Miracle-dz/UniFAR-FTUs huggingface dataset:
TRPV1 controls innate immunity during Citrobacter rodentium enteric infection

Mucosal immunity is critical to host protection from enteric pathogens and must be carefully controlled to prevent immunopathology. Regulation of immune responses can occur through a diverse range of mechanisms including bi-directional communication with the neurons. Among which include specialized sensory neurons that detect noxious stimuli due to the expression of transient receptor potential vanilloid receptor 1 (TRPV1) ion channel and have a significant role in the coordination of host-protective responses to enteric bacterial pathogens. Here we have used the mouse-adapted attaching and effacing pathogen Citrobacter rodentium to assess the specific role of the TRPV1 channel in coordinating the host response. TRPV1 knockout (TRPV1-/-) mice had a significantly higher C. rodentium burden in the distal colon and fecal pellets compared to wild-type (WT) mice. Increased bacterial burden was correlated with significantly increased colonic crypt hyperplasia and proliferating intestinal epithelial cells in TRPV1-/- mice compared to WT. Despite the increased C. rodentium burden and histopathology, the recruitment of colonic T cells producing IFNγ, IL-17, or IL-22 was similar between TRPV1-/- and WT mice. In evaluating the innate immune response, we identified that colonic neutrophil recruitment in C. rodentium infected TRPV1-/- mice was significantly reduced compared to WT mice; however, this was independent of neutrophil development and maturation within the bone marrow compartment. TRPV1-/- mice were found to have significantly decreased expression of the neutrophil-specific chemokine Cxcl6 and the adhesion molecules Icam1 in the distal colon compared to WT mice. Corroborating these findings, a significant reduction in ICAM-1 and VCAM-1, but not MAdCAM-1 protein on the surface of colonic blood endothelial cells from C. rodentium infected TRPV1-/- mice compared to WT was observed. These findings demonstrate the critical role of TRPV1 in regulating the host protective responses to enteric bacterial pathogens, and mucosal immune responses. Author Summary Neuroimmune communications are vital in regulating the immune response to invading pathogens. Here, we show that during a gastrointestinal infection, pain-sensing neuronal fibers can modulate the immune response to recruit phagocytic neutrophils via upregulation of cell adhesion molecules on local blood endothelial cells. This research elucidates a novel impact of the pain-sensing ion channel, TRPV1, on host-pathogen interactions in the gastrointestinal tract as well as a potential methodology for modulating the immune response during enteric infections.
Graph Attention Site Prediction (GrASP): Identifying Druggable Binding Sites Using Graph Neural Networks with Attention

Identifying and discovering druggable protein binding sites is an important early step in computer-aided drug discovery but remains a difficult task where most campaigns rely on a priori knowledge of binding sites from experiments. Here we present a binding site prediction method called Graph Attention Site Prediction (GrASP) and re-evaluate assumptions in nearly every step in the site prediction workflow from dataset preparation to model evaluation. GrASP is able to achieve state-of-the-art performance at recovering binding sites in PDB structures while maintaining a high degree of precision which will minimize wasted computation in downstream tasks such as docking and free energy perturbation.
Connexin 41.8 mediates the correct temporal induction of haematopoietic stem and progenitor cells

Haematopoietic stem and progenitor cells (HSPCs) derive from a subset of endothelial cells (ECs), known as haemogenic ECs by the process of endothelial-to-haematopoietic transition (EHT). Although many factors involved in EHT have been elucidated, we still have a poor understanding of the temporal regulation of this process. Mitochondrial-derived reactive oxygen species (ROS) have been shown to stabilise hypoxia-inducible factors 1/2α (Hif1/2α), allowing them to positively regulate EHT. Here, we show a developmental delay in EHT and HSPC induction in a gap junction mutant, connexin (cx)41.8 (orthologous to mammalian CX40), in zebrafish. In mammalian cells, CX40 has been shown to localise to the mitochondria. We demonstrate that Cx41.8 is important for the correct temporal generation of mitochondrial ROS, which stabilise the Hif pathway, allowing for the subsequent specification of the haemogenic endothelium. Taken together, our data indicate that Cx41.8 mediates the correct induction of HSPCs.
Integrative analysis of DNA replication origins and ORC/MCM binding sites in human cells reveals a lack of overlap

