Miracle-dz/UniFAR-FTUs huggingface dataset:
Adenylyl cyclase activating polypeptide reduces phosphorylation and toxicity of the polyglutamine-expanded androgen receptor in spinobulbar muscular atrophy

Adenylyl cyclase activating polypeptide modifies androgen receptor phosphorylation and spinal and bulbar muscular atrophy pathogenesis. Purging X-tra protein aggregates An indirect attack on the causative aberrant protein might treat a fatal X-linked neurodegenerative disease. Spinal bulbar muscular atrophy (SBMA) is a fatal neuromuscular disorder caused by a genetic defect that gives rise to polyglutamine (polyQ) expansion in the androgen receptor protein (polyQ-AR). The run of glutamine residues produces a toxic misfolded protein that aggregates in cells. The toxic effects can be mitigated by the protein’s phosphorylation status. Polanco et al. took advantage of this property to attack the disease at its molecular origin. In pinpointing the cell signaling pathways that modulate polyQ-AR phosphorylation, the authors found that the cell cycle regulatory protein cyclin-dependent kinase 2 (CDK2) phosphorylated polyQ-AR at Ser96 and that this phosphorylation event increased and stabilized the protein, and enhanced its toxicity. A second cellular function—the adenylyl cyclase (AC)/protein kinase A (PKA) signaling pathway—negatively regulated Ser96 phosphorylation, which blunted protein stability and, in turn, its toxicity. The authors then translated these findings by engineering an analog of pituitary adenylyl cyclase activating polypeptide (PACAP), which activates the AC/PKA pathway. When SBMA mice were given the analog intranasally, they displayed reduced Ser96 phosphorylation, enhanced polyQ-AR degradation, and—most exciting of all—an obliteration of disease outcomes. Spinobulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. SBMA belongs to the family of polyQ diseases, which are fatal neurodegenerative disorders mainly caused by protein-mediated toxic gain-of-function mechanisms and characterized by deposition of misfolded proteins in the form of aggregates. The neurotoxicity of the polyQ proteins can be modified by phosphorylation at specific sites, thereby providing the rationale for the development of disease-specific treatments. We sought to identify signaling pathways that modulate polyQ-AR phosphorylation for therapy development. We report that cyclin-dependent kinase 2 (CDK2) phosphorylates polyQ-AR specifically at Ser96. Phosphorylation of polyQ-AR by CDK2 increased protein stabilization and toxicity and is negatively regulated by the adenylyl cyclase (AC)/protein kinase A (PKA) signaling pathway. To translate these findings into therapy, we developed an analog of pituitary adenylyl cyclase activating polypeptide (PACAP), a potent activator of the AC/PKA pathway. Chronic intranasal administration of the PACAP analog to knock-in SBMA mice reduced Ser96 phosphorylation, promoted polyQ-AR degradation, and ameliorated disease outcome. These results provide proof of principle that noninvasive therapy based on the use of PACAP analogs is a therapeutic option for SBMA.
Genetic detection of lymph node micrometastases in patients with gastric carcinoma by multiple‐marker reverse transcriptase‐polymerase chain reaction assay

Some patients with gastric carcinoma experience local disease recurrence despite undergoing curative resection of the tumor and regional lymph nodes (LNs), suggesting the presence of occult micrometastases. To evaluate the presence of gastric carcinoma micrometastasis in patients with otherwise histologically negative LNs, the authors established and tested a multiple‐marker reverse transcriptase‐polymerase chain reaction (RT‐PCR) assay.
Incidence of Injury Among Adolescent Soccer Players: A Comparative Study of Artificial and Natural Grass Turfs

