Miracle-dz/UniFAR-FTUs huggingface dataset:
Imaging electron-density fluctuations by multidimensional X-ray photon-coincidence diffraction

Significance X-ray diffraction is routinely used to monitor the ground-state electronic charge density of molecules or the motion of nuclei. In this work, we propose a spectroscopic measurement based on multidimensional photon-coincidence X-ray diffraction, which probes the correlation functions of the charge densities in momentum space. The inverse Fourier-transformed signal in real space, which is a combination of correlation functions of transition charge densities, allows us to identify the various scattering pathways that dominate the signal in momentum space and provides most valuable information on spontaneous electronic fluctuations and correlations. The ultrafast spontaneous electron-density fluctuation dynamics in molecules is studied theoretically by off-resonant multiple X-ray diffraction events. The time- and wavevector-resolved photon-coincidence signals give an image of electron-density fluctuations expressed through the four-point correlation function of the charge density in momentum space. A Fourier transform of the signal provides a real-space image of the multipoint charge-density correlation functions, which reveal snapshots of the evolving electron density in between the diffraction events. The proposed technique is illustrated by ab initio simulations of the momentum- and real-space inelastic scattering signals from a linear cyanotetracetylene molecule.
The power of the crowd: Prospects and pitfalls for citizen science in occupational health

Ashley C. Moore, Ashley A. Anderson, Marilee Long, Lauralynn T. McKernan, and John Volckens Department of Journalism and Media Communication, Colorado State University, Fort Collins, Colorado; National Institute for Occupational Safety and Health, Division of Surveillance, Hazard Evaluation & Field Studies, Cincinnati, Ohio; Department of Mechanical Engineering, Colorado State University, Fort Collins, Colorado
Insights into the structure–function relationship of both wild and mutant zinc transporter ZnT8 in human: a computational structural biology approach

Abstract Polymorphism rs13266634 in SLC30A8 causes abnormal synthesis, maturation and secretion of insulin, resulting in decrease in efficiency of glucose metabolism and diabetes. SLC30A8 encodes Zinc transporter 8 protein (ZnT8). Due to lack of NMR/crystal structures of complete ZnT8 transporter, insights into the structure, function and its interaction with different drugs is still not known. Therefore, in-silico methods were adopted in the present studies for predicting three-dimensional structure of ZnT8 transporter via comparative modelling approach and studying the impact of mutation (p.ARG325TRP) on architecture and function via simulation studies. Wild-type protein comprises 15 α-helix and 3 β-strands, while mutant consists of 12 α-helix and 2 β-strands, respectively. Interaction studies of mutant ZnT8 transporter with phytochemicals/drugs screened the best phytochemicals, which can retain the wild-type property. Molecular docking studies reveal that mutant proteins have better binding energy with ligands of LY-2608204, Roseoside, and Luzonoid B. Further molecular dynamic simulation analysis exhibited a strong binding of these ligands with mutant protein and displaying similar behaviour as that of wild type. ALA79, ILE80, and ARG215 are the common interacting amino acids with ligand in all three complexes. As the ligands passed ADMET tests, these may be utilized as anti-diabetic drugs in near future. Although earlier studies have reported anti-diabetic property of LY-2608204 and Roseoside, for the first time, this study reporting Luzonoid B may have anti-diabetic property besides elucidating the structure and functions of ZnT8 transporter.
Efficacy and Safety of Adjusted-Dose Prasugrel Compared With Clopidogrel in Japanese Patients With Acute Coronary Syndrome

