bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimizing data integration improves Gene Regulatory Network inference in Arabidopsis thaliana
Authors: Cassan Océane , Lecellier Charles-Henri , Martin Antoine , Bréhélin Laurent , Lèbre Sophie 
Published: September 2023

AbstractMotivationsGene Regulatory Networks (GRN) are traditionnally inferred from gene expression profiles monitoring a specific condition or treatment. In the last decade, integrative strategies have successfully emerged to guide GRN inference from gene expression with complementary prior data. However, datasets used as prior information and validation gold standards are often related and limited to a subset of genes. This lack of complete and independent evaluation calls for new criteria to robustly estimate the optimal intensity of prior data integration in the inference process.ResultsWe address this issue for two common regression-based GRN inference models, an integrative Random Forest (weigthedRF) and a generalized linear model with stability selection estimated under a weighted LASSO penalty (weightedLASSO). These approaches are applied to data from the root response to nitrate induction inArabidopsis thaliana. For each gene, we measure how the integration of transcription factor binding motifs influences model prediction. We propose a new approach, DIOgene, that uses model prediction error and a simulated null hypothesis for optimizing data integration strength in a hypothesis-driven, gene-specific manner. The resulting integration scheme reveals a strong diversity of optimal integration intensities between genes. In addition, it provides a good trade-off between prediction error minimization and validation on experimental interactions, while master regulators of nitrate induction can be accurately retrieved.Availability and implementationThe R code and notebooks demonstrating the use of the proposed approaches are available in the repositoryhttps://github.com/OceaneCsn/integrative_GRN_N_induction.
A size principle for bistability in mouse spinal motoneurons
Authors: Harris-Warrick Ronald M , Pecchi Emilie , Drouillas Benoît , Brocard Frédéric , Bos Rémi 
Published: September 2023

AbstractBistability in spinal motoneurons supports tonic spike activity in the absence of excitatory drive. Earlier work in adult preparations suggested that smaller motoneurons innervating slow antigravity muscle fibers are more likely to generate bistability for postural maintenance. However, whether large motoneurons innervating fast-fatigable muscle fibers display bistability related to postural tone is still controversial. To address this, we examined the relationship between soma size and bistability in lumbar ventrolateral α-motoneurons of ChAT-GFP and Hb9-GFP mice across different developmental stages: neonatal (P2-P7), young (P7-P14) and mature (P21-P25). We found that as neuron size increases, the prevalence of bistability rises. Smaller α-motoneurons lack bistability, while larger fast α-motoneurons (MMP-9+/Hb9+) with a soma area ≥ 400µm2exhibit significantly higher bistability. Ionic currents associated with bistability, including the persistent Nav1.6 current, thermosensitive Trpm5 Ca2+-activated Na+current and the slowly inactivating Kv1.2 current, also scale with cell size. Serotonin evokes full bistability in large motoneurons with partial bistable properties, but not in small motoneurons. Our study provides important insights into the neural mechanisms underlying bistability and how motoneuron size dictates this process.New and NoteworthyBistability is not a common feature of all mouse spinal motoneurons. It is absent in small, slow motoneurons but present in most large, fast motoneurons. This difference results from differential expression of ionic currents that enable bistability, which are highly expressed in large motoneurons but small or absent in small motoneurons. These results support a possible role for fast motoneurons in maintenance of tonic posture in addition to their known roles in fast movements.
In vivodissection of the mouse tyrosine catabolic pathway with CRISPR-Cas9 identifies modifier genes affecting hereditary tyrosinemia type 1
Authors: Rivest Jean-François , Carter Sophie , Goupil Claudia , Cyr Denis , Ung Roth-Visal , Soglio Dorothée Dal , Mac-Way Fabrice , Waters Paula J. , Paganelli Massimiliano , Doyon Yannick 
Published: September 2023