Based on experimentally determined average inter-origin distances of ∼100 kb, DNA replication initiates from ∼50,000 origins on human chromosomes in each cell cycle. The origins are believed to be specified by binding of factors like the Origin Recognition Complex (ORC) or CTCF or other features like G-quadruplexes. We have performed an integrative analysis of 113 genome-wide human origin profiles (from five different techniques) and 5 ORC-binding profiles to critically evaluate whether the most reproducible origins are specified by these features. Out of ∼7.5 million union origins identified by all datasets, only 0.27% were reproducibly obtained in at least 20 independent SNS-seq datasets and contained in initiation zones identified by each of three other techniques (20,250 shared origins), suggesting extensive variability in origin usage and identification. 21% of the shared origins overlap with transcriptional promoters, posing a conundrum. Although the shared origins overlap more than union origins with constitutive CTCF binding sites, G-quadruplex sites and activating histone marks, these overlaps are comparable or less than that of known Transcription Start Sites, so that these features could be enriched in origins because of the overlap of origins with epigenetically open, promoter-like sequences. Only 6.4% of the 20,250 shared origins were within 1 kb from any of the ∼13,000 reproducible ORC binding sites in human cancer cells, and only 4.5% were within 1 kb of the ∼11,000 union MCM2-7 binding sites in contrast to the nearly 100% overlap in the two comparisons in the yeast, S. cerevisiae. Thus, in human cancer cell lines, replication origins appear to be specified by highly variable stochastic events dependent on the high epigenetic accessibility around promoters, without extensive overlap between the most reproducible origins and currently known ORC- or MCM-binding sites.
The disks and spheroid of LTGs in the light of their early web-like organization

Abstract Cosmological hydrodynamical simulations show that the baryonic elements that at z = 0 form the stellar populations of late-type galaxies (LTGs), display, at high z, a gaseous web-like organization, where different singular structures (walls, filaments, nodes) show up. The analysis also shows that the spheroid-to-be elements are the first to be involved in the singular structures, while thick and thin disk-to-be elements chronologically follow them. We discuss how these differences at high z can explain the differences among these three components at z = 0.
Immune Implications of Gene Therapy for Hemophilia

Similar to any novel treatment strategy for hemophilia, gene therapy faces the question of the risk of formation of inhibitory antibodies to the therapeutic factor VIII or factor IX protein. Activation of CD4 þ or CD8 þ T cells could lead to antibody formation or cytotoxic T lymphocyte responses to transgene-expressing cells. Preclinical studies in animal models of hemophilia A and B with different mutations in the dysfunctional gene shed light on the risk for such immune responses and point toward strategies to avoid immune activation or even promote tolerance induction. The impacts of variables such as choice and design of gene transfer vector, underlying gene mutation, route of vector administration, and transient immune suppression are discussed. Maintenance of immunological hyporesponsiveness to the therapeutic gene product is critical for successful gene therapy. Recent studies provide evidence for tolerance induction to coagulation factor antigens by viral hepatic or neonatal in vivo gene transfer, by in utero gene delivery, and by oral or nasal administration of protein or peptides.
Frequency-offset separated oscillatory fields

A frequency-offset separated-oscillatory-field technique is presented. The technique is a modification of the Ramsey method of separated oscillatory fields [Phys. Rev. 76, 996 (1949)], in which the frequencies of the two separated oscillatory fields are slightly offset from each other, so that the relative phase of the two fields varies continuously with time. With this technique, the detection signal oscillates in time at the offset frequency, and the resonance frequency is obtained by using a simple straight-line fit of the phase of this signal. The technique has the advantages of being insensitive to the frequency response of the experimental system, of being sensitive only to noise at the offset frequency, and of allowing systematic effects to be more cleanly resolved due to the simple lineshape.
Development of wide area environment accelerator operation and diagnostics method

Remote operation and diagnostic systems for particle accelerators have been developed for beam operation and maintenance in various situations. Even though fully remote experiments are not necessary, the remote diagnosis and maintenance of the accelerator is required. Considering remote-operation operator interfaces (OPIs), the use of standard protocols such as the hypertext transfer protocol (HTTP) is advantageous, because system-dependent protocols are unnecessary between the remote client and the onsite server. Here, we have developed a client system based onWebSocket, which is a new protocol provided by the Internet Engineering Task Force for Web-based systems, as a next-generation Web-based OPI using the Experimental Physics and Industrial Control System Channel Access protocol. As a result of this implementation, WebSocket-based client systems have become available for remote operation. Also, as regards practical application, the remote operation of an accelerator via a wide area network (WAN) faces a number of challenges, e.g., the accelerator has both experimental device and radiation generator characteristics. Any error in remote control system operation could result in an immediate breakdown. Therefore, we propose the implementation of an operator intervention system for remote accelerator diagnostics and support that can obviate any differences between the local control room and remote locations. Here, remote-operation Web-based OPIs, which resolve security issues, are developed.
The continuous modeling of charge-stabilized colloidal suspensions in shear flows