Background: Prasugrel is an antiplatelet agent that shows more prompt, potent, and consistent platelet inhibition than clopidogrel. The objective of this study was to confirm the efficacy and safety of prasugrel at loading/maintenance doses of 20/3.75mg. Methods and Results: Japanese patients (n=1,363) with acute coronary syndrome undergoing percutaneous coronary intervention were randomized to either prasugrel (20/3.75mg) or clopidogrel (300/75mg), both in combination with aspirin (81–330mg for the first dose and 81–100mg/day thereafter), for 24–48 weeks. The primary efficacy endpoint was the incidence of major adverse cardiovascular events (MACE) at 24 weeks, defined as a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal ischemic stroke. We compared the incidence of MACE between the 2 groups using point estimates. Safety outcomes included the incidence of bleeding events until 2 weeks after the last dose. The incidence of MACE at 24 weeks was 9.4% in the prasugrel group and 11.8% in the clopidogrel group (risk reduction 23%, hazard ratio 0.77, 95% confidence interval 0.56–1.07). The incidence of non-coronary artery bypass graft-related major bleeding was similar in both groups (1.9% vs. 2.2%). Conclusions: Prasugrel 20/3.75mg was associated with a low incidence of ischemic events, similar to the results of TRITON-TIMI 38, and with a low risk of clinically serious bleeding in Japanese ACS patients. (Circ J 2014; 78: 1684–1692)
Comparative morphology of cheliceral muscles using high‐resolution X‐ray microcomputed‐tomography in palpimanoid spiders (Araneae, Palpimanoidea)

Spiders are important predators in terrestrial ecosystems, yet we know very little about the principal feeding structures of spiders, the chelicerae, which are functionally equivalent to “jaws” or “mandibles” and are an extremely important aspect of spider biology. In particular, members of Palpimanoidea have evolved highly unusual cheliceral morphologies and functions, including high‐speed, ballistic movements in mecysmaucheniid spiders, the fastest arachnid movements known thus far, and the elongated, highly maneuverable chelicerae of archaeids that use an attack‐at‐a‐distance strategy. Here, using micro‐Computed‐Tomography scanning techniques, we perform a comparative study to examine cheliceral muscle morphology in six different spider specimens representing five palpimanoid families. We provide a hypothesis for homology in palpimanoid cheliceral muscles and then compare and contrast these findings with previous studies on other non‐palpimanoid spiders. We document and discuss two sets of cheliceral muscles in palpimanoids that have not been previously observed in other spiders or which may represent a position shift compared to other spiders. In the palpimanoids, Palpimanus sp. , Huttonia sp. , and Colopea sp. showed similar cheliceral muscle anatomy. In Eriauchenius ranavalona, which has highly maneuverable chelicerae, some of the muscles have a more horizontal orientation, and there is a greater degree of cheliceral muscle divergence. In Zearchaea sp. and Aotearoa magna, some muscles have also shifted to a more horizontal orientation, and in Zearchaea sp. , a species with a ballistic, high‐speed predatory strike, there is a loss of cheliceral muscles. This research is a first step toward understanding cheliceral form and function across spiders.
Exercise Increases MAIT Cell Cytokine Expression but not Activation or Homing Markers.

Mucosal associated invariant T (MAIT) have properties of both the innate and adaptive immune systems but are an understudied population within exercise immunology. These lymphocytes aggregate at the mucous membranes, but it is unknown if submaximal exercise alters their circulating numbers or function. PURPOSE To determine the MAIT cell response to submaximal exercise on activation and homing marker expression and stimulated cytokine production. METHODS Twenty healthy, young, recreationally active males cycled for 40 min at 86% of VT following an overnight fast. Peripheral blood mononuclear cells were isolated and labelled to identify specific MAIT cell populations using flow cytometry. Cytokine production following stimulation was also determined. RESULTS MAIT cells were 2.9% of T-cells and increased to 3.9% after exercise and with recovery whereas cell numbers significantly increased by 91.5% following exercise before returning to resting levels. Chemokine and activation marker absolute cell number significantly increased while expression levels remained constant but the high levels of CCR5 may help direct MAIT cells to sites of inflammation. Following stimulation, TNFα expression significantly increased after exercise before returning to baseline with a similar trend for IFNγ. CONCLUSIONS MAIT cell numbers undergo a partial biphasic response following submaximal exercise and appear to be preferentially mobilized within T-cells; however, the magnitude of the submaximal response was attenuated relative to maximal exercise. Stimulated MAIT cells increase TNFα expression, indicating greater responsiveness to pathogens following acute exercise.
World Workshop on Oral Medicine VII: Biomarkers predicting lymphoma in the salivary glands of patients with Sjögren's syndrome-A systematic review.

