Miracle-dz/UniFAR-FTUs huggingface dataset:
How good are pathogenicity predictors in detecting benign variants?

Computational tools are widely used for interpreting variants detected in sequencing projects. The choice of computational tools is critical for reliable variant impact interpretation for precision medicine and should be based on systematic performance assessment. The performance of the methods varies widely in different performance assessments, for example due to the sizes of test datasets. To address this issue, we obtained 63,160 common amino acid substitutions (allele frequency ≥1% and <25%) from the Exome Aggregation Consortium (ExAC) database, which contains variants from 60,706 genomes or exomes. We evaluated the specificity, the capability to detect benign variants, for 10 variant interpretation tools. In addition to overall specificity of the tools, we tested their performance for variants in six geographical populations. PON-P2 had the best performance (95.5%) followed by FATHMM (86.4%) and VEST (83.5%). While these tools had excellent performance, the poorest method predicted more than one third of the benign variants to be disease-causing. The results allow choosing reliable methods for benign variant interpretation, for both research and clinical purposes, as well as provide a benchmark for method developers. AUTHOR SUMMARY In precision/personalized medicine of many conditions it is essential to investigate individual’s genome. Interpretation of the observed variation (mutation) sets is feasible only with computational approaches. We assessed the performance of variant pathogenicity/tolerance prediction programs on benign variants. Variants were obtained from high-quality ExAC database and selected to have minor allele frequency between 1 and 25%. We obtained 63,160 such cases and investigated 10 widely used predictors. Specificities of the methods showed large differences, from 0.64 to 0.96%, thus users of these methods have to be careful when choosing the one(s) they will use. We investigated further the performances on different populations, allele frequencies, separately for males and females, chromosome wise and for population unique and non-unique variants. The ranking of the tools remained the same in all these scenarios, i.e. the best methods were the best irrespective on how the data is filtered and grouped. This is to our knowledge the first evaluation of method performance on benign variants.
Education Attainment and Obesity: Differential Returns Based on Sexual Orientation

Background: Although high educational attainment is linked to better health and lower health risk behaviors, this effect may be systemically smaller for racial and ethnic minority groups compared to Whites. However, it is still unknown whether these diminished returns also apply to marginalization based on sexual orientation. Aims: In a national sample of adults which was composed of people of color, we compared straight and homosexual people for the association between education attainment and obesity. Methods: The Social Justice Sexuality Project (SJS-2010) is a cross-sectional national survey of health and wellbeing of predominantly people of color who identify as homosexual. The current analysis included 2884 adults (age 24 or more) who were either heterosexual (n = 260) or homosexual (n = 2624). The predictor variable was education attainment, and the outcome variable was obesity status (body mass index larger than 30 kg/m2 [kilograms per meter squared]). Demographic factors (age and gender), household income, nativity (US born vs. immigrant), and health (self-rated health and current smoking) were the covariates. Sexual orientation was the moderator. Results: In the pooled sample, high education attainment was protective against obesity status. Sexual orientation interacted with education attainment on odds of obesity, which was suggestive of stronger protective effects of high education attainment against obesity for heterosexual than homosexual individuals. Conclusion: High education attainment better protects heterosexual than homosexual people against obesity, a pattern similar to what has been observed for comparison of Whites and non-Whites. Smaller protective effects of education attainment on health behaviors of marginalized people are possibly, due to prejudice and discrimination that they experience. Discrimination may minimize stigmatized individuals’ abilities to mobilize their economic and human resources and translate them to tangible outcomes. This finding extends the Minorities’ Diminished Returns theory, suggesting that it is not just race/ethnicity but possibly any marginalizing and stigmatizing social identity that results in diminished returns of socioeconomic status resources.
Differences in Emotional and Pain-Related Language in Tweets About Dentists and Medical Doctors: Text Analysis of Twitter Content

