Miracle-dz/UniFAR-FTUs huggingface dataset:
Potential Role of Cytochrome c and Tryptase in Psoriasis and Psoriatic Arthritis Pathogenesis: Focus on Resistance to Apoptosis and Oxidative Stress

Psoriasis (PsO) is an autoimmune disease characterized by keratinocyte proliferation, chronic inflammation and mast cell activation. Up to 42% of patients with PsO may present psoriatic arthritis (PsA). PsO and PsA share common pathophysiological mechanisms: keratinocytes and fibroblast-like synoviocytes are resistant to apoptosis: this is one of the mechanism facilitating their hyperplasic growth, and at joint level, the destruction of articular cartilage, and bone erosion and/or proliferation. Several clinical studies regarding diseases characterized by impairment of cell death, either due to apoptosis or necrosis, reported cytochrome c release from the mitochondria into the extracellular space and finally into the circulation. The presence of elevated cytochrome c levels in serum has been demonstrated in diseases as inflammatory arthritis, myocardial infarction and stroke, and liver diseases. Cytochrome c is a signaling molecule essential for apoptotic cell death released from mitochondria to the cytosol allowing the interaction with protease, as the apoptosis protease activation factor, which lead to the activation of factor-1 and procaspase 9. It has been demonstrated that this efflux from the mitochondria is crucial to start the intracellular signaling responsible for apoptosis, then to the activation of the inflammatory process. Another inflammatory marker, the tryptase, a trypsin-like serine protease produced by mast cells, is released during inflammation, leading to the activation of several immune cells through proteinase-activated receptor-2. In this review, we aimed at discussing the role played by cytochrome c and tryptase in PsO and PsA pathogenesis. To this purpose, we searched pathogenetic mechanisms in PUBMED database and review on oxidative stress, cytochrome c and tryptase and their potential role during inflammation in PsO and PsA. To this regard, the cytochrome c release into the extracellular space and tryptase may have a role in skin and joint inflammation.
Statistical inference of the rate of RNA polymerase II elongation by total RNA sequencing

Abstract Motivation Sequencing total RNA without poly-A selection enables us to obtain a transcriptomic profile of nascent RNAs undergoing transcription with co-transcriptional splicing. In general, the RNA-seq reads exhibit a sawtooth pattern in a gene, which is characterized by a monotonically decreasing gradient across introns in the 5’–3’ direction, and by substantially higher levels of RNA-seq reads present in exonic regions. Such patterns result from the process of underlying transcription elongation by RNA polymerase II, which traverses the DNA strand in a 5’–3’ direction as it performs a complex series of mRNA synthesis and processing. Therefore, data of sequenced total RNAs could be utilized to infer the rate of transcription elongation by solving the inverse problem. Results Though solving the inverse problem in total RNA-seq has the great potential, statistical methods have not yet been fully developed. We demonstrate what extent the newly developed method can be useful. The objective is to reconstruct the spatial distribution of transcription elongation rates in a gene from a given noisy, sawtooth-like profile. It is necessary to recover the signal source of the elongation rates separately from several types of nuisance factors, such as unobserved modes of co-transcriptionally occurring mRNA splicing, which exert significant influences on the sawtooth shape. The present method was tested using published total RNA-seq data derived from mouse embryonic stem cells. We investigated the spatial characteristics of the estimated elongation rates, focusing especially on the relation to promoter-proximal pausing of RNA polymerase II, nucleosome occupancy and histone modification patterns. Availability and implementation A C implementation of PolSter and sample data are available at https://github.com/yoshida-lab/PolSter. Supplementary information Supplementary data are available at Bioinformatics online.
A Multi-Stage Framework With Context Information Fusion Structure For Skin Lesion Segmentation

