Miracle-dz/UniFAR-FTUs huggingface dataset:
Exosomal Transport of Hepatocyte‐Derived Drug‐Modified Proteins to the Immune System

Idiosyncratic drug‐induced liver injury (DILI) is a rare, often difficult‐to‐predict adverse reaction with complex pathomechanisms. However, it is now evident that certain forms of DILI are immune‐mediated and may involve the activation of drug‐specific T cells. Exosomes are cell‐derived vesicles that carry RNA, lipids, and protein cargo from their cell of origin to distant cells, and they may play a role in immune activation. Herein, primary human hepatocytes were treated with drugs associated with a high incidence of DILI (flucloxacillin, amoxicillin, isoniazid, and nitroso‐sulfamethoxazole) to characterize the proteins packaged within exosomes that are subsequently transported to dendritic cells for processing. Exosomes measured between 50 and 100 nm and expressed enriched CD63. Liquid chromatography–tandem mass spectrometry (LC/MS‐MS) identified 2,109 proteins, with 608 proteins being quantified across all exosome samples. Data are available through ProteomeXchange with identifier PXD010760. Analysis of gene ontologies revealed that exosomes mirrored whole human liver tissue in terms of the families of proteins present, regardless of drug treatment. However, exosomes from nitroso‐sulfamethoxazole‐treated hepatocytes selectively packaged a specific subset of proteins. LC/MS‐MS also revealed the presence of hepatocyte‐derived exosomal proteins covalently modified with amoxicillin, flucloxacillin, and nitroso‐sulfamethoxazole. Uptake of exosomes by monocyte‐derived dendritic cells occurred silently, mainly through phagocytosis, and was inhibited by latrunculin A. An amoxicillin‐modified 9‐mer peptide derived from the exosomal transcription factor protein SRY (sex determining region Y)‐box 30 activated naïve T cells from human leukocyte antigen A*02:01–positive human donors. Conclusion: This study shows that exosomes have the potential to transmit drug‐specific hepatocyte‐derived signals to the immune system and provide a pathway for the induction of drug hapten‐specific T‐cell responses.
Activated Fibroblast Program Orchestrates Tumor Initiation and Progression; Molecular Mechanisms and the Associated Therapeutic Strategies

Neoplastic epithelial cells coexist in carcinomas with various non-neoplastic stromal cells, together creating the tumor microenvironment. There is a growing interest in the cross-talk between tumor cells and stromal fibroblasts referred to as carcinoma-associated fibroblasts (CAFs), which are frequently present in human carcinomas. CAF populations extracted from different human carcinomas have been shown to possess the ability to influence the hallmarks of cancer. Indeed, several mechanisms underlying CAF-promoted tumorigenesis are elucidated. Activated fibroblasts in CAFs are characterized as alpha-smooth muscle actin-positive myofibroblasts and actin-negative fibroblasts, both of which are competent to support tumor growth and progression. There are, however, heterogeneous CAF populations presumably due to the diverse sources of their progenitors in the tumor-associated stroma. Thus, molecular markers allowing identification of bona fide CAF populations with tumor-promoting traits remain under investigation. CAFs and myofibroblasts in wound healing and fibrosis share biological properties and support epithelial cell growth, not only by remodeling the extracellular matrix, but also by producing numerous growth factors and inflammatory cytokines. Notably, accumulating evidence strongly suggests that anti-fibrosis agents suppress tumor development and progression. In this review, we highlight important tumor-promoting roles of CAFs based on their analogies with wound-derived myofibroblasts and discuss the potential therapeutic strategy targeting CAFs.
Send Orders of Reprints at Reprints@benthamscience.org the Developing Utility of Zebrafish Models for Cognitive Enhancers Research

