bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-precision spatial analysis of mouse courtship vocalization behavior reveals sex and strain differences
Authors: Oliveira-Stahl G. , Farboud S. , Sterling M. L. , Heckman J. J. , van Raalte B. , Lenferink D. , van der Stam A. , Smeets C. J. L. M. , Fisher S. E. , Englitz B. 
Published: October 2021

AbstractMice display a wide repertoire of vocalizations that varies with sex, strain, and context. Especially during social interaction, mice emit sequences of ultrasonic vocalizations (USVs) of high complexity. As animals of both sexes vocalize, a reliable attribution of USVs to their emitter is essential.The state-of-the-art in sound localization for USVs in 2D allows spatial localization at a resolution of multiple centimeters. However, animals interact at closer ranges, e.g. snout-to-snout. Hence, improved algorithms are required to reliably assign USVs. We present a novel algorithm, SLIM (Sound Localization via Intersecting Manifolds), that achieves a 3-fold improvement in accuracy (12-14.3mm) using only 4 microphones and extends to many microphones and localization in 3D. This accuracy allows reliable assignment of 84.3% of all USVs in our dataset.We apply SLIM to courtship interactions between adult C57Bl/6J wildtype mice and those carrying a heterozygous Foxp2 variant (R552H). The improved spatial accuracy reveals detailed vocalization preferences for specific spatial relations between the mice. Specifically, vocalization probability, duration, Wiener entropy, and frequency level differed in particular spatial relations between WT females, Foxp2-R552H and WT males.In conclusion, the improved attribution of vocalizations to their emitters provides a foundation for better understanding social vocal behaviors.
Dissecting tumor cell programs through group biology estimation in clinical single-cell transcriptomics
Authors: Johri Shreya , Bi Kevin , Titchen Breanna M. , Fu Jingxin , Conway Jake , Crowdis Jett P. , Volkes Natalie I. , Fan Zenghua , Fong Lawrence , Park Jihye , Liu David , He Meng Xiao , Van Allen Eliezer M. 
Published: October 2021

AbstractGiven the growing number of clinically integrated cancer single-cell transcriptomic studies, robust differential enrichment methods for gene signatures to dissect tumor cellular states for discovery and translation are critical. Current analysis strategies neither adequately represent the hierarchical structure of clinical single-cell transcriptomic datasets nor account for the variability in the number of recovered cells per sample, leading to results potentially confounded by sample-driven biology with high false positives instead of accurately representing true differential enrichment of group-level biology (e.g., treatment responders vs. non-responders). This problem is especially prominent for single-cell analyses of the tumor compartment, because high intra-patient similarity (as opposed to inter-patient similarity) results in stricter hierarchical structured data that confounds enrichment analysis. Furthermore, to identify signatures which are truly representative of the entire group, there is a need to quantify the robustness of otherwise statistically significant signatures to sample exclusion. Here, we present a new nonparametric statistical method, BEANIE, to account for these issues, and demonstrate its utility in two cancer cohorts stratified by clinical groups to reduce biological hypotheses and guide translational investigations. Using BEANIE, we show how the consideration of sample-specific versus group biology greatly decreases the false positive rate and guides identification of robust signatures that can also be corroborated across different cell type compartments.
PRMT1 regulates EGFR and Wnt signaling pathways and is a promising target for combinatorial treatment of breast cancer
Authors: Suresh Samyuktha , Huard Solène , Brisson Amélie , Némati Fariba , Poulard Coralie , Ye Mengliang , Martel Elise , Reyes Cécile , Silvestre David C. , Meseure Didier , Nicolas André , Gentien David , Le Romancer Muriel , Decaudin Didier , Roman-Roman Sergio , Dubois Thierry 
Published: October 2021

AbstractIdentifying new therapeutic strategies for triple-negative breast cancer (TNBC) patients is a priority as these patients are highly prone to relapse after chemotherapy. Here, we found that protein arginine methyltransferase 1 (PRMT1) is highly expressed in all breast cancer subtypes. Its depletion decreases cell survival by inducing DNA damage and apoptosis in various breast cancer cell lines. Transcriptomic analysis and chromatin immunoprecipitation revealed that PRMT1 regulates the epidermal growth factor receptor (EGFR) and the Wnt signaling pathways, reported to be activated in TNBC. The enzymatic activity of PRMT1 is also required to stimulate the canonical Wnt pathway. Recently developed type I PRMT inhibitors decrease breast cancer cell proliferation and show anti-tumor activity in a TNBC xenograft model. These inhibitors display synergistic interactions with some chemotherapies used to treat TNBC patients, as well as the EGFR inhibitor, erlotinib. Therefore, targeting PRMT1 in combination with drugs used in the clinic may improve current treatments for TNBC patients.SignificanceThis study highlights the requirement of PRMT1 for breast cancer cell survival and demonstrates the potential of targeting type I PRMTs in combination with chemotherapies in triple-negative breast cancer.
FABP7 Binds to Fatty Acid Micelles: Implications for Lipid Transport
Authors: Lenz Stefan , Bodnariuc Iulia , Renaud-Young Margaret , Shandro Tanille M. , MacCallum Justin L. 
Published: October 2021

