Miracle-dz/UniFAR-FTUs huggingface dataset:
Generalised Lindley shared additive frailty regression model for bivariate survival data

Abstract Frailty models are the possible choice to counter the problem of the unobserved heterogeneity in individual risks of disease and death. Based on earlier studies, shared frailty models can be utilised in the analysis of bivariate data related to survival times (e.g. matched pairs experiments, twin or family data). In this article, we assume that frailty acts additively to the hazard rate. A new class of shared frailty models based on generalised Lindley distribution is established. By assuming generalised Weibull and generalised log-logistic baseline distributions, we propose a new class of shared frailty models based on the additive hazard rate. We estimate the parameters in these frailty models and use the Bayesian paradigm of the Markov Chain Monte Carlo (MCMC) technique. Model selection criteria have been applied for the comparison of models. We analyse kidney infection data and suggest the best model.
A scheme to analyze conducting plates of resonant size using the conjugate-gradient method and the fast Fourier transform

A scheme for analyzing electrodynamic problems involving conducting plates of resonant size using the conjugate-gradient (CG) method and the fast Fourier transform (FFT) is presented in detail. The problems are analyzed by solving their corresponding electric-field integral equation. The procedure is made easy and systematic by using a sampling process with rooftop functions to represent the induced current and pulses to average the fields. These functions have been widely used in moment-method (MM) applications. The scheme is an efficient numerical tool, benefiting from the good convergence and low memory requirements of the CG and the low CPU time consumed in performing convolutions with the FFT. In comparison with the MM, the scheme avoids the storage of large matrices and reduces the computer time by an order of magnitude. Several results are presented and compared with analytical, numerical, or measured values that appear in the literature. >
Solar Semidiurnal Tide in the Thermosphere

Abstract A three-dimensional model is developed to study the behavior of the solar semidiurnal tide in the thermosphere. In this model, we include viscosity, thermal conductivity, Coriolis effects, the sphericity of the earth, and ion drag. Sources of excitation are absorption of solar radiation by H2O and O2 below the mesopause, and by O2 in the Schumann-Runge continuum, and O, O2, N2 in the extreme ultraviolet, in the thermosphere. The effects of mean wind below the thermosphere are obtained by joining our present results to the relevant solutions obtained by Lindzen and Hong (1974) at 100 km, modified, however, by the use of improved and corrected heating functions. Our calculations provide detailed predictions for all meteorological fields as functions of season, solar cycle, and other parameters. Among our findings are the following: In the present calculations, the semidiurnal tide between 100 and 130 km is dominated by the 2,4 mode excited below the thermosphere. Since the 2,4 mode decays more rapi.
Climate Change Impact on Potential Distribution of an Endemic Species Abies marocana Trabut

Abstract Global warming is becoming a major concern affecting many components of the biodiversity at a global scale and disproportionately affecting the integrity of ecosystems, particularly the habitat of endemic species. Understanding its impacts on most vulnerable species is essential to improve knowledge on the ecology of these species and for their long-term management and conservation. Abies marocana Trabut (Moroccan fir), a remarkable forest tree of the Mediterranean basin, is an endangered species that is present in discreet small areas of the Rif Mountains, which is highly vulnerable to the ongoing climate warming and facing severe anthropogenic pressures. For conservation and management purposes, our work focused on improving understanding of the impacts of future climate change on the distribution of this species through its habitat suitability modeling. The maximum entropy approach was used, which achieved good predictive abilities. Habitat suitability was identified and then predicted under current and future climate conditions. A significant change and a gradual regression of the habitat suitability to A. marocana was shown under different future climate scenarios. The magnitude of the simulated changes is important and tends to have negative consequences for Moroccan fir conservation. For this purpose, outputs from models are useful to improve our knowledge about the ecology of A. marocana, and predictive maps produced under current and future climate conditions constitute reflection tools available to scientists and managers to better integrate actual and future climate impacts into existing and upcoming management strategies to prevent any future locale extinction.
Transcriptome Analysis of Bovine Macrophages (BoMac) Cells after Infection with Bovine Immunodeficiency Virus

