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MBio Jun 2024Merkel cell polyomavirus (MCPyV) is a double-stranded tumor virus that is the main causative agent of Merkel cell carcinoma (MCC). The MCPyV large T antigen (LT), an...
UNLABELLED
Merkel cell polyomavirus (MCPyV) is a double-stranded tumor virus that is the main causative agent of Merkel cell carcinoma (MCC). The MCPyV large T antigen (LT), an essential viral DNA replication protein, maintains viral persistence by interacting with host Skp1-Cullin 1-F-box (SCF) E3 ubiquitin ligase complexes, which subsequently induces LT's proteasomal degradation, restricting MCPyV DNA replication. SCF E3 ubiquitin ligases require their substrates to be phosphorylated to bind them, utilizing phosphorylated serine residues as docking sites. The MCPyV LT unique region (MUR) is highly phosphorylated and plays a role in multiple host protein interactions, including SCF E3 ubiquitin ligases. Therefore, this domain highly governs LT stability. Though much work has been conducted to identify host factors that restrict MCPyV LT protein expression, the kinase(s) that cooperates with the SCF E3 ligase remains unknown. Here, we demonstrate that casein kinase 1 alpha (CK1α) negatively regulates MCPyV LT stability and LT-mediated replication by modulating interactions with the SCF β-TrCP. Specifically, we show that numerous CK1 isoforms (α, δ, ε) localize in close proximity to MCPyV LT through proximity ligation assays (PLA) and CK1α overexpression mainly resulted in decreased MCPyV LT protein expression. Inhibition of CK1α using short hairpin RNA (shRNA) and treatment of a CK1α inhibitor or an mTOR inhibitor, TORKinib, resulted in decreased β-TrCP interaction with LT, increased LT expression, and enhanced MCPyV replication. The expression level of the gene transcripts is higher in MCPyV-positive MCC, suggesting a vital role of CK1α in limiting MCPyV replication required for establishing persistent infection.
IMPORTANCE
Merkel cell polyomavirus (MCPyV) large tumor antigen is a polyphosphoprotein and the phosphorylation event is required to modulate various functions of LT, including viral replication. Therefore, cellular kinase pathways are indispensable for governing MCPyV polyomavirus infection and life cycle in coordinating with the immunosuppression environment at disease onset. Understanding the regulation mechanisms of MCPyV replication by viral and cellular factors will guide proper prevention strategies with targeted inhibitors for MCPyV-associated Merkel cell carcinoma (MCC) patients, who currently lack therapies.
PubMed: 38940554
DOI: 10.1128/mbio.01117-24 -
MSystems Jun 2024Winter is a relatively under-studied season in freshwater ecology. The paucity of wintertime surveys has led to a lack of knowledge regarding microbial community...
Winter is a relatively under-studied season in freshwater ecology. The paucity of wintertime surveys has led to a lack of knowledge regarding microbial community activity during the winter in Lake Erie, a North American Great Lake. Viruses shape microbial communities and regulate biogeochemical cycles by acting as top-down controls, yet very few efforts have been made to examine active virus populations during the winter in Lake Erie. Furthermore, climate change-driven declines in seasonal ice cover have been shown to influence microbial community structure, but no studies have compared viral community activity between different ice cover conditions. We surveyed surface water metatranscriptomes for viral hallmark genes as a proxy for active virus populations and compared activity metrics between ice-covered and ice-free conditions from two sampled winters. Transcriptionally active viral communities were detected in both winters, spanning diverse phylogenetic clades of putative bacteriophage (), giant viruses (, or NCLDV), and RNA viruses (). However, viral community activity metrics revealed pronounced differences between the ice-covered and ice-free winters. Viral community composition was distinct between winters and viral hallmark gene richness was reduced in the ice-covered relative to the ice-free conditions. In addition, the observed differences in viral communities correlated with microbial community activity metrics. Overall, these findings contribute to our understanding of the viral populations that are active during the winter in Lake Erie and suggest that viral community activity may be associated with ice cover extent.IMPORTANCEAs seasonal ice cover is projected to become increasingly rare on large temperate lakes, there is a need to understand how microbial communities might respond to changing ice conditions. Although it is widely recognized that viruses impact microbial community structure and function, there is little known regarding wintertime viral activity or the relationship between viral activity and ice cover extent. Our metatranscriptomic analyses indicated that viruses were transcriptionally active in the winter surface waters of Lake Erie. These findings also expanded the known diversity of viral lineages in the Great Lakes. Notably, viral community activity metrics were significantly different between the two sampled winters. The pronounced differences we observed in active viral communities between the ice-covered and ice-free samples merit further research regarding how viral communities will function in future, potentially ice-free, freshwater systems.
