Miracle-dz/UniFAR-FTUs huggingface dataset:
P2RX7 signaling drives the differentiation of Th1 cells through metabolic reprogramming for aerobic glycolysis

This study provides evidence on the molecular mechanisms by which P2RX7 signaling promotes the differentiation of Th1 cells. In vivo analysis was performed in the Plasmodium chabaudi model of malaria in view of the great relevance of this infectious disease for human health, as well as the great availability of data concerning Th1/Tfh differentiation. We show that P2RX7 induces T-bet expression and aerobic glycolysis in splenic CD4+ T cells that respond to malaria, at a time prior to Th1/Tfh polarization. Cell-intrinsic P2RX7 signaling sustains the glycolytic pathway and causes bioenergetic mitochondrial stress in activated CD4+ T cells. We also show in vitro the phenotypic similarities of Th1-conditioned CD4+ T cells that do not express P2RX7 and those in which the glycolytic pathway is pharmacologically inhibited. In addition, in vitro ATP synthase blockade and the consequent inhibition of oxidative phosphorylation, which drives cellular metabolism for aerobic glycolysis, is sufficient to promote rapid CD4+ T cell proliferation and polarization to the Th1 profile in the absence of P2RX7. These data demonstrate that P2RX7-mediated metabolic reprograming for aerobic glycolysis is a key event for Th1 differentiation and suggest that ATP synthase inhibition is a downstream effect of P2RX7 signaling that potentiates the Th1 response.
Semaphorin 4D induced inhibitory synaptogenesis restores benzodiazepine sensitivity in a mouse model of Status Epilepticus

Previously we demonstrated that intra-hippocampal infusion of purified, Semaphorin 4D (Sema4D) extracellular domain into the mouse hippocampus rapidly promotes formation of GABAergic synapses and decreases seizure susceptibility in mice. Given the relatively fast action of Sema4D treatment revealed by these studies, we sought to determine the time course of Sema4D treatment on hippocampal network activity using an acute hippocampal slice preparation. We performed long-term extracellular recordings from area CA1 encompassing a 2 hour application of Sema4D and found that hippocampal excitation is suppressed hours following treatment. We also asked if Sema4D treatment could ameliorate seizures in an acute seizure model: the kainic acid (KA) mouse model of Status Epilepticus (SE). We demonstrate that Sema4D treatment suppresses seizures and lessens benzodiazepine (BZD) insensitivity which is a hallmark of refractory SE. Lastly, we sought to explore alternative methods of Sema4D delivery to hippocampus and thus created an Adeno Associated Virus expressing the extracellular domain of Sema4D. Our data reveal that virally delivered, chronically overexpressed Sema4D extracellular domain promotes GABAergic synapse formation and suppresses seizure activity similar to the actions of purified Sema4D protein. These results provide proof of concept that Sema4D-mediated GABAergic synapse development could combat BZD insensitivity in intractable forms of epilepsy, and that viral delivery of Sema4D is an efficacious and promising delivery method.
Characterization of Three Variants of SARS-CoV-2 In Vivo Shows Host-Dependent Pathogenicity in Hamsters, While Not in K18-hACE2 Mice

Animal models are used in preclinical trials to test vaccines, antivirals, monoclonal antibodies, and immunomodulatory drug therapies against SARS-CoV-2. However, these drugs often do not produce equivalent results in human clinical trials. Here, we show how different animal models infected with some of the most clinically relevant SARS-CoV-2 variants, WA1/2020, B.1. 617.2/Delta, B.1. 1.529/Omicron and BA5.2/Omicron, have independent outcomes. We show that in mice, B.1. 617.2 is more pathogenic, followed by WA1, while B.1. 1.529 showed an absence of clinical signs. Only B.1. 1.529 was able to infect C57BL/6J mice, which lack the human ACE2 receptor. B.1. 1.529-infected ACE2 mice had different T cell profiles compared to infected K18-hACE2 mice, while viral shedding profiles and viral titers in lungs were similar between the ACE2 and the C57BL/6J mice. These data suggest B.1. 1.529 virus adaptation to a new host and shows that asymptomatic carriers can accumulate and shed virus. Next, we show how B.1. 617.2, WA1 and BA5.2/Omicron have similar viral replication kinetics, pathogenicity, and viral shedding profiles in hamsters, demonstrating that the increased pathogenicity of B.1. 617.2 observed in mice is host-dependent. Overall, these findings suggest that small animal models are useful to parallel human clinical data, but the experimental design places an important role in interpreting the data. IMPORTANCE There is a need to investigate SARS-CoV-2 variants phenotypes in different animal models due to the lack of reproducible outcomes when translating experiments to the human population. Our findings highlight the correlation of clinically relevant SARS-CoV-2 variants in animal models with human infections. Experimental design and understanding of correct animal models are essential to interpreting data to develop antivirals, vaccines, and other therapeutic compounds against COVID-19.
Knockdown of the TRPM4 channel alters cardiac electrophysiology and hemodynamics in a sex- and age-dependent manner in mice

