Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular dynamics simulations of the free and inhibitor-bound cruzain systems in aqueous solvent: insights on the inhibition mechanism in acidic pH

The major cysteine protease of Trypanosoma cruzi, cruzain (CRZ), has been described as a therapeutic target for Chagas’ disease, which affects millions of people worldwide. Thus, a series of CRZ inhibitors has been studied, including a new competitive inhibitor, Nequimed176 (NEQ176). Nevertheless, the structural and dynamic basis for CRZ inhibition remains unclear. Hoping to contribute to this ever-growing understanding of timescale dynamics in the CRZ inhibition mechanism, we have performed the first study using 100 ns of molecular dynamics (MD) simulations of two CRZ systems in an aqueous solvent under pH 5.5: CRZ in the apo form (ligand free) and CRZ complexed to NEQ176. According to the MD simulations, the enzyme adopts an open conformation in the apo form and a closed conformation in the NEQ176–CRZ complex. We also suggest that this closed conformation is related to the hydrogen-bonding interactions between NEQ176 and CRZ, which occurs through key residues, mainly Gly66, Met68, Asn69, and Leu160. In addition, the cross-correlation analysis shows evidence of the correlated motions among Ala110–Asp140, Leu160–Gly189, and Glu190–Gly215 subdomains, as well as, the movements related to Ala1–Thr59 and Asp60–Pro90 regions seem to be crucial for CRZ activity.
Effects of Chemical Form of Selenium on Plasma Biomarkers in a High-Dose Human Supplementation Trial

Intervention trials with different forms of selenium are under way to assess the effects of selenium supplements on the incidence of cancer and other diseases. Plasma selenium biomarkers respond to selenium administration and might be useful for assessing compliance and safety in these trials. The present study characterized the effects of selenium supplementation on plasma selenium biomarkers and urinary selenium excretion in selenium-replete subjects. Moderate (∼200 μg/d) to large (∼600 μg/d) selenium supplements in the forms sodium selenite, high-selenium yeast (yeast), and l-selenomethionine (selenomethionine) were administered. Subjects were randomized into 10 groups (placebo and three dose levels of each form of selenium). Plasma biomarkers (selenium concentration, selenoprotein P concentration, and glutathione peroxidase activity) were determined before supplementation and every 4 weeks for 16 weeks. Urinary selenium excretion was determined at 16 weeks. Supplementation with selenomethionine and yeast raised the plasma selenium concentration in a dose-dependent manner. Selenite did not. The increased selenium concentration correlated with the amount of selenomethionine administered. Neither glutathione peroxidase activity nor selenoprotein P concentration responded to selenium supplementation. Urinary selenium excretion was greater after selenomethionine than after selenite, with excretion after yeast being intermediate and not significantly different from either of the other two. We conclude that plasma selenium concentration is useful in monitoring compliance and safety of selenium supplementation as selenomethionine but not as selenite. Plasma selenium seems to reflect the selenomethionine content of yeast but not the other yeast selenium forms. As judged by urinary selenium excretion, selenium in the form of selenomethionine is better absorbed than selenite. (Cancer Epidemiol Biomarkers Prev 2006;15(4):804–10)
Endoscopic band ligation of Dieulafoy-like lesions in the upper gastrointestinal tract.

BACKGROUND AND STUDY AIMS Endoscopic band ligation (EBL) is currently considered to be the treatment of choice for esophageal variceal bleeding. This study reports on the efficacy and safety of EBL in patients with Dieulafoy-like bleeding lesions in the upper gastrointestinal tract. PATIENTS AND METHODS Between December 1994 and February 2000, 23 patients with upper gastrointestinal tract hemorrhage (median age 58, range 28-75) were treated using EBL. EBL was used as a rescue therapy in four patients and as the initial treatment in 19 patients. RESULTS The site of bleeding was the stomach in 10 patients, Billroth II anastomosis in 10, the first part of the duodenum in one, the second part of the duodenum in one, and the jejunum in one patient. Endoscopic band ligation was successful in 22 of the 23 patients. The remaining patient, a young man with a Dieulafoy-like lesion in the jejunum, had recurrent bleeding on day 5 after EBL and underwent elective surgery. CONCLUSIONS Endoscopic band ligation is an effective and safe endoscopic treatment for Dieulafoy-like lesions. It is easy to use and relatively inexpensive.
Effective Chemoimmunotherapy with Anti-TGFβ Antibody and Cyclophosphamide in a Mouse Model of Breast Cancer

