bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mating and ecdysone signaling modify growth, metabolism, and digestive efficiency in the femaleDrosophilagut
Authors: Kandelouei Tahmineh , Houghton Madeline E. , Lewis Mitchell R. , Keller Caroline C. , Marchetti Marco , Kang Xiaoyu , Edgar Bruce A. 
Published: November 2024

ABSTRACTAdaptive changes in organ size and physiology occur in most adult animals, but how these changes are regulated is not well understood. Previous research found that mating inDrosophilafemales drives not only increases in gut size and stem cell proliferation but also alters feeding behavior, intestinal gene expression, and whole-body lipid storage, suggesting altered gut metabolism. Here, we show that mating dramatically alters female gut metabolism and digestive function. In addition to promoting a preference for a high-protein diet, mating also altered levels of TCA cycle intermediates and fatty acids in the gut, increased total gut lipids and protein, reduced relative carbohydrate levels, and enhanced the efficiency of protein digestion relative to carbohydrate digestion. The expression of genes that mediate each of these metabolic processes was similarly altered. In addition, we noted the mating-dependent downregulation of oxidative stress response and autophagy genes. Mating-dependent increases in ecdysone signaling played an important role in re-programming many, but not all, of these changes in the female gut. This study contributes to our understanding of how steroid signaling alters gut physiology to adapt to the demands of reproduction.
Medication and pharmacogenomic effects on cross-sectional symptom severity and cognitive ability in schizophrenia
Authors: Lock Siobhan K. , Kappel Djenifer B. , Owen Michael J. , Walters James T.R. , O’Donovan Michael C. , Pardiñas Antonio F. , Legge Sophie E. 
Published: November 2024

AbstractBackgroundPeople with schizophrenia differ in the type and severity of symptoms experienced, as well as their response to medication. A better understanding of the factors that influence this heterogeneity is necessary for the development of individualised patient care. Here, we sought to investigate the relationships between phenotypic severity and both medication and pharmacogenomic variables in a cross-sectional sample of people with schizophrenia or schizoaffective disorder depressed type.MethodsConfirmatory factor analysis derived five dimensions relating to current symptoms (positive symptoms, negative symptoms of diminished expressivity, negative symptoms of reduced motivation and pleasure, depression and suicide) and cognitive ability in participants prescribed with antipsychotic medication. Linear models were fit to test for associations between medication and pharmacogenomic variables with dimension scores in the full sample (N = 585), and in a sub-sample of participants prescribed clozapine (N = 215).OutcomesLower cognitive ability was associated with higher chlorpromazine-equivalent daily antipsychotic dose and with the prescription of clozapine and anticholinergic medication. We also found associations between pharmacogenomics-inferred cytochrome P450 (CYP) enzyme activity and symptom dimensions. Increased genotype-predicted CYP2C19 and CYP3A5 activity were associated with reduced severity of positive and negative symptoms, respectively. Faster predicted CYP1A2 activity was associated with higher cognitive dimension scores in people taking clozapine.InterpretationOur results confirm the importance of taking account of medication history (and particularly antipsychotic type and dose) in assessing potential causes of cognitive impairment or poor functioning in patients with schizophrenia. We also highlight the potential for pharmacogenomic variation to be a useful tool to help guide drug prescription, although these findings require further validation.
Understanding the influence of leadership, organisation, and policy on delivering an integrated child health and social care service in community settings: A qualitative exploration using the SELFIE framework
Authors: Litchfield I , Harper L , Abbas S , Dutton F , Wolhuter C , Bird C 
Published: November 2024

