bluuebunny/crossref_metadata_2025_split huggingface dataset:
The brain dynamics of congenitally blind people seeing faces with sound
Authors: Matusz Pawel J. , Reich Lior , Stolz Louise A. , Retsa Chrysa , Tovar David A. , Striem-Amit Ella , Aggius-Vella Elena , Amedi Amir , Murray Micah M. 
Published: January 2025

SummarySensory substitution devices (SSDs) convert images to sounds to equip blind individuals with nominally visual functions, like face or letter sensitivity. Prior studies showed that image-to-sound SSDs engage cortices ordinarily specialised for visual functions. However, the brain dynamics of SSD-supported perception remains unknown. Either visual cortices are the first locus of discrimination of SSD percepts, or their activation is a byproduct of perceptual processes unfurling elsewhere, such as in auditory cortices. Resolving this uncertainty is critical for understanding whether the blind truly “see” via SSDs. Using electrical neuroimaging of EEG data from congenitally blind adults, we show for the first time that inferotemporal visual cortices are the earliest site of face sensitivity when conveyed via SSDs. The blind do indeed “see” with SSDs. By providing the temporal dynamics of SSD perception, our findings provide unique evidence for the theory that cortices are characterised by task-contingent functional organisation.HighlightsSensory substitution devices (SSDs) convert information from one sense to anotherSSDs can provide the blind with alternative access to visual informationBrain dynamics in visual cortices to SSD-conveyed object images are unknownEEG electrical neuroimaging revealed face sensitivity within 500ms post-sound onsetLocalized to fusiform regions, this face sensitivity shows the blind see with soundeTOC blurbWe show for the first time that inferotemporal visual cortices are the earliest site of face sensitivity when conveyed via SSDs. The blind do indeed “see” with SSDs. Our findings of the temporal dynamics of SSD perception uniquely support the theory that cortices are characterised by task-selective sensory-independent functional organisation.
Dissecting the molecular basis underlying mycobacterial cell-wall hydrolysis by the catalytic domains ofD29LysA andDS6ALysA phage endolysins
Authors: Ceballos-Zúñiga Fernando , Gálvez-Larrosa Laura , Muñoz Inés G. , Infantes Lourdes , Pérez-Dorado Inmaculada 
Published: January 2025

AbstractMycobacteria encompass a broad range of microorganisms that cause infections with a significant impact on human health, resulting in millions of deaths each year. From tuberculosis and leprosy, caused byMycobacterium tuberculosisandMycobacterium leprae, respectively, to infections caused by emerging/opportunistic pathogens such asMycobacterium abscessus. The battle to combat this health burden is further challenged by limitations in the treatments currently available and the rise of antimicrobial resistance. This underscores the need for new therapeutic strategies to combat these infections. Mycobacteriophage LysA endolysins are complex, multi-domain peptidoglycan hydrolases with reported antimicrobial relevance and the potential to treat mycobacterial infections. However, despite the therapeutic prospects of LysAs, our understanding of their mechanism of action remains limited. This study provides a comprehensive structural-functional analysis of the catalytic domains of two LysA endolysins encoded by the bacteriophagesD29andDS6A, which are known to infect pathogenic mycobacteria, includingM. tuberculosis. As part of this work, we have characterized the four catalytic domains present in both endolysins (D29N4/D29GH19 andDS6AGH19/DS6AAmi2B) both alone and in complex with PG analogues. To achieve this, we combined protein engineering, X-ray crystallography, small-angle X-ray scattering, andin silicotools. To our knowledge, this has led to the first experimental structures reported for mycobacteriophage endolysins, which reveals key aspects of peptidoglycan binding and hydrolysis byD29LysA andDS6ALysA lysins, as well as other homologous LysAs, including the hydrolase domains similar to those examined here. Altogether, this represents a significant step forward in understanding how mycobacterial cell-wall hydrolysis occurs by this important class of endolysins and opens the door to their future use in therapeutic applications as enzybiotics. Information that will allow the rational design ofa la carteenzymes with optimized lytic properties against mycobacterial pathogens.
Functional recovery of adult brain tissue arrested in time during cryopreservation by vitrification
Authors: German Alexander , Akdaş Enes Yağız , Flügel-Koch Cassandra , Fejtova Anna , Winkler Jürgen , Alzheimer Christian , Zheng Fang 
Published: January 2025