AbstractThe transport of hydrophobic molecules, including long-chain fatty acids, within cells is highly dynamic. Hydrophobic molecules are unable to freely diffuse through the aqueous cytoplasm without a transporter. Fatty acid binding proteins (FABP) transport these molecules to different cellular compartments. As part of their transport, FABPs often associate with cell membranes to acquire and deliver their bound cargo. Understanding the nature of this transport is becoming increasingly important because lipid signaling functions are associated with metabolic pathways impacting disease pathologies such as carcinomas, autism and schizophrenia. Herein, we focus on Brain fatty acid binding protein (FABP7), which demonstrates localization to the cytoplasm and nucleus, influencing transcription and fatty acid metabolism. We use a combined biophysical approach to elucidate the interaction between FABP7 and model membranes. Specifically, we use microscale thermophoresis to show that FABP7 can bind oleic acid (OA) and docosahexaenoic acid (DHA) micelles, while differential scanning fluorimetry experiments show binding lowers the melting temperature of FABP7. Structural data from NMR and multiscale molecular dynamics simulations reveals that the interaction between FABP7 and micelles is through FABP7’s portal region residues. Our simulations also capture binding events where fatty acids dissociate from the model membrane and bind to FABP7. Overall, our data reveals a novel interaction between FABP7 and OA or DHA micelles and provides key structural insight into the transport of hydrophobic molecules.SignificanceThis study examines how FABP7 binds to fatty acids at low and high fatty acid concentrations. Our binding assays, including microscale thermophoresis (MST) and Nile red fluorescence establish that FABP7 binds to both free fatty acids in solution and fatty acid micelles. NMR and computational experiments show that FABP7 specifically interacts with micelles through the portal region of the protein, thereby mediating ligand transfer into the binding cavity.
Extrachromosomal Amplification of Human Papillomavirus Episomes as a Mechanism of Cervical Carcinogenesis
Authors: Rossi Nicole M. , Dai Jieqiong , Xie Yi , Lou Hong , Boland Joseph F. , Yeager Meredith , Orozco Roberto , Alvirez Enrique , Mirabello Lisa , Gharzouzi Eduardo , Dean Michael 
Published: October 2021

SummaryIntegration of Human Papillomaviruses (HPV) is an important mechanism of carcinogenesis but is absent in a significant fraction of HPV16+ tumors. We applied long-read whole-genome sequencing (WGS) to cervical cancer cell lines and tumors. In two HPV16+ cell lines, we identified large tandem arrays of full-length and truncated viral genomes integrated into multiple locations indicating formation as extrachromosomal DNA (HPV superspreading). An HPV16+ cell line with episomal DNA has tandem arrays of full-length, truncated, and rearranged HPV16 genomes (multimer episomes). WGS of HPV16+ cervical tumors revealed that 11/20 with only episomal HPV (EP) have intact monomer episomes. The remaining nine EP tumors have multimer and rearranged HPV genomes. Most HPV rearrangements disrupt the E1 and E2 genes, and EP tumors overexpress the E6 and E7 viral oncogenes. Tumors with both episomal and integrated HPV16 display multimer episomes and concatemers of human and viral sequences. One tumor has a recurrent deletion of an inhibitory site regulating E6 and E7 expression, and another has a recurrent duplication consistent with HPV superspreading. Therefore, HPV16 can cause cancer without integration through aberrant episomal replication, forming rearranged and multimer episomes.
Clostridioides difficileinfection increases circulating p-cresol levels and dysregulates brain dopamine metabolism: linking gut-brain axis to autism spectrum disorders?
Authors: Vinithakumari Akhil A. , Padhi Piyush , Hernandez Belen , Je-Han Lin Susanne , Dunkerson-Kurzhumov Aaron , Showman Lucas , Breitzman Matthew , Stokes Caroline , Sulaiman Yousuf , Tangudu Chandra , Kuttappan Deepa Ashwarya , Muyyarikkandy Muhammed Shafeekh , Phillips Gregory , Anantharam Vellareddy , Perera Ann , Sponseller Brett , Kanthasamy Anumantha , Mooyottu Shankumar 
Published: October 2021

