7-2.9) in the USA and 7.6% (95%CI: 4.2-11.0) in Italy. These percentages were compared to the smoking prevalence of each country and statistically significant differences were found in them all (p <0.0001). By means of the meta-analysis, we offer epidemiological evidence showing that smokers were statistically less likely to be hospitalised (OR=0.18, 95%CI: 0.14-0.23, p<0.01). CRS and exacerbated inflammatory response are associated with aggravation of hospitalise patients. In this scenario, we hypothesise that nicotine, not smoking, could ameliorate the cytokine storm and severe related inflammatory response through the cholinergic-mediated anti-inflammatory pathway.

The current study assessed the influence of Anti Stripping Agents (ASA), Ground Tire Rubber (GTR) and waste polyethylene terephthalate (PET) on performance behavior of binder and Stone Matrix Asphalt (SMA) mixtures. Through this paper, the 85/100 penetration grade bitumen was utilized as original bitumen. Also, three liquid ASA’s (ASA (A), ASA (B), ASA (C)) were used as a mixture modifier. For this purpose, softening point, penetration, rotational viscosity, Dynamic Shear Rheometer, Multi Stress Creep Recovery (MSCR) and Linear Amplitude Sweep (LAS) tests were implemented to investigate the rheological properties of modified bitumen. For evaluating the behavior of modified mixtures several tests such as; Resilient Modulus, Tensile Strength, dynamic creep, wheel track and four-point beam fatigue tests were implemented. Based on MSCR test results, utilization of mentioned polymers enhanced the elasticity of bitumens and therefore the permanent deformation resistance of binders increases. Also by the addition of PET percentage, the rutting resistance improves. Results indicated that utilization of ASAs, PET and Crumb Rubber (CR) enhance the Resilient Modulus (Mr), Indirect Tensile Strength (ITS), rutting resistance, fatigue life and Fracture Energy (FE) of asphalt mixtures. Also based on results, modification of binder by PET/CR with a ratio of 50%/50% and ASA (B) have the highest fatigue life which indicates that this mixture has highest resistance against fatigue cracking.

An explanation of the origin of dark matter is suggested in this work. The argument is based on symmetry considerations about the concept of mass. In the Wigner's view, the rest mass and the spin of a free elementary particle in flat space-time are the two invariants that characterize the associated unitary irreducible representation of the Poincar\'e group. The Poincar\'e group has two and only two deformations with maximal symmetry. They describe respectively the de Sitter (dS) and Anti de Sitter (AdS) kinematic symmetries. Analogously to their shared flat space-time limit, two invariants, spin and energy scale for de Sitter and rest energy for Anti de Sitter, characterize the unitary irreducible representation associated with dS and AdS elementary systems. While the dS energy scale is a simple deformation of the Poincaré rest energy and so has a purely mass nature, AdS rest energy is the sum of a purely mass component and a kind of zero-point energy derived from the curvature. An analysis based on recent estimates on the chemical freeze-out temperature marking in Early Universe the phase transition quark-gluon plasma epoch to the hadron epoch supports the guess that dark matter energy might originate from an effective AdS curvature energy.

Caribbean sponges of the genus Smenospongia are a prolific source of chlorinated secondary metabolites. The use of molecular networking as a powerful dereplication tool revealed the presence in the metabolome of S. aurea of two new members of the smenamide family, namely smenamide F (1) and G (2). The structure of smenamide F (1) and G (2) was determined by spectroscopic analysis (NMR, MS, ECD). The relative and the absolute configuration at C-13, C-15, and C-16 was determined on the basis of the conformational rigidity of a 1,3-disubstituted alkyl chain system (i.e. the C-12/C-18 segment of compound 1). Smenamide F (1) and G (2) were shown to exert a selective moderate antiproliferative activity against cancer cell lines MCF-7 and MDA-MB-231, while being inactive against MG-63.

Lemon balm extracts by dry plant material of Melissa officinalis were tested against their efficacy against for different fungal species Alternaria alternata, Fusarium oxysporum, Aspergillus flavus and Beauveria bassiana. The aqueous phase of the extract was evaluated for antioxidant, antifungal and also anti-aflatoxigenic activity. A synergism evaluation was also performed concerning, the small quantity of lemon balm polar essential oil compounds extracted into the infusion and the water soluble compounds in the extract. The experiments were conducted in solid cultures and the growth inhibition was demonstrated by measuring mycelial diameter. Additionally, the effect on conidia production was also demonstrated. Lemon balm was also used for in situ test on Pistachia vera seed against Aspergillus flavus growth and aflatoxin production. Results revealed enhancement of fungal growth by lemon balm extracts however total inhibition of aflatoxins production on Pistachia vera seeds was observed, and both actions were tried to attributed to volatile and water soluble compounds identified based on GC/MS, HPLC/DAD and LC/MS, and the observed antioxidant activity. Volatile and water - soluble compounds found to be in absolute synergism in mycelium growth enhancement and the observed anti-aflatoxigenic activity addressed to the high antioxidant activity observed and synergistic action between the other water soluble phenolic compounds identified in the extract. The findings of this study underline the high biological active potential of lemon balm extracts under various screening test since for the first time full phytochemical analysis of lemon balm extracts.

In the present work, the charged B1, B2 and B3 bastons with the condition of k(mm) = k >> k(dd) > k(dm) = k(lq) = 0 are explained as the good candidates of the dark matters. The proposed rest mass (26.12 eV/c²) of the B1 dark matter is indirectly confirmed from the supernova 1987A data. The missing neutrinos are newly explained by using the dark matters and lepton charge force. The neutrino excess anomaly of the MinibooNE data is explained by the B1 dark matter scattering within the Cherenkov detectors. And the rest masses of 1.4 TeV/c² and 42.7 GeV/c² are assigned to the Le particle and the B2 dark matter, respectively, from the cosmic ray observations. In the present work, the Q1 baryon decays are used to explain the anti-Helium cosmic ray events. Because of the graviton evaporation and photon confinement, the very small Coulomb’s constant (k(dd)) of 10^x-54k and gravitation constant (G_N(dd)) of 10^xG_N for the charged dark matters at the present time are proposed. The x value can have the positive, zero or negative value around zero. Therefore, F_c(mm) > F_g(dd) (?) F_g(mm) > F_g(dm) > F_c(dd) > F_c(dm) = F_c(lq) = 0 for the proton-like particle.

The aim of this study is to emphasize on the clinical uses of amniotic membrane (AM) in multiple ocular disorders. AM possesses many properties including promotion of epithelialization, anti-fibrotic, anti-apoptotic, anti-angiogenic properties. Epithelial wound healing on the eye surface is promoted due to several epidermal and keratocyte growth factors as well as by its anti-inflammatory and anti-scarring effects due to interleukin-10, interleukin-1 receptor antagonists and inhibition of transforming growth factor- beta (TGF-β) signal transduction by AM in the corneal and conjunctival fibroblasts respectively. It plays a crucial role by functioning as a substitute of basement membrane (BM) and as a temporary graft material. It is not only being used as an eye graft but also its extract can be used as an eye drop for corneal and external eye diseases. So its proper preparation, preservation and clinical application can bring a revolutionary change in the treatment of different ocular disorders.

Malawi has developed an excellent, nation-wide system for monitoring people infected with HIV and keeping track of key epidemic markers. Their success lies in two things: the focus on simplicity and the use of data collection not only to track the epidemic and identify problems but also to give regular feedback and support to every clinic in the country. This achievement is the more remarkable given that Malawi is one of the poorest countries in the world, ranking 190 out of 194 countries by GDP, but has one of the most severe epidemics of HIV in the world, ranking 9th out of 168 countries by HIV prevalence. We first discuss the current state and likely future epidemic trends in Malawi: unless we know where we are and where we are going we cannot decide what to do or how to do it to in order to achieve a better outcome. We then discuss the history and development of Malawi’s patient monitoring system, as reported in their Integrated HIV Program Reports,ix which have been published quarterly since the beginning of 2004. We consider the current state of patient monitoring and support as reflected in the most recent report for the third quarter (Q3) of 2016 and comment on some of the questions that this raises. Finally, we consider ways in which the current system could be improved by strengthening Malawi’s analytical capacity and making better use of this unique data set. The focus here is on HIV in adultsv because if ART is initiated early in all adults living with HIV this should include testing all pregnant women for HIV and starting them on treatment immediately. However, PMTCT is especially important and care must be given to reducing MTCT and identifying the long-term child survivors of mother-to-child transmission and this demands a complementary assessment. There is an ongoing debate about the relative merits of treatment and prevention in reducing transmission and it should be made clear that the primary reason for starting people on treatment early is that it is in the best interest of the individual patient to start treatment as soon as possible after becoming infected. Allowing a person’s immune system to deteriorate to any degree is not consistent with the clinician’s commitment to ‘first do no harm’ and even those with the highest CD4⁺ cell count are at a substantially increased risk of death. What matters, therefore, is to get as many people as possible onto ART, ensure that they remain virally suppressed, and consider prevention in this context.

Polo-Like Kinase-1 (PLK1) is a key regulator of the G2/M cell cycle and has been linked to treatment resistance in prostate cancer (PCa). This study aimed to explore the correlation between PLK1 expression, determined through RNA-seq analysis, and clinical outcomes in PCa patients. We analyzed tumor samples from 452 patients diagnosed with prostate adenocarcinoma between 2014 and 2020, sourced from nine institutions affiliated with the Oncology Research Information Exchange Network (ORIEN). PLK1 expression levels were determined using RNA-seq data and stratified into high (≥75th percentile) vs. low (<75th percentile) expression. Univariate and multivariate Cox proportional hazard models compared overall survival between patients with low vs. high PLK1 expression, adjusting for age, race, PSA, and stage. Of the 452 tumors, 241 (53.3%) had high PLK1 and 211 (46.7%) had low PLK1 expression. Median follow-up was 2.74 years for low PLK1 and 2.71 years for high PLK1. No significant difference in overall survival was observed between low and high PLK1 groups in univariate (p=0.86; HR 1.09) or multivariate (p=1.0; HR 0.99) analyses. This study found no association between RNA-seq-based PLK1 expression and prognosis in PCa. PLK1 expression is not a prognostic marker for prostate cancer.

In this preliminary investigation, a concise molecular docking study using the Pyrx program screened thousands of compounds against the active site of HIV-1 reverse transcriptase. The Virtual Screening library was employed to assess binding energetics scores, focusing on identifying candidates with high Vina Scores. Eight compounds, including Tetrophan, Imatinib, Amentoflavone, Alprazolam, Bilobetin, Bafetinib, Nilotinib, and Ginketin, emerged as promising candidates with significant binding energies.Recognizing compounds that strongly bind to HIV-1 reverse transcriptase holds potential for antiretroviral drug development in the fight against HIV infection. Subsequently, the study evaluated the toxicity properties of these candidates using pKCSM. Amentoflavone, a natural biflavonoid found in Ginkgo biloba and Nilotinib, a tyrosine kinase inhibitor, demonstrated lower overall toxicity profiles compared to other candidates. Further toxicity analysis using Pro-Tox-II revealed Amentoflavone's higher predictive LD50, lower toxicity class, and reduced probabilities of hepatotoxicity, carcinogenicity, mutagenicity, and moderate immunotoxicity compared to Nilotinib. While Nilotinib, a pharmaceutical drug, exhibited higher probabilities of adverse effects in these categories. In summary, Amentoflavone and Nilotinib present as promising candidates with lower toxicity concerns. Amentoflavone, as a natural substance, showcases a more favorable toxicity profile than Nilotinib, offering valuable insights for potential therapeutic applications.

Bacillus amyloliquefaciens GL18 has been proven to have good resistance ability and can promote the growth of Avena sativa cultivar ‘Qingyan 1’. Herein, Illumina high-throughput transcriptome sequencing technology was used to analyze the differential expression of genes between the interaction group (LB) and the control group (LCK) when ‘Qingyan 1’ roots interacted with GL18 bacterial suspension or sterile water for 12 h under 4 °C low-temperature stress. The gene function annotation information was obtained using Gene Ontology (GO) functional classification and enrichment analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and annotation of differentially expressed genes was used to explore the related signal transduction pathway of ‘Qingyan 1’ response to cold stress induced by Bacillus GL18. The results showed that after ‘Qingyan 1’ seedlings interacted with GL18 bacterial suspension or sterile water for 12 h, comparing the LB with the LCK or CK (the control group at 26 °C), there were 12,061 and 25,489 differentially expressed genes, respectively. Their functions were mainly related to metabolic process, cellular process, catalytic activity, binding, and cellular parts, and they were significantly enriched in plant tissue growth and development, cell wall, organelle membrane synthesis, thiamine and its compounds, biosynthesis, polyamine decomposition, and other metabolic processes. Signal transduction was detected through KEGG pathway enrichment analysis, and corresponding genes, such as AUXI, PP2C, SNRK2, ABF, BRI1, and PIF4, were expressed. The expression of genes directly involved in plant growth was upregulated in the presence of GL18, as shown by real-time quantitative PCR analysis. It was speculated that the normal growth and development of ‘Qingyan 1’ under low-temperature stress promoted by GL18 is a result of the integration of multiple pathways in terms of regulating endogenous hormone metabolism, secondary metabolite synthesis, and photosynthesis.

The periodontal ligament (PDL) is a complex connective tissue that connects the tooth root to the dental alveolar bone and plays crucial mechanical roles. PDL also exhibits regenerative roles and regulatory functions to maintain per-iodontium integrity and homeostasis. While PDL exposure to oral microbial pathogens is common, virtually nothing is known regarding viral infections of PDL. In particular, human herpes simplex virus type 1 (HSV-1) persistently infects the oral cavity through infections of the oral epithelium, connective tis-sue and neurons. While the oral spread of HSV-1 is generally asymptomatic, this virus has also been implicated in various oral pathologies. In this study, using a primary cell model derived from PDL (PDL-cells), and whole surgical fragments of PDL, we provide evidence supporting the efficient infection of PDL by HSV-1 and the promotions of cytopathic effects. Infection of PDL by HSV-1 was also associated with an acute innate inflammatory response, as il-lustrated by the production of the antiviral interferons and pro-inflammatory cytokines. Furthermore, this inflammatory response to HSV-1 was exacerbated in the presence of bacterial-derived products, such as peptidoglycans. This work therefore highlights the ability of HSV-1 to infect mesenchymal cells from PDL, suggesting that PDL may serve as a viral reservoir for the perio-dontal spread of HSV-1. Moreover, this raises questions about HSV-1 oral pathogenesis, as HSV-1-associated cytopathic and inflammatory effects may contribute to profound alterations of PDL integrity and functioning.