Objective:To investigate the incidence of acute injuries and soccer-related chronic pain from long-term training and during matches in adolescent players using natural grass turfs (NT) and artificial turfs (AT). Design:Case-controlled prospective study. Setting:Institutional-level Fédération Internationale de Football Association Medical Centre of Excellence. Participants:Youth soccer players (12-17 years of age) from 6 teams, with a predominant tendency to train on either NT or AT, were included. Of 332 players enrolled in this study, 301 remained to completion. Interventions:Medically diagnosed acute injuries and chronic pain were recorded daily by team health care staff throughout 2005, and reports were provided monthly to the authors. Assessment of Risk Factors:Noninvasive prospective study. Independent Variables:Age and turf type. Main Outcome Measures:Acute injuries per 1000 player hours on each surface and chronic complaints per 1000 player hours were evaluated according to frequency of surface used ≥80% of the time. Incidence rate ratio (IRR) of acute injuries and chronic complaints during play on NT and AT was calculated. Results:There was no significant difference in the incidence of acute injuries between the 2 surfaces during training and competition. However, the AT group showed a significantly higher incidence of low back pain during training (IRR, 1.62; 95% confidence interval, 1.06-2.48). Early adolescence and prolonged training hours were factors associated with an increased incidence of chronic pain in the AT group. Conclusion:Adolescent players routinely training on AT for prolonged periods should be carefully monitored, even on AT conforming to new standards.
Students’ evaluations about climate change

ABSTRACT Scientists regularly evaluate alternative explanations of phenomena and solutions to problems. Students should similarly engage in critical evaluation when learning about scientific and engineering topics. However, students do not often demonstrate sophisticated evaluation skills in the classroom. The purpose of the present study was to investigate middle school students’ evaluations when confronted with alternative explanations of the complex and controversial topic of climate change. Through a qualitative analysis, we determined that students demonstrated four distinct categories of evaluation when writing about the connections between evidence and alternative explanations of climate change: (a) erroneous evaluation, (b) descriptive evaluation, (c) relational evaluation, and (d) critical evaluation. These categories represent different types of evaluation quality. A quantitative analysis revealed that types of evaluation, along with plausibility perceptions about the alternative explanations, were significant predictors of postinstructional knowledge about scientific principles underlying the climate change phenomenon. Specifically, more robust evaluations and greater plausibility toward the scientifically accepted model of human-induced climate change predicted greater knowledge. These findings demonstrate that instruction promoting critical evaluation and plausibility appraisal may promote greater understanding of socio-scientific topics and increased use of scientific thinking when considering alternative explanations, as is called for by recent science education reform efforts.
Negligible Motion Artifacts in Scalp Electroencephalography (EEG) During Treadmill Walking

Recent mobile brain/body imaging (MoBI) techniques based on active electrode scalp electroencephalogram (EEG) allow the acquisition and real-time analysis of brain dynamics during active unrestrained motor behavior involving whole body movements such as treadmill walking, over-ground walking and other locomotive and non-locomotive tasks. Unfortunately, MoBI protocols are prone to physiological and non-physiological artifacts, including motion artifacts that may contaminate the EEG recordings. A few attempts have been made to quantify these artifacts during locomotion tasks but with inconclusive results due in part to methodological pitfalls. In this paper, we investigate the potential contributions of motion artifacts in scalp EEG during treadmill walking at three different speeds (1.5, 3.0, and 4.5 km/h) using a wireless 64 channel active EEG system and a wireless inertial sensor attached to the subject’s head. The experimental setup was designed according to good measurement practices using state-of-the-art commercially available instruments, and the measurements were analyzed using Fourier analysis and wavelet coherence approaches. Contrary to prior claims, the subjects’ motion did not significantly affect their EEG during treadmill walking although precaution should be taken when gait speeds approach 4.5 km/h. Overall, these findings suggest how MoBI methods may be safely deployed in neural, cognitive, and rehabilitation engineering applications.
Detecting Stepping Stones

