Miracle-dz/UniFAR-FTUs huggingface dataset:
Dendritic plateau potentials can process spike sequences across multiple time-scales

The brain constantly processes information encoded in temporal sequences of spiking activity. This sequential activity emerges from sensory inputs as well as from the brain’s own recurrent connectivity and spans multiple dynamically changing timescales. Decoding the temporal order of spiking activity across these varying timescales is a critical function of the brain, but we do not yet understand its neural implementation. The problem is, that the passive dynamics of neural membrane potentials occur on a short millisecond timescale, whereas many cognitive tasks require the integration of information across much slower behavioral timescales. However, actively generated dendritic plateau potentials do occur on such longer timescales, and their essential role for many aspects of cognition has been firmly established by recent experiments. Here, we build on these discoveries and propose a new model of neural computation that emerges from the interaction of localized plateau potentials across a functionally compartmentalized dendritic tree. We show how this interaction offers a robust solution to the timing invariant detection and processing of sequential spike patterns in single neurons. Stochastic synaptic transmission complements the deterministic all-or-none plateau process and improves information transmission by allowing ensembles of neurons to produce graded responses to continuous combinations of features. We found that networks of such neurons can solve highly complex sequence detection tasks by breaking down long inputs into sequences of shorter, random features that can be classified reliably. These results suggest that active dendritic processes are fundamental to neural computation.
Obesogenic diet induces circuit-specific memory deficits in mice

Obesity is associated with neurocognitive dysfunction, including memory deficits. This is particularly worrisome during adolescence, which represents a crucial period for maturation of brain structures, such as the hippocampus which are crucial for cognition. In rodent models, we recently reported that memory impairments induced by obesogenic high-fat diet (HFD) intake during the periadolescent period can be reversed by chemogenetic manipulation of the ventral hippocampus (vHPC). Here, we used an intersectional viral approach in HFD-fed male mice to chemogenetically inactivate specific vHPC efferent pathways to nucleus accumbens or medial prefrontal cortex during memory tasks. We first demonstrated that HFD enhanced activation of both pathways after training and that our chemogenetic approach was effective in normalising this activation. Inactivation of the vHPC-nucleus accumbens pathway rescued HFD-induced deficits in recognition but not location memory. Conversely, inactivation of the vHPC-medial prefrontal cortex pathway restored location but not recognition memory impairments produced by HFD. Either pathway manipulation did not affect exploration, locomotion or anxiety-like behaviour. These findings suggest that HFD intake throughout adolescence impairs different types of memory through overactivation of specific hippocampal efferent pathways and that targeting these overactive pathways has therapeutic potential.
A new cortical parcellation based on systematic review of primate anatomical tracing studies on corticostriatal projections

Corticostriatal projections form the input level of a circuitry that connects the cerebral cortex, basal ganglia, and thalamus. Three distinct, functional subcircuits exist according to the tripartite model: Sensorimotor cortices projecting mainly to the dorsolateral striatum; associative cortices projecting to the dorsomedial striatum and limbic cortices projecting to the ventral striatum. However, there is to date no atlas that allows researchers to label cortical projection areas belonging to each of these subcircuits separately. To address this research gap, the aim of this study was threefold: First, to systematically review anatomical tracing studies that focused on corticostriatal projections in non-human primates, and to classify their findings according to the tripartite model. Second, to develop an atlas of the human cerebral cortex based on this classification. Third, to test the hypothesis that labels in this atlas show structural connectivity with specific striatal subregions in humans using diffusion-based tractography in a sample of 24 healthy participants. In total, 98 studies met the inclusion criteria for our systematic review. Information about projections from the cortex to the striatum was systematically extracted by Brodmann area, and cortical areas were classified by their dominant efferent projections. Taking known homological and functional similarities and differences between non-human primate and human cortical regions into account, a new human corticostriatal projection (CSP) atlas was developed. Using human diffusion-based tractography analyses, we found that the limbic and sensorimotor atlas labels showed preferential structural connectivity with the ventral and dorsolateral striatum, respectively. However, the pattern of structural connectivity for the associative label showed the greatest degree of overlap with other labels. We provide this new atlas as a freely available tool for neuroimaging studies, where it allows for the first-time delineation of anatomically informed regions-of-interest to study functional subcircuits within the corticostriatal circuitry. This tool will enable specific investigations of subcircuits involved in the pathogenesis of neuropsychiatric illness such as schizophrenia and bipolar disorders. Highlights - Systematic review of anatomical projections from the cerebral cortex to the striatum in non-human primates. - Development of a novel cortical atlas for use in neuroimaging studies focusing on the corticostriatal brain circuitry. - Tractography in human diffusion-weighted imaging data to test if associative, limbic, and sensorimotor cortical atlas labels show preferential connectivity to regions within the striatum.
Autophagy activity is inhibited by hnRNP R

