bluuebunny/crossref_metadata_2025_split huggingface dataset:
HisCl1regulates gustatory habituation in sweet taste neurons and mediates sugar ingestion inDrosophila
Authors: Kim Haein , Zhong Ziqing , Cui Xinyue , Sung Hayeon , Agrawal Naman , Jiang Tianxing , Dus Monica , Yapici Nilay 
Published: May 2024

SUMMARYSimilar to other animals, the fly,Drosophila melanogaster, reduces its responsiveness to tastants with repeated exposure, a phenomenon called gustatory habituation. Previous studies have focused on the circuit basis of gustatory habituation in the fly chemosensory system1,2. However, gustatory neurons reduce their firing rate during repeated stimulation3, suggesting that cell-autonomous mechanisms also contribute to habituation. Here, we used deep learning-based pose estimation and optogenetic stimulation to demonstrate that continuous activation of sweet taste neurons causes gustatory habituation in flies. We conducted a transgenic RNAi screen to identify genes involved in this process and found that knocking downHistamine-gated chloride channel subunit 1(HisCl1)in the sweet taste neurons significantly reduced gustatory habituation. Anatomical analysis showed thatHisCl1is expressed in the sweet taste neurons of various chemosensory organs. Using single sensilla electrophysiology, we showed that sweet taste neurons reduced their firing rate with prolonged exposure to sucrose. Knocking downHisCl1in sweet taste neurons suppressed gustatory habituation by reducing the spike frequency adaptation observed in these neurons during high-concentration sucrose stimulation. Finally, we showed that flies lackingHisCl1in sweet taste neurons increased their consumption of high-concentration sucrose solution at their first meal bout compared to control flies. Together, our results demonstrate that HisCl1 tunes spike frequency adaptation in sweet taste neurons and contributes to gustatory habituation and food intake regulation in flies. Since HisCl1 is highly conserved across many dipteran and hymenopteran species, our findings open a new direction in studying insect gustatory habituation.
TAK1 operates at the primary cilium in non-canonical TGFB/BMP signaling to control heart development
Authors: Doganli Canan , Baird Daniel A. , Ali Yeasmeen , Thomsen Oskar Kaaber , Audain Enrique , Jessen Line , Truelsen Pauline Munck , Mogensen Johanne Bay , Holm Maria Schrøder , Apolínová Kateřina , Buttò Lorenzo , Diamanti Maria , Fialová Jindřiška Leischner , Wade Emma M. , Robertson Stephen P. , Pedersen Lotte Bang , Argiro Laurent , Lescroart Fabienne , Hitz Marc-Phillip , Christensen Søren Tvorup , Larsen Lars Allan 
Published: May 2024

SummaryTransforming Growth Factor-Beta-Activated Kinase 1 (TAK1/MAP3K7), along with its upstream regulators TAK1-Binding Protein 2 (TAB2) and the catalytic alpha-subunit of Protein Kinase A (PKA-Cα/PRKACA), has been identified as a pivotal player in regulation of developmental processes. Haploinsufficiency of TAB2 causes Congenital Heart Disease (CHD) and rare variants in PKA-Cα and TAK1 cause cardioacrofacial dysplasia (CAFD), and Frontometaphyseal Dysplasia (FMD) and cardiospondylocarpofacial syndrome (CSCFS), respectively, rare multisystem syndromes, where CHD may appear in the clinical spectrum. We hypothesized that TAK1 plays a significant role in heart development and CHD and addressed this by genetic analysis in CHD patient cohorts and experiments in cell and animal models. Exome sequencing data from 1,471 CHD patients with extracardiac anomalies (syndromic CHD, sCHD), 2,405 patients with nonsyndromic CHD (nsCHD) and 45,082 controls showed increased burden of rareTAB2andTAK1variants in sCHD, but not in nsCHD. Detailed characterization oftak1-/-andtab2-/-zebrafish mutants revealed cardiac defects (dilated atrium, trabeculation defects, tachycardia and reduced contractility) as well as extracardiac developmental anomalies. RNA sequencing oftak1-/-mutant hearts showed downregulation of genes encoding core cardiac transcription factors, sarcomeric proteins and extracellular matrix proteins. Experiments with cell cultures and analysis of zebrafish larvae and gastruloids indicated that TAK1 via TAB2 and PKA-Cα is activated at the primary cilium during cardiomyogenesis and that TAK1 activation at this site is enhanced by cardiomyogenic signaling molecules, including ligands of the TGFB/BMP superfamily. Consistent with these findings, CRISPR/Cas9-mediated editing of TAK1 or administration of small molecule inhibitors targeting TAK1 inhibited ciliary signaling and cardiomyocyte differentiationin vitro, while FMD-causing mutations in TAK1 reduced its ciliary localization. In conclusion, our data establishes a central role for TAK1 and its upstream regulators in cardiac development and syndromic CHD, coordinated via the primary cilium.
Screening and identification of key biomarkers associated with endometriosis using bioinformatics and next generation sequencing data analysis
Authors: Vastrad Basavaraj , Vastrad Chanabasayya 
Published: May 2024

