bluuebunny/crossref_metadata_2025_split huggingface dataset:
Protein SUMOylation promotes cAMP-independent EPAC1 activation
Authors: Yang Wenli , Mei Fang C. , Lin Wei , White Mark A. , Li Li , Li Yue , Pan Sheng , Cheng Xiaodong 
Published: January 2024

AbstractExchange protein directly activated by cAMP (EPAC1) mediates the intracellular functions of a critical stress-response second messenger, cAMP. Herein, we report that EPAC1 is a cellular substrate of protein SUMOylation, a prevalent stress-response posttranslational modification. Site-specific mapping of SUMOylation by mass spectrometer leads to identifying K561 as a primary SUMOylation site in EPAC1. Sequence and site-directed mutagenesis analyses reveal a functional SUMO-interacting motif required for cellular SUMOylation of EPAC1. SUMO modification of EPAC1 mediates its heat shock-induced Rap1/2 activation in a cAMP-independent manner. Structural modeling and molecular dynamics simulation studies demonstrate that SUMO substituent on K561 of EPAC1 promotes Rap1 interaction by increasing the buried surface area between the SUMOylated receptor and its effector. Our studies identify a functional SUMOylation site in EPAC1 and unveil a novel mechanism in which SUMOylation of EPAC1 leads to its autonomous activation. The findings of SUMOylation-mediated activation of EPAC1 not only provide new insights into our understanding of cellular regulation of EPAC1 but also will open up a new field of experimentation concerning the cross-talk between cAMP/EPAC1 signaling and protein SUMOylation, two major cellular stress response pathways, during cellular homeostasis.
scDirect: key transcription factor identification for directing cell state transitions based on single-cell multi-omics data
Authors: Li Chen , Chen Sijie , Chen Yixin , Bian Haiyang , Hao Minsheng , Wei Lei , Zhang Xuegong 
Published: January 2024

AbstractCell state transitions are complicated processes that occur in various life activities. Understanding and artificially manipulating them have been longstanding challenges. Substantial experiments reveal that the transitions could be directed by several key transcription factors (TFs). Here we present scDirect, a computational framework to identify key TFs based on single-cell RNA-seq and ATAC-seq data. scDirect models the TF identification task as a linear inverse problem, and solve it with gene regulatory networks enhanced by a graph attention network. Through a benchmarking on a single-cell human embryonic stem cell atlas, we demonstrate the robustness and superiority of scDirect against alternative analysis methods on TF identification. We apply scDirect on various datasets, and scDirect exhibits high capability in identifying key TFs in cell differentiation and somatic cell conversion. Furthermore, scDirect can efficiently identify TF combinations for cell reprogramming, many of which have been experimentally validated. We envision that scDirect can utilize rapidly increasing single-cell datasets to identify key TFs for directing cell state transitions and may become an effective tool to facilitate cell engineering and regenerative medicine.
A 39.8kb flavi-like virus uses a novel strategy for overcoming the RNA virus error threshold
Authors: Petrone Mary E. , Grove Joe , Mifsud Jonathon C. O. , Parry Rhys H. , Marzinelli Ezequiel M. , Holmes Edward C. 
Published: January 2024

ABSTRACTIt is commonly held that there is a fundamental relationship between genome size and error rate, manifest as a notional “error threshold” that sets an upper limit on genome sizes. The genome sizes of RNA viruses, which have intrinsically high mutation rates due to a lack of mechanisms for error correction, must therefore be small to avoid accumulating an excessive number of deleterious mutations that will ultimately lead to population extinction. The proposed exceptions to this evolutionary rule are RNA viruses from the orderNidovirales(such as coronaviruses) that encode an error correcting exonuclease, enabling them to reach genome lengths greater than 40kb. The recent discovery of large genome flavi-like viruses (Flaviviridae), which comprise genomes up to 27kb in length yet seemingly do not encode exonuclease domains, has led to the proposal that a proofreading mechanism is required to facilitate the expansion of RNA virus genomes above 30kb. Herein, we describe a 39.8kb flavi-like virus identified in aHaliclonasponge metatranscriptome that does not encode an exonuclease. Structural analysis revealed that this virus may have instead captured bacterial domains associated with nucleic acid metabolism that have not been previously found in RNA viruses. Phylogenetic analysis placed this virus as a divergent pesti-like lineage, such that we have provisionally termed it Maximus pesti-like virus. This virus represents the first instance of a flavi-like virus achieving a genome size comparable to that of theNidoviralesand demonstrates that RNA viruses have evolved multiple solutions to overcome the error threshold.
Two-photon all-optical electrophysiology for the dissection of larval zebrafish brain functional connectivity
Authors: Turrini Lapo , Ricci Pietro , Sorelli Michele , de Vito Giuseppe , Marchetti Marco , Vanzi Francesco , Pavone Francesco S. 
Published: January 2024

