Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacophore model and atom-based 3D quantitative structure activity relationship (QSAR) of human immunodeficiency virus-1 (HIV-1) capsid assembly inhibitors

Abstract A potential anti-Human Immunodeficiency Virus (HIV) agent with novel mode of action is urgently needed to fight against drug resistance HIV. The HIV capsid protein is important for both late and early stages of the viral replication cycle and emerged as a promising target for the developing of small molecule inhibitors of HIV. We design a Pharmacophore and 3D Quantitative structure activity relationship (QSAR) model for HIV Capsid Protein inhibitors, which helps to identify overall aspects of molecular structure that govern activity and for the prediction of novel HIV Capsid inhibitors. The hypothesis was developed with a survival score of 3.6. The features, that is, two aromatic rings, one hydrophobic site and two acceptor regions were present in all the active compounds with good fitness score. Pharmacophore model was then validated by a partial least square and regression-based PHASE 3D QSAR cross-validation. The leave-n-out cross validation for test set (Q2) of the hypothesis is 0.636, the standard deviation (SD) value is 0.338, and the variance ratio (F-test) value is 74.5. Hypothesis also showed a leave-n-out cross validation for training set (R2, 0.928). Interestingly, the predicted activity of true test set compounds was found in the close vicinity of their experimental activity suggesting the methodology used and models generated can be applied to identify potential new chemical entities with better HIV-1 capsid assembly inhibition. Communicated by Ramaswamy H. Sarma
Prickle isoforms determine handedness of helical morphogenesis

Subcellular asymmetry directed by the planar cell polarity (PCP) signaling pathway orients numerous morphogenetic events in both invertebrates and vertebrates. Here, we describe a morphogenetic movement in which the intertwined socket and shaft cells of the Drosophila anterior wing margin mechanosensory bristles undergo PCP-directed apical rotation, inducing twisting that results in a helical structure of defined chirality. We show that the Frizzled/Vang PCP signaling module coordinates polarity among and between bristles and surrounding cells to direct this rotation. Furthermore, we show that dynamic interplay between two isoforms of the Prickle protein determines right- or left-handed bristle morphogenesis. We provide evidence that, Frizzled/Vang signaling couples to the Fat/Dachsous PCP directional signal in opposite directions depending on whether Pkpk or Pksple predominates. Dynamic interplay between Pk isoforms is likely to be an important determinant of PCP outcomes in diverse contexts. Similar mechanisms may orient other lateralizing morphogenetic processes.
Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update.

PURPOSE To update key recommendations of the American Society of Clinical Oncology/College of American Pathologists estrogen (ER) and progesterone receptor (PgR) testing in breast cancer guideline. METHODS A multidisciplinary international Expert Panel was convened to update the clinical practice guideline recommendations informed by a systematic review of the medical literature. RECOMMENDATIONS The Expert Panel continues to recommend ER testing of invasive breast cancers by validated immunohistochemistry as the standard for predicting which patients may benefit from endocrine therapy, and no other assays are recommended for this purpose. Breast cancer samples with 1% to 100% of tumor nuclei positive should be interpreted as ER positive. However, the Expert Panel acknowledges that there are limited data on endocrine therapy benefit for cancers with 1% to 10% of cells staining ER positive. Samples with these results should be reported using a new reporting category, ER Low Positive, with a recommended comment. A sample is considered ER negative if < 1% or 0% of tumor cell nuclei are immunoreactive. Additional strategies recommended to promote optimal performance, interpretation, and reporting of cases with an initial low to no ER staining result include establishing a laboratory-specific standard operating procedure describing additional steps used by the laboratory to confirm/adjudicate results. The status of controls should be reported for cases with 0% to 10% staining. Similar principles apply to PgR testing, which is used primarily for prognostic purposes in the setting of an ER-positive cancer. Testing of ductal carcinoma in situ (DCIS) for ER is recommended to determine potential benefit of endocrine therapies to reduce risk of future breast cancer, while testing DCIS for PgR is considered optional. Additional information can be found at www.asco. org/breast-cancer-guidelines.
Activating transcription factor 6 reduces Aβ1–42 and restores memory in Alzheimer’s disease model mice