Background TRPM4 is a calcium-activated, voltage-modulated, non-selective ion channel widely expressed in various types of cells and tissues. TRPM4 regulates the influx of sodium ions, thus playing a role in regulating the membrane potential. In the heart, TRPM4 is expressed in both cardiomyocytes and cells of the conductive pathways. Clinical studies have linked TRPM4 mutations to several cardiac disorders. While data from experimental studies have demonstrated TRPM4’s functional significance in cardiac physiology, its exact roles in the heart remain unclear. Aim To investigate the role of TRPM4 in cardiac physiology in a newly generated knockdown Trpm4 mouse model. Methods and results Male and female Trpm4 knockdown (Trpm4 -/-) and wild-type mice 5- to 12-weeks-old (young) or 24-week-old or more (adult) were characterized using a multimodal approach, encompassing surface electrocardiograms (ECG), echocardiography recordings, pseudo and intracardiac ECGs, western blots, and mRNA quantifications. The assessment of cardiac electrophysiology by surface ECGs revealed no significant differences between wild type and Trpm4 -/- 5- to 12-weeks-old mice of either sex. Above 24 weeks of age, adult male Trpm4 -/- mice showed significantly reduced heart rate and increased heart rate variability. Echocardiography reveals that only adult male Trpm4 -/- mice exhibited slight left ventricular hypertrophic alterations with an alteration of the mitral valve pressure half time, the mitral valve E/A ratio, the isovolumetric relaxation time, and the mitral valve deceleration. In addition, an assessment of the right ventricular systolic function by scanning the pulmonary valve highlighted an alteration in pulmonary valve peak velocity and pressure in male Trpm4 -/- adult mice. Finally, intracardiac ECG recordings showed that the application of 5 µM NBA triggered a third-degree atrioventricular block on 40% of wild-type hearts only. Conclusions These results confirm the important role of TRPM4 in the proper structure and electrical function of the heart. It also reveals significant differences between male and female animals that have never been reported before. In addition, the investigation of the effects of NBA on heart function highlights the role of TRPM4 in atrioventricular conduction and provides the first evidence showing the efficacy of this compound on native cardiac tissues.
Efficient Calculation of Non-local Thermodynamic Equilibrium Effects in Multithreaded Hydrodynamic Simulations of Solar Flares

Understanding the dynamics of the chromosphere is crucial to understanding energy transport across the solar atmosphere. The chromosphere is optically thick at many wavelengths and described by non-local thermodynamic equilibrium (NLTE), making it difficult to interpret observations. Furthermore, there is considerable evidence that the atmosphere is filamented, and that current instruments do not resolve small-scale features. In flares, it is likely that multithreaded models are required to describe the heating. The combination of NLTE effects and multithreaded modeling requires computationally demanding calculations, which has motivated the development of a model that can efficiently treat both. We describe the implementation of a solver in a hydrodynamic code for the hydrogen level populations that approximates the NLTE solutions. We derive an accurate electron density across the atmosphere that includes the effects of nonequilibrium ionization for helium and metals. We show the effects on hydrodynamic simulations, which are used to synthesize light curves using a postprocessing radiative transfer code. We demonstrate the utility of this model on IRIS observations of a small flare. We show that the Doppler shifts in Mg ii, C ii, and O i can be explained with a multithreaded model of loops subjected to electron beam heating, so long as NLTE effects are treated. The intensities, however, do not match the observed values very well, which is due to assumptions about the initial atmosphere. We briefly show how altering the initial atmosphere can drastically alter line profiles and derived quantities and suggest that it should be tuned to preflare observations.
Gonadal Sex and Sex-Chromosome Complement Interact to Affect Ethanol Consumption in Adolescent Four Core Genotypes Mice

