bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cited4a limits cardiomyocyte dedifferentiation and proliferation during zebrafish heart regeneration
Authors: Forman-Rubinsky Rachel , Feng Wei , Schlegel Brent T. , Paul Angela , Zuppo Daniel , Kedziora Katarzyna , Stoltz Donna , Watkins Simon , Rajasundaram Dhivyaa , Li Guang , Tsang Michael 
Published: December 2024

AbstractCardiac regeneration involves the interplay of complex interactions between many different cell types, including cardiomyocytes. The exact mechanism that enables cardiomyocytes to undergo dedifferentiation and proliferation to replace lost cells has been intensely studied. Here we report a single nuclear RNA sequencing profile of the injured zebrafish heart and identify distinct cardiomyocyte populations in the injured heart. These cardiomyocyte populations have diverse functions, including stress response, myofibril assembly, proliferation and contraction. The contracting cardiomyocyte population also involves the activation of maturation pathways as an early response to injury. This intriguing finding suggests that constant maintenance of a distinctive terminally differentiated cardiomyocyte population is important for cardiac function during regeneration. To test this hypothesis, we determined thatcited4a,a p300/CBP transcriptional coactivator, is induced after injury in the mature cardiomyocyte population. Moreover, loss-of-cited4amutants presented increased dedifferentiation, proliferation and accelerated heart regeneration. Thus, suppressing cardiomyocyte maturation pathway activity in injured hearts could be an approach to promote heart regeneration.
Brain responses vary in duration - modeling strategies and challenges
Authors: Skukies René , Schepers Judith , Ehinger Benedikt 
Published: December 2024

AbstractTypically, event-related brain responses are calculated invariant to the underlying event duration, even in cases where event durations observably vary: with reaction times, fixation durations, word lengths, or varying stimulus durations. Additionally, an often co-occurring consequence of differing event durations is a variable overlap of the responses to subsequent events. While the problem of overlap e.g. in fMRI and EEG is successfully addressed using linear deconvolution, it is unclear whether deconvolution and duration covariate modeling can be jointly used, as both are dependent on the same inter-event-distance variability. Here, we first show that failing to explicitly account for event durations can lead to spurious results and thus are important to consider. Next, we propose and compare several methods based on multiple regression to explicitly account for stimulus durations. Using simulations, we find that non-linear spline regression of the duration effect outperforms other candidate approaches. Finally, we show that non-linear event duration modeling is compatible with linear overlap correction in time, making it a flexible and appropriate tool to model overlapping brain signals. This allows us to reconcile the analysis of stimulus responses with e.g. condition-biased reaction times, condition-biased stimulus duration, or fixation-related activity with condition-biased fixation durations. While in this paper we focus on EEG analyses, these findings generalize to LFPs, fMRI BOLD-responses, pupil dilation responses, and other overlapping signals.
Chasing non-existent “microRNAs” in cancer
Authors: Orang Ayla , Warnock Nicholas I , Migault Melodie , Dredge B Kate , Bert Andrew G , Bracken Julie M , Gregory Philip A , Pillman Katherine A , Goodall Gregory J , Bracken Cameron P 
Published: December 2024

AbstractMicroRNAs (miRNAs) are important regulators of gene expression whose dysregulation is widely linked to tumourigenesis, tumour progression and Epithelial-Mesenchymal Transition (EMT), a developmental process that promotes metastasis when inappropriately activated. However, controversy has emerged regarding how many functional miRNAs are encoded in the genome, and to what extent non-regulatory products of RNA degradation have been mis-identified as miRNAs. Central to miRNA function is their capacity to associate with an Argonaute (AGO) protein and form an RNA-Induced Silencing Complex (RISC), which mediates target mRNA suppression. We report that numerous “miRNAs” previously reported in EMT and cancer contexts, are not incorporated into RISC and are not capable of endogenously silencing target genes, despite the fact that hundreds of publications in the cancer field describe their roles. Apparent function can be driven through the expression of artificial miRNA mimics which is not necessarily reflective of any endogenous gene regulatory function. We present biochemical and bioinformatic criteria that can be used to distinguish functional miRNAs from mistakenly annotated RNA fragments.
Impact of Mycotoxins and Glyphosate residue on the Gut Microbiome and Resistome of European Fallow Deer
Authors: Tóth Adrienn Gréta , Nagy Sára Ágnes , Lakatos István , Solymosi Norbert , Stágel Anikó , Paholcsek Melinda , Posta Katalin , Ferenczi Szilamér , Szőke Zsuzsanna 
Published: December 2024