Abstract Introduction Bovine immunodeficiency virus (BIV) is found worldwide in cattle under natural conditions. However, the effect of BIV infection on immune functions has not been fully characterised. Material and Methods Transcriptome analysis of BoMac cells after in vitro infection with BIV was performed using BLOPlus bovine microarrays. Genes identified as differentially expressed were subjected to functional analysis with the Ingenuity Pathway Analysis software (IPA). Results Out of 1,743 genes with altered expression, 1,315 were mapped as unique molecules. In total, 718 genes were identified as upregulated and 597 genes as downregulated. Differentially expressed genes were involved in 16 pathways related to immune response. The most enriched canonical pathway was leukocyte extravasation signalling. Interleukin-15 (IL-15) production was indicated as the most activated pathway and the 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) signalling pathway was the most inhibited one. In addition, the study showed that the inflammatory response was decreased during BIV infection. Conclusion This is the first report to describe the microarray analysis of changes in gene expression upon BIV infection of bovine macrophages. Our data indicated how BIV influences the expression of genes and signalling pathways engaged in the immune response.
The lipid transfer proteins Nir2 and Nir3 sustain phosphoinositide signaling and actin dynamics during phagocytosis

Changes in membrane phosphoinositides and local Ca2+ elevations at sites of particle capture coordinate the dynamic remodeling of the actin cytoskeleton during phagocytosis. Here, we show that the phosphatidylinositol (PI) transfer proteins PITPNM1 (Nir2) and PITPNM2 (Nir3) maintain PI(4,5)P2 homeostasis at phagocytic cups, thereby promoting actin contractility and the sealing of phagosomes. Nir3 and to a lesser extent Nir2 accumulated in ER cisternae juxtaposed to phagocytic cups when expressed in phagocytic mouse fibroblasts. CRISPR-Cas9 editing of Nir2 and Nir3 genes decreased plasma membrane PI(4,5)P2 levels, store-operated Ca2+ entry (SOCE), and receptor-mediated phagocytosis, stalling particle capture at cup stage. Re-expression of either Nir2 or Nir3 restored phagocytosis, but not SOCE, proportionally to the PM PI(4,5)P2 levels. Phagosomes forming in Nir2/3-edited cells had decreased overall PI(4,5)P2 levels but normal periphagosomal Ca2+ signals. Nir2/3 editing reduced the density of contractile actin rings at sites of particle capture, causing repetitive low-intensity contractile events indicative of abortive phagosome closure. We conclude that Nir-mediated lipid transfer maintains phosphoinositide homeostasis at phagocytic cups, thereby sustaining the signals that initiate the remodeling of the actin cytoskeleton during phagocytosis. Summary statement Changes in membrane phosphoinositides coordinate actin remodeling during phagocytosis, but whether lipid transport proteins contribute to this process is not known. Here, we show that the phosphatidylinositol transfer proteins Nir2 and Nir3 are recruited to phagocytic cups and drive the formation of contractile actin rings during particle engulfment. Using gene editing and re-expression, we show that Nir2 and Nir3 maintain PI(4,5)P2 signaling competence at phagocytic cups and promote the actin-dependent sealing of phagocytic vacuoles. These observations establish that lipid transport proteins maintain the phosphoinositide signals that drive the remodeling of the actin cytoskeleton during phagocytosis.
Recursive splicing discovery using lariats in total RNA sequencing

