Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural Basis of Phosphoinositide Binding to Kindlin-2 Protein Pleckstrin Homology Domain in Regulating Integrin Activation*

Background: Kindlin-2 is a key regulator of integrin activation. Results: Kindlin-2 contains a PH domain with a distinct binding pocket for phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) that promotes talin-mediated integrin activation. Conclusion: PIP3-mediated membrane binding of kindlin-2 is crucial for the cooperation of kindlin-2 with talin in activating integrin. Significance: Learning how kindlin-2 functions is crucial for understanding the integrin-mediated cell adhesion. Kindlins are a subclass of FERM-containing proteins that have recently emerged as key regulators of integrin receptor activation and signaling. As compared with the conventional FERM domain, the kindlin FERM domain contains an inserted pleckstrin homology (PH) domain that recognizes membrane phosphoinositides, including phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3). Using NMR spectroscopy, we show that PIP3 site-specifically binds to kindlin-2 PH with substantial chemical shift changes that are much larger than PIP2. This suggests an enhanced association of kindlin-2 with membrane as mediated by PIP3 upon its conversion from PIP2 by phosphoinositide-3 kinase, a known regulator of integrin activation. We determined the NMR structure of the kindlin-2 PH domain bound to the head group of PIP3, inositol 1,3,4,5-tetraphosphate (IP4). The structure reveals a canonical PH domain fold, yet with a distinct IP4 binding pocket that appears highly conserved for the kindlin family members. Functional experiments demonstrate that although wild type kindlin-2 is capable of cooperating with integrin activator talin to induce synergistic integrin αIIbβ3 activation, this ability is significantly impaired for a phosphoinositide binding-defective kindlin-2 mutant. These results define a specific PIP3 recognition mode for the kindlin PH domain. Moreover, they shed light upon a mechanism as to how the PH domain mediates membrane engagement of kindlin-2 to promote its binding to integrin and cooperation with talin for regulation of integrin activation.
Boosting the Value of Online Class Forum Facilities

We provide experimental results that help automate two related tasks around online instructional forum use. We showhow forum posts can automatically be evaluated for inclusion in a course specific frequently asked questions list. Wefurther show how computer algorithms can help instructorsidentify students who deserve course credit for their participation in the class forum. We deploy forum usage statisticsthat are readily available in most online forum facilities totrain two algorithms. For the FAQ inclusion task we train alogistic regression to an accuracy of 0.78. As ground truthwe asked teaching assistants of one course to provide expertjudgment for use in the regression training phase. For theacademic credit apportioning task we again used experts tocompare pairs of forum contributions. Using those judgmentswe trained a support vector machine to approximate the resulting rankings of posts. We reached a ranking accuracy of 76%, where accuracy reflects minimization of faulty pairwise rankings compared to the expert gold set.
YB-1 regulates tiRNA-induced Stress Granule formation but not translational repression

Stress-induced angiogenin (ANG)-mediated tRNA cleavage promotes a cascade of cellular events that starts with production of tRNA-derived stress-induced RNAs (tiRNAs) and culminates with enhanced cell survival. This stress response program relies on a subset tiRNAs that inhibit translation initiation and induce the assembly of stress granules (SGs), cytoplasmic ribonucleoprotein complexes with cytoprotective and pro-survival properties. SG-promoting tiRNAs bear oligoguanine motifs at their 5′-ends, assemble G-quadruplex-like structures and interact with the translational silencer YB-1. We used CRISPR/Cas9-based genetic manipulations and biochemical approaches to examine the role of YB-1 in tiRNA-mediated translational repression and SG assembly. We found that YB-1 directly binds to tiRNAs via its cold shock domain. This interaction is required for packaging of tiRNA-repressed mRNAs into SGs but is dispensable for tiRNA-mediated translational repression. Our studies reveal the functional role of YB-1 in the ANG-mediated stress response program.
The Involvement of the Chemokine Receptor CXCR2 in Neutrophil Recruitment in LPS‐Induced Inflammation and in Mycobacterium avium Infection