AbstractCryopreserving adult brain tissue is challenging due to damage from ice formation, and traditional freezing methods fail to maintain neural architecture and function. Vitrification is a promising alternative to freezing, but its application to brain tissue has remained largely unexplored. Here, we demonstrate near-physiological recovery of adult mouse hippocampal slices after vitrification and rewarming. Key features of this cognitive hub are preserved, including structural integrity, metabolic responsiveness, neuronal excitability, and synaptic transmission and plasticity. Notably, hippocampal long-term potentiation was well preserved, indicating that the cellular machinery of learning and memory remains operational. These findings extend the knowledge of brain recovery after hypothermic shutdown to recovery after complete cessation of molecular mobility through vitrification. This suggests that brain tissue can be arrested in time and reactivated, opening avenues for potential clinical applications.TeaserBrain tissue is arrested in time by vitrification and reactivated, with neuronal and synaptic function preserved.
Old World alphaviruses use distinct mechanisms to infect brain microvascular endothelial cells for neuroinvasion
Authors: Alvarez Pablo A. , Tang Ashley , Winters Declan M. , Kaushal Prashant , Medina Angelica , Kaczor-Urbanowicz Karolina E. , Ramirez Reyes Bryan , Kaake Robyn M. , Fregoso Oliver I. , Pyle April D. , Bouhaddou Mehdi , Tang Hengli , Li Melody M.H. 
Published: January 2025

SUMMARYSeveral alphaviruses bypass the blood-brain barrier (BBB), causing debilitating or fatal encephalitis. Sindbis virus (SINV) has been extensively studiedin vivoto understand alphavirus neuropathogenesis; yet the molecular details of neuroinvasion at the BBB remain poorly understood. We investigated alphavirus-BBB interactions by pairing a physiologically relevant, human pluripotent stem cell derived model of brain microvascular endothelial cells (BMECs) with SINV strains of opposite neuroinvasiveness. Our system demonstrates that SINV neuroinvasion correlates with robust infection of the BBB. Specifically, SINV genetic determinants of neuroinvasion enhance viral entry into BMECs. We also identify solute carrier family 2 member 3 (SLC2A3, also named GLUT3) as a potential BMEC-specific entry factor exploited for neuroinvasion. Strikingly, efficient BBB infection is a conserved phenotype that correlates with the neuroinvasive capacity of several Old World alphaviruses, including chikungunya virus. Here, we reveal BBB infection as a shared pathway for alphavirus neuroinvasion that can be targeted for preventing alphavirus-induced encephalitis.
Causal modeling of gene effects from regulators to programs to traits: integration of genetic associations and Perturb-seq
Authors: Ota Mineto , Spence Jeffrey P. , Zeng Tony , Dann Emma , Marson Alexander , Pritchard Jonathan K. 
Published: January 2025

AbstractGenetic association studies provide a unique tool for identifying causal links from genes to human traits and diseases. However, it is challenging to determine the biological mechanisms underlying most associations, and we lack genome-scale approaches for inferring causal mechanistic pathways from genes to cellular functions to traits. Here we propose new approaches to bridge this gap by combining quantitative estimates of gene-trait relationships from loss-of-function burden tests with gene-regulatory connections inferred from Perturb-seq experiments in relevant cell types. By combining these two forms of data, we aim to build causal graphs in which the directional associations of genes with a trait can be explained by their regulatory effects on biological programs or direct effects on the trait. As a proof-of-concept, we constructed a causal graph of the gene regulatory hierarchy that jointly controls three partially co-regulated blood traits. We propose that perturbation studies in trait-relevant cell types, coupled with gene-level effect sizes for traits, can bridge the gap between genetics and biology.
Protocol for a qualitative study exploring older adults’ experience of mental health and wellbeing in work-related later life transitions
Authors: Woodhouse Rebecca , McMillan Dean , Wadman Ruth 
Published: January 2025