ABSTRACTMycotoxins and herbicides residue significant threats to animal health. This study investigated the impact of these toxins on the gut microbiome of the fallow deer, a valuable game species. We analyzed the intestinal contents of deer exposed to varying levels of zearalenone (ZEA) and other mycotoxins and toxic compounds such as aflatoxins, deoxynivalenol, fumonisin B1 and glyphosate residues. Metagenomic analysis revealed significant alterations in the bacterial community composition, particularly in the abundance of specific taxa. Higher ZEA levels were associated with decreased alpha diversity, whereas higher aflatoxin levels had the opposite effect. We also observed changes in the abundance of antibiotic resistance genes (ARGs), suggesting a potential link between mycotoxin exposure and antimicrobial resistance. Furthermore, five complete bacterial genomes were assembled from the metagenomic data. These findings highlight the complex interplay between environmental toxins, the gut microbiota, and animal health. Understanding these interactions is crucial for developing strategies to mitigate the negative effects of toxin exposure on wildlife populations.
Structural, genetic, and adaptive basis of superhydrophobicity in rice leaves
Authors: Hiraiwa Asuka , Aiga Saori , Zhu Tian , Mimura Manaki , Yoshikawa Takanori , Sato Yutaka , Itoh Jun-ichi 
Published: December 2024

AbstractIn most plants, leaf surfaces exhibit water-repellent properties, which protect against pathogens and weather. Plants such as lotus and rice have evolved outstanding water-repellent properties, so-called superhydrophobicity. However, the structural and genetic basis of these properties in crop plants remains unclear. In this study, we identified the genes and microstructures responsible for superhydrophobicity by analyzing water repellence in rice mutants and cultivars, as well as wildOryzaspecies. Analysis of the surface structure of mutant leaves revealed that the degree of water repellency in rice largely depends on the accumulation of cuticular wax. Meanwhile, although papillae differentiation contributes minorly to water repellency, it is suggested to play a crucial role in achieving superhydrophobicity. These morphological characteristics are regulated by at least five previously characterized genes. We also found that superhydrophobicity is present in ancestral species, is retained by most cultivated rice, and appears to have evolved independently of rice domestication. Understanding the mechanisms of water repellence and their applications should provide important insight into the natural design of water repellence, as well as a basis for future innovation.
Multi-scale parameterization of neural rhythmicity with lagged Hilbert autocoherence
Authors: Zhang Siqi , Szul Maciej J , Papadopoulos Sotirios , Massera Alice , Rayson Holly , Bonaiuto James J 
Published: December 2024

AbstractAnalysis of neural activity in different frequency bands is ubiquitous in systems and cognitive neuroscience. Recent analytical breakthroughs and theoretical developments rely on phase maintenance of oscillatory signals without considering whether or not this assumption is met. Lagged (auto)coherence, the coherence between a signal and itself at increasing temporal delays, has been proposed as a way to quantify the rhythmicity, or periodicity, of a signal. However, current Fourier-based lagged autocoherence algorithms suffer from poor spectral accuracy and resolution, aliasing effects that become more pronounced at higher frequencies, and conflation with amplitude covariation, especially in frequency ranges in which the signal power is low. We introduce a continuous lagged autocoherence metric, lagged Hilbert autocoherence, that addresses these shortcomings by using multiplication in the frequency domain for precise bandpass filtering, instantaneous analytic signals via the Hilbert transform, and thresholding using the amplitude covariation of surrogate data generated by an autoregressive model. We show that this version of lagged coherence yields vastly higher spectral accuracy and resolution than lagged Fourier autocoherence, and that this unlocks additional, increasingly fine-grained applications. This includes examination of: 1) frequency-specific differences in rhythmicity between conditions, 2) changes in signal rhythmicity during learning, and 3) the relationship between frequency-specific rhythmicity and behavior, trial-by-trial. Lagged Hilbert autocoherence thus offers a significant toolset advancement for analysis of neurophysiological rhythmicity.
Cholinergic waves have a modest influence on the transcriptome of retinal ganglion cells
Authors: Somaiya Rachana Deven , Po Matthew A. , Feller Marla B. , Shekhar Karthik 
Published: December 2024

