bluuebunny/crossref_metadata_2025_split huggingface dataset:
Towards precision well-being in medical education
Authors: Thesen Thomas , Marrero Wesley , Konopasky Abigail , Duncan Matthew , Blackmon Karen 
Published: June 2023

AbstractProblemThe escalating mental health crisis among medical students is often met with generalized solutions that overlook substantial individual variations. Furthermore, an exclusive focus on mental illness tends to overshadow the necessity of fostering the positive aspects of medical trainee well-being. This Innovation Report introduces a novel, data-driven precision well-being approach for medical education that is built on a more comprehensive and individualized view of mental health.ApproachOur approach to precision well-being centers on categorizing medical students into distinct and meaningful groups based on their holistic mental health, enabling the future development of tailored wellness support and interventions. We applied k-means clustering, an unsupervised machine learning technique commonly used in precision medicine, to uncover patterns within multidimensional mental health data of medical students. Using data from 3,632 medical students, we formulated our clusters based on recognized metrics for depression, anxiety, and flourishing.OutcomesOur analysis identified three distinct clusters, each demonstrating unique patterns along the mental health spectrum. Students in the “Healthy Flourishers” cluster expressed no signs of anxiety or depression and simultaneously reported high levels of flourishing, while students in the “Getting By” cluster reported mild anxiety and depression and diminished flourishing. Students in the “At-Risk” cluster expressed high anxiety and depression, minimal flourishing, and increased suicidality. These results represent an integrated, comprehensive empirical model that classifies individual medical students into distinct well-being categories, creating a way for more personalized mental health support strategies.Next StepsThe three-cluster model’s generalizability needs to be improved by incorporating longitudinal data from diverse medical student populations. Integrating physiological markers from wearable devices may improve individualized insights. The model can be used to monitor students’ transitions between clusters, determine influencing factors, form individual risk profiles, and evaluate the effectiveness of personalized intervention strategies stratified by cluster membership.
Infection by the lungwormRhabdias pseudosphaerocephalaaffects the expression of immune-related microRNAs by its co-evolved host, the cane toadRhinella marina
Authors: Chan Tsering C. L. , Yagound Boris , Brown Gregory P. , Eyck Harrison J. F. , Shine Richard , Rollins Lee A. 
Published: June 2023

AbstractParasites may suppress the immune function of an infected host using microRNAs (miRNAs) to prevent protein production. Nonetheless, little is known about the diversity of miRNAs and their mode(s) of action. In this study, we investigated the effects of infection by a parasitic lungworm (Rhabdias pseudosphaerocephala) on miRNA and mRNA expression of its host, the invasive cane toad (Rhinella marina). We compared miRNA and mRNA expression in naïve toads that had never been infected by lungworms to toads that were infected with lungworms for the first time in their lives, and to toads that were infected the second time in their lives (i.e., had two consecutive infections). In total, we identified 434 known miRNAs and 106 potential novel miRNAs. Compared to uninfected toads, infected animals upregulated five (single-infection treatment) or four (multiple-infection treatment) miRNAs. Seven of these differentially expressed miRNAs were associated with gene pathways related to the immune response, potentially reflecting immunosuppression of cane toads by their parasites. Infected hosts did not respond with substantial mRNA transcription, with only one differentially expressed gene between control and single-infection hosts. Our study suggests that miRNA-mediated interactions may play a role in mediating the interaction between the parasite and its host. Our findings clarify the role of miRNAs in host-parasite interactions, in a system in which an ongoing range expansion by the host has generated substantial divergence in host-parasite interactions.
Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells
Authors: Brunet Lisa , Alexandre David , Lee Jiyoung , Blanquer-Rosselló Maria del Mar , Guernet Alexis , Chhouri Houssein , Kherrouche Zoulika , Arabo Arnaud , Yao Shen , Godefroy David , Dehedin Julie , Li Jian-Rong , Duparc Céline , Jamme Philippe , Vinchent Audrey , Bérard Caroline , Tulasne David , Arena Sabrina , Bardelli Alberto , Cheng Chao , Cho Byoung Chul , Coulouarn Cédric , Aaronson Stuart A. , Cortot Alexis B. , Anouar Youssef , Grumolato Luca 
Published: June 2023