AbstractIntroductionIt’s understood in the UK that integrated care is well-placed to address the prevalence of chronic conditions, obesity, and mental ill health in children and young people (CYP) living in minoritized and economically-marginalised communities in high-income countries. The Sparkbrook Childrens’ Zone is an example of a place-based integrated health and social care service situated in a super-diverse community in a large post-industrial city, developed to support children and young people. To realise its potential, it’s important to understand the organizational and infrastructural requirements of a service combining clinical and non-clinical staff from a range of organisations and backgrounds. This will improve the current service offer and inform the design and delivery of similar initiatives.Materials and Methods,We conducted a qualitative exploration of the experiences of staff delivering the service and used a directed content analysis to populate and present the results within the Sustainable integrated chronic care model for multi-morbidity: delivery, financing, and performance (SELFIE) framework. The analysis presented here focuses on the domains of Leadership and Governance, Workforce, Financing, and Information and Research.ResultsA total of 14 staff were interviewed including clinicians from primary and secondary care, social care providers, local voluntary groups, and school-based family mentors. Staff described the gap between integration at system level and the absence of process and support to deliver a unified health and social care service in real-world environments. The benefits of supportive and accessible leadership, and an open, learning environment were described, as was the trust developed through meaningful consultations with local communities. The lack of administrative support was noticeable, particularly when managing a workforce drawn from multiple organisations, as was the lack of secure funding and the need for reliable long-term evidence to inform decisions on design and funding.ConclusionsDespite decades of structural reform aimed at integrating the health and social care system in the UK, there was a surprising lack of system-level practical support for delivering a place-based integrated health and care service. The balance remained to be struck between the need to demonstrate benefits for short term funding cycles and the reliability of evidence being gathered from a complex and evolving service.
Profiling Epigenetic Aging at Cell-Type Resolution Through Long-Read Sequencing
Authors: Eames Alec , Moqri Mahdi , Poganik Jesse R. , Gladyshev Vadim N. 
Published: November 2024

AbstractDNA methylation can give rise to robust biomarkers of aging, yet most studies profile it at the bulk tissue level, which masks cell type-specific alterations that may follow distinct aging trajectories. Long-read sequencing technology enables methylation profiling of extended DNA fragments, which allows mapping to their cell type of origin. In this study, we introduce a framework for evaluating cell type-specific aging using long-read sequencing data, without the need for cell sorting. Leveraging cell type-specific methylation patterns, we map long-read fragments to individual cell types and generate cell type-specific methylation profiles, which are used as input to a newly developed probabilistic aging model, LongReadAge, capable of predicting epigenetic age at the cell-type level. We apply LongReadAge to track aging of myeloid cells and lymphocytes from bulk leukocyte data as well as circulating cell-free DNA, demonstrating robust performance in predicting age despite limited shared features across samples. This approach provides a novel method for profiling the dynamics of epigenetic aging at cell-type resolution.
Histone H3 N-terminal recognition by the PHD finger of PHRF1 is required for proper DNA damage response
Authors: Jain Kanishk , Tchara Pata-Eting Kougnassoukou , Mengistalem Amanuel B. , Holland Aidan P. , Bowman Christopher N. , Marunde Matthew R. , Popova Irina K. , Cooke Spencer W. , Krajewski Krzysztof , Keogh Michael-Christopher , Lambert Jean-Philippe , Strahl Brian D. 
Published: November 2024

ABSTRACTPlant homeodomain (PHD) fingers are critical effectors of histone post-translational modifications (PTMs), acting as regulators of gene expression and genome integrity, and frequently presenting in human disease. While most PHD fingers recognize unmodified and methylated states of histone H3 lysine 4 (H3K4), the specific functions of many of the over 100 PHD finger-containing proteins in humans remain poorly understood, despite their significant implications in disease processes. In this study, we undertook a comprehensive analysis of one such poorly characterized PHD finger-containing protein, PHRF1. Using biochemical, molecular, and cellular approaches, we show that PHRF1 robustly binds to histone H3, specifically at its N-terminal region. Through RNA-seq and proteomic analyses, we also find that PHRF1 is intricately involved in transcriptional and RNA splicing regulation and plays a significant role in DNA damage response (DDR). Crucially, mutagenesis of proline 221 to leucine (P221L) in the PHD finger of PHRF1 abolishes histone interaction and fails to rescue defective DDR. These findings underscore the importance of PHRF1-H3 interaction in maintaining genome integrity and provide insight into how PHD fingers contribute to chromatin biology.
The nucleocapsid (N) proteins of different human coronaviruses demonstrate a variable capacity to induce the formation of cytoplasmic condensates
Authors: Tikhomirova Maria A. , Kuzmenko Oleg L. , Arifulin Eugene A. , Shirokova Olesya M. , Musinova Yana R. , Sheval Eugene V. 
Published: November 2024