AbstractEndometriosis is a common cause of endometrial-type mucosa outside the uterine cavity with symptoms such as painful periods, chronic pelvic pain, pain with intercourse and infertility. However, the early diagnosis of endometriosis is still restricted. The purpose of this investigation is to identify and validate the key biomarkers of endometriosis. Next generation sequencing (NGS) dataset GSE243039 was obtained from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) between endometriosis and normal control samples were identified. After screening of DEGs, gene ontology (GO) and REACTOME pathway enrichment analyses were performed. Furthermore, a protein-protein interaction (PPI) network was constructed and modules were analysed using the Human Integrated Protein-Protein Interaction rEference (HIPIE) database and Cytoscape software, and hub genes were identified. Subsequantely, a network between miRNAs and hub genes, and network between TFss and hub genes were constructed using the miRNet and NetworkAnalyst tool, and possible key miRNAs and TFs were predicted. Finally, receiver operating characteristic curve (ROC) analysis was used to validate the hub genes. A total of 958 DEGs, including 479 up regulated genes and 479 down regulated genes, were screened between endometriosis and normal control samples. GO and REACTOME pathway enrichment analyses of the 958 DEGs showed that they were mainly involved in multicellular organismal process, developmental process, signaling by GPCR and muscle contraction. Further analysis of the PPI network and modules identified 10 hub genes, including VCAM1, SNCA, PRKCB, ADRB2, FOXQ1, MDFI, ACTBL2, PRKD1, DAPK1 and ACTC1. Possible target miRNAs, including hsa-mir-3143 and hsa-mir-2110, and target TFs, including TCF3 and CLOCK, were predicted by constructing a miRNA-hub gene regulatory network and TF-hub gene regulatory network. This investigation used bioinformatics techniques to explore the potential and novel biomarkers. These biomarkers might provide new ideas and methods for the early diagnosis, treatment, and monitoring of endometriosis.
Unlocking DOE potential selecting the most appropriate design for rAAV optimization
Authors: Tzimou Konstantina , Catalán-Tatjer David , Nielsen Lars K. , Lavado-García Jesús 
Published: May 2024

ABSTRACTThe production of recombinant adeno-associated virus (rAAV) for gene therapy via triple transfection is a highly intricate process involving many cellular interactions. Each of the different elements encoded in the three required plasmids—pHelper, pRepCap, and pGOI— play a distinct role and affect different cellular pathways when producing rAAVs. The expression balance of these different elements emphasizes the critical need to fine-tune the concentration of all three plasmids and transfection reagents effectively.The use of design of experiments (DOE) to find optimal plasmid and transfection reagent ratios is a powerful method to streamline the process. However, the choice of the DOE method and the design construction is crucial to avoid misleading results. In this work, we examined and compared four distinct DOE approaches: a rotatable central composite design (RCCD), a Box-Behnken design (BBD), a face-centered central composite design (FCCD), and a mixture design (MD). We compared the ability of the different models to predict optimal ratios, interactions among the three plasmids and transfection reagent, and the essentiality of studying the variability caused by uncontrolled random effects using blocking.Our findings revealed that MD, when coupled with FCCD, outperformed all other tested models. This outcome underscores the importance of selecting a model that can effectively account for the biological context, ultimately yielding superior results in optimizing rAAV production.
Semaglutide interferes with postnatal growth in a diet-dependent manner
Authors: Joly Amélie , Rebiffé Lucas , Dusabyinema Yves , Dellinger Julien , Leulier François , Vadder Filipe De 
Published: May 2024

