Miracle-dz/UniFAR-FTUs huggingface dataset:
Immune cells and bone formation in ankylosing spondylitis.

OBJECTIVES The aims of this study were to examine immune cell proportions in peripheral blood of patients with ankylosing spondylitis (AS) and to investigate relationships between immune cells, level of bone formation related molecules, and radiographic changes. METHODS Forty-nine AS patients and 53 age- and sex-matched healthy controls (HCs) were enrolled in this study. Clinical parameters were extensively evaluated in the study subjects. CD4+ T-cells, CD8+ T-cells, CD56+ T-cells, natural killer cells, and natural killer T (NKT) cells in peripheral blood were measured by flow cytometry. Serum levels of Dickkopf-1 and bone morphogenic proteins were determined using enzyme linked immunosorbent assays. Modified Stokes AS spinal scores were used to assess radiographic changes. RESULTS Patients were found to have a significantly higher percentages of CD56+T-cells than healthy controls (median 1.31% vs. 0.53%, p<0.001), whereas percentages of peripheral blood natural killer T (NKT) cell were lower in patients than in controls (median 0.07 % vs. 0.10%, p=0.010). Moreover, mean CD 56+T to NKT cell ratio was markedly higher in patients. Although no significant correlations were observed between the immune cell percentages and bone formation-related molecule levels, interestingly, patients with a higher CD56+T to NKT cell ratio at baseline were found to develop greater radiographic changes (r=0.79, p=0.007, age and disease duration adjusted) during 3 years of radiographic follow-up. CONCLUSIONS An altered T-cell compartment, particularly with respect to CD56+ T and NKT cells, was observed in AS patients and could contribute to radiographic changes in AS.
Results of Surgery in Patients with Refractory Extratemporal Epilepsy with Normal or Nonlocalizing Magnetic Resonance Findings Investigated with Subdural Grids

Summary: Purpose: To study the efficacy of extensive coverage of the brain surface with subdural grids in defining extratemporal cortical areas amenable for resection in patients with refractory extratemporal epilepy (R‐ExTE) and normal or nonlocalizing magnetic resonance imaging (MRI) scans.
Fragmented QRS may predict postoperative atrial fibrillation in patients undergoing isolated coronary artery bypass graft surgery.

OBJECTIVE Fragmented QRS complexes (fQRS) are defined as various RSR' patterns in 2 contiguous leads corresponding to a major coronary artery territory. Although the reason of association between fQRS and cardiac events was documented as cardiac fibrosis, the predictive role of fQRS was not studied for postoperative atrial fibrillation (POAF) which is a frequent and serious complication in patients undergoing isolated coronary artery bypass graft (CABG) surgery. Therefore, this issue was investigated in the present study. METHODS The current study has a prospective observational design. Two hundred and seventy two eligible patients who underwent isolated CABG surgery were enrolled consecutively. The patients were divided in two groups with post-op atrial fibrillation (AF) and non-AF. The occurrence of new-onset AF following CABG and the relationship with fQRS were searched. The logistic regression analysis was used to determine independent predictors for POAF. The sensitivity and specificity of study variables in predicting POAF were calculated using a receiver-operating characteristic curve (ROC). RESULTS POAF occurred in 62 of 272 patients (22.8%). Patients with POAF were generally older (p<0.001) and female (p=0.006), with preexisting hypertension (p=0.008), lower hemoglobin levels (p=0.011), chronic obstructive lung disease (p=0.003), prolonged QRS time (p=0.004), and higher EUROSCORE (p<0.001) compared to non-AF patients. Patients with POAF had lower left ventricular ejection fraction (p<0.001) and high fQRS rate (p<0.001), but similar left atrial size (LA, p=NS). Interestingly, LA size was significantly enlarged in patients with fQRS (3.8±0.6 vs. 4.1±0.5 cm, p=0.002). In addition, the patients with POAF had prolonged stay in the cardiac surgery intensive-care unit (p<0.001) and extended in-hospital care (p=0.001). New-onset POAF was significantly related to the presence and number of fQRS. In the logistic regression analysis, only age (OR: 1.044, 95% CI: 1.008-1.082, p=0.016), female gender (OR: 2.347, 95% CI: 1.079-5.106, p=0.031), the presence and number of fQRS (OR: 6.020, 95% CI: 3.152-11.5 and OR: 1.522, 95% CI: 1.282-1.807, both of, p<0.001) were independent predictors of POAF. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and the diagnostic accuracy (DA) of presence of fQRS on pre-op electrocardiogram to predict POAF were 66%, 76%, 45%, 88% and 74%, respectively. The area under ROC was found as 0.733 (p<0.001, 95% CI: 0.657-0.810). CONCLUSION In our study, we found that new-onset POAF was independently related to the presence and number of fQRS in patients undergoing CABG surgery. In addition, fQRS on pre-op surface ECG had high predictive values for new-onset POAF.
Dependent stressful life events and prior depressive episodes in the prediction of major depression: the problem of causal inference in psychiatric epidemiology.