Flows of concentrated colloidal suspensions may exhibit a rich set of behaviors due to both hydrodynamic and colloidal interactions between the particles. Colloidal flows are generally modeled with an effective Navier–Stokes equation and a mass balance for the solid phase involving a diffusion coefficient given by the generalized Stokes–Einstein relation. This picture corresponds to a near equilibrium regime in which entropic and colloidal forces dominate over hydrodynamic interactions, the latter being totally ignored. On the other hand, suspension flows far from equilibrium require the modeling of significant hydrodynamic stresses responsible in particular for shear-induced migration, a phenomenon known to occur in some industrial processes involving colloids, such as ultrafiltration. The choice of the proper model ingredients requires a knowledge of the domains in parameter space in which colloidal or hydrodynamic effects are dominant. In this article, such a phase diagram is established for a channel flow of charge-stabilized colloids with a version of the suspension balance model including both colloidal and hydrodynamic effects at the continuous level. It is shown that the classical Peclet number is not sufficient to characterize the flow regime. The phase boundary between the colloidal and hydrodynamic regimes exhibits an original shape explained by the dependence of electrostatic interactions with the colloidal surface charge, and in particular by the phenomenon of ionic condensation. We also show that the phase diagram can be predicted based on the knowledge of a rescaled Peclet number comparing the hydrodynamic stress scale to the bulk modulus of the suspension. The criterion determined here provides important guidelines for the efficient modeling of colloidal flows.
Evaluating Infants and Children with Interstitial Lung Disease

The ﬁeld of children’s interstitial lung disease (chILD) has been confusing for clinicians and families. It is fraught with imperfect pediatric deﬁnitions and classiﬁcation systems, limited understanding of underlying molecular mechanisms, pathophysiology and natural history, and inadequate clinical networks to improve care. To address these issues two large efforts have focused on chILD: a European Respiratory Society (ERS) Task Force on chronic interstitial lung disease in children and the National Institute of Health (NIH)-sponsored Rare Lung Disease Consortium (RLDC). Collaborative efforts in chILD research have retrospectively studied large numbers of children with ILD using different strategies. Both efforts have yielded new concepts and approaches to the evaluation of pediatric patients with ILD. Diagnostic techniques have also evolved to provide more advanced testing in children. This article reviews the current evaluation for children with ILD and highlights areas of controversy.
Lattice Compression of Polynomial Matrices

This thesis investigates lattice compression of polynomial matrices over finite fields. For an m×n matrix, the goal of lattice compression is to find an m×(m+k) matrix, for some relatively small k, such that the lattice span of two matrices are equivalent. For any m × n polynomial matrix with degree bound d, it can be compressed by multiplying by a random n× (m + k) matrix B with degree bound s. In this thesis, we prove that there is a positive probability that L(A) = L(AB) with k(s+1) = Θ(log md). This is shown to hold even when s = 0 (i.e., where B is a matrix of constants). We also design a competitive probabilistic lattice compression algorithm of the Las Vegas type that has a positive probability of success on any input and requires O~(nmθ−1B(d)) field operations.
Reading and Mathematics Differences for English Language Learners Enrolled in Dual Language or Exit Programs.

In this investigation, the relationship between bilingual education program type (i.e., dual language programs or exit programs) and English Language Learner reading and mathematics test scores was examined. Data were obtained on English Language Learners who were enrolled in Grades 3, 4, 5, and 6 in Texas public schools for the 2008-2009, 2009-2010, and 2010-2011 school years. In all 24 analyses, the reading and mathematics scores of English Language Learners who attended a dual language program were consistently higher than the scores of the English Language Learners who were enrolled in an exit program. As grade level increased from Grade 3 to Grade 6, the achievement gap in reading and in mathematics between dual language and exit programs also increased.
Diffusion-Weighted Imaging of Bone Marrow

In diffusion-weighted magnetic resonance imaging (DWI-MRI), the observed MRI signal intensity is attenuated by the self-diffusion of water molecules. DWI can provide information about the microscopic structure and organization of biological tissue and thus can depict various pathological changes of organs or tissues. DWI has been successfully used for the characterization of bone marrow alterations or lesions, and in particular for the differentiation of benign and malignant vertebral compression fractures. In this review article, the basics of DWI are introduced, and several pulse sequences that have been used for DWI of the bone marrow are described. Subsequently, an extensive overview about diffusion studies of the bone marrow and in particular of DWI of vertebral compression fractures is provided.
Clinical Gene Transfer Studies for Hemophilia B