AbstractObjectiveGlucagon-like peptide 1 receptor agonists (GLP-1RAs) have been shown to impact glucose homeostasis and, more recently, the somatotropic axis. While the effects of GLP-1RAs have been extensively studied in the context of diet-induced obesity, their impact on physiology in other nutritional contexts have been less explored. We investigated the potential beneficial effects of the GLP-1RA semaglutide during juvenile protein malnutrition, a dietary challenge known to cause stunted growth and to disrupt metabolic homeostasis.MethodsWe used a murine model to assess the effects of twice-weekly subcutaneous injections of semaglutide during juvenile protein malnutrition. Glucose metabolism was evaluated throughin vivooral glucose tolerance test,ex vivoglucose-stimulated insulin secretion in isolated pancreatic islets and histology of the pancreas. We combined linear growth monitoring, analysis of the growth hormone/insulin-like growth factor 1 signaling pathway and liver bulk RNA sequencing to characterize the effects of semaglutide on the somatotropic axis during juvenile protein malnutrition.ResultsSemaglutide improved glucose tolerance in control and malnourished mice, but differentially impacted pancreatic islet physiology depending on the dietary protein intake. While semaglutide did not alter growth in control conditions, it further inhibited growth of malnourished mice associated with reduction in fat but not lean mass. Surprisingly, semaglutide had no discernible effect on the functionality of the somatotropic axis in malnourished mice. Liver transcriptomics revealed that semaglutide may interfere with the growth of malnourished juvenile mice by altering circadian rhythm and thermogenesis.ConclusionsOur data reveal that semaglutide interacts differentially with the physiology of juvenile mice depending on their dietary protein intake. We found that semaglutide influences glucose metabolism and linear growth in a diet-dependent manner, underscoring the importance of examining the effects of GLP-1RAs across various nutritional contexts and developmental stages.Highlights-Semaglutide hampers the growth of protein-malnourished, but not control-fed, juvenile animals.-The effects of semaglutide on linear growth are independent of alterations in the somatotropic axis.-Semaglutide differentially alters glucose metabolism of juvenile mice depending on their dietary protein intake.
Culture of human retinal explants as an ex vivo model for retinal gene therapy
Authors: Alsalloum Almaqdad , Khubetsova Madina , Mityaeva Olga , Volchkov Pavel 
Published: May 2024

AbstractOptogenetic gene therapy may employ recombinant adeno-associated virus (AAV) vectors for specific preclinical applications in the treatment of inherited retinal diseases. Human retinal explants as an ex vivo model assist determine cellular tropism and the level of subsequent gene expression followed by delivery of viral vectors. Extracts of retinal tissue can be obtained and cultured for a certain time; thus, it is possible to transduce and confirm the effectiveness of the virus using various methods, including immunohistochemical staining. Consequently, we described method for harvesting and culturing human retinal fragments from divergent parts of the retina that differ anatomically and molecularly. The fragments were fixed, sectioned and stained. A dissociation method has also been described to obtain a retinal cell suspension that can be used in other experiments such as flow cytometry or mRNA/protein level expression assays.
Timing Matters: Lessons From Perinatal Neurogenesis in the Olfactory Bulb
Authors: Liberia Teresa , Han Kimberly , Meller Sarah , Martin-Lopez Eduardo , Greer Charles A. 
Published: May 2024

ABSTRACTIn the olfactory bulb odorant receptor specific input converges into glomeruli. Deep to the glomeruli coding of odor information is tuned by local synaptic circuits. Deciphering the dendritic organization of granule cells relative to the secondary dendrites of projection neurons is a pivotal for understanding odor processing. We carried out a detailed interrogation of the granule cells including the timing of neurogenesis, laminar distribution and synaptogenesis between granule cells and projection neurons. In brief, the granule cells develop following a outside in maturation pattern from embryogenesis to adulthood following a developmental continuum. Granule cells born one week after birth exhibit a unique sublayer specific distribution pattern, marking a transition between embryonic or neonatal and adult stages. Integration into reciprocal synaptic circuits occurred 10 days post neurogenesis, We conclude that timing of neurogenesis dictates the anatomical configuration of granule cells within the olfactory bulb, which in turn regulates a preferential synaptic integration with either mitral cell or tufted cell secondary dendrites.Summary StatementThe integration and distribution of granule cells into the olfactory bulb is determined by the timing of neurogenesis. Location of somata shifts from superficial to deep during development.
Disentangling cell-intrinsic and extrinsic factors underlying evolution
Authors: Starr Alexander L. , Nishimura Toshiya , Igarashi Kyomi J. , Funamoto Chihiro , Nakauchi Hiromitsu , Fraser Hunter B. 
Published: May 2024

