Miracle-dz/UniFAR-FTUs huggingface dataset:
Synaptotagmin 7 outperforms synaptotagmin 1 to open and stabilize nascent fusion pores via robust membrane penetration

Ca 2+ -triggered exocytosis is a crucial aspect of neuronal and neuroendocrine cell function, yet many of the underlying molecular mechanisms that regulate these processes are unknown. Here, we contrast the biophysical properties of two prominent neuronal Ca 2+ sensors, synaptotagmin (syt) 1 and syt7. In both proteins, four Ca 2+ -binding loops partially penetrate bilayers that harbor anionic phospholipids, and mutagenesis studies suggest that these interactions are important for function. However, these mutations also alter the interaction of syts with the SNARE proteins that directly catalyze membrane fusion. To directly assess the role of syt membrane penetration, we took a different approach and found that Ca 2+ -syt1-membrane interactions are strongly influenced by membrane order; tight lateral packing of phosphatidylserine abrogates syt1 binding to lipid bilayers due to impaired membrane penetration. Function could be restored by making the membrane penetration loops more hydrophobic, or by inclusion of cholesterol. In sharp contrast, syt7 unexpectedly exhibited robust membrane binding and penetration activity, regardless of the lipid acyl chain structure. Thus, syt7 is a ‘super-penetrator’. We exploited these observations to specifically isolate and examine the role of membrane penetration in syt function. By altering bilayer composition, rather than protein structure, we disentangled the roles of syt-membrane versus syt-SNARE interactions. Using nanodisc-black lipid membrane electrophysiology, we demonstrate that membrane penetration underlies the ability of syts to directly regulate reconstituted, exocytic fusion pores in response to Ca 2+ . Quantification of a liposome titration in the presence of NBD-labelled syt1 C2AB. The protein concentration was fixed a 250 nM and the fluorescence at 525 nm was monitored as the concentration of lipid increased from 0-500 µM. Error bars represent standard error of the mean from triplicate experiments performed on separate days with fresh materials.
Introducing Mouffet, a unified framework to make model creation easier and more reproducible

Biological and ecological models are being increasingly used to explain the natural world. Model creation is an iterative process requiring two steps: training and evaluating the models. However, this process can become complex when multiple models are trained and evaluated at the same time. Besides, development steps can be lost, reducing the reproducibility of model creation. We introduce Mouffet, an open-source Python framework that aims to make model creation easier, more robust, and more reproducible. It provides a set of configuration files and high-level Python interfaces that help managing data, training, and evaluating models. To improve reproducibility, every step of the model creation process, including the options used, are saved. Mouffet introduces the notion of scenarios that allow users to define multiple training or evaluation tasks in a single configuration file. This not only facilitates model creation but enables users to define experimental plans to study the effect of selected parameters on training or evaluation. While initially developed for deep learning models, Mouffet is independent of the implementation of the models. Therefore, it could be successfully used to compare different modelling approaches. Besides, its ease of use makes it a choice tool for ecologists, even when not familiar with complex model creation.
Metabolic differences and differentially expressed genes between C57BL/6J and C57BL/6N mice substrains

C57BL/6J (B6J) and C57BL/6N (B6N) mice are the most frequently used substrains in C57BL/6 (B6) inbred mice, serving as physiological models for in vivo studies and as background strains to build transgenic mice. However, little attention has been paid to the phenotypic differences between B6J and B6N mice, and they have often been attributed to mutations in the nicotinamide nucleotide transhydrogenase (Nnt) gene, which was found only in B6J. Nevertheless, phenotypic differences between the two that cannot be explained by Nnt mutations alone, especially in metabolic traits, indicate the presence of genetic variants associated with metabolism other than Nnt. We aimed to identify these genetic differences between B6J and B6N mice. Our results provide insights into differentially expressed genes (DEGs) in adipose tissues, skeletal muscle, liver, hypothalamus, and hippocampus, and phenotypic differences in metabolic traits between B6J and B6N. B6J mice had significantly lower body weight than B6N mice, regardless of a normal or high-fat diet. Blood insulin levels in B6J mice were significantly lower than those in B6N mice and glucose levels during dietary obesity were higher in B6J mice. Metabolic assessments revealed greater physical activity, less food intake, and higher energy expenditure in B6J mice than in B6N mice. Among the DEGs that were highly expressed in B6J mice compared to B6N mice, three genes—insulin degrading enzyme, adenylosuccinate synthase 2, and ectonucleotide triphosphate diphosphohydrolase 4—and the DEGs that had lower expression in B6J mice compared to B6N mice—Nnt, WD repeat and FYVE domain containing 1, and dynein light chain Tctex-type 1—were overlapped in all seven tissues. Our study provides insights into DEGs between B6J and B6N, which will be useful for substrain selection for mouse experiments, avoiding erroneous experimental results, and reviewing the results of studies that have used B6J, B6N, or mixed substrains.
Architecture and dynamics of a novel desmosome-endoplasmic reticulum organelle