AbstractOne of the most audacious goals of modern neuroscience is unraveling the complex web of causal relations underlying the activity of neuronal populations on a whole-brain scale. This endeavor, prohibitive just a couple of decades ago, has recently become within reach owing to the advancements in optical methods and the advent of genetically encoded indicators/actuators. These techniques, applied to the translucent larval zebrafish have enabled recording and manipulation of the activity of extensive neuronal populations spanning the entire vertebrate brain. Here, we present the conception of a custom two-photon optical system, coupling light-sheet imaging and 3D excitation with acousto-optic deflectors for simultaneous high-speed volumetric recording and optogenetic stimulation. By employing a zebrafish line with pan-neuronal expression of both the calcium reporter GCaMP6s and the red-shifted opsin ReaChR, we implemented a crosstalk-free, noninvasive all-optical approach and applied it to the reconstruction of the functional connectivity of the left habenula.
Transient interactions between the fuzzy coat and the cross-β core of brain-derived Aβ42 filaments
Authors: Milanesi Maria , Brotzakis Z. Faidon , Vendruscolo Michele 
Published: January 2024

AbstractA wide range of human disorders, including Alzheimer’s disease (AD), are characterised by the aberrant formation of amyloid fibrils. Amyloid fibrils are filamentous structures characterized by the presence of a highly-ordered cross-β core. In many cases, this core structure is flanked by disordered regions, often referred to as fuzzy coat. The structural properties of fuzzy coats, and the way in which they interact with their environments, however, have not been described in full detail to date. Here, we generated the conformational ensembles of two brain-derived amyloid filaments of Aβ42, corresponding respectively to familial and sporadic forms of AD. The approach that we used, called metadynamic electron microscopy metainference (MEMMI), enabled us to provide a characterization of the transient interactions between the fuzzy coat and the cross-β core of the filaments. These calculations indicated that the familial AD filaments are less soluble than the sporadic AD filaments, and that the fuzzy coat contributes to increasing the solubility of both types of filament. In addition, by analyzing the deviations between the density maps from cryo-EM and from the MEMMI structural ensembles, we observed a slowing down in the diffusion of water and sodium ions near the surface of the filaments, offering insight into the hydration dynamics of amyloid fibrils. These results illustrate how the metainference approach can help analyse cryo-EM maps for the characterisation of the properties of amyloid fibrils.
Dynamic fusion of genomics and functional network connectivity in UK biobank reveals static and time-varying SNP manifolds
Authors: Chen Jiayu , Iraji Armin , Fu Zening , Andrés-Camazón Pablo , Thapaliya Bishal , Liu Jingyu , Calhoun Vince D. 
Published: January 2024

ABSTRACTMany psychiatric and neurological disorders show significant heritability, indicating strong genetic influence. In parallel, dynamic functional network connectivity (dFNC) measures functional temporal coupling between brain networks in a time-varying manner and has proven to identify disease-related changes in the brain. However, it remains largely unclear how genetic risk contributes to brain dysconnectivity that further manifests into clinical symptoms. The current work aimed to address this gap by proposing a novel joint ICA (jICA)-based “dynamic fusion” framework to identify dynamically tuned SNP manifolds by linking static SNPs to dynamic functional information of the brain. The sliding window approach was utilized to estimate four dFNC states and compute subject-level state-specific dFNC features. Each state of dFNC features were then combined with 12946 SZ risk SNPs for jICA decomposition, resulting in four parallel fusions in 32861 European ancestry individuals within the UK Biobank cohort. The identified joint SNP-dFNC components were further validated for SZ relevance in an aggregated SZ cohort, and compared for across-state similarity to indicate level of dynamism. The results supported that dynamic fusion yielded “static” and “dynamic” components (i.e., high and low across-state similarity, respectively) for SNP and dFNC modalities. As expected, the SNP components presented a mixture of static and dynamic manifolds, with the latter largely driven by fusion with dFNC. We also showed that some of the dynamic SNP manifolds uniquely elicited by fusion with state-specific dFNC features complemented each other in terms of biological interpretation. This dynamic fusion framework thus allows expanding the SNP modality to manifolds in the time dimension, which provides a unique lens to elicit unique SNP correlates of dFNC otherwise unseen, promising additional insights on how genetic risk links to disease-related dysconnectivity.
Intimate partner violence in Nepal: Analysis of Nepal Demographic and Health survey 2022
Authors: Sapkota Parash Mani , Pandey Achyut Raj , Adhikari Bikram , Shrestha Grishu , Piya Reecha , Lamichhane Bipul , Garu Shristi , Joshi Deepak , Baral Sushil Chandra 
Published: January 2024

