bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex chromosomes as supergenes of speciation: why amphibians defy the rules?
Authors: Dufresnes Christophe , Crochet Pierre-André 
Published: June 2022

As reflected by the two rules of speciation (Haldane's rule and the large X-/Z-effect), sex chromosomes are expected to behave like supergenes of speciation: they recombine only in one sex (XX females or ZZ males), supposedly recruit sexually antagonistic genes and evolve faster than autosomes, which can all contribute to pre-zygotic and post-zygotic isolation. While this has been mainly studied in organisms with conserved sex-determining systems and highly differentiated (heteromorphic) sex chromosomes like mammals, birds and some insects, these expectations are less clear in organismal groups where sex chromosomes repeatedly change and remain mostly homomorphic, like amphibians. In this article, we review the proposed roles of sex-linked genes in isolating nascent lineages throughout the speciation continuum and discuss their support in amphibians given current knowledge of sex chromosome evolution and speciation modes. Given their frequent recombination and lack of differentiation, we argue that amphibian sex chromosomes are not expected to become supergenes of speciation, which is reflected by the rarity of empirical studies consistent with a ‘large sex chromosome effect’ in frogs and toads. The diversity of sex chromosome systems in amphibians has a high potential to disentangle the evolutionary mechanisms responsible for the emergence of sex-linked speciation genes in other organisms.
This article is part of the theme issue ‘Genomic architecture of supergenes: causes and evolutionary consequences’.
Searching for signatures of sexually antagonistic selection on stickleback sex chromosomes
Authors: Dagilis Andrius J. , Sardell Jason M. , Josephson Matthew P. , Su Yiheng , Kirkpatrick Mark , Peichel Catherine L. 
Published: June 2022

Intralocus sexually antagonistic selection occurs when an allele is beneficial to one sex but detrimental to the other. This form of selection is thought to be key to the evolution of sex chromosomes but is hard to detect. Here we perform an analysis of phased young sex chromosomes to look for signals of sexually antagonistic selection in the Japan Sea stickleback (Gasterosteus nipponicus). Phasing allows us to date the suppression of recombination on the sex chromosome and provides unprecedented resolution to identify sexually antagonistic selection in the recombining region of the chromosome. We identify four windows with elevated divergence between the X and Y in the recombining region, all in or very near genes associated with phenotypes potentially under sexually antagonistic selection in humans. We are unable, however, to rule out the alternative hypothesis that the peaks of divergence result from demographic effects. Thus, although sexually antagonistic selection is a key hypothesis for the formation of supergenes on sex chromosomes, it remains challenging to detect.This article is part of the theme issue ‘Genomic architecture of supergenes: causes and evolutionary consequences’.
Genomic architecture and functional effects of potential human inversion supergenes
Authors: Campoy Elena , Puig Marta , Yakymenko Illya , Lerga-Jaso Jon , Cáceres Mario 
Published: June 2022

Supergenes are involved in adaptation in multiple organisms, but they are little known in humans. Genomic inversions are the most common mechanism of supergene generation and maintenance. Here, we review the information about two large inversions that are the best examples of potential human supergenes. In addition, we do an integrative analysis of the newest data to understand better their functional effects and underlying genetic changes. We have found that the highly divergent haplotypes of the 17q21.31 inversion of approximately 1.5 Mb have multiple phenotypic associations, with consistent effects in brain-related traits, red and white blood cells, lung function, male and female characteristics and disease risk. By combining gene expression and nucleotide variation data, we also analysed the molecular differences between haplotypes, including gene duplications, amino acid substitutions and regulatory changes, and identifyCRHR1, KANLS1andMAPTas good candidates to be responsible for these phenotypes. The situation is more complex for the 8p23.1 inversion, where there is no clear genetic differentiation. However, the inversion is associated with several related phenotypes and gene expression differences that could be linked to haplotypes specific of one orientation. Our work, therefore, contributes to the characterization of both exceptional variants and illustrates the important role of inversions.This article is part of the theme issue ‘Genomic architecture of supergenes: causes and evolutionary consequences’.
Microglia shape the embryonic development of mammalian respiratory networks
Authors: Cabirol Marie-Jeanne , Cardoit Laura , Courtand Gilles , Mayeur Marie-Eve , Simmers John , Pascual Olivier , Thoby-Brisson Muriel 
Published: June 2022