Knockout mice for CXC receptor 2 (CXCR2) chemokine receptor were used to study the recruitment of neutrophils during acute and chronic inflammatory responses. When treated with lipopolysaccharide (LPS), either intraperitoneally or intratracheally, these animals had a significant reduction in the neutrophil recruitment in the first 24–48 h as compared with control mice. During 15 days of intraperitoneal infection by Mycobacterium avium, the knockout mice showed significantly reduced numbers of neutrophils in the peritoneal cavity as compared with the control mice. In contrast, the recruitment of neutrophils to the lungs during an aerogenic M. avium infection was not affected by the CXCR2 mutation throughout the 60 days of the study. Finally, we could not find any impact of the mutation on the mycobacterial growth of the infected animals. These findings indicate that CXCR2 may be essentially involved in acute inflammatory responses where an early and rapid recruitment of neutrophils is observed.
Brief Report: Active Ingredients for Adherence to a Tracker-Based Physical Activity Intervention in Older Adults

Objectives: To identify factors associated with weekly adherence to a 12-week tracker-based activity intervention in older adults. Method: Using generalized linear mixed models in a secondary analysis (N = 35), we examined factors associated with weekly adherence (defined as wore the Jawbone Up24 tracker for ≥5 days and completed weekly calls). Factors examined included individual characteristics, gave and received virtual support, achieved step goals, barrier and task self-efficacy, and self-comment. Results: Participants’ (Mage = 61.7, SDage = 5.7) adherence changed from 86% (Week 1) to 74% (Week 12). Achieved the previous week’s goal (β = 1.13, p = .01) and received virtual support (β = 0.01, p = .02) significantly increased the odds of weekly adherence. Discussion: Achieved step goals and received virtual support were associated with improved adherence to our tracker-based activity intervention, which has promising potential to be translated into the clinical setting to promote active lifestyles.
Kinetic analysis of Dictyostelium discoideum myosin motor domains with glycine-to-alanine mutations in the reactive thiol region.

Three conserved glycine residues in the reactive thiol region of Dictyostelium discoideummyosin II were replaced by alanine residues. The resulting mutants G680A, G684A, and G691A were expressed in the soluble myosin head fragment M761-2R [Anson, M. , Geeves, M. A. , Kurzawa, S. E. , and Manstein, D. J. (1996) EMBO J. 15, 6069-6074] and characterized using transient kinetic methods. Mutant G691A showed no major alterations except for a marked increase in basal Mg2+-ATPase activity. Phosphate release seemed to be facilitated by this mutation, and the addition of actin to G691A stimulated ATP turnover not more than 3-fold. In comparison to M761-2R, mutant constructs G691A and G684A showed a 4-fold reduction in the rate of the ATP cleavage step. Most other changes in the kinetic properties of G684A were small ( approximately 2-fold). In contrast, substitution of G680 by an alanine residue led to large changes in nucleotide binding. Compared to M761-2R, rates of nucleotide binding were 20-30-fold slower and the affinity for mantADP was approximately 10-fold increased due to a 200-fold reduction in the dissociation rate constant of mantADP. The ATP-induced dissociation of actin from the acto.680A complex was normal, but the communication between ADP and actin binding was altered such that the two sites are thermodynamically uncoupled but kinetically actin still accelerates ADP release.
A Novel Transcriptional Activator, tubX, Is Required for the Stability of Bacillus sphaericus Mosquitocidal Plasmid pBsph