AbstractLater life transitions occur in the later years of life and can cause significant disruption to a person’s usual daily routine and lifestyle. Transitions that are specifically related to work, such as retirement, can cause sudden changes to an individual’s financial, social and psychological environment and for some, may negatively impact on mental health and wellbeing. This protocol outlines a qualitative study to explore the experiences of adults who have experienced a negative impact on their mental health or wellbeing due to a work-related transition in later life. Semi-structed interviews will be completed with people aged 50 and over to gain a deeper understanding of 1) the mental health and wellbeing of people undertaking later life transitions; 2) the context surrounding the transitions (such as due to ill-health or redundancy); and 3) the types of support they received or may have benefitted from. Research in this area is scarce and this study will help us to better understand the experience of those who have encountered such difficulties to help develop appropriate interventions and support in this area.
The essential role of 2,4-dienoyl-CoA reductase for degradation of complex fatty acid mixtures
Authors: Schiaffi Veronica , Pavoncello Viola , Barras Frédéric , Bouveret Emmanuelle 
Published: January 2025

ABSTRACTFatty acids (FAs) can be used as carbon and energy source by most bacteria. FAs are very diverse and show variations in aliphatic chain length, degree and kind of branching, and number of double bonds. After their import in the cell and their activation by a thioester link to Coenzyme A, fatty acids are degraded by the β-oxidation machinery constituted of the Fad proteins. The core enzymes of the β-oxidation machinery can degrade most FAs, except for those FAs that bear an unsaturation at an even-numbered carbon. Such FAs include arachidonic acid or linoleic acid, which are essential FAs in the mammalian diet. We studied the role of the 2,4-dienoyl-CoA reductase FadH inE. colimetabolism of FAs. We showed thatfadHis essential for growth on linoleic acid and that Cys residues acting as ligands for FadH-bound [Fe-S] cluster are essential for activityin vivo. Moreover, we showed that when it is mixed with other FAs, linoleic acid prevents growth of thefadHmutant. These results suggest a specific metabolic burden imposed by linoleic acid degradation, which might prove important in the context of the natural gut environment with mixed FA composition. Eukaryotes also use 2,4-dienoyl-CoA reductases for β-oxidation of FAs in mitochondria but these eukaryotic enzymes belong to a different family than FadH, with different co-factors equipment and mechanism. Yet, we showed that eukaryotic 2,4-dienoyl-CoA reductases can complement theE. coli fadHmutant for growth on linoleic acid and for relief of linoleate mediated jamming of the β-oxidation. Altogether these studies demonstrate the key role of prokaryotic and eukaryotic 2,4-dienoyl-CoA reductases in a complex environment containing mixtures of saturated and unsaturated FAs, as found in the gut or in the surrounding of cancer cells.
Polygenic viral factors enable efficient mosquito-borne transmission of African Zika virus
Authors: Torii Shiho , Lord Jennifer S. , Lavina Morgane , Prot Matthieu , Lecuyer Alicia , Diagne Cheikh T. , Faye Oumar , Faye Ousmane , Sall Amadou A. , Bonsall Michael B. , Simon-Lorière Etienne , Montagutelli Xavier , Lambrechts Louis 
Published: January 2025

AbstractZika virus (ZIKV) is a mosquito-borne flavivirus primarily transmitted among humans byAedes aegypti. Over the past two decades, it has caused significant outbreaks associated with birth defects and neurological disorders. Phylogenetically, ZIKV consists of two main genotypes referred to as the African and Asian lineages, each exhibiting distinct biological properties. African lineage strains are transmitted more efficiently by mosquitoes, but pinpointing the genetic basis of this difference has remained challenging. Here, we address this question by comparing recent African and Asian strains using chimeric viruses, in which segments of the parental genomes are swapped. Our results show that the structural genes from the African strain enhance viral internalization, while the non-structural genes improve genome replication and infectious particle production in mosquito cells.In vivomosquito transmission is most significantly influenced by the structural genes, although no single viral gene alone determines this effect. Additionally, we develop a stochastic model ofin vivoviral dynamics in mosquitoes that mirrors the observed patterns, suggesting that the primary difference between the African and Asian strains lies in their ability to traverse the mosquito salivary glands. Overall, our findings suggest that the polygenic nature of ZIKV transmissibility has prevented Asian lineage strains from achieving the same epidemic potential as African lineage strains, underscoring the importance of lineage-specific adaptive landscapes in shaping ZIKV evolution and emergence.
Rdh10-mediated Retinoic Acid Signaling Regulates the Neural Crest Cell Microenvironment During ENS Formation
Authors: Butler Tjaden Naomi E. , Shannon Stephen R. , Seidel Christopher W. , Childers Melissa , Aoto Kazushi , Sandell Lisa L. , Trainor Paul A. 
Published: January 2025