One widely-used technique by which network attackers attain anonymity and complicate their apprehension is by employing stepping stones: they launch attacks not from their own computer but from intermediary hosts that they previously compromised. We develop an efficient algorithm for detecting stepping stones by monitoring a site's Internet access link. The algorithm is based on the distinctive characteristics (packet size, timing) of interactive traffic, and not on connection contents, and hence can be used to find stepping stones even when the traffic is encrypted. We evaluate the algorithm on large Internet access traces and find that it performs quite well. However, the success of the algorithm is tempered by the discovery that large sites have many users who routinely traverse stepping stones for a variety of legitimate reasons. Hence, stepping-stone detection also requires a significant policy component for separating allowable stepping-stone pairs from surreptitious access.
The Effect of Moving Windows on Software Effort Estimation: Comparative Study with CART

BACKGROUND: Several studies in software effort estimation have found that it can be effective to use a window of recent projects as training data for building an effort estimation model. The previous studies evaluated the use of a window with popular estimation models: linear regression (LR) and estimation by analogy (EbA). Many effort estimation models have been proposed, and the generality of windowing approach still remains uncertain for other effort estimation models, especially for those based on different theory. OBJECTIVE: This study investigates the effect of using a window on estimation accuracy with Classification and regression trees (CART). CART was recently found as a good performance method, and is based on a different theory from LR and EbA. METHOD: We compared the estimation accuracy of a windowing approach and growing approach with the same data set and procedure as the past studies. RESULTS: There is a difference in the estimation accuracy between using a window and not using a window. However, the effctive range of using windows on CART is narrower than that on LR. CONCLUSIONS: Windowing is also effective with CART. However, the range of effectiveness is narrower. The results contribute to the generality of the effectiveness of windowing approach.
PlantPAN 2.0: an update of plant promoter analysis navigator for reconstructing transcriptional regulatory networks in plants

Transcription factors (TFs) are sequence-specific DNA-binding proteins acting as critical regulators of gene expression. The Plant Promoter Analysis Navigator (PlantPAN; http://PlantPAN2.itps.ncku.edu.tw) provides an informative resource for detecting transcription factor binding sites (TFBSs), corresponding TFs, and other important regulatory elements (CpG islands and tandem repeats) in a promoter or a set of plant promoters. Additionally, TFBSs, CpG islands, and tandem repeats in the conserve regions between similar gene promoters are also identified. The current PlantPAN release (version 2.0) contains 16 960 TFs and 1143 TF binding site matrices among 76 plant species. In addition to updating of the annotation information, adding experimentally verified TF matrices, and making improvements in the visualization of transcriptional regulatory networks, several new features and functions are incorporated. These features include: (i) comprehensive curation of TF information (response conditions, target genes, and sequence logos of binding motifs, etc.), (ii) co-expression profiles of TFs and their target genes under various conditions, (iii) protein-protein interactions among TFs and their co-factors, (iv) TF-target networks, and (v) downstream promoter elements. Furthermore, a dynamic transcriptional regulatory network under various conditions is provided in PlantPAN 2.0. The PlantPAN 2.0 is a systematic platform for plant promoter analysis and reconstructing transcriptional regulatory networks.
CXCR4 Antagonist AMD3100 Modulates Claudin Expression and Intestinal Barrier Function in Experimental Colitis

Ulcerative colitis is a gastrointestinal disorder characterized by local inflammation and impaired epithelial barrier. Previous studies demonstrated that CXC chemokine receptor 4 (CXCR4) antagonists could reduce colonic inflammation and mucosal damage in dextran sulfate sodium (DSS)-induced colitis. Whether CXCR4 antagonist has action on intestinal barrier and the possible mechanism, is largely undefined. In the present study, the experimental colitis was induced by administration of 5% DSS for 7 days, and CXCR4 antagonist AMD3100 was administered intraperitoneally once daily during the study period. For in vitro study, HT-29/B6 colonic cells were treated with cytokines or AMD3100 for 24 h until assay. DSS-induced colitis was characterized by morphologic changes in mice. In AMD3100-treated mice, epithelial destruction, inflammatory infiltration, and submucosal edema were markedly reduced, and the disease activity index was also significantly decreased. Increased intestinal permeability in DSS-induced colitis was also significantly reduced by AMD3100. The expressions of colonic claudin-1, claudin-3, claudin-5, claudin-7 and claudin-8 were markedly decreased after DSS administration, whereas colonic claudin-2 expression was significantly decreased. Treatment with AMD3100 prevented all these changes. However, AMD3100 had no influence on claudin-3, claudin-5, claudin-7 and claudin-8 expression in HT-29/B6 cells. Cytokines as TNF-α, IL-6, and IFN-γ increased apoptosis and monolayer permeability, inhibited the wound-healing and the claudin-3, claudin-7 and claudin-8 expression in HT-29/B6 cells. We suggest that AMD3100 acted on colonic claudin expression and intestinal barrier function, at least partly, in a cytokine-dependent pathway.
Predicting disulfide connectivity from protein sequence using multiple sequence feature vectors and secondary structure