ABSTRACTNon-small cell lung cancers (NSCLCs) treated with tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) almost invariably relapse in the long term, due to the emergence of subpopulations of resistant cells. Here we show that the lack of sensitivity of these cells to EGFR-TKIs constitutes a vulnerability that can be potentially targeted. Through a DNA barcoding approach, we demonstrate that the clinically approved drug sorafenib specifically abolishes the selective advantage of EGFR-TKI-resistant cells, while preserving the response of EGFR-TKI-sensitive cells, thus resulting in overall inhibition of clonal evolution within the tumor cell mass population. Sorafenib is active against multiple mechanisms of resistance/tolerance to EGFR-TKIs and its effects depend on early inhibition of MAPK interacting kinase (MNK) activity and signal transducer and activator of transcription 3 (STAT3) phosphorylation, and later down-regulation of MCL1 and EGFR. Using several xenograft and allograft models to recapitulate different mechanisms and kinetics of acquired resistance, we show that the sorafenib-EGFR-TKI combination can substantially delay tumor growth and promote the recruitment of inflammatory cells. Together, our findings indicate that sorafenib can substantially prolong the response to EGFR-TKIs by targeting NSCLC capacity to adapt to treatment through the emergence of resistant cells.
Centriole elimination duringC. elegansoogenesis initiates with loss of the central tube protein SAS-1
Authors: Pierron Marie , Woglar Alexander , Busso Coralie , Jha Keshav , Mikeladze-Dvali Tamara , Croisier Marie , Gönczy Pierre 
Published: June 2023

SUMMARYCentrioles are lost during oogenesis in most metazoans, ensuring that the zygote is endowed with the correct number of two centrioles, which are paternally contributed. How centriole architecture is dismantled during oogenesis is not understood. Here, we analyze with unprecedent detail the ultrastructural and molecular changes during oogenesis centriole elimination inC. elegans. Centriole elimination begins with loss of the so-called central tube and organelle widening, followed by microtubule disassembly. The resulting cluster of centriolar proteins then disappears gradually, usually moving in a microtubule- and dynein-dependent manner to the plasma membrane. Moreover, we find that neither Polo-like kinases nor the PCM, which modulate oogenesis centriole elimination inDrosophila, do so inC. elegans. Furthermore, we demonstrate that the central tube protein SAS-1 normally departs first from the organelle, which loses integrity earlier insas-1mutants. Overall, our work provides novel mechanistic insights regarding the fundamental process of oogenesis centriole elimination.
Spatiotemporal dynamics of hippocampal-cortical networks underlying the unique phenomenological properties of trauma-related intrusive memories
Authors: Clancy Kevin J. , Devignes Quentin , Ren Boyu , Pollmann Yara , Nielsen Sienna R. , Howell Kristin , Kumar Poornima , Belleau Emily L. , Rosso Isabelle M. 
Published: June 2023

ABSTRACTTrauma-related intrusive memories (TR-IMs) possess unique phenomenological properties that contribute to adverse post-traumatic outcomes, positioning them as critical intervention targets. However, transdiagnostic treatments for TR-IMs are scarce, as their underlying mechanisms have been investigated separate from their unique phenomenological properties. Extant models of more general episodic memory highlight dynamic hippocampal-cortical interactions that vary along the anterior-posterior axis of the hippocampus (HPC) to support different cognitive-affective and sensory-perceptual features of memory. Extending this work into the unique properties of TR-IMs, we conducted a study of eighty-four trauma-exposed adults who completed daily ecological momentary assessments of TR-IM properties followed by resting-state functional magnetic resonance imaging (rs-fMRI). Spatiotemporal dynamics of anterior and posterior hippocampal (a/pHPC)-cortical networks were assessed using co-activation pattern analysis to investigate their associations with different properties of TR-IMs. Emotional intensity of TR-IMs was inversely associated with the frequency and persistence of an aHPC-default mode network co-activation pattern. Conversely, sensory features of TR-IMs were associated with more frequent co-activation of the HPC with sensory cortices and the ventral attention network, and the reliving of TR-IMs in the “here-and-now” was associated with more persistent co-activation of the pHPC and the visual cortex. Notably, no associations were found between HPC-cortical network dynamics and conventional symptom measures, including TR-IM frequency or retrospective recall, underscoring the utility of ecological assessments of memory properties in identifying the neural substrates of memory properties. These findings provide novel mechanistic insights into the unique features of TR-IMs that are critical for the development of individualized, transdiagnostic treatments for this pervasive, difficult-to-treat symptom.
Loop-extruding Smc5/6 organizes transcription-induced positive DNA supercoils
Authors: Jeppsson Kristian , Pradhan Biswajit , Sutani Takashi , Sakata Toyonori , Igarashi Miki Umeda , Berta Davide Giorgio , Kanno Takaharu , Nakato Ryuichiro , Shirahige Katsuhiko , Kim Eugene , Björkegren Camilla 
Published: June 2023