ABSTRACT Stable maintenance of the low-copy-number plasmid pBsph in Bacillus sphaericus requires a partitioning (par) system that consists of a filament-forming protein, B. sphaericus TubZ (TubZ-Bs); a centromere-binding protein, TubR-Bs; and a centromere-like DNA site, tubC, composed of three blocks (I, II, and III) of 12-bp degenerate repeats. Previous studies have shown that mini-pBsph replicons encoding the TubZ system are segregationally highly unstable, whereas the native pBsph is stably maintained. However, the mechanism underlying the stability discrepancy between pBsph and its minireplicon is poorly understood. Here orf187 (encoding TubX), a gene downstream of tubZ-Bs, was found to play a role in plasmid stabilization. Null mutation or overexpression of tubX resulted in a defect in pBsph stability and a significant decrease in the level of tubRZ-Bs expression, and the TubX-null phenotype was suppressed by ectopic expression of a wild-type copy of tubX and additional tubRZ-Bs. An electrophoresis mobility shift assay (EMSA) and a DNase I footprinting assay revealed that the TubX protein bound directly to five 8-bp degenerate repeats located in the par promoter region and that TubX competed with TubR-Bs for binding to the par promoter. Further studies demonstrated that TubX significantly stimulated the transcription of the par operon in the absence of tubR-Bs, and a higher level of gene activation was observed when tubR-Bs was present. These results suggested that TubX positively regulates tubRZ-Bs transcription by interfering with TubR-Bs-mediated repression and binding directly to the tubRZ-Bs promoter region.
Genetic Dissection of Pyrimidine Biosynthesis and Salvage in Leishmania donovani*

Background: Leishmania synthesize pyrimidine nucleotides via biosynthetic and salvage pathways. Results: Genetic blocks in pyrimidine biosynthesis and/or salvage can impact both life cycle stages of Leishmania. Conclusion: Pyrimidine biosynthesis and salvage both contribute to Leishmania homeostasis in animal infections. Significance: Functional characterization of pyrimidine pathways is crucial for understanding pyrimidine metabolism and validation of potential drug targets and vaccine strains. Protozoan parasites of the Leishmania genus express the metabolic machinery to synthesize pyrimidine nucleotides via both de novo and salvage pathways. To evaluate the relative contributions of pyrimidine biosynthesis and salvage to pyrimidine homeostasis in both life cycle stages of Leishmania donovani, individual mutant lines deficient in either carbamoyl phosphate synthetase (CPS), the first enzyme in pyrimidine biosynthesis, uracil phosphoribosyltransferase (UPRT), a salvage enzyme, or both CPS and UPRT were constructed. The Δcps lesion conferred pyrimidine auxotrophy and a growth requirement for medium supplementation with one of a plethora of pyrimidine nucleosides or nucleobases, although only dihydroorotate or orotate could circumvent the pyrimidine auxotrophy of the Δcps/Δuprt double knockout. The Δuprt null mutant was prototrophic for pyrimidines but could not salvage uracil or any pyrimidine nucleoside. The capability of the Δcps parasites to infect mice was somewhat diminished but still robust, indicating active pyrimidine salvage by the amastigote form of the parasite, but the Δcps/Δuprt mutant was completely attenuated with no persistent parasites detected after a 4-week infection. Complementation of the Δcps/Δuprt clone with either CPS or UPRT restored infectivity. These data establish that an intact pyrimidine biosynthesis pathway is essential for the growth of the promastigote form of L. donovani in culture, that all uracil and pyrimidine nucleoside salvage in the parasite is mediated by UPRT, and that both the biosynthetic and salvage pathways contribute to a robust infection of the mammalian host by the amastigote. These findings impact potential therapeutic design and vaccine strategies for visceral leishmaniasis.
Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency.

