Miracle-dz/UniFAR-FTUs huggingface dataset:
Integrated Proteomics Identifies Neuritin (NRN1) as a Mediator of Cognitive Resilience to Alzheimer’s Disease

We present an integrative proteomic strategy for the nomination and validation of proteins associated with cognitive resilience to Alzheimer’s disease (AD). Correlation network analysis across distinct stages of AD was used to prioritize protein modules linked to resilience. Neuritin (NRN1), a hub protein in a module associated with synaptic biology, was identified as a top candidate of resilience and selected for functional validation in cultured neurons. NRN1 provided dendritic spine resilience against amyloid-β (Aβ), and NRN1 blocked Aβ-induced neuronal hyperexcitability. The impact of exogenous NRN1 on the proteome of cultured neurons was assessed and integrated with the AD brain network. This revealed over-lapping synapse-related biology that linked NRN1-induced changes in cultured neurons with human pathways associated with AD resilience. Collectively, this highlights the utility of integrating the proteome from human brain and model systems to prioritize therapeutic targets that mediate resilience to AD.
GM-CSF drives immune-mediated glomerular disease by licensing monocyte-derived cells to produce MMP12

Glomerulonephritis is a group of immune-mediated diseases that cause inflammation within the glomerulus and adjacent compartments of the kidney and is a major cause of end-stage renal disease. T cells are among the main drivers of glomerulonephritis. However, the T cell subsets, cytokine networks, and downstream effector mechanisms that lead to renal tissue injury are largely unknown, which has hindered the development of targeted therapies. Here we identify a population of GM-CSF-producing T cells that accumulates in the kidneys of patients with ANCA-associated glomerulonephritis, infiltrates the renal tissue in a mouse model of glomerulonephritis, and promotes tissue destruction and loss of renal function. Mechanistically, we show that GM-CSF producing T cells licence monocyte-derived cells to produce matrix metalloproteinase 12 (MMP12), which cleaves components of the glomerular basement membrane and exacerbates renal pathology. These findings provide a mechanistic rationale for the immunopathology of T cell-mediated diseases and identify the “GM-CSF – monocyte-derived cells – MMP12” pathway as a promising therapeutic target in treatment of glomerulonephritis.
Structures of perforin-2 in solution and on a membrane reveal mechanisms for pore formation

Perforin-2 (PFN2, MPEG1) is a key pore-forming protein in mammalian innate immunity restricting intracellular bacteria proliferation. It forms a membrane-bound pre-pore complex that converts to a pore-forming structure upon acidification; but its mechanism of conformational transition has been debated. Here we used cryo-electron microscopy, tomography and subtomogram averaging to determine structures of PFN2 in pre-pore and pore conformations in isolation and bound to liposomes. In isolation and upon acidification, the pre-assembled complete pre-pore rings convert to pores in both flat ring and twisted conformations. The twisted pore structure suggests an intermediate or alternative state to the flat conformation, and a capacity to distort the underlying membrane during membrane insertion. On membranes, in situ assembled PFN2 pre-pores display various degrees of completeness; whereas PFN2 pores are mainly incomplete arc structures that follow the same subunit packing arrangements as found in isolation. Both assemblies on membranes use their P2 β-hairpin for binding to the lipid membrane surface. These structural snapshots in different states reveal a molecular mechanism for PFN2 pre-pore to pore transition on a targeted membrane.
Dose-dependent suppression of hippocampal contextual memory formation, place cells, and spatial engrams by the NMDAR antagonist (R)-CPP