SUMMARYThe Structural Maintenance of Chromosome (SMC) protein complexes cohesin, condensin and the Smc5/6 complex (Smc5/6) are essential for chromosome function. At the molecular level, these complexes fold DNA by loop extrusion. Accordingly, cohesin creates chromosome loops in interphase, and condensin compacts mitotic chromosomes. However, the role of Smc5/6’s recently discovered DNA loop extrusion activity is unknown. Here, we uncover that Smc5/6 associates with transcription-induced positively supercoiled chromosomal DNA at cohesin-dependent chromosome loop boundaries. Mechanistically, single-molecule imaging reveals that dimers of Smc5/6 specifically recognize the tip of positively supercoiled DNA plectonemes, and efficiently initiates loop extrusion to gather the supercoiled DNA into a large plectonemic loop. Finally, Hi-C analysis shows that Smc5/6 links chromosomal regions containing transcription-induced positive supercoiling incis. Altogether, our findings indicate that Smc5/6 controls the three-dimensional organization of chromosomes by recognizing and initiating loop extrusion on positively supercoiled DNA.
Genome-wide identification of silencers in human cells
Authors: Zhu Xiusheng , Wang Chao , Kong Dashuai , Luo Jing , Deng Biao , Gu Yi , Kong Siyuan , Huang Lei , Liu Yuwen , Zhang Yubo 
Published: June 2023

AbstractTranscriptional regulation is a complex process that is controlled by a variety of factors, including enhancers and silencers. Silencers, also known as repressor elements, play a crucial role in the fine-tuning of gene expression by inhibiting or suppressing transcription in the human genome. Although significant progresses have been made, genome-wide silencer research is still in its early stages. Here, we used a genome-wide method called massively parallel reporter assays (MPRAs) to identify silencers in three human cell lines: K562, LNCap, and HEK293T. We identified 739,434, 643,484, and 491,952 silencer regions in these cell lines, respectively. We found that most of the silencers we identified had inhibitory activity and significantly enriched inhibitory motifs. These results confirm that silencers are ubiquitous in the human genome and play an important role in regulating gene expression. Therefore, our study provides a general strategy for genome-wide functional identification of silencer elements. This information could be used to better understand the mechanisms of gene regulation and to develop new therapeutic strategies for diseases that are caused by dysregulation of gene expression.
Reversal of carbapenem resistance inPseudomonas aeruginosaby camelid single domain antibody fragment (VHH) against the C4 dicarboxylate transporter
Authors: Nagraj Anil Kumar , Shukla Manjiri , Kulkarni Mansi , Patil Pratik , Borgave Mrunal , Banerjee Sanjiban K 
Published: June 2023