SummaryA key goal of developmental biology is to determine the extent to which cells and organs develop autonomously, as opposed to requiring interactions with other cells or environmental factors. Chimeras have played a foundational role in this by enabling qualitative classification of cell-intrinsically vs. extrinsically driven processes. Here, we extend this framework to precisely decompose evolutionary divergence in any quantitative trait into cell-intrinsic, extrinsic, and intrinsic-extrinsic interaction components. Applying this framework to thousands of gene expression levels in reciprocal rat-mouse chimeras, we found that the majority of their divergence is attributable to cell-intrinsic factors, though extrinsic factors also play an integral role. For example, a rat-like extracellular environment extrinsically up-regulates the expression of a key transcriptional regulator of the endoplasmic reticulum (ER) stress response in some but not all cell types, which in turn strongly predicts extrinsic up-regulation of its target genes and of the ER stress response pathway as a whole. This effect is also seen at the protein level, suggesting propagation through multiple regulatory levels. Applying our framework to a cellular trait, neuronal differentiation, revealed a complex interaction of intrinsic and extrinsic factors. Finally, we show that imprinted genes are dramatically mis-expressed in species-mismatched environments, suggesting that mismatch between rapidly evolving intrinsic and extrinsic mechanisms controlling gene imprinting may contribute to barriers to interspecies chimerism. Overall, our conceptual framework opens new avenues to investigate the mechanistic basis of developmental processes and evolutionary divergence across myriad quantitative traits in any multicellular organism.
Non-cell-autonomous regulation of mTORC2 by Hedgehog signaling maintains lipid homeostasis
Authors: VanDerMolen Kylie R. , Newman Martin A. , Breen Peter C. , Huff Laura A. , Dowen Robert H. 
Published: May 2024

ABSTRACTOrganisms must appropriately allocate energetic resources between essential cellular processes to maintain homeostasis and in turn, maximize fitness. The nutritional and homeostatic regulators of energy homeostasis have been studied in detail; however, how developmental signals might impinge on these pathways to govern cellular metabolism is poorly understood. Here, we identify a non-canonical role for Hedgehog (Hh), a classic regulator of development, in maintaining intestinal lipid homeostasis inC. elegans. We find that expression of two Hh ligands, GRD-3 and GRD-4, is controlled by the LIN-29/EGR transcription factor in the hypodermis, where the Hh secretion factor CHE-14/Dispatched also facilitates non-cell autonomous Hh signaling. We demonstrate, usingC. elegansand mouse hepatocytes, that Hh metabolic regulation does not occur through the canonical Hh transcription factor, TRA-1/GLI, but rather through non-canonical signaling that engages mTOR Complex 2 (mTORC2) in the intestine. Hh mutants display impaired lipid homeostasis, including reduced lipoprotein synthesis and fat accumulation, decreased growth, and upregulation of autophagy factors, mimicking loss of mTORC2. Additionally, we found that Hh inhibits p38 MAPK signaling in parallel to mTORC2 activation and that both pathways act together to modulate of lipid homeostasis. Our findings show a non-canonical role for Hedgehog signaling in lipid metabolism via regulation of core homeostatic pathways and reveal a new mechanism by which developmental timing events govern metabolic decisions.
scBSP: A fast and accurate tool for identifying spatially variable genes from spatial transcriptomic data
Authors: Li Jinpu , Wang Yiqing , Raina Mauminah Azam , Xu Chunhui , Su Li , Guo Qi , Ma Qin , Wang Juexin , Xu Dong 
Published: May 2024