Whereas cognitive impairment is a common symptom in multiple brain disorders, predictive and high-throughput animal models of cognition and behavior are becoming increasingly important in the field of translational neuroscience research. In particular, reliable models of the cognitive deficits characteristic of numerous neurobehavioral disorders such as Alzheimer's disease and schizophrenia have become a significant focus of investigation. While rodents have traditionally been used to study cognitive phenotypes, zebrafish (Danio rerio) are gaining popularity as an excellent model to complement current translational neuroscience research. Here we discuss recent advances in pharmacological and genetic approaches using zebrafish models to study cognitive impairments and to discover novel cognitive enhancers and neuroprotective mechanisms.
Direct Interaction of the Spinal Muscular Atrophy Disease Protein SMN with the Small Nucleolar RNA-associated Protein Fibrillarin*

Disruption of the survival motor neuron (SMN) gene leads to selective loss of spinal motor neurons, resulting in the fatal human neurodegenerative disorder spinal muscular atrophy (SMA). SMN has been shown to function in spliceosomal small nuclear ribonucleoprotein (snRNP) biogenesis and pre-mRNA splicing. We have demonstrated that SMN also interacts with fibrillarin, a highly conserved nucleolar protein that is associated with all Box C/D small nucleolar RNAs and functions in processing and modification of rRNA. Fibrillarin and SMN co-immunoprecipitate from HeLa cell extracts indicating that the proteins exist as a complex in vivo. Furthermore, in vitro binding studies indicate that the interaction between SMN and fibrillarin is direct and salt-stable. We show that the glycine/arginine-rich domain of fibrillarin is necessary and sufficient for SMN binding and that the region of SMN encoded by exon 3, including the Tudor domain, mediates the binding of fibrillarin. Tudor domain missense mutations, including one found in an SMA patient, impair the interaction between SMN and fibrillarin (as well as the common snRNP protein SmB). Our results suggest a function for SMN in small nucleolar RNP biogenesis (akin to its known role as an snRNP assembly factor) and reveal a potential link between small nucleolar RNP biogenesis and SMA.
Matrix Mapping on Crossbar Memory Arrays with Resistive Interconnects and Its Use in In-Memory Compression of Biosignals

Recent advances in nanoscale resistive memory devices offer promising opportunities for in-memory computing with their capability of simultaneous information storage and processing. The relationship between current and memory conductance can be utilized to perform matrix-vector multiplication for data-intensive tasks, such as training and inference in machine learning and analysis of continuous data stream. This work implements a mapping algorithm of memory conductance for matrix-vector multiplication using a realistic crossbar model with finite cell-to-cell resistance. An iterative simulation calculates the matrix-specific local junction voltages at each crosspoint, and systematically compensates the voltage drop by multiplying the memory conductance with the ratio between the applied and real junction potential. The calibration factors depend both on the location of the crosspoints and the matrix structure. This modification enabled the compression of Electrocardiographic signals, which was not possible with uncalibrated conductance. The results suggest potential utilities of the calibration scheme in the processing of data generated from mobile sensing or communication devices that requires energy/areal efficiencies.
Genomes to natural products PRediction Informatics for Secondary Metabolomes (PRISM)

Microbial natural products are an invaluable source of evolved bioactive small molecules and pharmaceutical agents. Next-generation and metagenomic sequencing indicates untapped genomic potential, yet high rediscovery rates of known metabolites increasingly frustrate conventional natural product screening programs. New methods to connect biosynthetic gene clusters to novel chemical scaffolds are therefore critical to enable the targeted discovery of genetically encoded natural products. Here, we present PRISM, a computational resource for the identification of biosynthetic gene clusters, prediction of genetically encoded nonribosomal peptides and type I and II polyketides, and bio- and cheminformatic dereplication of known natural products. PRISM implements novel algorithms which render it uniquely capable of predicting type II polyketides, deoxygenated sugars, and starter units, making it a comprehensive genome-guided chemical structure prediction engine. A library of 57 tailoring reactions is leveraged for combinatorial scaffold library generation when multiple potential substrates are consistent with biosynthetic logic. We compare the accuracy of PRISM to existing genomic analysis platforms. PRISM is an open-source, user-friendly web application available at http://magarveylab.ca/prism/.
Gata3 is required for the functional maturation of inner hair cells and their innervation in the mouse cochlea

