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Tail-Tape-Fused Virion and Non-Virion RNA Polymerases of a Thermophilic Virus with An Extremely Long Tail
Get PDFThermus thermophilus bacteriophage P23-45 encodes a giant 5,002-residue tail tape measure protein (TMP) that defines the length of its extraordinarily long tail. Here, we show that the N-terminal portion of P23-45 TMP is an unusual RNA polymerase (RNAP) homologous to cellular RNAPs. The TMP-fused virion RNAP transcribes pre-early phage genes, including a gene that encodes another, non-virion RNAP, that transcribes early and some middle phage genes. We report the crystal structures of both P23-45 RNAPs. The non-virion RNAP has a crab-claw-like architecture. By contrast, the virion RNAP adopts a unique flat structure without a clamp. Structure and sequence comparisons of the P23-45 RNAPs with other RNAPs suggest that, despite the extensive functional differences, the two P23-45 RNAPs originate from an ancient gene duplication in an ancestral phage. Our findings demonstrate striking adaptability of RNAPs that can be attained within a single virus species
Diversity in Osteopathic Medical School Admissions and the COMPASS Program: An Update
Get PDFIn the United States, the 40 colleges of osteopathic medicine and 157 schools of allopathic medicine face challenges in recruiting candidates who are underrepresented in medicine (URiM), and gaps in racial disparity appear to be widening. In this commentary, the authors provide an analysis of the data collected from 8 years of conducting a URiM recruitment and welcoming social events. The event is sponsored by a student special interest group called Creating Osteopathic Minority Physicians Who Achieve Scholastic Success (COMPASS) at the Touro College of Osteopathic Medicine - New York (TouroCOM-NY). The results of the 8-year data analysis supports the conclusion that the COMPASS program has benefited the school environment through increased diversity
Ksp1 Is an Autophagic Receptor Protein for the Snx4-Assisted Autophagy of Ssn2/Med13
Get PDFKsp1 is a casein II-like kinase whose activity prevents aberrant macroautophagy/autophagy induction in nutrient-rich conditions in yeast. Here, we describe a kinase-independent role of Ksp1 as a novel autophagic receptor protein for Ssn2/Med13, a known cargo of Snx4-assisted autophagy of transcription factors. In this pathway, a subset of conserved transcriptional regulators, Ssn2/Med13, Rim15, and Msn2, are selectively targeted for vacuolar proteolysis following nitrogen starvation, assisted by the sorting nexin heterodimer Snx4-Atg20. Here we show that phagophores also engulf Ksp1 alongside its cargo for vacuolar proteolysis. Ksp1 directly associates with Atg8 following nitrogen starvation at the interface of an Atg8-family interacting motif (AIM)/LC3-interacting region (LIR) in Ksp1 and the LIR/AIM docking site (LDS) in Atg8. Mutating the LDS site prevents the autophagic degradation of Ksp1. However, deletion of the C terminal canonical AIM still permitted Ssn2/Med13 proteolysis, suggesting that additional non-canonical AIMs may mediate the Ksp1-Atg8 interaction. Ksp1 is recruited to the perivacuolar phagophore assembly site by Atg29, a member of the trimeric scaffold complex. This interaction is independent of Atg8 and Snx4, suggesting that Ksp1 is recruited early to phagophores, with Snx4 delivering Ssn2/Med13 thereafter. Finally, normal cell survival following prolonged nitrogen starvation requires Ksp1. Together, these studies define a kinase-independent role for Ksp1 as an autophagic receptor protein mediating Ssn2/Med13 degradation. They also suggest that phagophores built by the trimeric scaffold complex are capable of receptor-mediated autophagy. These results demonstrate the dual functionality of Ksp1, whose kinase activity prevents autophagy while it plays a scaffolding role supporting autophagic degradation
Binding Mechanism of the Active Form of Molnupiravir to RdRp of SARS-CoV-2 and Designing Potential Analogues: Insights from Molecular Dynamics Simulations.