Autophagy is a self-eating intracellular degradation process in eukaryotic cell. Muti-pathways have been found can regulate autophagy activity through different mechanisms. In this study, we found that a nuclear abundant RNA binding protein, hnRNP R is involved in autophagy process by binding with ATG3, p62, Lamp1, LC3 and ATG9. On the other hand, hnRNP R also can regulate autophagy, we found depletion hnRNP R can activate the autophagy flux and activity. Furthermore, we also checked that autophagy has not connection with stress granules. This finding highlights some novel and nuclear located RNA binding proteins play important role in the regulation of autophagy activity.
POSTRE: a tool to predict the pathological effects of human structural variants

Understanding the pathological impact of non-coding genetic variation is a major challenge in medical genetics. Accumulating evidences indicate that a significant fraction of genetic alterations, including structural variants (SVs), can cause human disease by altering the function of non-coding regulatory elements, such as enhancers. In the case of SVs, described pathomechanisms include changes in enhancer dosage and long-range enhancer-gene communication. However, there is still a clear gap between the need to predict and interpret the medical impact of non-coding variants, and the existence of tools to properly perform these tasks. To reduce this gap, we have developed POSTRE (Prediction Of STRuctural variant Effects), a computational tool to predict the pathogenicity of SVs implicated in a broad range of human congenital disorders. By considering disease-relevant cellular contexts, POSTRE identifies SVs with either coding or long-range pathological consequences with high specificity and sensitivity. Furthermore, POSTRE not only identifies pathogenic SVs, but also predicts the disease-causative genes and the underlying pathological mechanism (e.g, gene deletion, enhancer disconnection, enhancer adoption, etc.). POSTRE is available at https://github.com/vicsanga/Postre.
Species-specific protein–protein interactions govern the humanization of the 20S proteasome in yeast

Yeast and humans share thousands of genes despite a billion years of evolutionary divergence. While many human genes can functionally replace their yeast counterparts, nearly half of the tested shared genes cannot. For example, most yeast proteasome subunits are humanizable, except subunits comprising the β-ring core, including β2 (HsPSMB7). We developed a high-throughput pipeline to humanize yeast proteasomes by generating a large library of Hsβ2 mutants and screening them for complementation of yeast β2 (ScPup1). Variants capable of replacing ScPup1 included (1) those impacting local protein-protein interactions (PPIs), with most affecting interactions between the β2 C-terminal tail and the adjacent β3 subunit, and (2) those affecting β2 proteolytic activity. Exchanging the full-length tail of human β2 with that of ScPup1 enabled complementation. Moreover, wild-type human β2 replaced yeast β2 if the adjacent human β3 subunit was also provided. Unexpectedly, yeast proteasomes bearing a catalytically inactive HsPSMB7-T44A variant blocking precursor autoprocessing were viable, suggesting an intact propeptide stabilizes late assembly intermediates. Our data reveal roles for specific PPIs governing functional replaceability across vast evolutionary distances.
Evaluating the differential expression of TAM family receptors and efferocytosis activities in differentiated and polarized THP-1 macrophage