Hemophilia B, a deﬁciency of functional factor IX (FIX), has been extensively explored as a model for gene transfer. Two U.S. Food and Drug Administration-approved clinical studies for hemophilia B have been undertaken, both using adeno-associated viral vectors (AAV). AAV vectors have tropism for liver, muscle, central nervous system, and the respiratory tract; both skeletal muscle and liver have been used as target tissues in the hemophilia B studies. In both studies, proof of principle was ﬁrst established in the hemophilia B dog model, with long-term expression of canine FIX at therapeutic levels achieved before clinical studies were initiated. In the AAV-FIX muscle trial, vector was introduced into skeletal muscle of the upper and lower extremities of eight human patients by direct intramuscular injection. Muscle biopsies taken 2 to 10 months postinjection demonstrated gene transfer and expression (by Southern blot and immunoﬂuorescence, respectively) in all patients, but circulating FIX levels were generally not > 1%, and escalation of dose to levels that proved therapeutic in animals was thwarted by feasibility issues regarding the number of injections required. Nevertheless, the study demonstrated that parenteral injection of AAV-FIX was safe at the doses tested, and could result in long-term expression of the transgene. Moreover, the general characteristics of transduction of human muscle were similar to those observed in other animal models. The safety and efﬁcacy data established in the ﬁrst trial formed the basis for a second trial in which AAV-FIX is administered systemically to target the liver. The liver study is currently ongoing, with six patients enrolled to date.
Advanced MR Imaging Techniques for Skeletal Muscle Evaluation

Diagnostic imaging procedures for muscle evaluation have typically provided basic information concerning gross anatomical change resulting from pathology. Up until recently the musculoskeletal radiologist has been fairly limited to using simple proton-density weighted fat-saturated and short tau inversion recovery magnetic resonance imaging scans for assessment of skeletal muscle. Recent advances, however, have resulted in development of newer scans and postprocessing methods that provide much more than gross muscle structure. Scans providing ﬁne structure, muscle function, and metabolism can easily be done using clinical scanners. Here we describe how diffusion tensor imaging (DTI) and blood oxygenation level-dependent (BOLD) imaging together can provide detailed information on muscle structural and functional changes. DTI is useful for visualizing muscle tears, and BOLD can be used for vascular insufﬁciency (e.g., compartment syndrome). In clinical sites that are gaining experience using these techniques, imaging of muscle pathology is becoming increasingly thorough. In the future, these methods will reduce the need for invasive approaches to study muscle pathology.
The Need for Investigations to Elucidate Causes and Effects of Abnormal Uterine Bleeding

This article describes a modern perspective on the basic investigations for abnormal uterine bleeding (AUB) in low-resource settings compared with a much more detailed approach for high-resource settings, bearing in mind issues of effectiveness and cost effectiveness. AUB includes any one or more of several symptoms, and it should be evaluated for the characteristics of the woman’s speciﬁc bleeding pattern, her ‘‘complaint’’ and the presence of other symptoms (especially pain), the impact on several aspects of body functioning and lifestyle, and the underlying cause(s), especially cancer. Ideally, the evaluation is comprehensive, considering each of the potential etiological domains deﬁned by the International Federation of Gynecology and Obstetrics PALM-COEIN system for the classiﬁcation of causes. However, the detail of the questions and the extent of investigations will be signiﬁcantly inﬂuenced by the technologies available and the time allotted for a consultation. In general, investigations should be performed only if they will make a material difference to the management approaches that can be offered. This should be an important consideration when a range of costly high-technology tests is accessible or when certain tests only have limited availability.
The Role of Corticosteroids in Chronic Obstructive Pulmonary Disease

Oral corticosteroids are powerful relatively nonspeciﬁc antiinﬂammatory agents with a range of well-characterized side effects. There is good evidence to show that they accelerate the rate of resolution of exacerbations of COPD and relapse is less likely if patients receive these drugs. Maintenance therapy with oral preparations is associated with worse mortality and skeletal muscle myopathy is a particular problem. Corticosteroids have little effect on biopsy proven inﬂammation or its surrogates in COPD and did not change the rate of decline of FEV 1 over a range of spirometric disease severity in a number of trials each lasting 3 years. However, meta-analysis of the data suggests that a small effect (up to 10ml /year) might be present. There is more consistent evidence for an effect on postbronchodilator FEV 1 with both ﬂuticasone propionate and budesonide. In patients with a postbronchodilator FEV 1 < 50% predicted where self-reported exacerbations become more common, inhaled corticosteroids can reduce the number of attacks. This effect is the major factor accounting for the reduction in deterioration in health status seen in patients who receive inhaled corticosteroids. Inhaled corticosteroids are much safer than oral therapy, although they do have a predictably higher incidence of candidiasis and hoarseness of the voice. Skin bruising is seen in patients with better lung function who use these drugs. Triamcinolone use is associated with reduction in bone density but this was not seen with budesonide. Combining an inhaled corticosteroid and a long-acting beta-agonist in the same inhaler increases the efﬁcacy of the latte drug in COPD patients, with a signiﬁcantly larger improvement in FEV 1 , a larger reduction in reported breathlessness, and a reduction in exacerbation numbers in those with severe disease where beta-agonists appear to be less effective. Inhaled corticosteroids are not suitable for monotherapy in COPD but can be helpfully combined with an inhaled bronchodilator in patients with symptomatic disease.