Miracle-dz/UniFAR-FTUs huggingface dataset:
Linear age‐course effects on the associations between body mass index, triglycerides, and female breast and male liver cancer risk: An internal replication study of 800,000 individuals

Apart from the consistently observed differential association between obesity and breast cancer risk by menopausal status, the associations between obesity and other metabolic imbalances with risks of cancers have not been systematically investigated across the age‐course. We created two random 50–50% cohorts from six European cohorts comprising 813,927 individuals. In the “discovery cohort”, we used Cox regression with attained age as time‐scale and tested interactions between body mass index (BMI), blood pressure, plasma glucose, triglycerides and cholesterol, and attained age in relation to cancer risk. Results with a p‐value below 0.05 were additionally tested in the “replication cohort” where a replicated result was considered evidence of a linear interaction with attained age. These findings were investigated by flexible parametric survival models for any age‐plateaus in their shape of associations with cancer risk across age. Consistent with other studies, BMI was negatively related to breast cancer risk (n cases = 11,723) among younger (premenopausal) women. However, the association remained negative for several years after menopause and, although gradually weakening over age, the association became positive only at 62 years of age. This linear and positive age‐interaction was also found for triglycerides and breast cancer, and for BMI and triglycerides in relation to liver cancer among men (n cases = 444). These findings are unlikely to be due to chance owing to the replication. The linear age‐interactions in breast cancer may suggest an influence by other age‐related factors than menopause; however, further investigation of age‐related effect modifiers in both breast and liver cancer is needed.
Etiological and Clinical Characteristics of HLA-B27-associated Uveitis in a Tertiary Referral Center

Objectives: To investigate the demographic, etiologic, and clinical features of HLA-B27-associated uveitis. Materials and Methods: The clinical records of 91 patients diagnosed with HLA-B27-associated uveitis at the Ulucanlar Eye Training and Research Hospital between the years of 2005 and 2016 were reviewed. Each patient’s presenting complaints, best-corrected visual acuities in first and last visits, biomicroscopic and fundoscopic examination findings, frequency and seasonal distribution of attacks, and demographic data such as age and sex were noted. Therapeutic approaches, duration of follow-up, and complications were analyzed. Results: A total of 91 patients (179 eyes) aged 19-82 years (mean age 46.52±13.06 years) were included. Forty-three patients (47.3%) were female and 48 (52.7%) were male. Bilateral involvement was observed in 44 (48.4%) and unilateral involvement was observed in 47 (51.6%) patients. The most frequent complaint was redness (67%), followed by decreased and/or blurred vision (50.5%). The mean follow-up time was 38.2 months (range, 1-245 months). Anterior uveitis was most common anatomical subtype, seen in 86 (94.5%) of the patients. Mean number of attacks was 1.93±1.45 per patient-year and a significantly higher number of uveitis attacks (47%) occurred in winter. Twenty-four patients (26.3%) were diagnosed with ankylosing spondylitis. Fibrinous uveitis was detected in 36 patients (39.5%). Posterior synechia developed in 41 (22.9%) and hypopyon developed in 7 (3.9%) eyes. The most common complications were cataract (n=12, 6.7%) and ocular hypertension (n=15, 8.3%). Conclusion: Ninety-one (6.3%) of the 1422 patients followed in our uvea clinic were diagnosed with HLA-B27-associated uveitis. HLA-B27-associated uveitis is characterized by acute, recurring sudden-onset iridocyclitis with a moderate to severe amount of fibrin and cells in the anterior chamber, and is easily treatable. Visual prognosis is good despite the complications.
Cell Biology International