AbstractGastrointestinal illnesses are one of the most common comorbidities reported in patients with neurodevelopmental diseases, including autism spectrum disorders (ASD). Gut dysbiosis, overgrowth ofC. difficile, and gut microbiota-associated alterations in central neurotransmission have been implicated in ASD, where the dopaminergic axis plays an important role in the disease pathogenesis. HumanC. difficilestrains produce a significant amount of the toxic metabolite p-cresol, an inhibitor of dopamine beta-hydroxylase (DBH), which catalyzes the conversion of dopamine (DA) to norepinephrine (NE). p-Cresol is known to precipitate and exacerbate autistic behavior in rodents by increasing DA levels and altering DA receptor sensitivity in brain regions relevant to ASD. Therefore, we hypothesized thatC. difficileinfection dysregulates dopaminergic metabolism by increasing p-cresol levels in the gut and systemic circulation, and by inhibiting brain DBH, ultimately leading to elevated DA in different brain regions. For testing this hypothesis, we induced antibiotic-associatedC. difficileinfection in mice and determined the gut and serum p-cresol levels, serum DBH activity, and dopamine and its metabolite levels in different brain regions relevant to ASD. The results showed thatC. difficileinfection causes a significant increase in striatal DA, accompanied by significantly altered levels of DA metabolites and NE in different brain regions (p < 0.05). In addition, significantly increased circulating p-cresol levels and reduced DBH activity were observed inC. difficileinfected mice (p < 0.05). Therefore, the results from this study suggest a potential link betweenC. difficileinfection and alterations in the dopaminergic axis implicated in the precipitation and aggravation of ASD.
The mechanosensitive TRPV2 calcium channel controls human melanoma invasiveness and metastatic potential
Authors: Shoji Kenji F. , Bayet Elsa , Devedec Dahiana Le , Mallavialle Aude , Marionneau-Lambot Séverine , Leverrier-Penna Sabrina , Rambow Florian , Perret Raul , Joussaume Aurélie , Viel Roselyne , Fautrel Alain , Khammari Amir , Constantin Bruno , Tartare-Deckert Sophie , Penna Aubin 
Published: October 2021

ABSTRACTDiscovery of therapeutic targets against metastasis is of primary importance since being the main cause of cancer-related death. Melanoma is a highly aggressive cancer endowed with a unique capacity of rapidly metastasizing. Deregulation of calcium homeostasis has been involved in numerous cellular metastatic behaviors, although the molecular determinants supporting these processes often remain unclear. Here, we evidenced a prominent expression of the plasma membrane TRPV2 calcium channel as a distinctive feature of melanoma tumors, directly related to melanoma metastatic progression and dissemination. In vitro as well as in vivo, TRPV2 activity was sufficient to confer both migratory and invasive phenotypes to non-invasive melanoma cells, while conversely upon TRPV2 silencing, highly metastatic melanoma cells failed to retain their malignant behaviors. We established a model whereupon activation of the mechanosensitive TRPV2 channel, localized in highly dynamic nascent adhesion clusters, directly regulates calpain-dependent cleavage of the adhesive protein talin together with F-actin network. By operating at the crossroad of the tumor microenvironment and the intracellular machinery, mechanosensitive TRPV2 channel controls melanoma cells aggressiveness. Finally in human melanoma tumor samples, TRPV2 overexpression represents a molecular marker of advanced malignancy and bad prognosis, highlighting a new therapeutic option for migrastatics in the treatment of metastatic melanoma.SignificanceOne essential feature of metastatic cells is enhanced motility and invasiveness. This study evidences TRPV2 channel control over metastatic melanoma invasiveness, highlights new migration regulatory mechanisms, and reveals this channel as a biomarker and migrastatic target for the treatment of advanced melanoma.
Retinal self-organization: a model of RGC and SAC mosaic formation
Authors: de Montigny Jean , Sernagor Evelyne , Bauer Roman 
Published: October 2021

