Miracle-dz/UniFAR-FTUs huggingface dataset:
The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600.

BACKGROUND BRAF inhibitors (BRAFi) improve survival in metastatic melanoma patients (MMP) but the duration of clinical benefit is limited by development of drug resistance. Here, we investigated whether the expression of programmed death-ligand 1 (PD-L1) and the density of tumor-infiltrating mononuclear cells (TIMC) predict the occurrence of resistance, hence affecting the clinical outcome in BRAFi-treated MMP. METHODS PD-L1 expression (cutoff 5%) was analyzed by immunohistochemistry with two different antibodies in BRAF(V600)-mutated formalin-fixed and paraffin-embedded samples from 80 consecutive MMP treated with BRAFi at a single institution. TIMC were evaluated by conventional hematoxylin and eosin staining. RESULTS Forty-six and 34 patients received vemurafenib and dabrafenib, respectively. Membranous expression of PD-L1 was detected in 28/80 (35%) of patients. At multivariate analysis, absence of tumoral PD-L1 staining [odd ratio (OR) 10.8, 95% confidence interval (CI) 2.7-43.3, P < 0.001] and the presence of TIMC (OR 6.5, 95% CI 1.7-24.3, P < 0.005) were associated with a better response to treatment. Median progression-free survival (PFS) and overall survival were 10 and 15 months, respectively. By multivariate assessment, PD-L1 expression [hazard ratio (HR) 4.3, 95% CI 2.1-8.7, P < 0.0001] and absence of TIMC (HR 2.5, 95% CI 1.4-4.7, P < 0.002) correlated with shorter PFS. PD-L1 overexpression (HR 6.2, 95% CI 2.8-14.2, P < 0.0001) and absence of TIMC (HR 3.1, 95% CI 1.5-6.5, P < 0.002) were independent prognostic factors for melanoma-specific survival. CONCLUSION Our results provide the first proof-of-principle evidence for the predictive and prognostic relevance of PD-L1 immunohistochemical expression and density of immune cell infiltration in BRAF(V600)-mutated MMP treated with BRAFi.
Solution NMR Structure and Functional Analysis of the Integral Membrane Protein YgaP from Escherichia coli

Background: E. coli YgaP is a membrane-bound sulfurtransferase with a cytoplasmic rhodanese domain. Results: The three-dimensional structure is composed of a cytoplasmic rhodanese domain and two transmembrane helices forming the interface of the homodimer. Conclusion: The structure-activity relationship of YgaP suggests a sulfurtransferase activity. Significance: YgaP may have a role in the detoxification of CN− to the less toxic SCN−. The solution NMR structure of the α-helical integral membrane protein YgaP from Escherichia coli in mixed 1,2-diheptanoyl-sn-glycerol-3-phosphocholine/1-myristoyl-2-hydroxy-sn-glycero-3-phospho-(1′-rac-glycerol) micelles is presented. In these micelles, YgaP forms a homodimer with the two transmembrane helices being the dimer interface, whereas the N-terminal cytoplasmic domain includes a rhodanese-fold in accordance to its sequence homology to the rhodanese family of sulfurtransferases. The enzymatic sulfur transfer activity of full-length YgaP as well as of the N-terminal rhodanese domain only was investigated performing a series of titrations with sodium thiosulfate and potassium cyanide monitored by NMR and EPR. The data indicate the thiosulfate concentration-dependent addition of several sulfur atoms to the catalytic Cys-63, which process can be reversed by the addition of potassium cyanide. The catalytic reaction induces thereby conformational changes within the rhodanese domain, as well as on the transmembrane α-helices of YgaP. These results provide insights into a potential mechanism of YgaP during the catalytic thiosulfate activity in vivo.
Role of IRS-3 in the Insulin Signaling of IRS-1-deficient Brown Adipocytes*

Insulin receptor substrate-1 (IRS-1) plays an essential role in mediating the insulin signals that trigger mitogenesis, lipid synthesis, and uncoupling protein-1 gene expression in mouse brown adipocytes. Expression of IRS-3 is restricted mainly to white adipose tissue; expression of this IRS protein is virtually absent in brown adipocytes. We have tested the capacity of IRS-3 to mediate insulin actions in IRS-1-deficient brown adipocytes. Thus, we expressed exogenous IRS-3 in immortalized IRS-1–/– brown adipocytes at a level comparable with that of endogenous IRS-3 in white adipose tissue. Under these conditions, IRS-3 signaling in response to insulin was observed, as revealed by tyrosine phosphorylation of IRS-3, and the activation of phosphatidylinositol (PI) 3-kinase associated with this recombinant protein. However, although insulin promoted the association of Grb-2 with recombinant IRS-3 in IRS-1–/– cells, the exogenous expression of this IRS family member failed to activate p42/44 MAPK and mitogenesis in brown adipocytes lacking IRS-1. Downstream of PI 3-kinase, IRS-3 expression restored insulin-induced Akt phosphorylation, which is impaired by the lack of IRS-1 signaling. Whereas the generation of IRS-3 signals enhanced adipocyte determination and differentiation-dependent factor 1/sterol regulatory element-binding protein (ADD-1/SREBP-1c) and fatty acid synthase mRNA and protein expression, activation of this pathway was unable to reconstitute CCAAT/enhancer-binding protein α and uncoupling protein-1 transactivation and gene expression in response to insulin. Similar results were obtained following insulin-like growth factor-I stimulation. In brown adipocytes expressing the IRS-3F4 mutant, the association of the p85α regulatory subunit via Src homology 2 binding was lost, but insulin nevertheless induced PI 3-kinase activity and Akt phosphorylation in a wortmannin-dependent manner. In contrast, activation of IRS-3F4 signaling failed to restore the induction of ADD-1/SREBP-1c and fatty acid synthase gene expression in IRS-1-deficient brown adipocytes. These studies demonstrate that recombinant IRS-3 may reconstitute some, but not all, of the signals required for insulin action in brown adipocytes. Thus, our data further implicate a unique role for IRS-1 in triggering insulin action in brown adipocytes.
The fine structural changes in the corneal endothelium during graft rejection.