Abstract Objectives Amyloid plaques are the most important pathological hallmarks of Alzheimer’s disease. The deposition of amyloid plaques will cause ER Stress. Activating Transcription Factor 6(ATF6) is a sensor of ER Stress. However, the role of ATF6 in Alzheimer’s disease has not been reported yet. Methods The levels of β-site APP-cleaving enzyme 1 (BACE1) and Aβ1–42 were detected by Western blot, ELISA and Thioflavin S staining. Y maze and Morris water maze tests were used to detect the learning and memory functions. Dual luciferase assay was used to test the promoter activity of BACE1 and ADAM17. Results In our study, we found that the expression of ATF6 was reduced in APPswe/PSNdE9 (APP/PS1) Alzheimer’s disease model mice compared with wild type mice. Furthermore, in LN229 cell, we found that ATF6 reduced the expression of full length amyloid precursor protein (APP) in protein level. At the same time, the overexpression of ATF6 strikingly reduced the level of Aβ1–42. Interestingly, ATF6 also downregulated the promoter activity of BACE1. And some behavioral experiments like Y maze and Morris water maze test indicated that ATF6 could protect retention of spatial memory in APP/PS1 mice. Conclusion Our findings indicated that ATF6 rescued the amyloid pathology by downregulating BACE1. Therefore, we suggest that ATF6 could be a potential hub for targeting treatment of the Alzheimer’s disease.
Usability: Adoption, Measurement, Value

Objective We searched for the application of usability in the literature with a focus on adoption, measurements employed, and demonstrated value. Five human factors domains served as a platform for our reflection, which included the last 20 years. Background As usability studies continue to accumulate, there has been only a little past reflection on usability and contributions across a variety of applications. Our research provides a background for general usability, and we target specific usability research subareas within transportation, aging populations, autistic populations, telehealth, and cybersecurity. Method “Usability” research was explored across five different domains within human factors. The goal was not to perform an exhaustive review but, rather, sample usability practices within several specific subareas. We focused on answering three questions: How was usability adopted? How was it measured? How was it framed in terms of value? Conclusion We found that usability is very domain specific. Usability benchmarking studies and empirical standards are rare. The value associated with improving usability ranged widely—from monetary benefits to saving lives. Thus, researchers are motivated to further improve usability practices. A number of data collection and interpretation challenges still call for solutions. Application Findings offer insight into the development of usability, as applied across a variety of subdomains. Our reflection ought to inform future theory development efforts. We are concerned about the lack of established benchmarks, which can help ground data interpretation. Future research should address this gap in the literature. We note that our findings can be used to develop better training materials for future usability researchers.
Spanish Guidelines for Diagnosis, Management, Treatment and Prevention of DRESS syndrome.

BACKGROUND AND OBJECTIVE The DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) is a complex multisystemic severe drug hypersensitivity reaction whose diagnosis and management are troublesome. It involves the management by different specialists. The correct identification of the culprit drug is essential for future safe therapeutical options for the patient. There are no previous Spanish guidelines or consensus statements on DRESS syndrome. Objective: To draft a review and guidelines on the clinical and allergy diagnosis, management treatment and prevention of DRESS syndrome in light of currently available scientific evidence and the experience of multidisciplinary experts. METHODS These guidelines have been elaborated by a panel of allergy specialists from the Drug Allergy Committee of the Spanish Society of Allergy and Clinical Immunology (SEAIC), together with other medical specialists involved in the management of DRESS syndrome and researchers from PIELenRed consortium. A review was conducted of scientific papers on DRESS syndrome and the expert panel evaluated the quality of the evidence of the literature and provided grades of recommendation. Wherever evidence was lacking, a consensus was reached among the experts. RESULTS The first Spanish guidelines on DRESS syndrome are now being published. Important aspects as practical recommendations about clinical diagnosis, identification of the culprit drug through the Spanish pharmacovigilance system algorithm and allergy study have been addressed. Management, treatment and prevention recommendations are provided. Algorithms about management of DRESS in acute and recovery phase have been elaborated. An expert consensus step-wise guidelines for management and treatment of DRESS syndrome are provided.
Tissue microRNA-182 expression level and its potential prognostic value for papillary thyroid carcinoma.

