bioRxiv : the preprint server for biology最新文献

{"title":"RNAi-based screen for pigmentation in <i>Drosophila melanogaster</i> reveals regulators of brain dopamine and sleep.","authors":"Samantha L Deal, Danqing Bei, Shelley B Gibson, Harim Delgado-Seo, Yoko Fujita, Kyla Wilwayco, Elaine S Seto, Amita Sehgal, Shinya Yamamoto","doi":"10.1101/2023.07.20.549932","DOIUrl":"10.1101/2023.07.20.549932","url":null,"abstract":"<p><p>The dopaminergic system has been extensively studied for its role in behavior and neurological diseases. Despite this, we still know little about how dopamine levels are regulated <i>in vivo</i> . To identify regulators of dopamine, we utilized <i>Drosophila melanogaster</i> cuticle pigmentation as a readout, where dopamine is used as a precursor to melanin. We started by measuring dopamine from known pigmentation mutants (e.g. <i>tan</i> , <i>ebony</i> , <i>black</i> ) and then performed an RNAi-based screen to identify new regulators. We found 153 hits, which were enriched for developmental signaling pathways and mitochondria-associated proteins. From 35 prioritized candidates, 11 had an effect on head dopamine levels. Effects on brain dopamine were mild even when the rate-limiting synthesis enzyme <i>Tyrosine hydroxylase (TH)</i> was knocked down, suggesting changes in dopamine levels are tightly regulated in the nervous system. We pursued two of our hits that reduced brain dopamine levels, <i>clueless</i> and <i>mask</i> . Further examination suggests that <i>mask</i> regulates transcription of <i>TH</i> and affects dopamine-dependent sleep patterns. In summary, by studying genes that affect cuticle pigmentation, we were able to identify genes that affect dopamine metabolism as well as a novel regulator of behavior.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"51 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11996387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89188842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Olfactory inputs to appetite neurons in the hypothalamus.","authors":"Donghui Kuang, Naresh K Hanchate, Chia-Ying Lee, Ashley Heck, Xiaolan Ye, Michidsaran Erdenebileg, Linda B Buck","doi":"10.1101/2023.02.28.530282","DOIUrl":"10.1101/2023.02.28.530282","url":null,"abstract":"<p><p>The sense of smell has potent effects on appetite, but the underlying neural pathways remain undefined. Here we investigated how olfactory signals reach two subsets of appetite-linked neurons in the hypothalamic arcuate nucleus: AgRP (agouti-related peptide) neurons, which stimulate appetite, and POMC (pro-opiomelanocortin) neurons, which suppress it. Using polysynaptic viral tracing, we show that AgRP and POMC neurons receive indirect input from partially overlapping but distinct areas of the olfactory cortex, indicating that they process different sets of olfactory information. We also identify different complements of neurons directly upstream of AgRP and POMC neurons that can relay olfactory cortical signals to the appetite neurons. Single cell transcriptomics shows heterogeneous expression of neuromodulator receptors among AgRP neurons, suggesting variations in the signals they receive. Integrated viral tracing and RNA localization further reveals selected brain areas where upstream neurons express cognate receptor ligands. Together, these findings outline multiple pathways by which distinct olfactory and modulatory signals are differentially routed to neurons that promote versus inhibit appetite.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10002664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9092525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Slice-PASEF: Maximising Ion Utilisation in LC-MS Proteomics.","authors":"Ludwig R Sinn, Lukasz Szyrwiel, Justus Grossmann, Kate Lau, Katharina Faisst, Di Qin, Florian Mutschler, Luke Khoury, Andrew Leduc, Markus Ralser, Fabian Coscia, Matthias Selbach, Nikolai Slavov, Nagarjuna Nagaraj, Martin Steger, Vadim Demichev","doi":"10.1101/2022.10.31.514544","DOIUrl":"10.1101/2022.10.31.514544","url":null,"abstract":"<p><p>Quantitative mass spectrometry (MS)-based proteomics has become a streamlined technology with a wide range of usage. Many emerging applications, such as single-cell proteomics, spatial proteomics of tissue sections and the profiling of low-abundant posttranslational modifications, require the analysis of minimal sample amounts and are thus constrained by the sensitivity of the workflow. Here, we present Slice-PASEF, a mass spectrometry technology that leverages trapped ion mobility separation of ions to attain the theoretical maximum of tandem MS sensitivity. We implement Slice-PASEF using a new module in our DIA-NN software and show that Slice-PASEF uniquely enables precise quantitative proteomics of low sample amounts. We further demonstrate its utility towards a range of applications, including single cell proteomics and degrader drug screens via ubiquitinomics.