AbstractIn the early stages of development, correlated activity known as retinal waves causes periodic depolarizations of retinal ganglion cells (RGCs). The β2KO mouse, which lacks the β2 subunit of the nicotinic acetylcholine receptor, serves as a model for understanding the role of these cholinergic waves. β2KO mice have disruptions in several developmental processes of the visual system, including reduced retinotopic and eye-specific refinement of RGC axonal projections to their primary brain targets and an impact on the retinal circuits underlying direction selectivity. However, the effects of this mutation on gene expression in individual functional RGC types remain unclear. Here, we performed single-cell RNA sequencing on RGCs isolated at the end of the first postnatal week from wild-type and β2KO mice. We found that in β2KO mice, the molecular programs governing RGC differentiation were not impacted and the magnitude of transcriptional changes was modest compared to those observed during two days of normal postnatal maturation. This contrasts with the substantial transcriptomic changes seen in downstream visual system areas under wave disruption in recent studies. However, we identified ∼238 genes whose expression was altered in a type-specific manner. We confirmed this result viain situhybridization and whole-cell recording by focusing on one of the downregulated genes in aRGCs,Kcnk9, which encodes the two-pore domain leak potassium channel TASK3. Our study reveals a limited transcriptomic impact of cholinergic signaling in the retina and instead of affecting all RGCs uniformly, these waves show subtle modulation of molecular programs in a type-specific manner.SIGNIFICANCE STATEMENTSpontaneous retinal waves are critical for the development of the mammalian visual system. However, their role in transcriptional regulation in the retina across the diverse retinal ganglion cell (RGC) types that underpin the detection and transmission of visual features is unclear. Using single-cell RNA sequencing, we analyzed RGC transcriptome from wild-type mice and mice with disrupted retinal waves. We identified several genes that show RGC-type-specific regulation in their expression, including multiple neuropeptides and ion channels. However, wave-dependent changes in the transcriptome were more subtle than developmental changes, indicating that spontaneous activity-dependent molecular changes in retinal ganglion cells are not primarily manifested at the transcriptomic level.
An all-atom view into the disordered interaction interface of the TRIM5αPRYSPRY domain and the HIV capsid
Authors: Haas-Neill Liam , Meneksedag-Erol Deniz , Andeejani Ibraheem , Rauscher Sarah 
Published: December 2024

AbstractTripartite motif-containing protein 5, alpha isoform (TRIM5α) is an innate immune factor that provides rhesus macaques with immunity to HIV. Despite high sequence similarity to rhesus TRIM5α, human TRIM5αdoes not restrict HIV without the introduction of mutations. The structural underpinnings of this functional difference are poorly understood because the interaction interface between the HIV capsid and TRIM5αinvolves intrinsically disordered regions. Here, we use all-atom molecular dynamics simulations to study several TRIM5αvariants: rhesus TRIM5α, human TRIM5α, and human TRIM5αwith the R332P mutation (a mutation known to enhance HIV restriction). Our data reveal differences in the conformational ensembles of wild-type and R332P human TRIM5α, including a significant increase in the formation of a turn that includes the mutation site residue. We also carried out simulations of rhesus TRIM5αin complex with the HIV capsid protein. Our results indicate that the variable loops of TRIM5αare highly flexible, both in solution and in the complex with the capsid protein, indicative of a fuzzy interaction interface. Simulations of the complex suggest a plausible mechanism for HIV restriction by TRIM5αwith the R332P mutation; replacing the positively charged arginine with a neutral residue enhances electrostatic interactions with residue R82 of the capsid protein. Overall, our simulations provide a first view of the atomistic details of the HIV capsid-TRIM5αbinding interface, providing a potential molecular mechanism for the observed functional differences between variants of the TRIM5αprotein.
Conceptualizing Ribosomal mRNA Unwinding Utilizing DMS MaP-Seq
Authors: Kellenberger Preston A. , Cornish Peter V. 
Published: December 2024