ABSTRACTHereditary tyrosinemia type 1 is an autosomal recessive disorder caused by mutations (pathogenic variants) in fumarylacetoacetate hydrolase, an enzyme involved in tyrosine degradation. Its loss results in the accumulation of toxic metabolites that mainly affect the liver and kidneys and can lead to severe liver disease and liver cancer. Tyrosinemia type 1 has a global prevalence of approximately 1 in 100,000 births but can reach up to 1 in 1,500 births in some regions of Québec, Canada. Mutating functionally related ‘modifier’ genes (i.e., genes that, when mutated, affect the phenotypic impacts of mutations in other genes) is an emerging strategy for treating human genetic diseases.In vivosomatic genome editing in animal models of these diseases is a powerful means to identify modifier genes and fuel treatment development. In this study, we demonstrate that mutating additional enzymes in the tyrosine catabolic pathway through liver-specific genome editing can relieve or worsen the phenotypic severity of a murine model of tyrosinemia type 1. Neonatal gene delivery using recombinant adeno-associated viral vectors expressingStaphylococcus aureusCas9 under the control of a liver-specific promoter led to efficient gene disruption and metabolic rewiring of the pathway, with systemic effects that were distinct from the phenotypes observed in whole-body knockout models. Our work illustrates the value of usingin vivogenome editing in model organisms to study the direct effects of combining pathological mutations with modifier gene mutations in isogenic settings.
Changes in the urinary proteome of rats after short-term intake of magnesium threonate
Authors: Shen Ziyun , Yang Minhui , Wang Haitong , Liu Yuqing , Gao Youhe 
Published: September 2023

AbstractMagnesium is an important mineral in living organisms and has multiple functions in the human body, wherein it plays an important therapeutic and preventive role in a variety of diseases. In the present study, urine samples of rats before and after gavage of magnesium threonate were collected, and the urinary proteome was identified using the LC-MS/MS technique and analyzed using various databases. The results illustrated that the urinary proteome of rats was significantly altered after short-term intake of magnesium supplements and that the differential proteins and the biological functions were related to magnesium. This study innovatively establishes a method to study nutrients from the perspective of urine proteomics. This work demonstrates that the urinary proteome is capable of reflecting the effects of nutrient intake on the organism in a more systematic and comprehensive manner and has the potential to provide clues for clinical nutrition research and practice.
Resident memory T cell development is associated with AP-1 transcription factor upregulation across anatomical niches
Authors: Smith Neal P. , Yan Yu , Pan Youdong , Williams Jason B. , Manakongtreecheep Kasidet , Pant Shishir , Zhao Jingxia , Tian Tian , Pan Timothy , Stingley Claire , Wu Kevin , Zhang Jiang , Kley Alexander L. , Sorger Peter K. , Villani Alexandra-Chloé , Kupper Thomas S. 
Published: October 2023

AbstractTissue-resident memory T (TRM) cells play a central role in immune responses to pathogens across all barrier tissues after infection. However, the underlying mechanisms that drive TRMdifferentiation and priming for their recall effector function remains unclear. In this study, we leveraged both newly generated and publicly available single-cell RNA-sequencing (scRNAseq) data generated across 10 developmental time points to define features of CD8 TRMacross both skin and small-intestine intraepithelial lymphocytes (siIEL). We employed linear modeling to capture temporally-associated gene programs that increase their expression levels in T cell subsets transitioning from an effector to a memory T cell state. In addition to capturing tissue-specific gene programs, we defined a consensus TRMsignature of 60 genes across skin and siIEL that can effectively distinguish TRMfrom circulating T cell populations, providing a more specific TRMsignature than what was previously generated by comparing bulk TRMto naïve or non-tissue resident memory populations. This updated TRMsignature included the AP-1 transcription factor family membersFos, FosbandFosl2. Moreover, ATACseq analysis detected an enrichment of AP-1-specific motifs at open chromatin sites in mature TRM.CyCIFtissue imaging detected nuclear co-localization of AP-1 membersFosbandJunbin resting CD8 TRM>100 days post-infection. Taken together, these results reveal a critical role of AP-1 transcription factor members in TRMbiology and suggests a novel mechanism for rapid reactivation of resting TRMin tissue upon antigen encounter.
Stem cell-specific ecdysone signaling regulates the development and function of aDrosophilasleep homeostat
Authors: Wani Adil R , Chowdhury Budhaditya , Luong Jenny , Chaya Gonzalo Morales , Patel Krishna , Isaacman-Beck Jesse , Shafer Orie , Kayser Matthew S. , Syed Mubarak Hussain 
Published: October 2023