AbstractMicroglia, brain-resident macrophages, play key roles during prenatal development in defining neural circuitry function, including ensuring proper synaptic wiring and maintaining homeostasis. Mammalian breathing rhythmogenesis arises from interacting brainstem neural networks that are assembled during embryonic development, but the specific role of microglia in this process remains unknown. Here, we investigated the anatomical and functional consequences of respiratory circuit formation in the absence of microglia. We first established the normal distribution of microglia within the wild-type (WT, Pu.1+/+) mouse brainstem at embryonic ages when the respiratory networks are known to emerge (embryonic day (E) 14.5 for the parafacial respiratory group (epF) and E16.5 for the preBötzinger complex (preBötC)). In transgenic mice depleted of microglia (Pu.1-/- mutant), we performed anatomical staining, calcium imaging and electrophysiological recordings of neuronal activities in vitro to assess the status of these circuits at their respective times of functional emergence. Spontaneous respiratory-related activity recorded from reduced in vitro preparations showed an abnormally slow rhythm frequency expressed by the epF at E14.5, the preBötC at E16.5 and in the phrenic motor nerves from E16.5 onwards. These deficits were associated with a reduced number of active epF neurons, defects in commissural projections that couple the bilateral preBötC half-centers, and an accompanying decrease in their functional coordination. These abnormalities probably contribute to eventual neonatal death, since plethysmography revealed that E18.5 Pu.1-/- embryos are unable to sustain breathing activity ex utero. Our results thus point to a crucial contribution of microglia in the proper establishment of the central respiratory command during embryonic development.
Conjugative IncC plasmid entry triggers the SOS response and promotes effective transfer of the integrative antibiotic resistance element SGI1
Authors: Pons Marine C. , Praud Karine , Re Sandra Da , Cloeckaert Axel , Doublet Benoît 
Published: June 2022

ABSTRACTThe broad host range IncC plasmid family and the integrative mobilizable Salmonella Genomic Island 1 (SGI1) and its derivatives enable the spread of medically-important antibiotic resistance genes among Gram-negative pathogens. Although several aspects of the complex functional interactions between IncC plasmids and SGI1 have been recently deciphered regarding their conjugative transfer and incompatibility, the biological signal resulting in the hijacking of the conjugative plasmid by the integrative mobilizable element remains unknown. Here, we demonstrate that the conjugative entry of IncC/IncA plasmids is detected at an early stage by SGI1 through the transient activation of the SOS response, which induces the expression of the SGI1 master activators SgaDC, shown to play a crucial role in the complex biology between SGI1 and IncC plasmids. Besides, we developed an original tripartite conjugation approach to directly monitor SGI1 mobilization in a time-dependent manner following conjugative entry of IncC plasmids. Finally, we propose an updated biological model of the conjugative mobilization of the chromosomal resistance element SGI1 by IncC plasmids.IMPORTANCEAntimicrobial resistance has become a major public health issue, particularly with the increase in multidrug resistance (MDR) in both animal and human pathogenic bacteria, and with the emergence of resistance to medically important antibiotics. The spread between bacteria of successful mobile genetic elements such as conjugative plasmids and integrative elements conferring multidrug resistance is the main driving force in the dissemination of acquired antibiotic resistances among Gram-negative bacteria. Broad-host range IncC plasmids and their integrative mobilizable SGI1 counterparts contribute to the spread of critically-important resistance genes (e.g., ESBLs, and carbapenemases). A better knowledge of the complex biology of these broad-host range mobile elements will help to understand the dissemination of antimicrobial resistance genes that occurred across γ-proteobacteria borders.
AAV-mediated neuronal expression of a scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models
Authors: Selles Maria Clara , Fortuna Juliana T.S. , Cercato Magali C. , Santos Luis Eduardo , Domett Luciana , Bitencourt Andre L.B. , Carraro Mariane Favero , Souza Amanda S. , Janickova Helena , de Souza Jorge M. , Alves-Leon Soniza , Prado Vania F. , Prado Marco A. M. , Epstein Alberto L. , Salvetti Anna , Arancio Ottavio , Klein William L. , Sebollela Adriano , De Felice Fernanda G. , Jerusalinsky Diana A. , Ferreira Sergio T. 
Published: June 2022