A common way to study the functional importance of N-methyl-D-aspartate receptors (NMDARs) in hippocampal memory-encoding circuits is by administering NMDAR antagonists. We recently compared the effects of (R,S)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), a competitive NMDAR antagonist, on suppression of memory in vivo versus suppression of NMDAR-mediated field EPSPs (fEPSPNMDA) and long-term potentiation (LTP) in vitro. Surprisingly, we found that concentrations that block contextual conditioning in vivo are ineffective at blocking the fEPSPNMDA or LTP in vitro. Here we tested one possible explanation for the mismatch – that the hippocampus is relatively resistant to CPP compared to other brain structures engaged in contextual fear conditioning. We used the context pre-exposure facilitation effect (CPFE) paradigm to isolate the hippocampal component of contextual learning, and in-vivo calcium imaging of place cells and spatial engrams to directly assess hippocampal spatial coding. We found that, by both measures, the active enantiomer (R)-CPP did interfere with hippocampal function at concentrations below those that block fEPSPs or LTP. We conclude that the alternative – that CPP interferes with memory by targeting NMDARs in interneurons rather than pyramidal neurons – is the more likely explanation.
Lymphatic dysfunction in lupus contributes to cutaneous photosensitivity and lymph node B cell responses

Photosensitivity in lupus and subsequent systemic disease flares contribute to disease burden and is incompletely understood. Skin communicates with lymphoid tissues via lymphatics and reduced lymphatic flow in murine models results in skin inflammation and autoimmunity. Here, we demonstrate that the skin of lupus patients and multiple murine lupus models are characterized by lymphatic flow dysfunction. Improving lymphatic flow in murine lupus models via manual lymphatic drainage or by utilizing a transgenic model with increased lymphatics ameliorated cutaneous photosensitivity and diminished draining lymph node germinal center B cell and plasmablast responses. Improved lymphatic flow limited B cell responses via acting on a stromal-immune circuit previously described by our lab. Increased lymphatic flow increases stromal CCL2, which modulates monocyte function and limits B cell responses. This work provides a link between cutaneous photosensitivity and systemic disease in lupus and suggests that improving lymphatic flow or targeting the lymph node microenvironment could be potential therapeutic targets.
Social environment and chronological age shape eusocial insect species : 1 the case of the ant workers . 2

a Université de Strasbourg, CNRS, IPHC UMR 7178 – 23 rue du Loess, 67037 Strasbourg 5 Cedex 2, France 6 b Infrastructure Nationale de Protéomique ProFI – 25 rue Becquerel, 67037 Strasbourg 7 Cedex 2, France 8 c Plant Imaging & Mass Spectrometry (PIMS), Institut de biologie moléculaire des plantes, 9 CNRS, Université de Strasbourg, 12 rue du Général Zimmer, 67084 Strasbourg, France. 10 d Institut Universitaire de France, 1 rue Descartes, 75231 Paris Cedex, France 11 12 *Corresponding author: Martin Quque 13
GADMA2: more efficient and flexible demographic inference from genetic data

Background Inference of complex demographic histories is a source of information about events that happened in the past of studied populations. Existing methods for demographic inference typically require input from the researcher in the form of a parameterized model. With an increased variety of methods and tools, each with its own interface, the model specification becomes tedious and error-prone. Moreover, optimization algorithms used to find model parameters sometimes turn out to be inefficient, for instance, by being not properly tuned or highly dependent on a user-provided initialization. The open-source software GADMA addresses these problems, providing automatic demographic inference. It proposes a common interface for several likelihood engines and provides global parameters optimization based on a genetic algorithm. Results Here, we introduce the new GADMA2 software and provide a detailed description of the added and expanded features. It has a renovated core code base, new likelihood engines, an updated optimization algorithm and a flexible setup for automatic model construction. We provide a full overview of GADMA2 enhancements, compare the performance of supported likelihood engines on simulated data and demonstrate an example of GADMA2 usage on two empirical datasets. Conclusions We demonstrate the better performance of a genetic algorithm in GADMA2 by comparing it to the initial version and other existing optimization approaches. Our experiments on simulated data indicate that GADMA2’s likelihood engines are able to provide accurate estimations of demographic parameters even for misspecified models. We improve model parameters for two empirical datasets of inbred species.
Candesartan treatment preserves learning and working memory in female TgF344-AD rats