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12424990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83073606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamics of Neutrophilia at the Neurovascular Unit Arising from Repeated Pulmonary Inflammation.","authors":"Wesley Chiang, Herman Li, Linh Le, Jennifer David-Bercholz, Ana Caceres, Kamryn S Stecyk, Mariah Marrero, Amanda Pereira, Claire Lim, Danial Ahmad, James L McGrath, Ania K Majewska, Niccolò Terrando, Harris A Gelbard","doi":"10.1101/2023.10.16.562508","DOIUrl":"10.1101/2023.10.16.562508","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;The role of neutrophils in mediating neurovascular vulnerability has been increasingly implicated in various acute inflammatory models of neuroimmune crosstalk between the periphery and the brain. Whether neurovascular vulnerability is similarly modulated in the context of frequent, but not acute, inflammatory activation in the periphery is the aim of our study. Such a model of frequent inflammatory irritation is pertinent to understanding the neurologic risk of constant exposure to aerosolized environmental hazards leading to progressive pulmonary disease.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;To model repeated pulmonary inflammation, we applied a three-dose regimen of intranasal (i.n.) lipopolysaccharide (LPS) in C57BL/6J mice and studied the impact on the inflammatory environment of the brain, with a specific focus on neutrophil dynamics at the neurovascular unit (NVU). Tissue and circulatory inflammatory profiles were screened via bronchoalveolar lavage (BAL) protein content and cellularity, transcript analysis of brain tissue, and flow cytometry of peripheral blood. Intravital two-photon microscopy (2PM) of the brain vasculature identified neutrophil dynamics at the NVU. Immunofluorescence validated neutrophil dynamics and identified neuroinflammatory hallmarks and peripheral immune factor interactions at the NVU. In vivo findings were corroborated and replicated in murine and human microphysiological systems (MPS) modeling the blood-brain barrier as a proxy demonstration of the translational relevance of our findings.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;2PM of tdTomato-Ly6G+ neutrophils demonstrated increased levels of circulating neutrophils and corresponding engagement with the brain vasculature after the three-dose repeated i.n. exposure regimen. Neutrophilia at the NVU was corroborated with increased transcript levels of &lt;i&gt;Ly6G&lt;/i&gt; and other pro-inflammatory markers. This coordination between endothelial physiology and neutrophil phenotypes was recapitulated in murine and human MPS models. System-wide neutrophilia in the lung and circulation was found to be cotemporaneous to neutrophilia at the NVU based on the cellularity of BAL and peripheral blood samples collected at the same endpoints. Immunohistochemical analysis of brain tissue implicates temporal coordination between vascular surface adhesion molecules with changes in neutrophil dynamics from adhesion, crawling, stalling, and transmigration. Extravasation of neutrophils was complemented by sustained paravascular deposition of fibrinogen and microgliosis up to 72 hours after the final i.n. dosing. Microglia-associated effector functions for synaptic pruning and regulation of neutrophil activity demonstrated distinct temporal profiles.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;Our results identify systemic levels of neutrophilia accompanied by ingress and extravascular accumulation in brain parenchyma that correlated with sustained microglial activation. This neut","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71415630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reconstructing the 3D genome organization of Neanderthals reveals that chromatin folding shaped phenotypic and sequence divergence.","authors":"Evonne McArthur, David C Rinker, Yang Cheng, Qixuan Wang, Juan Wang, Erin N Gilbertson, Geoff Fudenberg, Maureen Pittman, Kathleen Keough, Feng Yue, Katherine S Pollard, John A Capra","doi":"10.1101/2022.02.07.479462","DOIUrl":"10.1101/2022.02.07.479462","url":null,"abstract":"<p><p>Changes in gene regulation were a major driver of the divergence of archaic hominins (AHs)-Neanderthals and Denisovans-and modern humans (MHs). The three-dimensional (3D) folding of the genome is critical for regulating gene expression; however, its role in recent human evolution has not been explored because the degradation of ancient samples does not permit experimental determination of AH 3D genome folding. To fill this gap, we apply novel deep learning methods for inferring 3D genome organization from DNA