AbstractBrain accumulation of soluble oligomers of the amyloid-β peptide (AβOs) has been implicated in synapse failure and memory impairment in Alzheimer’s disease. Here, we show that treatment with NUsc1, a single-chain variable fragment antibody (scFv) that selectively targets AβOs, prevents the inhibition of long-term potentiation in hippocampal slices and memory impairment induced by AβOs in mice. As a therapeutic approach for intracerebral antibody delivery, we developed an adeno-associated virus vector to drive neuronal expression of NUsc1 (AAV-NUsc1) within the brain. Transduction by AAV-NUsc1 induced NUsc1 expression and secretion in adult human brain slices, and inhibited AβO binding to neurons and AβO-induced loss of dendritic spine loss in primary rat hippocampal cultures. Treatment of mice with AAV-NUsc1 prevented memory impairment induced by AβOs and, importantly, reversed memory deficits in aged APPswe/PS1ΔE9 Alzheimer’s disease model mice. These results support the feasibility of gene-mediated immunotherapy using single-chain antibodies as a potential therapeutic approach in Alzheimer’s disease.
Exogenous NaV1.1 activity in excitatory and inhibitory neurons reverts Dravet syndrome comorbidities when delivered post-symptom onset in mice with Dravet
Authors: Fadila Saja , Beucher Bertrand , Reyes Iria González-Dopeso , Mavashov Anat , Brusel Marina , Anderson Karen , Goldberg Ethan M , Ricobaraza Ana , Hernandez-Alcoceba Ruben , Kremer Eric J , Rubinstein Moran 
Published: June 2022

AbstractDravet syndrome (DS), an intractable childhood epileptic encephalopathy with a high fatality rate, is caused by loss-of-function mutations in one allele of SCN1A, which encodes NaV1.1. In contrast to other epilepsies, pharmaceutical treatment for DS is limited. Here, we demonstrate that viral vector-mediated delivery of a codon-modified SCN1A cDNA improves DS comorbidities in juvenile and adolescent DS mice (Scn1aA1783V/WT). Notably, bilateral vector injections into the hippocampus or thalamus of DS mice improved the survival of the mice, reduced the occurrence of epileptic spikes, provided protection from thermally-induced seizures, and corrected background electrocorticography activity. Together, our results provide a proof-of-concept for the potential of SCN1A delivery as a therapeutic approach for infants and adolescents with DS-associated comorbidities.
Seeing the forest and the tree: Building representations of both individual and collective dynamics with transformers
Authors: Liu Ran , Azabou Mehdi , Dabagia Max , Xiao Jingyun , Dyer Eva L. 
Published: June 2022

AbstractComplex time-varying systems are often studied by abstracting away from the dynamics of individual components to build a model of the population-level dynamics from the start. However, when building a population-level description, it can be easy to lose sight of each individual and how they contribute to the larger picture. In this paper, we present a novel transformer architecture for learning from time-varying data that builds descriptions of both the individual as well as the collective population dynamics. Rather than combining all of our data into our model at the onset, we develop a separable architecture that operates on individual time-series first before passing them forward; this induces a permutation-invariance property and can be used to transfer across systems of different size and order. After demonstrating that our model can be applied to successfully recover complex interactions and dynamics in many-body systems, we apply our approach to populations of neurons in the nervous system. On neural activity datasets, we show that our model not only yields robust decoding performance, but also provides impressive performance in transfer across recordings of different animals without any neuron-level correspondence. By enabling flexible pre-training that can be transferred to neural recordings of different size and order, our work provides a first step towards creating a foundation model for neural decoding.
A Machine Learning Approach Towards the Differentiation Between Interoceptive and Exteroceptive Attention
Authors: Zuo Zoey X. , Price Cynthia J. , Farb Norman A. S. 
Published: June 2022