PubMed: 38940524
DOI: 10.1128/msystems.00753-24 -
Nursing Open Jul 2024To examine changes in advanced nurse practitioner (ANP) well-being, satisfaction and motivation over a four-year period. (Review)
Review
AIMS
To examine changes in advanced nurse practitioner (ANP) well-being, satisfaction and motivation over a four-year period.
DESIGN
Longitudinal Cohort study.
METHODS
Surveys were carried out each year from 2019 to 2022 with the same cohort of ANPs in the United Kingdom (UK). The survey consisted of demographics, questions on contemporary issues in advanced practice, National Health Service (NHS) staff survey questions and validated questionnaires. A core set of questions were asked every year with some changes in response to the COVID-19 pandemic.
RESULTS
Response rate ranged from 40% to 59% and appeared to be affected by COVID-19. Staff satisfaction with pay and the well-being score were stable throughout. Other questions on well-being, job satisfaction and motivation saw statistically significant reductions after 4 years. Open-ended questions about ongoing well-being concerns show participants are concerned about exhaustion levels caused by workload, staffing issues, abuse from patients and colleagues' mental health.
CONCLUSION
The findings highlight a decline in ANP well-being, job satisfaction and motivation post-COVID-19. Reasons for this, explored in the qualitative data, show that ANPs have faced extremely difficult working conditions. Urgent action is required to prevent a workforce retention crisis as many nursing staff are close to retirement and may not be motivated to remain in post.
IMPACT
This study has followed ANPs through the most challenging years the NHS has ever seen. Job satisfaction, motivation and enjoyment of the job all significantly reduced over time. In many areas, the ANP role has been used to fill medical workforce gaps, and this will become harder to do if ANPs are dissatisfied, disaffected and struggling with stress and burnout. Addressing these issues should be a priority for policymakers and managers.
PATIENT OR PUBLIC CONTRIBUTION
None as this study focussed on staff. Staff stakeholders involved in the design and conduct of the study.
Topics: Humans; Job Satisfaction; COVID-19; United Kingdom; Nurse Practitioners; Female; Male; Longitudinal Studies; Surveys and Questionnaires; Adult; Middle Aged; SARS-CoV-2; Motivation; Cohort Studies; State Medicine; Pandemics; Workload; Burnout, Professional
PubMed: 38940475
DOI: 10.1002/nop2.2218 -
Journal of Medical Virology Jul 2024The dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission are influenced by a variety of factors, including social restrictions and the...
The dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission are influenced by a variety of factors, including social restrictions and the emergence of distinct variants. In this study, we delve into the origins and dissemination of the Alpha, Delta, and Omicron-BA.1 variants of concern in Galicia, northwest Spain. For this, we leveraged genomic data collected by the EPICOVIGAL Consortium and from the GISAID database, along with mobility information from other Spanish regions and foreign countries. Our analysis indicates that initial introductions during the Alpha phase were predominantly from other Spanish regions and France. However, as the pandemic progressed, introductions from Portugal and the United States became increasingly significant. The number of detected introductions varied from 96 and 101 for Alpha and Delta to 39 for Omicron-BA.1. Most of these introductions left a low number of descendants (<10), suggesting a limited impact on the evolution of the pandemic in Galicia. Notably, Galicia's major coastal cities emerged as critical hubs for viral transmission, highlighting their role in sustaining and spreading the virus. This research emphasizes the critical role of regional connectivity in the spread of SARS-CoV-2 and offers essential insights for enhancing public health strategies and surveillance measures.
Topics: Spain; COVID-19; Humans; SARS-CoV-2; Genome, Viral; Phylogeny; Pandemics
PubMed: 38940448
DOI: 10.1002/jmv.29773 -
Molecular Medicine Reports Aug 2024The coronavirus disease 2019 pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) seriously affected global public health security. Studies... (Review)
Review
The coronavirus disease 2019 pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) seriously affected global public health security. Studies on vaccines, neutralizing antibodies (NAbs) and small molecule antiviral drugs are currently ongoing. In particular, NAbs have emerged as promising therapeutic agents due to their well‑defined mechanism, high specificity, superior safety profile, ease of large‑scale production and simultaneous application for both prevention and treatment of viral infection. Numerous NAb therapeutics have entered the clinical research stages, demonstrating promising therapeutic and preventive effects. These agents have been used for outbreak prevention and control under urgent authorization processes. The present review summarizes the molecular targets of SARS‑CoV‑2‑associated NAbs and screening and identification techniques for NAb development. Moreover, the current shortcomings and challenges that persist with the use of NAbs are discussed. The aim of the present review is to offer a reference for the development of NAbs for any future emergent infectious diseases, including SARS‑CoV‑2.