AbstractExamining the dynamicity of RNA structure has deepened our understanding of its vast biological functions. Perhaps the protein complex that encounters the most diverse landscape of RNA structure is the ribosome. In translation, the ribosome must linearize countless mRNA conformations for proper protein production. Some RNA structures, however, reliably make up sequences which hinder the ability of the ribosome to maintain its reading frame. Arguably, the most well-studied of these structures is the RNA pseudoknot. Here, we present an approach utilizing dimethyl sulfate probing with mutational profiling and sequencing (DMS MaP-Seq) to precisely examine RNA unwinding. DMS MaP-Seq is a method typically used in predicting RNA secondary structure. Instead, we employ the method to understand the unfolding of the Sugarcane Yellow Leaf Virus pseudoknot (ScYLVPK). We demonstrate that the unwinding of ScYLVPKis inherently different with regards to the ribosome and temperature. Additionally, we find that minor-groove triplex interactions support coaxial stacking, providing a major source of stability to ScYLVPKin ribosomal unwinding.
Efficacy and Best Practices of Health-care worker Smoking Cessation Treatment in Sub-Saharan Africa
Authors: Davison W. , Sime M. , Khan W. , Yamoah E. , Bhurji K. , Surti R. 
Published: December 2024

AbstractBackgroundTobacco smoking causes over 8 million deaths annually worldwide and is expected to increase by 148% in sub-Saharan Africa by 2030. This puts significant strain on already heavily burdened healthcare systems. Healthcare workers (HCWs) are at the forefront of patient care and play a crucial role in smoking cessation (SC) efforts.ObjectivesTo assesses the effectiveness and identify barriers to smoking cessation provision by HCWs in sub-Saharan Africa.MethodA systematic review was conducted in accordance with PRISMA guidelines to retrieve studies relevant to the implementation of SC strategies in sub-Saharan Africa and research on the barriers and facilitators of the adoption of SC practices. Studies were retrieved from PubMed, Medline, Ovid, Cochrane Library and Scopus; all included literature was published in English after 2014. Risk of bias and methodological quality were evaluated through the Critical Appraisal Skills Programme (CASP) tool.ResultsTwelve studies met the inclusion criteria. HCWs in sub-Saharan with formal training were more likely to offer SC interventions, with lack of training and resources identified as key barriers. Greater HCW engagement with patients also facilitated SC efforts. Inadequate resources, cultural differences and structural failures were further barriers. Socioeconomic and educational differences also influenced quit attempts, with wealthier and better-educated individuals more likely to quit.DiscussionHCW competency and training significantly impacts SC efforts, suggesting the need for comprehensive programs to boost HCW skills and knowledge. Socioeconomic and cultural factors also affected SC outcomes, highlighting the need for tailored health campaigns.However, the heterogenicity of the evidence base makes it challenging to compare SC interventions and determine if identified barriers are only region specific or generalisable.ConclusionHCW training and support is crucial for SC provision across sub-Saharan Africa, but structural barriers and sociocultural challenges must be addressed for these programs to succeed. Interventions should therefore both empower HCWs and be tailored to the local area.
Structure and Cl-Conductance Properties of the Open State of Human CFTR
Authors: Zeng Zhi-Wei , Ing Christopher E. , Pomès Régis 
Published: December 2024

AbstractThe cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that plays a vital role in water and ion secretion on epithelial surfaces. Loss of function in CFTR causes the life-threatening disease cystic fibrosis (CF). The functionally open state of CFTR has so far eluded detailed structural characterization. Although multiple near-atomic resolution structures of CFTR have been solved under conditions that promote channel opening, they all lack a continuous ion conduction pathway. In recent molecular dynamics (MD) simulations, structural fluctuations of human CFTR in a hydrated lipid bilayer led to the observation of transient Cl-conducting states, but the stability and conduction properties of these putative open states were not established. Here, we conduct massively repeated simulations initiated from these Cl-permeable conformations. Reproducible structural relaxation of the pore leads to a stable open conformation featuring five symmetrically arranged pore-lining helices. Unlike previously reported structures, this novel penta-helical arrangement reproduces experimentally determined properties of the open pore, including a Cl-conductance close to that measured at physiological voltages. Together, our results support the validity of this newly identified pore conformation as a model of the fully open channel. Detailed analysis highlights the role of cationic pore-lining residues in the Cl-permeation mechanism and suggests that the kinks observed in several transmembrane helices play a role in channel gating.
Naturally ornate RNA-only complexes revealed by cryo-EM
Authors: Kretsch Rachael C. , Wu Yuan , Shabalina Svetlana A. , Lee Hyunbin , Nye Grace , Koonin Eugene V. , Gao Alex , Chiu Wah , Das Rhiju 
Published: December 2024