The computer-aided diagnosis (CAD) systems can highly improve the reliability and efficiency of melanoma recognition. As a crucial step of CAD, skin lesion segmentation has the unsatisfactory accuracy in existing methods due to large variability in lesion appearance and artifacts. In this work, we propose a framework employing multi-stage UNets (MS-UNet) in the auto-context scheme to segment skin lesion accurately end-to-end. We apply two approaches to boost the performance of MS-UNet. First, UNet is coupled with a context information fusion structure (CIFS) to integrate the low-level and context information in the multi-scale feature space. Second, to alleviate the gradient vanishing problem, we use deep supervision mechanism through supervising MS-UNet by minimizing a weighted Jaccard distance loss function. Three out of five commonly used performance metrics, including Jaccard index and Dice coefficient, show that our approach outperforms the state-of the-art deep learning based methods on the ISBI 2016 Skin Lesion Challenge dataset.
Visualization of Genomic Loci in Living Cells with BiFC‐TALE

Tracking the dynamics of genomic loci is essential for understanding a variety of cellular processes. However, earlier methods have all suffered from a low signal‐to‐background ratio (SBR), mainly caused by the background fluorescence from diffuse full‐length fluorescent proteins in the nucleus. We have developed a novel method (BiFC‐TALE) for labeling and tracking genomic loci in live mammalian cells, combining bimolecular fluorescence complementation (BiFC) and transcription activator–like effector (TALE) technologies. Since only the sequences‐targeted BiFC fragments can be pulled together by TALE modules to recombine intact fluorescent proteins, the background fluorescence in the living nucleus can be largely reduced, which significantly improves SBR. Using telomere and centromere labeling as examples, this unit describes in detail the design and implementation of BiFC‐TALE system. © 2018 by John Wiley & Sons, Inc.
Microbial Transplantation With Human Gut Commensals Containing CutC Is Sufficient to Transmit Enhanced Platelet Reactivity and Thrombosis Potential

Rationale: Gut microbes influence cardiovascular disease and thrombosis risks through the production of trimethylamine N-oxide (TMAO). Microbiota-dependent generation of trimethylamine (TMA)—the precursor to TMAO—is rate limiting in the metaorganismal TMAO pathway in most humans and is catalyzed by several distinct microbial choline TMA-lyases, including the proteins encoded by the cutC/D (choline utilization C/D) genes in multiple human commensals. Objective: Direct demonstration that the gut microbial cutC gene is sufficient to transmit enhanced platelet reactivity and thrombosis potential in a host via TMA/TMAO generation has not yet been reported. Methods and Results: Herein, we use gnotobiotic mice and a series of microbial colonization studies to show that microbial cutC-dependent TMA/TMAO production is sufficient to transmit heightened platelet reactivity and thrombosis potential in a host. Specifically, we examine in vivo thrombosis potential employing germ-free mice colonized with either high TMA-producing stable human fecal polymcrobial communities or a defined CutC-deficient background microbial community coupled with a CutC-expressing human commensal±genetic disruption of its cutC gene (ie, Clostridium sporogenes &Dgr;cutC). Conclusions: Collectively, these studies point to the microbial choline TMA-lyase pathway as a rational molecular target for the treatment of atherothrombotic heart disease.
High-Dimensional Profiling Reveals Heterogeneity of the Th17 Subset and Its Association With Systemic Immunomodulatory Treatment in Non-infectious Uveitis

Background: Non-infectious uveitis (NIU) is a severe intra ocular inflammation, which frequently requires prompt systemic immunosuppressive therapy (IMT) to halt the development of vision-threatening complications. IMT is considered when NIU cannot be treated with corticosteroids alone, which is unpredictable in advance. Previous studies have linked blood cell subsets to glucocorticoid sensitivity, which suggests that the composition of blood leukocytes may early identify patients that will require IMT. Objective: To map the blood leukocyte composition of NIU and identify cell subsets that stratify patients that required IMT during follow-up. Methods: We performed controlled flow cytometry experiments measuring a total of 37 protein markers in the blood of 30 IMT free patients with active non-infectious anterior, intermediate, and posterior uveitis, and compared these to 15 age and sex matched healthy controls. Results from manual gating were validated by automatic unsupervised gating using FlowSOM. Results: Patients with uveitis displayed lower relative frequencies of Natural Killer cells and higher relative frequencies of memory T cells, in particular the CCR6+ lineages. These results were confirmed by automatic gating by unsupervised clustering using FlowSOM. We observed considerable heterogeneity in memory T cell subsets and abundance of CXCR3-CCR6+ (Th17) cells between the uveitis subtypes. Importantly, regardless of the uveitis subtype, patients that eventually required IMT in the course of the study follow-up exhibited increased CCR6+ T cell abundance before commencing therapy. Conclusion: High-dimensional immunoprofiling in NIU patients shows that clinically distinct forms of human NIU exhibit shared as well as unique immune cell perturbations in the peripheral blood and link CCR6+ T cell abundance to systemic immunomodulatory treatment.
Crossing the Logarithmic Barrier for Dynamic Boolean Data Structure Lower Bounds