CONTEXT Primary ovarian insufficiency (POI) is caused by ovarian follicle depletion or follicle dysfunction. The phenotypic spectrum ranges from absence of pubertal maturation to early menopause. Genes involved in essential steps in chromosome synapsis and recombination during meiosis, such as synaptonemal complex central element 1 (SYCE1), have been shown to cause POI in animal models. We describe for the first time a homozygous mutation in SYCE1 in humans. OBJECTIVE To identify the genetic cause of POI in an Israeli Arab family with a consanguineous pedigree. SETTING AND DESIGN A family-based genetic study conducted at a tertiary medical center. PATIENTS Two daughters of consanguineous parents (first cousins) from a 13-member family were diagnosed with POI. Genotyping was performed in the index patients, their parents, and four unaffected siblings. INTERVENTION DNA from the affected sisters was subjected to whole-exome sequencing. The genotypes of interest were confirmed and genotypes of the additional family members were determined by Sanger sequencing. Genotyping was also performed in 90 ethnically matched control individuals. RESULTS A nonsense homozygous mutation (c.613C>T) was identified in the SYCE1 gene in both affected sisters. The parents and three brothers were heterozygous for the mutation, and an unaffected sister did not carry the mutation. The mutation was not identified in the DNA samples from the 90 control subjects. CONCLUSIONS Given the known function of the SYCE1 gene, we suggest that the nonsense mutation identified accounts for the POI phenotype. These results highlight the importance of the synaptonemal complex and meiosis in ovarian function.
Kullback–Leibler upper confidence bounds for optimal sequential allocation

We consider optimal sequential allocation in the context of the so-called stochastic multi-armed bandit model. We describe a generic index policy, in the sense of Gittins (1979), based on upper confidence bounds of the arm payoffs computed using the Kullback-Leibler divergence. We consider two classes of distributions for which instances of this general idea are analyzed: The kl-UCB algorithm is designed for one-parameter exponential families and the empirical KL-UCB algorithm for bounded and finitely supported distributions. Our main contribution is a unified finite-time analysis of the regret of these algorithms that asymptotically matches the lower bounds of Lai and Robbins (1985) and Burnetas and Katehakis (1996), respectively. We also investigate the behavior of these algorithms when used with general bounded rewards, showing in particular that they provide significant improvements over the state-of-the-art.
Network-on-Chip basierende Laufzeitsysteme für dynamische rekonfigurierbare Hardware

Die Kombination aus Standardprozessoren und rekonfigurierbarer Hardware hat sich in Forschung und kommerziellen Anwendungen mit schnell veranderlichen Parametern und Protokollen als flexible und leistungsfahige Architektur erwiesen. Jedoch werden die Moglichkeiten der dynamischen partiellen Rekonfigurierbarkeit noch nicht ausgenutzt, durch die eine weitere Steigerung der Anpassungsfahigkeit moglich ware. Die Kontrolle und Steuerung konnte der ohnehin schon vorhandene Prozessor und das darauf laufende Betriebssystem ubernehmen. Da aber Umsetzbarkeit und Leistung des Gesamtsystems erheblich von der Schnittstelle zwischen rekonfigurierbarer Hardware und nutzender Anwendung abhangt, sind hier skalierbare und zukunftsweisende Architekturen erforderlich. Im Rahmen dieses Beitrags werden Aspekte zur Erweiterung eines bestehenden Betriebssystems um dynamisch rekonfigurierbare Hardware und dessen Anbindung behandelt. Es wird ein Network-on-Chip basierter Protokollstack vorgestellt und ein Ausblick auf die prototypische Implementierung gegeben.
Type and severity of intimate partner violence and its relationship with PTSD in HIV-infected women

HIV has an impact on the presence and severity of both intimate partner violence (IPV) and posttraumatic stress disorder (PTSD) in infected women. However, the relationship of type and severity of IPV with PTSD in this population has not been adequately explored. We focus on the association between the type and severity of IPV and HIV status and PTSD in a sample of South African women. One hundred and sixty-nine women (114 HIV-positive and 55 HIV-negative controls), matched for geographical area, education, and socio-economic status, were recruited from HIV clinics. Clinical and demographic data were collected, including data on childhood trauma, other traumatic life events, IPV, posttraumatic stress symptoms, problematic alcohol use, and depressive symptoms. HIV-positive women had significantly more depressive symptoms, alcohol abuse, and childhood trauma exposure as well as significantly higher rates of PTSD (25.4%) when compared with uninfected women (10.9%). No significant group differences in the rate, pattern, and severity of physical, sexual, psychological, injury, and negotiation IPV were found. In logistic regression analysis, the rate and severity category of IPV did not significantly predict PTSD in HIV-positive women when childhood trauma and life events were controlled for. Our results indicate the need for screening for alcohol abuse, PTSD and depressive symptoms at HIV wellness, and ARV clinics. The high rates of PTSD in HIV-positive women indicate the need for specialized programs to manage PTSD and minimize negative sequelae in this population. These results also highlight the need for improved screening and prevention of childhood trauma and IPV both in infected and uninfected women.
Effects of a Parent-Child Interactive Program for Families on Reducing the Exposure of School-Aged Children to Household Smoking.