Apis mellifera, especially weak ones, are highly vulnerable to Carpoglyphus lactis mites, which can rapidly infest and consume stored pollen, leading to weakened colonies and potentially colony collapse. This study aimed to ascertain and investigate the prevalence of this mite in honeybee colonies across 9 provinces in the Republic of Korea (ROK). A total of 615 honeybee colonies were collected, from 66 apiaries during the spring and 58 apiaries during the summer of 2023. A 1,242 bp segment of the the Cytochrome c oxidase subunit 1 (COI) gene was amplified using the polymerase chain reaction method. The detection levels of C. lactis in the honeybees were compared between winter and summer. Based on the COI sequence analysis, the nucleotide sequence similarity of C. lactis mites isolated in the ROK with those from China (NC048990.1) was found to be 99.5%, and with those from the United Kingdom (KY922482.1) was 99.3%. This study is the first report of C. lactis in Korean apiaries. The findings in this study demonstrate a significantly higher detection rate in winter, which is 4.1 times greater than that in summer (p &lt; 0.001). Furthermore, the results underscore the usefulness of molecular diagnostic techniques for detecting C. lactis mites.

Background: SARS-CoV-2 Omicron JN.1 has the highest number of amino acid mutations in its receptor binding domain (RBD) and has acquired a hallmark L455S mutation. The immune evasion capability of JN.1 is a subject of scientific investigation. The US CDC used RT-qPCR SGTF as the proxy indicator of JN.1 infections for evaluation of the effectiveness of updated monovalent XBB.1.5 COVID-19 vaccines against JN.1 and recommended that all persons aged ≥6 months should receive an updated COVID-19 vaccine dose. Objective: Recommend Sanger sequencing for diagnosis of JN.1 infections to generate the data based on which guidelines are made to direct vaccination policies. Methods: The RNA in nasopharyngeal swab specimens from patients with clinical respiratory infection was subjected to nested RT-PCR, targeting a 398-base segment of the N-gene and a 445-base segment of the RBD of SARS-CoV-2 for amplification. The DNA sequences were analyzed for amino acid mutations. Results: The N-gene sequence showed Q229K, usually associated with Omicron BA.2.86 (+JN.1). The RBD sequence showed 24 amino acid mutations, including the hallmark L455S mutation for JN.1 and the V483del for BA.2.86 lineage. Conclusions: The CDC should consider Sanger sequencing of the RBD to diagnose JN.1 infections for statistical analysis in making vaccination policies.

Background: Maternal diabetes mellitus (MDM) is associated with increased risks for adverse neonatal outcomes. However, the impact of MDM on neonatal outcomes in Bisha, a city in Saudi Arabia, is not well-documented. This study aims to investigate the impact of MDM on neonatal outcomes in the Maternity and Children’s Hospital (MCH), Bisha, Saudi Arabia. Methods: A retrospective cohort study was conducted on 181 pregnant women with diabetes and their neonates diagnosed at Maternity and Children’s Hospital (MCH), Bisha, Saudi Arabia, between October 5, 2020, and November 5, 2022. The primary outcome was a composite of adverse neonatal outcomes, including stillbirth, neonatal death, macrosomia, preterm birth, respiratory distress syndrome, hypoglycemia, and congenital anomalies. Logistic regression analyses were used to adjust for potential confounders. Results: The total sample size was 181. The average age of patients was 34 years (SD=6.45). The majority of the patients were diagnosed with GDM, 147 (81.2%), and pre-GDM, 34 (18.8%). Neonates born to mothers with MDM had a higher risk of adverse neonatal outcomes compared to those born to mothers without MDM (adjusted odds ratio [aOR] = 1.46, 95% confidence interval [CI]: 1.25-1.70). The risks of macrosomia (aOR = 1.74, 95% CI: 1.38-2.19), LBW (aOR = 1.32, 95% CI: 1.06-1.66), and RDS (aOR = 1.57, 95% CI: 1.28-1.93) were significantly higher among neonates born to mothers with MDM. Types of DM were statistically significant with some neonatal outcomes: hypoglycemia (p-value = 0.017), macrosomia (p-value = 0.050), and neonatal death (p-value = 0.017). Conclusion: MDM is associated with an increased risk of adverse neonatal outcomes in Bisha. Early identification and management of MDM may improve neonatal outcomes and reduce the burden of neonatal morbidity and mortality in this population.

Tumor necrosis factor (TNF) is a pleiotropic cytokine regulating many physiological and pathological immune-mediated processes. Although initially described as a tumor-cytotoxic agent, over time, it has also been recognized as an essential pro-inflammatory cytokine implicated in the pathogenesis of different autoimmune diseases, such as multiple sclerosis (MS). Several studies have shown an increase in TNF expression both in acute and chronic active MS brain lesions, as well as its involvement in maintaining a chronic inflammatory intrathecal process known as “compartmentalized inflammation”, which contributes to disease progression and disability accumulation in MS, even more than acute inflammatory activity. Indeed, high TNF levels were observed in the serum and cerebrospinal fluid of subjects with MS and correlated to disease severity, promoting axonal damage and, consequently, neurodegeneration. In this review we discuss the current knowledge of TNF and its receptors involvement in MS progression, focusing on disability progression independent of relapse activity (PIRA), meant as the disability accumulation evident in relapsing MS patients not related to acute inflammatory events.

In this preliminary investigation, a concise molecular docking study using the Pyrx program screened thousands of compounds against the active site of HIV-1 reverse transcriptase. The Virtual Screening library was employed to assess binding energetics scores, focusing on identifying candidates with high Vina Scores. Eight compounds, including Tetrophan, Imatinib, Amentoflavone, Alprazolam, Bilobetin, Bafetinib, Nilotinib, and Ginketin, emerged as promising candidates with significant binding energies.Recognizing compounds that strongly bind to HIV-1 reverse transcriptase holds potential for antiretroviral drug development in the fight against HIV infection. Subsequently, the study evaluated the toxicity properties of these candidates using pKCSM. Amentoflavone, a natural biflavonoid found in Ginkgo biloba and Nilotinib, a tyrosine kinase inhibitor, demonstrated lower overall toxicity profiles compared to other candidates. Further toxicity analysis using Pro-Tox-II revealed Amentoflavone's higher predictive LD50, lower toxicity class, and reduced probabilities of hepatotoxicity, carcinogenicity, mutagenicity, and moderate immunotoxicity compared to Nilotinib. While Nilotinib, a pharmaceutical drug, exhibited higher probabilities of adverse effects in these categories. In summary, Amentoflavone and Nilotinib present as promising candidates with lower toxicity concerns. Amentoflavone, as a natural substance, showcases a more favorable toxicity profile than Nilotinib, offering valuable insights for potential therapeutic applications.

Hyperplastic dental follicles (HDFs) represent odontogenic hamartomatous lesions originating from pericoronal tissues and are often associated with impacted or embedded teeth. These lesions may occasionally feature unique calcifying bodies, known as calcifying whorled nodules (CWN), characterized by stromal cells arranged in a whorled or spiral fashion. CWNs are typically observed in multiple calcifying hyperplastic dental follicles or regional odontodysplasia. In our study, we examined 40 cases of HDFs, including nine instances with characteristics of CWNs, which were infrequently accompanied by odontodysplasia. Histological examination was conducted on all 40 cases, with immunohistochemical analysis performed on 21 of them. Among the cases with CWN, nine affected a single embedded tooth, with one exception. CWNs exhibited diverse calcifications featuring sparse or entirely deposited psammoma bodies, and some displayed dentinoid formation. Immunohistochemically, stromal cells of HDFs were frequently positive for CD56 and nestin. In contrast, CWNs were negative for CD56 but positive for nestin and HES1, with a few DSP-positive calcified bodies. Our results revealed that hamartomatous calcifying HFDs can impact multiple and single-embedded teeth. CWNs composed of nestin and HES1-positive ectomesenchymal cells demonstrated the potential to differentiate into odontoblasts and contribute to dentin matrix formation under the influence of HES1. This study is the first report documenting odontoblastic differentiation in HDFs.

Phα1β a spider peptide, purified from the venom of Phoneutria nigriventer inhibits high voltage calcium channels and is antagonist of TRPA1 receptor two important pain transduction path-ways. In the last 15 years, we have showed, in preclinical tests with Phα1β native and recombi-nant in rodent models of pain the potential of Phα1β to become a new analgesic drug. Evaluation of new drug on human ERG channel is requirement of the regulatory agencies. For the hERG channel inhibition assay it was used the commercial kit FLIPR® Potassium Assay. It was tested the effect of Phα1β and as positive control dofetilide, a well characterized hERG block-er. Phα1β 56, 225, 450 and 900 pMol caused at a higher concentration a very weak inhibition of the hERG channel activity of about 13.47 % with channel inhibition at 50%, IC50 > 900 pMol. Dofetilide (0.0001 - 10 µM), a known hERG inhibitor, caused a well-known, concentra-tion-dependent inhibition of the hERG channel with a mean IC50 of 0.1642 µM (0.1189 – 0.2282 µM. For the cytotoxicity assay, Phα1β concentrations of 56, 225, 450 and 900 pMol incubated for 24 h with HEK293-hERG cells did not alter the viability of the HEK293-hERG cells. It is con-cluded that Phα1β even at high concentrations does not interfere with hERG channels.

Background. Waning of neutralizing and cell-mediated immune response after the primary vac-cine cycle (PVC) and the first booster dose (BD) is of concern, especially for PLWH with a CD4 count ≤200 cells/ mm3.Methods.Neutralizing antibodies (nAbs) titers by microneutralization assay against WD614G /Omicron BA.1 and IFNγ production by ELISA assay were measured in samples of PLWH at 4 time points [2 and 4 months post-PVC (T1 and T2), 2 weeks and 5 months after the BD (T3 and T4)]. Participants were stratified by CD4 count after PVC (LCD4, <200/mm3; ICD4, 201-500/mm3 and HCD4, >500/mm3). Mixed models were used to compare mean responses over T1-T4 across CD4 groups. Results. 314 PLWH on ART (LCD4=56; ICD4=120; HCD4=138) were enrolled. At T2, levels of nAbs were significantly lower in LCD4 vs ICD4/HCD4 (p=0.04). BD was crucial for increasing nAbs titres above 1:40 at T3 and up to T4 for WD614G. A positive T cell response after PVC was observed in all groups, regardless of CD4 (p=0.31). Conclusions. Waning of nAbs after PVC was more important in LCD4 group. BD managed to re-establish higher levels of nAbs against WD614G which were retained for 5 months. The level of T-cellular response was significantly higher in HCD4 and ICD4 compared to the LCD4 group although it remained above detectable levels over the entire study period regardless of CD4 count. Keywords: HIV-1 infection; SARS-CoV-2 infection;

In this paper, we concentrate on the study of the properties of residual Tsallis entropy for order statistics. Order statistics have an important role in reliability structural engineering for example for modelling lifetimes of series and parallel systems. The residual Tsallis entropy of ith order statistic from a continuous distribution function and its deviation from the residual Tsallis entropy of ith order statistics from a uniform distribution is investigated. In a mathematical framework, a method to express the residual Tsallis entropy of the ith order statistic from a continuous distribution in terms of the residual Tsallis entropy of the ith order statistic from a uniform distribution is provided. This approach may provide insight into the behavior and properties of the residual Tsallis entropy for order statistics. Further, we study the monotonicity properties of the residual Tsallis entropy of order statistics under dierent conditions. By studying these properties, deeper understanding of the relationship between the position of order statistics and the resulting residual Tsallis entropy is gained.

: Ovarian cancer has a dismal prognosis. Standard treatment following surgery relies on platinum-based chemotherapy. However, sizeable percentages of patients are unresponsive. Identification of markers predicting response to chemotherapy might help select eligible patients while sparing unresponsive ones treatment-associated toxicity. Cancer/testis antigens (CTA) are expressed by healthy germ cells and malignant cells of diverse histological origin. This expression profile identifies them as attractive targets of cancer immunotherapies. We analyzed correlations between expression of MAGE-A10 and New York esophageal-1 cancer (NY-ESO-1) CTAs at protein level and effectiveness of platinum-based chemotherapy in patients with advanced-stage high-grade serous ovarian carcinoma (HGSOC). MAGE-A10 and NY-ESO-1 protein expression was analyzed by immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded samples from 93 patients with advanced-stage HGSOC treated at our institutions between January 1996 and December 2013. Correlation between expression of these markers and response to platinum-based chemotherapy, evaluated according to RECIST 1.1 criteria, platinum sensitivity, measured as platinum free interval (PFI), progression free (PFS) and overall survival (OS) was explored. MAGE-A10 protein expression predicts unresponsiveness to platinum-based chemotherapy (p=0.005), poor platinum sensitivity (p<0.001), and poor PFS (p<0.001) and OS (p<0.001). Multiva-riate analysis identifies MAGE-A10 protein expression as independent predictor of poor platinum sensitivity (p=0.005) and shorter OS (p<0.001). Instead, no correlation was observed between NY-ESO-1 protein expression and response to platinum-based chemotherapy (p=0.832), platinum sensitivity (p= 0.168), PFS (p=0.126) and OS (p=0.335). MAGE-A10 protein expression reliably identifies advanced-stage HGSOC unresponsive to platinum-based chemotherapy. Targeted im-munotherapy could represent an important alternative therapeutic option in these cancers.

Tdp1 and Tdp2 are DNA repair enzymes that repair DNA damages caused by various agents, including anticancer drugs. Thus, these enzymes resist anticancer therapy and could be the reasons of resistance to such widely used drugs as topotecan and etoposide. In the present work, we found compounds capable of inhibiting both enzymes among derivatives of (-)-usnic acid. Both (+)- and (-)-enantiomers of compounds act equally effectively against Tdp1, and only (-)-enantiomers inhibited Tdp2. Surprisingly, the compounds protect HEK293FT wild type cells from the cytotoxic effect of etoposide but potentiate it against Tdp2 knockout cells. We assume that the sensitizing effect of the compounds in the absence of Tdp2 is associated with effective inhibition of Tdp1, which could take over the functions of Tdp2.