AbstractComplex behaviors arise from neural circuits that are assembled from diverse cell types. Sleep is a conserved and essential behavior, yet little is known regarding how the nervous system generates neuron types of the sleep-wake circuit. Here, we focus on the specification ofDrosophilasleep-promoting neurons—long-field tangential input neurons that project to the dorsal layers of the fan-shaped body neuropil in the central complex (CX). We use lineage analysis and genetic birth dating to identify two bilateral Type II neural stem cells that generate these dorsal fan-shaped body (dFB) neurons. We show that adult dFB neurons express Ecdysone-induced protein E93, and loss of Ecdysone signaling or E93 in Type II NSCs results in the misspecification of the adult dFB neurons. Finally, we show that E93 knockdown in Type II NSCs affects adult sleep behavior. Our results provide insight into how extrinsic hormonal signaling acts on NSCs to generate neuronal diversity required for adult sleep behavior. These findings suggest that some adult sleep disorders might derive from defects in stem cell-specific temporal neurodevelopmental programs.
TRIM72 restricts lyssavirus infection by inducing K48-linked ubiquitination and proteasome degradation of the matrix protein
Authors: Sui Baokun , Zheng Jiaxin , Fu Zhenfang , Zhao Ling , Zhou Ming 
Published: September 2023

AbstractThe tripartite motif (TRIM) protein family is the largest subfamily of E3 ubiquitin ligases, playing a crucial role in the antiviral process. In this study, we found that TRIM72, a member of the TRIM protein family, was increased in neuronal cells and mouse brains following rabies lyssavirus (RABV) infection. Over-expression of TRIM72 significantly reduced the viral titer of RABV in neuronal cells and mitigated the pathogenicity of RABV in mice. Furthermore, we found that TRIM72 over-expression effectively prevents the release of RABV. In terms of the mechanism, TRIM72 promotes the K48-linked ubiquitination of RABV Matrix protein (M), leading to the degradation of M through the proteasome pathway. TRIM72 directly interacts with M and the interaction sites were identified and confirmed through TRIM72-M interaction model construction and mutation analysis. Further investigation revealed that the degradation of M induced by TRIM72 was attributed to TRIM72’s promotion of ubiquitination at site K195 in M. Importantly, the K195 site was found to be partially conserved among lyssavirus’s M proteins, and TRIM72 over-expression induced the degradation of these lyssavirus M proteins. In summary, our study has uncovered a TRIM family protein, TRIM72, that can restrict lyssavirus replication by degrading M, and we have identified a novel ubiquitination site (K195) in lyssavirus M.Author SummaryRabies, caused by lyssaviruses, most often by rabies virus, the most lethal zoonotic disease, is responsible for approximately 59000 human deaths globally each year. Lyssavirus M protein displays an essential role in lyssavirus assembly and budding. Here, we found that TRIM family protein TRIM72 directly interacts with lyssavirus M thereby promoting the K48-linked ubiquitination of M, leading to the degradation of M through the proteasome pathway, restricting lyssavirus release. Moreover, we identified a novel important ubiquitination site (K195) in lyssavirus M. Prior to our study, there had been no reports of a direct interaction between TRIM72 and viral proteins, an antiviral function of TRIM72 was proved in our study. It is possible that TRIM72 interacts and ubiquitinates other viral proteins from various viruses, which warrants further investigation. This research contributes to our understanding of how TRIM72 and other TRIM proteins play a role in defending against viral invasions and may inspire further research in this field.
A locomotion-based assay to measure prepulse inhibition in zebrafish larvae
Authors: Read Emily , Hindges Robert 
Published: September 2023