AbstractThe COVID-19 pandemic has hastened the problem of nosocomial drug-resistant pathogens and is exerting a huge toll on hospitalized patients in critical care settings. Most small molecule antibiotics are susceptible to bacterial resistance mechanisms and constantly becoming ineffective leading to rapid shrinkage of the antibiotic armamentarium.Pseudomonas aeruginosa, one of the most common pathogens in hospital-born infection and considered critically dangerous by WHO and CDC, is extremely difficult to treat with frontline drugs, the carbapenems. In this study, we developed a camelid antibody fragment (VHH) library against wholeP. aeruginosaand isolated a highly potent neutralizing hit (PsC23) that selectively targetsP. aeruginosa .At 25 µg/mL, PsC23 inhibited growth of the ATCC 27853 and a locally isolated carbapenem resistant MCC 50428P. aeruginosa. The target of PsC23 is the C4 dicarboxylate transporter that transports C4 metabolites to the glyoxylate shunt during oxidative stress that is present in pathogens but not the human host. This ultimately results in the blockade of the shunt affecting bacterial energy transduction that leads to disruption of drug efflux. Interestingly, in a neutropenic mouse with MCC 50428 systemic infection, PsC23 in combination with meropenem completely reversed the drug resistance and eliminated the pathogens from the blood. PsC23 was stable in human serum and had no hemolytic or cytotoxic effect on human cells. Taken together, this VHH if co administered with the currently available carbapenems would reverse carbapenem resistance and could be used to effectively controlP. aeruginosain critical care settings.
Mapping MAVE data for use in human genomics applications
Authors: Arbesfeld Jeremy A. , Da Estelle Y. , Stevenson James S. , Kuzma Kori , Paul Anika , Farris Tierra , Capodanno Benjamin J. , Grindstaff Sally B. , Riehle Kevin , Saraiva-Agostinho Nuno , Safer Jordan F. , Milosavljevic Aleksandar , Foreman Julia , Firth Helen V. , Hunt Sarah E. , Iqbal Sumaiya , Cline Melissa S. , Rubin Alan F. , Wagner Alex H. 
Published: June 2023

AbstractThe large-scale experimental measures of variant functional assays submitted to MaveDB have the potential to provide key information for resolving variants of uncertain significance, but the reporting of results relative to assayed sequence hinders their downstream utility. The Atlas of Variant Effects Alliance mapped multiplexed assays of variant effect data to human reference sequences, creating a robust set of machine-readable homology mappings. This method processed approximately 2.5 million protein and genomic variants in MaveDB, successfully mapping 98.61% of examined variants and disseminating data to resources such as the UCSC Genome Browser and Ensembl Variant Effect Predictor.
Differential roles of diet on development and spinal cord regeneration in larval zebrafish
Authors: Purifoy Emily J. , Mruk Karen 
Published: June 2023

AbstractThe zebrafish is a powerful model organism for studying development and regeneration. However, there is a lack of a standardized reference diet. Most studies evaluate the rate of growth, survival and fecundity. In this study, we compare three diets and their effects on growth and regeneration after a spinal cord injury (SCI). Fish were fed daily for one week with daily measurements of overall length and width of spinal injury. Significant different in length after the trial were observed between live feed and commercial feeds. Similarly, differences in rate of regeneration were observed. Our data highlights the need for establishing a standardized diet for regeneration studies to improve research reproducibility.
RIBO-former: leveraging ribosome profiling information to improve the detection of translated open reading frames
Authors: Clauwaert Jim , McVey Zahra , Gupta Ramneek , Menschaert Gerben 
Published: June 2023

AbstractRibosome profiling is a deep sequencing technique used to chart translation by means of mRNA ribosome occupancy. It has been instrumental in the detection of non-canonical coding sequences. Because of the complex nature of next-generation sequencing data, existing solutions that seek to identify translated open reading frames from the data are still not perfect. We propose RIBO-former, a new approach featuring several innovations for thede novoannotation of translated coding sequences. RIBO-former is built using recent transformer models that have achieved considerable advancements in the field of natural language processing. The presented deep learning approach allows to omit several pre-processing steps as features are automatically extracted from the data. We discuss various steps that improve the detection of coding sequences and show that read length information of all mapped reads can be leveraged to improve the predictive performance of the tool. Our results show RIBO-former to outperform previous methodologies. Additionally, through our study we find support for the existence of translated non-canonical ORFs, present along existing coding sequences or on long non-coding RNAs. Furthermore, several polycistronic mRNAs with multiple translated coding regions were detected.
1LocusSim a mobile-friendly simulator for teaching population genetics
Authors: Carvajal-Rodríguez Antonio 
Published: June 2023