Background Targeting the renin angiotensin system, especially with angiotensin receptor II blockers (ARB), and related vascular dysfunction is a promising therapeutic intervention for cognitive impairment including Alzheimer’s Disease (AD). The underlying mechanisms of the effects of ARB is unclear. This study sought to examine if treatment with candesartan, an ARB, affects neurobehavioral manifestation and the underlying neuro- and vascular mechanisms in male and female TgF344-AD rats. Methods Candesartan or vehicle was administered to TgF344-AD rats (n=127) daily from 12-months to 18-months of age. Behavioral assays (spontaneous alternation test, novel object recognition, water radial arm maze) and neuropathologic assessment were completed along with brain proteome and measures of contractility in 12- and 18-month rat brains. Results Untreated 18-month TgF344-AD showed impairments in learning and increased perseverative working memory errors on the water radial arm maze (WRAM). These behavioral changes were corrected with candesartan treatment in female rats only. Treatment with candesartan was also associated with improved vascular reactivity and reduced blood pressure in both wild type and TgF344-AD male and female rats. Although there was no effect on amyloid-β, treatment with candesartan reduced whole brain clusterin, an AD-risk associated protein, and GFAP in female TgF344-AD. Conclusions Our results demonstrate that candesartan administered in the early stages of AD has a sexual dimorphic response in Tgf344-AD rat, where it reduced cognitive disturbances only in female TgF344-AD rat. These effects appear to be independent of changes in blood pressure and amyloid-β reduction and are likely mediated through mechanisms related to clusterin and GFAP pathways.
Analyzing single-cell bisulfite sequencing data with scbs

– Single-cell bisulfite sequencing (scBS) allows for assessing DNA methylation at single-base pair and single-cell resolution. Analyzing the big data sets thus obtained requires preprocessing to reduce data size, improve signal over noise, and provide inter-pretability. Typically, this is simply done by dividing the genome into large tiles and averaging in these. We show that this coarse-graining dilutes signal, and suggest improved approaches to determine more informative regions to quantify methylation in, and a better quantitation method than simple averaging. We demonstrate how our approach enables better distinguishing of cell types and reduces demands on cell number. We also show that our method of finding variably methylated regions finds biologically meaningful loci. Finally, we present a software tool, scbs , that implements this approach and offers further functionality required to work with scBS data.
The Chlamydomonas Genome Project, version 6: Reference assemblies for mating-type plus and minus strains reveal extensive structural mutation in the laboratory

Five versions of the Chlamydomonas reinhardtii reference genome have been produced over the last two decades. Here we present version 6, bringing significant advances in assembly quality and structural annotations. PacBio-based chromosome-level assemblies for two laboratory strains, CC-503 and CC-4532, provide resources for the plus and minus mating type alleles. We corrected major misassemblies in previous versions and validated our assemblies via linkage analyses. Contiguity increased over ten-fold and >80% of filled gaps are within genes. We used Iso-Seq and deep RNA-seq datasets to improve structural annotations, and updated gene symbols and textual annotation of functionally characterized genes via extensive curation. We discovered that the cell wall-less classical reference strain CC-503 exhibits genomic instability potentially caused by deletion of RECQ3 helicase, with major structural mutations identified that affect >100 genes. We therefore present the CC-4532 assembly as the primary reference, although this strain also carries unique structural mutations and is experiencing rapid proliferation of a Gypsy retrotransposon. We expect all laboratory strains to harbor gene-disrupting mutations, which should be considered when interpreting and comparing experimental results across laboratories and over time. Collectively, the resources presented here herald a new era of Chlamydomonas genomics and will provide the foundation for continued research in this important reference.
Toward a more informative representation of the fetal–neonatal brain connectome using variational autoencoder