The endoplasmic reticulum (ER) forms a dynamic network that contacts other cellular membranes to regulate stress responses, calcium signaling, and lipid transfer. Using high-resolution volume electron microscopy, we find that the ER forms a previously unknown association with keratin intermediate filaments and desmosomal cell-cell junctions. Peripheral ER assembles into mirror image-like arrangements at desmosomes and exhibits nanometer proximity to keratin filaments and the desmosome cytoplasmic plaque. ER tubules exhibit stable associations with desmosomes, and perturbation of desmosomes or keratin filaments alters ER organization and mobility. These findings indicate that desmosomes and the keratin cytoskeleton pattern the distribution of the ER network. Overall, this study reveals a previously unknown subcellular architecture defined by the structural integration of ER tubules with an epithelial intercellular junction. One-Sentence Summary The desmosome adhesive junction regulates the organization and dynamics of the endoplasmic reticulum network.
A novel RHH family transcription factor aCcr1 and its viral homologs dictate cell cycle progression in archaea

Cell cycle regulation is of paramount importance for all forms of life. Here we report that a conserved and essential cell cycle-specific transcription factor (designated as aCcr1) and its viral homologs control cell division in Sulfolobales. We show that the transcription level of accr1 reaches peak during active cell division (D-phase) subsequent to the expression of CdvA, an archaea-specific cell division protein. Cells over-expressing the 58-aa-long RHH (ribbon-helix-helix) family cellular transcription factor as well as the homologs encoded by large spindle-shaped viruses Acidianus two-tailed virus (ATV) and Sulfolobus monocaudavirus 3 (SMV3) display significant growth retardation and cell division failure, manifested as enlarged cells with multiple chromosomes. aCcr1 over-expression results in downregulation of 17 genes (>4-folds) including cdvA. A conserved motif, aCcr1-box, located between the TATA-binding box and the translation initiation site in the promoters of 13 out of the 17 highly repressed genes, is critical for aCcr1 binding. The aCcr1-box is present in the promoters of cdvA genes across Sulfolobales, suggesting that aCcr1-mediated cdvA repression is an evolutionarily conserved mechanism by which archaeal cells dictate cytokinesis progression, whereas their viruses take advantage of this mechanism to manipulate the host cell cycle.
A novel closed-loop control algorithm to disrupt pathological neuronal oscillations – implementation and validation in vitro