AbstractSummaryBiology students often struggle with the fundamental concepts of evolutionary genetics, including genetic drift, mutation, and selection. To address this problem, 1LocusSim was developed to simulate the interaction of different factors, such as population size, mutation, selection, and dominance, to study their effect on allelic frequency during evolution. With 1LocusSim, students can compare theoretical results with simulation outputs and solve and analyze different problems of population genetics. The 1LocusSim web has a responsive design which means that it has been specifically designed to be used on smartphones. To demonstrate its use, I review the classical overdominance model of population genetics and highlight a characteristic that is often not explicitly stated. Specifically, it is emphasized that the equilibrium of the model does not depend on the homozygous selection coefficients but rather on the ratio of the selection coefficients. This is already clear from the classical formula but maybe not so much for students. Also it implies that the equilibrium can be expressed solely in terms of the dominance coefficienth. To verify these theoretical prediction, I utilize the simulator and calculate the equilibrium for the well-known case of sickle cell anaemia.Simulating basic population genetic models on smartphones can be a powerful learning aid that fosters critical skills and opens up new opportunities for Biology students. By utilizing this tool, students can learn at their own pace and convenience, anywhere and anytime.Software and data availability1LocusSim if freely available athttps://1LocusSim-biosdev.pythonanywhere.com/. Website implemented under the Bottle micro web-framework for Python, with all major browsers supported.Contactacraaj@uvigo.esSupplementary informationThe manual and examples are available from the help button of the program or directly athttps://acraaj.webs.uvigo.es/1LocusSim/1LocusSim_EN.html. Both the program and the manual pages are in English and Spanish.
The Role of Sympathetic Innervation in Neonatal Muscle Growth and Neuromuscular Contractures
Authors: Runkel Mason T. , Tarabishi Albaraa , Shay-Winkler Kritton , Emmert Marianne E. , Goh Qingnian , Cornwall Roger 
Published: June 2023

AbstractNeonatal brachial plexus injury (NBPI), a leading cause of pediatric upper limb paralysis, results in disabling and incurable muscle contractures that are driven by impaired longitudinal growth of denervated muscles. A rare form of NBPI, which maintains both afferent and sympathetic muscle innervation despite motor denervation, protects against contractures. We have previously ruled out a role for NRG/ErbB signaling, the predominant pathway governing antegrade afferent neuromuscular transmission, in modulating the formation of contractures. Our current study therefore investigated the contributions of sympathetic innervation of skeletal muscle in modulating NBPI-induced contractures. Through chemical sympathectomy and pharmacologic modification with a β2-adrenergic agonist, we discovered that sympathetic innervation alone is neither required nor sufficient to modulate contracture formation in neonatal mice. Despite this, sympathetic innervation plays an intriguing sex-specific role in mediating neonatal muscle growth, as the cross-sectional area (CSA) and volume of normally innervated male muscles were diminished by ablation of sympathetic neurons and increased by β-adrenergic stimulation. Intriguingly, the robust alterations in CSA occurred with minimal changes to normal longitudinal muscle growth as determined by sarcomere length. Instead, β-adrenergic stimulation exacerbated sarcomere overstretch in denervated male muscles, indicating potentially discrete regulation of muscle width and length. Future investigations into the mechanistic underpinnings of these distinct aspects of muscle growth are thus essential for improving clinical outcomes in patients affected by muscle disorders in which both length and width are affected.
Body mass and growth rates predict protein intake across animals
Authors: Talal Stav , Harrison Jon F. , Farington Ruth , Youngblood Jacob P. , Medina Hector E. , Overson Rick , Cease Arianne J. 
Published: June 2023

AbstractOrganisms require dietary macronutrients in specific ratios to maximize performance, and variation in macronutrient requirements plays a central role in niche determination. Although it is well-recognized that development and body size can have strong and predictable effects on many aspects of organismal function, we lack a predictive understanding of ontogenetic or scaling effects on macronutrient intake. We determined protein and carbohydrate intake throughout development on lab populations of locusts and tested whether lab responses can predict results for field populations. Self-selected protein:carbohydrate targets declined dramatically through ontogeny, due primarily to declines in mass-specific protein consumption rates which were highly correlated with declines in specific growth rates. Importantly, lab results for protein consumption rates predicted results for field-collected locusts. However, field locusts consumed nearly double the carbohydrate, likely due to higher activity and metabolic rates. Combining our results with the available data for animals, both across species and during ontogeny, protein consumption scaled predictably and hypometrically, demonstrating a new scaling rule key for understanding nutritional ecology.