Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer

Germline mutations in checkpoint kinase 2 (CHEK2), a multiple cancer‐predisposing gene, increase breast cancer (BC) risk; however, risk estimates differ substantially in published studies. We analyzed germline CHEK2 variants in 1,928 high‐risk Czech breast/ovarian cancer (BC/OC) patients and 3,360 population‐matched controls (PMCs). For a functional classification of VUS, we developed a complementation assay in human nontransformed RPE1‐CHEK2‐knockout cells quantifying CHK2‐specific phosphorylation of endogenous protein KAP1. We identified 10 truncations in 46 (2.39%) patients and in 11 (0.33%) PMC (p = 1.1 × 10−14). Two types of large intragenic rearrangements (LGR) were found in 20/46 mutation carriers. Truncations significantly increased unilateral BC risk (OR = 7.94; 95%CI 3.90–17.47; p = 1.1 × 10−14) and were more frequent in patients with bilateral BC (4/149; 2.68%; p = 0.003), double primary BC/OC (3/79; 3.80%; p = 0.004), male BC (3/48; 6.25%; p = 8.6 × 10−4), but not with OC (3/354; 0.85%; p = 0.14). Additionally, we found 26 missense VUS in 88 (4.56%) patients and 131 (3.90%) PMC (p = 0.22). Using our functional assay, 11 variants identified in 15 (0.78%) patients and 6 (0.18%) PMC were scored deleterious (p = 0.002). Frequencies of functionally intermediate and neutral variants did not differ between patients and PMC. Functionally deleterious CHEK2 missense variants significantly increased BC risk (OR = 3.90; 95%CI 1.24–13.35; p = 0.009) and marginally OC risk (OR = 4.77; 95%CI 0.77–22.47; p = 0.047); however, carriers low frequency will require evaluation in larger studies. Our study highlights importance of LGR detection for CHEK2 analysis, careful consideration of ethnicity in both cases and controls for risk estimates, and demonstrates promising potential of newly developed human nontransformed cell line assay for functional CHEK2 VUS classification.
GATA‐1 isoforms differently contribute to the production and compartmentation of reactive oxygen species in the myeloid leukemia cell line K562

Maintenance of a balanced expression of the two isoforms of the transcription factor GATA‐1, the full‐length protein (GATA‐1FL) and a shorter isoform (GATA‐1 S), contributes to control hematopoiesis, whereas their dysregulation can alter the differentiation/proliferation potential of hematopoietic precursors thereby eventually leading to a variety of hematopoietic disorders. Although it is well established that these isoforms play opposite roles in these remarkable processes, most of the molecular pathways involved remain unknown.
Kinetic analysis of cyclophilin-catalyzed prolyl cis/trans isomerization by dynamic NMR spectroscopy.

To investigate the kinetics of the prolyl peptide bond cis/trans isomerization of N-succinyl-Ala-Phe-Pro-Phe-(4)-nitroanilide catalyzed by peptidyl prolyl cis/trans isomerases (PPIases), one-dimensional dynamic 1H NMR spectroscopy was employed. To this end line shape analyses of proton signals were performed at various concentrations of both cytosolic porcine kidney cyclophilin (Cyp18) and peptide substrate. Catalysis of the cis/trans isomerization by Cyp18 is best described by a four-site exchange model, where the four sites represent the cis and trans isomers free in solution and bound to the enzyme. Combination of dynamic NMR spectroscopy with the classical protease-coupled PPIase assay allowed determination of the complete set of the microscopic rate constants describing the four site exchange model. The comparison of the rate constants of cis-->trans isomerization of the peptide free in solution and bound to cyclophilin yields an acceleration factor of 3.5 x 10(5). Dissociation of the Michaelis complexes are of the same order of magnitude as the isomerization rates on the enzyme. Therefore, all microscopic rate constants contribute to the steady state parameters. For the first time, the kcat (620 s-1) and KM (220 microM) value for the trans isomer in addition to the values of the cis isomer (kcat = 680 s-1, KM = 80 microM) could be determined under reversible conditions at pH 6.0 and 10 degrees C. The affinity of Cyp18 for the cis isomer is 4 times higher than for the trans isomer. This results in a shift of the cis/trans equilibrium toward the cis isomer. (ABSTRACT TRUNCATED AT 250 WORDS)
Tooth defects of EEC and AEC syndrome caused by heterozygous TP63 mutations in three Chinese families and genotype‐phenotype correlation analyses of TP63‐related disorders

