bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of Host Cell Serine Protease Inhibitor MM3122 against SARS-CoV-2 for Treatment and Prevention of COVID-19
Authors: Boon Adrianus C.M. , L. Bricker Traci , Fritch Ethan J. , Leist Sarah R. , Gully Kendra , Baric Ralph S. , Graham Rachel L. , Troan Brigid V. , Mahoney Matthew , Janetka James W. 
Published: February 2024

ABSTRACTWe have developed a novel class of peptidomimetic inhibitors targeting several host cell human serine proteases including transmembrane protease serine 2 (TMPRSS2), matriptase and hepsin. TMPRSS2 is a membrane associated protease which is highly expressed in the upper and lower respiratory tract and is utilized by SARS-CoV-2 and other viruses to proteolytically process their glycoproteins, enabling host cell receptor binding, entry, replication, and dissemination of new virion particles. We have previously shown that compound MM3122 exhibited sub nanomolar potency against all three proteases and displayed potent antiviral effects against SARS-CoV-2 in a cell-viability assay. Herein, we demonstrate that MM3122 potently inhibits viral replication in human lung epithelial cells and is also effective against the EG.5.1 variant of SARS-CoV-2. Further, we have evaluated MM3122 in a mouse model of COVID-19 and have demonstrated that MM3122 administered intraperitoneally (IP) before (prophylactic) or after (therapeutic) SARS-CoV-2 infection had significant protective effects against weight loss and lung congestion, and reduced pathology. Amelioration of COVID-19 disease was associated with a reduction in pro-inflammatory cytokines and chemokines production after SARS-CoV-2 infection. Prophylactic, but not therapeutic, administration of MM3122 also reduced virus titers in the lungs of SARS-CoV-2 infected mice. Therefore, MM3122 is a promising lead candidate small molecule drug for the treatment and prevention of infections caused by SARS-CoV-2 and other coronaviruses.IMPORTANCESARS-CoV-2 and other emerging RNA coronaviruses are a present and future threat in causing widespread endemic and pandemic infection and disease. In this paper, we have shown that the novel host-cell protease inhibitor, MM3122, blocks SARS-CoV-2 viral replication and is efficacious as both a prophylactic and therapeutic drug for the treatment of COVID-19 in mice. Targeting host proteins and pathways in antiviral therapy is an underexplored area of research but this approach promises to avoid drug resistance by the virus, which is common in current antiviral treatments.
Dengue severity by serotype and immune status in 19 years of pediatric clinical studies in Nicaragua
Authors: Narvaez Federico , Montenegro Carlos , Juarez Jose Guillermo , Zambrana José Victor , Gonzalez Karla , Videa Elsa , Arguello Sonia , Barrios Fanny , Ojeda Sergio , Plazaola Miguel , Sanchez Nery , Camprubí-Ferrer Daniel , Kuan Guillermina , Bailey Gabriela Paz , Harris Eva , Balmaseda Angel 
Published: February 2024

AbstractSummaryDengue, a major public health threat, is a viral infection spread by mosquitoes that can cause a range of symptoms from mild to life-threatening. Our study analyzed 19 years of data from two pediatric studies in children 2 to 17 years of age in Managua, Nicaragua. We aimed to understand how dengue severity varies with different serotypes of dengue virus (DENV1-4) and whether the child had a previous dengue infection. We found that DENV2 and DENV3 caused the most sever disease in children. DENV3 lead to sever outcomes in both primary (first-time) and secondary (repeat) infections, while DENV2 is particularly severe in secondary infections. These findings highlight the importance of a balanced dengue vaccine that can protect against all four virus strains, as current vaccines show varying effectiveness. Our research emphasizes the need for effective prevention and treatment strategies to manage dengue, particularly in regions where the virus is widespread.BackgroundDengue virus, a major global health threat, consists of four serotypes (DENV1-4) that cause a range of clinical manifestations from mild to severe and potentially fatal disease.MethodsThis study, based on 19 years of data from the Pediatric Dengue Cohort Study and Pediatric Dengue Hospital-based Study in Managua, Nicaragua, investigates the relationship of serotype and immune status with dengue severity. Dengue cases were confirmed by molecular, serological, and/or virological methods, and sudy participants 6 months to 17 years old were followed during their hospital stay or as ambulatory patients.ResultsWe enrolled a total of 15,266 participants, of whom 3,227 (21%) were positive for DENV infection. Of 2,630 cases with serotype result by RT-PCR, 557 corresponded to DENV1, 992 to DENV2, 759 to DENV3 and 322 to DENV4. Severe disease was more prevalent among secondary DENV2 and DENV4 cases, while similar disease severity was observed in both primary and secondary DENV1 and DENV3 cases. According to the 1997 World Health Organization (WHO) severity classification, both DENV2 and DENV3 caused a higher proportion of severe disease compared to other serotypes, whereas DENV3 caused the greatest percentage of severity according to the WHO-2009 classification. DENV2 was associated with increased odds of pleural effusion and low platelet count, while DENV3 was associated with both hypotensive and compensated shock.ConclusionsThese findings demonstrate differences in dengue severity by serotype and immune status and emphasize the critical need for a dengue vaccine with balanced effectiveness against all four serotypes, particularly as existing vaccines show variable efficacy by serotype and serostatus.
SARS-CoV-2 virus in Raw Wastewater from Student Residence Halls with concomitant 16S rRNA Bacterial Community Structure changes
Authors: Li Y. , Ash K. T. , Joyner D. C. , Williams D. E. , Hazen T. C. 
Published: February 2024