AbstractIntroductionIntimate partner violence (IPV) is a major public health issue in Nepal. IPV has social and economic impacts among women, adolescent girls, wider society. In this study we aimed to determine factors associated with intimate partner violence among women aged 15-49 currently in intimate relationship.MethodsWe conducted secondary data analysis of the Nepal Demographic and Health Survey 2022. IPV was measured in three domains-experience of physical violence, emotional violence, and sexual violence. Weighted univariate and multivariate logistic regression analysis was applied to determine factors associated with intimate partner violence. The results of logistic regression were presented as odds ratio and their 95% CI.ResultsOf 3853 women, 27.2% had experienced any form of IPV. The prevalence of physical violence, emotional violence and sexual violence were 23.2%, 12.8 and 7.1% respectively. Higher odds of physical violence were reported among women aged 35-49 years (AOR: 2.13, 95%CI: 1.58-2.87), women without formal education (AOR: 1.51, 95%CI: 1.10-2.06) and women who justified wife beating (AOR: 1.23, 95%CI: 1.00-1.52). Women from poor households (AOR: 1.61, 95%CI: 1.12-2.35) and women with uneducated partners (AOR: 1.66, 95%CI: 1.08-2.58) were at higher risk of experiencing sexual violence. Women with unemployed husbands reported higher risk of physical violence (AOR: 2.72, 95%CI: 1.45-5.06) and emotional violence (AOR: 1.61, 95%CI: 1.12-2.35). Women who were afraid of their partners, women who experienced parental violence, women with partners who were sometimes or often drunk, and women with controlling partners were many folds more likely to experience all forms of IPV.ConclusionThe prevalence of all forms of IPV were high among Nepalese women. Various sociodemographic, partner-related, and women empowerment related factors were positively associated with experiencing IPV. Acknowledging and addressing all these factors is essential to mitigating the alarming rates of IPV in this population.
Sodium Valproate Modulates Cortical Morphology in Juvenile Myoclonic Epilepsy
Authors: Pimentel Bernardo Crespo , Kuchukhidze Giorgi , Xiao Fenglai , Caciagli Lorenzo , Höfler Julia , Rainer Lucas , Kronbichler Martin , Vollmar Christian , Duncan John S , Trinka Eugen , Koepp Matthias , Wandschneider Britta 
Published: January 2024

AbstractImportanceIdiopathic generalized epilepsy syndromes in are associated with cortical thinning of the premotor areas. Whether this represents an underlying disease signature, a consequence of seizure activity or is related to anti-seizure medication is unknown.ObjectiveTo investigate valproate-related effects on cortical morphology in people with juvenile myoclonic epilepsy (JME), one of the most common IGE syndromes.DesignRetrospective neuroimaging case-control study.SettingRecruitment took place in epilepsy clinics in two European epilepsy referral centers.ParticipantsWe matched individuals with JME on valproate (n=36) to a group of healthy controls (n=36), as well as individuals with JME not on valproate (n=36) and a group of people with temporal lobe epilepsy (n=19) on valproate using propensity scores for age, sex, occurrence of bilateral tonic-clonic seizures and drug refractoriness.Main outcomes and MeasuresAll participants underwent structural T1-weighted brain imaging and MRI-derived vertex-wise measurements of cortical thickness were calculated. Results were reported in effect-sizes using cohen’sd.ResultsCompared to healthy controls, individuals with JME on valproate demonstrated cortical thinning bilaterally in the precentral gyri (left:d= -1.0,p<.001; right: d = -1.0,p<.001). This effect was localized to the left precentral gyrus when comparing JME on VPA with individuals with JME not on valproate (d= -0.89;p<.01) or with individuals with temporal lobe epilepsy on valproate (d = -0.18, p<.001). No significant differences in cortical thickness were detected between individuals with JME not on valproate and healthy controls. Cortical thinning in precentral gyrus, postcentral gyrus and superior frontal was more marked with increasing valproate dose (left:t= -6,65,p<.0001; right:t= -5,20,p<.0001).Conclusions and RelevanceIn this cross-sectional study of 91 patients with epilepsy, valproate treatment was associated with JME-specific and dose-dependent cortical thinning of the precentral gyri. Our findings suggest a valproate-induced reorganization of disease-specific areas in JME that may not only help explain the high efficacy of this medication in IGEs but also potentially account for previously described changes of cortical thickness in this disease group.
An Analysis of Two-Spirit, Lesbian, Gay, Bisexual, Transgender and Queer Research Funded by Canadian Institutes of Health Research
Authors: Namchuk Amanda B. , Stranges Tori N. , Splinter Tallinn F.L. , Moore Katherine N. , Logie Carmen H. , Galea Liisa A.M. 
Published: January 2024