The physiological maturation of auditory hair cells and their innervation requires precise temporal and spatial control of cell differentiation. The transcription factor gata3 is essential for the earliest stages of auditory system development and for survival and synaptogenesis in auditory sensory afferent neurons. We show that during postnatal development in the mouse inner ear gata3 is required for the biophysical maturation, growth and innervation of inner hair cells; in contrast, it is required only for the survival of outer hair cells. Loss of gata3 in inner hair cells causes progressive hearing loss and accounts for at least some of the deafness associated with the human hypoparathyroidism, deafness and renal anomaly (HDR) syndrome. The results show that gata3 is critical for later stages of mammalian auditory system development where it plays distinct, complementary roles in the coordinated maturation of sensory hair cells and their innervation.
Coordinates transformations in nonlinear time-delay systems

When considering nonlinear time delay systems, the definition of an invertible change of coordinates is no more granted. Starting from a set of n - 1 exact differentials independent over K(δ] in the variables x(t), . , x(t-sD), with D a constant commensurate delay and x an n dimensional variable, we give necessary and sufficient conditions for the existence of an exact one-form such that to get a basis for spanK(δ]{dx[0]}.
Parent Education and Training for autism spectrum disorders: Scoping the evidence

Empowering families of children with autism spectrum disorder through education and training is best practice. A wide range of Parent Education and Training programmes are delivered around the globe, but there is limited knowledge about the characteristics of these programmes, or about the research methods and outcomes used to evaluate them, particularly in countries outside the United States. We, therefore, performed a scoping review of all peer-reviewed Parent Education and Training publications outside the United States. A search was conducted between March and May 2017. Four reviewers extracted data and performed a mixed-methods quality appraisal of publications. Thirty-seven publications representing 32 unique programmes were identified. Publications described a highly diverse range of Parent Education and Training programmes across 20 countries and all continents except South America. The majority were group-based, but varied significantly in goals, modalities and duration. The majority of studies (86.4%) reported positive outcomes in relation to the core study objectives and only two studies reported some negative findings. Quality appraisal rated only 27% of studies to have met all the methodological quality criteria. Implementation factors such as manualisation, fidelity and cost were commented on infrequently. In spite of the clear need for Parent Education and Training programmes, our findings show that the research evidence-base in autism spectrum disorder outside the United States is relatively small, non-representative and in need of methodological quality improvements.
Dynamic Game Balancing: An Evaluation of User Satisfaction

User satisfaction in computer games seems to be influenced by game balance, the level of challenge faced by the user. This work presents an evaluation, performed by human players, of dynamic game balancing approaches. The results indicate that adaptive approaches are more effective. This paper also enumerates some issues encountered in evaluating users' satisfaction, in the context of games, and depicts some learned lessons.
Muscle-like fatigue-resistant hydrogels by mechanical training

Significance The combinational muscle-like properties including high fatigue resistance, high strength, superior compliance, and high water content are highly desirable for various applications of soft biomaterials such as hydrogels. These combinational properties, largely attributed to the aligned nanofibrils in natural muscles, have not been achieved in synthetic hydrogels. Here, we propose a strategy of mechanical training to impart hydrogels with an extremely high fatigue threshold (1,250 J/m2) and strength (5.2 MPa), while maintaining a high water content (84 wt %) and a low Young’s modulus (200 kPa), reaching combinational muscle-like properties with aligned nanofibrillar architectures. We further achieve isotropically enhanced properties by three-dimensionally printing the hydrogels into microstructures. Skeletal muscles possess the combinational properties of high fatigue resistance (1,000 J/m2), high strength (1 MPa), low Young’s modulus (100 kPa), and high water content (70 to 80 wt %), which have not been achieved in synthetic hydrogels. The muscle-like properties are highly desirable for hydrogels’ nascent applications in load-bearing artificial tissues and soft devices. Here, we propose a strategy of mechanical training to achieve the aligned nanofibrillar architectures of skeletal muscles in synthetic hydrogels, resulting in the combinational muscle-like properties. These properties are obtained through the training-induced alignment of nanofibrils, without additional chemical modifications or additives. In situ confocal microscopy of the hydrogels’ fracturing processes reveals that the fatigue resistance results from the crack pinning by the aligned nanofibrils, which require much higher energy to fracture than the corresponding amorphous polymer chains. This strategy is particularly applicable for 3D-printed microstructures of hydrogels, in which we can achieve isotropically fatigue-resistant, strong yet compliant properties.
The Pedigrees of DOGs (Dust-Obscured Galaxies)

