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In-silico study of approved drugs as potential inhibitors against 3CLpro and other viral proteins of CoVID-19

The global pandemic, due to the emergence of COVID-19, has created a public health crisis. It has a huge morbidity rate that was never comprehended in the recent decades. Despite numerous efforts, potent antiviral drugs are lacking. Repurposing of drugs presents a low-cost and rapid solution for finding new drugs by exploiting known drugs. In this study, we employed an integrated In-Silico approach using molecular docking and machine learning regression models to explore the potential inhibitors against key proteins of SARS-CoV-2. A library of 5903 drugs from the ZINC database was retrieved and screened against three crucial viral targets: Spike glycoprotein (7LM9), main protease 3CLpro (7JSU), and Nucleocapsid protein (7DE1). Binding affinities were predicted by using molecular docking, and subsequent predictive regression models, Decision Tree Regression (DTR), Gradient Boosting, XGBoost, Extra Trees, KNNR, and MLP, were constructed employing MACCS molecular fingerprints. Among them, the DTR model had better predictive performance, as indicated by the highest R² and lowest RMSE. The highest ranked compounds possessed good binding affinities (−12.6 to −19.7 kcal/mol) and favorable pharmacokinetics. Importantly, five novel candidate compounds, namely ZINC003873365, ZINC085432544, ZINC008214470, ZINC085536956, and ZINC261494640, had multi-target potential and optimal binding interaction. This computational analysis yields useful information for lead prioritization and sets the stage for additional in vitro and in vivo confirmation of these drug candidates to combat COVID-19.

Structure of lymphostatin, a large multi-functional virulence factor of pathogenic Escherichia coli

Abstract Lymphostatin is a key virulence factor of enteropathogenic and enterohaemorrhagic Escherichia coli , playing roles in bacterial colonisation of the gut and in the inhibition of lymphocyte proliferation and proinflammatory responses. The protein’s glycosyltransferase and cysteine protease motifs are required for activity against lymphocytes, but high-resolution structural information has proven elusive. Here, we describe the structure of lymphostatin from enteropathogenic E. coli O127:H6 , determined by electron cryo-microscopy at different pH values. We observe three conformations of a highly complex molecule with two glycosyltransferase domains, one PaToxP-like protease domain, an ADP-ribosyltransferase domain, a vertex domain and a delivery domain. Long linkers hold these domains together and occlude the catalytic sites of the N-terminal glycosyltransferase and protease domains. Lymphostatin binds to bovine T-lymphocytes and HEK-293T cells, forming clusters at the plasma membrane that are internalized. With six distinct domains, lymphostatin can be regarded as a multitool of pathogenic Escherichia coli , enabling complex interactions with host cells.

Domestication as the driver of lower chronic stress levels in fish in catch-and-release recreational fisheries and aquaculture versus wild conspecifics

The manipulation of species’ attributes through selective breeding can produce domesticated traits including decreased stress responses (i.e., selecting for high stress resilience). Common carp Cyprinus carpio (“carp”) have been domesticated for centuries, with domesticated forms frequently used to enhance recreational catch-and-release fisheries around the world. In Atlantic salmon Salmo salar (“salmon”), two primary strains are evident, a wild strain and domesticated aquaculture strain. Here, we compared scale cortisol concentrations (a biomarker of fish chronic stress levels) between domesticated carp in catch-and-release pond fisheries and wild carp in waters with no angling. Carp of low scale cortisol concentration were apparent in all sampled populations, suggesting individuals of low stress sensitivity are encountered in both wild and domesticated strains, and in natural and captive environments. Carp with relatively high levels of scale cortisol were, however, only present in wild carp, suggesting high phenotypic variability in their chronic stress responses, with some individuals being highly sensitive to stress. In some wild carp, elevated scale cortisol concentrations could also have been indicative of adaptive responses to their heterogenous environments. We then compared wild versus farmed salmon scale cortisol levels, and found a similar pattern, with relatively high scale cortisol levels only detected in wild fish. These results indicate that while domesticated carp and salmon are exposed to potentially stressful environments, they appear to have some resilience against the adverse effects of chronic stress.