This paper proves the first super-logarithmic lower bounds on the cell probe complexity of dynamic boolean (a.k.a. decision) data structure problems, a long-standing milestone in data structure lower bounds. We introduce a new method for proving dynamic cell probe lower bounds and use it to prove a $\tilde{\Omega}(\text{lg}^{1.5}n)$ lower bound on the operational time of a wide range of boolean data structure problems, most notably, on the query time of dynamic range counting over $\mathbb{F}_{2}$ ([Pat07]). Proving an $\omega(\text{lg}\ n)$ lower bound for this problem was explicitly posed as one of five important open problems in the late Mihai Pătraşcu's obituary [Tho13]. This result also implies the first $\omega(\text{lg}\ n)$ lower bound for the classical 2D range counting problem, one of the most fundamental data structure problems in computational geometry and spatial databases. We derive similar lower bounds for boolean versions of dynamic polynomial evaluation and 2D rectangle stabbing, and for the (non-boolean) problems of range selection and range median. Our technical centerpiece is a new way of “weakly” simulating dynamic data structures using efficient one-way communication protocols with small advantage over random guessing. This simulation involves a surprising excursion to low-degree (Chebychev) polynomials which may be of independent interest, and offers an entirely new algorithmic angle on the “cell sampling” method of Panigrahy et al. [PTW10].
Incremental one‐class classification on stationary data stream using two‐quarter sphere

Data stream is a sequence of data that has unique features. In many data streams, data from one concept is available, and detection of other types of data in data stream is an essential task. One‐class classification is a famous approach to data classification when data from one class is accessible. The principal task of one‐class classification is separating input data in two different parts: target and outlier data. One of the main challenges concerning data classification on the stationary data streams is the response time, which causes negative effects on effective runtime. Most classifiers, that have been proposed on Rd feature space, solve a quadratic problem for classification that leads to extreme runtime increase. In this paper, an incremental one‐class classification on stationary data streams is proposed using two‐quarter sphere (IOCTQ) in order to achieve lower computation cost of classification time, and a linear optimization problem is solved. IOCTQ divides one data classification problem into two data classifiers, and each data point will be individually classified in one‐quarter sphere. The two‐quarter spheres can be run parallel. The results of the experiments have been compared with state‐of‐the‐art methods and show superiority of the IOCTQ method in classification accuracy and time complexity.
Label-Retaining, Putative Mesenchymal Stem Cells Contribute to Myometrial Repair During Uterine Involution.

Uterine remodeling during pregnancy is a fundamental, dynamic process required for successful propagation of eutherian species. The uterus can increase in size up to 40-fold during pregnancy, which is largely attributed to expansion of the myometrium by hyperplasia and hypertrophy. After pregnancy, the uterus repairs the remodeled or "damaged" tissue during uterine involution (INV). Little is known about this repair process, particularly the role of mesenchymal stem/progenitor cells. The objective of this study was to identify and characterize putative mesenchymal stem/progenitor cells in the murine myometrium using a combination of label retention and mesenchymal stem cell (MSC) marker expression and a pregnancy and uterine INV model. Tet-off transgenic mice with the Cre-lox system were used to specifically label mesenchymal cells (ie, myometrial and endometrial stromal cells) within the uterus while avoiding other cell types (eg, epithelial, immune, and endothelial cells) to identify slowly dividing cells and assess their stem cell qualities. We identified myometrial label-retaining cells (LRCs) that persisted for at least 3 months, expressed CD146 and CD140b (MSC markers), and proliferated at a higher rate during uterine INV compared with nonlabeled cells. The LRCs did not appear to express either estrogen receptor alpha or progesterone receptor, nor did the number of LRCs change at different estrous stages or in response to exogenous estradiol or progesterone administration, suggesting that LRCs were not involved in normal estrous cycling. The results from this study provide important insight into putative stem/progenitor cells in the myometrium and their possible role in uterine physiology.
Regrasp Planning Considering Bipedal Stability Constraints