Tissue homeostasis is tightly balanced between cell death and renewal. Each day, as many as 1011 cells die in the human body that need to be removed and replaced. The clearance of apoptotic cells, termed efferocytosis, is crucial to tissue homeostasis. Central to this process is macrophage-mediated efferocytosis. Apart from general phagocytosis, efferocytosis is apoptotic cell-specific, which aids in clearing dead cells and preventing the accumulation of self-antigens released by the apoptotic cells. The TAM family receptor kinases (TYRO3, AXL, MERTK) and ligands (GAS6 and PROS) play important roles in engaging the apoptotic cells to initiate efferocytic engulfment and the downstream cellular responses. Dysregulated efferocytic function in macrophages is associated with human diseases such as atherosclerosis, lupus, lung fibrosis, and cancer. Conversely, understanding the regulation and molecular mechanisms of macrophage efferocytosis can potentially lead to beneficial treatments for the above diseases. Despite numerous efferocytosis studies that use primary and cell line-derived macrophages, there has not been a thorough characterization of a cell line system that can be reliably used for efferocytosis assays. Consequently, many macrophage efferocytosis assays reported do not clearly distinguish efferocytosis from phagocytosis. Here we evaluated the THP-1 cell line as a potential human macrophage cell line system for efferocytosis studies. Consequently, many macrophage efferocytosis assays reported do not clearly distinguish efferocytosis from phagocytosis. Through the study we examined the differential expression of the TAM family receptors and their ligands in the various THP-1 macrophage differentiation and polarization states. We also characterized the THP-1 cell line as a reliable system for performing in vitro efferocytosis studies.
Cell Transfer of Sensitivity - after Trogocytosis Allows a Functional Cell Proper Regrafting of Ig-Like Transcript 2

The acquisition by T cells of exogenous ligands originally expressed by APC has been already described. However, reports essentially focused on the outward signaling of acquired ligands and their effects on surroundings cells. We investigated the function of transferred receptors (not ligands) on the T cells that acquired them (not on cells they interact with). We show that inhibitory Ig-like transcript 2 receptors efﬁciently transfer from monocytes to autologous T cells by trogocytosis and integrate within the plasma membrane of the acquirer T cells. Furthermore, the acquired receptors can access compatible signaling machinery within acquirer T cells and use it to signal and alter the functions of their new host cells. These data are a formal demonstration that a transferred molecule may send signals to its new host cell. We also provide evidence that sensitivity to modulatory molecules can be acquired from other cells and introduce the notion of intercellular transfer of sensitivities. The Journal of Immunology , 2011, 186: 2210–2218. phosphatase-1 and -2 phosphatases In ILT2-transfected cells, ILT2 phosphorylation could be induced by cross-linking or by the protein tyrosine phosphatase inhibitor pervanadate (PV). ILT2 signaling depends on binding to HLA class I molecules, and ILT2’s highest afﬁnity ligand is HLA-G a review on HLA-G, Ref. 15). In this study, we demonstrate the ILT2 transfers from monocytes to autologous activated T cells by trogocytosis and the proper integration of transferred ILT2 within the plasma membrane of a new host cell. Furthermore, we show that transferred ILT2 behaved as an endogenously produced molecule, capable of using the intracellular biochemical machinery of its new cell and send inward-oriented signals, which are then responsible for the acquirer T cell functional inhibition. These data are a formal demonstration that a transferred molecule may send signals to its new host cell after ligand engagement. They imply that sensitivity to modulatory molecules can be acquired from other cells.
Wearable Fall Detection System Using Barometric Pressure Sensors and Machine Learning

—As the global population is aging, healthcare systems in developed countries are facing many new challenges, such as insufficient human resources for quality patient monitoring and elderly care. One of the major health threats to elderly patients is falling, which could cause severe injuries and the associated complications can lead to mortality. To reduce the potential damage caused by falling, there are many wearable-based monitoring systems commercially available, but they often suffer from high false alarm rates and high costs. Most of the available solutions are based on embedded Inertial Measurement Units (IMUs), which can easily detect a sudden slip fall or a sudden trip fall from standing, but often fail to detect short falls, such as falling from a bed or a chair when an elderly is trying to get up. In this paper, a wearable fall detection system using barometric pressure sensors is proposed. The system is capable of detecting falls from high and low positions with high accuracy, and it was tested using a dataset collected from 10 healthy subjects and validated using a 5-fold inter-subject cross-validation.
ONE-IN-THREE 3SAT is in P