Ectrodactyly‐Ectodermal dysplasia‐Cleft lip/palate (EEC) syndrome and Ankyloblepharon‐Ectodermal defects‐Cleft lip/palate (AEC) syndrome belong to p63 syndromes, a group of rare disorders exhibiting a wide variety of clinical manifestations. TP63 mutations have been reported to be associated with both EEC and AEC.
A Double Multivariate Exponentially Weighted Moving Average (dMEWMA) Control Chart for a Process Location Monitoring

A new control scheme, dMEWMA, for detecting shifts in the mean vector of multivariately normally distributed quality characteristics is presented. It is shown that the ARL performance of dMEWMA depends on the mean and variance-covariance matricies only through the non-centrality parameter value. Through Monte Carlo simulations, the performance of dMEWMA for detecting various shifts is compared to the competing control schemes, MEWMA and Hotelling's χ2. It is concluded that dMEWMA outperforms MEWMA and Hotelling's χ2 control schemes for small and larger shifts. In comparison to MEWMA control schemes, dMEWMA schemes are optimal for larger values of the smoothing parameter λ and perform much better for very small shifts in the process mean. Finally, an example to illustrate the construction of the dMEWMA control scheme is introduced.
Brucellosis awareness and knowledge in communities worldwide: A systematic review and meta-analysis of 79 observational studies

Background Brucellosis is regarded as a major zoonotic infection worldwide. Awareness and knowledge of brucellosis among occupational workers is considered an important aspect of brucellosis control in both humans and animals. The aim of this study was to explore the distributions of the pooled awareness level and the knowledge level of the disease worldwide. Methods A meta-analysis was carried out to obtain pooled brucellosis awareness levels and knowledge levels of respondents regarding the zoonotic nature of brucellosis, mode of brucellosis transmission, and brucellosis symptoms in animals and humans. The analysis was conducted and reported in accordance with the Preferred Reporting Items for Systematic Review and Meta-analyses guidelines. Results A total of seventy-nine original articles reporting the brucellosis awareness levels of in populations from 22 countries were assessed. The total pooled awareness level of brucellosis was 55.5%, and the pooled awareness levels regarding the zoonotic nature of brucellosis, mode of brucellosis transmission, signs of human brucellosis and signs of animal brucellosis were 37.6%, 35.9%, 41.6%, and 28.4% respectively. The pooled awareness level was higher than the brucellosis-related knowledge level. Subgroup analyses showed that no obvious differences in brucellosis awareness levels between high-risk populations in Asia and Africa. Health workers (including human health workers and veterinarians) had the greatest overall awareness and knowledge of human brucellosis. The overall awareness levels and knowledge levels of livestock owners (farmers) and herders were higher than those of dairy farmers and abattoir workers. In addition, awareness and knowledge levels were higher among people who were involved in bovine, caprine and ovine animal production or in caprine and ovine animal production than among people who were involved in only bovine animal production. Conclusions Insufficient awareness and knowledge of brucellosis were observed in the original studies conducted mainly in Asia and Africa. Interventions to improve public knowledge about brucellosis are urgently needed.
CD markers variations in chronic lymphocytic leukemia: New insights into prognosis

Chronic lymphocytic leukemia (CLL) is one of the most commonly occurring adult leukemias that is associated with clonal accumulation of mature apoptosis‐resistant B‐cells in bone marrow, peripheral blood, and specific tissues. Different pathogenesis factors can contribute to the aggression of the clinical course in this disease. Cytogenetic abnormalities and surface biomarkers of neoplastic CLL cells can be effective in the outcome of CLL, and the examination of changing CD markers expressions in the progression of CLL can be related to the prognosis of this disease. Changing expression levels of CD markers on lymphocytes and other cells in CLL patients can play a role in the aggressive clinical outcomes such as organomegaly, immunodeficiency, and advanced disease stages through their interaction with CLL microenvironment. Given the involvement of CD markers in the pathogenesis of CLL, it can be stated that recognizing the expression changes of CD markers in the cells involved in CLL can be a proper approach to evaluate prognosis among these patients.
Metabolomics Reveal Altered Postprandial Lipid Metabolism After a High-Carbohydrate Meal in Men at High Genetic Risk of Diabetes.