sequence to Neanderthal, Denisovan, and diverse MH genomes. Using the resulting 3D contact maps across the genome, we identify 167 distinct regions with diverged 3D genome organization between AHs and MHs. We show that these 3D-diverged loci are enriched for genes related to the function and morphology of the eye, supra-orbital ridges, hair, lungs, immune response, and cognition. Despite these specific diverged loci, the 3D genome of AHs and MHs is more similar than expected based on sequence divergence, suggesting that the pressure to maintain 3D genome organization constrained hominin sequence evolution. We also find that 3D genome organization constrained the landscape of AH ancestry in MHs today: regions more tolerant of 3D variation are enriched for introgression in modern Eurasians. Finally, we identify loci where modern Eurasians have inherited novel 3D genome folding patterns from AH ancestors and validate folding differences in a high-frequency locus using Hi-C, revealing a putative molecular mechanism for phenotypes associated with archaic introgression. In summary, our application of deep learning to predict archaic 3D genome organization illustrates the potential of inferring molecular phenotypes from ancient DNA to reveal previously unobservable biological differences.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12424642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90754300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tensor-cell2cell v2 unravels coordinated dynamics of protein- and metabolite-mediated cell-cell communication.","authors":"Erick Armingol, Reid O Larsen, Lia Gale, Martin Cequeira, Hratch Baghdassarian, Nathan E Lewis","doi":"10.1101/2022.11.02.514917","DOIUrl":"10.1101/2022.11.02.514917","url":null,"abstract":"<p><p>Cell-cell communication dynamically changes across time while involving diverse cell populations and ligand types such as proteins and metabolites. While single-cell transcriptomics enables its inference, existing tools typically analyze ligand types separately and overlook their coordinated activity. Here, we present Tensor-cell2cell v2, a computational tool that can jointly analyze protein- and metabolite-mediated communication over time using coupled tensor component analysis, while preserving each modality of inferred communication scores independently, as well as their data structures and distributions. Applied to brain organoid development, Tensor-cell2cell v2 uncovers dynamic, coordinated communication programs involving key proteins and metabolites across relevant cell types across specific time points.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12424845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87616422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How Occam's razor guides human decision-making.","authors":"Eugenio Piasini, Shuze Liu, Pratik Chaudhari, Vijay Balasubramanian, Joshua I Gold","doi":"10.1101/2023.01.10.523479","DOIUrl":"10.1101/2023.01.10.523479","url":null,"abstract":"<p><p>Occam's razor is the principle that, all else being equal, simpler explanations should be preferred over more complex ones. This principle is thought to guide human decision-making, but the nature of this guidance is not known. Here we used preregistered behavioral experiments to show that people tend to prefer the simpler of two alternative explanations for uncertain data. These preferences match predictions of formal theories of model selection that penalize excessive flexibility. These penalties emerge when considering not just the best explanation but the integral over all possible, relevant explanations. We further show that these simplicity preferences persist in humans, but not in certain artificial neural networks, even when they are maladaptive. Our results imply that principled notions of statistical model selection, including integrating over possible, latent causes to avoid overfitting to noisy observations, may play a central role in human decision-making.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9882019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10790279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rab10 inactivation promotes AMPAR trafficking and spine enlargement during long-term potentiation.","authors":"Jie Wang, Jun Nishiyama, Paula Parra-Bueno, Elwy Okaz, Goksu Oz, Xiaodan Liu, Tetsuya Watabe, Irena Suponitsky-Kroyter, Timothy E McGraw, Erzsebet M Szatmari, Ryohei Yasuda","doi":"10.1101/2022.05.17.492345","DOIUrl":"10.1101/2022.05.17.492345","url":null,"abstract":"<p><p>Rab-dependent membrane trafficking is critical for changing the structure and function of dendritic spines during synaptic plasticity. Here, we developed highly sensitive sensors to monitor Rab protein activity in single dendritic spines undergoing structural long-term potentiation (sLTP) in rodent organotypic hippocampal slices. During sLTP, Rab10 was persistently inactivated (>30 min) in the stimulated spines, whereas Rab4 was transiently activated over ∼5 min. Inhibiting or deleting Rab10 enhanced sLTP, electrophysiological LTP and AMPA receptor (AMPAR) trafficking during sLTP. In contrast, disrupting Rab4 impaired sLTP only in the first few minutes, and decreased AMPAR trafficking during sLTP. Thus, our results suggest that Rab10 and Rab4 oppositely regulate AMPAR trafficking during sLTP, and inactivation of Rab10 signaling facilitates the induction of LTP and associated spine structural plasticity.