Cardiac fibrosis is associated with various cardiovascular diseases and can eventually lead to heart failure. Dysregulation of long non‐coding RNAs (lncRNAs) are recognized as one of the key mechanisms of cardiac diseases. However, the roles and underlying mechanisms of lncRNAs in cardiac fibrosis have not been explicitly defined. Here, we investigated the role of an antisense (AS) lncRNA from the Ras association domain‐containing protein 1 isoform A (RASSF1A) gene locus, named RASSF1‐AS1, in the development of cardiac fibrosis. Cardiac fibrosis mouse model was established by isoproterenol injection. We found that RASSF1A protein was downregulated, whereas RASSF1‐AS1 was markedly upregulated during cardiac fibrosis. Overexpression and knockdown of mouse primary cardiac fibroblasts showed that RASSF1‐AS1 negatively regulated RASSF1A expression at the post‐transcriptional level. According to the landscape analysis and sense‐AS binding evaluation, RASSF1‐AS1 partially overlaps with RASSF1A messenger RNA (mRNA) at the exon2 region. RNA pull‐down and luciferase activity assays confirmed that RASSF1‐AS1 directly bound to RASSF1A mRNA and suppressed its translation. Furthermore, wild‐type RASSF1‐AS1 had a promoting effect on nuclear factor‐κB activation and cardiac fibrosis, but mutated RASSF1‐AS1, in which the binding region was deleted, had no effect. In conclusion, RASSF1‐AS1 inhibits the translation of RASSF1A to exacerbate cardiac fibrosis in mice, indicating a potential application of RASSF1‐AS1 as a therapy target for cardiac fibrosis.
Tramadol overdose as a cause of serotonin syndrome: a case series

Introduction. Tramadol overdose impairs consciousness and may induce ECG changes and convulsions. These effects may be opioid and/or serotonin related. This study describes clinical manifestations, electrophysiological and hemodynamic findings, and the frequency of potential serotonin syndrome in tramadol overdose in a case series. It also focuses on potential factors by which convulsions could be predicted. Methods. This is a prospective observational case series. All cases admitted with suspected tramadol overdose from September 1, 2006 to August 31, 2007 were included. Results. Tramadol overdose accounted for 1.2% of all poisonings (n = 158), of which 65% were tramadol only. It was predominantly male (63%). Mean (SD) age was 22.6 (7.4) years. Among these cases, 24 (15%) experienced seizure and in 10 (6%) cases creatine phosphokinase increased. Death occurred in one patient. Seizure occurred more frequently in patients with tramadol use only [odds ratio 3.0, 95% confidence interval 1.1, 8.4] and mydriasis (odds ratio 8.9, 95% confidence interval 1.9, 42.4) on admission. Eight cases were treated for potential serotonin syndrome. Concurrent intoxication with central nervous system depressants, age, alleged dose, consciousness level, respiratory rate, history of drug abuse, and naloxone administration was not associated with the occurrence of seizures. Conclusion. In tramadol overdose, mydriasis or tachycardia appears to indicate a higher risk for seizure. Management may need to be focused on both μ-opioid agonism and potential mild serotonin syndrome.
Commentary on "The Challenge of Transforming the Diagnostic System of Personality Disorders".

Author(s): Hopwood, Christopher J; Krueger, Robert F; Watson, David; Widiger, Thomas A; Althoff, Robert R; Ansell, Emily B; Bach, Bo; Bagby, R Michael; Blais, Mark A; Bornovalova, Marina A; Chmielewski, Michael; Cicero, David C; Conway, Christopher; De Clerq, Barbara; De Fruyt, Filip; Docherty, Anna R; Eaton, Nicholas R; Edens, John F; Forbes, Miriam K; Forbush, Kelsie T; Hengartner, Michael P; Ivanova, Masha Y; Leising, Daniel; Lukowitsky, Mark R; Lynam, Donald R; Markon, Kristian E; Miller, Joshua D; Morey, Leslie C; Mullins-Sweatt, Stephanie N; Ormel, Johan; Patrick, Christopher J; Pincus, Aaron L; Ruggero, Camilo; Samuel, Douglas B; Sellbom, Martin; Tackett, Jennifer L; Thomas, Katherine M; Trull, Timothy J; Vachon, David D; Waldman, Irwin D; Waszczuk, Monika A; Waugh, Mark H; Wright, Aidan GC; Yalch, Mathew M; Zald, David H; Zimmermann, Johannes
Clinical practice visits: a rapid review

Practice visits are a peer review activity where one or more healthcare providers visit the practice of another in the same field. The purpose of this exercise is for visitors to observe and review a host’s practice in a non‐punitive manner and provide them with constructive feedback as required; ultimately to improve practice quality and patient care.
Effects of a 12-Month Randomized Controlled Trial of Aerobic or Resistance Exercise During and Following Cancer Treatment in Women