Can a pill replace exercise? Swigging this molecule gives mice benefits of working out

Coordinated early immune response in the lungs is required for effective control of SARS-CoV-2 replication

Abstract Despite waning of virus-neutralizing antibodies, protection against severe SARS-CoV-2 in the majority of immune individuals remains high, but the underlying immune mechanisms are incompletely understood. Here, rhesus macaques with pre-existing immunity from Novavax WA-1 and/or P.1 vaccines and WA-1 or P.1 infection are immunized with a bivalent WA-1/Omicron BA.5 Novavax vaccine ten months after the last exposure. The boost vaccination primarily increases the frequency of cross-reactive spike (S)-specific antibodies and B cells instead of inducing de novo BA.5-specific responses. Reinfection with heterologous Omicron XBB.1.5 six months after the boost vaccination results in low levels of virus replication in the respiratory tract compared with virus-naïve results from other studies. Whereas systemic S-specific immunity remains largely unchanged in all animals, the animals with complete protection from infection exhibit a stronger influx of S-specific IgG, monocytes, B cells and T cells into the bronchioalveolar space combined with expansion of CD69+CD103+ lung tissue-resident, S-specific CD8 T cells compared to actively infected animals. Our results underscore the importance of localized respiratory immune responses in mediating protection from Omicron reinfection and provide guidance for future vaccine development.

Population attributable fraction of risk factors for anemia among children aged 6–59 months: A multilevel complex data analysis using modified poisson regression model in Sub-Saharan Africa

Background Anemia among children under five remains a significant public health concern in sub-Saharan Africa (SSA). While numerous studies have examined its associated factors, limited evidence exists on the public health impact of modifiable risk factors. This study assessed the population-attributable fraction (PAF) of risk factors for anemia among children aged 6–59 months across 27 SSA countries. Methods A secondary data analysis was conducted using Demographic and Health Survey (DHS) data from 27 SSA countries, including a weighted sample of 124,285 children. Data management and analysis were done using STATA-14 software. The presence of clustering was assessed using the Intra-cluster Correlation Coefficient (ICC), Median Odds Ratio (MOR), and Likelihood Ratio Test (LRT). A multilevel modified Poisson regression model was employed to estimate adjusted Prevalence Odds Ratios (aPOR) and the corresponding PAF with 95% Confidence Intervals (CI), and the Population Attributable Fraction (PAF) with the 95% CI was estimated using the aPOR and the prevalence of exposure. Results The overall prevalence of anemia among children in SSA was 61.99% (95% CI: 61.73, 62.27). Significant risk factors included maternal anemia (PAF = 7.37%), low maternal education (PAF = 5.86% for no formal education), poor household wealth status (PAF = 3.52% for the poorest), lack of media exposure (PAF = 0.76%), child undernutrition (stunting PAF = 1.31%, underweight PAF = 0.84%), diarrheal (PAF = 1.19%) and febrile illness (PAF = 2.26%), and unimproved toilet facilities (PAF = 1.02%). Conclusion Maternal anemia, low maternal educational status, poverty, poor sanitation, inadequate media access, unimproved toilet facilities, and childhood illness significantly contribute to anemia in SSA. Targeted interventions to improve maternal and child health, enhance education, and ensure better nutrition and sanitation could help reduce childhood anemia in the region.

Predictive goal coding by dentate gyrus somatostatin-expressing interneurons in male mice

Abstract To select appropriate behaviour, individuals must rely on encoding of relevant features within their environment in the context of current and past experiences. This function has been linked to goal-associated activity patterns of hippocampal principal cells. Using single-unit recordings from optogenetically identified somatostatin-expressing interneurons (SOMIs) in the dentate gyrus of head-fixed mice trained in a spatial goal-oriented reward-learning task in virtual realities, we show that SOMI activity temporally precedes reward-locations in expert mice characterized by goal-anticipatory behaviour. Predictive goal-encoding by SOMIs is lost after translocation of learned goals to novel previously unrewarded sites leading to rapid reductions in anticipatory behaviour and fast reconfiguration of SOMI activity to times after reward onset in association with reward consumption at novel goal-sites. Chemogenetic silencing of SOMIs caused a loss of memory that trained goal-sites were no longer available. Thus, our data reveal the ability of SOMIs to flexibly encode goal-locations depending on current and past experiences to bias behavioral outcomes.