A simple mid-infrared-to-optical color criterion of R-[24]>14 Vega mag results in a robust selection of approximately half of the redshift 2 ultraluminous infrared galaxy (ULIRG) population. These `Dust-Obscured Galaxies', or DOGs, have many properties that suggest that they are good candidates for systems in a transition phase between gas-rich mergers and QSOs.
THE DETERMINANTS OF THE SEPARATION HAZARD IN A MODEL WITH LEARNING AND TIME-VARYING MATCH QUALITY THIS VERSION : DECEMBER 2007

Abstract. People and organizations enter relationships, learn about them, adapt to them, and sometimes decide to leave them. This paper develops a learning model of relationship dissolution. The model also allows relationship quality to vary over time, following an AR(1) process. The model nests two possible assumptions about the causes of relationship dissolution. One is that relationships dissolve when agents find out that they are in fact bad (pure learning model). The other is that relationships dissolve because they change over time (pure shocks model). This paper analyzes the effect of parameters on agents’ separation decision and the resulting separation hazard. It also examines how one can empirically distinguish between the pure learning model, the pure shocks model, and a mixed model. Observing an increasing and then decreasing separation hazard is not sufficient evidence for the pure learning model. The shape of the variance of the transition function is enough to distinguish between the three models. One can also use the impact of a bad observation on the separation hazard to make such a distinction.
Algorithmic Stability and Hypothesis Complexity

We introduce a notion of algorithmic stability of learning algorithms---that we term \emph{argument stability}---that captures stability of the hypothesis output by the learning algorithm in the normed space of functions from which hypotheses are selected. The main result of the paper bounds the generalization error of any learning algorithm in terms of its argument stability. The bounds are based on martingale inequalities in the Banach space to which the hypotheses belong. We apply the general bounds to bound the performance of some learning algorithms based on empirical risk minimization and stochastic gradient descent.
Single-Field Non-Mydriatic Fundus Photography for Diabetic Retinopathy Screening: A Systematic Review and Meta-Analysis

Purpose: Single-field non-mydriatic fundus photography (NMFP) has been used to detect diabetic retinopathy (DR) in many studies; however, its value in a general clinical setting has not been established. Here we performed a meta-analysis to evaluate its diagnostic effectiveness. Method: We systematically searched PubMed, EMBASE, and Cochrane databases for candidate studies published through May 19, 2018. A random-effect model was used to calculate the diagnostic indicators including the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), area under the curve (AUC), and 95% confidence intervals. Results: Ten prospective studies were ultimately included. The pooled sensitivity, specificity, PLR, NLR, and DOR were 0.68, 0.94, 11.2, 0.34 and 33, respectively. The AUC was 0.88. Subgroup analysis showed that single-field NMFP had a respective sensitivity and specificity of 0.73 and 0.91 when compared to standard 7-field mydriatic stereoscopic photography (7SF), and 0.54 and 0.98 when compared to slit-lamp biomicroscopy as reference standard. Conclusions: Single-field NMFP is inadequate to detect DR. Additionally, it showed higher sensitivity and lower specificity when 7SF was used as reference standard, as compared to slit-lamp biomicroscopy, suggesting that different reference standards used in DR screening might have affected the diagnostic results.
Allometry and advancing age significantly structure craniofacial variation in adult female baboons