AbstractThe enteric nervous system (ENS) is formed from vagal neural crest cells (NCC), which generate most of the neurons and glia that regulate gastrointestinal function. Defects in the migration or differentiation of NCC in the gut can result in gastrointestinal disorders such as Hirschsprung disease (HSCR). Although mutations in many genes have been associated with the etiology of HSCR, a significant proportion of affected individuals have an undetermined genetic diagnosis. Therefore, it’s important to identify new genes, modifiers and environmental factors that regulate ENS development and disease. Rdh10 catalyzes the first oxidative step in the metabolism of vitamin A to its active metabolite, RA, and is therefore a central regulator of vitamin A metabolism and retinoic acid (RA) synthesis during embryogenesis. We discovered thatretinol dehydrogenase 10(Rdh10) loss-of-function mouse embryos exhibit intestinal aganglionosis, characteristic of HSCR. Vagal NCC form and migrate inRdh10mutant embryos but fail to invade the foregut.Rdh10is highly expressed in the mesenchyme surrounding the entrance to the foregut and is essential between E7.5-E9.5 for NCC invasion into the gut. Comparative RNA-sequencing revealed downregulation of theRet-Gdnf-Gfrα1gene signaling network inRdh10mutants, which is critical for vagal NCC chemotaxis. Furthermore, the composition of the extracellular matrix through which NCC migrate is also altered, in part by increased collagen deposition. Collectively this restricts NCC entry into the gut, demonstrating thatRdh10-mediated vitamin A metabolism and RA signaling pleiotropically regulates the NCC microenvironment during ENS formation and in the pathogenesis of intestinal aganglionosis.
Large-scale genomic analysis reveals the distribution and diversity of Type VI Secretion Systems inEscherichia coli
Authors: Nesporova Kristina , Govers Sander K. 
Published: January 2025

AbstractThe type VI secretion system (T6SS) is a versatile nanomachine that injects effectors into target cells, playing a role in bacterial competition and virulence. While widespread in Gram-negative bacteria, T6SS prevalence varies across species and strains, and its distribution inEscherichia coliremains underexplored despiteE. colibeing an important intestinal (IPEC) and extraintestinal (ExPEC) pathogen. Here, we examined the prevalence and distribution of T6SS subclasses (T6SSi) across 131610E. coligenomes, which we annotated for clinical relevance. T6SS genes were identified while focusing on the three subclasses of T6SSigene clusters known to be present inE. coli:T6SSi1, T6SSi2, and T6SSi4b. Across phylogenetic groups, T6SSi1was broadly present, while T6SSi2showed associations with B1, B2, and G, and T6SSi4bwas rare. T6SSi1was primarily associated with IPEC, and T6SSi2with ExPEC. Even clearer patterns emerged at the sequence type (ST) level or when strains were further categorized into pathovars. For example, both the most dominant ExPEC and IPEC ST (ST131 and ST11, respectively) displayed niche-specific T6SS trends, with non-complete T6SSs being more associated with humans. In a final step, we evaluated the co-occurrence of T6SSs with other virulence-associated genes (VAGs) and multidrug resistance (MDR). This analysis confirmed the association of T6SSi1and T6SSi2with IPEC- and ExPEC-associated VAGs, respectively, and revealed a negative correlation between complete T6SSisubclasses and MDR. Together, our work provides a comprehensive overview of the diversity of T6SSs acrossE. coli, shedding more light on their potential contribution to pathogenicity in this species.ImportanceOur study represents a large-scale analysis of T6SSs across one of the most comprehensive collections ofE. coligenomes to date. In doing so, we updated several misconceptions on T6SSs distribution and other genomic properties ofE. colistrains, which originated from smaller scale studies and were subsequently extrapolated in the literature. This includes the prevalence and distribution of T6SSisubclasses across phylogenetic groups (e.g., T6SSi2is not prevalent in phylogroup D), the association of specific virulence factors with IPEC and/or ExPEC (e.g., hemolysin A is more often associated with IPEC and not a typical ExPEC characteristic), and characteristics of pathogenic STs (e.g., ST131 displays distinct genomic properties based on its environmental niche). As such, this study not only advances our understanding of T6SS inE. coli, but also serves as a valuable resource for future studies on the clinical relevance and distribution of other genetic elements.
Convergent Agonist and Heat Activation of Nociceptor TRPM3
Authors: Kumar Sushant , Jin Fei , Park Sung Jin , Choi Wooyoung , Keuning Sarah I. , Massimino Richard P. , Vu Simon , Lü Wei , Du Juan 
Published: January 2025