Differential interactions of ToLCNDV with different betasatellites reveal complex viral dynamics in N. benthamiana

Tomato leaf curl New Delhi virus (ToLCNDV), a bipartite begomovirus prevalent in Old World and major cotton-growing regions of Pakistan, has increasingly been found associated with diverse betasatellites. Although betasatellites, small circular DNA satellites, are typically associated with monopartite begomoviruses, they are known to enhance disease severity (pathogenicity), increase viral DNA accumulation, and expand virus host ranges. This study investigated the interaction between ToLCNDV and three widely distributed betasatellites – cotton leaf curl Multan betasatellite strain Multan (Mβ), cotton leaf curl Multan betasatellite strain Burewala (Bβ) and tobacco leaf curl betasatellite (Tbβ) – in Nicotiana benthamiana plants, focusing on the potential emergence of novel viral combinations in cotton-growing regions. Infectious clones of ToLCNDV (either DNA-A [TA] alone or with DNA-B [TB]) were co-inoculated with each betasatellite clone. Results revealed intriguing complexity and variability in interactions: betasatellite with TA/TB affected TB accumulation, suggesting a competition between them, while TA levels increased only in the presence of TB, not apparently with Bβ. Interestingly, Tβ accumulated to the higher levels in plants, followed by Bβ and Mβ, highlighting betasatellite-specific interactions. These findings suggest that ToLCNDV-betasatellite interactions are more intricate than simple antagonism. The co-occurence of ToLCNDV with diverse betasatellites in cotton-growing regions of Pakistan increases the likelihood of the emergence of novel and potentially more pathogenic viral combinations. These intricate interactions have significant implications for understanding the dynamics of CLCuD disease.

Constitutive expression of the transcriptional co-activator IκBζ promotes melanoma growth and immunotherapy resistance

Abstract IκBζ, a rather unknown co-regulator of NF-κB, can either activate or repress a subset of NF-κB target genes. While its role as an inducibly expressed, transcriptional regulator of cytokines and chemokines in immune cells is established, IκBζ’s function in solid cancer remains unclear. Here we show that IκBζ protein is constitutively expressed in a subfraction of melanoma cell lines, and around 30% of all melanoma cases, independently of its mRNA levels or known mutations. Deleting IκBζ in melanoma abrogates the activity and chromatin association of STAT3 and NF-κB, thereby reducing the expression of the pro-proliferative cytokines IL-1β and IL-6, thus impairing melanoma cell growth. Additionally, IκBζ suppresses Cxcl9, Cxcl10, and Ccl5 expression via HDAC3 and EZH2, which impairs the recruitment of NK and CD8+ T cells into the tumor, causing resistance to α-PD-1 immunotherapy in mice. Thus, tumor-derived IκBζ may serve as a therapeutic target and prognostic marker for melanoma with high tumor cell proliferation, cytotoxic T- and NK-cell exclusion, and unfavorable immunotherapy responses.

The impact of 8-week re-training following a 14-week period of training cessation on Greco-Roman Wrestlers

Background This study aimed to examine the changes in physical and physiological conditions in elite wrestlers from the Turkish National Wrestling Team, who experienced 14 weeks of restricted physical activity during the COVID-19 lockdown, followed by an 8-week period of retraining and competition. Methods Twenty male elite wrestlers from the National Greco-Roman Wrestling Team participated in the research. Heart Rate Variability values were measured during the training cessation period and for 8 weeks of subsequent training and then interpreted for training periods with different workloads. Body fat percentage values, initially measured during training cessation, were recorded at 2-week intervals during the training period. To determine the fitness status of wrestlers, the Specific Wrestling Fitness Test was used before and following the 8 weeks of training period. Results A gradual decrease in both body fat percentage and weight was observed throughout the course of the training period. The SWFT scores showed significant improvements (31.40 ± 2.91 vs. 37.40 ± 3.22) following the training period. Heart rate variability decreased during the detraining period, progressively improved throughout the 8-week retraining, and subsequently declined during the competition phase, reaching levels similar to those observed during training cessation. Conclusions Our results suggest that athletes undergo identical reactions in their autonomous nervous system during both competition and training cessation period. Obtaining a comprehensive understanding of these changes can enable coaches and athletes to make accurate decisions in order to optimize training adaptations and attain overall athletic success. Furthermore, over a period of eight weeks following a long non-training period, significant improvements in athletes’ body fat, muscle mass and wrestling performance can be achieved along with training. Moreover, HRV monitoring revealed that autonomic nervous system balance was compromised during both the 14-week detraining and the subsequent competition phases, underlining the need for careful training load management to optimize recovery and performance readiness.