TGFβ is reportedly responsible for accumulation of CD4+Foxp3+ regulatory T cells (Tregs) in tumor. Thus, we treated mouse 4T1 mammary carcinoma with 1D11, a neutralizing anti-TGFβ (1,2,3) antibody. The treatment delayed tumor growth, but unexpectedly increased the proportion of Tregs in tumor. In vitro, 1D11 enhanced while TGFβ potently inhibited the proliferation of Tregs. To enhance the anti-tumor effects, 1D11 was administered with cyclophosphamide which was reported to eliminate intratumoral Tregs. This combination resulted in long term tumor-free survival of up to 80% of mice, and the tumor-free mice were more resistant to re-challenge with tumor. To examine the phenotype of tumor infiltrating immune cells, 4T1-tumor bearing mice were treated with 1D11 and a lower dose of cyclophosphamide. This treatment markedly inhibited tumor growth, and was accompanied by massive infiltration of IFNγ-producing T cells. Furthermore, this combination markedly decreased the number of splenic CD11b+Gr1+ cells, and increased their expression levels of MHC II and CD80. In a spontaneous 4T1 lung metastasis model with resection of primary tumor, this combination therapy markedly increased the survival of mice, indicating it was effective in reducing lethal metastasis burden. Taken together, our data show that anti-TGFβ antibody and cyclophosphamide represents an effective chemoimmunotherapeutic combination.
Assessment and Validating the Quality of Educational Web Sites using Subtractive Clustering

Researchers have studied qualitative and quantitative methods to assess the quality of website. Previous studies had determined criteria such as quality of service. Human behavior, namely the objective perspective, is the essential source to obtain human thinking and real doings. For this reason, data mining approaches are used to acquire the objective source. In this research, proposed subtractive clustering is applied in evaluating educational web sites from the fuzzy objective perspective. An empirical study is carried out to validate the model capability. Results indicate that in the recommended algorithm are closer to the real data.
EVI1 oncoprotein interacts with a large and complex network of proteins and integrates signals through protein phosphorylation

Significance Although ecotropic viral integration site 1 (EVI1) oncogenic transcription factor was discovered in 1988, its molecular functions and regulations are still underexplored. Through characterization of few EVI1-interacting proteins, EVI1 was identified as dynamic modulator of transcription and chromatin remodeling. We used proteomics approaches to define the EVI1 interactome. We found associations of EVI1 with not only transcriptional regulators, but also components of signaling pathways, DNA repair, DNA recombination, and mitosis complexes. We also identified functional EVI1 phosphorylation sites modified by casein-kinase II and protein phosphatase-1α that impact EVI1 activity. Thus, our study provides critical molecular insights on EVI1 action and regulation. Ecotropic viral integration site-1 (EVI1) is an oncogenic zinc finger transcription factor whose expression is frequently up-regulated in myeloid leukemia and epithelial cancers. To better understand the mechanisms underlying EVI1-associated disease, we sought to define the EVI1 interactome in cancer cells. By using stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomics, we could confidently assign 78 proteins as EVI1-interacting partners for FLAG-tagged EVI1. Subsequently, we showed that 22 of 27 tested interacting proteins could coimmunoprecipitate with endogenous EVI1 protein, which represented an 81.5% validation rate. Additionally, by comparing the stable isotope labeling by amino acids in cell culture (SILAC) data with high-throughput yeast two hybrid results, we showed that five of these proteins interacted directly with EVI1. Functional classification of EVI1-interacting proteins revealed associations with cellular transcription machinery; modulators of transcription; components of WNT, TGF-β, and RAS pathways; and proteins regulating DNA repair, recombination, and mitosis. We also identified EVI1 phosphorylation sites by MS analysis and showed that Ser538 and Ser858 can be phosphorylated and dephosphorylated by two EVI1 interactome proteins, casein kinase II and protein phosphatase-1α. Finally, mutations that impair EVI1 phosphorylation at these sites reduced EVI1 DNA binding through its C-terminal zinc finger domain and induced cancer cell proliferation. Collectively, these combinatorial proteomic approaches demonstrate that EVI1 interacts with large and complex networks of proteins, which integrate signals from various different signaling pathways important for oncogenesis. Comprehensive analysis of the EVI1 interactome has thus provided an important resource for dissecting the molecular mechanisms of EVI1-associated disease.
Pharmacotherapy for primary delusional jealousy, a retrospective observational study of 32 cases with Othello syndrome