AbstractPurposeGender identity and sexual orientation are essential factors that must be incorporated into health research to ensure we unearth comprehensive and inclusive insights about the healthcare needs and experiences of diverse people. Despite the calls for more focus on sex and gender in health research, scant attention has been paid to gender identity or sexual orientation. Past research found that 0.35% of Canadian Institutes of Health Research (CIHR) grant abstracts mentioned studying lesbian, gay, bisexual, transgender, queer and/or Two-Spirit (2S/LGBTQ+)-specific health outcomes. However, the nature of that research was not explored.MethodsHere we examine the publicly available database of grant abstracts funded by CIHR from 2009-2020 to analyze what type of 2S/LGBTQ+-specific health outcomes would be studied.ResultsWe found that 58% of awarded grant abstracts mentioned studying sexually transmitted diseases, the majority of which were on human immunodeficiency virus (HIV). Less than 7% of funded 2S/LGBTQ+ grant abstracts mentioned studying cisgender women. Almost 40% mentioned including trans women/girls, and 30% mentioned including trans men/ boys. None of the studies examined mentioned work with the Two-Spirit community.ConclusionThese results reflect larger social and health inequities that require structural level changes in research to support lesbian, bisexual and queer women’s health.
Identification of KIFC1 as a putative vulnerability in lung cancers with centrosome amplification
Authors: Zhang Christopher , Wu Benson , Wu Yin Fang , di Ciano-Oliveira Caterina , Soria-Bretones Isabel , Pham Nhu-An , Elia Andrew J. , Chari Raj , Lam Wan L. , Bray Mark R. , Mak Tak W. , Tsao Ming-Sound , Cescon David W. , Thu Kelsie L. 
Published: January 2024

AbstractCentrosome amplification (CA), an abnormal increase in the number of centrosomes in the cell, is a recurrent phenomenon in lung and other malignancies. Although CA contributes to tumor development and progression by promoting genomic instability (GIN), it also induces mitotic stress that jeopardizes cellular integrity. The presence of extra centrosomes leads to the formation of multipolar mitotic spindles prone to causing lethal chromosome segregation errors during cell division. To sustain the benefits of CA, malignant cells are dependent on adaptive mechanisms to mitigate its detrimental consequences, and these mechanisms represent therapeutic vulnerabilities. We aimed to discover genetic dependencies associated with CA in lung cancer. Combining a CRISPR/Cas9 functional genomics screen with analyses of tumor genomic data, we identified the motor protein KIFC1 as a putative vulnerability specifically in lung cancers with CA. KIFC1 expression was positively correlated with CA in lung adenocarcinoma (LUAD) cell lines and with a gene expression signature predictive of CA in LUAD tumor tissues. HighKIFC1expression was associated with worse patient outcomes, smoking history, and indicators of GIN. KIFC1 loss-of-function sensitized LUAD cells to potentiation of CA and sensitization was associated with a diminished ability of KIFC1-depleted cells to cluster extra centrosomes into pseudo-bipolar mitotic spindles. Our work suggests that KIFC1 inhibition represents a novel approach for potentiating GIN to lethal levels in LC with CA by forcing cells to divide with multipolar spindles, rationalizing the clinical development of KIFC1 inhibitors and further studies to investigate its therapeutic potential.
The Scalable Variant Call Representation: Enabling Genetic Analysis Beyond One Million Genomes
Authors: Poterba Timothy , Vittal Christopher , King Daniel , Goldstein Daniel , Goldstein Jacqueline I. , Schultz Patrick , Karczewski Konrad J. , Seed Cotton , Neale Benjamin M. 
Published: January 2024