A patient in her early 20s presented with constant and progressive lower abdominal and back pain, mainly on the right side of the abdomen, purulent vaginal discharge and pyrexia. Radio-logical assessment revealed a possible tuboovarian abscess and incidental diagnosis of ipsilateral renal agenesis. The patient was treated for pelvic inflammatory disease (PID), however after antibiotic administration and since the symptoms were not resolving, an abdominal MRI was requested which revealed a uterus didelphys with two cervices, an obstructed haemivagina and evidence of haematocolpos. The diagnosis of OHVIRA syndrome was confirmed and the patient underwent an excision of the vaginal septum, drainage of the haematopyocolpos and laparoscopic drainage of the tuboovarian abscess. She achieved a good recovery.

Regulation (EU) No 305/2011 lays down harmonized conditions for marketing construction products in the European Union. One of its consequences has been the introduction of the product standard EN 50575 and standard EN 130501-6, concerning power, control, and communication cables permanently installed in buildings to prevent the risk of a fire and its consequences. EN 13501-6 provides the reaction to fire classifications for cables, the test methods to be performed, the requirements to meet a specific reaction to fire, and additional classifications for smoke production, flaming droplets, and acidity. EN 60754-2 is the technical standard used to assess acidity, and it defines three classes: a1, a2, and a3 (the less performant), based on pH and conductivity measurements. Due to the release of hydrogen chloride during the combustion, acidity is the weak point of PVC cables, which are not yet capable of achieving the a1 or a2 classes required in specific locations according to a fire risk assessment. EN 13501-6 does not include EN 60754-1. Both EN 60754-1 and EN 60754-2 are common standards for determining halogen gas content, acidity, and conductivity, respectively. They involve the same type of tube furnace but with different heating regimes, final temperatures, and detection methods. EN 60754-2 must be performed at temperatures between 935 – 965 °C. The paper demonstrates that, when EN 60754-2 is carried out with the thermal profile of EN 60754-1 or at 500 °C in isothermal conditions, the evolution of hydrogen chloride changes significantly if potent acid scavengers are utilized in the PVC compounds. The reason lies behind the kinetic of hydrogen chloride release during the combustion of PVC compounds: the higher the temperature or faster the heat release, the quicker hydrogen chloride evolution and the lower the probability for the acid scavenger to trap it. That further highlights the "fragility" of EN 60754-2 as a tool for assessing the risks associated with the release of hydrogen chloride in case of fire

Polycyclic aromatic hydrocarbons (PAHs) have been reported to cause oxidative stress in metabolic processes. This study aimed to evaluate the relationship between exposure to PAHs, including benzo[a]pyrene (BaP) and 1-nitropyrene (1-NP), in the atmosphere and oxidative stress levels in the human body. This study included 44 Korean adults who lived in Cheongju, South Korea. Atmospheric BaP and 1-NP concentrations and urinary 6-hydroxy-1-nitropyrene (6-OHNP), N-acetyl-1-aminopyrene (1-NAAP), and 1-hydroxypyrene (1-OHP) concentrations were measured. The oxidative stress level was assessed by measuring urinary thiobarbituric acid reactive substances (TBARS) and 8-hydroxydeoxyguanosine (8-OHdG) concentrations. Urinary TBARS and 6-OHNP concentrations significantly differed between winter and summer. BaP exposure was significantly associated with urinary 8-OHdG concentrations in summer. However, atmospheric 1-NP did not show a significant correlation with oxidative stress marker concentrations. Urinary 1-NAAP concentration was a significant determinant for urinary 8-OHdG concentration in summer. Oxidative stress in the body increases in proportion to inhalation exposure to BaP, and more 8-OHdG is produced in the body as the amount of 1-NP, which is metabolized to 1-AP or 1-NAAP, increases.

The human polyamines spermine and spermidine are essential for cell function, and their properties have been extensively studied. However, research results of experiments conducted without understanding the properties of polyamines have been evaluated and published by reviewers who appear to have little knowledge of the properties of polyamines. It is sad that some studies repeat what was done more than half a century ago before polyamines were characterized. First, I explain the basic properties of polyamines that researchers need to know. Then, the relationship between changes in polyamine levels in the body and age- and lifestyle-related diseases is discussed. In addition, the epigenetic mechanism of action of polyamines in relation to healthy longevity and, conversely, age- and lifestyle-related diseases and the progression of senescence are discussed. Spermine, which increases with a polyamine-rich diet, acts to suppress aberrant gene methylation and proinflammatory status associated with aging. Meanwhile, chronic inflammation associated with aging induces the enzyme activity of spermine oxidase, which breaks down spermine and produces acrolein, resulting in reduced spermine levels. Acrolein, a toxic aldehyde that increases with age- and lifestyle-related diseases, is thought to accelerate these diseases.

Tapping panel dryness (TPD) syndrome is a complex disease of Rubber tree (Hevea brasiliensis L.) which causes cessation of latex drainage upon tapping of rubber tree. Rubber tree virus (RTV1) was identified as a novel pathogen associated with rubber tree and a potential causal agent of TPD. RTV1 is a monopartite RNA virus that is linear, non-enveloped and has a single-stranded (ss) positive RNA genome of approximately 6081 nucleotides and is composed of two major open reading frames (ORFs), ORF1 (polyprotein), and ORF2 (movement protein. This study aimed to investigate the possibility of rubber genome encoded tree microRNAs (miRNAs) as novel therapeutic targets against RTV1 using in silico algorithms. Mature rubber tree miRNAs are retrieved from the miRBase database and are used for hybridization of RTV1 using five different five different computational algorithms including miRanda, RNA22, RNAhybrid and psRNATarget. A total of eleven common rubber tree miRNAs were identified based on consensus genomic positions. The consensus of four algorithms predicted the hybridization sites of hbr-miR396a and hbr-miR398 at common locus positions 6676, 1840 respectively. To validate the prediction, secondary structures of the consensual rubber tree miRNAs and free energy of duplex binding were calculated using the RNAfold and RNAcofold algorithms respectively. We created a plot between rubber tree miRNAs and RTV1 ORFs by using Circos algorithm. In this study, we predicted eleven consensual rubber tree miRNAs. Among these miRNAs, hbr-miR398 was identified as the most effectual miRNA that may target the ORF1 gene of the RTV1 genome. The predicted data will be important in the development of rubber trees resistant to RTV1.

Like 18F-FDG, 99mTc-1-thio-D-glucose (99mTc-TG) also binds to GLUT receptors. The aim of this Phase I study was to evaluate the safety, biodistribution and dosimetry of 99mTc-TG. Twelve lym-phoma patients were injected with 729±102 MBq 99mTc-TG. Whole-body planar imaging was per-formed in 10 patients at 2, 4, 6 and 24 h after injection. In all 12 patients SPECT/CT (at 2 h) and SPECT (at 4 and 6 h) imaging was performed. Vital signs and possible side effects were monitored during imaging and up to 7 days after injection. 99mTc-TG injections were well tolerated and no side effects or alterations in blood and urine analyses data were observed. The highest absorbed dose was in the kidneys and urinary bladder wall, followed by the adrenals, prostate, bone mar-row, lungs, myocardium, ovaries, uterus, liver and gall bladder wall. 99mTc-TG SPECT/CT re-vealed foci of high activity uptake in the lymph nodes of all nine patients with known nodal le-sions. Extranodal lesions were detected in all nine cases. In one patient, a lesion in the humerus head, which was not detected by CT, was visualized using 99mTc-TG. Potentially, 99mTc-TG SPECT can be considered as an additional diagnostic method for imaging GLUT receptors in lymphoma patients.

In the present study, we studied the effect of apolipoprotein A-1 (APOA1) on the spatial and molecular characteristics of bone marrow adipocytes, using well-characterized ApoA1 knockout mice. APOA1 is a central regulator of high-density lipoprotein cholesterol (HDL-C) metabolism, and thus HDL; our recent work showed that deficiency of APOA1 increases bone marrow adiposity in mice. We found that ApoA1 deficient mice have greatly elevated adipocytes within their bone marrow compared to wild type counterparts. Morphologically, the increased adipocytes were similar to white adipocytes, and displayed proximal tibial-end localization. Marrow adipocytes from wild type mice were significantly fewer and did not display bone-end distribution pattern. The mRNA levels of the brown/beige adipocyte-specific markers Ucp1, Dio2, Pat2, Pgc1a, and the expression of leptin were greatly reduced in the ApoA1 knock-out in comparison to the wild-type mice. In the knock-out mice adiponectin was remarkably elevated. In keeping with the close ties of hematopoietic stem cells and marrow adipocytes, we found that the elevated adiposity in the ApoA1 knock out mice is associated with a significant reduction of the hematopoietic stem cells and common myeloid, but not common lymphoid, progenitors. Moreover, the “beiging”-related marker osteopontin and the angiogenic factor VEGF were also reduced in the ApoA1 knock-out mice, further supporting the notion that APOA1, and most probably HDL-C, regulate bone marrow microenvironment, favouring beige/brown adipocyte characteristics.

We study the μ-μ45-T phase diagram of the 2+1-dimensional Gross-Neveu model, where μ denotes the ordinary chemical potential, μ45 the chiral chemical potential and T the temperature. We use the mean-field approximation and two different lattice regularizations with naive chiral fermions. An inhomogeneous phase at finite lattice spacing is found for one of the two regularizations. Our results suggest that there is no inhomogeneous phase in the continuum limit. We show that a chiral chemical potential is equivalent to an isospin chemical potential. Thus, all results presented in this work can also be interpreted in the context of isospin imbalance.

The Grand Ethiopian Renaissance Dam (GERD), formerly known as the Millennium Dam, is currently under construction and has been filling at a fast rate without sufficient known analysis on possible impacts on the body of the structure. The filling of GERD not only has an impact on the Blue Nile Basin hydrology, water storages and flow but also pose massive risks in case of collapse. Rosaries Dam located in Sudan at only 116 km downstream of GERD, along with the 20 million Sudanese benefiting from that dam, would be seriously threatened in case of the collapse of GERD. In this study, through the analysis of Sentinal-1 satellite imagery we show concerning deformation patterns associated with different sections of the GERD’s Main Dam (structure RCC Dam type) and the Saddle Dam (Embankment Dam type). We processed 109 descending mode scenes from Sentinel-1 SAR imagery, from December 2016 to July 2021, using the Differential Synthetic Aperture Radar Interferometry technique to demonstrate the deformation trends of both - the GERD’s Main and Saddle Dams. The time-series generated from the analysis clearly indicates different displacement trends at various sections of the GERD as well as the Saddle Dam. Results of the multi temporal data analysis on and around the project area show inconsistent subsidence at the extremities of the GERD Main Dam, especially the west side of the dam where we recorded varying displacements in the range of 10 mm to 90 mm at the crest of the dam. We conducted the current analysis after masking the images with a coherence value of 0.9 and hence, the subsequent results are extremely reliable and accurate. Further decomposition of the subsiding rate has revealed higher vertical displacement over the west side of the GERD’s Main Dam as compared to the east side. The local geological structures consisting of weak zones under the GERD’s accompanying Saddle Dam adds further instability to its structure. We identified seven critical nodes on the Saddle Dam that match the tectonic faults lying underneath it, and which display a varying degree of vertical displacements. In fact, the nodes located next to each other displayed varying displacement trends: one or more nodes displayed subsidence since 2017 while the other node in the same section displayed uplift. The geological weak zones underneath and the weight of the Saddle Dam itself may somewhat explain this inconsistency and the non-uniform vertical displacements. For the most affected cells, we observed a total displacement value of ~90 mm during the whole study period (~20 mm/year) for the Main Dam while the value of the total displacement for the Saddle dam is ~380 mm during the same period (~85 mm/year). Analysis through CoastSat tool also suggested a non-uniformity in trends of surface water-edge at the two extremities of the Main Dam.

The aim of this study was to build a tool to analyze, using artificial intelligence, the sentiment perception of users who answered two questions from the CSQ – 8 questionnaires with raw Spanish free-text. Their responses are related to mindfulness, which is a novel technique used to control stress and anxiety caused by different factors in daily life. As such, we proposed an online course where this method was applied in order to improve the quality of life of health care professionals in COVID 19 pandemic times. We also carried out an evaluation of the satis-faction level of the participants involved, with a view to establishing strategies to improve fu-ture experiences. To automatically perform this task, we used Natural Language Processing (NLP) models such as swivel embedding, neural networks and transfer learning, so as to classify the inputs into the following 3 categories: negative, neutral and positive. Due to the lim-ited amount of data available - 86 registers for the first and 68 for the second - transfer learning techniques were required. The length of the text had no limit from the user’s standpoint, and our approach attained a maximum accuracy of 93.02 % and 90.53 % respectively based on ground truth labeled by 3 experts. Finally, we proposed a complementary analysis, using com-puter graphic text representation based on word frequency, to help researchers identify relevant information about the opinions with an objective approach to sentiment. The main conclusion drawn from this work is that the application of NLP techniques in small amounts of data using transfer learning is able to obtain enough accuracy in sentiment analysis and text classification stages

Immunotherapy has been considered for years as a viable and attractive treatment option for patients with cancer. Among immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionized the treatment of several subtypes of tumours. These approaches aimed at restoring an effective anti-tumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells, and the clinical development of monoclonal antibodies targeting checkpoint receptors. Leading therapies in solid tumours are mainly focused on the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed-death 1 (PD-1) pathways. These approaches have found a promising testing ground in both Hodgkin lymphoma and non-Hodgkin lymphoma, mainly because in these diseases the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Although several trials have already demonstrated evidence of therapeutic activity with some checkpoint inhibitors in lymphoma, many of the immunologic lessons learned from solid tumours may not directly translate to lymphoid malignancies. In this sense, the mechanisms of effective antitumor responses are different between the different lymphoma subtypes, while the reasons for this substantial difference remain partially unknown. This review will discuss the current advances of immune-checkpoint blockade therapies in B-cell lymphoma and will build a projection of how the field may evolve in the near future. In particular, we will analyze the current strategies being evaluated both preclinically and clinically with the aim to foster the use of immune-checkpoint inhibitors in non-Hodgkin lymphoma, including combination approaches with chemotherapeutics, biological agents and/or different immunologic therapies.