Background Social media provides people with easy ways to communicate their attitudes and feelings to a wide audience. Many people, unfortunately, have negative associations and feelings about dental treatment due to former painful experiences. Previous research indicates that there might be a pervasive and negative occupational stereotype related to dentists and that this stereotype is expressed in many different venues, including movies and literature. Objective This study investigates the language used in relation to dentists and medical doctors on the social media platform Twitter. The purpose is to compare the professions in terms of the use of emotional and pain-related words, which might underlie and reflect the pervasive negative stereotype identified in relation to dentists. We hypothesized that (A) tweets about dentists will have more negative emotion-related words than those about medical doctors and (B) pain-related words occur more frequently in tweets about dentists than in those about medical doctors. Methods Twitter content (“tweets”) about dentists and medical doctors was collected using the Twitter application program interface 140Dev over a 4-week period in 2015, scanning the search terms “dentist” and “doctor”. Word content of the selected tweets was analyzed using Linguistic Inquiry and Word Count software. The research hypotheses were investigated using nonparametric Wilcoxon-Mann-Whitney tests. Results Over 2.3 million tweets were collected in total, of which about one-third contained the word “dentist” and about two-thirds contained the word “doctor. ” Hypothesis A was supported since a higher proportion of negative words was used in tweets about dentists than in those about medical doctors (z=−10.47; P<.001). Similarly, tests showed a difference in the proportions of anger words (z=−12.54; P<.001), anxiety words (z=−6.96; P<.001), and sadness words (z=−9.58; P<.001), with higher proportions of these words in tweets about dentists than in those about doctors. Also, Hypothesis B was supported since a higher proportion of pain-related words was used in tweets about dentists than in those about doctors (z=−8.02; P<.001). Conclusions The results from this study suggest that stereotypes regarding dentists and dental treatment are spread through social media such as Twitter and that social media also might represent an avenue for improving messaging and disseminating more positive attitudes toward dentists and dental treatment.
Petrocarbon evolution: Ramped pyrolysis/oxidation and isotopic studies of contaminated oil sediments from the Deepwater Horizon oil spill in the Gulf of Mexico

Hydrocarbons released during the Deepwater Horizon (DWH) oil spill weathered due to exposure to oxygen, light, and microbes. During weathering, the hydrocarbons’ reactivity and lability was altered, but it remained identifiable as “petrocarbon” due to its retention of the distinctive isotope signatures (14C and 13C) of petroleum. Relative to the initial estimates of the quantity of oil-residue deposited in Gulf sediments based on 2010–2011 data, the overall coverage and quantity of the fossil carbon on the seafloor has been attenuated. To analyze recovery of oil contaminated deep-sea sediments in the northern Gulf of Mexico we tracked the carbon isotopic composition (13C and 14C, radiocarbon) of bulk sedimentary organic carbon through time at 4 sites. Using ramped pyrolysis/oxidation, we determined the thermochemical stability of sediment organic matter at 5 sites, two of these in time series. There were clear differences between crude oil (which decomposed at a lower temperature during ramped oxidation), natural hydrocarbon seep sediment (decomposing at a higher temperature; Δ14C = -912‰) and our control site (decomposing at a moderate temperature; Δ14C = -189‰), in both the stability (ability to withstand ramped temperatures in oxic conditions) and carbon isotope signatures. We observed recovery toward our control site bulk Δ14C composition at sites further from the wellhead in ~4 years, whereas sites in closer proximity had longer recovery times. The thermographs also indicated temporal changes in the composition of contaminated sediment, with shifts towards higher temperature CO2 evolution over time at a site near the wellhead, and loss of higher temperature CO2 peaks at a more distant site.
Identification of B-cell translocation gene 1-controlled gene networks in diffuse large B-cell lymphoma: A study based on bioinformatics analysis