Get PDFMolnupiravir, an FDA-approved nucleoside prodrug for treating COVID-19, converts into N4-hydroxycytidine triphosphate (NHC-TP), which integrates into SARS-CoV-2 RNA by its RNA-dependent RNA polymerase (RdRp) causing lethal mutations in viral proteins. Due to the risk of RdRp-mediated drug resistance and potential off-target effects on host polymerases (e.g., human polymerase II/HPolII), it is crucial to understand NHC-TP interactions at polymerase active sites for developing new, resistance-proof treatments. In this study, we used molecular dynamics (MD) simulations to probe key interactions between NHC-TP and SARS-CoV-2 RdRp and designed novel NHC-TP analogues with greater selectivity for SARS-CoV-2 RdRp over HPolII by a virtual screening workflow. We docked NHC-TP to a modified SARS-CoV-2 RdRp-Remdesivir triphosphate structure (PDB ID: 7BV2) and generated 71 NHC-TP analogues with bulky substituents to increase the interaction with RdRP and to reduce HPolII incorporation. MD simulations assessed the stability, binding affinity, and site interactions of these analogues. The top 7 candidates, with favorable ADMET properties, likely inhibit replication via potential dual mechanisms (the replicative stalling and the induction of lethal mutations) while maintaining selectivity for SARS-CoV-2 RdRp
Correcting misperceptions about very low nicotine cigarettes for cigarette-only smokers, dual/poly smokers, other tobacco users, and non-tobacco users
Get PDFBackground The U.S. Food and Drug Administration authorized the sale and marketing of two very low nicotine cigarettes (VLNC) as modified risk tobacco products. The misperception that VLNC are healthier than regular cigarettes is common. This study explores effective message strategies to inform the public about health risks associated with VLNC use, encourage cigarette smokers to try VLNC, and prevent other tobacco users and non-users from product initiation. Methods Following the Reasoned Action approach, a VLNC educational message was developed based on the salient beliefs associated with behavioral intention. The message was tested in an online survey conducted in 2018, where 410 participants were randomly assigned to one of the two message conditions (no-message, VLNC message). Message effects were assessed across four tobacco-use groups (non-tobacco users, cigarette-only smokers, cigarette dual/poly smokers, other tobacco users). Results Compared to the no-message control, the VLNC message condition showed lower nicotine risk perception for all participants, lower misbelief in VLNC safety for non-users and cigarette-only smokers, higher belief in VLNC carcinogenicity for other tobacco users, stronger belief in second-hand smoke harm for cigarette dual/poly smokers and other tobacco users, and higher VLNC intention for cigarette-only smokers. Conclusions Different messages are needed for different types of tobacco users. Both cigarette smokers and other tobacco users could benefit from messages that acknowledge the non-addictiveness but emphasize the health risks of VLNC. Regulators could consider making physical harm statements a requirement for VLNC packaging and marketing. New strategies need to be explored to inform cigarette dual/poly smokers
Measuring integrated accessibility for sustainable mobility: a fuzzy set approach case study
Get PDFSustainable transportation is vital to climate justice and social equity. Despite the efforts to achieve sustainability, there is still a lack of adequate measurement that integrates land use and transportation systems, which can be barriers to planning implementation. With methodological improvements in fuzzy theory application, this study develops an integrated index to measure the sustainability of multimodal accessibility. We do so by defining a fuzziness degree based on the different trip purposes and modes of transportation with a case study in Isfahan, Iran. Sustainable accessibility indicators were developed for walking, biking, and public transportation to represent the performance of each transportation system, considering the integration with land-use patterns. We analyze transportation modes and the accessibility to five main urban activities, including employment opportunities, education, healthcare, shopping, and recreation services, based on the travel distances, followed by a statistical integration method with Principal Components Analysis (PCA) for each travel mode. The outcome provides insights for urban planners and transportation planners to effectively evaluate the degree of integration between transportation and land-use systems and contribute to enhancing sustainable accessibility
From books to the bedside: post-graduation impact of \u27Week On the Wards\u27 on medical education.
Get PDFBACKGROUND: The transition between preclinical and clinical years during medical school has been shown to be challenging. Cooper Medical School of Rowan University (CMSRU) implements one required two-week-long shadowing program for first and one one-week-long shadowing program for second-year medical students called Week On the Wards (WOW). The goal of this study is to ascertain whether students who completed the WOW curriculum found it beneficial over the long-term. Specifically, we want to evaluate alumni\u27s impression of the program\u27s influence on career, specialty choice, professional development, personal development, and confidence.
METHODS: To evaluate our program, we developed, validated, and distributed a survey via email in the autumn of 2023. Our population included alumni from the classes of 2019-2022, irrespective of race and gender. After following steps for survey development, it was validated via focus group using qualitative methods. The survey consisted of 19 questions answerable on a 5-point Likert scale, a Yes/No/Unsure/Maybe section, and an optional open-ended response question. Descriptive analysis was done to report the percent responses.