Background Sex differences in ethanol consumption have been reported in both humans and laboratory rodents, but the independent/dependent contributions of genetic and hormonal sex◻biasing mechanisms to these phenotypes have not yet been fully explored. Methods To examine the contributions of sex-chromosome complement (SCC) and gonadal sex (GS) to ethanol consumption, we studied adolescent (28-32 days old) four core genotypes (FCG) mice (C57BL/6J background; FCG model allows for independent assortment of GS and SCC) using a modified drinking-in-the-dark (DID) procedure. Mice were offered concurrent access to 20%, 10% and 0% ethanol (in water) in four daily 2-hour sessions. Consumption at the level of individual bouts was recorded. Results Although all four genotype groups preferred the 20% ethanol over 10% and 0%, and showed similar consumption of the 10% and 0% solutions, the group rankings for consumption of the 20% ethanol solution were XX+testes > XY+testes > XY+ovaries > XX+ovaries. Thus, an interaction was observed between SCC and GS for which the simple effect of SCC was greatest in mice with ovaries (XY > XX) and the simple effect of GS was greatest in XX mice (testes > ovaries). Moreover, these effects varied in magnitude across and within drinking sessions. The behavioral microstructure of ethanol consumption (i.e., parameterization of within-session discriminable drinking bouts) support the validity of our 3-bottle modification of the DID procedure as a model of binge-like consumption as: (1) the consumption rate of the 20% ethanol solution was ~80 g EtOH/kg/h within a bout (~12 s/bout, ~3 bouts/session), (2) most of this ethanol consumption was completed in a single bout and (3) within-session ethanol consumption was greater earlier than later, indicating “front loading. ” Conclusions These results indicate that SCC and GS interact on ethanol consumption in adolescent FCG mice on a C57BL/6J background to affect binge-like consumption from the very initiation of access and that these effects are dynamic as they varied both across and within sessions. Highlights Gonadal sex and sex-chromosome complement interact on ethanol consumption in adolescent four core genotypes mice In adolescent four core genotypes mice, mice with testes drink more ethanol than mice with ovaries, particularly in the presence of an XX karyotype In adolescent four core genotypes mice, XY mice drink more ethanol than XX mice, but only in mice with ovaries The effects of sex-biasing biological factors on the patterns of ethanol consumption by adolescent four core genotypes mice that we observed in our 3-bottle Drinking-in-the-Dark procedure showed face validity with some of the sex/gender differences observed in human adolescents
AI-Enabled Classification of Head and Neck Tumors using Convolutional Neural Networks with Dynamic Optical Contrast Imaging

Background Recent advances in artificial intelligence (AI) in the field of imaging have resulted in new opportunities for automated tumor detection and margin assessment. In particular, AI deep learning techniques such as the Convolutional Neural Network (CNN) have greatly advanced the field of computer vision. Here we introduce the application of a CNN model for use with Dynamic Optical Contrast Imaging (DOCI), an imaging technique developed by our group that creates a unique molecular signature on tissue targets by obtaining the autofluorescence decay of several spectral bands in the UV-Vis range. Methods 21 patients undergoing surgical resection for tonsillar squamous cell carcinoma (SCC) were identified on a prospective basis. DOCI images were analyzed and compared to the pathology results as ground truth. A CNN model was used to segment sections of DOCI images and provide a percentage chance of tumor presence, allowing for automated tumor margin delineation without a-priori knowledge of the tumor tissue composition. Results CNN outputs yielded a 99.98% confidence in classifying non-tumor tissue and 76.02% confidence in classifying tumor tissue. Conclusions Our results indicate that a CNN-based classification model for DOCI allows for real-time analysis of tissue, providing improved sensitivity and accuracy of determining true margins and thus enabling the head and neck cancer surgeon to save healthy tissue and improve patient outcomes.
Numerical Investigation of Nonlinear Wave Interaction in a Two-Dimensional Boundary Layer.