ONE − IN − THREE 3 S AT is the problem of deciding whether a given boolean formula φ in 3 CNF has a truth assignment such that each clause in φ has exactly one true literal. This problem is NP − complete . If any single NP − complete problem can be solved in polynomial time, then P = NP . In this work, we prove ONE − IN − THREE 3 S AT ∈ P , and therefore, P = NP .
Long-term cost and utility consequences of short-term clinically important deterioration in patients with chronic obstructive pulmonary disease: results from the TORCH study

Purpose: Clinically important deterioration (CID) in chronic obstructive pulmonary disease (COPD) is a novel composite endpoint that assesses disease stability. The association between short-term CID and future economic and quality of life (QoL) outcomes has not been previously assessed. This analysis considers 3-year data from the TOwards a Revolution in COPD Health (TORCH) study, to examine this question. Patients and methods: This post hoc analysis of TORCH (NCT00268216) compared costs and utilities at 3 years among patients without CID (CID-) and with CID (CID+) at 24 weeks. A positive CID status was de ﬁ ned as either: a deterioration in forced expiratory volume in 1 second (FEV 1 ) of ≥ 100 mL from baseline; or a ≥ 4-unit increase from baseline in St George ’ s Respiratory Questionnaire (SGRQ) total score; or the incidence of a moderate/ severe exacerbation. Patients from all treatment arms were included. Utility change was based on the EQ-5D utility index. Costs were based on healthcare resource utilization from 24 weeks to end of follow-up combined with unit costs for the UK (2016 GBP), and reported as per patient per year (PPPY). Adjusted estimates were generated controlling for baseline characteristics, treatment assignment, and number of CID criteria met. Results: Overall, 3,769 patients completed the study and were included in the analysis (stable CID- patients, n=1,832; unstable CID+ patients, n=1,937). At the end of follow-up, CID- patients had higher mean (95% con ﬁ dence interval [CI]) utility scores than CID+ patients (0.752 [0.738, 0.765] vs 0.697 [0.685, 0.71]; difference +0.054; P <0.001), and lower costs PPPY (£538 vs £916; difference: £378 [95% CI: £244, £521]; P <0.001). The cost differential was primarily driven by the difference in general hospital ward days ( P =0.003). Conclusion: This study demonstrated that achieving early stability in COPD by preventing short-term CID is associated with better preservation of future QoL alongside reduced healthcare service costs. However, the impact of early CID on a patient ’ s future quality of life, healthcare service use and associated costs, is unknown. Data from the 3-year TOwards a Revolution in COPD Health (TORCH) clinical trial in moderate-to-very-severe COPD was examined in patients with early stability (CID- patients) or early instability (CID+ patients) during 6 months of treatment. In the current analysis, we compared the outcomes between CID- and CID+ patients in terms of subsequent annual costs, use of healthcare services and quality of life from the time their short-term CID statuswas con ﬁ rmed until the end of the study (up to 2.5 years). Compared with CID+ patients, stable CID-patients had a better future quality of life and had lower future annual costs mainly due to lower hospital admission costs. These results suggest that achieving early disease stability in COPD might lead to better quality of life and healthcare cost savings in the long term.
The PRACE Data Analytics Service Service description and results

This paper describes the work completed in the scope of PRACE 5IP/WP6 - Service 6 Data Analytics in Task 6.2: Design and Development of new Service prototypes. Among the technical domains covered by the “Data analytics” term, we decided to focus on the current trends that show a growing interest in the community of data scientists: machine learning and deep learning techniques, which make use of automated algorithms, as they can offer faster dataset analysis than more conventional methods. Thus, we evaluated how these techniques can benefit from HPC environments with powerful CPUs and GPUs to manage the models’ complexity and accelerate the training, as well as to handle the increased amount of training data. We describe the PRACE Data Analytics service that relies on a set of coherent components: frameworks, libraries, tools and additional features to support, facilitate and promote the data analytics activities in PRACE and help users in running their machine and deep learning tasks over the PRACE systems. Then, we present the results we obtained for a set of deep learning benchmarks and real use cases we ran on the different PRACE architectures while using these components, that confirm their efficiency.
High Fat Diet and Childhood Diseases Maternal High Fat Diets and Offspring Diseases

