bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intrinsic neural diversity quenches the dynamic volatility of neural networks
Authors: Hutt Axel , Rich Scott , Valiante Taufik A , Lefebvre Jérémie 
Published: August 2022

AbstractHeterogeneity is the norm in biology. The brain is no different: neuronal cell-types are myriad, reflected through their cellular morphology, type, excitability, connectivity motifs and ion channel distributions. While this biophysical diversity enriches neural systems’ dynamical repertoire, it remains challenging to reconcile with the robustness and persistence of brain function over time. To better understand the relationship between heterogeneity and resilience, we analyzed both analytically and numerically a non-linear sparse neural network with balanced excitatory and inhibitory connections evolving over long time scales. We examined how neural diversity expressed as excitability heterogeneity in this network influences its dynamic volatility (i.e., its susceptibility to critical transitions). We exposed this network to slowly-varying modulatory fluctuations, continuously interrogating its stability and resilience. Our results show that excitability heterogeneity implements a homeostatic control mechanism tuning network stability in a context-dependent way. Such diversity was also found to enhance network resilience, quenching the volatility of its dynamics, effectively making the system independent of changes in many control parameters, such as population size, connection probability, strength and variability of synaptic weights as well as modulatory drive. Taken together, these results highlight the fundamental role played by cell-type heterogeneity in the robustness of brain function in the face of change.Significance StatementContemporary research has identified widespread cell-to-cell intrinsic diversity in the brain, manifest through variations in biophysical features such as neuronal excitability. A natural question that arises from this phenomenon is what functional role, if any, this heterogeneity might serve. Combining computational and mathematical techniques, this interdisciplinary research shows that intrinsic cell-to-cell diversity, far from mere developmental noise, represents a homeostatic control mechanism, promoting the resilience of neuronal circuits. These results highlight the importance of diversity in the robustness and persistence of brain function over time and in the face of change.
Changes in social position predict survival in bottlenose dolphins
Authors: Rankin Robert William , Foroughirad Vivienne Jilla , Krzyszczyk Ewa Beata , Frère Céline H , Mann Janet 
Published: August 2022

1AbstractSocial bonds and social structure are important features of animal systems that impact individual fitness. Few studies have examined how temporal dynamics in individual social bonds predict fitness outcomes. This is critical to understand given the high variation in types of social structures and strategies within populations of social mammals, both across time and among individuals. If individually-differentiated social bonds are important, it might be the change in bonds which has fitness consequences, not the absolute number of bonds nor their strength. We investigated how network dynamics predict survival in a wild population of bottlenose dolphins using a 35-year longitudinal study. In particular, we were interested in two sex-specific measures of the “widowhood effect”, as well as a more general investigation into the predictability of mortality from changes in higher-order social network metrics. We used two inferential frameworks to provide complimentary evidence for or against hypotheses; namely, a gradient-boosting predictivist approach with relative importance measures, and an inclusion probabilities approach based on stability-selection. We found evidence of a widowhood effect among males but not females. Surprisingly, the most robust predictor of survival was closeness-centrality, whereby the loss of closeness centrality preceded death. This finding, that absolute network position may not be as relevant to survival as changes in network status, is consistent with a large social-psychological literature in humans on the impacts of loss of social capital, dissolution of close friendships, and loss through death of partners (widowhood effect). This study highlights the critical nature of social connections and how its disruption can be a matter of life and death.
Pathogen transmission modes determine contact network structure, altering other pathogen characteristics
Authors: Collier Melissa , Albery Gregory F , McDonald Grant C. , Bansal Shweta 
Published: August 2022