Recent advances in functional magnetic resonance imaging (fMRI) have helped elucidate previously inaccessible trajectories of early-life prenatal and neonatal brain development. To date, the interpretation of fetal-neonatal fMRI data has relied on linear analytic models, akin to adult neuroimaging data. However, unlike the adult brain, the fetal and newborn brain develops extraordinarily rapidly, far outpacing any other brain development period across the lifespan. Consequently, conventional linear computational models may not adequately capture these accelerated and complex neurodevelopmental trajectories during this critical period of brain development along the prenatal-neonatal continuum. To obtain a nuanced understanding of fetal-neonatal brain development, including non-linear growth, for the first time, we developed quantitative, systems-wide representations of neuronal circuitry in a large sample (>700) of fetuses, preterm, and full-term neonates using an unsupervised deep generative model called Variational Autoencoder (VAE), a model previously shown to be superior to linear models in representing complex resting state data in healthy adults. Here, we demonstrated that non-linear brain features, i.e., latent variables, derived with the VAE, carried important individual neural signatures, leading to improved representation of prenatal-neonatal brain maturational patterns and more accurate and stable age prediction compared to linear models. Using the VAE decoder, we also revealed distinct functional brain networks spanning the sensory and default mode networks. Using the VAE, we are able to reliably capture and quantify complex, non-linear fetal-neonatal functional neural connectivity. This will lay the critical foundation for detailed mapping of healthy and aberrant functional brain signatures that have their origins in fetal life.
Simple Human Response Times are Governed by Dual Anticipatory Processes with Distinct and Distributed Neural Signatures

Human behavior can be highly sensitive to anticipation, but the mechanisms underlying this sensitivity are poorly understood. We obtained intracranial electrocephalography (iEEG) measurements in neurosurgical patients as they performed a simple sensory-motor task with variable (short or long) foreperiod delays that affected anticipation of the cue to respond. Participants showed two forms of anticipatory response biases, distinguished by more premature false alarms (FAs) or faster response times (RTs) on long-delay trials. These biases had distinct neural signatures in prestimulus neural activity modulations that were distributed and intermixed across the brain: the FA bias was most evident in preparatory motor activity immediately prior to response-cue presentation, whereas the RT bias was most evident in visuospatial activity at the beginning of the foreperiod. These results suggest that human anticipatory behavior emerges from a combination of motor-preparatory and attention-like modulations of neural activity, implemented by anatomically widespread and intermixed, but functionally identifiable, brain networks. Graphical Abstract
The fat body cortical actin network regulates Drosophila inter-organ nutrient trafficking, signaling, and adipose cell size

Defective nutrient storage and adipocyte enlargement (hypertrophy) are emerging features of metabolic syndrome and type 2 diabetes. Within adipose tissues, how the cytoskeletal network contributes to adipose cell size, nutrient uptake, fat storage, and signaling remain poorly understood. Utilizing the Drosophila larval fat body (FB) as a model adipose tissue, we show that a specific actin isoform—Act5C—forms the cortical actin network necessary to expand adipocyte cell size for biomass storage in development. Additionally, we uncover a non-canonical role for the cortical actin cytoskeleton in inter-organ lipid trafficking. We find Act5C localizes to the FB cell surface and cell-cell boundaries, where it intimately contacts peripheral LDs (pLDs), forming a cortical actin network for cell architectural support. FB-specific loss of Act5C perturbs FB triglyceride (TG) storage and LD morphology, resulting in developmentally delayed larvae that fail to develop into flies. Utilizing temporal RNAi-depletion approaches, we reveal that Act5C is indispensable post-embryogenesis during larval feeding as FB cells expand and store fat. Act5C-deficient FBs fail to grow, leading to lipodystrophic larvae unable to accrue sufficient biomass for complete metamorphosis. In line with this, Act5C-deficient larvae display blunted insulin signaling and reduced feeding. Mechanistically, we also show this diminished signaling correlates with decreased lipophorin (Lpp) lipoprotein-mediated lipid trafficking, and find Act5C is required for Lpp secretion from the FB for lipid transport. Collectively, we propose that the Act5C-dependent cortical actin network of Drosophila adipose tissue is required for adipose tissue size-expansion and organismal energy homeostasis in development, and plays an essential role in inter-organ nutrient transport and signaling.
Sex-dimorphic and age-dependent organization of 24 hour gene expression rhythms in human