This paper presents a Center of Mass (CoM) based manipulation and regrasp planner that implements stability constraints to preserve the robot balance. The planner provides a graph of IK-feasible, collision-free and stable motion sequences, constructed using an energy based motion planning algorithm. It assures that the assembly motions are stable and prevent the robot from falling while performing dexterous tasks in different situations. Furthermore, the constraints are also used to perform an RRT-inspired task-related stability estimation in several simulations. The estimation can be used to select between single-arm and dual-arm regrasping configurations to achieve more stability and robustness for a given manipulation task. To validate the planner and the task-related stability estimations, several tests are performed in simulations and real-world experiments involving the HRP5P humanoid robot, the 5th generation of the HRP robot family. The experiment results suggest that the planner and the task-related stability estimation provide robust behavior for the humanoid robot while performing regrasp tasks.
Synthesis and Evaluation of Spumigin Analogues Library with Thrombin Inhibitory Activity

Spumigins are marine natural products derived from cyanobacteria Nodularia spumigena, which mimics the structure of the d-Phe-Pro-Arg sequence and is crucial for binding to the active site of serine proteases thrombin and factor Xa. Biological evaluation of spumigins showed that spumigins with a (2S,4S)-4-methylproline central core represent potential lead compounds for the development of a new structural type of direct thrombin inhibitors. Herein, we represent synthesis and thrombin inhibitory activity of a focused library of spumigins analogues with indoline ring or l-proline as a central core. Novel compounds show additional insight into the structure and biological effects of spumigins. The most active analogue was found to be a derivative containing l-proline central core with low micromolar thrombin inhibitory activity.
Mice With Decreased Number of Interneurons Exhibit Aberrant Spontaneous and Oscillatory Activity in the Cortex

GABAergic (γ-aminobutyric acid) neurons are inhibitory neurons and protect neural tissue from excessive excitation. Cortical GABAergic neurons play a pivotal role for the generation of synchronized cortical network oscillations. Imbalance between excitatory and inhibitory mechanisms underlies many neuropsychiatric disorders and is correlated with abnormalities in oscillatory activity, especially in the gamma frequency range (30–80 Hz). We investigated the functional changes in cortical network activity in response to developmentally reduced inhibition in the adult mouse barrel cortex (BC). We used a mouse model that displays ∼50% fewer cortical interneurons due to the loss of Rac1 protein from Nkx2.1/Cre-expressing cells [Rac1 conditional knockout (cKO) mice], to examine how this developmental loss of cortical interneurons may affect basal synaptic transmission, synaptic plasticity, spontaneous activity, and neuronal oscillations in the adult BC. The decrease in the number of interneurons increased basal synaptic transmission, as examined by recording field excitatory postsynaptic potentials (fEPSPs) from layer II networks in the Rac1 cKO mouse cortex, decreased long-term potentiation (LTP) in response to tetanic stimulation but did not alter the pair-pulse ratio (PPR). Furthermore, under spontaneous recording conditions, Rac1 cKO brain slices exhibit enhanced sensitivity and susceptibility to emergent spontaneous activity. We also find that this developmental decrease in the number of cortical interneurons results in local neuronal networks with alterations in neuronal oscillations, exhibiting decreased power in low frequencies (delta, theta, alpha) and gamma frequency range (30–80 Hz) with an extra aberrant peak in high gamma frequency range (80–150 Hz). Therefore, our data show that disruption in GABAergic inhibition alters synaptic properties and plasticity, while it additionally disrupts the cortical neuronal synchronization in the adult BC.
Research participants as collaborators: Background, experience and policies from the PREVENT Dementia and EPAD programmes