Promoter choice is an essential consideration for transgene expression in gene therapy. The expression of multiple genes requires ribosomal entry or skip sites, or the use of multiple promoters. Promoters systems comprised of two separate, divergent promoters may significantly increase the size of genetic cassettes intended for use in gene therapy. However, an alternative approach is to use a single, compact bidirectional promoter. We identified strong and stable bidirectional activity of the RPBSA synthetic promoter comprised of a fragment of the human Rpl13a promoter, together with additional intron / exon structures. The Rpl13a-based promoter drove long-term bidirectional activity of fluorescent proteins. Similar results were obtained for the EF1-α and LMP2/TAP1 promoters. However, in a lentiviral vector, the divergent bidirectional systems failed to produce sufficient titres to translate into an expression system for dual chimeric antigen receptors (CAR) expression. Although bidirectional promoters show excellent applicability to drive short RNA in Sleeping Beauty transposon systems, their possible use in the lentiviral applications requiring longer and more complex RNA, such as dual CAR cassettes, is limited.

Neuroinflammation, defined as inflammatory reactions mediated by cytokines, chemokines, reactive oxygen species, and secondary messengers in the central nervous system (CNS) including the brain and spinal cord is the basis of many neurological disorders. Recently, erythropoietin (EPO) has been considered and studied as a modulator of neuroinflammation. On this article minireview of pathophysiology of neuroinflammation and the neuroprotective effects of EPO is discussed and a case of subacute huge subdural hematoma with double mydriasis operated urgently, treated with low daily dose (vs high dose once or twice a month in the literature) of EPO and recovered fully and discharged home with good consciousness is reported. In addition, the probable unfavorable outcome of erythropoietin administration in patients with neuroinflammation in COVID-19 is considered.

Either stereo reactants or stereo catalysis from achiral or chiral molecules are prerequisite to obtain pure enantiomeric lipid derivatives. We reviewed a few plausible organic syntheses of phospholipids under prebiotic conditions with a special attention to the starting materials as pro-chiral dihydroxyacetone and dihydroxyacetone phosphate (DHAP), which are the key molecules to break symmetry in phospholipids. The advantages of homochiral membranes compared to those of heterochiral membranes were analysed in term of specific recognition, optimal functions of enzymes, membrane fluidity and topological packing. All biological membranes contain enantiomeric lipids in modern bacteria, eukarya and archaea. The contemporary archaea, comprising of methanogens, halobacteria and thermoacidophiles are living under extreme conditions reminiscent of primitive environment and may indicate the origin of one ancient evolution path of lipid biosynthesis. The analysis of lipid metabolism reveals that all modern cells including archaea synthetize enantiomeric lipid precursors from prochiral DHAP. sn-glycerol-1-phosphate dehydrogenase (G1PDH), usually found in archaea, catalyses the formation of sn-glycerol-1-phosphate (G1P), while sn-glycerol-3-phosphate dehydrogenase (G3PDH) catalyses the formation of sn-glycerol-3-phosphate (G3P) in bacteria and eukarya. The selective enzymatic activity seems to be the main strategy that evolution retained to obtain enantiomeric pure lipids. The occurrence of two genes encoding for G1PDH and G3PDH, served to build up an evolution tree and the basis of our review focusing on the evolution of these two genes. Gene encoding for G3PDH in Eukarya may originate from G3PDH gene found in rare archaea indicating that archaea appeared earlier in the evolution tree than eukarya. Archaea and bacteria evolved probably separately, due to their distinct respective genes coding for G1PDH and G3PDH. The suggested hypothesis is that catalysis of homochiral G1P or G3P from DHAP are more efficient than those leading to racemic G1P and G3P, since there are no enzymes able to synthesize racemic G1P and G3P from DHAP. We propose that G1PDH or G3DPH, which are not “image mirror enzymes” but belonging to distinct family of proteins, emerged separately during evolution. They were probably selected for their efficient catalytic activities during evolution from large libraries of vesicles containing various biopolymers, including amino acids, carbohydrates, nucleic acids, lipids, and meteorite components to induce chemical imbalance.

The premise regarding COVID-19 disease is that it is a spectrum which begins with infection with viral SARS-CoV-2 exposure via airborne or oral virus particles. The individual response to it depends on many factors including co-morbid conditions. An important aspect of SARS-CoV-2 virus infection is the cytokine storm that develops after the infection. The immuno-chemical chaos created in this cytokine storm is to the benefit of the virus. In this meta analysis the authors explore ways to let the cytokine storm die down by looking into the role of histamine. Histamine is a metabolic product of the essential aminoacid histidine. Histamine has 4 known receptors: H1, H2, H3 and H4. The immunoglobulines IgE and IgM are indicative for a COVID-19 infection. This immune response is related to inflammation. Inflammation, in turn, runs mainly via histamine after e.g. virus inoculation. The goal of the meta-study is to gather evidence to primarily block the H4 receptor (H4R) in gastrointestinal cells to diminish the cytokine overproduction in the $\approx$ 30\% of the patients suffering from gastrointestinal problems caused by SARS-CoV-2. Our concept is as follows. If we can strike a careful balance between hampering the gastrointestinal spreading of the virus and histamine antagonists to tackle the cytokine storm, then the natural immunity can later on come on line again and attack the virus without being led astray by cytokine chaos. We will concentrate on H4R but also look at H1R and H2R related effects. The proposed substances in our systemic approach can be balanced for an effective early treatment. The nature of our work is by its method and results theoretical. In that respect we also may note the structural chemistry indol skeleton resemblance among a number of different drugs.

For any odd positive integer $x$, define $(x_n)_{n\geqslant 0} $ and $(a_n )_{n\geqslant 1} $ by setting $x_{0}=x, \,\, x_n =\cfrac{3x_{n-1} +1}{2^{a_n }}$ such that all $x_n $ are odd. The 3x+1 problem asserts that there is an $x_n =1$ for all $x$. Usually, $(x_n )_{n\geqslant 0} $ is called the trajectory of $x$. In this paper, we concentrate on $(a_n )_{n\geqslant 1} $ and call it the E-sequence of $x$. The idea is that, we consider any infinite sequence $(a_n )_{n\geqslant 1} $ of positive integers and call it an E-sequence. We then define $(a_n )_{n\geqslant 1} $ to be $\Omega-$convergent to $x$ if it is the E-sequence of $x$ and to be $\Omega-$divergent if it is not the E-sequence of any odd positive integer. We prove a remarkable fact that the $\Omega-$divergence of all non-periodic E-sequences implies the periodicity of $(x_n )_{n\geqslant 0} $ for all $x_0$. The principal results of this paper are to prove the $\Omega-$divergence of several classes of non-periodic E-sequences. Especially, we prove that all non-periodic E-sequences $(a_n )_{n\geqslant 1} $ with $\mathop {\overline {\lim } }\limits_{n\to \infty } \cfrac{b_n }{n}>\log _23$ are $\Omega-$divergent by using the Wendel's inequality and the Matthews and Watts's formula $x_n =\cfrac{3^n x_0 }{2^{b_n }}\prod\limits_{k=0}^{n-1} {(1+\cfrac{1}{3x_k })} $, where $b_n =\sum\limits_{k=1}^n {a_k } $. These results present a possible way to prove the periodicity of trajectories of all positive integers in the 3x + 1 problem and we call it the E-sequence approach.

Vitamin D and ω-3 fatty acids (ω-3) co-supplementation potentially improve type 1 diabetes (T1D) by attenuating autoimmunity and counteracting inflammation.This cohort study preliminary to a randomized control trial (RCT) is aimed to evaluate, in a series of T1D children assuming Mediterranean diet and taking cholecalciferol 1000U/day fromT1D onset, if ω-3 co-supplementation preserves the residual endogen insulin secretion (REIS).Therefore, 22 new onsets of 2017 received ω-3 [eicosapentenoic acid (EPA) plus docosahexaenoic acid (DHA), 60mg/kg/day], and were compared retrospectively vs. 37 previous onsets without ω-3 supplementation. HbA1c%, daily insulin demand (IU/Kg/day) and IDAA1c, a composite index (calculated as IU/Kg/dayx4 + HbA1c%) as surrogate of REIS, were evaluated at recruitment (T0) and 12 months later (T12). In the ω-3 supplemented group, dietary intakes were evaluated at T0 and T12. As outcome, decreased insulin demand (p<0.01), particularly pre-meal boluses (p<0.01), and IDAA1c (p<0.05), were found in the ω-3 group while HbA1c% were not different in the two groups. Diet analysis, at T12 vs. T0, showed that the intake of arachidonic acid (AA) was decreased (p<0.01) in the ω-3 supplemented group while other nutrients were unchanged; at T0, the AA intake was inversely correlated with HbA1c% (p<0.05; r;.0.411). In conclusion, the results suggest that vitamin D plus ω-3 co-supplementation and AA reduction in Mediterranean diet display benefits for T1D children and deserve further investigation.

The XChem facility at Diamond Light Source offers fragment screening by X-ray crystallography as a general access user program. The main advantage of X-ray crystallography as a primary fragment screen is that it yields directly the location and pose of the fragment hits, whether within pockets of interest or merely on surface sites: this is the key information for structure-based design and for enabling synthesis of follow-up molecules. Extensive streamlining of the screening experiment at XChem has engendered a very active user programme that is generating large amounts of data: in 2017, 36 academic and industry groups generated 35,000 datasets of uniquely soaked crystals. It has also generated a large number of learnings concerning the main remaining bottleneck, namely obtaining a suitable crystal system that will support a successful fragment screen. Here we discuss the practicalities of generating screen-ready crystals that have useful electron density maps, and how to ensure they will be successfully reproduced and usable at a facility outside the home lab.

Akt1 is a proto-oncogene that is over active in most cancers. Akt1 activation requires phosphorylation at Thr308; phosphorylation at Ser473 further enhances catalytic activity. Akt1 activity is also regulated via interactions between the kinase domain and the N-terminal auto-inhibitory pleckstrin homology (PH) domain. As it was previously difficult to produce Akt1 in site-specifically phosphorylated forms, the contribution of each activating phosphorylation site to auto-inhibition was unknown. Using a combination of genetic code expansion and in vivo enzymatic phosphorylation, we produced Akt1 variants containing programmed phosphorylation to probe the interplay between Akt1 phosphorylation status and the auto-inhibitory function of the PH domain. Deletion of the PH domain increased the enzyme activity for all three phosphorylated Akt1 variants. For the doubly phosphorylated enzyme, deletion of the PH domain relieved auto-inhibition by 295-fold. We next found that phosphorylation at Ser473 provided resistance to chemical inhibition by Akti-1/2 inhibitor VIII. The Akti-1/2 inhibitor was most effective against pAkt1T308 and showed 4-fold decreased potency with Akt1 variants phosphorylated at Ser473. The data highlight the need to design more potent Akt1 inhibitors that are effective against the doubly phosphorylated and most pathogenic form of Akt1.

Chloracne is the major skin symptom caused by dioxin intoxication. Dioxin activates the aryl hydrocarbon receptor (AHR)–cytochrome p450 1A1 (CYP1A1) system, generates oxidative stress, and induces hyperkeratinization of keratinocytes and sebocytes leading to chloracne. Nuclear factor-erythroid 2-related factor-2 (NRF2) is a master switch inducing expression of various antioxidative enzymes such as heme oxygenase-1. Cinnamaldehyde is an antioxidant phytochemical that inhibits AHR–CYP1A1 signaling and activates the NRF2–antioxidative axis. The cinnamaldehyde-containing Kampo herbal medicine Keishibukuryogan is capable of improving chloracne in Yusho patients who are highly contaminated with dioxin. Agents with dual functions in promoting AHR–CYP1A1 inhibition and NRF2 activation may be useful in managing dioxin-related health hazards.

The turnover of the RNA molecules is determined by the rates of transcription and RNA degradation. Several methods have been developed to study mRNA turnover since the beginnings of molecular biology. Here we summarize the main methods to measure RNA half-life: transcription inhibition, gene control and metabolic labelling. These methods were used to detect the cellular activity of the mRNAs degradation machinery, including the exo-ribonuclease Xrn1 and the exosome. Less progress has been made in the study of the differential stability of mature RNAs because the different methods have often yielded inconsistent results so that an mRNA considered to be stable can be classified as unstable by another method. Recent advances in the systematic comparison of different method variants in yeast have permitted the identification of the least invasive methodologies that reflect half-lives the most faithfully, which is expected to open the way for a consistent quantitative analysis of the determinants of mRNA stability.

Food allergies are common worldwide and have become a major public health concern; more than 220 million people are estimated to suffer from food allergies worldwide. On the other hand, polyphenols, phenolic substances found in plants, have attracted attention for their health-promoting functions, including their anti-allergic effects. In this study, we examined the potential inhibitory effects of 80% ethanol extracts from 22 different vegetables on the degranulation process in RBL-2H3 cells. Our aim was to identify vegetables that could prevent and treat type I allergic diseases. We found strong inhibition of degranulation by the extracts of perilla and chives. Furthermore, we verified the respective efficacy via animal experiments, which revealed that the anaphylactic symptoms caused by ovalbumin (OVA) load were alleviated in OVA allergy model mice that ingested vegetable extracts of perilla and chives. These phenomena were suggested to be caused by induction of suppression in the expression of subunits that constitute the high-affinity IgE receptor, particularly the α-chain of FcεR I. Notably, the anti-allergic effects of vegetables that can be consumed daily are expected to result in the discovery of new anti-immediate allergenic drugs based on the components of these vegetables.