AbstractInteroception, the representation of the body’s internal state, plays a central role in emotion, motivation, and wellbeing. Interoceptive attention is qualitatively different from attention to the external senses and may recruit a distinct neural system, but the neural separability of interoceptive and exteroceptive attention is unclear. We used a machine learning approach to classify neural correlates of interoceptive and exteroceptive attention in a randomized control trial of interoceptive training (MABT). Participants in the training and control groups attended fMRI assessment before and after an 8-week intervention period (N = 44 scans). The imaging paradigm manipulated attention targets (breath vs. visual stimulus) and reporting demands (active reporting vs. passive monitoring). Machine learning models achieved high accuracy in distinguishing between interoceptive and exteroceptive attention using both in-sample and more stringent out-of-sample tests. We then explored the potential of these classifiers in “reading out” mental states in a sustained interoceptive attention task. Participants were classified as maintaining an active reporting state for only ∼90s of each 3-minute sustained attention period. Within this active period, interoceptive training enhanced participants’ ability to sustain interoceptive attention. These findings demonstrate that interoceptive and exteroceptive attention engage reliable and distinct neural networks; machine learning classifiers trained on this distinction show promise for assessing the stability of interoceptive attention, with implications for the future assessment of mental health and treatment response.
Thinking like a structural biologist: A pocket-based 3D molecule generative model fueled by electron density
Authors: Wang Lvwei , Bai Rong , Shi Xiaoxuan , Zhang Wei , Cui Yinuo , Wang Xiaoman , Wang Cheng , Chang Haoyu , Zhang Yingsheng , Zhou Jielong , Peng Wei , Zhou Wenbiao , Huang Bo 
Published: June 2022

AbstractWe report for the first time the use of experimental electron density (ED) as training data for the generation of drug-like three-dimensional molecules based on the structure of a target protein pocket. Similar to a structural biologist building molecules based on their ED, our model functions with two main components: a generative adversarial network (GAN) to generate the ligand ED in the input pocket and an ED interpretation module for molecule generation. The model was tested on three targets including kinase (HPK1), protease (Covid19-3CL), and nuclear receptor (VDR), and evaluated with a reference dataset composed of over 8,000 compounds that have their activities reported in the literature. The evaluation examined the chemical validity, chemical space distribution-based diversity, and similarity with reference active compounds concerning the molecular structure and pocket-binding mode. Our model can reproduce classical active compounds and can also generate novel molecules with similar binding modes as active compounds, making it a promising tool for library generation supporting high-throughput virtual screening. Our model is available as an online service to academic users via https://edmg.stonewise.cn/#/create.
Perturbed fatty-acid metabolism is linked to localized chromatin hyperacetylation, increased stress-response gene expression and resistance to oxidative stress
Authors: Princová Jarmila , Salat-Canela Clàudia , Daněk Petr , Marešová Anna , de Cubas Laura , Bähler Jürg , Ayté José , Hidalgo Elena , Převorovský Martin 
Published: June 2022