AbstractPathogen traits can vary greatly and impact the ability of a pathogen to persist in a population. Although this variation is fundamental to disease ecology, little is known about the evolutionary pressures that drive these differences, particularly where they interact with host behavior. We hypothesized that host behaviors relevant to different transmission routes give rise to differences in contact network structure, constraining the space over which pathogen traits can evolve to maximize fitness. Our analysis of 232 contact networks across mammals, birds, reptiles, amphibians, arthropods, fish, and mollusks found that contact network topology varies by contact events, most notably in networks that are representative of fluid-exchange transmission. Using infectious disease model simulations, we showed that these differences in network structure suggest pathogens transmitted through fluid-exchange contact events will need traits associated with high transmissibility to successfully proliferate, compared to pathogens that transmit through other types of contact. These findings were supported through a review of known traits of pathogens that transmit in humans. Our work demonstrates that contact network structure may drive the evolution of compensatory pathogen traits according to transmission strategy, providing essential context for understanding pathogen evolution and ecology.
Reprogramming of fish somatic cells for nuclear transfer is primed by Xenopus egg extract
Authors: Chênais Nathalie , Le Cam Aurelie , Guillet Brigitte , Lareyre Jean-Jacques , Labbé Catherine 
Published: August 2022

ABSTRACTSomatic cell reprogramming in vitro prior to nuclear transfer is one strategy expected to improve clone survival during development. In this study, we investigated the reprogramming extent of fish fin somatic cells after in vitro exposure to Xenopus egg extract and subsequent culture. Using a cDNA microarray approach, we observed drastic changes in the gene expression profile of the treated cells. Several actors of the TGFβ and Wnt/β-catenin signaling pathways, as well as some mesenchymal markers, were inhibited in treated cells, while several epithelial markers were upregulated. This was associated with morphological changes of the cells in culture, suggesting that egg extract drove somatic cells towards a mesenchymal-epithelial transition (MET), the hallmark of somatic reprogramming in induced pluripotent stem cells (iPSCs). However, treated cells were also characterized by a strong decrease in de novo lipid biosynthesis metabolism, the lack of re-expression of pou2 and nanog pluripotency markers, and absence of DNA methylation remodeling of their promoter region. In all, this study showed that Xenopus egg extract treatment initiated an in vitro reprogramming of fin somatic cells in culture. Although not thorough, the induced changes have primed the somatic chromatin for a better embryonic reprogramming upon nuclear transfer.
Syntaxin-6 delays prion protein fibril formation and prolongs presence of toxic aggregation intermediates
Authors: Sangar Daljit , Hill Elizabeth , Jack Kezia , Batchelor Mark , Mistry Beenaben , Ribes Juan M. , Jackson Graham S. , Mead Simon , Bieschke Jan 
Published: August 2022

AbstractPrions replicate via the autocatalytic conversion of cellular prion protein (PrPC) into fibrillar assemblies of misfolded PrP. While this process has been extensively studied in vivo and in vitro, non-physiological reaction conditions of fibril formation in vitro have precluded the identification and mechanistic analysis of cellular proteins, which may alter PrP self-assembly and prion replication. Here, we have developed a fibril formation assay for recombinant murine and human PrP (23-231) under near-native conditions (NAA) to study the effect of cellular proteins, which may be risk factors or potential therapeutic targets in prion disease. Genetic screening suggests that variants that increase syntaxin-6 expression in the brain (gene: STX6) are risk factors for sporadic Creutzfeldt-Jakob disease (CJD). Analysis of the protein in NAA revealed counterintuitively that syntaxin-6 is a potent inhibitor of PrP fibril formation. It significantly delayed the lag phase of fibril formation at highly sub-stoichiometric molar ratios. However, when assessing toxicity of different aggregation time points to primary neurons, syntaxin-6 prolonged the presence of neurotoxic PrP species. Electron microscopy and super-resolution fluorescence microscopy revealed that, instead of highly ordered fibrils, in the presence of syntaxin-6 PrP formed less-ordered aggregates containing syntaxin-6. These data strongly suggest that the protein can directly alter the initial phase of PrP self-assembly and, uniquely, can act as an ‘anti-chaperone’, which promotes toxic aggregation intermediates by inhibiting fibril formation.
Vimentin intermediate filaments provide structural stability to the mammalian Golgi apparatus
Authors: Vitali Teresa , Witkos Tomasz M. , Cutiongco Marie F.A. , Yan Guanhua , Mironov Alexander A. , Swift Joe , Lowe Martin 
Published: August 2022