AbstractThe detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in sewage is well-established, but the concomitant changes in microbial compositions during the pandemic remain insufficiently explored. This study investigates the impact of the SARS-CoV-2 virus on microbial compositions in raw sewage, utilizing 16S rRNA sequencing to analyze wastewater samples collected from six dormitories over a one-year field trial at the University of Tennessee, Knoxville. The concentration of SARS-CoV-2 RNA was assessed using a reverse transcription-quantitative polymerase chain reaction. Significant variations in bacterial composition were evident across the six dormitories, highlighting the importance of independently considering spatial differences when evaluating the raw wastewater microbiome. Positive samples for SARS-CoV-2 exhibited a prominent representation of exclusive species across all dormitories, coupled with significantly reduced bacterial diversity compared to negative samples. The correlation observed between the relative abundance of enteric pathogens and potential pathogens at sampling sites introduces a significant dimension to our understanding of COVID-19, especially the notable correlation observed in positive SARS-CoV-2 samples. Furthermore, the significant correlation in the relative abundance of potential pathogens between positive and negative SARS-CoV-2 raw sewage samples may be linked to the enduring effects of microbial dysbiosis observed during COVID-19 recovery. These findings provide valuable insights into the microbial dynamics in raw sewage during the COVID-19 pandemic.
Restrained memory CD8+T cell responses favors viral persistence and elevated IgG responses in patients with severe Long COVID
Authors: Rodriguez Lucie , Tan Ziyang , Lakshmikanth Tadepally , Wang Jun , Barcenilla Hugo , Swank Zoe , Zuo Fanglei , Abolhassani Hassan , Pavlovitch-Bedzyk Ana Jimena , Wang Chunlin , Gonzalez Laura , Mugabo Constantin Habimana , Johnsson Anette , Chen Yang , James Anna , Mikes Jaromir , Kleberg Linn , Sundling Christopher , Björnson Mikael , Bonnier Malin Nygren , Ståhlberg Marcus , Runold Michael , Björkander Sophia , Melén Erik , Meyts Isabelle , Weyenbergh Johan Van , Hammarström Qian-Pan , Davis Mark M , Walt David R. , Landegren Nils ,   COVID Human Genetic Effort, Aiuti Alessandro , Casari Giorgio , Casanova Jean-Laurent , Jamoulle Marc , Bruchfeld Judith , Brodin Petter 
Published: February 2024