Age-related macular degeneration (AMD) is an eye disease and the most common cause of vision loss in the Western World. In its advanced stage, AMD occurs in two clinically distinguished forms: dry and wet, but only wet AMD is treatable. However, the treatment based on repeated injections with vascular endothelial growth factor A (VEGFA) antagonists may at best stop the disease progression and prevent or delay vision loss but without an improvement of visual dysfunction. Moreover, it is a serious mental and financial burden for patients and may be linked with some complications. The recent first success of intravitreal gene therapy with ADVM-022, which transformed retinal cells to continuous production of aflibercept, a VEGF antagonist, after a single injection, has opened a revolutionary perspective in wet AMD treatment. Promising results obtained so far in other ongoing clinical trials support this perspective. In this narrative/hypothesis review, we present basic information on wet AMD pathogenesis and treatment, the idea of gene therapy in retinal diseases, update evidence on completed and ongoing clinical trials with gene therapy for wet AMD, and perspectives on the road to the clinic of “one and done” therapy for wet AMD to replace a lifetime of injections. Gene editing targeting the VEGFA gene is also presented as another gene therapy strategy to improve wet AMD management.

Abstract Big datasets are becoming increasingly common and can be challenging to understand and apply in public health. One method for lowering the dimensionality of these datasets and improving interpretability while minimizing information loss is data reduction using principal component analysis (PCA). It achieves this by successively maximizing variance through the creation of new, uncorrelated variables. PCA is an adaptive data analysis technique because it simplifies the process of finding new variables, or principal components, by solving an eigenvalue or eigenvector problem. These new variables are determined by the dataset being used, rather than by the analyst starting from scratch. It is also adaptable in another way because varieties of the method have been designed to adjust to various data structures and types. However, there are serious problems in the theoretical understanding and practical application of PCA in public health researchers, whereas its application is becoming popular in developing countries. Therefore, this article, which concentrated on using PCA to reduce data, began by outlining the fundamental concepts of PCA and going over what it can and cannot do, as well as when and how to use it. We also discussed the fundamental assumptions, benefits, and drawbacks of PCA. Furthermore, this article demonstrated and resolved PCA practical application problems in public health that most scholars are unaware of, such as variable preparation, variable inclusion and exclusion criteria for PCA, iteration steps, wealth index analysis, interpretation, and ranking.

Background. Type 2 diabetes mellitus (T2DM) is becoming a major global health concern, especially in poorer nations. The high prevalence of obesity and the ensuing diabetes I attributed to rapid economic progress, physical inactivity, consumption of high-calorie foods, and changing lifestyles. Objectives. We investigated the role of interleukins-10 , 19 and 22 with varying levels of obesity in T2DM in the Asir region of Saudi Arabia. Materials and methods. 170 confirmed T2DM patients and a control group were enrolled. The demographic data, serum levels of IL-10, IL-19, and IL-22, and biochemical indices were assessed in patients and control groups by standard procedures. Results. T2DM patients were divided into four groups: A (normal body weight), B (Overweight), C (obese), and D (highly obese). Both male and female T2DM subjects in Group A showed significant decreases in IL-10 levels as compared to controls; however, there were insignificant changes in IL-10 levels in Groups C and D. T2DM patients in groups C and D, in both males and females, depicted very significant (p 0.001) increases in IL-19 levels as compared to controls and group A. Patient groups A to D displayed a progressive elevation of Il-22 levels irrespective of gender, although significant alterations were seen only in groups B to D, with p 0.05 for group B and p 0.01 for groups C and D respectively, as compared to healthy controls. Conclusions. IL-10 showed a strong relationship with T2DM in males with varying degrees of obesity, but females depicted relatively higher IL-10 levels in obese and highly obese groups, pointing to a protective phenomenon. IL-19 levels showed significant increases in all four groups, irrespective of gender. IL-22 appears to be unrelated to T2DM per se but shows an association with varying degrees of obesity.

In recent years there has been increasing interest in the discovery of new natural herbal remedies for the treatment of common conditions such as diabetes and inflammatory diseases. In this context, this paper analyzed the antidiabetic and anti-inflammatory potential of two plants of the genus Artemisia: Artemisia absinthium (wormwood) and Artemisia vulgaris (mugwort) and Trigonella foenum-graecum (fenugreek) plants less studied from this point of view. Thus, hydroal-coholic extracts (50% EtOH v/v, 10% mass) were made, which were processed by membrane technologies, micro- and ultrafiltration, in order to concentrate the biologically active principles. The extracts were then analyzed in terms of content in active principles of interest (polyphenols, flavones). The antidiabetic activity of the extracts was analyzed by testing their ability to inhibit α-amylase and α-glucosidase and the anti-inflammatory activity by testing the ability to inhibit hyaluronidase (HYA) and lipoxygenase (LOX). Thus, the T. foenum-graecum extracts showed a high inhibitory activity on α-amylase 3.22 ± 0.3 g / mL (compared to the standard used - IC50 acarbose = 3.5 g / mL) and a high inhibitory activity on LOX: 19.69 ± 0.52 g/mL (compared to all standards used). The concentrated extract of Artemisia vulgaris showed increased activity of inhibition of α-amylase - IC50 = 8.57 ± 2.31g/mL and moderate activity of inhibition of HYA - IC50 = 17.18 g/mL compared to ibuprofen, the standard used - IC50 = 5.73 g/mL. The concentrated extract of Artemisia absinthium showed a pronounced activity of inhibition of LOX - IC50 = 19.71 g / mL, compared to the standard - rutin - IC50 = 22.34 g/mL).

Helicobacter pylori is a gastric pathogen that infects nearly half of the global population and is recognized as a group 1 carcinogen by the Word Health Organization. The global rise in antibiotic resistance has increased clinical challenges in treating H. pylori infections. Biofilm growth has been proposed to contribute to H. pylori’s chronic colonization of the host stomach, treatment failures, and the eventual development of gastric diseases. Several components of H. pylori have been identified to promote biofilm growth, and several of these may also facilitate antibiotic tolerance, including the extracellular matrix, outer membrane proteins, the coccoid morphology, modulated metabolism, efflux pumps, and virulence factors. Recent developments in therapeutic approaches targeting H. pylori biofilm have shown that synthetic compounds, such as small molecule drugs and plant-derived compounds, are effective at eradicating H. pylori biofilms. These combined topics highlight the necessity for biofilm-based research in H. pylori, to improve current H. pylori targeted therapeutic approaches and alleviate relative public health burden. In this review we discuss recent discoveries that have decoded the life cycle of H. pylori biofilms and current biofilm targeted treatment strategies.

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative treatment modality, frequently applied in patients suffering from haematological malignancies. In the last two decades, there have been multiple randomised controlled trials (RCTs), review articles, and meta-analyses addressing the efficacy of rabbit anti-thymocyte globulin (r-ATG) as a graft-versus-host disease (GvHD) prophylaxis. Nevertheless, only a few aimed to compare the effectiveness of different r-ATG formulations. We performed a systematic literature review of articles published since 2017 to this day utilising PubMed, Scopus, Cochrane, and MEDLINE, with the main endpoints being prophylaxis of acute GvHD (aGvHD) and chronic GvHD (cGvHD). We subjected to scrutiny a total of 5 studies, of which 4 compared the differences between Thymoglobulin (ATG-T) and Grafalon (ATG-G), and 1 discussed the impact of ATG-T dose. Overall cGvHD, aGvHD grades II-IV, TRM, OS, NRM, LFS, relapse, overall infections, and EBV reactivation do not seem to be affected by the type of utilised rATG. However, data on aGvHD grades III-IV, GRFS, moderate-severe cGvHD, and CMV reactivation is conflicting. Through our research, we sought to summarise the most recent findings concerning r-ATGs in allo-HCT, and provide insight into the differences between the targets and origin of various ATG formulations.

The storage of biochemical information, which is a prerequisite for the development of the first cell, is an unsolved problem affecting all concepts of the origin of life. However, if the protected environment in the continental crust is taken into account, completely new possibilities emerge for identifying processes that may have been crucial for the formation of the first cell. Under this background, we can hypothesize that cellular life began, with a self-sustaining cycle of molecular reaction steps and information storage of peptide sequences in RNA in a crustal depth of approximately 1000 m. This cycle was made possible in an open system bound to gas-permeable tectonic fracture zones with a high proportion of CO₂ and/or N₂. It can be assumed that a large number of RNA-like molecular strands formed in the crustal environment, from which a special RNA was selected by flotation processes, which formed the basis of a proto-tRNA. The formation of peptides and vesicles in supercritical CO₂ and the chemical evolution of peptides have already been proven at conditions of the upper continental crust. The behavior of individual amino acids in connection with vesicle formation deserves special interest. Hydrophobic amino acids accumulate in the vesicle membrane, with their position in the membrane depending on the degree of hydrophobicity. Selection of a proto-tRNA with an acceptor arm ending with the bases CCA resulted in a distinctive property. The position of adenine at the tip of the acceptor arm permitted it to penetrate the membrane, allowing it to be linked to an amino acid at the 3'-OH position of the terminal ribose. The penetration depth was controlled by the hydrophobicity of the opposite anti-codon, with adenine always occupying the middle position for the hydrothermally formed hydrophobic amino acids. When the vesicle membrane was closely occupied by proto-tRNAs, the anti-codons acted as templates and stored the sequence of the peptides that form. In the cases of hydrophilic anti-codons, the acceptor arm does not reach far enough into the membrane. This allowed hydrophilic amino acids to be linked to 2´-OH.

Ophelia syndrome is characterized by the coincidence of severe neuropsychiatric symptoms, classical Hodgkin lymphoma, and the presence of antibodies to the metabotropic glutamate 5 receptor (mGluR5). Little is known about the pathogenetic link between these symptoms and the role that anti-mGluR5-antibodies play. We investigated lymphoma tissue from patients with Ophelia syndrome and with isolated classical Hodgkin lymphoma by quantitative immunocytochemistry for mGluR5-expression. Further, we studied the L-1236, L-428, L-540, SUP-HD1, KM-H2, and HDLM-2 classical Hodgkin lymphoma cell lines by FACS and Western blot for mGluR5-expression, and by transcriptome analysis. mGluR5 surface expression differed significantly in terms of receptor density, distribution pattern, and percentage of positive cells. Highest expression levels were found in the L-1236 line. RNA-sequencing revealed more than 800 genes that were higher expressed in the L-1236 line in comparison to the other classical Hodgkin lymphoma cell lines. High mGluR5-expression was associated with upregulation of PI3K/AKT and MAPK pathways and of downstream targets (e.g. EGR1) known to be involved in classical Hodgkin lymphoma progression. Finally, mGluR5 expression was increased in the classical Hodgkin lymphoma-tissue of our Ophelia syndrome patient in contrast to five classical Hodgkin lymphoma-patients without autoimmune encephalitis. Given the association of encephalitis and classical Hodgkin lymphoma in Ophelia syndrome, it is possible that mGluR5-expression on classical Hodgkin lymphoma cells not only drives tumor progression but also triggers anti-mGluR5 encephalitis even before classical Hodgkin lymphoma becomes manifest.

Mild cognitive impairment (MCI) and mild dementia are a clinically relevant health problem in the elderly and Alzheimer's disease being the most common neurodegenerative disorder. Furthermore, MCI and mild dementia are characterized by a deterioration of cognitive function and their diagnosis is mainly based on cognitive examination and, the prognosis of the disease seems to be an essential reason for the diagnosis, because there is a high risk of cognitive decline in the two syndromes. This review describes the effectiveness of Ginkgo biloba (EGb761®) leaf extract for the treatment of dementia syndrome and EGb761® combination therapy with other medications for symptomatic dementia. Tebonin® is a drug of plant origin based on the active ingredient “Ginkgo biloba”. This drug has shown encouraging results, improving cognitive function, neuropsychiatric disorders and consequent reduction of caregiver stress and maintenance of autonomy in patients with age-related cognitive decline, MCI and mild dementia. Nowadays, there is little evidence to support the efficacy of EGb761® combination therapy with anti-dementia drugs and, therefore, more evidence is needed to evaluate the role of EGb761® in mixed therapy.

SARS-CoV-2 is the betacoronavirus responsible for the COVID-19 pandemic. It was listed as a potential global health threat by WHO due to high mortality, high basic reproduction number and lack of clinically approved drugs and vaccines for COVID-19. The genomic sequence of the virus responsible for COVID-19, as well as the experimentally determined three dimensional structure of the Main protease (Mpro) are available. The reported structure of the target Mpro was utilized in this study to identify potential drugs for COVID-19 using molecular docking based virtual screening of all approved drugs. The results of this study confirm preliminary reports that some of the drugs approved for treatment of other viral infections have the potential for treatment of COVID-19. Selected antiviral drugs, approved for human therapeutic applications, were ranked for potential effectiveness against COVID-19, based on predicted binding energy to the target Mpro of SARS-CoV-2, and novel candidates for drug repurposing were identified in this study. In addition, potential mechanisms for beneficial off target effects of some drugs in clinical trials were identified by using molecular docking.

Abstract: The aim of this study is to emphasize on the clinical uses of amniotic membrane (AM) in multiple ocular disorders. AM possesses many properties including promotion of epithelialization, anti-fibrotic, anti-apoptotic, anti-angiogenic properties. Epithelial wound healing on the eye surface is promoted due to several epidermal and keratocyte growth factors as well as by its anti-inflammatory and anti-scarring effects due to interleukin-10, interleukin-1 receptor antagonists and inhibition of transforming growth factor- beta (TGF-β) signal transduction by AM in the corneal and conjunctival fibroblasts respectively. It plays a crucial role by functioning as a substitute of basement membrane (BM) and as a temporary graft material. It is not only being used as an eye graft but also its extract can be used as an eye drop for corneal and external eye diseases. So its proper preparation, preservation and clinical application can bring a revolutionary change in the treatment of different ocular disorders.