ABSTRACTSpatially resolved transcriptomics have enabled the inference of gene expression patterns within two and three-dimensional space, while introducing computational challenges due to growing spatial resolutions and sparse expressions. Here, we introduce scBSP, an open-source, versatile, and user-friendly package designed for identifying spatially variable genes in large-scale spatial transcriptomics. scBSP implements sparse matrix operation to significantly increase the computational efficiency in both computational time and memory usage, processing the high-definition spatial transcriptomics data for 19,950 genes on 181,367 spots within 10 seconds. Applied to diverse sequencing data and simulations, scBSP efficiently identifies spatially variable genes, demonstrating fast computational speed and consistency across various sequencing techniques and spatial resolutions for both two and three-dimensional data with up to millions of cells. On a sample with hundreds of thousands of sports, scBSP identifies SVGs accurately in seconds to on a typical desktop computer.
NEK1 modulates neurite outgrowth in motor neurons through coordinating retromer formation
Authors: Huang Xuan , Oses-Prieto Juan A. , Kawaguchi Riki , Perrault Laura , Frost Devlin , Chen Kuchuan , Guo Feng , Zhang Bingjie , Zhao Pinghan , Ho Tammy Szu-Yu , Pandey Roshan , Geschwind Daniel , Burlingame Alma L. , Woolf Clifford J. 
Published: May 2024

SUMMARYLoss of function of a cell cycle-associated geneNEK1causes amyotrophic lateral sclerosis (ALS), but how this leads to motor neuron degeneration is unknown. We studied the function ofNEK1in human stem cell-derived motor neurons and found that loss ofNEK1causes decreased neurite length accompanied by transcriptional alterations. We also found that NEK1 interacts with and modulates the formation of the retromer, and that impaired retromer function contributes to neurite outgrowth deficits. We identified SMC3, which interacts with NEK1 during the cell cycle, as a kinase substrate of NEK1 in motor neurons. Notably, loss of SMC3 not only recapitulates the decreased neurite outgrowth, but also affects retromer formation. We suggest that NEK1 interacts with multiple proteins in postmitotic neurons to coordinate retromer formation, and that loss of this leads to impaired neurite outgrowth.
Promoting Vigorous Intermittent Lifestyle Physical Activity (VILPA) in middle-aged adults: An evaluation of the MovSnax mobile app
Authors: Thøgersen-Ntoumani Cecilie , Grunseit Anne , Holtermann Andreas , Steiner Sarah , Tudor-Locke Catrine , Koster Annemarie , Johnson Nathan , Maher Carol , Ahmadi Matthew , Chau Josephine Y. , Stamatakis Emmanuel 
Published: May 2024

AbstractBackgroundMost adults fail to meet the moderate to vigorous physical activity-based recommendations needed to maintain or improve health. Vigorous Intermittent Lifestyle Physical Activity (VILPA) refers to short (1-2 mins) high-intensity activities that are integrated into activities of daily living. VILPA has shown strong potential to improve health and addresses commonly reported barriers to physical activity. However, it is unknown how VILPA can best be promoted among the adult population. This study aimed to evaluate the usability, user engagement, and satisfaction of a mobile application (MovSnax) designed to promote VILPA.MethodsA concurrent mixed methods design was used. It comprised four parts. Part A was a survey withn=8 mHealth and physical activity experts who had used the app over 7-10 days. Part B was think- aloud interviews withn=5 end-users aged 40-65 years old. Part C was a survey with a new group of 40-65-year-old end-users (n=35) who had used the MovSnax app over 7-10 days. Part D was semi- structured interviews withn=18 participants who took part in Part C. Directed content analysis was used to analyze the results from Parts A, B, and D, and descriptive statistics were used to analyze findings from Part C.ResultsParticipants reported positive views on the MovSnax app for promoting VILPA but also identified usability issues such as unclear purpose, difficulties in manual data entry, and limited customization options. Across the different data collections, they consistently emphasized the need for more motivational features, clearer feedback, and gamification elements to enhance engagement. Quantitative assessment showed satisfactory scores on objective measures but lower ratings on subjective aspects, possibly due to unfamiliarity with the VILPA concept and/or technical barriers.ConclusionsThe MovSnax app, tested in the present study, is the world’s first digital tool aimed specifically at increasing VILPA. The findings of the present study underscore the need for further app refinement, focusing on clarifying its purpose and instructions, boosting user engagement through personalization and added motivational elements, enhancing accuracy in detecting VILPA bouts, implementing clearer feedback mechanisms, expanding customization choices (such as font size and comparative data), and ensuring transparent and meaningful activity tracking.