AbstractThe Variant Call Format (VCF) is widely used in genome sequencing but scales poorly. For instance, we estimate a 150,000 genome VCF would occupy 900 TiB, making it both costly and complicated to produce and analyze. The issue stems from VCF’s requirement to densely represent both reference-genotypes and allele-indexed arrays. These requirements lead to unnecessary data duplication and, ultimately, very large files.To address these challenges, we introduce the Scalable Variant Call Representation (SVCR). This representation reduces file sizes by ensuring they scale linearly with samples. SVCR achieves this by adopting reference blocks from the Genomic Variant Call Format (GVCF) and employing local allele indices. SVCR is also lossless and mergeable, allowing for N+1 and N+K incremental joint-calling.We present two implementations of SVCR: SVCR-VCF, which encodes SVCR in VCF format, and VDS, which uses Hail’s native format. Our experiments confirm the linear scalability of SVCR-VCF and VDS, in contrast to the super-linear growth seen with standard VCF files. We also discuss the VDS Combiner, a scalable, open-source tool for producing a VDS from GVCFs and unique features of VDS which enable rapid data analysis. SVCR, and VDS in particular, ensure the scientific community can generate, analyze, and disseminate genetics datasets with millions of samples.
Reannotation of the zebra finch genome reveals undiscovered transcriptional complexity
Authors: Richard Hugues , Wiedenhoeft John , Scharff Constance , Adam Iris 
Published: January 2024

ABSTRACTThe zebra finch has become a paradigmatic model system to mechanistically investigate vocal communication from genes to behavior. Here, we report 1) a comprehensive map of the polyadenylated fraction of the transcriptome of the male zebra finch telencephalon at two ages, during the song learning phase at 50 days and when fully adult at 2 years as well as 2) as an expanded and refined annotation of the zebra finch genome based on our transcriptome data. Using high‐throughput next generation sequencing of paired‐end strand‐ specific cDNA fragments, we detected over 50% of the annotated protein coding transcripts (ENSEMBL v.55) in the telencephalon at both stages. We exploited the information gained from the paired‐end sequence reads and from reads falling onto splice junctions to update the existing annotation (ENS55) with new transcript structures and alternative splicing events. The dataset allowed to refine 2822 of the available gene models by extending them in the 3’‐UTR and to detect 11391 undiscovered transcriptional units in non‐coding regions. Our results illustrate the value of continuously incorporating new transcriptional evidence into existing annotations.
Reduced intra-tendinous sliding in Achilles tendinopathy during active plantarflexion regardless of horizontal foot position
Authors: Lecompte Laura , Crouzier Marion , Bogaerts Stijn , Scheys Lennart , Vanwanseele Benedicte 
Published: January 2024

ABSTRACTThe Achilles tendon consists of three subtendons with the ability to slide relative to each other. As optimal intra-tendinous sliding is thought to reduce the overall stress in the tendon, alterations in sliding behavior could potentially play a role in the development of Achilles tendinopathy. The aims of this study were to investigate the difference in intra-tendinous sliding within the Achilles tendon during isometric contractions between asymptomatic controls and patients with Achilles tendinopathy and the effect of changing the horizontal foot position on intra-tendinous sliding in both groups. 29 participants (13 Achilles tendinopathy, 16 controls) performed isometric plantarflexion contractions at 60% of their maximal voluntary contraction (MVC), in toes-neutral, and at 30% MVC in toes-neutral, toes-in and toes-out positions during which ultrasound images were recorded. Intra-tendinous sliding was estimated as the superficial-to-middle and middle-to-deep relative displacement. Our results indicate that patients with Achilles tendinopathy present lower intra-tendinous sliding compared to asymptomatic controls. Regarding the horizontal foot position in both groups, the toes-out foot position resulted in increased sliding compared to both toes-neutral and toes-out foot position. We provided evidence that patients with Achilles tendinopathy show lower intra-tendinous sliding compared to asymptomatic controls. Since intra-tendinous sliding is a physiological feature of the Achilles tendon, the external foot position holds promise to increase sliding in patients with Achilles tendinopathy and promote healthy tendon behavior. Future research should investigate if implementing this external foot position in rehabilitation programs stimulates sliding within the Achilles tendon and improves clinical outcome.