B-cell translocation gene 1 (BTG1) is a member of the BTG/transducer of Erb family. The present study evaluated the impact of BTG1 gene expression on the clinical outcome of diffuse large B-cell lymphoma (DLBCL) and investigated potential mechanisms using the Gene Expression Omnibus (GEO) database. The gene expression profile datasets GSE31312, GSE10846, GSE65420 and GSE87371 were downloaded from the GEO database. BTG1 expression and clinicopathological data were obtained from the GSE31312 dataset. In 498 cases, the expression of BTG1 in DLBCL was associated with treatment response (χ2=19.020; P<0.001) and International Prognostic Index score (χ2=5.320; P=0.025). Using the Kaplan-Meier method, it was identified that the expression of BTG1 was associated with overall survival (OS) and progression-free survival (PFS) times. Univariate and multivariate Cox regression analysis demonstrated that BTG1 was an independent predictive factor for OS and PFS. From the overlapping analysis of 407 BTG1-associated genes and 22,187 DLBCL-associated genes, 401 genes were identified as BTG1-associated DLBCL genes. Pathway analysis revealed that BTG1-associated DLBCL genes were associated with cancer progression and DLBCL signaling pathways. Subsequently, a protein-protein interaction network was constructed of the BTG1-associated genes, which consisted of 235 genes and 601 interactions. Additionally, 24 genes with high degrees in the network were identified as hub genes, which included genes associated with ‘ribosome’ [ribosomal protein (RP) L11, RPL3, RPS29, RPL19, RPL15 and RPL12], ‘cell cycle’ (ubiquitin carboxyl extension protein 52, ATM and Ras homolog family member H), ‘mitogen-activated protein kinase pathway’ (mitogen-activated protein kinase 1), ‘histone modification’ (ASH1-like protein) and ‘transcription/translation’ (eukaryotic translation initiation factor 3 subunit E, eukaryotic translation elongation factor 1 δ, transcription termination factor 1, cAMP responsive element binding protein 1 and RNA polymerase II subunit F). In conclusion, BTG1 may serve as a predictive biomarker for DLBCL prognosis. Additionally, bioinformatics analysis indicated that BTG1 may exhibit key functions in the progression and development of DLBCL.
Survival benefit of adjuvant chemotherapy for patients with poorly differentiated stage IIA colon cancer

Background: The effect of adjuvant chemotherapy on stage II colon cancer remains constantly controversial. Recently, however, several studies have reported the definite survival benefit of adjuvant chemotherapy (ACT) in T4 disease (stage IIB and IIC) among stage II colon cancer patients. The following study investigates the efficacy of ACT in patients with poorly differentiated stage IIA colon cancer. Methods: The first cohort of eligible patients (N=38384) diagnosed with stage IIA colon cancer was selected from the Surveillance, Epidemiology, and End Results database (SEER) between January 1, 2004, and December 31, 2010. Cox proportional hazards regression analyses and Kaplan-Meier curves were used to evaluate the survival benefit following ACT. Our findings were also evaluated in Fudan University Shanghai Cancer Center (FUSCC) cohort form FUSCC database. Results: In SEER cohort, poorly differentiated or undifferentiated tumor grade was associated with 21.5% increased cancer-specific mortality in patients who did not receive ACT (HR=1.215, 1.004-1.469, P=0.045, using poorly differentiated or undifferentiated ACT as a reference). In FUSCC cohort, poorly differentiated or undifferentiated tumor grade was also associated with increased DFS in patients who received ACT (HR = 0.160, 95% CI = 0.017-1.505, P=0.109, using poorly differentiated or undifferentiated, non-ACT as a reference). In addition, patients with poorly differentiated or undifferentiated tumor who did not receive ACT had a higher risk of distant metastasis and recurrence compared to patients who received ACT (log-rank P=0.027 and 0.119, respectively). Conclusion: ACT decreased the recurrence rate and distant metastasis rate thus improving prognosis for poorly differentiated or undifferentiated stage IIA colon cancer.
Artificial Intelligence for the Detection of Diabetic Retinopathy in Primary Care: Protocol for Algorithm Development