Topics: Humans; Antibodies, Neutralizing; SARS-CoV-2; COVID-19; Antibodies, Viral; Antiviral Agents; Animals
PubMed: 38940338
DOI: 10.3892/mmr.2024.13272 -
Biomeditsinskaia Khimiia Jun 2024Electrochemical profiling of formaldehyde-inactivated poliovirus particles demonstrated a relationship between the D-antigen concentration and the intensity of the...
Electrochemical profiling of formaldehyde-inactivated poliovirus particles demonstrated a relationship between the D-antigen concentration and the intensity of the maximum amplitude currents of the poliovirus samples. The resultant signal was therefore identified as electrochemical oxidation of the surface proteins of the poliovirus. Using registration of electrooxidation of amino acid residues of the capsid proteins, a comparative electrochemical analysis of poliovirus particles inactivated by electrons accelerated with doses of 5 kGy, 10 kGy, 15 kGy, 25 kGy, 30 kGy at room temperature was carried out. An increase in the radiation dose was accompanied by an increase in electrooxidation signals. A significant increase in the signals of electrooxidation of poliovirus capsid proteins was detected upon irradiation at doses of 15-30 kGy. The data obtained suggest that the change in the profile and increase in the electrooxidation signals of poliovirus capsid proteins are associated with an increase in the degree of structural reorganization of surface proteins and insufficient preservation of the D-antigen under these conditions of poliovirus inactivation.
Topics: Poliovirus; Capsid Proteins; Virus Inactivation; Oxidation-Reduction; Formaldehyde; Humans; Virion
PubMed: 38940205
DOI: 10.18097/PBMC20247003161 -
Bioinformatics (Oxford, England) Jun 2024The emergence of COVID-19 (C19) created incredible worldwide challenges but offers unique opportunities to understand the physiology of its risk factors and their...
MOTIVATION
The emergence of COVID-19 (C19) created incredible worldwide challenges but offers unique opportunities to understand the physiology of its risk factors and their interactions with complex disease conditions, such as metabolic syndrome. To address the challenges of discovering clinically relevant interactions, we employed a unique approach for epidemiological analysis powered by redescription-based topological data analysis (RTDA).
RESULTS
Here, RTDA was applied to Explorys data to discover associations among severe C19 and metabolic syndrome. This approach was able to further explore the probative value of drug prescriptions to capture the involvement of RAAS and hypertension with C19, as well as modification of risk factor impact by hyperlipidemia (HL) on severe C19. RTDA found higher-order relationships between RAAS pathway and severe C19 along with demographic variables of age, gender, and comorbidities such as obesity, statin prescriptions, HL, chronic kidney failure, and disproportionately affecting Black individuals. RTDA combined with CuNA (cumulant-based network analysis) yielded a higher-order interaction network derived from cumulants that furthered supported the central role that RAAS plays. TDA techniques can provide a novel outlook beyond typical logistic regressions in epidemiology. From an observational cohort of electronic medical records, it can find out how RAAS drugs interact with comorbidities, such as hypertension and HL, of patients with severe bouts of C19. Where single variable association tests with outcome can struggle, TDA's higher-order interaction network between different variables enables the discovery of the comorbidities of a disease such as C19 work in concert.
AVAILABILITY AND IMPLEMENTATION
Code for performing TDA/RTDA is available in https://github.com/IBM/Matilda and code for CuNA can be found in https://github.com/BiomedSciAI/Geno4SD/.
SUPPLEMENTARY INFORMATION
Supplementary data are available at Bioinformatics online.
Topics: Humans; Metabolic Syndrome; COVID-19; Renin-Angiotensin System; Hyperlipidemias; Male; Female; SARS-CoV-2; Middle Aged; Aged; Comorbidity; Hypertension; Risk Factors
PubMed: 38940159
DOI: 10.1093/bioinformatics/btae235 -
Bioinformatics (Oxford, England) Jun 2024We learn more effectively through experience and reflection than through passive reception of information. Bioinformatics offers an excellent opportunity for...
MOTIVATION
We learn more effectively through experience and reflection than through passive reception of information. Bioinformatics offers an excellent opportunity for project-based learning. Molecular data are abundant and accessible in open repositories, and important concepts in biology can be rediscovered by reanalyzing the data.