AbstractTo date, seven human coronaviruses (HCoVs) have been identified. Four of these viruses typically manifest as a mild respiratory disease, whereas the remaining three can cause severe conditions that often result in death. The reasons for these differences remain poorly understood, but may be related to the properties of individual viral proteins. The nucleocapsid (N) protein plays a crucial role in the packaging of viral genomic RNA and the modification of host cells during infection, in part due to its capacity to form dynamic biological condensates via liquid-liquid phase separation (LLPS). In this study, we investigated the capacity of N proteins derived from all HCoVs to form condensates when transiently expressed in cultured human cells. A fraction of the transfected cells were observed to contain cytoplasmic granules in which the most of the N proteins were accumulated. Notably, the N proteins of SARS-CoV and SARS-CoV-2 showed a significantly reduced tendency to form cytoplasmic condensates. The condensate formation was not a consequence of overexpression of N proteins, as is typical for LLPS-inducing proteins. These condensates contained components of stress granules (SGs), indicating that the expression of N proteins caused the formation of SGs, which integrate N proteins. Thus, the N proteins of two closely related viruses, SARS-CoV and SARS-CoV-2, have the capacity to antagonize SG induction and/or assembly, in contrast to all other known HCoVs.
Verification of radical pair mechanism predictions for weak magnetic field effects on superoxide in planarians
Authors: Rishabh  , Vučković Jana , Zadeh-Haghighi Hadi , Beane Wendy S. , Simon Christoph 
Published: November 2024

AbstractSuperoxide concentration and tissue regeneration in planarians exhibit a complex non-monotonic dependence on the strength of an applied weak magnetic field. While this is difficult to understand based on classical physics, a recently proposed quantum model based on a flavinsuperoxide radical pair mechanism could replicate the previously observed superoxide concentrations. However, this model also predicts increased superoxide concentrations for both lower and higher fields. This seemed to conflict with earlier experimental observations on blastema sizes, which were correlated with superoxide in the previously observed regime but were known not to follow the predicted trends for lower and higher fields. Motivated by this apparent contradiction, we here directly experimentally tested the predictions of the quantum model for superoxide for lower and higher fields. To our own surprise, our experiments confirmed the predictions of the radical pair model for superoxide, and incorporating interactions with multiple nuclei further improved the model’s agreement with the experimental data. While open questions remain regarding the exact relationship between blastema sizes and superoxide, which is revealed to be more complex than previously observed, and the detailed properties of the underlying radical pair, our results significantly support a quantum biological explanation for the observed magnetic field effects.
Structural molecular and developmental evidence for cell-type diversity in cnidarian mechanosensory neurons
Authors: Baranyk Julia , Malir Kristen , A. P. Silva Miguel , Rieck Sakura , Scheve Gracie , Nakanishi Nagayasu 
Published: November 2024

AbstractDeploying a conserved mechanosensory neuron known as the concentric hair cell, cnidarians have evolved diverse mechanoreceptors from hydroid filiform tentacles to jellyfish statocysts. However, it is unknown whether cnidarian mechanoreceptor evolution has relied solely on repurposing a single ancestral mechanosensory neuron type. Here we report evidence for cell-type diversity of mechanosensory neurons in sea-anemone cnidarianNematostella vectensis.Uncovered in the ectoderm of feeding tentacles are conventional type I hair cells and previously unrecognized type II hair cells differing in the structure of apical sensory apparatus and synapses. Moreover, we identify TRP channel-encoding genepolycystin-1as a type-II-hair-cell-specific essential mediator of gentle touch response. Ontogenically, type I and type II hair cells derive from distinct postmitotic precursors that begin forming at different phases of larval development. Taken together, our findings suggest that anatomically, molecularly, and developmentally distinct mechanosensory neurons diversified within Cnidaria, or prior to the divergence of Cnidaria and Bilateria.
Filamentation profile reveals several transcription regulators that contribute to differences betweenCandida albicansandCandida dubliniensis
Authors: Meza-Davalos Teresa , García-Ortega Luis F. , Mancera Eugenio 
Published: November 2024