INTRODUCTION Parental smoking has been identified as the major source of children's exposure to environmental tobacco smoke (ETS). Therefore, parental involvement is critical in ETS exposure prevention programs. This study examined the effects of a parent-child interactive program on reducing children's exposure to ETS at home and enhancing parents' and children's prevention strategies. METHODS A clustered randomized controlled trial was administered to 75 families of school-aged children from six primary schools in New Taipei City, Taiwan. Families in the intervention group received a parent-child interactive intervention, and parents in the control group received written materials on tobacco hazards. Data on children's exposure and the prevention of children's exposure to ETS at home were obtained at baseline, 8-week, and 20-week or 6-month assessments. RESULTS The percentage of children with urine cotinine levels greater than or equal to 6 ng/ml was significantly lower in the intervention group than it was in the control group at both the 8-week and 6-month assessments. The intervention significantly reduced parental smoking in the presence of children and increased parents' prevention of children's ETS exposure and children's ETS avoidance behavior from the baseline to the 20-week assessment. CONCLUSIONS This is a preliminary study design aimed at creating a program for reducing children's ETS exposure at home. Further research to produce evidence supporting the application of the parent-child interactive program in primary schools is suggested. The theoretical basis of the intervention design can serve as a reference for nursing education and the design of health education programs.
A volumetric object detection framework with dual-energy CT

In this paper we present a new efficient framework that implements volumetric object detection for dual energy CT. First, we improve the original H-L curve table method with 28 elements, to get accurate material information by reconstruction. Then, we use the material information to localize suspicious regions and apply our volumetric object detection function. We reduce the dimension of the detection from 3D to 2D by using central slices, and use boosting 2d Haar features to achieve the 2D detection. Finally, we succeed in locating the target in our real world circumstance simulated baggage.
Artificial Intelligence Techniques for Modelling of Temperature in the Metal Cutting Process

© 2012 Tanikić and Despotović. , licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Artificial Intelligence Techniques for Modelling of Temperature in the Metal Cutting Process
Unifying analytic and statically-typed quasiquotes

Metaprograms are programs that manipulate (generate, analyze and evaluate) other programs. These tasks are greatly facilitated by quasiquotation, a technique to construct and deconstruct program fragments using quoted code templates expressed in the syntax of the manipulated language. We argue that two main flavors of quasiquotes have existed so far: Lisp-style quasiquotes, which can both construct and deconstruct programs but may produce code that contains type mismatches and unbound variables; and MetaML-style quasiquotes, which rely on static typing to prevent these errors, but can only construct programs. In this paper, we show how to combine the advantages of both flavors into a unified framework: we allow the construction, deconstruction and evaluation of program fragments while ensuring that generated programs are well-typed and well-scoped, a combination unseen in previous work. We formalize our approach as λ{}, a multi-stage calculus with code pattern matching and rewriting, and prove its type safety. We also present its realization in Squid, a metaprogramming framework for Scala, leveraging Scala’s expressive type system. To demonstrate the usefulness of our approach, we introduce speculative rewrite rules, a novel code transformation technique that makes decisive use of these capabilities, and we outline how it simplifies the design of some crucial query compiler optimizations.