AbstractSensory gating, assessed using a prepulse inhibition assay (PPI), is a promising endophenotype of neuropsychiatric disorders that can be measured in larval zebrafish models. However, current PPI assays require high-speed cameras to capture rapid c-bend startle behaviours. In this study, we designed and employed a PPI paradigm that uses locomotion as read-out of startle responses. PPI percentage was measured at a maximum of 86% and this was reduced to 42% upon administration of an NMDA receptor antagonist, MK-801. This work provides the foundation for simpler and more accessible PPI assays using larval zebrafish to model key endophenotypes of neurodevelopmental disorders.
Neural Evidence of Functional Compensation for Fluid Intelligence in Healthy Ageing
Authors: Knights Ethan , Henson Richard N. , Morcom Alexa M. , Mitchell Daniel J. , Tsvetanov Kamen A. 
Published: September 2023

AbstractFunctional compensation is a common notion in the neuroscience of healthy ageing, whereby older adults are proposed to recruit additional brain activity to compensate for reduced cognitive function. However, whether this additional brain activity in older participants actually helps their cognitive performance remains debated. We examined brain activity and cognitive performance in a human lifespan sample (N=223) while they performed a problem-solving task (based on Cattell’s test of fluid intelligence) during functional magnetic resonance imaging (fMRI). Whole-brain univariate analysis revealed that activity in bilateral cuneal cortex for hard vs. easy problems increased both with age and with performance, even when adjusting for an estimate of age-related differences in cerebrovascular reactivity. Multivariate Bayesian decoding further demonstrated that age increased the likelihood that activation patterns in this cuneal region provided non-redundant information about the two task conditions, beyond that of the multiple-demand network generally activated in this task. This constitutes some of the strongest evidence yet for functional compensation in healthy ageing, at least in this brain region during visual problem-solving.
Extensive co-regulation of neighbouring genes complicates the use of eQTLs in target gene prioritisation
Authors: Tambets Ralf , Kolde Anastassia , Kolberg Peep , Love Michael I , Alasoo Kaur 
Published: September 2023

AbstractIdentifying causal genes underlying genome-wide association studies (GWAS) is a fundamental problem in human genetics. Although colocalisation with gene expression quantitative trait loci (eQTLs) is often used to prioritise GWAS target genes, systematic benchmarking has been limited due to unavailability of large ground truth datasets. Here, we re-analysed plasma protein QTL data from 3,301 individuals of the INTERVAL cohort together with 131 eQTL Catalogue datasets. Focusing on variants located within or close to the affected protein identified 793 proteins with at least onecis-pQTL where we could assume that the most likely causal gene was the gene coding for the protein. We then benchmarked the ability ofcis-eQTLs to recover these causal genes by comparing three Bayesian colocalisation methods (coloc.susie, coloc.abf and CLPP) and five Mendelian randomisation (MR) approaches (three varieties of inverse-variance weighted MR, MR-RAPS, and MRLocus). We found that assigning fine-mapped pQTLs to their closest protein coding genes outperformed all colocalisation methods regarding both precision (71.9%) and recall (76.9%). Furthermore, the colocalisation method with the highest recall (coloc.susie - 46.3%) also had the lowest precision (45.1%). Combining evidence from multiple conditionally distinct colocalising QTLs with MR increased precision to 81%, but this was accompanied by a large reduction in recall to 7.1%. Furthermore, the choice of the MR method greatly affected performance, with the standard inverse-variance weighted MR often producing many false positives. Our results highlight that linking GWAS variants to target genes remains challenging with eQTL evidence alone, and prioritising novel targets requires triangulation of evidence from multiple sources.
Cell type-specific gene expression dynamics during human brain maturation
Authors: Steyn Christina , Mishi Ruvimbo , Fillmore Stephanie , Verhoog Matthijs B. , More Jessica , Rohlwink Ursula K. , Melvill Roger , Butler James , Enslin Johannes M. N. , Jacobs Muazzam , Sauka-Spengler Tatjana , Greco Maria , Quiñones Sadi , Dulla Chris G. , Raimondo Joseph V. , Figaji Anthony , Hockman Dorit 
Published: September 2023