ABSTRACTCandida dubliniensisis the most closely related species toC. albicans,one of the leading causes of fungal infections in humans. However, despite sharing many characteristics,C. dubliniensisis significantly less pathogenic. To better understand the molecular underpinnings of these dissimilarities, we focused on the regulation of filamentation, a developmental trait fundamental for host colonization. We generated a collection of 44C. dubliniensisnull mutants of transcription regulators whose orthologs inC. albicanshad been previously implicated in filamentous growth. These regulators are very similar at the sequence level, but phenotypic screening identified several mutants with contrasting interspecific filamentation phenotypes, beyond previously known differences. Bcr1, a well-known regulator of biofilm formation, stands out as its mutant only showed a filamentation defect inC. dubliniensis. Phenotypic and transcriptional characterization showed that thebcr1defect is condition dependent and that this regulator plays a central role in the filamentation ofC. dubliniensis, possibly by regulating the hyphal activator Ume6. Overall, our results suggest that several regulatory pathways are involved in the filamentation differences betweenC. albicansandC. dubliniensisand show that theC. dubliniensismutant collection is a valuable resource to compare, at a molecular level, these two species of medical relevance.AUTHOR SUMMARYThe yeastCandida albicansis one of the most important fungal pathogens for humans. Its ability to form filamentous cells is central for the colonization of the human body. AlthoughCandida dubliniensis, the closest known relative toC. albicans, is also able to filament, it is a much rarer cause of disease. Part of the virulence differences between these species have been attributed to their filamentation dissimilarities, but we are just starting to understand the regulatory pathways that control filamentation inC. dubliniensis. Here, we generated a collection of gene-deletion mutants inC. dubliniensisof the orthologs of transcription regulators that have been associated with filamentation inC. albicans. Comparative profile of the collection revealed that several regulators contribute to the filamentation dissimilarities between the two species. Among these, our results identified Bcr1 as a regulator with a prominent role controlling filamentation inC. dubliniensis, showing that its target genes have considerably changed betweenC. albicansandC. dubliniensis. Our findings and the collection of mutants that we generated open new opportunities to better understand the molecular mechanisms that underlie the pathogenicity of these clinically important microorganisms.
Human eIF2A has a minimal role in translation initiation and in uORF-mediated translational control
Authors: Roiuk Mykola , Neff Marilena , Teleman Aurelio A. 
Published: November 2024

SUMMARYInitiation of translation on eukaryotic mRNAs requires a 40S ribosome loaded with an initiator tRNA in order to scan for, and to identify, an initiation codon. Under most conditions, the initiator tRNA is recruited to the ribosome as part of a ternary complex composed of initiator tRNA, eIF2 and GTP. Although this function of recruiting the initiator tRNA was originally ascribed to another factor, eIF2A, it was later disproven and shown to belong to eIF2. Nonetheless, eIF2A is still considered a translation initiation factor because it binds the ribosome and shows genetic interactions with other initiation factors such as eIF4E. The exact function of eIF2A during translation initiation, however, remains unclear. We systematically test here by ribosome profiling and luciferase reporter assays the role of eIF2A in translation initiation, including translation of upstream ORFs that are either initiated with a canonical AUG or near-cognate codons. Since eIF2A is thought to take over the function of eIF2 when eIF2 is inhibited, we also test conditions where the integrate stress response is activated, thereby leading to eIF2 inactivation. In none of our assays, however, could we detect a role of eIF2A in translation initiation. We propose that instead eIF2A may be playing a function related to other aspects of RNA biology.
Integrative Computational Framework,Dyscovr, Links Mutated Driver Genes to Expression Dysregulation Across 19 Cancer Types
Authors: Geraghty Sara , Boyer Jacob A. , Fazel-Zarandi Mahya , Arzouni Nibal , Ryseck Rolf-Peter , McBride Matthew J. , Parsons Lance R. , Rabinowitz Joshua D. , Singh Mona 
Published: November 2024