CONTEXT Most environmental risk factors for psychiatric disorders cannot be studied experimentally, making causal attributions difficult. Can we address this question by using together 2 major methods for causal inference: natural experiments and specialized statistical methods? OBJECTIVE To determine the causal relationship between dependent stressful life events (dSLEs) and prior depressive episodes (PDEs) and major depression (MD). DESIGN Assessment of risk factors and episodes of MD at interview. Statistical analyses used the co-twin control and propensity score-matching methods. SETTING General community. PARTICIPANTS Four thousand nine hundred ten male and female twins from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. MAIN OUTCOME MEASURE Episodes of MD. RESULTS We found that dSLEs were strongly associated with risk for MD in female (odds ratio [OR], 5.85) and male (4.55) twins in the entire sample and, at considerably lower levels, in female (2.29) and male (2.19) monozygotic twins discordant for dSLE exposure. A case-control sample matched on propensity score showed a moderate association in female (OR, 1.79) and male (1.53) twins. A PDE strongly predicted risk for MD in female (OR, 3.68) and male (5.20) twins in the entire sample. In monozygotic pairs discordant for exposure, the association was weaker in male (OR, 1.41) and absent in female (1.00) twins. A case-control sample matched on propensity score showed a moderate association between PDE and depressive episodes in male (OR, 1.58) and female twins (1.66). CONCLUSIONS Although dSLEs have a modest causal effect on the risk for MD, a large proportion of the observed association is noncausal. The same pattern is seen for PDEs, although the causal impact is somewhat more tenuous. For environmental exposures in psychiatry that cannot be studied experimentally, co-twin control and propensity scoring methods--which have complementary strengths and weaknesses--can provide similar results, suggesting their joint use can help with the critical question of causal inference.
Molecular dynamics simulation, binding free energy calculation and unbinding pathway analysis on selectivity difference between FKBP51 and FKBP52: Insight into the molecular mechanism of isoform selectivity

As co‐chaperones of the 90‐kDa heat shock protein(HSP90), FK506 binding protein 51 (FKBP51) and FK506 binding protein 52 (FKBP52) modulate the maturation of steroid hormone receptor through their specific FK1 domains (FKBP12‐like domain 1). The inhibitors targeting FK1 domains are potential therapies for endocrine‐related physiological disorders. However, the structural conservation of the FK1 domains between FKBP51 and FKBP52 make it difficult to obtain satisfactory selectivity in FK506‐based drug design. Fortunately, a series of iFit ligands synthesized by Hausch et al exhibited excellent selectivity for FKBP51, providing new opportunity for design selective inhibitors. We performed molecular dynamics simulation, binding free energy calculation and unbinding pathway analysis to reveal selective mechanism for the inhibitor iFit4 binding with FKBP51 and FKBP52. The conformational stability evaluation of the “Phe67‐in” and “Phe67‐out” states implies that FKBP51 and FKBP52 have different preferences for “Phe67‐in” and “Phe67‐out” states, which we suggest as the determinant factor for the selectivity for FKBP51. The binding free energy calculations demonstrate that nonpolar interaction is favorable for the inhibitors binding, while the polar interaction and entropy contribution are adverse for the inhibitors binding. According to the results from binding free energy decomposition, the electrostatic difference of residue 85 causes the most significant thermodynamics effects on the binding of iFit4 to FKBP51 and FKBP52. Furthermore, the importance of substructure units on iFit4 were further evaluated by unbinding pathway analysis and residue‐residue contact analysis between iFit4 and the proteins. The results will provide new clues for the design of selective inhibitors for FKBP51.
Membrane protein redistribution during differentiation of cultured human erythroleukemic cells