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12154598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79706128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A multipotent cell type from term human placenta.","authors":"Sangeetha Vadakke-Madathil, Esmaa Bouhamida, Bingyan J Wang, Prabhu Mathiyalagan, Parichitran Ayyamperumal, Amir Khan, Micayla Oniskey, Carlos Santos-Gallegos, Michael Hadley, Lori Croft, Fumiko Dekio, Joseph Tripodi, Vesna Najfeld, Rachel Brody, Shari Gelber, Rhoda Sperling, Hina W Chaudhry","doi":"10.1101/2023.08.02.551028","DOIUrl":"10.1101/2023.08.02.551028","url":null,"abstract":"<p><p>We report a population of multipotent cells isolated from term human placentas that exhibit clonal expansion and migratory capacity, along with a gene expression profile that indicates immune privilege. Previously known largely for its role in early placentation, the developmental regulator CDX2 marks cells capable of differentiating into cardiomyocytes and vascular lineages. Building on our prior findings that murine Cdx2 cells improved cardiac function in mice after myocardial infarction (MI), we isolated CDX2⁺ cells from placentas of 180 healthy pregnancies. These human CDX2 cells spontaneously generate cardiac and vascular lineages <i>in vitro, in vivo,</i> and express transcriptomic signatures associated with cardiogenesis, vasculogenesis, immune modulation, and chemotaxis. When administered to NOD/SCID mice after MI, the cells restore cardiac function. Additionally, CDX2 cells can be clonally propagated while retaining cardiovascular differentiation potential. Our findings support the therapeutic potential of placental CDX2 cells as an ethically accessible and regenerative strategy for cardiovascular disease.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10418244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9991211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Morphometrics of the preserved post-surgical hemisphere in pediatric drug-resistant epilepsy and implications for post-operative cognition.","authors":"Michael C Granovetter, Anne Margarette S Maallo, Christina Patterson, Daniel Glen, Marlene Behrmann","doi":"10.1101/2023.09.24.559189","DOIUrl":"10.1101/2023.09.24.559189","url":null,"abstract":"<p><p>Characterization of the structural integrity of cortex in adults who have undergone resection for epilepsy treatment has, in some cases, revealed persistent or even accelerated cortical atrophy but, in others, the converse is evident, and atrophy decelerates or even reverses. Whether this variability applies to a pediatric population, for whom postoperative plasticity may be greater than in adulthood, remains to be determined. Furthermore, understanding the morphometrics of this patient population is important, as cognitive gains have been associated with the anatomical status of preserved cortex post-resection. Here, we used high-resolution structural T1 magnetic resonance imaging data to compare the (1) gross anatomy, (2) cortical thickness, volume, and surface area for 34 cortical regions, and (3) volume for nine subcortical regions of 32 pediatric post-surgical cases and 51 healthy controls. Patients with either a preserved right hemisphere (RH) or left hemisphere (LH) had lower total white matter volume and select subcortical structures' volumes, relative to controls; lateral ventricle size of both preserved RH and LH patients was also significantly larger than that of controls. However, relative to controls, only patients with a preserved RH had significantly lower total gray matter volume and lower thickness, volume, and surface area in multiple cortical regions, primarily in frontal and temporal cortex. The differences in preserved RH cortex of LH resection patients may relate to transfer of language function from the resected LH. Our findings lay the foundation for future studies probing associations of the morphometric differences in pediatric epilepsy surgery patients with neuropsychological outcomes.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10557613/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41175810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}