OBJECTIVE To conduct a systematic review of studies exploring potential biomarkers for development, course, and efficacy of treatment of lymphomas in salivary glands of patients with Sjögren's syndrome. MATERIAL AND METHODS Eligible studies were identified through a comprehensive search of two databases, that is, PubMed and EMBASE. Quality of included articles was assessed with the "Quality In Prognosis Studies" (QUIPS) tool. The "CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies" (CHARMS) was used to facilitate data extraction. RESULTS Fifty-eight studies met the inclusion criteria. Only one study assessed the progression of lymphoma. Moderate risk of bias was detected in "outcome measurement," "study participation," and "study confounding" domains. Parotid gland enlargement, mixed monoclonal cryoglobulins, and low C4 levels represented strongest predictors of lymphoma development. The role of histological biomarkers, and specifically germinal centers, remains controversial. Clinical and methodological heterogeneity across studies precluded conduct of a meta-analysis. CONCLUSIONS Specific biomarkers in combination with clinical manifestations represent potential candidates for advancing precision medicine approaches to lymphoma prediction in patients with Sjögren's syndrome. Current focus has increasingly been on genetic and epigenetic markers as candidate predictors. Predictive accuracy of key biomarker candidates remains to be tested in well-designed prospectively followed Sjögren's syndrome cohorts.
CorNET: Deep Learning Framework for PPG-Based Heart Rate Estimation and Biometric Identification in Ambulant Environment

Advancements in wireless sensor network technologies have enabled the proliferation of miniaturized body-worn sensors, capable of long-term pervasive biomedical signal monitoring. Remote cardiovascular monitoring has been one of the beneficiaries of this development, resulting in non-invasive, photoplethysmography (PPG) sensors being used in ambulatory settings. Wrist-worn PPG, although a popular alternative to electrocardiogram, suffers from motion artifacts inherent in daily life. Hence, in this paper, we present a novel deep learning framework (CorNET) to efficiently estimate heart rate (HR) information and perform biometric identification (BId) using only a wrist-worn, single-channel PPG signal collected in ambulant environment. We have formulated a completely personalized data-driven approach, using a four-layer deep neural network. Two convolution neural network layers are used in conjunction with two long short-term memory layers, followed by a dense output layer for modeling the temporal sequence inherent within the pulsatile signal representative of cardiac activity. The final dense layer is customized with respect to the application, functioning as: regression layer—having a single neuron to predict HR; classification layer—two neurons that identify a subject among a group. The proposed network was evaluated on the TROIKA dataset having 22 PPG records collected during various physical activities. We achieve a mean absolute error of 1.47 ± 3.37 beats per minute for HR estimation and an average accuracy of 96% for BId on 20 subjects. CorNET was further evaluated successfully in an ambulant use-case scenario with custom sensors for two subjects.
Exploring the challenges of computational enzyme design by rebuilding the active site of a dehalogenase

Significance The goal of rational computer-aided enzyme design is hampered by the lack of knowledge of the maximum possible rate enhancement. We address this problem by considering the enzyme DhlA, which is naturally adapted for the degradation of dihalogenated ethanes. Using empirical valence bond calculations, we determine the effect of finding mutations that reduce the catalysis and then introducing mutations that restore catalysis. One of our predicted cycles is confirmed experimentally, while the other attempt remains inconclusive. We believe that the proposed strategy provides a very powerful way of validating and refining approaches for computational enzyme design. Rational enzyme design presents a major challenge that has not been overcome by computational approaches. One of the key challenges is the difficulty in assessing the magnitude of the maximum possible catalytic activity. In an attempt to overcome this challenge, we introduce a strategy that takes an active enzyme (assuming that its activity is close to the maximum possible activity), design mutations that reduce the catalytic activity, and then try to restore that catalysis by mutating other residues. Here we take as a test case the enzyme haloalkane dehalogenase (DhlA), with a 1,2-dichloroethane substrate. We start by demonstrating our ability to reproduce the results of single mutations. Next, we design mutations that reduce the enzyme activity and finally design double mutations that are aimed at restoring the activity. Using the computational predictions as a guide, we conduct an experimental study that confirms our prediction in one case and leads to inconclusive results in another case with 1,2-dichloroethane as substrate. Interestingly, one of our predicted double mutants catalyzes dehalogenation of 1,2-dibromoethane more efficiently than the wild-type enzyme.
L' apprenabilité des concepts évaluée au moyen d'un modèle multi-agent de la complexité des communications en mémoire de travail