AbstractThe Golgi apparatus comprises a connected ribbon of stacked cisternal membranes localized to the perinuclear region of most vertebrate cells. The position and morphology of this organelle depends upon interactions with microtubules and the actin cytoskeleton. In contrast, we know relatively little about the relationship of the Golgi apparatus with intermediate filaments. In this study we show that the Golgi is in close physical proximity to vimentin intermediate filaments (IFs) in cultured mouse and human cells. We also show that the trans-Golgi network coiled-coil protein GORAB can physically associate with IFs. Although loss of vimentin and/or GORAB does not have major effects upon Golgi morphology at steady-state, the Golgi undergoes more rapid disassembly upon chemical disruption with the drug brefeldin A, and slower reassembly upon drug washout, in vimentin knockout cells. Moreover, loss of vimentin causes reduced Golgi ribbon integrity when cells are cultured on high stiffness hydrogels, which is exacerbated by loss of GORAB. These results indicate that vimentin IFs contribute to the structural stability of the Golgi apparatus, and suggest a role for GORAB in this process.
Elasmobranchs’ metabarcoding requires a pragmatic approach to reach its promises
Authors: Cruz Marcelo Merten , Sauvage Thomas , Chariton Anthony , de Freitas Thales Renato Ochotorena 
Published: August 2022

AbstractHuman impacts have been eroding marine ecosystems in such a way that biodiversity patterns are changing. Therefore, policies and science-based solutions are indispensable for monitoring threats to the most impacted species. In such effort, the analysis of elasmobranchs’ environmental traces via eDNA metabarcoding represent a candidate tool for effective monitoring and conservation that is often advocated to be cost-effective and easily replicated. Here, we tested a realistic approach to monitor future changes through elasmobranchs’ metabarcoding with published primers, in which, elasmobranch diversity from the coastal waters of the Fernando de Noronha Archipelago (Brazil) was studied here. We detected a total of three elasmobranch species, namelyHypanus berthalutzae, Ginglymostoma cirratum, andPrionace glaucaamong numerous other fish species. Even though the technique proved to be a useful tool, some practical constraints were identified, and primarily caused by currently published environmental primers. In order to ensure the broad application of the method, we pointed out feasible adjustments to the problematic parameters based on our survey and other elasmobranch metabarcoding studies. The current drawbacks of the approach need to be considered by managers, conservation actors, and researchers, who are considering this methodology in order to avoid unrealistic promises for the cost incurred.
Reprograming human fibroblasts into Sertoli cells: a tool for personalized medicine
Authors: Parivesh Abhinav , Délot Emmanuèle , Reyes Alejandra , Ryan Janelle , Bhattacharya Surajit , Harley Vincent , Vilain Eric 
Published: August 2022

AbstractDisorders/Differences of Sex Development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. With overlapping phenotypes and multiple genes involved, poor diagnostic yields are achieved for many of these conditions. The current DSD diagnostic regimen can be augmented by investigating transcriptome/proteome in vivo, but it is hampered by the unavailability of affected gonadal tissue at the relevant developmental stage. We try to mitigate this limitation by reprogramming readily available skin tissue-derived dermal fibroblasts into Sertoli cells (SC), which could then be deployed for different diagnostic strategies. SCs form the target cell type of choice because they act like an organizing center of embryonic gonadal development and many DSD arise when these developmental processes go awry.We employed a computational predictive algorithm for cell conversions called Mogrify to predict the transcription factors (TFs) required for direct reprogramming of human dermal fibroblasts into SCs. We established trans-differentiation culture conditions where stable transgenic expression of these TFs was achieved in 46, XY adult dermal fibroblasts using lentiviral vectors. The resulting Sertoli like cells (SLCs) were validated for SC phenotype using several approaches. SLCs exhibited Sertoli-like morphological and cellular properties as revealed by morphometry and xCelligence cell behavior assays. They also showed Sertoli-specific expression of molecular markers such as SOX9, PTGDS, BMP4, or DMRT1 as revealed by IF imaging, RNAseq and qPCR. The SLC transcriptome shared about two thirds of its differentially expressed genes with a human adult SC transcriptome and expressed markers typical of embryonic SCs. Notably, SLCs lacked expression of markers of other gonadal cell types such as Leydig, germ, peritubular myoid or granulosa cells.The trans-differentiation method was applied to a variety of commercially available 46, XY fibroblasts derived from patients with DSD and to a 46, XX cell line. The DSD SLCs displayed altered levels of trans-differentiation in comparison to normal 46, XY-derived SLCs, thus showcasing the robustness of this new trans-differentiation model.
Assessment of anti-inflammatory bioactivity of extracellular vesicles is susceptible to error via media component contamination
Authors: Kronstadt Stephanie M. , Van Heyningen Lauren Hoorens , Aranda Amaya , Jay Steven M. 
Published: August 2022