Human erythroleukemic (K562) cells differentiate along the erythroid differentiation pathway in vitro when 0.05 mM hemin is included in the growth medium. In the presence of the inducer the cells continue to proliferate and, after a delay of 24 to 48 h, start to synthesize hemoglobin. However, during differentiation, no changes in the major cell surface proteins were detected using lactoperoxidase-catalyzed iodination, and no change in the synthesis of spectrin, the major cytoskeletal protein of the mature erythrocyte, was detected by specific immune precipitation. Despite this absence of major changes in cell surface proteins, profound changes take place in the organization of the cell membranes. A process similar but not identical to the enucleation observed in erythroid differentiation in vivo occurs in which a smooth-surfaced cell, about 10 micrometers in diameter, is divided from the nucleus-containing part of the cell. With the exception of ribosomes, these reticulocyte-like cells contain no organelles when examined by transmission electron microscopy, but contain much of the parent cell's hemoglobin, spectrin, and glycophorin.
Low protein cage-layer diets and amino acids.

Abstract PREVIOUS studies at this station by Britzman and Carlson (1965) have shown that a 10% protein layer diet supplemented with methionine was adequate for 50 to 60% egg production for 7 months. This diet was made up largely of corn but contained some soybean meal. Further supplementation with amino acids did not enhance egg production, egg size, Haugh unit values, shell thickness or body weight. Dietary additions of methionine, lysine, glycine, valine, arginine, isoleucine and tryptophan, in that order, were added consecutively at the level of 125% of the standard of Johnson and Fisher (1958) to test for the effect of supplemental responses. Another basal diet used by Britzman and Carlson (1965) was formulated by diluting a typical diet with glucose. It was calculated to contain 11 percent protein and contained a ratio of corn to soybean meal protein of 60:40 as recommended by Bray (1960). This basal diet was…
Quantification of Chemotaxis to Naphthalene by Pseudomonas putida G7

ABSTRACT The capillary assay was used to quantify the chemotactic response of Pseudomonas putida G7 to naphthalene. Experiments were conducted in which the cell concentration in the assay chamber, the naphthalene concentration in the capillary, or the incubation time was varied. Data from these experiments were evaluated with a model that accounted for the effect of diffusion on the distribution of substrate and the transport of cells from the chamber through the capillary orifice. By fitting a numerical solution of this model to the data, it was possible to determine the chemotactic sensitivity coefficient, χ0. The mean of the best-fit values for χ0from the three types of experiments was 7.2 × 10−5cm2/s. A less computationally intensive model based on earlier approaches that ignore cell transport in the chamber resulted in χ0 values that were approximately three times higher. The models evaluated in the present study could simulate the results of capillary assays only at low chamber cell concentrations, for which the effect of consumption on the distribution of substrate was negligible. Results from this work suggest that it is possible to use the capillary assay to quantify taxis towards environmentally relevant chemoeffectors that have low aqueous solubility.
Loss of ADAM17-Mediated Tumor Necrosis Factor Alpha Signaling in Intestinal Cells Attenuates Mucosal Atrophy in a Mouse Model of Parenteral Nutrition

ABSTRACT Total parenteral nutrition (TPN) is commonly used clinically to sustain patients; however, TPN is associated with profound mucosal atrophy, which may adversely affect clinical outcomes. Using a mouse TPN model, removing enteral nutrition leads to decreased crypt proliferation, increased intestinal epithelial cell (IEC) apoptosis and increased mucosal tumor necrosis factor alpha (TNF-α) expression that ultimately produces mucosal atrophy. Upregulation of TNF-α signaling plays a central role in mediating TPN-induced mucosal atrophy without intact epidermal growth factor receptor (EGFR) signaling. Currently, the mechanism and the tissue-specific contributions of TNF-α signaling to TPN-induced mucosal atrophy remain unclear. ADAM17 is an ectodomain sheddase that can modulate the signaling activity of several cytokine/growth factor receptor families, including the TNF-α/TNF receptor and ErbB ligand/EGFR pathways. Using TPN-treated IEC-specific ADAM17-deficient mice, the present study demonstrates that a loss of soluble TNF-α signaling from IECs attenuates TPN-induced mucosal atrophy. Importantly, this response remains dependent on the maintenance of functional EGFR signaling in IECs. TNF-α blockade in wild-type mice receiving TPN confirmed that soluble TNF-α signaling is responsible for downregulation of EGFR signaling in IECs. These results demonstrate that ADAM17-mediated TNF-α signaling from IECs has a significant role in the development of the proinflammatory state and mucosal atrophy observed in TPN-treated mice.
Autoreactive IgE Is Prevalent in Systemic Lupus Erythematosus and Is Associated with Increased Disease Activity and Nephritis