Using a stringent approach to map lariat reads, this study provides evidence for recursive splicing in a broader range of intron sizes than previously reported and details a new location for recursive splicing at the distal end of exons. Recursive splicing is a non-canonical splicing mechanism in which an intron is removed in segments via multiple splicing reactions. Relatively few recursive splice sites have been identified with high confidence in human introns, and more comprehensive analyses are needed to better characterize where recursive splicing happens and whether or not it has a regulatory function. In this study, we use an unbiased approach using intron lariats to search for recursive splice sites in constitutive introns and alternative exons in the human transcriptome. We find evidence for recursive splicing in a broader range of intron sizes than previously reported and detail a new location for recursive splicing at the distal ends of cassette exons. In addition, we identify evidence for the conservation of these recursive splice sites among higher vertebrates and the use of these sites to influence alternative exon exclusion. Together, our data demonstrate the prevalence of recursive splicing and its potential influence on gene expression through alternatively spliced isoforms.
Discovering individual-specific gait signatures from data-driven models of neuromechanical dynamics

Locomotion results from the interactions of highly nonlinear neural and biomechanical dynamics. Accordingly, understanding gait dynamics across behavioral conditions and individuals based on detailed modeling of the underlying neuromechanical system has proven difficult. Here, we develop a data-driven and generative modeling approach that recapitulates the dynamical features of gait behaviors to enable more holistic and interpretable characterizations and comparisons of gait dynamics. Specifically, gait dynamics of multiple individuals are predicted by a dynamical model that defines a common, low-dimensional, latent space to compare group and individual differences. We find that highly individualized dynamics – i.e., gait signatures – for healthy older adults and stroke survivors during treadmill walking are conserved across gait speed. Gait signatures further reveal individual differences in gait dynamics, even in individuals with similar functional deficits. Moreover, components of gait signatures can be biomechanically interpreted and manipulated to reveal their relationships to observed spatiotemporal joint coordination patterns. Lastly, the gait dynamics model can predict the time evolution of joint coordination based on an initial static posture. Our gait signatures framework thus provides a generalizable, holistic method for characterizing and predicting cyclic, dynamical motor behavior that may generalize across species, pathologies, and gait perturbations. Author Summary In this manuscript, we introduce a novel, machine learning-based framework for quantifying, characterizing, and modifying the underlying neuromechanical dynamics that drive unique gait patterns. Standard methods for evaluating movement typically focus on extracting discrete gait variables ignoring the complex inter-limb and inter-joint spatiotemporal dependencies that occur during gait. Popular physiologically realistic modeling approaches encode these spatiotemporal dependencies but are too complex to characterize individual differences in the factors driving unique gait patterns or disorders. To circumvent these modeling complications, we develop a phenomenological model of gait that enables more holistic and interpretable characterizations of gait, encoding these complex spatiotemporal dependencies between humans’ joint angles arising from joint neural and biomechanical constraints. Our coined ‘gait signature’ framework provides a path towards understanding the neuromechanics of locomotion. This framework has potential utility for clinical researchers prescribing individualized therapies for pathologies or biomechanists interested in animal locomotion or other periodic movements assessed across different pathologies, neural perturbations, and or conditions.
Unbalancing cAMP and Ras/MAPK pathways as a therapeutic strategy for cutaneous neurofibromas

Cutaneous neurofibromas (cNFs) are benign Schwann cell (SC) tumors arising from subepidermal glia. Neurofibromatosis Type 1 (NF1) individuals may develop thousands of cNFs, greatly affecting their quality of life. cNF growth is governed by the proliferation of NF1(-/-) SCs, highly influenced by the interaction with a NF1(+/-) microenvironment, consisting of fibroblasts (FBs), immune cells, etc. To decompose crosstalk between SCs and the microenvironment we used single cultures and co-cultures of cNF-derived SCs and FBs and identified an expression signature specific to SC-FB interaction. This signature was enriched in genes involved in immune cell migration, that were functionally validated by secretion analysis of SC-FB co-cultures, suggesting a role of SC-FB crosstalk in immune cell recruitment. The signature also captured components of different developmental signaling pathways, among them, the cAMP elevator G protein-coupled receptor 68 (GPR68). Activation of Gpr68 by Ogerin reduced the viability and proliferation of cNF-derived SCs and SC-FB co-cultures. Moreover, Ogerin in combination with the MEKi Selumetinib induced loss of viability, SC differentiation, and death. These results were corroborated using an iPSC-derived 3D neurofibromasphere model. The unbalancing of the Ras and cAMP pathways by combining a MEKi and a cAMP elevator arises as a potential treatment for cNFs.
Impact of cannabis use on immune cell populations and the viral reservoir in people with HIV on suppressive antiretroviral therapy