Adaptive feedback control of neuronal activity is a powerful technique for both revealing and repairing neuronal function, but our knowledge on its effective implementation is still very limited. Presently, electrical brain stimulation, a well-stablished therapeutic to address neurological disorders such as Parkinson’s disease and epilepsy, typically relies on open-loop protocols. However, electrical stimulation should adapt to the neuronal activity and control the pathological dynamics with minimal perturbations. Here we tested for the first time in neuronal populations ( in vitro ), a popular control technique used in multiple computational studies to disrupt pathological neuronal oscillations - Delayed Feedback Control (DFC). We show that DFC may worsen the oscillatory behaviour, promoting faster bursting. Alternatively, we developed and validated an alternative method, adaptive DFC (aDFC), which monitors the ongoing periodicity and self-tunes accordingly. aDFC disrupts the collective neuronal oscillation and leads to a decrease in network synchrony, making it a better candidate for therapeutic neurostimulation. the current oscillation phase. We show that aDFC reduces the synchronization of the network and efficiently disrupts the basal oscillation. On this process, we identified and characterized a new feature of neuronal networks that should be taken in consideration in future studies: self-organized neuronal cultures have different propensities for modulation, conditioned by their intrinsic population dynamics. Using computer simulations, we showed that this controllability can be conditioned by specific parameters of the network architecture, namely the excitatory/inhibitory balance and overall synaptic weights of the network connections. Finally, we showed that aDFC, but not DFC or random stimulation, can lead to a state of asynchronous firing in a network that is capable of sustaining this type of activity spontaneously.
Faecal virome of the Australian grey-headed flying fox from urban/suburban environments contains novel coronaviruses, retroviruses and sapoviruses

Bats are important reservoirs for viruses of public health and veterinary concern. Virus studies in Australian bats usually target the families Paramyxoviridae, Coronaviridae and Rhabdoviridae, with little known about their overall virome composition. We used metatranscriptomic sequencing to characterise the faecal virome of grey-headed flying foxes from three colonies in urban/suburban locations from two Australian states. We identified viruses from three mammalian-infecting (Coronaviridae, Caliciviridae, Retroviridae) and one possible mammalian-infecting (Birnaviridae) family. Of particular interest were a novel bat betacoronavirus (subgenus Nobecovirus) and a novel bat sapovirus (Caliciviridae), the first identified in Australian bats, as well as a potentially exogenous retrovirus. The novel betacoronavirus was detected in two sampling locations 1,375 km apart and falls in a viral lineage likely with a long association with bats. This study highlights the utility of unbiased sequencing of faecal samples for identifying novel viruses and revealing broad-scale patterns of virus ecology and evolution.
A yeast-based tool for mammalian DGATs inhibitors screening

Dysregulation of lipid metabolism is associated with obesity, metabolic diseases but there is also increasing evidences of a relationship between lipid bodies (LBs) excess and some cancer. LBs synthesis requires diacylglycerol acyltransferases (DGATs) which catalyses the last step of triacylglycerol (TAG) synthesis, the main storage lipid form in lipid bodies. DGATs and in particular DGAT2, are therefore considered as potential therapeutic targets for the control of these pathologies. Here, the murine and the human DGAT2 were overexpressed in the oleaginous yeast Yarrowia lipolytica deleted for all DGATs activities, for evaluating the functionality of the enzymes in this heterologous host and to evaluate DGAT activity inhibitors. This work provide evidence that mammalian DGATs expressed in Y. lipolytica is a useful tool for screening chemical libraries to identify potential inhibitors or activators of these enzymes of therapeutic interest.
Predicting the principal components of cortical morphological variables

The generating mechanism for the gyrification of the mammalian cerebral cortex remains a central open question in neuroscience. Although many models have been proposed over the years, very few were able to provide empirically testable predictions. In this paper, we assume a model in which the cortex folds for all species of mammals according to a simple mechanism of effective free energy minimization of a growing self-avoiding surface subjected to inhomogeneous bulk stresses, to derive a new set of summary morphological variables that capture the most salient aspects of cortical shape and size. In terms of these new variables, we seek to understand the variance present in two morphometric datasets: a human MRI harmonized multi-site dataset comprised by 3324 healthy controls (CTL) from 4 to 96 years old and a collection of different mammalian cortices with morphological measurements extracted manually. This is done using a standard Principal Component Analysis (PCA) of the cortical morphometric space. We prove there is a remarkable coincidence (typically less than 8◦) between the resulting principal components vectors in each datasets and the directions corresponding to the new variables. This shows that the new, theoretically-derived variables are a set of natural and independent morphometrics with which to express cortical shape and size.
Regulation of TRIB1 abundance in hepatoma models