This dissertation reports a study on the compressibility of information in working memory in order to define a metric of communicational complexity. In the multi-agent system described, the work of each agent represents that of a working memory unit. The multi-agent system cooperatively learns concepts based on Boolean dimensions. The objective of agents is to elaborate common knowledge from distributed one. The present model produces for each concept learned a minimal inter-agent communication protocol describing the processing load in working memory. Communication protocol complexity is seen as the result of two sources of complexity: the number of agents required (i. E. The Kolmogorov complexity) and the number of times these agents are used (i. E. Logical depth). 900 participants, from 4 years old to adulthood, completed rule-based classification tasks in 2, 3 and 4 dimensions. The computation of logical depth and the ordering of communication protocols in a lattice were confirmed.
Dysfunctional and Proinflammatory Regulatory T-Lymphocytes Are Essential for Adverse Cardiac Remodeling in Ischemic Cardiomyopathy

Background: Heart failure (HF) is a state of inappropriately sustained inflammation, suggesting the loss of normal immunosuppressive mechanisms. Regulatory T-lymphocytes (Tregs) are considered key suppressors of immune responses; however, their role in HF is unknown. We hypothesized that Tregs are dysfunctional in ischemic cardiomyopathy and HF, and they promote immune activation and left ventricular (LV) remodeling. Methods: Adult male wild-type C57BL/6 mice, Foxp3-diphtheria toxin receptor transgenic mice, and tumor necrosis factor (TNF) &agr; receptor-1 (TNFR1)−/− mice underwent nonreperfused myocardial infarction to induce HF or sham operation. LV remodeling was assessed by echocardiography as well as histological and molecular phenotyping. Alterations in Treg profile and function were examined by flow cytometry, immunostaining, and in vitro cell assays. Results: Compared with wild-type sham mice, CD4+Foxp3+ Tregs in wild-type HF mice robustly expanded in the heart, circulation, spleen, and lymph nodes in a phasic manner after myocardial infarction, beyond the early phase of wound healing, and exhibited proinflammatory T helper 1-type features with interferon-&ggr;, TNF&agr;, and TNFR1 expression, loss of immunomodulatory capacity, heightened proliferation, and potentiated antiangiogenic and profibrotic properties. Selective Treg ablation in Foxp3-diphtheria toxin receptor mice with ischemic cardiomyopathy reversed LV remodeling and dysfunction, alleviating hypertrophy and fibrosis, while suppressing circulating CD4+ T cells and systemic inflammation and enhancing tissue neovascularization. Tregs reconstituted after ablation exhibited restoration of immunosuppressive capacity and normalized TNFR1 expression. Treg dysfunction was also tightly coupled to Treg-endothelial cell contact- and TNFR1-dependent inhibition of angiogenesis and the mobilization and tissue infiltration of CD34+Flk1+ circulating angiogenic cells in a C-C chemokine ligand 5/C-C chemokine receptor 5-dependent manner. Anti-CD25-mediated Treg depletion in wild-type mice imparted similar benefits on LV remodeling, circulating angiogenic cells, and tissue neovascularization. Conclusions: Proinflammatory and antiangiogenic Tregs play an essential pathogenetic role in chronic ischemic HF to promote immune activation and pathological LV remodeling. The restoration of normal Treg function may be a viable approach to therapeutic immunomodulation in this disease.
Incomplete Multiview Spectral Clustering With Adaptive Graph Learning

In this paper, we propose a general framework for incomplete multiview clustering. The proposed method is the first work that exploits the graph learning and spectral clustering techniques to learn the common representation for incomplete multiview clustering. First, owing to the good performance of low-rank representation in discovering the intrinsic subspace structure of data, we adopt it to adaptively construct the graph of each view. Second, a spectral constraint is used to achieve the low-dimensional representation of each view based on the spectral clustering. Third, we further introduce a co-regularization term to learn the common representation of samples for all views, and then use the ${k}$ -means to partition the data into their respective groups. An efficient iterative algorithm is provided to optimize the model. Experimental results conducted on seven incomplete multiview datasets show that the proposed method achieves the best performance in comparison with some state-of-the-art methods, which proves the effectiveness of the proposed method in incomplete multiview clustering.
HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4+CD8+ thymocytes for CD4-lineage commitment