HIV infection remains incurable due to the persistence of a viral reservoir during antiretroviral therapy. Cannabis (CB) use is prevalent amongst people with HIV (PWH), but the impact of CB on the latent HIV reservoir has not been investigated. Peripheral CD4 and CD8 T cells from a cohort of CB-using PWH and a matched cohort of non-users on antiretroviral therapy were evaluated for expression of maturation/activation markers, HIV-specific T cell responses, and the frequency of intact proviral DNA. CB use was associated with increased abundance of naïve T cells, reduced effector T cells, and reduced expression of activation markers. CB users also exhibited reduced levels of exhausted and senescent T cells compared to non-using controls. HIV-specific CD8 T cell responses were unaffected by CB use. While the abundance of intact proviruses was not significantly affected by CB use across the whole cohort, we observed that, for participants with high frequency of NKG2A or CD16 expression in NK cells, CB use was associated with a smaller intact HIV reservoir. This analysis is consistent with the hypothesis that CB use reduces activation, exhaustion and senescence in the T cells of PWH and may influence the size of the HIV reservoir.
LegNet: resetting the bar in deep learning for accurate prediction of promoter activity and variant effects from massive parallel reporter assays

Parallel reporter assays provide rich data to decipher gene regulatory regions with deep learning. Here we introduce LegNet, a convolutional network architecture that secured the first place for our autosome.org team in the DREAM 2022 challenge of predicting gene expression from gigantic parallel reporter assays. To construct LegNet, we drew inspiration from EfficientNetV2 and reformulated the sequence-to-expression regression problem as a soft-classification task. Here, with published data, we demonstrate that LegNet outperforms existing models and accurately predicts gene expression per se as well as the effects of sequence alterations, such as single-nucleotide variants
Tactile Stimulation Designs Adapted to Clinical Settings Result in Reliable fMRI-based Somatosensory Digit Maps

A wide range of neurological diseases with impaired motor functioning of the upper extremities are accompanied by impairments of somatosensory functioning, which are often undescribed but can provide crucial information for diagnostics, treatment selection, and follow-up. Therefore, a reliable description of the functional representation of the digits in the somatosensory cortex would be a highly valuable, but currently lacking, tool in the clinical context. Task-based functional Magnetic Resonance Imaging of passive tactile stimulation provides an indirect, but valid description of the layout of the digit map in the primary somatosensory cortex. However, to fulfill the specific requirements for clinical application, the presently established approaches need to be adapted and subsequently assessed for feasibility and retest reliability, in order to provide informative parameters for the description of the evoked digit activations. Accordingly, the present high-field 3T fMRI study compares the performance of two established digit mapping designs - travelling wave (TW) and blocked design (BD) - for passive tactile stimulation of the five digits, adapted to reduce the time requirements to just below 15 minutes. To be able to assess the retest reliability unaffected by any clinical conditions, the study was performed on neurotypical participants. The results show that both stimulation designs evoke significant and distinct activation clusters in the primary somatosensory cortex of all participants for all five digits. The average spatial locations of the center of gravities across participants show the common succession of distinct digit representation along the central sulcus. The cortical extent elicited activation, which is generally larger for the thumb and the index finger, also shows comparable average values across the two approaches. Less overlap of activation between neighboring digits was obtained in BD, consistent with the distinct single digit neuronal representations. A high retest reliability was obtained for the location of the digit activation, displaying stable center of gravity locations across sessions for both stimulation designs. This is contrasted by only medium to low retest reliability for the extent and overlap of the digit activations, indicating discrepancies across sessions. These results demonstrate the capacity of shortened fMRI digit mapping approaches (both TW and BD) to obtain the full layout of single digit cortical activations on the level of the individual, which together with the high reliability of the location of the digit representation over time indicates both approaches are clinically applicable.
Robotically-induced auditory-verbal hallucinations: combining self-monitoring and strong perceptual priors