MOTIVATION Disulfide bonds are primary covalent crosslinks between two cysteine residues in proteins that play critical roles in stabilizing the protein structures and are commonly found in extracy-toplasmatic or secreted proteins. In protein folding prediction, the localization of disulfide bonds can greatly reduce the search in conformational space. Therefore, there is a great need to develop computational methods capable of accurately predicting disulfide connectivity patterns in proteins that could have potentially important applications. RESULTS We have developed a novel method to predict disulfide connectivity patterns from protein primary sequence, using a support vector regression (SVR) approach based on multiple sequence feature vectors and predicted secondary structure by the PSIPRED program. The results indicate that our method could achieve a prediction accuracy of 74.4% and 77.9%, respectively, when averaged on proteins with two to five disulfide bridges using 4-fold cross-validation, measured on the protein and cysteine pair on a well-defined non-homologous dataset. We assessed the effects of different sequence encoding schemes on the prediction performance of disulfide connectivity. It has been shown that the sequence encoding scheme based on multiple sequence feature vectors coupled with predicted secondary structure can significantly improve the prediction accuracy, thus enabling our method to outperform most of other currently available predictors. Our work provides a complementary approach to the current algorithms that should be useful in computationally assigning disulfide connectivity patterns and helps in the annotation of protein sequences generated by large-scale whole-genome projects. AVAILABILITY The prediction web server and Supplementary Material are accessible at http://foo.maths. uq.edu. au/~huber/disulfide
Chronic Low Dose Rate Ionizing Radiation Exposure Induces Premature Senescence in Human Fibroblasts that Correlates with Up Regulation of Proteins Involved in Protection against Oxidative Stress

The risks of non-cancerous diseases associated with exposure to low doses of radiation are at present not validated by epidemiological data, and pose a great challenge to the scientific community of radiation protection research. Here, we show that premature senescence is induced in human fibroblasts when exposed to chronic low dose rate (LDR) exposure (5 or 15 mGy/h) of gamma rays from a 137Cs source. Using a proteomic approach we determined differentially expressed proteins in cells after chronic LDR radiation compared to control cells. We identified numerous proteins involved in protection against oxidative stress, suggesting that these pathways protect against premature senescence. In order to further study the role of oxidative stress for radiation induced premature senescence, we also used human fibroblasts, isolated from a patient with a congenital deficiency in glutathione synthetase (GS). We found that these GS deficient cells entered premature senescence after a significantly shorter time of chronic LDR exposure as compared to the GS proficient cells. In conclusion, we show that chronic LDR exposure induces premature senescence in human fibroblasts, and propose that a stress induced increase in reactive oxygen species (ROS) is mechanistically involved.
Does Transendocardial Injection of Mesenchymal Stem Cells Improve Myocardial Function Locally or Globally?: An Analysis From the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) Randomized Trial