Maternal High Fat Diets (HFDs) together with obesity represents a special problem that can lead to poor fetal development, resulting in harmful, persistent effects on offspring, including predisposition on obesity and its associated metabolic disorders as well as certain types of cancer. However, the mechanisms underpinning these programming effects induced by maternal HFDs and/or obesity remain poorly defined. Given the increasing number of obese women entering pregnancy and the current obesity epidemic, there is an urgent need to gain more insights into possible underlying mechanisms and to develop effective therapeutic strategies.
Modiﬁed Lattice Landau Gauge

We propose a modiﬁed lattice Landau gauge based on stereographically projecting the link variables on the circle S 1 → R for compact U ( 1 ) or the 3-sphere S 3 → R 3 for SU ( 2 ) before imposing the Landau gauge condition. This can reduce the number of Gribov copies exponentially and solves the Gribov problem in compact U ( 1 ) where it is a lattice artifact. Applied to the maximal Abelian subgroup this might be just enough to avoid the perfect cancellation amongst the Gribov copies in a lattice BRST formulation for SU ( N ) and thus to avoid the Neuberger 0/0 problem. The continuum limit of the Landau gauge remains unchanged.
Ontogenesis of 30-Hydroxysteroid Dehydrogenase A 5 -A 4 Isomerase in the Rat Ovary as Studied by Immunocytochemistry and In Situ Hybridization

The enzyme complex 3-hydroxy-5-ene-steroid dehydrogenase and steroid 5-4-ene isomerase (3{-HSD) is involved in the biosynthesis of all classes of active steroids, namely glucocorticoids, mineralocorticoids, and sex steroids. To obtain more infor-mation about the age-specific expression and localization of 3[-HSD during development in the rat ovary, two complementary cytochemical techniques were used, immunocytochemical localization with antibodies against purified human placental 3-HSD, and 3-HSD mRNA localization achieved by in situ hybridization with a [35S]-labeled cDNA encoding 3P-HSD. In the fetal ovary, no significant immunolabeling or hybridization signal could be observed. The first expression of the enzyme was observed 6 days after birth, immunolabeling as well as autoradiographic reaction being found in a few interstitial gland cells. At the 10th day of postnatal life, the theca interna cells of growing follicles appeared to be labeled with both techniques. The granulosa cells of growing follicles also exhibited hybridization signal, whereas no immunostaining could be detected in these cells at any of the time intervals studied. At puberty, 3-HSD was localized in theca interna and granulosa cells of the growing and mature follicles as well as in the interstitial gland and corpus luteum cells. Similar results were obtained in 40-day-old and adult animals. The present data indicate a progressive expression of 3,-HSD in different morphological structures during ovarian development in the rat.
657 The NH 2 -terminal peptide of (cid:2) –smooth muscle actin inhibits force generation by the myoﬁbroblast in vitro and in

Switzerland yoﬁbroblasts are specialized ﬁbroblasts responsible for granulation tissue contraction and the soft tissue retractions occurring during ﬁbrocontractive diseases. The marker of ﬁbroblast-myoﬁbroblast modulation is the neo expression of (cid:2) –smooth muscle actin ( (cid:2) -SMA), the actin isoform typical of vascular smooth muscle cells that has been suggested to play an important role in myoﬁbroblast force generation. Actin isoforms differ slightly in their NH 2 terminal sequences; these conserved differences suggest different functions. When the NH 2 -terminal sequence of (cid:2) -SMA Ac-EEED is delivered to cultured myoﬁbroblast in the form of a fusion peptide (FP) with a cell penetrating sequence, it inhibits their contractile activity; moreover, M upon topical administration in vivo it inhibits the contraction of rat wound granulation tissue. The NH 2 -terminal peptide of (cid:2) –skeletal actin has no effect on myoﬁbroblasts, whereas the NH 2 -terminal peptide of (cid:3) –cytoplasmic actin abolishes the immunoﬂuorescence staining for this isoform without inﬂuencing (cid:2) -SMA distribution and cell contraction. The FPs represent a new tool to better understand the speciﬁc functions of actin isoforms. Our ﬁndings support the crucial role of (cid:2) -SMA in wound contraction. The