Abstract Weight gain is common during and following cancer treatment and contributes to many adverse health consequences and increased risk of recurrence for cancer survivors. The purpose of this longitudinal randomized controlled trial was to compare differences in weight change and body composition among newly diagnosed cancer survivors receiving chemotherapy who were randomly assigned to usual care control, aerobic exercise, or resistance exercise interventions. It was hypothesized that cancer survivors become more sedentary during treatment, leading to positive energy balance that in turn worsens body composition. One hundred one subjects completed the 12-month study. Data collected included body composition (body weight and dual energy x-ray absorptiometry scan), aerobic capacity (12-minute walk), and muscle strength (1 repetition maximum). Aerobic exercisers were found to have significant improvements in body composition, aerobic capacity, and muscle strength. Resistance exercisers also benefitted, but were less compliant with the intervention over time. Thus, exercise during and following cancer treatment is an important intervention to maintain and perhaps improve body composition of cancer survivors, which may improve survival, reduce comorbidities, and improve quality of life.
Cholesterol depletion inhibits Na+,K+-ATPase activity in a near-native membrane environment

Cholesterol's effects on Na+,K+-ATPase reconstituted in phospholipid vesicles have been extensively studied. However, previous studies have reported both cholesterol-mediated stimulation and inhibition of Na+,K+-ATPase activity. Here, using partial reaction kinetics determined via stopped-flow experiments, we studied cholesterol's effect on Na+,K+-ATPase in a near-native environment in which purified membrane fragments were depleted of cholesterol with methyl-β-cyclodextrin (mβCD). The mβCD-treated Na+,K+-ATPase had significantly reduced overall activity and exhibited decreased observed rate constants for ATP phosphorylation (ENa3+ → E2P, i.e. phosphorylation by ATP and Na+ occlusion from the cytoplasm) and K+ deocclusion with subsequent intracellular Na+ binding (E2K2+ → E1Na3+). However, cholesterol depletion did not affect the observed rate constant for K+ occlusion by phosphorylated Na+,K+-ATPase on the extracellular face and subsequent dephosphorylation (E2P → E2K2+). Thus, partial reactions involving cation binding and release at the protein's intracellular side were most dependent on cholesterol. Fluorescence measurements with the probe eosin indicated that cholesterol depletion stabilizes the unphosphorylated E2 state relative to E1, and the cholesterol depletion-induced slowing of ATP phosphorylation kinetics was consistent with partial conversion of Na+,K+-ATPase into the E2 state, requiring a slow E2 → E1 transition before the phosphorylation. Molecular dynamics simulations of Na+,K+-ATPase in membranes with 40 mol % cholesterol revealed cholesterol interaction sites that differ markedly among protein conformations. They further indicated state-dependent effects on membrane shape, with the E2 state being likely disfavored in cholesterol-rich bilayers relative to the E1P state because of a greater hydrophobic mismatch. In summary, cholesterol extraction from membranes significantly decreases Na+,K+-ATPase steady-state activity.
Bone marrow endothelial cell-derived interleukin-4 contributes to thrombocytopenia in acute myeloid leukemia

Normal hematopoiesis can be disrupted by the leukemic bone marrow microenvironment, which leads to cytopenia-associated symptoms including anemia, hemorrhage and infection. Thrombocytopenia is a major and sometimes fatal complication in patients with acute leukemia. However, the mechanisms underlying defective thrombopoiesis in leukemia have not been fully elucidated. In the steady state, platelets are continuously produced by megakaryocytes. Using an MLL-AF9-induced acute myeloid leukemia mouse model, we demonstrated a preserved number and proportion of megakaryocyte-primed hematopoietic stem cell subsets, but weakened megakaryocytic differentiation via both canonical and non-canonical routes. This primarily accounted for the dramatic reduction of megakaryocytic progenitors observed in acute myeloid leukemia bone marrow and a severe disruption of the maturation of megakaryocytes. Additionally, we discovered overproduction of interleukin-4 from bone marrow endothelial cells in acute myeloid leukemia and observed inhibitory effects of interleukin-4 throughout the process of megakaryopoiesis in vivo. Furthermore, we observed that inhibition of interleukin-4 in combination with induction chemotherapy not only promoted recovery of platelet counts, but also prolonged the duration of remission in our acute myeloid leukemia mouse model. Our study elucidates a new link between interleukin-4 signaling and defective megakaryopoiesis in acute myeloid leukemia bone marrow, thereby offering a potential therapeutic target in acute myeloid leukemia.
Complexities of Type I Interferon Biology: Lessons from LCMV