AbstractIndividual retinal cell types exhibit semi-regular spatial patterns called retinal mosaics. These mosaics enable uniform sampling of visual information and are formed to varying degrees across cell types. Retinal ganglion cells (RGC) and amacrine cells (including starburst amacrine cells (SAC)) are notably known to exhibit such layouts. Mechanisms responsible for the formation of such organised structures and their requirements are still not well understood. Mosaic formation follows three main principles: (1) homotypic cells prevent nearby cells from adopting the same type, (2) cell tangential migration, with homotypic cell repulsion, (3) cell death (with RGCs exhibiting high rates of apoptosis).Here, we use BioDynaMo, an agent-based simulation framework, to build a detailed and mechanistic model of mosaic formation. In particular, we investigate the implications of the three theories for RGC’s mosaic formation. We report that the cell migration mechanism yields the most regular mosaics and that cell death can create regular mosaics only if the death rate is kept below 30%, after which cell death has a negative impact on mosaic regularity. In addition, and in accordance with recent studies, we propose here that low density RGC type mosaics exhibit on average low regularities, and thus we question the relevance of regular spacing as a criterion for a group of RGCs to form a RGC type.We also investigate SAC mosaics formation and possible interactions between the ganglion cell layer (GCL) and inner nuclear layer (INL) populations. Investigations are conducted both experimentally and by applying our simulation model to the SAC population. We report that homotypic interactions between the GCL and INL populations during mosaics creation are required to reproduce the observed SAC mosaics’ characteristics. This suggests that the GCL and INL populations of SACs might not be independent during retinal development.Author SummaryRetinal function depends on cells self-organisation during early development. Understanding the mechanisms underlying this self-organisation could improve not only our comprehension of the retina and its development but also of the cortex. Ultimately, this could lead to novel therapeutic approaches for developmental diseases. Computational models can be of precious help to study this process of self-organisation, given that they are biologically plausible. In this sense, it is important that implemented developmental mechanisms follow the principle of locally available information, without any global knowledge or external supervisor. Here, we follow this principle to investigate mosaic formation during retinal development. In this work, we demonstrate that tangential migration is the only mechanism able to form regular mosaics and that the GCL/INL SAC populations might not be independent during their mosaic formation. More, we question the relevance of regular spacing for RGC types classification.
Allosteric stabilization of calcium and phosphoinositide dual binding engages three synaptotagmins in fast exocytosis
Authors: Kobbersmed Janus R. L. , Berns Manon M. M. , Ditlevsen Susanne , Sørensen Jakob B. , Walter Alexander M. 
Published: October 2021

AbstractSynaptic communication relies on the fusion of synaptic vesicles with the plasma membrane, which leads to neurotransmitter release. This exocytosis is triggered by brief and local elevations of intracellular Ca2+ with remarkably high sensitivity. How this is molecularly achieved is unknown. While synaptotagmins confer the Ca2+ sensitivity of neurotransmitter exocytosis, biochemical measurements reported Ca2+ affinities too low to account for synaptic function. However, synaptotagmin’s Ca2+ affinity increases upon binding the plasma membrane phospholipid PI(4,5)P2 and, vice versa, Ca2+-binding increases synaptotagmin’s PI(4,5)P2 affinity, indicating a stabilization of the Ca2+/PI(4,5)P2 dual-bound syt. We here devise a molecular exocytosis model based on this positive allosteric stabilization and the assumptions that (1.) synaptotagmin Ca2+/PI(4,5)P2 dual binding lowers the energy barrier for vesicle fusion and that (2.) the effect of multiple synaptotagmins on the energy barrier is additive. The model, which relies on biochemically measured Ca2+/PI(4,5)P2 affinities and protein copy numbers, reproduced the steep Ca2+ dependency of neurotransmitter release. Our results indicate that each synaptotagmin dual binding Ca2+/PI(4,5)P2 lowers the energy barrier for vesicle fusion by 4.85 kBT and that allosteric stabilization of this state enables the synchronized engagement of three synaptotagmins for fast exocytosis. Furthermore, we show that mutations altering synaptotagmin’s allosteric properties may show dominant-negative effects, even though synaptotagmins act independently on the energy barrier, and that dynamic changes of local PI(4,5)P2 (e.g. upon vesicle movement) dramatically impact synaptic responses. We conclude that allosterically stabilized Ca2+/PI(4,5)P2 dual binding enables synaptotagmins to exert their coordinated function in neurotransmission.
Quantitative fragmentomics allow affinity mapping of interactomes
Authors: Gogl Gergo , Zambo Boglarka , Kostmann Camille , Cousido-Siah Alexandra , Morlet Bastien , Durbesson Fabien , Negroni Luc , Eberling Pascal , Jane Pau , Nomine Yves , Zeke Andras , Østergaard Søren , Monsellier Elodie , Vincentelli Renaud , Trave Gilles 
Published: October 2021