BACKGROUND The transcription factor 7-like 2 (TCF7L2) gene confers one of the strongest genetic predispositions to type 2 diabetes, but diabetes development can be modified by diet. OBJECTIVE The aim of our study was to evaluate postprandial metabolic alterations in healthy men with a high genetic risk of diabetes, after two meals with varying macronutrient content. METHODS The study was conducted in 21 homozygous nondiabetic men carrying the high-risk (HR, n = 8, age: 31.2 ± 6.3 y, body mass index (BMI, kg/m2) 28.5 ± 8.1) or low-risk (LR, n = 13, age: 35.2 ± 10.3 y, BMI: 28.1 ± 6.4) genotypes at the rs7901695 locus. During two meal challenge test visits subjects received standardized isocaloric (450 kcal) liquid meals: high-carbohydrate (HC, carbohydrates: 89% of energy) and normo-carbohydrate (NC, carbohydrates: 45% of energy). Fasting (0 min) and postprandial (30, 60, 120, 180 min) plasma samples were analyzed for metabolite profiles through untargeted metabolomics. Metabolic fingerprinting was performed on an ultra-high-performance liquid chromatography (UHPLC) system connected to an iFunnel quadrupole-time-of-flight (Q-TOF) mass spectrometer. RESULTS In HR-genotype men, after the intake of an HC-meal, we noted a significantly lower area under the curves (AUCs) of postprandial plasma concentrations of most of the phospholipids (-37% to -53%, variable importance in the projection (VIP) = 1.2-1.5), lysophospholipids (-29% to -86%, VIP = 1.1-2.6), sphingolipids (-32% to -47%, VIP = 1.1-1.3), as well as arachidonic (-36%, VIP = 1.4) and oleic (-63%, VIP = 1.3) acids, their metabolites: keto- and hydoxy-fatty acids (-38% to -78%, VIP = 1.3-2.5), leukotrienes (-65% to -83%, VIP = 1.4-2.2), uric acid (-59%, VIP = 1.5), and pyroglutamic acid (-65%, VIP = 1.8). The AUCs of postprandial sphingosine concentrations were higher (125-832%, VIP = 1.9-3.2) after the NC-meal, AUCs of acylcarnitines were lower (-21% to -61%, VIP = 1.1-2.4), and AUCs of fatty acid amides were higher (51-508%, VIP = 1.7-3.1) after the intake of both meals. CONCLUSIONS In nondiabetic men carrying the TCF7L2 HR genotype, subtle but detectable modifications in intermediate lipid metabolism are induced by an HC-meal. This trial was registered at www.clinicaltrials. gov as NCT03792685.
Familiarity, Navigation, and Comprehension: Key Dimensions of Health Literacy in Pap Test Use among Korean American Women

Health literacy consists of multiple dimensions such as print and oral literacy or numeracy. Different dimensions of health literacy may have more salient impact on certain health behaviors and outcomes. Yet, evidence is limited regarding which dimensions particularly affect cervical cancer screening. The objective of this study was to examine the role of different dimensions of health literacy in cervical cancer screening among Korean American women. We used baseline data obtained from 560 Korean American women in a community-based health literacy-focused intervention study. Backward stepwise logistic regression analysis revealed that familiarity (adjusted odds ratio [AOR] = 1.20, 95% confidence interval [CI] = 1.11–1.31) and navigational health literacy (AOR = 1.10, 95% CI = 1.04–1.16) were associated with lifetime Pap test use and comprehension (AOR = 1.08, 95% CI = 1.02–1.14) with triennial Pap test screening. Prior exposure to healthcare settings and knowing how to navigate the healthcare system were more important than other health literacy dimensions for lifetime Pap test use. Understanding cancer screening-related words was most relevant to triennial Pap test use. In addition to addressing system factors such as insurance and physicians’ recommendations, interventions to increase Pap test screening targeted at Korean American women are needed to address certain dimensions of health literacy such as familiarity, navigation, and comprehension.
Milestones in Early Poliomyelitis Research (1840 to 1949)