AbstractExtracellular vesicles (EVs) are widely implicated as novel diagnostic and therapeutic modalities for a wide range of diseases. Thus, optimization of EV biomanufacturing is of high interest. In the course of developing parameters for a HEK293T EV production platform, we examined the combinatorial effects of cell culture conditions (i.e., static vs dynamic) and isolation techniques (i.e., ultracentrifugation vs tangential flow filtration vs size-exclusion chromatography) on functional characteristics of HEK293T EVs, including anti-inflammatory bioactivity using a well-established LPS-stimulated mouse macrophage model. We unexpectedly found that, depending on culture condition and isolation strategy, HEK293T EVs appeared to significantly suppress the secretion of pro-inflammatory cytokines (i.e., IL-6, RANTES) in the stimulated mouse macrophages. Further examination revealed that these results were most likely due to fetal bovine serum (FBS) EV contamination in HEK293T EV preparations. Thus, future research assessing the anti-inflammatory effects of EVs should be designed to account for this phenomenon.
Learning-dependent evolution of odor mixture representations in piriform cortex
Authors: Berners-Lee Alice , Shtrahman Elizabeth , Grimaud Julien , Murthy Venkatesh N. 
Published: August 2022

AbstractRodents can learn from exposure to rewarding odors to make better and quicker decisions. The piriform cortex is thought to be important for learning complex odor associations, however it is not understood exactly how it learns to remember discriminations between many, sometimes overlapping, odor mixtures. We investigated how odor mixtures are represented in the posterior piriform cortex (pPC) of mice while they learn to discriminate a unique target odor mixture against hundreds of nontarget mixtures. We find that a significant proportion of pPC neurons discriminate between the target and all other nontarget odor mixtures. Neurons that prefer the target odor mixture tend to respond with brief increases in firing rate at odor onset compared to other neurons, which exhibit sustained and/or decreased firing. We allowed mice to continue training after they had reached high levels of performance and find that pPC neurons become more selective for target odor mixtures as well as for randomly chosen repeated nontarget odor mixtures that mice did not have to discriminate from other nontargets. These single unit changes during overtraining are accompanied by better categorization decoding at the population level, even though behavioral metrics of mice such as reward rate and latency to respond do not change. However, when difficult ambiguous trial types are introduced, the robustness of the target selectivity is correlated with better performance on the difficult trials. Taken together, these data reveal pPC as a dynamic and robust system that can optimize for both current and possible future task demands at once.
Stable kinetochore-microtubule attachment requires loop-dependent Ndc80-Ndc80 binding
Authors: Polley Soumitra , Müschenborn Helen , Terbeck Melina , De Antoni Anna , Vetter Ingrid R. , Dogterom Marileen , Musacchio Andrea , Volkov Vladimir A. , Huis in ‘t Veld Pim J. 
Published: August 2022