AbstractDuring the COVID-19 pandemic it was widely described that certain individuals infected by SARS-CoV-2 experience persistent disease signs and symptoms, Long COVID, which in some cases is very severe with life changing consequences. To maximize our chances of identifying the underpinnings of this illness, we have focused on 121 of the most severe cases from >1000 patients screened in specialized clinics in Sweden and Belgium. We restricted this study to subjects with objective measures of organ damage or dysfunction, >3 months following a verified, but mild-to-moderate SARS-CoV-2 infection. By performing systems-level immunological testing and comparisons to controls fully convalescent following a similar mild/moderate COVID-19 episode, we identify elevated serological responses to SARS-CoV-2 in severe Long COVID suggestive of chronic antigen stimulation. Persistent viral reservoirs have been proposed in Long COVID and using multiple orthogonal methods for detection of SARS-CoV-2 RNA and protein in plasma we identify a subset of patients with detectable antigens, but with minimal overlap across assays, and no correlation to symptoms or immune measurements. Elevated serologic responses to SARS-CoV-2 on the other hand were inversely correlated with clonally expanded memory CD8+T cells, indicating that restrained clonal expansion enables viral persistence, chronic antigen exposure and elevated IgG responses, even if antigen-detection in blood is not universally possible.
Thalamocortical network neuromodulation for epilepsy
Authors: Agashe Shruti , Alcala-Zermeno Juan Luis , Osman Gamaleldin M. , Starnes Keith , Brinkmann Benjamin H. , Sheffield Doug , Leyde Kent , Stead Matt , Miller Kai J. , Van Gompel Jamie J. , Worrell Gregory A. , Lundstrom Brian N. , Gregg Nicholas M. 
Published: February 2024

ObjectivesDespite the growing interest in network-guided neuromodulation for epilepsy, uncertainty about the safety and long-term efficacy of thalamocortical stimulation persist. Our evaluation focused on the use of a 4-lead open-loop implantable pulse generator (IPG) for thalamocortical network neuromodulation.MethodsWe retrospectively reviewed seven subjects with diverse seizure networks (SNs)—poorly localized, regional, or multifocal—undergoing thalamocortical neuromodulation. Employing a 4-lead system, electrodes targeted both thalamic and cortical SN nodes. We assessed seizure severity, life satisfaction, and sleep quality on a 10-point scale, and seizure frequency via telephone interviews and chart review. Six subjects underwent open-loop stimulation trials during intracranial EEG (iEEG) to confirm SN engagement and optimize settings, targeting the suppression of interictal epileptiform discharges (IEDs) and seizures. Outcomes were assessed by Wilcoxon sign-rank test, 0.05 significance level.ResultsAfter a median of 17 months post-implantation (range 13–60), subjects had a median disabling seizure reduction of 93% (range 50-100%, p=0.0156), with 100% responder rate (≥50% reduction in seizure frequency). The median improvement in seizure severity was 3.5 out of 10 points (p=0.0312), life satisfaction 4.5 points (p= 0.0312), and quality of sleep 3 points (p=0.062). No perioperative complications occurred. Rare transient seizure exacerbations and stimulation-related sensory/motor side effects resolved with parameter adjustments. One subject required surgical revision due to delayed infection. Six subjects had permanent electrode placement refined by iEEG trial stimulation; five subjects had >90% reduction in seizure frequency during iEEG stimulation.SignificanceThalamocortical network neuromodulation using a 4-lead open-loop system is safe, and is associated with significant improvements in seizure control and patient quality of life. Trial stimulation during iEEG shows promise for enhancing SN engagement and parameter optimization, but requires further study. Prospective controlled trials are needed to establish the validity of thalamocortical network neuromodulation for epilepsy.Key PointsThalamocortical neuromodulation with a 4-lead open-loop stimulation system is feasible and safe, and is associated with significant improvements in seizure control and life satisfaction.Trials of therapeutic stimulation during phase 2 iEEG monitoring has the potential to refine seizure network engagement and optimize stimulation parameters, for more effective chronic neuromodulation.Prospective controlled trials are needed to validate the efficacy of thalamocortical network neuromodulation.
Individual patterns of activity predict the response to physical exercise as an intervention in mild to moderate depression
Authors: Spulber Stefan , Ceccatelli Sandra , Forsell Yvonne 
Published: February 2024