SUMMARYThough somatic mutations play a critical role in driving cancer initiation and progression, the systems-level functional impacts of these mutations—particularly, how they alter expression across the genome and give rise to cancer hallmarks—are not yet well-understood, even for well-studied cancer driver genes. To address this, we designed an integrative machine learning model, Dyscovr, that leverages mutation, gene expression, copy number alteration (CNA), methylation, and clinical data to uncover putative relationships between nonsynonymous mutations in key cancer driver genes and transcriptional changes across the genome. We applied Dyscovr pan-cancer and within 19 individual cancer types, finding both broadly relevant and cancer type-specific links between driver genes and putative targets, including a subset we further identify as exhibiting negative genetic relationships. Our work newly implicates–and validates in cell lines–KBTBD2and mutantPIK3CAas putative synthetic lethals in breast cancer, suggesting a novel combinatorial treatment approach.HIGHLIGHTSIntegrative framework Dyscovr links mutations within cancer drivers to downstream expression changesDyscovr uncovers known and novel targets of cancer-driver genesDyscovr reveals clinically important negative genetic interaction pairingsWeb platform to explore uncovered driver gene-target relationshipseTOC BLURBAn integrative computational framework, Dyscovr, links mutated cancer driver genes to expression changes in putative target genes within and across 19 TCGA cancer types. Dyscovr’s results include experimentally verifiable synthetic lethal driver-target pairings.Graphical abstract
Beyond the Surface: Revealing the Depths of Brain Activity by Predicting fMRI from EEG with Deep Learning
Authors: Semenkov Ilia , Rudych Pavel , Ossadtchi Alex 
Published: November 2024

AbstractElectroencephalography (EEG) and functional magnetic resonance imaging (fMRI) are the two most commonly used non-invasive methods for studying brain function, having different but complementary strengths: high temporal resolution of the former and high spatial resolution of the latter. Crucially, fMRI is vital for studying subcortical areas, as those are practically out of reach for conventional EEG. At the same time, EEG is cost-effective and, thus, often preferable to fMRI if comparable information could be extracted which is not the case then the deep subcortical brain activity is of interest. Here we explore the possibility of recovering subcortical hemodynamics from the non-invasively recorded scalp EEG signals. To this end, we have developed a lightweight EEG-to-fMRI neural network and using an extended and publicly available dataset with concurrently recorded EEG-fMRI data show that our model allows for the prediction of the detailed Blood Oxygenation Level Dependent (BOLD) activity of 7 bilaterally symmetric subcortical structures solely from multichannel EEG data. We report the performance significantly above chance and exceeding the scores achieved for a single subcortical structure and obtained on the proprietary datasets. In contrast to the studies focusing on a single subcortical region in our approach we were able to decode multichannel EEG into 14 + 4 region-specific variations of BOLD signals measured relative to their mean hemodynamic activity. The use of relative BOLD signals allowed us to exert control over the artificial inflation of decoding accuracy scores when the decoder predicts the common mode component that is likely to have a non-neuronal origin (heartbeat, movement, etc). Finally, we interpreted our model. The electrical activity of the sensorimotor cortex appeared to contribute most to the prediction of the subcortical hemodynamics. Also, the hemodynamics of the thalamus has the smallest delay with respect to the EEG signals. Both observations are physiologically plausible and ensure the potential reliability of the decoder. Taken together, these findings pave the road towards the creation of low-cost AI-powered EEG-based fMRI digital twin technology capable of tracking subcortical activity in an ecological setting. The technology, once mature, will find numerous applications from fundamental neuroscience through diagnostics to neurorehabilitation and affective neurointerfaces.12