ABSTRACTDuring cell division, kinetochores link chromosomes to spindle microtubules. The Ndc80 complex, a crucial microtubule binder, populates each kinetochore with dozens of copies. Whether adjacent Ndc80 complexes cooperate to promote microtubule binding remains unclear. Here we demonstrate that the Ndc80 loop, a short sequence identified across eukaryotes and predicted to interrupt the Ndc80 coiled-coil, promotes direct interactions between full-length Ndc80 complexes. Both in dividing cells and in a fully reconstituted system, these interactions are essential for the formation of force-resistant kinetochore-microtubule attachments, explaining why deletion of the loop ablates chromosome congression. The loop may fold into a more rigid structure than previously assumed and we identify point mutations that impair Ndc80-Ndc80 interactions and recapitulate the effects of loop depletion. The loop also promotes spindle checkpoint signaling, suggesting that the organisation of adjacent Ndc80 complexes is crucial to couple kinetochore-microtubule binding to cell cycle control.
Genome-wide prediction of disease variants with a deep protein language model
Authors: Brandes Nadav , Goldman Grant , Wang Charlotte H. , Ye Chun Jimmie , Ntranos Vasilis 
Published: August 2022

AbstractDistinguishing between damaging and neutral missense variants is an ongoing challenge in human genetics, with profound implications for clinical diagnosis, genetic studies and protein engineering. Recently, deep-learning models have achieved state-of-the-art performance in classifying variants as pathogenic or benign. However, these models are currently unable to provide predictions over all missense variants, either because of dependency on close protein homologs or due to software limitations. Here we leveraged ESM1b, a 650M-parameter protein language model, to predict the functional impact of human coding variation at scale. To overcome existing technical limitations, we developed a modified ESM1b workflow and functionalized, for the first time, all proteins in the human genome, resulting in predictions for all ∼450M possible missense variant effects. ESM1b was able to distinguish between pathogenic and benign variants across ∼150K variants annotated in ClinVar and HGMD, outperforming existing state-of-the-art methods. ESM1b also exceeded the state of the art at predicting the experimental results of deep mutational scans. We further annotated ∼2M variants across ∼9K alternatively-spliced genes as damaging in certain protein isoforms while neutral in others, demonstrating the importance of considering all isoforms when functionalizing variant effects. The complete catalog of variant effect predictions is available at: https://huggingface.co/spaces/ntranoslab/esm_variants.
Fgf8 promotes survival of nephron progenitors by regulating BAX/BAK-mediated apoptosis
Authors: Anderson Matthew J. , Misaghian Salvia , Sharma Nirmala , Perantoni Alan O. , Lewandoski Mark 
Published: August 2022

AbstractFibroblast growth factors (Fgfs) have long been implicated in processes critical to embryonic development, such as cell survival, migration, and differentiation. Several mouse models of organ development ascribe a prosurvival requirement specifically to FGF8. Here, we explore the potential role of prosurvival FGF8 signaling in kidney development. We have previously demonstrated that conditional deletion of Fgf8 in the mesodermal progenitors that give rise to the kidney leads to renal aplasia in the mutant neonate. Deleterious consequences caused by loss of FGF8 begin to manifest by E14.5 when massive aberrant cell death occurs in the cortical nephrogenic zone in the rudimentary kidney as well as in the renal vesicles that give rise to the nephrons. To rescue cell death in the Fgf8 mutant kidney, we inactivate the genes encoding the pro-apoptotic factors BAK and BAX. In a wild-type background, the loss of Bak and Bax abrogates normal cell death and has minimal effect on renal development. However, in Fgf8 mutants, the combined loss of Bak and Bax rescues aberrant cell death in the kidneys and restores some measure of kidney development: 1) the nephron progenitor population is greatly increased; 2) some glomeruli form, which are rarely observed in Fgf8 mutants; and 3) kidney size is rescued by about 50% at E18.5. The development of functional nephrons, however, is not rescued. Thus, FGF8 signaling is required for nephron progenitor survival by regulating BAK / BAX and for subsequent steps involving, as yet, undefined roles in kidney development.