AbstractThe human brain undergoes protracted post-natal maturation, guided by dynamic changes in gene expression. Most studies exploring these processes have used bulk tissue analyses, which mask cell type-specific gene expression dynamics. Here, using single nucleus (sn)RNA-seq on temporal lobe tissue, including samples of African ancestry, we build a joint paediatric and adult atlas of 75 cell subtypes, which we verify with spatial transcriptomics. We explore the differences between paediatric and adult cell types, revealing the genes and pathways that change during brain maturation. Our results highlight excitatory neuron subtypes, including theLTKandFREMsubtypes, that show elevated expression of genes associated with cognition and synaptic plasticity in paediatric tissue. The new resources we present here improve our understanding of the brain during its development and contribute to global efforts to build an inclusive brain cell map.
A Sodium-dependent Trehalose Transporter Contributes to Anhydrobiosis in Insect Cell Line, Pv11
Authors: Mizutani Kosuke , Yoshida Yuki , Nakanishi Eita , Miyata Yugo , Tokumoto Shoko , Fuse Hiroto , Gusev Oleg , Kikuta Shingo , Kikawada Takahiro 
Published: September 2023

AbstractPv11 is the only animal cell culture that, when preconditioned with a high concentration of trehalose, can be preserved in the dry state at room temperature for more than one year while retaining the ability to resume proliferation. This extreme desiccation tolerance is referred to as anhydrobiosis. Here we identified a novel transporter that contributes to the recovery of Pv11 cells from anhydrobiosis. In general, the SLC5 family of secondary active transporters co-transport Na+and carbohydrates including glucose. Here we identified a novel transporter STRT1 (sodium-ion trehalose transporter 1) belonging to the SLC5 family that is highly expressed in Pv11 cells and transports trehalose with Na+dependency. This is the first report of an SLC5 family member that transports a naturally occurring disaccharide, such as trehalose. Knockout of theStrt1gene significantly reduced the viability of Pv11 cells upon rehydration after desiccation. During rehydration, when intracellular trehalose is no longer needed,Strt1-knockout cells released the disaccharide more slowly than the parent cell line. During rehydration, Pv11 cells became roughly spherical due to osmotic pressure changes, but then returned to their original spindle shape after about 30 min.Strt1-knockout cells, however, required about 50 min to adopt their normal morphology. STRT1 probably regulates intracellular osmolality by releasing unwanted intracellular trehalose with Na+, thereby facilitating the recovery of normal cell morphology during rehydration. STRT1 likely improves the viability of dried Pv11 cells by rapidly alleviating the significant physical stresses that arise during rehydration.Significance StatementThis is the first report of an SLC5 family member, STRT1 (sodium ion trehalose transporter 1), with Na+-dependent trehalose transport activity. AStrt1-knockout cell line revealed that STRT1 likely plays an important role during anhydrobiosis in Pv11 cells: it efficiently discharges unwanted trehalose in the presence of Na+during rehydration of dried Pv11 cells, effectively reducing intracellular osmolality and thereby restoring cell morphology to a normal state.
Aedes albopictusis present in the lowlands of southern Zambia
Authors: Matute Daniel R. , Cooper Brandon S. 
Published: September 2023

ABSTRACTIdentifying the current geographic range of disease vectors is a critical first step towards determining effective mechanisms for controlling and potentially eradicating them. This is particularly true given that historical vector ranges may expand due to changing climates and human activity. TheAedessubgenusStegomyiacontains over 100 species, and among them,Ae. aegyptiandAe. albopictusmosquitoes represent the largest concern for public health, spreading dengue, chikungunya, and Zika viruses. WhileAe. aegyptihas been observed in the country of Zambia for decades,Ae. albopictushas not. In 2015 we sampled four urban and two rural areas in Zambia forAedesspecies. Using DNA barcoding, we confirmed the presence of immature and adultAe. albopictusat two rural sites: Siavonga and Livingstone. These genotypes seem most closely related to specimens previously collected in Mozambique based on CO1 sequence from mtDNA. We resampled Siavonga and Livingstone sites in 2019, again observing immature and adultAe. albopictusat both sites. RelativeAe. albopictusfrequencies were similar between sites, with the exception of immature life stages, which were higher in Siavonga than in Livingstone in 2019. WhileAe. albopictusfrequencies did not vary through time in Livingstone, both immature and adult frequencies increased through time in Siavonga. This report serves to document the presence ofAe. albopictusin Zambia, which will contribute to the process of determining the potential public health implications of this disease vector in Central Africa.