To determine whether primary delusional jealousy can be treated effectively with antipsychotics or antidepressants, and whether any clinical variables are associated with response to pharmacotherapy, we carried out a retrospective case series observational study by reviewing clinical records of patients with an International Classification of Disease, 9th ed., diagnostic code of 297 (delusional disorders) who were treated at the Department of Psychiatry of a university affiliated hospital from January 2010 to December 2015. Only those records showing obvious delusional jealousy not secondary to other medical conditions, dementia, or schizophrenia were scrutinized thoroughly with respect to types of pharmacotherapy, treatment response, and other demographic and clinical variables likely to be associated with clinical outcomes. All except one of 32 patients, 16 men and 16 women, between 37 and 79 (60.9±10.6) years of age, were treated with low-dose antipsychotics. The general response was favorable as 19 (59.4%) were rated as good and 13 as inadequate responders (seven partial and six limited). Compared with antipsychotic monotherapy, concomitant therapy with antidepressants had a higher rate of good response, although statistically insignificant (75 vs. 53%, P=0.21). Younger age (P=0.01) and presentation at the index visit with their suspected unfaithful spouse were associated with a good response (P=0.036); comorbidity with delusions other than the jealous type was associated with a poor response (P=0.006). The overall outcome for delusional jealousy looks promising if the patients can accept pharmacotherapy in an outpatient setting.
The effects of firm size and risk on Capital Structure decisions of Insurance Industry in Kenya

Capital structure has been one of the most controversial issues in the field of finance during past years. There are a number of existing theories and empirical studies observing patterns involved in choosing a capital structure, however until now, there is no universal one. The purpose of the study was to carry out empirical test, to determine the influence of firm specific factors as suggested by various theories on the capital structure of Kenyan insurance firms. The study population involved all the registered insurance firms, the research targeted firms that had a continua’s operation between 2003 and 2012 and the analysis was based on the year-end observations for ten consecutive years. The study used panel data methodology and two independent variables size and firm risk were analyzed as the firm specific determinants of capital structure which was used as the dependent variable, the relationship between independent variable and the dependent variable was moderated by the management control. Statistical data was collected from audited year-end financial reports filled with Kenya insurance regulatory authority (IRA) was analyzed; this research used secondary data only. Panel regression analysis was done using the statistical package (EVIEWS version 8) to establish the relationship between independent and dependent variables. The panel regression results indicated that size had a significant influence on capital structure with moderating effect of the management control while risk was not significant. However without moderation of the management control the two independent variables were not significant. The moderator and the interaction between the moderator and the two independent variables were found to be significant. This means that the management of insurance firms exerts significant moderating influence on the relationship between the two firm factors and capital structure. These results were found to agree with the proponents of Agency theory in as far as the influence of the management control is concerned.
Feasibility of 11C-Acetate PET/CT for Imaging of Fatty Acid Synthesis in the Atherosclerotic Vessel Wall

Fatty acids are a common constituent of atherosclerotic plaque and may be synthesized in the plaque itself. Fatty acid synthesis requires acetyl-coenzyme-A (CoA) as a main substrate, which is produced from acetate. Currently, 11C-acetate PET/CT is used for the evaluation of malignancies. There are no data concerning its potential for the characterization of atherosclerotic plaque. Therefore, the purpose of the present study was to examine the prevalence, distribution, and topographic relationship of arterial 11C-acetate uptake and vascular calcification in major arteries. Methods: Thirty-six patients were examined by whole-body 11C-acetate PET/CT. Tracer uptake in various arterial segments was analyzed both qualitatively and semiquantitatively by measuring the blood-pool–corrected standardized uptake value (target-to-background ratio). CT images were used to measure calcified plaque burden. Results: 11C-acetate uptake was observed at 220 sites in 32 (88.8%) of the 36 study patients, and mean target-to-background ratio was 2.5 ± 1.0. Calcified atherosclerotic lesions were observed at 483 sites in 30 (83.3%) patients. Sixty-four (29.1%) of the 220 lesions with marked 11C-acetate uptake were colocalized with arterial calcification. However, only 13.3% of all arterial calcification sites demonstrated increased radiotracer accumulation. Conclusion: Our data indicate the feasibility of using 11C-acetate PET/CT for imaging of fatty acid synthesis in the atherosclerotic vessel wall. This study provides a rationale to incorporating 11C-acetate PET into further preclinical and clinical studies to obtain new insights into fatty acid synthesis in atherosclerotic lesions and to evaluate whether it may be used to monitor pharmacologic intervention with fatty acid synthase inhibitors.
Diabetes in American Indians of Washington, Oregon, and Idaho