Over the past decades, infection of mice with lymphocytic choriomeningitis virus (LCMV) has provided an invaluable insight into our understanding of immune responses to viruses. In particular, this model has clarified the central roles that type I interferons play in initiating and regulating host responses. The use of different strains of LCMV and routes of infection has allowed us to understand how type I interferons are critical in controlling virus replication and fostering effective antiviral immunity, but also how they promote virus persistence and functional exhaustion of the immune response. Accordingly, these discoveries have formed the foundation for the development of novel treatments for acute and chronic viral infections and even extend into the management of malignant tumors. Here we review the fundamental insights into type I interferon biology gained using LCMV as a model and how the diversity of LCMV strains, dose, and route of administration have been used to dissect the molecular mechanisms underpinning acute versus persistent infection. We also identify gaps in the knowledge regarding LCMV regulation of antiviral immunity. Due to its unique properties, LCMV will continue to remain a vital part of the immunologists’ toolbox.
Genomic Instability and Cytotoxicity in Buccal Mucosal Cells of Workers in Banana Farming Evaluated by Micronucleus Test

Background/Aim: Studies have demonstrated the biological consequences of environmental contamination caused by human pesticide exposure following banana production. The aim of this study was to evaluate genomic instability and cytotoxicity in buccal mucosal cells of workers in banana farming. Materials and Methods: For this purpose, a total of 21 male workers in banana farming in the Ribeira Valley were included in the experimental group. A total of 20 individuals, not occupationally exposed to pesticides, were included in the control group. Results: The frequency of micronuclei was significantly increased (p<0.05) in buccal mucosa cells from workers of banana farming when compared to the control group. Furthermore, a high frequency of karyolysis was detected in buccal mucosaI cells in these individuals. No significant differences were found in pyknosis or karryorhexis when compared to controls. Conclusion: Taken together, our results indicate that workers in banana farming represent a group in high risk for carcinogenesis since chromosomal damage and cellular death are increased in these individuals.
Risk factors and an early prediction model for persistent methamphetamine‐related psychiatric symptoms

Methamphetamine (MA)‐related psychiatric symptoms (MAP) are serious comorbidities of MA use and result in many social problems such as violence and suicide. We investigated the sociodemographic and genetic risk factors for persistent MAP of MA users (MUs) and constructed an early MAP prediction model. Derivation and replication samples had 1734 and 905 MUs, respectively. Symptom Checklist 90, Childhood Trauma Questionnaire, Attention‐Deficit Hyperactivity Disorder (ADHD) Rating Scale‐IV, and Social Support Rating Scale were used to assess the past‐year prevalence of general MAP and life events retrospectively. Genome‐wide association study (GWAS) was used to analyze MAP‐related genetic factors. The prediction model was constructed by integrating the risk life events and clinical and genetic features using logistic regression. Of the 2639 MUs, 1293 (48.83%) had past‐year MAP. The severity of MA addiction (SMA), childhood trauma, childhood ADHD symptoms, and social support were reliable risk factors for persistent MAP. By integrating these risk factors and the polygenic risk score from GWAS from derivation samples, the area under the curve (AUC) of the predictive model for MAP was 0.754 (95% CI 0.717~0.771). The risk factors and prediction model were also verified in replication samples. In addition, SMA, ADHD, and social support were mediators for the effect of the risk genetic factor on persistent MAP. Our study identified several risk factors for persistent MAP and will be helpful for developing scalable tools for the prevention of persistent and general MAP.
Biofilm formation by staphylococci in health-related environments and recent reports on their control using natural compounds