BACKGROUND In previous study, qRT-PCR analysis revealed significantly higher miR-182 levels in papillary thyroid carcinoma (PTC) than matched normal tissues. However, the clinical significance and prognostic value of miR-182 have not been investigated in PTC until now. METHODS 151 pairs of PTC and adjacent normal thyroid tissues were obtained from Affiliated Hospital of Weifang Medical University from February 2008 to January 2015. The Chi square test was used to analyze the relationship between miR-182 expression and the clinicopathological characteristics. We used the Kaplan-Meier method and the log-rank test in univariate survival analysis, and we used the Cox proportional hazards regression model in our multivariate analysis. RESULTS The relative expression of miR-182 in PTC samples was significantly higher than that of matched normal tissues (P<0.001). The high expression level of tissue miR-182 was statistically correlated with extrathyroidal invasion (P=0.009), cervical lymphnode metastasis (P=0.015), and TNM staging (P=0.001). The Kaplan-Meier method revealed that higher miR-182 expression level was correlated with significantly reduced overall survival. Furthermore, multivariate survival analysis revealed that miR-182 expression level (HR=2.882, 95% CI: 1.289-10.928, P=0.013) was significantly correlated with the poor prognosis of PTC patients. CONCLUSIONS Overexpression of miR-182 is associated with aggressive clinicopathologic characteristics of PTC, and miR-182 might be a novel prognostic molecular marker of PTC.
Targeted sequencing reveals KLF4 gene associated with NSCL/P in Western Han Chinese.

OBJECTIVE Non-syndromic cleft lip with or without palate (NSCL/P) is one of the most common congenital birth defects affected by both gene and environmental modifiers. Recent studies revealed that KLF4 played an important role during craniofacial development. This study aimed to evaluate the association between KLF4 gene variations and NSCL/P in a Western Han Chinese population. METHODS In this study, 159 unrelated cases with NSCL/P were recruited. We used targeted region sequencing around KLF4 gene, and single variation association analysis and gene-based burden analysis were then performed. RESULTS 116 SNPs and 30 indels were found. Burden analysis showed no statistical significance. Association analysis results showed rs6477574 (P = 0.014 and OR = 1.58), rs112488950 (P = 0.0024 and OR = 1.98) and rs111357138 (P = 0.0025 and OR = 1.96) were associated with NSCL/P. CONCLUSIONS The results revealed that KLF4 variations were associated with NSCL/P in a Western Han Chinese population, providing a new reference for future genetic study of NSCL/P.
Stereotactic body radiation therapy for medically inoperable early-stage lung cancer: Tata Memorial Hospital perspective and practice recommendations

Background: Stereotactic body radiotherapy (SBRT) is now considered the standard treatment for medically inoperable early-stage non-small lung cell cancer (ES-NSCLC). Purpose: There is a paucity of data related to outcomes with SBRT in ES-NSCLC from the developing countries. We report the early outcomes of ES-NSCLC patients treated with SBRT at our institute. Materials and Methods: Between 2007 and 2015, 40 consecutive patients with histologically proven ES-NSCLC were treated with SBRT. Median age was 71 years (range: 46–88 years) and median Charlson comorbidity index (CCI) was 3. The majority had stage I (70%) and 45% of the tumors were centrally located. The median tumor diameter was 3.8 cm (range: 2–7.6 cm). The mean gross tumor volume was 41 cc (range: 4–139 cc) and the mean planning target volume (PTV) was 141 cc (range: 27–251 cc). Varying dose and fraction (fr) sizes were used depending on tumor location, tumor size, and treatment period. The median biologically effective dose (BED) was 77 Gy10 (range: 77–105 Gy10) for the initial cohort (2007–2012) and 105 Gy10 (range: 77–132 Gy10) for the subsequent cohort (2013–2015). Results: After a median follow-up of 16 months (range: 3–99 months), the 2-year local control (LC), overall survival, and cancer-specific survival (CSS) rates were 94%, 41%, and 62%, respectively. The univariate and multivariate analysis determined CCI >3 and PTV >80.6 cc as significant predictors of worse OS and CSS (P< 0.01). The clinical stage, tumor location, BED, and treatment period (2007–2012 vs. 2013–2015) did not significantly predict any of the outcomes. The most common acute toxicities were skin erythema (10%), grade 1 esophagitis (8%), and exacerbation of previous chronic obstructive pulmonary disease (10%). Grade ≥2 late radiation pneumonitis was seen in 17.5%. One patient developed a rib fracture. No neurological or vascular complications were seen. Conclusions: SBRT results in excellent local control (LC) and acceptable survival in medically inoperable ES-NSCLC with minimal adverse effects. Charlson comorbidity index and target volume are important prognostic factors and may aid in patient selection.
Efficacy of statistical process control procedures to identify deviations in continuously measured physiologic and behavioral variables in beef steers experimentally challenged with Mannheimia haemolytica.