Rationale: Transendocardial stem cell injection (TESI) with mesenchymal stem cells improves remodeling in chronic ischemic cardiomyopathy, but the effect of the injection site remains unknown. Objective: To address whether TESI exerts its effects at the site of injection only or also in remote areas, we hypothesized that segmental myocardial scar and segmental ejection fraction improve to a greater extent in injected than in noninjected segments. Methods and Results: Biplane ventriculographic and endocardial tracings were recorded. TESI was guided to 10 sites in infarct-border zones. Sites were mapped according to the 17-myocardial segment model. As a result, 510 segments were analyzed in 30 patients before and 13 months after TESI. Segmental early enhancement defect (a measure of scar size) was reduced by TESI in both injected (−43.7±4.4%; n=95; P<0.01) and noninjected segments (−25.1±7.8%; n=148; P<0.001; between-group comparison P<0.05). Conversely, segmental ejection fraction (a measure of contractile performance) improved in injected scar segments (19.9±3.3–26.3±3.5%; P=0.003) but not in noninjected scar segments (21.3±2.6–23.5±3.2%; P=0.20; between-group comparison P<0.05). Furthermore, segmental ejection fraction in injected scar segments improved to a greater degree in patients with baseline segmental ejection fraction <20% (12.1±1.2–19.9±2.7%; n=18; P=0.003), versus <20% (31.7±3.4–35.5±3.3%; n=12; P=0.33, between-group comparison P<0.0001). Conclusions: These findings illustrate a dichotomy in regional responses to TESI. Although scar size reduction was evident in all scar segments, scar size reduction and ventricular functional responses preferentially occurred at the sites of TESI versus non-TESI sites. Furthermore, improvement was greatest when segmental left ventricular dysfunction was severe.
Generation of Donor-specific T Regulatory Type 1 Cells From Patients on Dialysis for Cell Therapy After Kidney Transplantation

Background T regulatory type 1 (Tr1) cell–mediated induction of tolerance in preclinical models of transplantation is remarkably effective. The clinical application of such a therapy in patients on dialysis undergoing kidney transplantation should take into account the possible alterations of the immune system observed in these patients. Herein, we aimed at testing the ability to generate donor-specific Tr1 cell–enriched lymphocytes from patients on dialysis on the waiting list for kidney transplantation. Methods The Tr1 cell–enriched lymphocytes were generated by coculturing interleukin-10–producing dendritic cells obtained from healthy donors with peripheral blood mononuclear cells (PBMCs) of patients on dialysis, following the same protocol used in a previous cell therapy clinical trial to prevent graft-versus-host disease. Alternatively, purified CD4+ T cells were used instead of total PBMCs. The ability to generate clinical-grade Tr1 cell–enriched products was defined by testing the reduced response to restimulation with mature dendritic cells generated from the original donor (i.e., anergy assay). Results The Tr1 cell–enriched medicinal products generated from PBMCs of patients on dialysis showed a low anergic phenotype, incompatible with their eventual clinical application. This was irrespective of HLA matching with the donor or the intrinsically reduced ability to proliferate in response to alloantigens. On the contrary, the use of purified CD4+ T cells isolated from patients on dialysis led to the generation of a highly anergic donor-specific medicinal product containing an average of 10% Tr1 cells. Conclusions The Tr1 cell–enriched medicinal products can be efficiently generated from patients on dialysis by carefully tailoring the protocol on the patients' immunological characteristics.
MS MARCO: A Human Generated MAchine Reading COmprehension Dataset

This paper presents our recent work on the design and development of a new, large scale dataset, which we name MS MARCO, for MAchine Reading COmprehension. This new dataset is aimed to overcome a number of well-known weaknesses of previous publicly available datasets for the same task of reading comprehension and question answering. In MS MARCO, all questions are sampled from real anonymized user queries. The context passages, from which answers in the dataset are derived, are extracted from real web documents using the most advanced version of the Bing search engine. The answers to the queries are human generated. Finally, a subset of these queries has multiple answers. We aim to release one million queries and the corresponding answers in the dataset, which, to the best of our knowledge, is the most comprehensive real-world dataset of its kind in both quantity and quality. We are currently releasing 100,000 queries with their corresponding answers to inspire work in reading comprehension and question answering along with gathering feedback from the research community.