Abstract : A spectral method is used to solve for the unsteady, two-dimensional flow over a flat plate in the Reynolds number range of transition. The physical problem considered is the propagation of large amplitude (nonlinear) Tollmien-Schlichting waves in a boundary layer. The solutions are generally in qualitative agreement with nonlinear stability theories in that: (1) nonlinear effects can be destabilizing, (2) the growth/decay behavior of the primary mode is changed only slightly by nonlinear effects, and (3) the second temporal harmonic is usually a second spatial harmonic. There are, however, regions in the flow in which both (1) and (3) are not true. Details of the solution in such a region are given to illustrate the complex nonlinear wave interactions possible in a boundary layer. (Author)
Models for Evolution of Dusty and E/S0 Galaxies Seen in Multiband Surveys

Phenomenological models for evolution of dusty and E/S0 galaxies, respectively, are developed to address two major questions concerning galaxy populations in deep infrared (IR) surveys: (1) Do normal late-type galaxies or starburst galaxies (including galaxies with obscured active galactic nuclei) dominate among sources in deep IR surveys? (2) How much do E/S0 galaxies contribute to the counts in deep mid-infrared (MIR: 3-20 μm) surveys? Among three new models for evolution of dusty galaxies, it is assumed in model S1 that starburst galaxies are the dominant population and in model S2 that normal galaxies dominate. Model S3 is an intermediate model. Comparing the model predictions with a wide range of observational data collected from the literature, we find that none of these models can be ruled out, given the uncertainties of the data. We show that the most direct method to distinguish these models is to compare the predicted color distributions of IR galaxies with observations, which will soon be available from the SIRTF Wide-Area Infrared Extragalactic (SWIRE) survey. The models for E/S0 galaxies follow a simple passive evolution approach. Among the three E/S0 models (E1, E2, and E3) investigated in this paper, model E2, which is specified by a peak formation redshift zpeak = 2 and an e-folding formation timescale ω = 2 Gyr, fits the data best. This suggests a synchronization between the evolution of E/S0 galaxies and that of starburst galaxies, in the sense that the peak of the formation function of E/S0 galaxies (zpeak = 2) is close to the peak of the evolution functions of starburst galaxies (zpeak = 1.4). We find that E/S0 galaxies contribute about 10%-30% of the counts in the MIR bands of less than 10 μm and up to 30%-50% of the optical/near-IR counts in the bright end. Their contributions to counts in the UV (2000 Å) and in the longer wavelength IR (≥12 μm) bands are negligible. Taking into account this contribution, new predictions for counts and confusion limits in the SIRTF bands are presented.
A Bayesian model for human directional localization of broadband static sound sources

Humans estimate sound-source directions by combining prior beliefs with sensory evidence. Prior beliefs represent statistical knowledge about the environment while sensory evidence is acquired from auditory features such as interaural disparities and monaural spectral shapes. Models of directional sound localization often impose constraints on the contribution of these features to either the horizontal or vertical dimension. Instead, we propose a Bayesian model that more flexibly incorporates each feature according to its spatial precision and integrates prior beliefs in the inference process. We applied the model to directional localization of a single, broadband, stationary sound source presented to a static human listener in an anechoic environment. We simplified interaural features to be broadband and compared two model variants, each considering a different type of monaural spectral features: magnitude profiles and gradient profiles. Both model variants were fitted to the baseline performance of five listeners and evaluated on the effects of localizing with non-individual head-related transfer functions (HRTFs) and sounds with rippled spectrum. The model variant with spectral gradient profiles outperformed other localization models. This model variant appears particularly useful for the evaluation of HRTFs and may serve as a basis for future extensions towards modeling dynamic listening conditions.
How many cues are sexy ? Evolution of mate preference towards multiple traits in sympatric species