AbstractPhysical exercise (PE) as antidepressive intervention is a promising alternative, as shown by multiple meta-analyses. However, there is no consensus regarding optimal intensity and duration of exercise, and there are no objective criteria available for personalized indication of treatment. The aims of this study were (1) to evaluate whether individual activity patterns before intervention can predict the response to treatment; and (2) to evaluate whether the patient outcome can be improved by using prior information on treatment efficacy at individual level. The study included subjects with mild to moderate depression randomized to three levels of exercise intensity in the Regassa study. Using a previously developed pipeline for data analysis, we have generated linear regression ensembles to predict the response to treatment using features extracted from actigraphy recordings. To understand the contribution of individual features, we performed a Bayesian analysis of coefficients, and found that different levels of PE intensity yield distinct signatures in enriched feature subsets. Next, we used the trained ensembles for a counterfactual analysis of response and remission rate provided prior knowledge of response to treatment outcome. The response to either PE regime was estimated for all patients, irrespective of original treatment assignment. Each patient was then virtually allocated to the PE regime predicted to yield best outcome, and the response and remission rates were compared against simulated random assignment to treatment. The counterfactual analysis showed that assignment to best individual PE regime yields significantly higher (increase by 28%) remission rates as compared to random assignment to treatment, which is accounted for by improved response in about 32% of the patients as compared to observed treatment outcome. While it is not possible to claim individual protocol optimization, our data suggest it may be possible to identify a PE regime to yield the best results for a patient based on individual circadian patterns of activity.
Association between altitude and death from COVID-19 in subjects with diabetes mellitus during the first wave: cross sectional study of the National Death Index
Authors: Ambrosio-Ojose Raúl Manuel , Casquero-Zambrano Cesar Josué , Vasquez-Hassinger Tery , Yovera-Aldana Marlon 
Published: February 2024

ABSTRACTBackgroundIn high Andean areas, there is greater insulin sensitivity which may be a protective factor against complications in subjects with diabetes mellitus.ObjectiveDetermine the association between altitude of residence and death from COVID-19 in deaths with diabetes mellitus in Peru during the first wave..MethodsWe carried out a cross-sectional analysis of deaths registered in the National Death System of Peru (SINADEF in Spanish). We selected Peruvians with diabetes mellitus identified by presenting the diagnosis in any of the six boxes on the certificate. The dependent variable was death from COVID-19 as the basic cause of death, located in last place among causes A, B, C and D according to the Pan American Health Organization. The independent variable was the altitude of residence, categorized as less than 1 500 m a.s.l, 1 500 to 2 499 m a.s.l. and greater than 2 500 m a.sl. Through a multilevel analysis by geographic region and using a Poisson regression, we obtained the risk ratios of death from COVID-19 according to the altitude of residence. We adjusted by individual and contextual variables.ResultsWe included 16 406 deaths with diabetes mellitus between March-December 2020. 34.3% died from Covid19 and 9.7% came from areas above 2 500 m. The proportion of deaths from COVID-19 of those with residence altitude above 2 500 m was 20% lower compared to residents below 1 500 m (RR: 0.80; 95% CI: 0.70 – 0.91; p<0.001), adjusted for individual and socioeconomic factors. Its influence is also shown as the altitude changes every 100, 250, 500 and 1000 m a.s.l., through multilevel analysis.ConclusionA higher altitude of residence is associated with a lower proportion of deaths from COVID-19 in people with diabetes mellitus during the first wave in Peru. The study contribute to expanding knowledge of the effects of altitude with respect to mortality in people with diabetes mellitus in a context of a highly contagious and virulent infectious disease.
Identification of Mitosis Stages Using Artificial Neural Networks for 3D Time Lapse Cell Sequences
Authors: Dincer Tolga , Stegmaier Johannes , Jose Abin 
Published: February 2024

ABSTRACTCells, the fundamental units of life, are central to medical research, particularly in cancer studies due to their rapid, uncontrolled division. Understanding cell behavior is crucial, with a focus on mitosis, which has distinct cell division stages. However, precise detection of these phases, especially mitosis initiation in 3D, remains an underexplored research area. Our work explores 3D cell behavior, leveraging the increasing computational capabilities and prevalence of 3D imaging techniques. We introduce diverse 3D Convolutional Neural Network (CNN) architectures such as a base 3D CNN model, 3D CNN binary model, and 3D CNN pairwise model. An ensemble model based on the 3D CNN architectures shows higher classification accuracy on two time-series datasets. This research gives better insights into understanding cell behaviour in a multidimensional manner, contributing to medical research. To the best of our understanding, we are the first to delve into the utilization of Convolutional Neural Network architectures for the 3D classification of mitosis stages.
Gene-edited primary muscle stem cells rescue dysferlin-deficient muscular dystrophy
Authors: Escobar Helena , di Francescantonio Silvia , Marg Andreas , Zhogov Alexej , Krishna Supriya , Metzler Eric , Petkova Mina , Daumke Oliver , Kühn Ralf , Spuler Simone 
Published: February 2024