The presence of autoantibodies in systemic lupus erythematosus, particularly those of the IgG subclass, have long been associated with disease onset and activity. Here we explored the prevalence of autoreactive IgE in SLE and its relevance to disease in French (n = 79) and United States (US) (n = 117) cohorts with a mean age of 41.5±12.7 and 43.6±15.3 years and disease duration of 13.5±8.5 and 16.6±11.9 years, respectively. Our findings show that approximately 65% of all SLE subjects studied produced IgE antibodies to the seven autoantigens tested. This positivity was increased to almost 83% when only those subjects with active disease were considered. SLE subjects who were positive for anti-dsDNA, -Sm, and -SSB/La -specific IgE showed a highly significant association in the levels of these antibodies with disease activity similar to that of the corresponding IgG's. A strong association of IgE autoantibodies with active nephritis was also found in the combined cohort analysis. A test of the predictive value of autoreactive IgE’s and IgGs for disease activity (SLE Disease Activity Index (SLEDAI) ≥4) revealed that the best predictors were dsDNA-specific IgE and IgG, and that the age of an SLE subject influenced this predictive model. The finding argue that the overall levels of IgE autoantibodies, independently or in combination with IgG autoantibodies, may serve as indicators of active disease.
The FtsQ protein of Escherichia coli: membrane topology, abundance, and cell division phenotypes due to overproduction and insertion mutations

The ftsQ gene is one of several genes thought to be specifically required for septum formation in Escherichia coli. Published work on the cell division behavior of ftsQ temperature-sensitive mutants suggested that the FtsQ product is required throughout the whole process of septum formation. Here we provide additional support for this hypothesis based on microscopic observations of the cell division defects resulting from insertional and temperature-sensitive mutations in the ftsQ gene, and constitutive overexpression of its gene product. On the basis of the published, predicted amino acid sequence of the FtsQ protein and our analysis of fusion proteins of the FtsQ protein to bacterial alkaline phosphatase, we conclude that FtsQ is a simple cytoplasmic membrane protein with a approximately 25-amino-acid cytoplasmic domain and a approximately 225-amino-acid periplasmic domain. We estimate that the FtsQ protein is present at about 22 copies per cell.
Ezh2 Regulates Transcriptional and Posttranslational Expression of T-bet and Promotes Th1 Cell Responses Mediating Aplastic Anemia in Mice

Acquired aplastic anemia (AA) is a potentially fatal bone marrow (BM) failure syndrome. IFN-γ–producing Th1 CD4+ T cells mediate the immune destruction of hematopoietic cells, and they are central to the pathogenesis. However, the molecular events that control the development of BM-destructive Th1 cells remain largely unknown. Ezh2 is a chromatin-modifying enzyme that regulates multiple cellular processes primarily by silencing gene expression. We recently reported that Ezh2 is crucial for inflammatory T cell responses after allogeneic BM transplantation. To elucidate whether Ezh2 mediates pathogenic Th1 responses in AA and the mechanism of Ezh2 action in regulating Th1 cells, we studied the effects of Ezh2 inhibition in CD4+ T cells using a mouse model of human AA. Conditionally deleting Ezh2 in mature T cells dramatically reduced the production of BM-destructive Th1 cells in vivo, decreased BM-infiltrating Th1 cells, and rescued mice from BM failure. Ezh2 inhibition resulted in significant decrease in the expression of Tbx21 and Stat4, which encode transcription factors T-bet and STAT4, respectively. Introduction of T-bet but not STAT4 into Ezh2-deficient T cells fully rescued their differentiation into Th1 cells mediating AA. Ezh2 bound to the Tbx21 promoter in Th1 cells and directly activated Tbx21 transcription. Unexpectedly, Ezh2 was also required to prevent proteasome-mediated degradation of T-bet protein in Th1 cells. Our results demonstrate that Ezh2 promotes the generation of BM-destructive Th1 cells through a mechanism of transcriptional and posttranscriptional regulation of T-bet. These results also highlight the therapeutic potential of Ezh2 inhibition in reducing AA and other autoimmune diseases.
Primary thrombophilia in México VII: the V617F mutation of JAK2 is not a frequent cause of thrombosis