ABSTRACTOxidative stress is associated with cardiovascular and neurodegenerative diseases, diabetes, cancer, psychiatric disorders and aging. In order to counteract, eliminate and/or adapt to the sources of stress, cells possess elaborate stress-response mechanisms, which also operate at the level of regulating transcription. Interestingly, it is becoming apparent that the metabolic state of the cell and certain metabolites can directly control the epigenetic information and gene expression. In the fission yeastSchizosaccharomyces pombe, the conserved Sty1 stress-activated protein kinase cascade is the main pathway responding to most types of stresses, and regulates the transcription of hundreds of genes via the Atf1 transcription factor. Here we report that fission yeast cells defective in fatty acid synthesis (cbf11, mga2and ACC/cut6mutants) show increased expression of a subset of stress-response genes. This altered gene expression depends on Sty1, and the Gcn5 and Mst1 histone acetyltransferases, is associated with increased acetylation of histone H3 at lysine 9 in the corresponding gene promoters, and results in increased cellular resistance to oxidative stress. Since both fatty-acid synthesis and histone acetylation compete for the same substrate, acetyl-CoA, we propose that changes in lipid metabolism can regulate the chromatin and transcription of specific stress-response genes, which in turn might help cells to maintain redox homeostasis.
The Role of UBE2-Conjugating Enzymes in the Mechanism of MuRF1 Ubiquitylation
Authors: Dawson Peter W.J. , Baehr Leslie M. , Hughes David C. , Knowles Timothy J. , Sridhar Pooja , Bodine Sue C. , Lai Yu-Chiang 
Published: June 2022

ABSTRACTMuRF1 (Muscle-specific RING finger protein 1; gene name TRIM63) is a ubiquitin E3 ligase, associated with the progression of muscle atrophy. As a RING (Really Interesting New Gene)-type E3 ligase, its unique activity of ubiquitylation is driven by a specific interaction with UBE2 (ubiquitin conjugating enzyme) to ubiquitylate its substrate protein. The understanding of MuRF1 function remains unclear as candidate UBE2 has not been elucidated and thus the mechanism of ubiquitylation is inconclusive. In the present study, we screened human ubiquitin dependent E2s using in-vitro ubiquitylation assays. We found that MuRF1 engages in ubiquitylation/auto-ubiquitylation with UBE2D, UBE2E, UBE2N/V families and UBE2W. Our result indicated that MuRF1 can cause mono-ubiquitylation, K48, and K63 specific poly-ubiquitin chains in a UBE2-dependent manner. Interestingly, we identified a two-step UBE2-dependent mechanism by which UBE2W allows MuRF1 to mono-ubiquitylate which then acts as an anchor for UBE2N/V and UBE2D generated poly-ubiquitin chain formation. Furthermore, MuRF1 was shown to cooperate with the identified interacting UBE2s to directly ubiquitylate substrates Titin (A168-A170), Desmin, and MYLPF (Myosin Light Chain, Phosphorylatable, Fast Skeletal Muscle; also called Myosin Light Regulatory Chain 2). Our work presents a novel insight into the mechanisms that underpin MuRF1 activity by highlighting the diversity of MuRF1 ubiquitylation enabled by different UBE2s.
Nanog organizes transcription bodies
Authors: Kuznetsova Ksenia , Ugolini Martino , Wu Edlyn , Lalit Manan , Oda Haruka , Sato Yuko , Kimura Hiroshi , Jug Florian , Vastenhouw Nadine 
Published: June 2022

ABSTRACTThe localization of transcriptional activity in specialized transcription bodies is a hallmark of gene expression in eukaryotic cells. How proteins of the transcriptional machinery come together to form such bodies, however, is unclear. Here, we take advantage of two large, isolated, and long-lived transcription bodies that reproducibly form during early zebrafish embryogenesis, to characterize the dynamics of transcription body formation. Once formed, these transcription bodies are enriched for initiating and elongating RNA polymerase II, as well as the transcription factors Nanog and Sox19b. Analyzing the events leading up to transcription, we find that Nanog and Sox19b cluster prior to transcription, and independently of RNA accumulation. The clustering of transcription factors is sequential; Nanog clusters first, and this is required for the clustering of Sox19b and the initiation of transcription. Mutant analysis revealed that both the DNA-binding domain, as well as one of the two intrinsically disordered regions of Nanog are required to organize the two bodies of transcriptional activity. Taken together, our data suggests that the clustering of transcription factors dictates the formation of transcription bodies.HIGHLIGHTSTranscription factors cluster prior to, and independently of transcriptionNanog organizes transcription bodies: it is required for the clustering of Sox19b as well as RNA polymerase IIThis organizing activity requires its DNA binding domain as well as one of its intrinsically disordered regionsTranscription elongation results in the disassembly of transcription factor clusters