Background Diabetic retinopathy (DR) is one of the most important causes of blindness worldwide, especially in developed countries. In diabetic patients, periodic examination of the back of the eye using a nonmydriatic camera has been widely demonstrated to be an effective system to control and prevent the onset of DR. Convolutional neural networks have been used to detect DR, achieving very high sensitivities and specificities. Objective The objective of this is paper was to develop an artificial intelligence (AI) algorithm for the detection of signs of DR in diabetic patients and to scientifically validate the algorithm to be used as a screening tool in primary care. Methods Under this project, 2 studies will be conducted in a concomitant way: (1) Development of an algorithm with AI to detect signs of DR in patients with diabetes and (2) A prospective study comparing the diagnostic capacity of the AI algorithm with respect to the actual system of family physicians evaluating the images. The standard reference to compare with will be a blinded double reading conducted by retina specialists. For the development of the AI algorithm, different iterations and workouts will be performed on the same set of data. Before starting each new workout, the strategy of dividing the set date into 2 groups will be used randomly. A group with 80% of the images will be used during the training (training dataset), and the remaining 20% images will be used to validate the results (validation dataset) of each cycle (epoch). During the prospective study, true-positive, true-negative, false-positive, and false-negative values will be calculated again. From here, we will obtain the resulting confusion matrix and other indicators to measure the performance of the algorithm. Results Cession of the images began at the end of 2018. The development of the AI algorithm is calculated to last about 3 to 4 months. Inclusion of patients in the cohort will start in early 2019 and is expected to last 3 to 4 months. Preliminary results are expected to be published by the end of 2019. Conclusions The study will allow the development of an algorithm based on AI that can demonstrate an equal or superior performance, and that constitutes a complement or an alternative, to the current screening of DR in diabetic patients. International Registered Report Identifier (IRRID) PRR1-10.2196/12539
Myc-induced nuclear antigen constrains a latent intestinal epithelial cell-intrinsic anthelmintic pathway

Expulsion of parasitic gastrointestinal nematodes requires diverse effector mechanisms coordinated by a Th2-type response. The evolutionarily conserved JmjC protein; Myc Induced Nuclear Antigen (Mina) has been shown to repress IL4, a key Th2 cytokine, suggesting Mina may negatively regulate nematode expulsion. Here we report that expulsion of the parasitic nematode Trichuris muris was indeed accelerated in Mina deficient mice. Unexpectedly, this was associated not with an elevated Th2- but rather an impaired Th1-type response. Further reciprocal bone marrow chimera and conditional KO experiments demonstrated that retarded parasite expulsion and a normal Th1-type response both required Mina in intestinal epithelial cells (IECs). Transcriptional profiling experiments in IECs revealed anti-microbial α-defensin peptides to be the major target of Mina-dependent retention of worms in infected mice. In vitro exposure to recombinant α-defensin peptides caused cytotoxic damage to whipworms. These results identify a latent IEC-intrinsic anthelmintic pathway actively constrained by Mina and point to α-defensins as important effectors that together with Mina may be attractive therapeutic targets for the control of nematode infection.
Comprehensive Analysis of Aberrantly Expressed ceRNA network in gastric cancer with and without H.pylori infection

Objective: This study mainly focused on revealing ceRNA network in gastric cancer (GC) with Hp infection after comparing with GC without Hp infection and exploring the biological function and prognostic relevance of related molecules. Methods: The RNA expression profile data of GC patients with or without Hp infection were extracted from TCGA GDC data portal, including 20 GC cases with Hp infection and 168 GC cases without Hp infection. Differentially expressed lncRNAs, miRNAs and mRNAs were unveiled by package edgeR of R, and lncRNA-miRNA-mRNA ceRNA network was constructed by integrating the miRNA target information and the expression data of lncRNAs, miRNAs and mRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of aberrantly expressed mRNAs were performed to identify the related biological functions and pathologic pathways, and protein-protein interaction (PPI) network was constructed by STRING database. The overall survival (OS) of aberrantly expression lncRNAs and miRNAs were analyzed by package survival of R. A total of 30 gastric cancer tissues were used to validate the bioinformatics analysis results by real-time PCR. Results: Among the 32 differentially expressed miRNAs, 27 differentially expressed lncRNAs and 257 differentially expressed mRNAs were identified by comparing GC patients with and without Hp infection. Totally 10 miRNA, 11 lncRNA, 219 mRNA were included to build ceRNA network. GO and KEGG analysis revealed that differentially expressed mRNAs involved in the ceRNA network were mainly involved in extracellular exosomes, structural molecular activities, proteolysis and P13K-Akt signaling pathways. And PPI analysis obtained six hub genes of NTS, APOC3, OTX2, KRT13, CALCA, GNG4. Survival analysis showed that four lncRNAs (LINC01254, LINC01287, LINC01524, U95743.1) and four miRNAs (miR-302a, miR-302b, miR-1286, miR-378g) were associated with overall survival of GC with Hp infection. The real-time PCR results showed that, the levels of LINCO1254, LINCO1287, LINCO1524, U95743.1 were significantly higher in Hp positive GC patients than Hp negative patients (P=0.02, 0.048, 0.04, 0.036, respectively). Conclusion: Using TCGA database for data mining, we have successfully constructed a ceRNA regulatory network of GC with Hp infection, consisting of 10 lncRNAs, 11 miRNAs and 219 mRNAs. These findings might provide critical clues for the regulatory role of ceRNA network in the development of GC with Hp infection.
Hypoxia and Neurodegeneration