RESULTS: The survey was emailed to 353 alumni, with 72 completed responses returned. Majority of respondents agreed or strongly agreed that the WOW program showcased the importance of teamwork in medicine (80.6%), helped them learn to apply medical knowledge (77.8%), influenced their decision regarding which residency/specialty they chose (72.2%), provided an example of how teamwork in medicine is necessary for patient safety and effective care (66.6%), and increased their confidence in their networking skills (66.6%). Alumni nearly unanimously agreed that the WOW program was a useful part of their medical school education (93.1%) and that it should be continued for future classes (94.4%).
CONCLUSION: Our results highlight the sustained importance of early preclinical exposure to clinical environments in students\u27 future career decisions, in their understanding of the clinical applications of learned preclinical topics, and the importance of teamwork in medicine
Phosphorylation-driven epichaperome assembly is a regulator of cellular adaptability and proliferation.
Get PDFThe intricate network of protein-chaperone interactions is crucial for maintaining cellular function. Recent discoveries have unveiled the existence of specialized chaperone assemblies, known as epichaperomes, which serve as scaffolding platforms that orchestrate the reconfiguration of protein-protein interaction networks, thereby enhancing cellular adaptability and proliferation. This study explores the structural and regulatory aspects of epichaperomes, with a particular focus on the role of post-translational modifications (PTMs) in their formation and function. A key finding is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 within an intrinsically disordered region, as critical determinants of epichaperome assembly. Our data demonstrate that phosphorylation of these serine residues enhances HSP90\u27s interactions with other chaperones and co-chaperones, creating a microenvironment conducive to epichaperome formation. Moreover, we establish a direct link between epichaperome function and cellular physiology, particularly in contexts where robust proliferation and adaptive behavior are essential, such as in cancer and pluripotent stem cell maintenance. These findings not only provide mechanistic insights but also hold promise for the development of novel therapeutic strategies targeting chaperone assemblies in diseases characterized by epichaperome dysregulation, thereby bridging the gap between fundamental research and precision medicine
Metal additive manufacturing of damage-controlled elements for structural protection of steel members
Get PDFThis paper develops hybrid steel members by integrating additively manufactured, ultra-lightweight, damage-controlled elements (DCEs) into hot-rolled structural steel members. This approach relies on segmenting a structural member into distinct sections; one or two segments are enlarged to be capacity protected; however, another end or middle DCE segment is optimized to emulate the conventional member’s strength and stiffness. A small-scale DCE was topologically optimized and then additively manufactured using a powder bed fusion technique through a direct metal laser sintering process of 17-4PH stainless steel and then was experimentally tested to study the buckling behavior under compression. The experimental testing of the optimized DCE shows a compressive strength of 81,000 times the specimen’s weight with stable post-peak buckling behavior. Numerical simulation confirms experimental results, showing a good correlation in fracture energy. A parametric study on four DCE specimens, scaled up by three, four, five, and six times, was performed and compared to hollow structural sections (HSS) of A500 Gr. C in tensile and compression strengths. The numerical simulation shows a linear relation between the weight ratio and HSS length. Additionally, numerical simulation of conventional member, DCE (scaled by three), and three hybrid members revealed that failure occurred in DCE as intended
Species delimitation, discovery and conservation in a tiger beetle species complex despite discordant genetic data.
Get PDFIn an age of species declines, delineating and discovering biodiversity is critical for both taxonomic accuracy and conservation. In recent years, there has been a movement away from using exclusively morphological characters to delineate and describe taxa and an increase in the use of molecular markers to describe diversity or through integrative taxonomy, which employs traditional morphological characters, as well as genetic or other data. Tiger beetles are charismatic, of conservation concern, and much work has been done on the morphological delineation of species and subspecies, but few of these taxa have been tested with genetic analyses. In this study, we tested morphologically based taxonomic hypotheses of polymorphic tiger beetles in the Eunota circumpicta (LaFerté-Sénectère, 1841) species complex using multilocus genomic and mtDNA analyses. We find multiple cryptic species within the previous taxonomic concept of Eunota circumpicta, some of which were historically recognized as subspecies. We found that the mtDNA and genomic datasets did not identify the same taxonomic units and that the mtDNA was most at odds with all other genetic and morphological patterns. Overall, we describe new cryptic diversity, which raises important conservation concerns, and provide a working example for testing species and subspecies validity despite discordant data