Tribbles related homolog 1 (TRIB1) contributes to lipid and glucose homeostasis by facilitating the degradation of cognate cargos by the proteasome. We previously reported that TRIB1 was unstable in non-hepatic cellular models. Moreover, inclusion of proteasome inhibitors failed to prevent TRIB1 loss, consistent with the involvement of proteasome independent degradative processes. In view of the key role of TRIB1 in liver function, we continue our exploration of TRIB1 regulation pathways in two commonly used human hepatocyte models, HuH-7 and HepG2 cells. Proteasome inhibitors potently upregulated both endogenous and recombinant TRIB1 mRNA and protein levels. Increased transcript abundance was independent of MAPK activation while ER stress was a relatively mild inducer. Despite increasing TRIB1 protein abundance and stabilizing bulk ubiquitination, proteasome inhibition failed to stabilize TRIB1, pointing to the predominance of proteasome independent protein degradation processes controlling TRIB1 protein abundance in hepatomas. Proteasome inhibition via downregulation of its PSMB3 regulatory subunit, in contrast to its chemical inhibition, had minimal impact on TRIB1 levels. Moreover, immunoprecipitation experiments showed no evidence of TRIB1 ubiquitination. Cytoplasmic retained TRIB1 was unstable, indicating that TRIB1 lability is regulated prior to its nuclear import. Substitution of the TRIB1 PEST-like region with a GST helical region or N-terminal deletions failed to fully stabilize TRIB1. Finally, inclusion of protease or autophagy inhibitors in vivo did not rescue TRIB1 stability. This work excludes proteasome-mediated degradation as a significant contributor to TRIB1 instability and identifies transcriptional regulation as a prominent mechanism regulating TRIB1 abundance in liver models in response to proteasome inhibition.
Identity-by-descent-based estimation of the X chromosome effective population size with application to sex-specific demographic history

The effective size of a population (Ne) in the recent past can be estimated through analysis of identity-by-descent (IBD) segments. Several methods have been developed for estimating Ne from autosomal IBD segments, but no such effort has been made with X chromosome IBD segments. In this work, we propose a method to estimate the X chromosome effective population size from X chromosome IBD segments. We show how to use the estimated autosome Ne and X chromosome Ne to estimate female and male effective population sizes. We demonstrate the accuracy of our autosome and X chromosome Ne estimation with simulated data. We find that estimated female and male effective population sizes generally reflect the simulated sex-specific effective population sizes across the past 100 generations, but that short-term differences between the estimated sex-specific Ne across tens of generations may not reliably indicate true sex-specific differences. We analyzed the effective size of populations represented by samples of sequenced UK White British and UK Indian individuals from the UK Biobank.
The trouble with triples: Examining the impact of measurement error in mediation analysis

Mediation analysis is used in genetic mapping studies to identify candidate gene mediators of quantitative trait loci (QTL). We consider genetic mediation analysis of triplets - sets of three variables consisting of a target trait, the genotype at a QTL for the target trait, and a candidate mediator that is the abundance of a transcript or protein whose coding gene co-locates with the QTL. We show that, in the presence of measurement error, mediation analysis can infer partial mediation even in the absence of a causal relationship between the candidate mediator and the target. We describe a measurement error model and a corresponding latent variable model with estimable parameters that are combinations of the causal effects and measurement errors across all three variables. The relative magnitudes of the latent variable correlations determine whether or not mediation analysis will tend to infer the correct causal relationship in large samples. We examine case studies that illustrate the common failure modes of genetic mediation analysis and demonstrate how to evaluate the effects of measurement error. While genetic mediation analysis is a powerful tool for identifying candidate genes, we recommend caution when interpreting mediation analysis findings.
Demographic variation and demographic niches of trees species in the Barro Colorado Forest