Prion-induced ferroptosis is facilitated by RAC3

Abstract Prions are infectious agents that initiate transmissible spongiform encephalopathies, causing devastating neuronal destruction in Creutzfeldt-Jakob and Kuru disease. Rapid cell death depends on presence of the endogenous prion protein PrPC, but its mechanistic contribution to pathogenesis is unclear. Here we investigate the molecular role of PrPC, reactive oxygen species and lipid metabolism in ferroptosis susceptibility, a regulated cell death process characterized by lipid peroxidation. We discover that elevated expression of the cellular prion PrPC creates a relaxed oxidative milieu that favors accumulation of unsaturated long-chain phospholipids responsible for ferroptotic death. This condition is sustained by the luminal protein glutathione peroxidase 8, which detoxifies reactive species produced by protein misfolding. Consequently, both PrPC and infectious Creutzfeldt-Jakob disease (CJD) prions trigger ferroptotic markers and sensitization. This lethality is further enhanced by RAC3, a small GTPase. Depletion of RAC3 is observed solely in pathologically afflicted cortices in CJD patients, revealing a synergistic modulation of lipids and reactive species that drives ferroptosis susceptibility. Together, the results show that PrPC initially suppresses oxidative stress, attenuates cellular defenses, and establishes a systemic vulnerability to the ferroptotic cascade. These results provide insight into the mechanism underlying regulation of ferroptosis in prion diseases and highlight potential therapeutic targets for diseases involving dysregulated cell death processes.

Transcriptomic sequencing and expression verification of identified genes modulating the alkali stress tolerance and endogenous photosynthetic activities of industrial hemp plant

Hemp (Cannabis sativa L.) has a long cultivation history around the world. In northeast part of China, the alkaline soil geology severely reduces crop production. In this study, we tried to evaluate the impacts of alkali-induced stress on the photosynthetic status and physiological indices of hemp plants. The microscopic evaluation of endogenous ultrastructure clearly demonstrated significant oxidative damage to the structure of the photosynthetic tissues associated with the membrane, resulting from an increase in the levels of MGDG and DGDG. The deformed photosynthetic apparatus induced by alkali-stress significantly inhibited the biosynthesis process of photosynthetic pigments, causing 49.25%, 52.72%, 65.31%, and 28.13% loss in total Chl, Chl a, Chl b, and carotenoids, respectively. Meanwhile, the reduction in chlorophyll fluorescence parameters (Pn (74.62%), Gs (39.69%), and Tr (83.77%)) along with the obviously increased MDA (28.57%) and H2O2 (35.18%) content exhibited that the inhibitory effect of alkali-stress not only decreased the photosynthetic efficiency by intercepting the nutrient supply but also generated excessive ROS, resulting in oxidative stress. Transcriptomic analysis (RNA-sequencing) revealed the considerably enriched GO terms as well as KEGG pathways that exposed the significant DEGs. The qPCR expression evaluation of down-regulated chlorophyll biosynthesis-related major genes (GOGAT (LOC115699366) and HEMA (LOC133032634)) and photosystem-related major genes (PSB (LOC115701338) and HCF (LOC115707994)) exhibited important molecular evidence for modulating the photosynthesis activity of hemp plant under devastating mechanism of alkali-stress. However, the transcript patterns of photorespiration-related genes (GOX (LOC115697365) and GDC (LOC115707082)) showed a slower decreasing trend at late stress stage (at 24 ~ 48 h), and the transcription of SGAT gene (LOC115699360) was even enhanced by stress treatment at 48 h, probably in an attempt to adjust cellular carbon balance and elevate the antioxidant properties induced by alkali-stress.

Resistance Gene-Guided Genome Mining Reveals RPL10 as the Target of Ligustrone A

Author Correction: Beta activity in human anterior cingulate cortex mediates reward biases

rbpTransformer: A novel deep learning model for prediction of piRNA and mRNA bindings

An important issue in biotechnology is predicting whether a piRNA and an mRNA will or will not bind. Research and treatment of diseases, drug discovery, and the silencing and regulation of genes, transposons, and genomic stability may all benefit from accurate binding predictions. The literature offers numerous deep-learning models for piRNA and mRNA binding prediction. However, a proper adjustment of the effective transformer model and the impact of important design alternatives has not been evaluated thoroughly. This paper summarizes the models available in the literature, briefly introduces transformers, then offers a novel deep learning model and evaluates various design alternatives, including k-mer size, number of core modules, choice of optimization algorithm, and whether to use self-attention. The results show that rbpTransformer can be a good candidate for building deep AI models to predict the binding of piRNA and mRNA sequences with an AUC value of 94.38%. The test results also reveal how the design affects the model’s accuracy.

Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy

The impact and return-on-investment of evidence-based practice in conservation and environmental management: A machine learning-assisted scoping review protocol

Evidence-based Practice (EBP) is a vital principle, with its origins in the 1970s, that has transformed the disciplines of medicine and healthcare. The use of best available evidence to inform decisions and best practice has since spread across other disciplines, including in the environmental sciences through evidence-based conservation and environmental management. However, ironically there only appears to be a single scoping review on the impacts and return-on-investment of EBP in healthcare and it is unclear whether any such evidence exists in the broad field of conservation and environmental management. In this scoping review, we aim to explore the extent to which evaluations of the impacts and return-on-investment of EBP and evidence use have been conducted in conservation and environmental management on both human and environmental outcomes. We will search at least ten different electronic bibliographic platforms, databases, and search engines for published and grey literature, from 1992 to 2025 – there will be no geographical or language restrictions on the documents included. A machine learning-assisted review process will be followed using open source tools (ASReview and SysRev) and following the comprehensive SYstematic review Methodology Blending Active Learning and Snowballing (SYMBALS). The findings from the scoping review will be useful to inform organisations and practitioners considering implementing EBP on its benefits and costs and will also highlight potential research gaps on the impact of EBP and evidence use.

AAV-based delivery of RNAi targeting ataxin-2 improves survival and pathology in TDP-43 mice

Clinical characteristics and outcomes of intraocular lens dislocation: an eight-year retrospective study

Objective To investigate the clinical characteristics, risk factors, and short-term visual outcomes following surgical management of intraocular lens (IOL) dislocation, aiming to inform risk stratification and individualized treatment strategies. Methods A retrospective analysis was conducted on 155 patients (166 eyes) diagnosed with IOL dislocation between 2016 and 2024. Data collected included demographic information, ocular and systemic risk factors, surgical interventions, uncorrected distance visual acuity (UDVA) before and after surgery, and postoperative complications. Comparative analyses were performed to assess the short-term efficacy and safety of different surgical approaches. Results The mean patient age was 55 years, with 86.75% presenting unilateral dislocation. Predominant risk factors identified were high myopia (38.55%) and prior vitrectomy (17.47%). A total of 89.16% of IOL dislocations were classified as late-onset. Of the 154 eyes that underwent surgical intervention, both IOL repositioning and exchange procedures resulted in significant improvements in UDVA (P < 0.05). Postoperative transient intraocular pressure elevations were observed without significant differences between surgical methods, resolving within three days in all cases. Conclusion High myopia and prior vitrectomy are significant risk factors for IOL dislocation. Surgical correction, whether through repositioning or exchange, is effective and safe, leading to substantial visual acuity improvements. Proactive identification and management of high-risk individuals are crucial for preventing IOL dislocation and optimizing patient outcomes.

Polymer microbubbles as universal platform to accelerate polymer mechanochemistry

Abstract The flow-induced activation of mechanophores embedded in linear polymers by ultrasound (US) suffers from slow mechanochemical conversions at the commonly used frequency of 20 kHz and in many cases remains ineffective with higher MHz frequencies. Here, we present polymeric microbubbles (PMBs) as a platform that accelerates the mechanochemical activation of several mechanophores under both 20 kHz and MHz irradiation. MHz irradiation generated by biocompatible high-intensity focused US (HIFU). Through their pressure-sensitive gas core, PMBs act as acousto-mechanical transducers for the transformation of sound energy into stretching and compression forces as well as fracturing the polymer shell by the volume oscillation of PMB. We investigate three different mechanophores among which one flex-activation derivative was unexpectedly activated by US. Through a combination of experiments and computation, we find that PMBs likely exert compressive force onto the copolymerized mechanophores rather than the typical elongational forces solvated chain fragments experience in flow. We thereby underscore the mechanochemical properties of the PMB platform and its versatility for accelerated mechanochemical transformations with a perspective on biomedical applications.