AbstractMyriad families of natural RNAs have been proposed, but not yet experimentally shown, to form biologically important structures. Here we report three-dimensional structures of three large ornate bacterial RNAs using cryogenic electron microscopy at resolutions of 2.9-3.1 Å. Without precedent among previously characterized natural RNA molecules, Giant, Ornate, Lake- and Lactobacillales-Derived (GOLLD), Rumen-Originating, Ornate, Large (ROOL), and Ornate Large Extremophilic (OLE) RNAs form homo-oligomeric complexes whose stoichiometries are retained at concentrations lower than expected in the cell. OLE RNA forms a dimeric complex with long co-axial pipes spanning two monomers. Both GOLLD and ROOL form distinct RNA-only multimeric nanocages with diameters larger than the ribosome. Extensive intra- and intermolecular A-minor interactions, kissing loops, an unusual A-A helix, and other interactions stabilize the three complexes. Sequence covariation analysis of these large RNAs reveals evolutionary conservation of intermolecular interactions, supporting the biological importance of large, ornate RNA quaternary structures that can assemble without any involvement of proteins.
Cis-Regulatory Evolution of CCNB1IP1 Driving Gradual Increase of Cortical Size and Folding in primates
Authors: Hu Ting , Kong Yifan , Tan Yulian , Ma Pengcheng , Wang Jianhong , Sun Xuelian , Xiang Kun , Mao Bingyu , Wu Qingfeng , Yi Soojin V. , Shi Lei 
Published: December 2024

AbstractNeocortex expansion has a concerted relationship with folding, underlying evolution of human cognitive functions. However, molecular mechanisms underlying this significant evolutionary process remains unknown. Here, using tree shrew as an outgroup of primates, we identify a new regulatorCCNB1IP1,which acquired its expression before the emergence of primates. Following the evolution of cis-regulatory elements, the CCNB1IP1 expression has steadily increased over the course of primate brain evolution, mirroring the gradual increase of neocortex. Mechanistically, we elucidated that CCNB1IP1 expression can cause an increase in neural progenitors through shortening G1 phase. Consistently, the CCNB1IP1 knock-in mouse model exhibited traits associated with enhanced learning and memory abilities. Together, our study reveals how changes inCCNB1IP1expression may have contributed to the gradual evolution in primate brain.
Cell-type specific autophagy in human leukocytes
Authors: Dang Linh VP , Martin Alexis , Carosi Julian M , Gore Jemima , Singh Sanjna , Sargeant Timothy J 
Published: December 2024

AbstractAutophagy is a naturally conserved mechanism crucial for degrading and recycling damaged organelles and proteins to support cell survival. This process slows biological ageing and age-related disease in preclinical models. However, there has been little translation of autophagy to the clinic, and we have identified a lack of measurement tools for physiological human autophagy as a barrier. To address this, we have previously developed a direct measurement tool for autophagy in pooled human peripheral blood mononuclear cells (PBMCs) in the context of whole blood. In order to better understand how autophagy behaves and changes in humans, we measured human autophagic flux using flow cytometry in 19 cell sub-populations in whole blood to retain physiological flux. Autophagic flux was different between different cell types, being highest in B lymphocytes and lowest in T lymphocytes and monocytes. Autophagic flux also varied with sex, being higher in monocytes in females compared with males. In keeping with previous observations in humans, autophagy also increased with ageing at sub-population levels. Importantly, we found that only monocytes – specifically, non-classical monocytes – displayed increased autophagic flux following amino acid withdrawal, underscoring the importance of population selection for measurement of autophagic flux during nutrient restriction studies in humans. Collectively, these data show PBMC population level analysis improves sensitivity of human autophagic flux measurement.