Aim Despite the growing importance of public and patient involvement in biomedical research, comparatively little attention has been paid to the important role of research participants themselves. Our aim in this paper is to explore the impact research participant involvement has within the PREVENT and the European Prevention of Alzheimer’s Dementia (EPAD) projects. Method In this paper, we report the experiences of involving research participants as collaborators in prospective cohort studies exploring early changes in the brain as pathways towards and risks for dementia. We use minutes and feedback from members of the panel and steering committee to understand the experience and impact on the study. Results We describe the aims and structure of the participant panel established within the PREVENT Dementia study and highlight its contributions to the organisation, conduct and future of the study. Key areas of contribution identified include recruitment, inclusion of additional sub-studies, understanding the participant experience and contributing to the future of the study. Discussion We then describe how the PREVENT Dementia panel forms the basis for participant involvement within EPAD project.
IACO algorithm for weapon-target assignment problem in air combat

Weapon-target assignment (WTA) is a process of assigning weapons to targets based on the degree of threats. Taking into account the angle, speed, distance and ability threat, a WTA model is established for evaluation of the assignment. By integrating the improvements in path selection, pheromone update and pheromone concentration interval, a WTA algorithm based on improved ant colony optimization (IACO) is proposed. Compared with other three algorithms and classic ant colony optimization, the IACO requires fewer iterations and avoids local optima more effectively.
Applying Rapid Whole-Genome Sequencing To Predict Phenotypic Antimicrobial Susceptibility Testing Results among Carbapenem-Resistant Klebsiella pneumoniae Clinical Isolates

Standard antimicrobial susceptibility testing (AST) approaches lead to delays in the selection of optimal antimicrobial therapy. Here, we sought to determine the accuracy of antimicrobial resistance (AMR) determinants identified by Nanopore whole-genome sequencing in predicting AST results. ABSTRACT Standard antimicrobial susceptibility testing (AST) approaches lead to delays in the selection of optimal antimicrobial therapy. Here, we sought to determine the accuracy of antimicrobial resistance (AMR) determinants identified by Nanopore whole-genome sequencing in predicting AST results. Using a cohort of 40 clinical isolates (21 carbapenemase-producing carbapenem-resistant Klebsiella pneumoniae, 10 non-carbapenemase-producing carbapenem-resistant K. pneumoniae, and 9 carbapenem-susceptible K. pneumoniae isolates), three separate sequencing and analysis pipelines were performed, as follows: (i) a real-time Nanopore analysis approach identifying acquired AMR genes, (ii) an assembly-based Nanopore approach identifying acquired AMR genes and chromosomal mutations, and (iii) an approach using short-read correction of Nanopore assemblies. The short-read correction of Nanopore assemblies served as the reference standard to determine the accuracy of Nanopore sequencing results. With the real-time analysis approach, full annotation of acquired AMR genes occurred within 8 h from subcultured isolates. Assemblies sufficient for full resistance gene and single-nucleotide polymorphism annotation were available within 14 h from subcultured isolates. The overall agreement of genotypic results and anticipated AST results for the 40 K. pneumoniae isolates was 77% (range, 30% to 100%) and 92% (range, 80% to 100%) for the real-time approach and the assembly approach, respectively. Evaluating the patients contributing the 40 isolates, the real-time approach and assembly approach could shorten the median time to effective antibiotic therapy by 20 h and 26 h, respectively, compared to standard AST. Nanopore sequencing offers a rapid approach to both accurately identify resistance mechanisms and to predict AST results for K. pneumoniae isolates. Bioinformatics improvements enabling real-time alignment, coupled with rapid extraction and library preparation, will further enhance the accuracy and workflow of the Nanopore real-time approach.
Human-competitive Patches in Automatic Program Repair with Repairnator

Repairnator is a bot. It constantly monitors software bugs discovered during continuous integration of open-source software and tries to fix them automatically. If it succeeds to synthesize a valid patch, Repairnator proposes the patch to the human developers, disguised under a fake human identity. To date, Repairnator has been able to produce 5 patches that were accepted by the human developers and permanently merged in the code base. This is a milestone for human-competitiveness in software engineering research on automatic program repair.