AbstractDystrophy-associated fer-1-like protein (dysferlin) conducts plasma membrane repair. Mutations in theDYSFgene cause a panoply of genetic muscular dystrophies. We targeted a frequent loss-of-function,DYSFexon 44, founder frameshift mutation with mRNA-mediated delivery of SpCas9 in combination with a mutation-specific sgRNA to primary muscle stem cells from two homozygous patients. We observed a consistent >60% exon 44 re-framing, rescuing a full-length and functional dysferlin protein. A new mouse model harboring a humanizedDysfexon 44 with the founder mutation, hEx44mut, recapitulated the patients’ phenotype and an identical re-framing outcome in primary muscle stem cells. Finally, gene-edited murine primary muscle stem-cells were able to regenerate muscle and rescued dysferlin when transplanted back into hEx44mut hosts. These findings are the first to show that a CRISPR-mediated therapy can ameliorate dysferlin deficiency. We suggest that gene-edited primary muscle stem cells could exhibit utility, not only in treating dysferlin deficiency syndromes, but also perhaps other forms of muscular dystrophy.
DNA Methylome Regulates Virulence and Metabolism inPseudomonas syringae
Authors: Huang Jiadai , Chen Fang , Lu Beifang , Sun Yue , Li Youyue , Hua Canfeng , Deng Xin 
Published: February 2024

AbstractBacterial pathogens employ epigenetic mechanisms, including DNA methylation, to adapt to environmental changes, and these mechanisms play important roles in various biological processes.Pseudomonas syringaeis a model phytopathogenic bacterium, but its methylome is less well known than that of other species. In this study, we conducted single-molecule real-time sequencing to profile the DNA methylation landscape in three model pathovars ofP. syringae. We identified one Type-I restriction-modification system (HsdMSR), including the conserved sequence motif associated with N6-methyladenine (6mA). About 25%–40% of the genes involved in DNA methylation were conserved in two or more of the strains, revealing the functional conservation of methylation inP. syringae. Subsequent transcriptomic analysis highlighted the involvement of HsdMSR in virulent and metabolic pathways, including the Type III secretion system, biofilm formation, and translational efficiency. The regulatory effect of HsdMSR on transcription was dependent on both strands being fully 6mA methylated. Overall, this work illustrated the methylation profile inP. syringaeand the critical involvement of DNA methylation in regulating virulence and metabolism. Thus, this work contributes to a deeper understanding of epigenetic transcriptional control inP. syringaeand related bacteria.
EnteropathogenicE. colieffector Map regulates the depletion of the tight junction proteins occludin and claudin-4 via cathepsin B and Rab13-mediated mechanisms
Authors: Mandal Anupam , Walling Pangertoshi , Kansal Kritika , Aijaz Saima 
Published: February 2024

ABSTRACTInfections by EnteropathogenicE. coli(EPEC) cause acute diarrheal disease in infants accounting for severe morbidity and mortality. One of the underlying causes of the disease is the break-down of the intestinal barrier maintained by the tight junctions (TJs). EPEC uses a type 3 secretion system to translocate more than twenty effectors into infected cells which disrupt several functions of the host cells. The effectors EspF, Map, EspG1/G2 and NleA have been reported to disrupt the TJs and cause the leakage of charged ions and uncharged molecules through the barrier. We have reported earlier that EspF and Map cause the depletion of TJ proteins claudin-1, claudin-4 and occludin through both transcriptional and post-transcriptional mechanisms. Here, we show that the EPEC effector Map modulates the lysosomal protease, cathepsin B to deplete claudins and occludin. Expression of mutant Map proteins that lacked the mitochondrial targeting sequence (MTS) completely restored the total levels of occludin and its localization at the TJs and partially restored claudin-4 levels and its junctional localization. We also identified a novel interaction of Map with the GTPase Rab13. As Rab13 has been reported to mediate the recycling of occludin to the plasma membrane, its interaction with Map has important implications for the loss of TJ integrity in EPEC pathogenesis. Occludin regulates the passage of water and uncharged solutes through TJs and Map may block its recycling to compromise the TJs thus causing excessive leakage through the barrier.