The objective of this experiment was to determine if statistical process control (SPC) procedures coupled with remote continuous collection of feeding behavior patterns, accelerometer-based behaviors, and rumen temperature can accurately differentiate between animals experimentally inoculated with Mannheimia haemolytica (MH) or phosphate buffer solution (PBS). Thirty-six crossbred steers (BW = 352 ± 23 kg) seronegative for MH were randomly assigned to bronchoselective endoscopic inoculation with MH (n = 18) or PBS (n = 18). Electronic feed bunks were used to measure DMI and feeding behavior traits, accelerometer-based neck collars measured feeding- and activity-behavior traits, and ruminal thermo-boluses measured rumen temperature. Data were collected for 28 d prior to and following inoculation. Steers inoculated with MH exhibited elevated (P < 0.02) levels of neutrophils and rumen temperature indicating that MH challenge effectively stimulated immunologic responses. However, only 9 of the MH steers exhibited increased serum haptoglobin concentrations indicative of an acute phase protein response and 1 displayed clinical signs of disease. Shewhart charts (SPC procedure) were used for two analyses, and sensitivity was computed using all MH-challenged steers (n = 18), and a subset that included only MH-challenged haptoglobin-responsive steers (n = 9). Specificity was calculated using all PBS steers in both analyses. In haptoglobin-responsive only analysis, DMI and bunk visit (BV) duration had the greatest accuracy (89%), with accuracies for head-down (HD) duration, BV frequency, time to bunk and eating rate being less (83, 69, 53 and 61%, respectively). To address the diurnal nature of rumen temperature, data were averaged over 6-h intervals, and quarterly temperature models were evaluated separately. Accuracy for the 4th quarter rumen temperature was higher (78%) than the other quarterly temperature periods (1st = 56%, 2nd = 50% and 3rd = 67%). In general, the accelerometer-based behavior traits were highly specific ranging from 82% for ingestion to 100% for rest, rumination and standing. However, sensitivity of these traits were low (0 to 50%), such that the accuracies were moderate compared to feeding behavior and rumen temperature response variables. These results indicate that Shewhart procedures can effectively identify deviations in feeding behavior and rumen temperature patterns to enable sub-clinical detection of BRD in beef cattle.
Low prevalence of livestock‐associated methicillin‐resistant Staphylococcus aureus clonal complex 398 and mecC MRSA among human isolates in North‐West England

Livestock‐associated methicillin‐resistant Staphylococcus aureus (LA‐MRSA) is an important public health problem in many countries. Despite reports of such isolates being found in both animals and humans in the United Kingdom few data are available on the prevalence in humans of such isolates. A prevalence study was therefore undertaken in the north‐west of England.
Jeanne Calment's unique 122-year lifespan: facts and factors; longevity history in her genealogical tree.