The prevalence of diabetes among 29,000 American Indians living on or near 10 reservations in the Pacific Northwest was established from clinical data sources. The age- and sex-adjusted prevalence rate in 1987 was three times higher [95% confidence interval (Cl) 2.8–3.1] than the comparable United States rate in 1980. The ageadjusted prevalence for women was 1.3 times that for men (95% Cl 1.2–1.4). The prevalence varied by culture area. Reservation communities whose principal tribe came from the Great Basin culture area had 3.6 times more diabetes than found in the U. S. as a whole. Reservation communities whose principal tribe was from the Plateau culture had 3.0 times more diabetes than found in the U. S. , and those from the Northwest Coast culture had 1.9 times more diabetes than found in the U. S. The reasons for these variations are unknown and warrant investigation.
A retrospective study of survival in breast cancer patients undergoing deuterium depletion in addition to conventional therapies

There is increasing evidence that the heavy isotope of hydrogen, deuterium (D), has a pivotal role in cell signalling and that its depletion through the replacement of normal drinking water with deuterium-depleted water (DDW) results in tumour necrosis. The impact of D–depletion on breast cancer outcome was studied retrospectively. The normal daily water intake (150 ppm D) of 232 breast cancer patients was replaced with DDW (65-105 ppm D) for at least 91 days, without altering conventional treatment regimens. According to staging at initial diagnosis, patients with early stage breast cancer (n158) achieved a median survival time (MST) of 217 months (18.1 years), compared with 52 months (4.3 years) in patients with advanced disease (n74). The MST is pending in the subgroup of patients who were in remission at the start of DDW treatment; only one out of 48 patients died during the cumulative follow-up period of 221.1 years. Although single DDW treatment was effective, an outstandingly long MST of 24.4 years was attained in the subgroup of 53 patients who were treated with DDW at least twice. In comparison with published data, DDW treatment in combination with or as an extension of conventional therapies noticeably prolonged MST in certain subgroups of breast cancer patients. D-depletion may also be a highly effective therapy for preventing the recurrence of breast cancer. Furthermore, the method is safe and can be easily integrated into standard treatment regimens for breast cancer.
and Replication Forks Smc 5 / 6 Is Required for Repair at Collapsed

(2006) Smc5/6 is required for repair at collapsed replication forks. Molecular and Cellular Biology, 26 (24). pp. This document is made available in accordance with publisher policies and may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the URL above for details on accessing the published version. Copyright and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable, the material made available in SRO has been checked for eligibility before being made available. Copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way.
The misleading narrative of the canonical faculty productivity trajectory

Significance Scholarly productivity impacts nearly every aspect of a researcher’s career, from their initial placement as faculty to funding and tenure decisions. Historically, expectations for individuals rely on 60 years of research on aggregate trends, which suggest that productivity rises rapidly to an early-career peak and then gradually declines. Here we show, using comprehensive data on the publication and employment histories of an entire field of research, that the canonical narrative of “rapid rise, gradual decline” describes only about one-fifth of individual faculty, and the remaining four-fifths exhibit a rich diversity of productivity patterns. This suggests existing models and expectations for faculty productivity require revision, as they capture only one of many ways to have a successful career in science. A scientist may publish tens or hundreds of papers over a career, but these contributions are not evenly spaced in time. Sixty years of studies on career productivity patterns in a variety of fields suggest an intuitive and universal pattern: Productivity tends to rise rapidly to an early peak and then gradually declines. Here, we test the universality of this conventional narrative by analyzing the structures of individual faculty productivity time series, constructed from over 200,000 publications and matched with hiring data for 2,453 tenure-track faculty in all 205 PhD-granting computer science departments in the United States and Canada. Unlike prior studies, which considered only some faculty or some institutions, or lacked common career reference points, here we combine a large bibliographic dataset with comprehensive information on career transitions that covers an entire field of study. We show that the conventional narrative confidently describes only one-fifth of faculty, regardless of department prestige or researcher gender, and the remaining four-fifths of faculty exhibit a rich diversity of productivity patterns. To explain this diversity, we introduce a simple model of productivity trajectories and explore correlations between its parameters and researcher covariates, showing that departmental prestige predicts overall individual productivity and the timing of the transition from first- to last-author publications. These results demonstrate the unpredictability of productivity over time and open the door for new efforts to understand how environmental and individual factors shape scientific productivity.
Implicit structure for pen-based systems within a freeform interaction paradigm

This paper presents a scheme for extending an informal, pen-based whiteboard system (Tivoli on the Xerox LiveBoard) to provide a structured editing capability without violating its free expression and ease of use. The scheme supports list, text, table, and outline structures over handwritten scribbles and typed text. The scheme is based on the system temporarily perceiving the “implicit structure” that humans see in the material, which is called a WYPIWYG (What You Perceive Is What You Get) capability. The design techniques, principles, trade-offs, and limitations of the scheme are discussed. A notion of “freeform interaction” is proposed to position the system with respect to current user interface techniques.