Periods of chronic hypoxia, which can arise from numerous cardiorespiratory disorders, predispose individuals to the development of dementias, particularly Alzheimer's disease (AD). AD is characterized in part by the increased production of amyloid β peptide (Aβ), which forms the extracellular plaques by which the disease can be identified post mortem. Numerous studies have now shown that hypoxia, even in vitro, can increase production of Aβ in different cell types. Evidence has been produced to indicate hypoxia alters both expression of the Aβ precursor, APP, and also the expression of the secretase enzymes, which cleave Aβ from APP. Other studies implicate reduced Aβ degradation as a possible means by which hypoxia increases Aβ levels. Such variability may be attributable to cell‐specific responses to hypoxia. Further evidence indicates that some, but not all of the cellular adaptations to chronic hypoxia (including alteration of Ca2+ homeostasis) require Aβ formation. However, other aspects of hypoxic remodeling of cell function appear to occur independently of this process. The molecular and cellular responses to hypoxia contribute to our understanding of the clinical association of hypoxia and increased incidence of AD. However, it remains to be determined whether inhibition of one or more of the effects of hypoxia may be of benefit in arresting the development of this neurodegenerative disease.
Optimization of the Microwave-Assisted Extraction Process of Bioactive Compounds from Annatto Seeds (Bixa orellana L.)

This study deals with the extraction, optimization, and evaluation of the antioxidant and antimicrobial activities of bioactive compounds obtained from the seeds of annatto using microwave-assisted extraction as compared to leaching. Annatto seeds were subjected to a microwave treatment of 2450 MHz and power of 700 watts using a response surface design involving four factors: pH (4–11), solvent concentration (ethanol) (50–96%), solvent-to-seed ratio (2–10), and microwave exposure time (0–5 min). The contents of polyphenol compounds and bixin were taken as response variables. Subsequently, the antioxidant and antimicrobial activities were assessed at the optimal processing conditions predicted by the experimental design. Microwaves, solvent concentration, and the solvent-to-seed ratio showed a statistically significant effect for the extraction of polyphenol compounds and bixin. Thus, microwaves accelerated the extraction of those compounds and the slight increase in temperature caused some degradation of the polyphenol compounds. The microwave-assisted extraction increased the contents of polyphenols and bixin along with their antioxidant activity as compared to leaching extraction. However, this technique does not significantly improve the antimicrobial activity against Bacillus cereus and Staphylococcus aureus.
Multidimensional competences of supply chain managers: an empirical study

ABSTRACT Supply chain manager competences have attracted increasing attention from both practitioners and scholars in recent years. This paper conducted an explorative study to understand the dimensionality of supply chain manager competences. Online job advertisements for supply chain managers were collected as secondary data, since these advertisements reflect employers’ real job requirements. We adopted the multidimensional scaling (MDS) technique to process and analyse the data. Five dimensions of supply chain manager competences are identified: generic skills, functional skills, supply chain management (SCM) qualifications and leadership, SCM expertise, and industry-specific and senior management skills. Statistic tests indicate that supply chain manager competence saliences vary in different industries and regions.