Background: Cardiovascular comparisons between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and Sodium-glucose co-transporter-2 (SGLT-2) inhibitors in type 2 diabetes(T2D) remain an area of interest. Thus, the purpose of this meta-analysis is to compare the impact of these two drug classes on major CV outcomes, such as heart failure hospitalization(HHF), major adverse cardiovascular events (MACE), CV mortality, myocardial infarction, stroke, and all-cause mortality, with an emphasis on heart failure hospitalizations. Methods: PubMed (including MEDLINE), Google Scholar, Cochrane Central Library, PLOSONE, and Science Direct databases were searched for studies that compared GLP-1 RAs and SGLT-2 inhibitors in patients with type 2 diabetes. Six cohort studies were selected for the analysis. Odds ratios (OR) with 95% CI were calculated and a random-effects model was used to estimate the hazard ratios (HR) of the studies. The quality of the studies was evaluated using the Newcastle-Ottawa Scale (NOS), and publication bias was assessed using funnel plots and Egger’s test. Results: Pooled analysis demonstrated a significant reduction in heart failure hospitalizations with SGLT-2 inhibitors compared to GLP-1 RAs (HR: 0.78 [0.62–0.98], I² = 87%, p < 0.01). Cardiovascular mortality was also significantly reduced by SGLT-2 inhibitors (HR: 0.74 [0.31–1.67], I² = 87%, p < 0.01), and a modest reduction was observed for all-cause mortality (HR: 0.85 [0.44–1.64], I² = 17%, p = 0.27). While SGLT-2 inhibitors appeared to slightly reduce the risk of myocardial infarction (HR: 0.83 [0.74–0.92], I² = 0%, p = 0.85), no significant difference was observed for MACE (HR: 0.91 [0.82–1.01], I² = 0%, p = 0.70) or stroke (HR: 0.88 [0.77–1.00], I² = 0%, p = 0.85). Conclusions: Compared to GLP-1 receptor agonists, SGLT-2 inhibitors were more effective in lowering heart failure hospitalizations and cardiovascular mortality in patients with type 2 diabetes. It was also found that all-cause mortality and myocardial infarction were moderately reduced using oral agents. However, the differences were not significant for MACE or stroke. These results imply that SGLT-2 inhibitors may potentially provide better cardiovascular benefits, especially with respect to heart failure and cardiovascular mortality, than GLP-1 RA. Further research should be conducted to determine the effects of the long-term use of these therapies on stroke and other cardiovascular events.

Human oncoviruses are able to subvert telomerase function in cancer cells through multiple strategies. The activity of the catalytic subunit of telomerase (TERT) is commonly enhanced in virus-related cancers. Viral oncoproteins, such as high-risk human papillomavirus (HPV) E6, Epstein-Barr virus (EBV) LMP1, Kaposi sarcoma-associated herpesvirus (HHV-8) LANA, hepatitis B virus (HBV) HBVx, hepatitis C virus (HCV) core protein and human T-cell leukemia virus-1 (HTLV-1) tax protein, interact with regulatory elements in the infected cells and contribute to the transcriptional activation of TERT gene. Specifically, viral oncoproteins have been shown to bind TERT promoter, to induce post-transcriptional alterations of TERT mRNA and to cause epigenetic modifications, which have important effects on the regulation of telomeric and extra-telomeric functions of the telomerase. Other viruses, such as herpesviruses, operate by integrating their genomes within the telomeres or by inducing alternative lengthening of telomeres (ALT) in non-ALT cells. In this review, we recapitulate recent findings on virus-telomerase/telomeres interplay and the importance of TERT-related oncogenic pathways activated by cancer causing viruses.

The article describes the rational for inhibition of the angiotensin-converting enzyme 2 (ACE2) pathways as specific targets in patients infected by SARS-CoV-2 in order to prevent the establishment of positive feedback loops triggered by COVID-19 in some predisposed subjects. Making use of a large quantity of published reports in which human/rodent ACE2 pathway inhibitors were administered in vivo, it is hypothesized a possible therapeutic pharmacological intervention through an inhibition strategy of the zinc metalloprotease ACE2 and its downstream pathway for SARS-CoV-2 patients. Of even more interest, metal (zinc) chelators and renin inhibitors (both FDA approved drugs) may also work alone or in combination in inhibiting the positive feedback loops, initially triggered by COVID-19 and subsequently sustained by hypoxia independently on viral trigger, when both arms of renin-angiotensin system (ACE2 and ACE) are upregulated, leading to critical, advanced and untreatable stages of the disease.

Manzamines are complex polycyclic marine-derived β-carboline alkaloids with reported anticancer, immunostimulatory, anti-inflammatory, antibacterial, antiviral, antimalarial, neuritogenic, hyperlipidemia and atherosclerosis suppression bioactivities, putatively associated with inhibition of glycogen synthase kinase-3, cyclin-dependent kinase 5, and vacuolar ATPases. We hypothesized that additional and yet undiscovered molecular targets might be associated with Manzamine A (MZA) reported pharmacological properties. We report herein for the first time to our knowledge that MZA inhibited a 90kDa ribosomal protein kinase S6 (RSK1) when screened against a panel of 30 protein kinases. Furthermore in vitro RSK kinase assays demonstrated a 10-fold selectivity in potency of MZA against RSK1 versus RSK2. MZA’s differential binding and selectivity toward the two isoforms is also supported by computational docking experiments. Specifically, the RSK1-MZA (N- and C-termini) complexes appear to have stronger interactions and preferable energetics contrary to the RSK2-MZA ones. In addition, our computational strategy suggests that MZA binds to the N-terminal kinase domain of RSK1 rather than the C-terminal domain. RSK is a vertebrate family of cytosolic serine-threonine kinases that act downstream of the ras-ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway, which phosphorylates substrates shown to regulate several cellular processes including growth, survival and proliferation. Consequently, our findings have lead us to hypothesize that MZA and the 80 currently known manzamine-type alkaloids isolated from several sponge genera, may have novel pharmacological properties.

This study employs a bibliometric analysis of the emerging trends in the area of Money Laundering for Ter-rorism Financing to provide direction for future research in the area. The authors used VOSviewer and an-alysed 2577 published documents generated from the SCOPUS search using the PRISMA methodology. The findings reveal a growing research interest in this area, with a focus on understanding the complex inter-play between money laundering and terrorism financing. Emerging trends such as the use of cryptocurren-cies, trade-based money laundering, and the role of non-profit organizations in facilitating these activities are highlighted. The research contributes to the broader understanding of money laundering for terrorist financing by providing insights into the evolving research landscape and identifying areas for future re-search.

Rationale: A wide range of bioactive phytoconstituents from edible fungi, especially therapeutic mushrooms, have the potential to improve health, especially in the case of chronic illnesses. Known for its anti-cancer qualities, ganoderma lucidum has been the focus of multiple clinical studies. Existing systematic reviews imply that more clinical research and methodological refinement are necessary to support its usage as a primary cancer treatment.Objective: The objective of this research is to evaluate the anti-cancer potential of the bioactive phytoconstituents found in mushrooms, specifically Ganoderma lucidum, in a thorough manner. The aim is to conduct a critical assessment of the extant literature, pinpoint any deficiencies, and offer valuable perspectives on the methodological excellence and research requirements in this domain.Method(s): A thorough analysis of published clinical trials was carried out, with a focus on studies that examined the effectiveness of Ganoderma lucidum and other products derived from mushrooms in treating cancer. The study's design, stated results, and methodological rigor were all carefully examined to evaluate the validity and reliability of the conclusions.Results: Despite Ganoderma lucidum's potential against cancer, the evaluation finds insufficient data to support its widespread usage as a primary cancer treatment. Products made from mushrooms, which are frequently sold as dietary supplements, have anti-cancer claims. But since pre-approval is not required under US regulatory framework in order to market food supplements, these statements raise questions regarding their scientific validity.Conclusions/Recommendations: The study's result emphasizes the necessity of more methodological advancement in clinical studies examining Ganoderma lucidum's potential as an anti-cancer agent. It also highlights the significance of thorough scientific validation for goods made from mushrooms that make health claims. To establish accurate claims regarding their anti-cancer effects, recommendations include developing technological methods for the purification of bioactive substances and undertaking thorough studies of mushroom products from different geographical regions. The goal of this thorough analysis is to direct future investigations and support the ethical promotion and use of products derived from mushrooms for medical purposes.

The realization of a BRST cohomology of the 4D topological gauge-affine gravity is established in terms of a superconnection formalism. Identification of fields in the quantized theory is occurred directly as usual in terms of superconnection and its supercurvature components with the double covering of the general affine group GA¯(4,R). Then, by means of an appropriate decomposition of the metalinear double-covering group SL¯(5,R) with respect to the general linear double-covering group GL¯(4,R) one can easily obtain the enlargements of the fields while remaining consistent with the BRST algebra. This leads to the descent equations allowing us to build the observables of the theory by means of the BRST algebra constructed using a sa¯(5,R) algebra-valued superconnection. In particular, we discuss the construction of topological invariants with torsion.

Pachychoroid neovasculopathy (PNV) is a pachychoroid-spectrum disease. As blood circulation throughout the choroid may be involved in PNV pathogenesis, analysis using ultra-wide-field (UWF) fundus imaging is crucial. We evaluated choroidal thickness after half-fluence photodynamic therapy (PDT) combined with intravitreal aflibercept injection for PNV using UWF swept-source optical coherence tomography. Seventeen eyes with PNV that underwent half-fluence PDT with adjuvant single intravitreal aflibercept injection were analyzed. To compare choroidal thicknesses in the central and peripheral choroids, we set subfields <3, <9, and 9–18 mm from the fovea. The <9- and 9–18-mm subfields were divided into four quadrants. Choroidal thickness in each subfield decreased significantly after half-fluence PDT (P<0.001); this reduction was more pronounced in the central area. We also investigated the relationship between the dominant side of the deep choroidal veins that harbor choroidal vein efflux from the macula. When choroidal thickness in the supratemporal and infratemporal 9x9-mm subfields were evaluated, the ratio of choroidal thickness reduction was not significantly different between the dominant and non-dominant sides. The dominant side was not associated with the extent of choroidal thickness reduction in PNV. In conclusion, half-fluence PDT caused thinning of the entire choroid, especially in the central area, in PNV.

A hallmark of Alzheimer’s disease (AD) are the proteinaceous aggregates formed by the amyloid-beta peptide (Aβ) that is deposited inside the brain as amyloid plaques. The accumulation of aggregated Aβ may initiate or enhance pathologic processes in AD. According to the amyloid hypothesis any agent that has the capability to inhibit Aβ aggregation and/or destroy amyloid plaques represents a potential disease modifying drug. In 2023, a humanized IgG1 monoclonal antibody (lecanemab) against the Aβ soluble protofibrils was approved by US FDA for AD therapy thus providing compelling support to the amyloid hypothesis. To acquire a deeper insight on the in vivo Aβ aggregation, various animal models, including aged herbivores and carnivores, non-human primates, transgenic rodents, fish and worms are widely exploited. This review is based on the recent data obtained using transgenic animal AD models and presents experimental verification of the critical role in Aβ aggregation seeding of the interactions between zinc ions, Aβ with the isomerized Asp7 (isoD7- Aβ) and the α4β2 nicotinic acetylcholine receptor.

Human epidermal growth factor receptor 2 (HER2) belongs to the ErbB family, a group of four transmembrane glycoproteins with tyrosine kinase activity, all structurally related to the epidermal growth factor receptor (EGFR). These tyrosine kinases are involved in the transmission of cellular signals controlling normal cell growth and differentiation. If this transmission goes awry, it can lead to dysregulated growth of the cell. HER2 specifically can be implicated in the pathogenesis of at least eight malignancies. HER2 positivity quickly became a well characterized indicator of aggressiveness and poor prognosis, with high rates of disease progression and mortality. After realizing the implication of HER2, it first became investigated as a target for treatment in breast cancer, and later expanded to areas of research in other cancers types. To this day, the most therapeutic advancements of anti-HER2 therapy have been in breast cancer, however, there have been strong advancements made in the incorporation of anti HER2 therapy in other cancer types as well. This comprehensive review dissects HER2 to its core incorporating the most up to date information. The topics touched upon are discussed in detail and up to 200 published sources from the most highly recognized journals have been integrated. The importance of knowing about HER2 is exemplified by the groundbreaking advancements that have been made, and the change in treatment plans it has brought to the oncological world in the last twenty years. Since, its ground breaking discovery there has been significant breakthroughs in knowledge regarding the actual receptor, the receptors biology, its mechanism of action, advancements in tests to detect HER2 and significant strides on how to best incorporate targeted treatment. Due to the success of this field thus far, the review concludes by discussing the future of novel anti-HER2 therapy currently in development that everyone should be aware of.

Biofilm formation and lipopolysaccharide (LPS) are implicated in the pathogenesis of gastrointestinal (GI) diseases caused by Gram-negative such as Escherichia coli and Salmonella enterica serovar Typhimurium. Grape seeds, wine industry by-products, have antioxidant, antimicrobial, and anti-inflammatory activities. In the present study, the protective effect of procyanidin-rich grape seed extract (prGSE), from unfermented pomace of Vitis vinifera cv Bellone, on bacterial LPS-induced oxidative stress and epithelial barrier integrity damages has been studied in a model of Caco-2 cells. The in vitro activity of prGSE against formation of biofilm of S. Typhimurium and E. coli, has been investigated. In vivo, prGSE activity using infected Galleria mellonella larvae has been evaluated. The results showed that the prGSE, if administered with LPS, can significantly reduce the LPS-induced permeability alteration. Moreover, the ability of the extract to prevent Reactive Oxygen Species (ROS) production induced by LPS treatment of Caco-2 cells has been demonstrated. prGSE inhibited the biofilm formation of E. coli and S. Typhimurium. In in vivo activity, increased survival of infected G. mellonella larvae after treatment with prGSE has been demonstrated. In conclusion, grape seed extracts could be used in the reduction of GI damage caused by bacterial endotoxin and biofilm of Gram-negative bacteria.

Though early-stage colorectal cancer has a high 5-year survival rate of 65-92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair proficient patients to immunotherapy.

A New monogalactosyldiacylglycerol (MGDG), a known monogalactosylmonoacylglycerol (MGMG) and a known polyunsaturated fatty acid methyl ester (PUFAME) were isolated from the marine dinoflagellate Karenia mikimotoi. The planar structure of the glycolipids was elucidated using MS and NMR spectroscopic analyses and comparisons to the known glycolipid to confirm its structure. The isolation of PUFAME strongly supports the polyunsaturated fatty acid fragment of these glycolipids. The relative configuration of the sugar was deduced by comparisons of 3JHH values and proton chemical shifts with those of known glycolipids. All isolated compounds MGDG, MGMG and PUFAME (1-3) were evaluated for their antimicrobial and anti-inflammatory activity. All compounds modulated macrophage responses, with compound 3 exhibiting the greatest anti-inflammatory activity.