Abstract Staphylococci are Gram-positive bacteria that are ubiquitous in the environment and able to form biofilms on a range of surfaces. They have been associated with a range of human health issues such as medical device-related infection, localized skin infection, or direct infection caused by toxin production. The extracellular material produced by these bacteria resists antibiotics and host defence mechanism which complicates the treatment process. The commonly reported Staphylococcus species are Staphylococcus aureus and S. epidermidis as they inhabit human bodies. However, the emergence of other staphylococci, such as S. haemolyticus, S. lugdunensis, S. saprophyticus, S. capitis, S. saccharolyticus, S. warneri, S. cohnii, and S. hominis, is also of concern and they have been associated with biofilm formation. This review critically assesses recent cases on the biofilm formation by S. aureus, S. epidermidis, and other staphylococci reported in health-related environments. The control of biofilm formation by staphylococci using natural compounds is specifically discussed as they represent potential anti-biofilm agents which may reduce the burden of antibiotic resistance.
DNA barcoding and phylogeny of Calidris and Tringa (Aves: Scolopacidae)

Abstract The avian genera Calidris and Tringa are the largest of the widespread family of Scolopacidae. The phylogeny of members of the two genera is still a matter of controversial. Mitochondrial cytochrome c oxidase subunit I (COI) can serve as a fast and accurate marker for the identification and phylogeny of animal species. In this study, we analyzed the COI barcodes of thirty-one species of the two genera. All the species had distinct COI sequences. Two hundred and twenty-one variable sites were identified. Kimura two-parameter distances were calculated between barcodes. Neighbor-joining and maximum likelihood methods were used to construct phylogenetic trees. All the species could be discriminated by their distinct clades in the phylogenetic trees. The phylogenetic trees grouped all the species of Calidris and Tringa into different monophyletic clade, respectively. COI data showed a well-supported phylogeny for Calidris and Tringa species.
Sweet Immunity: Inulin Boosts Resistance of Lettuce (Lactuca sativa) against Grey Mold (Botrytis cinerea) in an Ethylene-Dependent Manner

The concept of “Sweet Immunity” postulates that sugar metabolism and signaling influence plant immune networks. In this study, we tested the potential of commercially available inulin-type fructans to limit disease symptoms caused by Botrytis cinerea in lettuce. Spraying mature lettuce leaves, with inulin-type fructans derived from burdock or chicory was as effective in reducing grey mold disease symptoms caused by Botrytis cinerea as spraying with oligogalacturonides (OGs). OGs are well-known defense elicitors in several plant species. Spraying with inulin and OGs induced accumulation of hydrogen peroxide and levels further increased upon pathogen infection. Inulin and OGs were no longer able to limit Botrytis infection when plants were treated with the ethylene signaling inhibitor 1-methylcyclopropene (1-MCP), indicating that a functional ethylene signaling pathway is needed for the enhanced defense response. Soluble sugars accumulated in leaves primed with OGs, while 1-MCP treatment had an overall negative effect on the sucrose pool. Accumulation of γ-aminobutyric acid (GABA), a stress-associated non-proteinogenic amino acid and possible signaling compound, was observed in inulin-treated samples after infection and negatively affected by the 1-MCP treatment. We have demonstrated for the first time that commercially available inulin-type fructans and OGs can improve the defensive capacity of lettuce, an economically important species. We discuss our results in the context of a possible recognition of fructans as Damage or Microbe Associated Molecular Patterns.
Oligomeric protein interference validates druggability of aspartate interconversion in Plasmodium falciparum

The appearance of multi‐drug resistant strains of malaria poses a major challenge to human health and validated drug targets are urgently required. To define a protein's function in vivo and thereby validate it as a drug target, highly specific tools are required that modify protein function with minimal cross‐reactivity. While modern genetic approaches often offer the desired level of target specificity, applying these techniques is frequently challenging—particularly in the most dangerous malaria parasite, Plasmodium falciparum. Our hypothesis is that such challenges can be addressed by incorporating mutant proteins within oligomeric protein complexes of the target organism in vivo. In this manuscript, we provide data to support our hypothesis by demonstrating that recombinant expression of mutant proteins within P. falciparum leverages the native protein oligomeric state to influence protein function in vivo, thereby providing a rapid validation of potential drug targets. Our data show that interference with aspartate metabolism in vivo leads to a significant hindrance in parasite survival and strongly suggest that enzymes integral to aspartate metabolism are promising targets for the discovery of novel antimalarials.