One goal for the 50-ha plot on Barro Colorado Island since its inception has been to understand demographic variability across the entire community of tree species. Early papers classified demographic response of many species to canopy gaps, culminating over the last decade with improved statistical methods that could quantify the response of growth, survival, and recruitment rates to increasing light for the entire community. We compile results from recent studies to illustrate the demographic trade-off between fast growth in high light and long life in deep shade. Growth and recruitment in high light are significantly correlated with mortality across species, and this trade-off is the primary demographic differentiation in the community. Here we add a new analysis of expected adult lifespan of 31 dominant canopy species spanning the growth-mortality axis. Using analytical solutions to matrices describing the lifetable, we demonstrate that the trade-off between high growth and long lifespan is not equalizing. The expected adult lifespan of a newly-recruited sapling is shorter in fast-growing pioneers than in long-lived shade-tolerant species: elevated growth rates of pioneers is insufficient to overcome their high death rates. If reproductive output were equal across the demographic axis, pioneer species could not persist. This suggests pioneers out-reproduce shade-tolerant species. The next goal is incorporating seed and seedling production into the demographic analysis to test the trade-off using lifetables having reproductive output included.
Timing along the cardiac cycle modulates neural signals of reward-based learning

Natural fluctuations in cardiac activity influence brain activity associated with sensory stimuli and affect perceptual decisions about low magnitude, near-threshold stimuli. However, little is known about the impact of fluctuations in heart activity on other internal representations. Here we investigate cardiac influences on learning-related internal representations – absolute and signed prediction errors. By combining machine learning techniques with electroencephalography (EEG) and both simple, direct indices of task performance and computational model-derived indices of learning, we demonstrate that just as people are more sensitive to low magnitude, near threshold sensory stimuli in certain cardiac phases, so are they more sensitive to low magnitude absolute prediction errors in the same cycles. Importantly, however, this occurs even when the low magnitude prediction errors are associated with clearly suprathreshold sensory events. In addition, participants exhibiting stronger difference in their prediction errors representations between cardiac cycles exhibited higher learning rates and greater task accuracy.
Force-dependent recruitment of Piezo1 drives adhesion maturation and calcium entry in normal but not tumor cells

Mechanosensing is an integral part of many physiological processes including stem cell differentiation, fibrosis, and cancer progression. Two major mechanosensing systems – focal adhesions and mechanosensitive ion channels, can convert mechanical features of the microenvironment into biochemical signals. We report here surprisingly that the mechanosensitive Ca2+-channel Piezo1, previously perceived to be diffusive on plasma membranes, binds to matrix adhesions in a force-dependent manner, promoting adhesion maturation and cell spreading in normal but not in tumor cells. In the absence of Piezo1, matrix adhesions are smaller in normal cells mimicking transformed cells where adhesions do not change with or without Piezo1. A novel adhesion-targeted calcium sensor shows robust Piezo1-dependent, calcium influx at adhesions in normal cells; but not in transformed cells. A linker domain in Piezo1 is needed for binding to adhesions and overexpression of the domain blocks Piezo1 binding to adhesions decreasing adhesion size and cell spread area. Thus, we suggest that Piezo1 is a novel component of focal adhesions in non-transformed cells that catalyzes adhesion maturation and growth through force-dependent calcium signaling, but this function is absent in most cancer cells.
Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction

Defects in insulin processing and granule maturation are linked to pancreatic beta-cell failure during type 2 diabetes (T2D). Phosphatidylinositol transfer protein alpha (PITPNA) stimulates activity of phosphatidylinositol (PtdIns) 4-OH kinase to produce sufficient PtdIns-4-phosphate (PtdIns-4-P) in the trans-Golgi network to promote insulin granule maturation. PITPNA in beta-cells of T2D human subjects is markedly reduced suggesting its depletion accompanies beta-cell dysfunction. Conditional deletion of Pitpna in the beta-cells of Ins-Cre;Pitpnaflox/flox mice leads to hyperglycemia resulting from decreased glucose-stimulated insulin secretion (GSIS) and reduced pancreatic beta-cell mass. Furthermore, PITPNA silencing in human islets confirmed its role in PtdIns-4-P synthesis and led to impaired insulin granule maturation and docking, GSIS, and proinsulin processing with evidence of ER stress. Restoration of PITPNA in islets of T2D human subjects reversed these beta-cell defects and identify PITPNA as a critical target linked to beta-cell failure in T2D.