Inducing hallucinations under controlled experimental conditions in non-hallucinating individuals represents a novel research avenue oriented towards understanding complex hallucinatory phenomena, avoiding confounds observed in patients. Auditory-verbal hallucinations (AVH) are one of the most common and distressing psychotic symptoms, whose etiology remains largely unknown. Two prominent accounts portray AVH either as a deficit in auditory-verbal self-monitoring, or as a result of overly strong perceptual priors. In order to test both theoretical models and evaluate their potential integration, we developed a robotic procedure able to induce self-monitoring perturbations (consisting of sensorimotor conflicts between poking movements and corresponding tactile feedback) and a perceptual prior associated with otherness sensations (i.e., feeling the presence of a non-existing another person). Here, in two independent studies, we show that this robotic procedure led to AVH-like phenomena in healthy individuals, which was further associated with delusional ideation. Specifically, a condition with stronger sensorimotor conflicts induced more AVH-like sensations (self-monitoring), while, in the otherness-related experimental condition, there were more AVH-like sensations when participants were detecting other-voice stimuli, compared to detecting self-voice stimuli (strong-priors). By demonstrating an experimental procedure able to induce AVH-like sensations in non-hallucinating individuals, we shed new light on AVH phenomenology, thereby integrating self-monitoring and strong-priors accounts.
Down regulation of the liver lipid metabolism induced by hypothyroidism in mice: metabolic flexibility favors compensatory mechanisms in white adipose tissue

In mammals, the maintenance of energy homeostasis relies on complex mechanisms requiring tight synchronization between peripheral organs and the brain. Thyroid hormones (TH), among their pleiotropic actions, play a central role in these regulations. Hypothyroidism, which is characterized by low circulating TH levels, slows down the metabolism, leading to a reduction in energy expenditure, as well as in lipid and glucose metabolism, and to insulin resistance. Our objective was to evaluate whether metabolic deregulations induced by hypothyroidism could be avoid by regulatory mechanisms involved in metabolic flexibility. To this aim, we compared the response to hypothyroidism in two mouse strains, the wild-derived WSB/EiJ mouse strain characterized by a diet-induced obesity (DIO) resistance due to its high metabolic flexibility phenotype and the C57BL/6J mice, prone to DIO. Adult mice were fed with a low-iodine diet supplemented with 6-n-propyl-2-thiouracyl (PTU) for 7 weeks to induce hypothyroidism. Our results show that hypothyroidism, characterized by a decrease in serum T4 levels, led to metabolic deregulations, as an alteration of lipid metabolism in the liver of both strains. However, the decrease in hepatic lipid synthesis was compensated in WSB/EiJ mice by a mobilization of lipid reserves from white adipose tissue, but not in the C57BL/6J mice. No peripheral or hypothalamic inflammatory response to hypothyroidism was observed in both strains. Moreover, gene expression analysis showed that hypothyroidism stimulates the hypothalamic orexigenic circuit in both strains, but unchanged Mc4r and LepR expression in hypothyroid WSB/EiJ mice strain, which reflect their adaptability to maintain their body weight, contrary to C57BL/6J mice. Our results show that WSB/EiJ mice displayed a phenotype of resistance to metabolic dysregulations induced by hypothyroidism, by compensatory mechanisms. This response as well as their resistance to HFD-induced obesity highlights their adaptive capacities to maintain metabolic homeostasis, namely, their high metabolic flexibility, despite serum hypothyroidism. This model sheds light on the importance of local thyroid homeostasis to maintain lipid metabolism and metabolic homeostasis.