AbstractHuman protein networks have been widely explored but most binding affinities remain unknown, hindering quantitative interactome-function studies. Yet interactomes rely on minimal interacting fragments displaying quantifiable affinities. Here we measured the affinities of 65,000 interactions involving PDZ domains and their target PDZ-binding motifs (PBM) within a human interactome region particularly relevant for viral infection and cancer. We calculate interactomic distances, identify hot spots for viral interference, generate binding profiles and specificity logos, and explain selected cases by crystallographic studies. Mass spectrometry experiments on cell extracts and literature surveys show that quantitative fragmentomics effectively complement protein interactomics by providing affinities and completeness of coverage, putting a full human interactome affinity survey within realistic reach. Finally, we show that interactome hijacking by the viral PBM of human papillomavirus (HPV) E6 oncoprotein deeply impacts the host cell proteome way beyond immediate E6 binders, illustrating the complex system-wide relationship between interactome and function.
Potential genetic robustness of Prnp and Sprn double knockout mouse embryos towards ShRNA-lentiviral inoculation
Authors: Rau Andrea , Passet Bruno , Castille Johan , Asset Alexandre , Lecardonnel Jérome , Moroldo Marco , Jaffrézic Florence , Laloë Denis , Moazami-Goudarzi Katayoun , Vilotte Jean-Luc 
Published: October 2021

AbstractShadoo, encoded by Sprn, and PrP, encoded by Prnp, are related proteins whose biological functions are still incompletely understood. Although previous knockdown experiments have suggested the necessity of Shadoo in the absence of PrP during early mouse embryogenesis, little impact of the double-knockout of these two loci was reported. To further investigate this apparent discrepancy, we compared the transcriptome of WT, Prnp0/0 and Prnp0/0, Sprn0/0 E6.5 mouse embryos following inoculation by Sprn-ShRNA or Prnp-ShRNA lentiviral vectors at the one-cell stage. Our results highlighted a significant induction of an apoptotic pathway in Prnp0/0 E6.5 mouse embryos inoculated with Sprn-ShRNA vectors alongside interferon and to a lesser extent inflammatory responses, confirming previous reported experiments. On the contrary, ShRNA vector inoculation in Prnp0/0, Sprn0/0 embryos did not induce apoptosis and resulted in lower interferon responses. Finally, comparisons of the transcriptome of WT and Prnp0/0, Sprn0/0 embryos revealed only slight differences, which may in part explain the genetic robustness observed in the latter genotype.HighlightsSprn-ShRNA lentivirus vector inoculation in Prnp knockout one-cell mouse embryos results in the induction of an apoptosis pathway at E6.5, alongside interferon and to a lesser extent inflammatory responses.Sprn- or Prnp-ShRNA lentivirus vector inoculations in Prnp/Sprn knockout one-cell mouse embryos induce lower interferon responses and no apoptotic pathway at E6.5.Although wild type and Prnp/Sprn knockout E6.5 mouse embryos are transcriptomically similar, some differences might explain this apparent resilience of the double knockout genotype.
Pattern Recognition Receptor for Bacterial Lipopolysaccharide in the Cytosol of Human Macrophages
Authors: Rojas-Lopez Maricarmen , Zajac Amanda S. , Wood Thomas E. , Miller Kelly A. , Gil-Marqués María Luisa , Hachey Austin C. , Kharbanda Vritti , Egger Keith T. , Goldberg Marcia B. 
Published: October 2021

AbstractEndotoxin - bacterial lipopolysaccharide (LPS) - is a driver of the lethal infection sepsis through activation of innate immune responses. When delivered to the cytosol of macrophages, LPS (cLPS) induces the assembly of an inflammasome that contains caspases-4/5 in humans or caspase-11 in mice. Whereas activation of all other inflammasomes is triggered by sensing of pathogen products by a specific host cytosolic pattern recognition receptor protein, whether pattern recognition receptors for cLPS exist has been doubted by many investigators, as caspases-4, -5, and -11 bind and activate LPS directlyin vitro. Here we show that the primate-specific protein NLRP11 is a pattern recognition receptor for cLPS required for efficient activation of the caspase-4 inflammasome in human macrophages.NLRP11is present in humans and other primates, but absent in mice, likely explaining why it has been missed in screens looking for innate immune signaling molecules, most of which have been carried out in mice. NLRP11 is a previously missing link and a component of the human caspase-4 inflammasome activation pathway.One Sentence SummaryDiscovery that human macrophages contain a cytosolic receptor for bacterial lipopolysaccharide.