The present review focuses on recent clinical trials that analyze the efficacy of intravitreal therapeutic agents for the treatment of dry age-related macular degeneration (AMD), such as neuroprotective drugs, and complement inhibitors, also called immunomodulatory or anti-inflammatory. A systematic literature search was performed to identify randomized controlled trials published prior to January 2019. Patients affected by dry AMD treated with intravitreal therapeutic agents were included. The changes in the correct visual acuity and the reduction in geographic atrophy progression were evaluated. Several new drugs have shown some promising results, including those targeting the complement cascade and agents called neuroprotective. The action potential of the two groups of drugs is to block the complement cascade model for immunomodulating agents, and prevent the degeneration and apoptosis of ganglion cells for the neuroprotectors, respectively. To the best of knowledge, and after extensive studies on the matter, there are still many investigations to be carried out on dry AMD in collaboration between researchers. They will have to identify truly effective molecules, understand the practical potential of pluripotent stem cells, and refine gene therapies. Only in-depth clinical trials will be able to allow the most appropriate and personalized treatments for each dry AMD patient.

A cursory look at Indian prime time news tells us much about the tone and tenor of the people associated with it. Exaggerations, hyperbole, and tempers run wild and news anchors flail in theatrical rage. News channels and news editors display their ideological affiliations subliminally. These affiliations — a factor of personal political stance, funding bodies, and investors — lead to partisan bias in the framing of news and, in some cases, can easily translate into racial prejudice. In this paper, I examine news coverage related to Muslims in India. I study the coverage of two issues specifically– love jihad and triple talaq –in prime time English news of two channels – Times Now and Republic TV. My analysis of the content, tone, and tenor of their coverage shows that these channels propagate associations between Islam and backwardness, ignorance and violence through consistent employment of the following tropes – ‘Muslim women need to be saved from Muslim men’, ‘Hindu women need to be saved from Muslim men’, and ‘Muslims are not fully Indian – they are anti-national’. I place this study of news media within the current political climate in India and briefly touch on the conversations it guides and provokes. This is also a call for further analysis on this subject to examine and evaluate how discourse manipulates public conversations and policy decisions.

pending

Indoleamine 2,3-dioxygenase 1 (IDO1) and IDO2, originated from gene duplication before vertebrate diver-gence. While IDO1 has a well-defined role in immune regulation, the biological role of IDO2 remains unclear. Discovered in 2007, IDO2 is located near the IDO1 gene. Because of their high sequence similarity, IDO2 was initially thought to be a tryptophan (Trp)-degrading enzyme like IDO1. Differently from what expected, IDO2 displays extremely low catalytic activity toward Trp. Nevertheless, many studies, often contradictory, tried to demonstrate that IDO2 modulates immune responses by catabolizing Trp into kynurenine, a hypothesis un-convincing and, let’s say, linked to the first life of IDO2. Here, we review its “new life”, the one in which IDO2 has a functional role beyond Trp metabolism. The IDO2’s evolutionary persistence across species, despite be-ing almost inactive as an enzyme, suggests it has some relevant biological importance. IDO2 expression in human normal cells is poor, but significant in various cancers, with two prevalent SNPs. Overall, the com-parison of IDO2 to IDO1 as a Trp-degrading enzyme may have led to misunderstandings about IDO2’s true physiological and pathological roles. New insights suggest that IDO2 might function more as a signaling molecule, particularly in cancer contexts, and further studies could reveal its potential as a target for cancer therapy.

Background: Several GLP-1 receptor agonists (GLP-1 RAs) are used to treat type 2 diabetes (T2DM). Their cardio- and renal protective effects and substantial weight loss have been evident and progressively expanded their role in the American Diabetes Association (ADA) guidelines, which are endorsed by the European Association for the Study of Diabetes (EASD). The increased demand leads to a global shortage. Methods: We utilized a repeated cross-sectional design, drawing data from national prescribing databases, to analyze six GLP-1 RAs: Dulaglutide, Enatide, Liraglutide, Lisenatide, Semaglutide, and Tirzepatide. AutoRegressive Integrated Moving Average (ARIMA) models with exogenous variables were applied to assess trends over time and regions. Results: The prescription rates significantly differ between regions. Wales shows the highest prescribing for most GLP-1 RAs. The ARIMA models indicated a significant increase in their prescribing after ADA guidelines 2022 (e.g., Dulaglutide: Post-ADA effect of 15.22, 95% CI: [12.97, 17.47]). Following GLP-1 RAs shortages in July 2023, the prescribing rates, particularly for Semaglutide, increased (Shortage effect: 74.36, 95% CI: [71.92, 76.80]). Model diagnostics, including the Akaike Information Criterion (AIC) and Durbin-Watson statistics, confirmed the robustness of these trends. Conclusion: Informed decisions should be made by considering prescribing trends before and after important events such as the issuing of new guidelines or safety alerts.

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic progressive neurological disorder and shares many radiological and clinical features with other more prevalent myelopathies. Here, we quantified spinal cord and brain volumes in adults with HAM/TSP in comparison with healthy volunteers (HVs) and participants diagnosed with multiple sclerosis (MS). Clinical disability and MRI were assessed in 24 HVs, 43 HAM/TSP, and 46 MS participants. Spinal cord cross-sectional area (SCCSA) and brain tissue volumes were measured and compared. HAM/TSP participants had significantly lower SCCSA at C2-3 (54.0±8 mm2), C4-5 (57.8±8 mm2), and T4-9 (22.7±4 mm2) and significantly elevated brain white matter hyperintensity (WMH) fraction (0.004±0.008) was compared to HVs (C2-3: 69.4±8 mm2, C4-5: 75.1±9 mm2, T4-9: 34.1±4 mm2; all p &lt; 0.0001; and WMH: 0.0004±0.0007; p &lt; 0.001). In HAM/TSP, SCCSA at all levels but not WMH showed the significant correlation with clinical disability scores. Brain white matter hyperintensities in HAM/TSP, therefore, may not be related to clinical disability. SCCSA and WMH in our limited MS cohort were higher than the HAM/TSP cohort (67.6±8 mm2, 72.7±9 mm2, 33.4±5 mm2; p &lt; 0.0001). Principal component analysis suggested that SCCSA and WMH may be used to differentiated HAM/TSP from MS. Understanding these differences may help establish early diagnostic criteria for HAM/TSP patients.

Smith-Magenis syndrome is a complex neurobehavioral genetic disorder. The spectrum of SMS phenotype is broad but commonly includes craniofacial, neurobehavioral, and otolaryngologic features. While the etiology of SMS is commonly attributed to one copy interstitial deletion in the 17p11.2 region (90-95% of cases), variants identified by sequence analysis in RAI1 have also been reported in 5-10% of cases. The phenotypic spectrum of patients with RAI1 sequence alterations is not clear. In this study, we report a 9-year-old male with global cognitive and psychomotor developmental delay, musculoskeletal and cardiovascular abnormalities, and dysmorphic craniofacial features. Whole genome quad analysis of the proband, unaffected parent, and unaffected brother identified a novel de novo RAI1:c.2736delC variant. This is the first report of this variant in the literature. This report also highlights the details of the genome analysis and this patient's phenotypic spectrum.

The catastrophic twin earthquakes that struck southern Turkey and northern Syria on February 6 2023, caused massive casualties and extensive damage to infrastructure, with the province of Hatay bearing the brunt of the impact. To investigate the potential of nighttime light (NTL) data for earthquake disaster assessment, we performed an analysis of pre- and post-earthquake NPP-VIIRS and SDGSAT-1 NTL data. The NTL change ratio (NCR) was employed to identify the extent of damage in Hatay Province following the earthquake to assess the impact on affected buildings and populations. NPP-VIIRS daily NTL Time-series data was used to establish an economic recovery framework for earthquake disasters in Hatay Province, assessing regional economic recovery after earthquake. The results revealed a strong correlation between the total reduced NTLs of NPP-VIIRS and SDGSAT-1 and the presence of severely and moderately damaged buildings. Conversely, the correlation with slightly damaged buildings was relatively weaker. Furthermore, the reduced NTLs of NPP-VIIRS provide a more precise identification of all earthquake damage compared to the SDGSAT-1 data, achieving an overall accuracy of 86.21% in earthquake damage identification and a Kappa coefficient of 0.72. In accordance with the earthquake economic recovery framework, as of the end of March 2024, neither the provincial economy nor any of its districts have fully restored to their pre-earthquake levels. The findings offered new and valuable insights into earthquake disaster assessment, assisting decision-makers in accurately assessing the level of disaster risk following an earthquake and efficiently allocating post-earthquake relief funds.

Traumatic brain injury (TBI) is an important global clinical issue, requiring not only prevention but also effective treatment. Following TBI, diverse parallel and intertwined pathological mechanisms affecting biochemical, neurochemical, and inflammatory pathways can have severe impact on the patient’s quality of life. The current review summarizes evidence for utility of amantadine in TBI in connection to its mechanism of action. Amantadine combining multiple mechanisms of action may offer both neuroprotective and neuroactivating effects in TBI patients. Indeed, use of amantadine in TBI has been encouraged by several clinical practice guidelines/recommendations. Amantadine is also available as infusion which may be of particular benefit in unconscious patients with TBI, due to immediate delivery to the central nervous system and the possibility of precise dosing. In other situations, orally administered amantadine may be used. There are several questions that remain to be addressed: Can amantadine be effective in disorders of consciousness requiring long-term treatment and in combination with drugs approved for treatment of TBI? Do the observed beneficial effects of amantadine extend to disorders of consciousness due to factors other than TBI? Well controlled clinical studies are warranted to ultimately confirm its utility in the TBI and provide answers these questions.

Digital weight-loss services (DWLSs) combining pharmacotherapy and health coaching have the potential to make a major contribution to the global struggle against obesity. However, there is currently no evidence to counter the widespread concern that these services enable large numbers of unsuitable patients to obtain Glucagon-like peptide-1 receptor agonists (GLP-1 RA). This study retrospectively analysed the rate at which the partner pharmacy network of Australia’s largest DWLS provider committed GLP-1 RA dispensing errors over a 6-month period. The analysis found that 191 (0.14%) of the 135131 dispensed Semaglutide orders contained an error. Non-compliant dose escalation (44.5%) and dispatch errors (32.5%) were the two most common error types. Most errors (89%) were deemed to have been of medium urgency, with 6.8% considered high urgency. A disproportionate number of high urgency cases were from wrong medication (31%) and general complaint errors (15%). A Chi-square test revealed a statistically higher dispensing error rate among orders to female patients (0.16%) compared to males (0.076%). The results lay an important foundation in digital pharmacy literature and suggest that comprehensive DWLSs have the potential to safely collaborate with third-party pharmacies in dispensing GLP-1 RAs.

The goal of the project was to understand how topography/bathymetry is imported and used in GeoFlood with an aim towards improving efficiency and computational cost of bathymetry handling in GeoFlood.GeoFlood is a software to simulate overland flooding basing on shallow water equations.Numerical methods and programming were used for this study.The GeoFlood was ran on a given data set (Malpasset data) and it was found out that indeed topography handling during simulations has to be improved to minimise the computational time and also improve the efficiency.Through this research, we also looked at the the shallow water equations, and the numerical techniques used to solve the equations

Background and Objectives: To assess femoral shaft bowing (FSB) in the coronal and sagittal planes and introduce the clinical implications of total knee arthroplasty (TKA) by analyzing a three-dimensional (3D) model with virtual implantation of the femoral component. Materials and Methods: Sixty-eight patients (average age: 69.1 years) underwent 3D model reconstruction, incorporating medullary canals, by importing computed tomography (CT) data into Mimics® software. A mechanical axis (MA) line was drawn from the midportion of the femoral head to the center of the intercondylar notch; proximal/distal straight centerlines (length, 60 mm; diameter, 1 mm) were placed in the center of the medulla canal. Acute angles between the two centerlines were measured as lateral and anterior bowing. The acute angle by distal centerline and MA line was measured as distal coronal and sagittal alignment in both anteroposterior (AP) and lateral views. The diameter of curve (DOC) of the medulla along the posterior border was measured. Results: The mean lateral bowing on the AP view was 3.71°, and the mean anterior bowing on the lateral view was 11.82°. The average DOC of the medullary canal was 1501.68 mm. The distal coronal alignment of all femurs was an average of 6.40°, and the distal sagittal alignment was 2.66°. Overall, 22 femurs had coronal bowing, 42 had sagittal bowing, and 15 had both. Conclusion: In Asians, FSB is present in coronal, sagittal, or both directions. Increased anterolateral FSB may lead to cortical abutment in the sagittal plane despite limited space in the coronal plane. During TKA, distal coronal alignment can guide distal femoral valgus cut angle, whereas distal sagittal alignment helps anticipate femoral component positioning, avoiding anterior notching. Osteotomy along the anterior cortical bone to prevent notching may result in outliers due to differences between distal sagittal alignment and distal anterior cortical axis.

Deep eutectic solvents (DESs) have emerged as viable alternatives to the toxic organic solvents. The most intriguing aspect of these solvents is perhaps the widely varying physicochemical properties emerging from the changes in the constituents that form DESs along with their composition. Based on the constituents, a DES can be hydro-philic/polar or hydrophobic/non-polar rendering vastly varying spectrum of polarity a possibility. DESs formed by mixing urea (U) with hydrated lanthanide salts, lanthanum nitrate hexahydrate (La : U), cerium nitrate hexahydrate (Ce : U), and gadolinium nitrate hexahydrate (Gd : U), respectively, exhibit very high polarity as manifested via probe-reported empirical parameters dipolarity/polarizability (π*). The highest π* of 1.70 exhibited by the DES (Gd : U) in 1 : 2 molar ratio is unprecedented. The π* ranges from 1.50 to 1.70 for these DESs, which is almost the highest reported for any solvent system. The π* decreases with increasing urea in the DES, however, the anomalous trends in H-bond donating acidity (α) and H-bond accepting basicity (β) appear to be due to the hydrated water of the lanthanide salt. The emission band maxima of fluo-rescence probe of “effective” dielectric constant (εeff) of the solubilizing media, py-rene-1-carboxaldehyde (PyCHO), in salt-rich DESs reflect higher cybotactic region di-polarity than even that offered by water. Probe Nile red aggregates readily in these DESs to form non-fluorescent H-aggregates; a characteristic of highly polar solvents. Behavior of probe pyranine also corroborates these outcomes as the (lanthanide salt : urea) DES system supports the formation of deprotonated form of the probe in the excited-state. The (lanthanide salt : urea) DES system offers solubilizing media of exceptionally high polarity, which is bound to expand their application potential.