Primate craniofacial growth is traditionally assumed to cease upon maturation or at least be negligible, whereas bony remodeling is typically associated with advanced adult age and, in particular, tooth loss. Therefore, size and shape of the craniofacial skeleton of young and middle‐aged adults should be stable. However, research on both modern and historic human samples suggests that portions of the CFS exhibit age‐related changes in mature individuals, both related to and independent of tooth loss. These results demonstrate that the age‐category ‘adult’ is heterogeneous, containing individuals demonstrating post‐maturational age‐related variation, but the topic remains understudied outside of humans and in the cranial vault and base. Our research quantifies variation in a sample of captive adult female baboons (n = 97) in an effort to understand how advancing age alters the mature CFS. Craniometric landmarks and sliding semilandmarks were collected from computed tomography (CT) scans of adult baboons aged 7–32 years old. To determine whether craniofacial morphology is sensitive to aging mechanisms and whether any such effects are differentially distributed throughout the cranium, geometric morphometric techniques were employed to compare the shapes of various cranial regions among individuals of increasing age. Unexpectedly, the biggest form differences were observed between young and middle‐aged adults, rather than between adults with full dentitions and those with some degree of tooth loss. Shape variation was greatest in masticatory and nuchal musculature attachment areas. Our results indicate that the craniofacial skeleton changes form during adulthood in baboons, raising interesting questions about the molecular and biological mechanisms governing these changes.
The N-terminal region of the ϵ subunit from cyanobacterial ATP synthase alone can inhibit ATPase activity

ATP hydrolysis activity catalyzed by chloroplast and proteobacterial ATP synthase is inhibited by their ϵ subunits. To clarify the function of the ϵ subunit from phototrophs, here we analyzed the ϵ subunit–mediated inhibition (ϵ-inhibition) of cyanobacterial F1-ATPase, a subcomplex of ATP synthase obtained from the thermophilic cyanobacterium Thermosynechococcus elongatus BP-1. We generated three C-terminal α-helix null ϵ-mutants; one lacked the C-terminal α-helices, and in the other two, the C-terminal conformation could be locked by a disulfide bond formed between two α-helices or an α-helix and a β-sandwich structure. All of these ϵ-mutants maintained ATPase-inhibiting competency. We then used single-molecule observation techniques to analyze the rotary motion of F1-ATPase in the presence of these ϵ-mutants. The stop angular position of the γ subunit in the presence of the ϵ-mutant was identical to that in the presence of the WT ϵ. Using magnetic tweezers, we examined recovery from the inhibited rotation and observed restoration of rotation by 80° forcing of the γ subunit in the case of the ADP-inhibited form, but not when the rotation was inhibited by the ϵ-mutants or by the WT ϵ subunit. These results imply that the C-terminal α-helix domain of the ϵ subunit of cyanobacterial enzyme does not directly inhibit ATP hydrolysis and that its N-terminal domain alone can inhibit the hydrolysis activity. Notably, this property differed from that of the proteobacterial ϵ, which could not tightly inhibit rotation. We conclude that phototrophs and heterotrophs differ in the ϵ subunit–mediated regulation of ATP synthase.
Direct oral anticoagulants for atrial fibrillation in patients with congenital factor VII deficiency

The management of anticoagulant therapy (OAT) in patients with factor VII (FVII) deficiency is a very challenging clinical issue, as warfarin further reduces FVII levels, thus potentially increasing bleeding risk. On the other hand, the International Normalized Ratio test is misleading in such patients, as they do not reflect the actual level of global inhibition of the coagulation system. We report here three cases of patients with a moderate FVII deficiency and receiving direct oral anticoagulants (DOAC) for prevention of cardioembolism in atrial fibrillation. Of note, two of them experienced a treatment failure while on warfarin, while DOAC treatment was not associated with thrombotic or hemorrhagic adverse events. DOAC are very attractive for the management of OAT in FVII deficient patients, because they do not require monitoring by tests affected by the inherited defect, and their mechanism of action is FVII‐independent.
Weak repetitions in strings

A weak repetition in a string consists of two or more adjacent substrings which are permutations of each other. We describe a straightforward \Theta(n 2 ) algorithm which computes all the weak repetitions in a given string of length n defined on an arbitrary alphabet A. Using results on Fibonacci and other simple strings, we prove that this algorithm is asymptotically optimal over all known encodings of the output.