While the impact of mate preference on adaptation and speciation has been extensively studied, the 2 evolutionary factors determining which and how many traits are targeted by mate choice are largely unknown. In sympatric species, trait distribution is shaped by similar selective pressure, promoting 4 similar adaptive traits in the diﬀerent species. When preference targets such adaptive traits, the similarity between species induce heterospeciﬁc matings and costs for the choosy partners. The 6 evolution of preference for diﬀerent traits thus likely depends on the ecological interactions between species. Using a mathematical model, we thus study the evolution of preference towards two evolving 8 traits shared by sympatric species and we investigate how selective regimes on traits, opportunity costs and sensory trade-oﬀ shape the evolution of preference for multiple traits. As expected, the 10 evolution of multiple traits preference is favored when females have access to a large number of mates and when there is limited sensory trade-oﬀ. More surprisingly, opportunity costs promote 12 preference based on adaptive traits, rather than on traits relevant for species recognition. Since adaptation reduces trait variability in males, the evolution of preferences based on adaptive traits 14 hardly suﬀers from opportunity costs. Our model thus highlights that the evolution of preferences for diﬀerent traits in sympatric species depends on within-species mating opportunities but also on 16 the niche overlap between species, tuning the heterospeciﬁc interactions.
In Silico Analysis of Novel VHL Germline Mutations in Iranian RCH Patients

Von Hippel-Lindau (VHL) syndrome is an autosomal dominant inherited multisystem neoplasia disorder caused by the VHL tumor suppressor gene, coding for VHL protein (pVHL), variants. Various types of VHL variants present different clinical phenotypes that later lead to events resulting in benign or malignant lesions including Retinal Capillary Hemangioblastoma (RCH). We reported on 3 novel mutation sites observed in 3 families (5 RCH patients), including c.511A>C, c.514C>T, and c.511A>T in exon 3 of the VHL gene. According to the ACMG classifications, c.514C>T and c.511A>T variations are likely pathogenic, and c.511A>C is a variant of uncertain significance (VUS) and in accordance with autosomal dominant inheritance. The location and impact of the incidence mutations on pVHL were computed using in silico analysis. The obtained structural information and computational analysis showed that the studied mutations induce conformational changes that limit the flexibility of the pVHL interaction interface with elonginB/C, elongin C/B, and cullin2, which is necessary for HIF1 alpha binding. The recently added gene variants and their related clinical phenotypes will improve the VHL diagnosis accuracy and the patients’ population carrying VHL gene mutations. These pioneering results could be a model for future functional studies.
ASO targeting temperature-controlled RBM3 poison exon splicing prevents neurodegeneration in vivo

Neurodegenerative diseases are increasingly prevalent in the aging population, yet currently no disease-modifying treatments are available. Increasing the expression of the cold-shock protein, RBM3, through therapeutic hypothermia is remarkably neuroprotective, but cooling poses a health risk itself, strongly limiting its clinical application. Selective upregulation of RBM3 at normothermia thus holds immense therapeutic potential. Here we identify a poison exon within the RBM3 gene that is solely responsible for cold-induced RBM3 expression. Genetic removal or ASO-mediated manipulation of this exon yields high RBM3 levels independent of cooling. Notably, a single administration of ASO to exclude the poison exon, using FDA-approved chemistry, results in long-lasting increase of RBM3 expression in mouse brains. In prion-diseased mice, this treatment leads to remarkable neuroprotection, with prevention of neuronal loss and spongiosis despite high levels of prion protein. RBM3-inducing ASOs could thus broadly deliver protection in humans in conditions ranging from acute brain injury to Alzheimer’s disease. One sentence summary Inducing cold shock protein RBM3 by modulating its alternative splicing at normothermia is neuroprotective in vivo
Time-resolved Ultraviolet Spectroscopy of the SW Sex Star DW UMa: Confirmation of a Hidden White Dwarf and the Ultraviolet Counterpart to Phase 0.5 Absorption Events

We present time-resolved ultraviolet (UV) spectroscopy of the SW Sex star DW UMa in the high state. We confirm that shortward of 1500 Å, the high-state UV continuum level is lower than the white dwarf (WD) dominated low-state level. We also do not see the WD contact phases in the high-state eclipse light curves. These results confirm our earlier finding that the WD in this system is hidden from view in the high state. On the basis of this, we caution that eclipse mapping of high-inclination SW Sex stars in the high state may yield incorrect or misleading results. In the context of DW UMa, we demonstrate explicitly that distance estimates obtained by recent eclipse-mapping studies cannot be reconciled with the WD-dominated low-state spectrum. We also show that the fluxes of the UV emission lines in the high state drop near orbital phase 0.5. This is the first detection of a UV counterpart to the class-defining phase 0.5 absorption seen in the optical emission lines of SW Sex stars.