Increasingly large numbers of people are using digital weight-loss services (DWLSs) to treat overweight or obesity. Although it is widely agreed that digital modalities improve access to care in general, obesity stakeholders remain concerned that many DWLSs are not comprehensive or sustainable enough to deliver meaningful health outcomes. This study adopted a mixed-methods approach to assess why and after how long patients tend to discontinue Austral-ia’s largest DWLS, a program that combines behavioural and pharmacological therapy under the guidance of a multidisciplinary care team. We found that in a cohort of patients who commenced the Eucalyptus DWLS between January and June 2022 (n=5604), mean program adherence was 171.2 (±158.2). Inadequate supply of a patient’s desired Glucose-like peptide-1 receptor agonist medication was the most common reason for discontinuation (43.7%), followed by program cost (26.2%), result dissatisfaction (9.9%), and service dissatisfaction (7.2%). Statistical tests revealed that ethnicity and age both had a significant effect on patient adherence. These findings suggest that DWLSs have the potential to improve access to comprehensive, continuous obesity care, but that care models need to improve upon the one observed in the Eucalyptus Australia DWLS to maximise program adherence.

Carbapenemase-producing Enterobacter spp. Serratia marcescens, Citrobacter freundii, Providencia spp. and Morganella morganii (CP-ESCPM) are increasingly identified as causative agents of nosocomial infections but are still not under systematic genomic surveillance. In this study, using a combination of whole genome sequencing and conjugation experiments, we sought to elucidate the genomic characteristics and transferability of resistance genes in clinical CP-ESCPM isolates from Bulgaria. Among the 36 sequenced isolates, NDM-1 (12/36), VIM-4 (11/36), VIM-86 (8/36) and OXA-48 (7/36) carbapenemases were identified; two isolates carried both NDM-1 and VIM-86. The majority of carbapenemase genes were found on self-conjugative plasmids. IncL plasmids were responsible for the spread of OXA-48 among E. hormaechei, C. freundii and S. marcescens. IncM2 plasmids were generally associated with the spread of NDM-1 in C. freundii and S. marcescens, and also of VIM-4 in C. freundii. IncC plasmids were involved in the spread of the recently described VIM-86 in P. stuartii isolates. IncC plasmids carrying blaNDM-1 and blaVIM-86 have been observed too. blaNDM-1 was also detected on IncX3 in S. marcescens and on IncT plasmid in M. morganii. The significant resistance transfer rates highlight the role of the ESCPM group as a reservoir of resistance determinants and stress the need for strengthening the infection control measures.

This study addresses the pressing need for flood extent and exposure information in data-scarce and vulnerable regions, with a specific focus on West Africa, particularly Senegal. Leveraging the Google Earth Engine (GEE) platform and integrating data from Sentinel-1 SAR, Global Surface Water, HydroSHEDS, Global Human Layer Settlement, and MODIS Land Cover, our primary ob-jective is to delineate flood extents and compare them with centennial flood-prone areas, offering a comprehensive assessment of exposure during the period from July to October 2022 across Sen-egal's 14 regions. The findings underscore a total inundation area of 2 951 square kilometers, impacting 297 142 people, 175 square kilometers of urban and 16 square kilometers of crops. Notably, August wit-nessed the largest flooded areas, reaching 780 square kilometers, constituting 0.40% of the coun-try's surface. Subsequent regions, including Saint-Louis, Ziguinchor, Fatick, and Matam, experi-enced varying extents of flooding, with August data showing a 1.34% overall overlap compared to centennial flood-prone areas derived from hydrological and hydraulic modeling. This low per-centage reveals the distinct purposes and natures of the two approaches (remote sensing and modeling), as well as their complementarity. Turning to flood exposure, August emerges as the most critical month, affecting 76 595 people (0.43% of the total population). Dakar, Diourbel, Thiès, and Saint-Louis regions bore substantial impacts, affecting 100 707, 57 648, 31 579, and 26 581 people, respectively. These findings emphasize the imperative for comprehensive disaster preparedness and mitigation efforts. The study provides a crucial national-scale perspective to guide Senegal's authorities in formulating effective flood management, intervention, and adaptation strategies.

Aims: This study aims to evaluate the impact of family-centered empowerment on Jordanian adolescents with type 1 diabetes (T1DM), focusing on their HbA1c levels, self-efficacy, and quality of life (QOL). Background: Poor glycemic management in adolescents with type 1 diabetes increases complications. Improved control is linked to various variables, but few studies focus on Middle Eastern populations. Methods: An experimental study involved 68 adolescents with T1DM visiting Jordanian Royal Medical Services' clinics. Two sets of participants were created: control (n = 34) and intervention (n = 34). Data was collected through face-to-face interviews and medical records. Results: The study found significant differences in self-efficacy scores between the intervention and control groups, with the intervention group experiencing a significant decrease in HbA1c readings and a significant difference in QOL between pre-program and post-program phases. Discussion: Family empowerment can significantly improve the lives of Jordanian teenagers with type 1 diabetes. This strategy leads to improved glycemic management, increased self-efficacy, and improved quality of life. Future treatments and health policies should recognize and value the critical role families play in the care of this population. Conclusion: The study suggests that patients with T1DM should receive continuous care education sessions, including self-care training, to improve their health. Nurses should also incorporate these training into treatment plans and educational programs for adolescents to enhance their QOL.

We report neutralization titer data against contemporary SARS-CoV-2 sublineages from an ongoing, open-label, phase 2/3 trial of a single 30-μg dose of monovalent Omicron XBB.1.5-adapted BNT162b2 vaccine. Healthy participants had previously received ≥3 doses of a US-authorized mRNA vaccine, with the most recent being a bivalent Omicron BA.4/BA.5-adapted vaccine administered ≥150 days before study vaccination. In this analysis, Omicron XBB.1.5, BA.2.86, and JN.1 serum neutralizing titers were assessed at baseline and 1 month after vaccination in a subset of ≥18-year-olds (N = 40) with evidence of previous SARS-CoV-2 infection. Immunogenicity was also evaluated in a demographically matched group of participants who received bivalent BA.4/BA.5-adapted BNT162b2 in another study (ClinicalTrials.gov Identifier: NCT05472038). The XBB.1.5-adapted BNT162b2 vaccine elicited higher XBB.1.5, BA.2.86, and JN.1 neutralizing titers than those elicited by bivalent BA.4/BA.5-adapted BNT162b2. Overall geometric mean fold rises in neutralizing titers from baseline to 1 month after vaccination were higher among participants who received XBB.1.5-adapted BNT162b2 than those who received bivalent BA.4/BA.5-adapted BNT162b2 for XBB.1.5 (7.6 vs 5.6), slightly higher for JN.1 (3.9 vs 3.5), and similar for BA.2.86 (4.8 vs 4.9). ClinicalTrials.gov Identifier: NCT05997290.

From a structural point of view, understanding interfacial electrostatic features of ligand-receptor complexes is crucial for biophysics-based design of therapeutics with improved efficacy and safety. Here, with a high-throughput structural feature extraction approach, this article reports a set of electrostatic structural features from glucagon-like peptide-1 (GLP-1) and GLP-1 receptor (GLP-1R) complex structures determined using experimental tools. Leveraging a set of computational structural biophysical analyses, this article systematically characterized the electrostatic interactions within the GLP-1-GLP-1R complexes with two sets of criteria to identify interfacial salt bridges and hydrogen bonds. Overall, the results here reveal intricate details of electrostatic interactions critical for GLP-1 binding to its receptor GLP-1R, providing biophysical insights into the stabilization of the GLP-1-GLP-1R complex structure and the molecular basis of GLP-1/GLP-1R signaling. Furthermore, the electrostatic structural features extracted from GLP-1 and GLP-1R complex structures are useful in the development of a machine learning-based ligand-receptor binding affinity calculating model, i.e., a GLP-1-GLP-1R-specific general intermolecular binding affinity calculator (GIBAC), paving the way for accelerated discovery and structure-based design of drug candidates targeting the GLP-1/GLP-1R system with improved efficacy and safety.

This study investigates the potential of natural compounds against HIV-1 protease, a critical enzyme in the replication cycle of human immunodeficiency virus type 1 (HIV-1). HIV-1 protease is essential for cleaving large precursor proteins into smaller functional proteins necessary for viral maturation and infectivity. Protease inhibitors, specifically targeting HIV-1 protease, effectively suppress viral replication, aiding in the management of HIV infection. Using the SWISS DOCK Server, several natural compounds were investigated for their potential as inhibitors of HIV-1 protease. Docking results revealed that Amentoflavone showed excellent binding affinity with high Estimated ΔG values, suggesting its potential as an inhibitor of HIV-1 protease. Additionally, Amentoflavone exhibited similar promising results when tested against Roussarcoma virus protease. These findings indicate the potential of Amentoflavone as a natural compound against HIV and warrant further investigation into its therapeutic applications.

In this paper, I introduce a new concept of representing numbers in base ; in other words, I have found new series for any number similar to series that could be written according to the collatz sequence which is called zi(n) in this article. These series need to end with 1. Then, we use two sets of rules to make a diagram which then proves the existence of such series for any number.In this diagram, by branching numbers into different branches in accordance to the modularity of 4 and continuing branching to the point that their numbers have enough common terms in their collatz series, we could reduce zi(n) to zi(k) so that k<n in any branch by Rule Number One. This diagram shows that zi(n) exists for every number, in other words, this proves the theorem (A) or zi-existence theorem. The proof of zi-existence theorem leads to a proof of the collatz conjecture because the collatz series could be written as a linear combination of such series that all of them end with 1, so the collatz series for any number ends with 1.

Renal uric acid (UA) reabsorption is mainly mediated by urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9). Dotinurad selectively inhibits URAT1 and do not inhibit other UA transporters such as GLUT9, ATP-binding cassette transporter G2 (ABCG2) and organic anion transporter1/3 (OAT1/3). We discovered that dotinurad improved metabolic parameters and renal function in hyperuricemic patients. We consider a significance of high selectivity in inhibiting URAT1 by dotinurad for metabolic syndrome, chronic kidney disease (CKD), and cardiovascular disease (CVD). Dotinurad inhibits selectively URAT1 and increases UA in the proximal tubules, and UA may compete with glucose for GLUT9, reducing glucose reabsorption. The inhibition of UA entry via URAT1 to liver and adipose tissues by dotinurad increased energy expenditure and decrease lipid synthesis and inflammation in rats. The inhibition of URAT1 in kidney, liver and adipose tissues improve metabolic parameters. CKD patients accumulate uremic toxins such as indoxyl sulfate (IS) in the body. ABCG2 regulates renal and intestinal excretion of IS which strongly affects CKD. OAT1/3 inhibitors suppress IS uptake into kidney, increasing plasma IS, which produces oxidative stress, inducing vascular endothelial dysfunction in CKD patients. The high-selective inhibition of URAT1 by dotinurad may be beneficial for metabolic syndrome, CKD and CVD.

This study investigates the therapeutic potential of new compound, potassium 2-[2-(2-oxo-4-phenylpyrrolidin-1-yl) acetamido]ethanesulfonate (Compound I), in depression. Willner's chronic unpredictable mild stress model of depression in 48 male Wistar rats was used a depression model. The rats were randomized into four groups, including an intact group, a Compound I group, a Fluoxetine group, and a control group receiving saline. Behavioral tests, such as the Porsolt forced swim test, hole-board test, elevated plus maze test, and light-dark box, were used to assess the animals' conditions. Our results demonstrated that Compound I effectively reduced the immobilization time of rats in the forced swim test, increased orientation and exploratory behavior, and decreased the latency period of going into the dark compartment compared to the control group. Hippocampal and striatal serotonin concentrations were increased in the Compound I group, and the compound also reduced the level of corticosterone in the blood plasma of rats compared to intact animals. These results suggest that Compound I has a reliable antidepressant activity, comparable to that of the reference antidepressant Fluoxetine.

We describe the development and validation of a HPLC-MS/MS method to assess the pharmacokinetics and tumour distribution of ZST316, an arginine analogue with inhibitory activity towards dimethylarginine dimethylaminohydrolase 1 (DDAH1) and vasculogenic mimicry, and its active metabolite L-257 in a xenograft model of triple negative breast cancer (TNBC). The method proved to be reproducible, precise, and highly accurate for the measurement of both compounds in plasma and tumour tissue following acute and chronic (five days) intraperitoneal administration of ZST316 (30mg/Kg daily) in six-week-old SCID mice inoculated with MDA-MB-231 TNBC cells. ZST316 was detected in tumour tissue and plasma after 1 hour (6.47 and 9.01M, respectively) and 24 hours (0.13 and 0.16M, respectively) following acute administration, without accumulation during chronic treatment. Similarly, the metabolite L-257 was found in tumour tissue and plasma after 1 hour (15.06 and 8.72M, respectively) and 24 hours (0.17 and 0.17M, respectively) following acute administration of ZST316, without accumulation during chronic treatment. The half-live after acute and chronic treatment ranged between 4.4-7.1hrs (plasma) and 4.5-5.0hrs (tumour) for ZST316, and 4.2-5.3hrs (plasma) and 3.6-4.9hrs (tumour) for L-257. The results of our study demonstrate the a) capacity to accurately measure ZST316 and L-257 concentrations in plasma and tumour tissue in mice using the newly developed HPLC-MS/MS method, b) rapid conversion of ZST316 into L-257, c) good intra-tumour penetration of both compounds, and d) lack of accumulation of both ZST316 and L-257 in plasma and tumour tissue during chronic administration. The new HPLC-MS/MS method is useful to investigate the in vivo effects of ZST316 and L-257 on vasculogenic mimicry, tumour mass, and metastatic burden in xenograft models of TNBC.