CD4 and CD8 T cells are vital components of the immune system. We found that histone deacetylase 3 (HDAC3) is critical for the development of CD4 T cells, as HDAC3-deficient DP thymocytes generate only CD8SP thymocytes in mice. In the absence of HDAC3, MHC Class II-restricted OT-II thymocytes are redirected to the CD8 cytotoxic lineage, which occurs with accelerated kinetics. Analysis of histone acetylation and RNA-seq reveals that HDAC3-deficient DP thymocytes are biased towards the CD8 lineage prior to positive selection. Commitment to the CD4 or CD8 lineage is determined by whether persistent TCR signaling or cytokine signaling predominates, respectively. Despite elevated IL-21R/γc/STAT5 signaling in HDAC3-deficient DP thymocytes, blocking IL-21R does not restore CD4 lineage commitment. Instead, HDAC3 binds directly to CD8-lineage promoting genes. Thus, HDAC3 is required to restrain CD8-lineage genes in DP thymocytes for the generation of CD4 T cells.
Caution is needed in interpreting HIV transmission chains by ultradeep sequencing

Objectives: Molecular epidemiology is applied to various aspects of HIV transmission analyses. With ultradeep sequencing (UDS), in-depth characterization of transmission episodes involving minority variants is permitted. We explored HIV-1 epidemiological linkage and evaluated characteristics of transmission dynamics and transmitted drug resistance (TDR) detection through the added value of UDS. Design: HIV pol gene fragments were sequenced by UDS and Sanger sequencing on samples of 70 HIV-1-infected, treatment-naive recently diagnosed MSM. Methods: Pairwise genetic distances and maximum likelihood phylogenies were computed. Transmission events were identified as clades with branch support at least 70% and intraclade genetic difference less than 4.5%. TDR mutations were recognized from the TDR consensus list. Transmission directionality, directness and inoculum size were inferred from tree topologies. Results: Both datasets concurred in the identification of seven transmission pairs and one cluster of three patients. With UDS, direction of transmission was inferred in four out of eight chains. Evidence for multiple founder viruses was found in two out of eight chains. No transmission of minority-resistant variants was evidenced. TDR mutations prevalence in protease and reverse transcriptase fragments was 4.3% with Sanger sequencing and 18.6% with UDS. Conclusion: Although Sanger sequencing and UDS identified the same transmission chains, UDS provided additional information on founder viruses, direction of transmission and levels of TDR. Nevertheless, topology of clusters was not always consistent across gene fragments, calling for a cautious interpretation of the data. Moreover, unobserved intermediary links cannot be excluded. Phylogenetic analysis use as a forensic technique for HIV transmission investigations is risky.
Bile acid analogues are activators of pyrin inflammasome

Bile acids are critical metabolites in the gastrointestinal tract and contribute to maintaining intestinal immune homeostasis through cross-talk with the gut microbiota. The conversion of bile acids by the gut microbiome is now recognized as a factor affecting both host metabolism and immune responses, but its physiological roles remain unclear. We conducted a screen for microbiome metabolites that would function as inflammasome activators and herein report the identification of 12-oxo-lithocholic acid (BAA485), a potential microbiome-derived bile acid metabolite. We demonstrate that the more potent analogue 11-oxo-12S-hydroxylithocholic acid methyl ester (BAA473) can induce secretion of interleukin-18 (IL-18) through activation of the inflammasome in both myeloid and intestinal epithelial cells. Using a genome-wide CRISPR screen with compound induced pyroptosis in THP-1 cells, we identified that inflammasome activation by BAA473 is pyrin-dependent (MEFV). To our knowledge, the bile acid analogues BAA485 and BAA473 are the first small molecule activators of the pyrin inflammasome. We surmise that pyrin inflammasome activation through microbiota-modified bile acid metabolites such as BAA473 and BAA485 plays a role in gut microbiota regulated intestinal immune response. The discovery of these two bioactive compounds may help to further unveil the importance of pyrin in gut homeostasis and autoimmune diseases.