AbstractDetecting noxious heat is vital for survival, triggering pain responses that protect against harm1,2. The TRPM3 channel is a key nociceptor for sensing noxious heat and a promising therapeutic target for pain treatment and neurological disorders such as epilepsy3–11. Here, we functionally and structurally characterized TRPM3 in response to diverse stimuli: the synthetic superagonist CIM0216Ref12, the anticonvulsant antagonist primidone13,14, and heat1,10,15. Our findings reveal that TRPM3 is intrinsically dynamic, with its intracellular domain (ICD) sampling both resting and activated states, though strongly favoring the resting state without stimulation. CIM0216 binds to the S1–S4 domain, inducing conformational changes in the ICD and shifting the equilibrium toward activation. Remarkably, heat induces similar ICD rearrangements, revealing a converged activation mechanism driven by chemical compounds and temperature. This mechanism is supported by functional data showing that mutations facilitating the ICD movement markedly increase the sensitivity of TRPM3 to both chemical and thermal signals. These findings establish a critical role of the ICD in temperature sensing in TRPM3, a mechanism likely conserved across the TRPM family. Finally, we show that primidone binds to the same site as CIM0216 but acts as an antagonist. This study provides a framework for understanding the thermal sensing mechanisms of temperature-sensitive ion channels and offers a structural foundation for developing TRPM3-target therapeutics for pain and neurological disorders.
Single cell Edit Detection and Identification Tool (scEDIT): computational workflow for efficient and economical single cell analysis of CRISPR edited cells
Authors: Suryawanshi Gajendra W 
Published: January 2025

AbstractRecent advances in single-cell DNA sequencing (scDNA-seq) and CRISPR technology have revolutionized gene therapy and drug discovery. However, data analysis requires expensive high-performance computing (HPC) clusters or large data servers, limiting reanalysis due to the lack of open-source software. To address this, we present scEDIT, a fast, lightweight, portable, and standalone software for pre- and post-processing CRISPR editing data from the Tapestri single-cell DNA-seq platform. scEDIT is memory-efficient, multithreaded, and compatible with most UNIX based systems. Tests using a low-cost desktop and public single cell CRISPR data demonstrate that the tool can efficiently process raw sequences, identify cell barcodes, count unedited and edited amplicons per cell, and outputs detailed filtered reads. Analysis of the single cell CRISPR data reveals indel patterns shared between in vitro experiments and unique indel profiles detected for in vivo study. Results further demonstrate the ability of single cell analysis in providing quantitative insights into the true zygosity of edited cell population. Although data shows a linear relation between indel frequencies by read count and cell count details of indel share between difference cells can only be truly explored with single cell data. The efficiency, stability, and portability of scEDIT makes it an invaluable tool for uncovering new insights into the single cell data without requiring expensive computational resources.