RESULTS
In the manuscript, we report on five hands-on assignments we designed for master's computer science students to train them in bioinformatics for genomics. These assignments are the cornerstones of our introductory bioinformatics course and are centered around the study of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). They assume no prior knowledge of molecular biology but do require programming skills. Through these assignments, students learn about genomes and genes, discover their composition and function, relate SARS-CoV-2 to other viruses, and learn about the body's response to infection. Student evaluation of the assignments confirms their usefulness and value, their appropriate mastery-level difficulty, and their interesting and motivating storyline.
AVAILABILITY AND IMPLEMENTATION
The course materials are freely available on GitHub at https://github.com/IB-ULFRI.
Topics: Computational Biology; SARS-CoV-2; Humans; COVID-19; Genomics; Students
PubMed: 38940150
DOI: 10.1093/bioinformatics/btae208 -
Bioinformatics (Oxford, England) Jun 2024Mutations are the crucial driving force for biological evolution as they can disrupt protein stability and protein-protein interactions which have notable impacts on...
MOTIVATION
Mutations are the crucial driving force for biological evolution as they can disrupt protein stability and protein-protein interactions which have notable impacts on protein structure, function, and expression. However, existing computational methods for protein mutation effects prediction are generally limited to single point mutations with global dependencies, and do not systematically take into account the local and global synergistic epistasis inherent in multiple point mutations.
RESULTS
To this end, we propose a novel spatial and sequential message passing neural network, named DDAffinity, to predict the changes in binding affinity caused by multiple point mutations based on protein 3D structures. Specifically, instead of being on the whole protein, we perform message passing on the k-nearest neighbor residue graphs to extract pocket features of the protein 3D structures. Furthermore, to learn global topological features, a two-step additive Gaussian noising strategy during training is applied to blur out local details of protein geometry. We evaluate DDAffinity on benchmark datasets and external validation datasets. Overall, the predictive performance of DDAffinity is significantly improved compared with state-of-the-art baselines on multiple point mutations, including end-to-end and pre-training based methods. The ablation studies indicate the reasonable design of all components of DDAffinity. In addition, applications in nonredundant blind testing, predicting mutation effects of SARS-CoV-2 RBD variants, and optimizing human antibody against SARS-CoV-2 illustrate the effectiveness of DDAffinity.
AVAILABILITY AND IMPLEMENTATION
DDAffinity is available at https://github.com/ak422/DDAffinity.
Topics: Point Mutation; SARS-CoV-2; Computational Biology; Protein Conformation; Humans; Neural Networks, Computer; Protein Binding; COVID-19; Proteins; Algorithms
PubMed: 38940145
DOI: 10.1093/bioinformatics/btae232 -
Annals of Agricultural and... Jun 2024Photobiomodulation with the use of light-emitting diodes (LEDs) seems to be a promising option for long COVID. This retrospective study evaluates the efficiency of LED...
INTRODUCTION AND OBJECTIVE
Photobiomodulation with the use of light-emitting diodes (LEDs) seems to be a promising option for long COVID. This retrospective study evaluates the efficiency of LED irradiation in the treatment of TE in the course of long COVID in patients with and without androgenetic alopecia.
MATERIAL AND METHODS
A retrospective single-centre chart review of patients with post-COVID hair loss was performed. 140 patients enrolled to the study were divided into four groups depending on the type of alopecia and treatment: 1) telogen effluvium with LED therapy (TE LED+), 2) telogen effluvium without LED therapy (TE LED-), 3) telogen effluvium and androgenetic alopecia with LED therapy (TE+AGA LED+), and 4) telogen effluvium and androgenetic alopecia without LED therapy (TE+AGA LED-). Clinical and trichoscopic parameters were compared.
RESULTS
After 12 weeks, cessation of hair loss and a negative hair pull test were more common in TE LED+ and TE+AGA LED+ in comparison to the patients without LED therapy (p<0.001, p=0.035, respectively). An increased number of thick hairs and an increased number of hairs within follicular units were more common in patients treated with LED irradiation, regardless of the type of alopecia, compared to the patients without LED therapy.
CONCLUSIONS
The study revealed that LED therapy is safe, well tolerated and seems to be a promising therapeutic option for TE in patients with long COVID. It can be used as adjuvant therapy leading to faster reduction of hair loss, enhancing hair regrowth as well as hair shaft thickness and density.
Topics: Humans; Alopecia; Retrospective Studies; Female; Middle Aged; COVID-19; Male; Adult; SARS-CoV-2; Low-Level Light Therapy; Aged; Hair; Treatment Outcome; Phototherapy
PubMed: 38940108
DOI: 10.26444/aaem/177238