Jeanne Calment's (JC) still unmatched validated human lifespan of 122 years and 164 days, over 3 years longer than any other, surprises many. While her case is broadly accepted as a golden standard of validation, her record age still raises skepticism among some. The probability of such a record to be achieved by someone born in the second half of the 19th century, in the world population documentarily eligible to age validation, and also in the G7 countries, can be calculated by applying some logistic and Gompertz mortality models to these populations, taken respectively from the age of 117 and of 100. This probability appears substantial, respectively 7.1% and 4.7%, when using a 4-parameters logistic model which I validated on the observed survivals of centenarians until the age of 118. A 3-year interval with the second oldest is then expected. The known facts and documents constitute consistent evidence that JC died at 122: regular official records during her life, her verified memories from her 19th-century life, her usage of specialized terms and of an abbreviation system specific to this period of time, photos, her signature and handwriting, testimonies from numerous witnesses of her life, plus the expertise of gerontologists. Meanwhile, nothing contradicts her record: the daughter-mother identity swap hypothesis appears unrealistic and not supported by any evidence; especially no plausible motive can be found, on the contrary. The latest paper which defends this hypothesis, "Bayesian assessment of the longevity of JC", contains major errors, making its result subjective and invalid. The study of JC's genealogical tree on 6 generations, using longevity performance and TIAL (Total immediate ancestor longevity) indicators, shows how, in two centuries, her ancestors have been living 10% longer on average at each generation, increasingly overperforming their French 25-year-old contemporaries, from around 7% in the early 18th (.).
[Comparison of Awareness about Alcohol Use during Pregnancy among Female College Students by Drinking Levels: Using the Theory of Planned Behavior].

PURPOSE The purpose of this study was to examine the awareness of alcohol use during pregnancy and factors influencing the intention to abstain from alcohol during pregnancy by drinking levels. METHODS Utilizing a comparative descriptive design, a total of 359 female college students were recruited. Measurements were Theory of Planned Behavior (TPB) variables related awareness of alcohol use during pregnancy, Korean Version of the Alcohol Use Disorders Identification Test, knowledge about alcohol use during pregnancy, and socio-demographic factors. Main variables were compared by drinking levels. The factors influencing the intention to abstain from alcohol during pregnancy were identified using hierarchical regression analysis. RESULTS Non-problematic alcohol behavior group (n=185) had higher the intention to abstain from alcohol during pregnancy than problematic alcohol behavior group (n=174) (t=3.13, p=.002). The significant TPB variables influencing the intention to abstain from alcohol during pregnancy were that attitudes (β =-.44, p<.001), subjective norms (β =.14, p=.026), and perceived behavior control (β =.19, p=.002) in non-problematic alcohol behavior group, whereas the corresponding variables in the problematic alcohol behavior group were attitudes (β =-.51, p<.001) and subjective norms (β =.21, p=.006). CONCLUSION It is necessary to increase the intention to abstain from alcohol during pregnancy for the female college students having problematic alcohol behavior. The following strategies are recommended for them; decreasing acceptable attitudes toward alcohol use during pregnancy and reinforcing the influence of social pressure toward to abstain from alcohol during pregnancy.
Tendon explant models for physiologically relevant in vitro study of tissue biology – a perspective

ABSTRACT Background: Tendon disorders increasingly afflict our aging society but we lack the scientific understanding to clinically address them. Clinically relevant models of tendon disease are urgently needed as established small animal models of tendinopathy fail to capture essential aspects of the disease. Two-dimensional and three-dimensional cell and tissue culture models are similarly limited, lacking many physiological extracellular matrix cues required to maintain tissue homeostasis or guide matrix remodeling. These cues reflect the biochemical and biomechanical status of the tissue, and encode information regarding the mechanical and metabolic competence of the tissue. Tendon explants overcome some of these limitations and have thus emerged as a valuable tool for the discovery and study of mechanisms associated with tendon homeostasis and pathophysiology. Tendon explants retain native cell-cell and cell-matrix connections, while allowing highly reproducible experimental control over extrinsic factors like mechanical loading and nutritional availability. In this sense tendon explant models can deliver insights that are otherwise impossible to obtain from in vivo animal or in vitro cell culture models. Purpose: In this review, we aimed to provide an overview of tissue explant models used in tendon research, with a specific focus on the value of explant culture systems for the controlled study of the tendon core tissue. We discuss their advantages, limitations and potential future utility. We include suggestions and technical recommendations for the successful use of tendon explant cultures and conclude with an outlook on how explant models may be leveraged with state-of-the-art biotechnologies to propel our understanding of tendon physiology and pathology.