I shall restrict my remarks to some papers on poliomyelitis, published in the period from 1840 to 1949, which I personally consider highly significant. The work on foot-and-mouth-disease by Friedrich Loeffler and Paul Frosch ([17][1]), first reported in 1897, has recently been reviewed several times
Characterization of host plant resistance to zebra chip disease from species-derived potato genotypes and the identification of new sources of zebra chip resistance

‘Candidatus Liberibacter solanacearum’ (Lso), an uncultivable phloem-limited phytopathogenic bacteria, is known to be associated with Zebra Chip disease (ZC), which represents a major threat to potato production in the US and elsewhere. This pathogen is transmitted by the phloem-feeding potato psyllid, Bactericera cockerelli Sulc (Hem. Triozidae). Currently, there are no reports of resistance to ZC in cultivated potatoes. This greenhouse study was conducted to evaluate Lso transmission success and the susceptibility of 11 potato breeding clones, representing diverge genetic background, to ZC, in relation to a susceptible commercial cultivar, Russet Burbank. Individual plants were exposed to two Lso-positive potato psyllids for 48 hours. The percentage of successful Lso transmission varied across the evaluated genotypes ranging between 7 and 57%. Freshly-cut and fried tubers showed significant variation in ZC symptom severity among the breeding clones, with several genotypes expressing relative tolerance when compared to Russet Burbank. None of the evaluated clones showed statistically lower Lso titers than Russet Burbank with the exception of one genotype in the second year of the study. However, the presence of a non-significant relationship between average symptom severity and Lso titer indicated variations in phenotypic responses (i.e. tolerance) to Lso existed among evaluated breeding lines. Breeding clones A07781-3LB, A07781-4LB and A07781-10LB had relatively lower Lso titer (low susceptibility) and tuber symptom expression (high tolerance) among the tested genotypes. As these three clones represent full siblings, the observed effects could be indicative of the presence of a genetic basis for resistance/tolerance to ZC. Findings provide a better understanding of resistance/tolerance to ZC, and contribute to continued efforts in breeding for resistance to this disease.
Color Preference of ICD-9 Schizophrenics and Normal Controls

Color preferences of 20 inpatients with ICD-9 diagnosis of schizophrenia were compared with those of 24 normal control subjects by means of the cards of the Luescher 8 Color Test. The only significant difference was found on the Luescher Anxiety Scale; however, this difference seems too weak for practical clinical use.
Cell‐specific actions of HIV‐Tat and morphine on opioid receptor expression in glia

HIV‐1 patients who abuse opiate‐based drugs, including heroin and morphine, are at a higher risk of developing HIV dementia. The effects of opiates are mediated predominantly through opioid receptors, which are expressed on glial cells. As HIV‐1 infection in the CNS is restricted to glial cells, experiments were designed to measure the cell‐specific effects of HIV Tat and morphine exposure on opioid receptor expression in both astrocytes and microglia. Specifically, the cell‐type‐specific pattern of mu opioid receptor (MOR), delta opioid receptor (DOR), and kappa opioid receptor (KOR) localization (surface vs. intracellular) and expression of opioid receptor mRNA were determined after exposure to morphine in the presence and the absence of Tat in primary cultured microglia and astrocytes. Data show that morphine treatment caused significantly decreased cell surface expression of opioid receptors in microglia but not in astrocytes. However, morphine treatment in the presence of Tat significantly increased intracellular expression of opioid receptors and prevented morphine‐induced cell surface opioid receptor down‐regulation in microglia. These findings document that cell surface opioid receptor expression is divergently regulated by morphine in microglia compared with in astrocytes, and further suggest that HIV‐Tat could exacerbate opioid receptor signaling in microglia by increasing receptor expression and/or altering ligand‐induced trafficking of opioid receptors. © 2008 Wiley‐Liss, Inc.
Glyphosate in yam from Ghana

ABSTRACT Glyphosate is used in Ghana on many crops including yam. There is the suspicion that there could be residue problems in the yam crop. Glyphosate as a polar compound is noted for its difficulty to be analysed in biological matrices. In this study, the method for glyphosate analysis based on FMOC-Cl derivatization was modified with a clean-up (CH2Cl2) step and validated to analyse glyphosate in yam by LC-MS/MS. The results showed that the validated method was efficient for the analysis of glyphosate in yam, with recoveries of 34%, linearity of 0.997, RSD of 7%, LOD of 0.04 mg kg−1, and LOQ of 0.12 mg kg−1. Out of 68 samples analysed from a field experiment and from markets, glyphosate was detected in 14 samples, but at levels below the LOQ. It is concluded that the yam contained glyphosate residues at very low levels which may not pose threat to human health.
The β2-Adrenoceptor Agonist Formoterol Stimulates Mitochondrial Biogenesis