The circadian clock modulates most of human physiology. However, the organization of tissue-specific gene expression rhythms is still poorly known, as well as age and sex dependencies. We leveraged the Genotype-Tissue Expression project (GTEx) using a novel algorithm to assign a unique circadian phase to 914 individuals and transfer time information from stronger to weaker clocks. These donor internal phases allowed us to identify and compare programs of rhythmic gene expression in 46 tissues. Clock transcripts showed highly conserved phase and amplitude relationships across tissues, and were tightly synchronized across the body. Tissue rhythmic gene expression programs differed in breadth, covering global and tissue-specific functions, including metabolic pathways and systemic responses such as heat shock. The circadian clock structure and amplitude was indistinguishable across sexes and age groups. However, overall gene expression rhythms were highly sex-dimorphic and more sustained in females. Moreover, rhythmic programs dampened with age across the body. Together, our stratified analysis unveiled a rich organization of sex- and age-specific circadian gene expression rhythms in humans. One sentence summary Circadian phase inference of 914 GTEx donors reveals sex- and age-dependent rhythmic gene expression programs across 46 human tissues.
Benefits of individualized brain anatomies and EEG electrode positions for auditory cortex localization

Due to its high temporal resolution and non-invasive nature, electroencephalography (EEG) is considered a method of great value for the field of auditory cognitive neuroscience. In performing source space analyses, localization accuracy poses a bottleneck, which precise forward models based on individualized attributes such as subject anatomy or electrode locations aim to overcome. Yet acquiring anatomical images or localizing EEG electrodes requires significant additional funds and processing time, making it an oftentimes inaccessible asset. Neuroscientific software offers template solutions, on which analyses can be based. For localizing the source of auditory evoked responses, we here compared the results of employing such template anatomies and electrode positions versus the subject-specific ones, as well as combinations of the two. All considered cases represented approaches commonly used in electrophysiological studies. We considered differences between two commonly used inverse solutions (dSPM, sLORETA) and targeted the primary auditory cortex; a notoriously small cortical region that is located within the lateral sulcus, thus more prone to errors in localization. Through systematical comparison of the outcomes in terms of auditory activity attributes and leakage quantification, we assessed how the individualization steps impacted the analyses outcomes. Both electrode locations as well as subject anatomies were found to have an effect, which though varied based on the configuration considered. When comparing the inverse solutions, we moreover found that dSPM more consistently benefited from individualization of subject characteristics. Based on the scientific question considered, our results may be used to facilitate the planning of auditory neuroscientific experiments in terms of expected infrastructure, personnel and funds.
Biphasic JNK–Erk Signaling Separates Induction and Maintenance of Cell Senescence after DNA Damage

Genotoxic stress in mammalian cells, including that caused by anti-cancer chemotherapy, can induce temporary cell cycle arrest, DNA damage-induced senescence (DDIS) or apoptotic cell death. Despite obvious clinical importance, it is unclear how the signals emerging from DNA damage are integrated together with other cellular signaling pathways monitoring the cell’s environment and/or internal state to control these different cell fates. Here, using a combination of single cell-based signaling measurements and tensor PLSR/PCA computational approaches, we show that the JNK and Erk MAPK signaling pathways regulate the initiation of senescence through the transcription factor AP-1 at early times after extrinsic DNA damage, and the Senescence Associated Secretory Phenotype, a hallmark of DDIS, at late times after damage. These results identify a time-based separation of function for the same signaling pathways beyond the classic DNA damage response that control the cell senescence decision and modulate the tumor microenvironment following genotoxic stress, and reveal a fundamental similarity between signaling mechanisms responsible for oncogene-induced senescence and senescence caused by extrinsic DNA damaging agents.