Abstract The study of the V617F JAK2 gene mutation has been used to identify the presence of an underlying myeloproliferative disorder (MPD) as the cause of unexplained thrombosis. In a group of 77 consecutive Mexican patients with a clinical marker of a primary thrombophilic condition, we looked for this JAK2 mutation and did not find any individual displaying it. Given these results, we conclude that an undetected MPD is a very improbable cause of thromboses in Mexican mestizos, a population where the prevalence of these disorders has been found to be lower than that found in Caucasian populations. Accordingly, it seems that the investigation for the V617F mutation of the JAK2 gene is not mandatory in all Mexican mestizo patients with unexplained thrombophilia and that this genetic study should be reserved for special cases, such as patients with thrombosis in uncommon sites or patients with cell counts suggesting the presence of an underlying MPD.
Sympathetic modulation of blood pressure variability

Although sympathetic nervous activity (SNA) displays oscillations synchronous with the heart beat and respiration, and between 0.1–0.4 Hz, it is apparent that each of these frequencies does not have the same effect on the vasculature. Frequencies above 1 Hz do not produce oscillations in the vasculature but instead contribute to the mean level of vasoconstriction. Slower oscillations in SNA result in a cycle of vasoconstriction and vasodilation within the vasculature, the amplitude of which, generally decreases with increasing frequency. Some studies indicate that, within the same species, differences exist in the frequency responses between vascular beds, such as the skin and gut. This differential responsiveness is also found between the medullary and cortical vasculature regions of the rabbit kidney. Low-pass filter properties have been described in the iliac circulation of rats, and evidence has been provided that noradrenaline reuptake mechanisms are not the frequency limiting step of the vasculature response. Recent studies on isolated rat vascular smooth muscle cells suggest that sympathetic modulation of vascular tone is limited by the α-adrenoceptor signal transduction into the cells and not by an intrinsic inability of the cells to contract and relax at higher rates.
Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis.

BACKGROUND Treatment of secondary hyperparathyroidism with vitamin D and calcium in patients receiving dialysis is often complicated by hypercalcemia and hyperphosphatemia, which may contribute to cardiovascular disease and adverse clinical outcomes. Calcimimetics target the calcium-sensing receptor and lower parathyroid hormone levels without increasing calcium and phosphorus levels. We report the results of two identical randomized, double-blind, placebo-controlled trials evaluating the safety and effectiveness of the calcimimetic agent cinacalcet hydrochloride. METHODS Patients who were receiving hemodialysis and who had inadequately controlled secondary hyperparathyroidism despite standard treatment were randomly assigned to receive cinacalcet (371 patients) or placebo (370 patients) for 26 weeks. Once-daily doses were increased from 30 mg to 180 mg to achieve intact parathyroid hormone levels of 250 pg per milliliter or less. The primary end point was the percentage of patients with values in this range during a 14-week efficacy-assessment phase. RESULTS Forty-three percent of the cinacalcet group reached the primary end point, as compared with 5 percent of the placebo group (P<0.001). Overall, mean parathyroid hormone values decreased 43 percent in those receiving cinacalcet but increased 9 percent in the placebo group (P<0.001). The serum calcium-phosphorus product declined by 15 percent in the cinacalcet group and remained unchanged in the placebo group (P<0.001). Cinacalcet effectively reduced parathyroid hormone levels independently of disease severity or changes in vitamin D sterol dose. CONCLUSIONS Cinacalcet lowers parathyroid hormone levels and improves calcium-phosphorus homeostasis in patients receiving hemodialysis who have uncontrolled secondary hyperparathyroidism.