Mitochondrial dysfunction is a common mediator of disease and organ injury. Although recent studies show that inducing mitochondrial biogenesis (MB) stimulates cell repair and regeneration, only a limited number of chemicals are known to induce MB. To examine the impact of the β-adrenoceptor (β-AR) signaling pathway on MB, primary renal proximal tubule cells (RPTC) and adult feline cardiomyocytes were exposed for 24 h to multiple β-AR agonists: isoproterenol (nonselective β-AR agonist), (±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate (BRL 37344) (selective β3-AR agonist), and formoterol (selective β2-AR agonist). The Seahorse Biosciences (North Billerica, MA) extracellular flux analyzer was used to quantify carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled oxygen consumption rate (OCR), a marker of maximal electron transport chain activity. Isoproterenol and BRL 37244 did not alter mitochondrial respiration at any of the concentrations examined. Formoterol exposure resulted in increases in both FCCP-uncoupled OCR and mitochondrial DNA (mtDNA) copy number. The effect of formoterol on OCR in RPTC was inhibited by the β-AR antagonist propranolol and the β2-AR inverse agonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol hydrochloride (ICI-118,551). Mice exposed to formoterol for 24 or 72 h exhibited increases in kidney and heart mtDNA copy number, peroxisome proliferator-activated receptor γ coactivator 1α, and multiple genes involved in the mitochondrial electron transport chain (F0 subunit 6 of transmembrane F-type ATP synthase, NADH dehydrogenase subunit 1, NADH dehydrogenase subunit 6, and NADH dehydrogenase [ubiquinone] 1β subcomplex subunit 8). Cheminformatic modeling, virtual chemical library screening, and experimental validation identified nisoxetine from the Sigma Library of Pharmacologically Active Compounds and two compounds from the ChemBridge DIVERSet that increased mitochondrial respiratory capacity. These data provide compelling evidence for the use and development of β2-AR ligands for therapeutic MB.
Deep convolutional neural networks for detecting secondary structures in protein density maps from cryo-electron microscopy

The detection of secondary structure of proteins using three dimensional (3D) cryo-electron microscopy (cryo-EM) images is still a challenging task when the spatial resolution of cryo-EM images is at medium level (5–10Å). Prior researches focused on the usage of local features that may not capture the global information of image objects. In this study, we propose to use deep learning methods to extract high representative global features and then automatically detect secondary structures of proteins. In particular, we build a convolutional neural network (CNN) classifier that predicts the probability of label for every individual voxel in 3D cryo-EM image with respect to the secondary structure elements of proteins such as α-helix, β-sheet and background. To effectively incorporate the 3D spatial information in protein structures, we propose to perform 3D convolutions in the convolutional layers of CNNs. We show that the proposed CNN classifier can outperform existing SVM method on identifying the secondary structure elements of proteins from 3D cryo-EM medium resolution images.
Roles for KRAS in pancreatic tumor development and progression.

The Kras gene is mutated to an oncogenic form in most pancreatic tumors. However, early attempts to use this molecule as a specific biomarker of the disease, or inhibit its activity as a cancer therapy, failed. This left a situation in which everyone was aware of the association between this important oncogene and pancreatic cancer, but no one knew what to do about it. Recent findings have changed this picture-many assumptions made about KRAS and its role in pancreatic cancer were found to be incorrect. Several factors have contributed to increased understanding of the activities of KRAS, including creation of genetically engineered mouse models, which have allowed for detailed analyses of pancreatic carcinogenesis in an intact animal with a competent immune system. Cancer genome sequencing projects have increased our understanding of the heterogeneity of individual tumors. We also have a better understanding of which oncogenes are important for tumor maintenance and are therefore called "drivers. " We review the advances and limitations of our knowledge about the role of Kras in development of pancreatic cancers and the important areas for future research.