Fully penetrating corneal grafts were made between unrelated albino rabbits. Rejection was induced, and was regularly accompanied by invasion of the host cornea by superficial vessels. Advancing rejection was evidenced by stromal haze and thickening in the rejected portion of the graft. It was possible to study the clinically normal unrejected portion, the interface between it and the affected portion, and the obviously abnormal portion of the graft, as well as the host region and scar. The endothelium of the clear portion of the graft was found to be infiltered by lymphocytes which penetrated between cells, but did not reach Descemet's membrane. The endothelial cell apparently closed over the lymphocytes after the invasion. The leukocytes, therefore, were in the endothelial intercellular space. In the interface between the clear and turbid portions of the grafts, fibrin present in the anterior chamber was found on the endothelial surface accompanied by mononuclear cells—mainly lymphocytes. They pushed between adjacent endothelial cells; in some instances they reached Descemet's membrane. The endothelial cells' cytoplasm was remarkably little affected in this area. Mitochondria, endoplasmic reticulum, and the terminal web appeared qualitatively normal. The cells, however, became attenuated in some portions and greatly thickened in others. Their surface adjacent to the anterior chamber was frequently covered by minute processes not found normally. In the region which appeared clinically hazy, it was obvious that Descemet's membrane was exposed to the aqueous humor in places. The membrane was otherwise covered by mononuclear leukocytes and remaining endothelial cells. Many of the latter were greatly rounded and apparently in a process of desquamation.
Predictors of Initiation for Predialysis Arteriovenous Fistula.

BACKGROUND AND OBJECTIVES The optimal timing of predialysis arteriovenous fistula surgery remains uncertain. We evaluated factors associated with hemodialysis initiation in patients undergoing predialysis arteriovenous fistula surgery and derived a model to predict future initiation of dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Our study retrospectively identified 308 patients undergoing predialysis arteriovenous fistula creation at a large medical center in 2006-2012 to determine whether they initiated hemodialysis. Multiple variable logistic regression analyzed which demographic and clinical factors predicted initiation of dialysis within 2 years of arteriovenous fistula surgery. A receiver operating characteristic area under the curve was used to quantify the predictive value of preoperative factors on the likelihood of initiating hemodialysis within 2 years. RESULTS Overall, hemodialysis was initiated within 6 months, 1 year, and 2 years in 119 (39%), 175 (57%), and 211 (68%) patients, respectively. Using multiple variable logistic regression, four factors were associated with hemodialysis initiation at 2 years: eGFR at access surgery (odds ratio, 0.45; 95% confidence interval, 0.31 to 0.64 per 5 ml/min per 1.73 m2; P<0.001), diabetes (odds ratio, 2.51; 95% confidence interval, 1.22 to 5.15; P=0.003), GFR trajectory (odds ratio, 1.54; 95% confidence interval, 1.09 to 2.17 per 3 ml/min per 1.73 m2 per year; P=0.01), and spot urine protein-to-creatinine ratio (odds ratio, 1.39; 95% confidence interval, 1.14 to 1.71 per 1 U; P<0.001). eGFR alone had a moderate predictive value for dialysis initiation (area under the curve =0.69; 95% confidence interval, 0.63 to 0.76; P<0.001), whereas the full model had a higher predictive value (area under the curve =0.83; 95% confidence interval, 0.77 to 0.88; P<0.001). CONCLUSIONS The likelihood of initiating hemodialysis within 2 years of predialysis arteriovenous fistula surgery is associated with eGFR at access surgery, diabetes, GFR trajectory, and magnitude of proteinuria. The combined use of all four variables improves the ability to predict future hemodialysis compared with the use of eGFR alone.
Importance of the splanchnic vascular bed in human blood pressure regulation.

Three-part experiment in which five subjects were exposed to lower body negative pressure (LBNP) at -50 mm Hg below the iliac crests. Duration of LBNP to earliest vagal symptoms was 7 to 21 min; all data are expressed as changes from control period to the last measurements before these symptoms. In part I, forearm blood flow (by Whitney gauge) fell 45% during LBNP. In part II, splanchnic blood flow (from arterial clearance hepatic extraction of indocyanine green) fell 32% and splanchnic vascular resistance rose 30%. In part III, cardiac output fell 28%, stroke volume 51%, and central blood volume 21%. Total peripheral resistance and heart rate rose 19% and 52%. Of the reduction in total vascular conductance, decreased splanchnic conductance accounted for approximately 33%; skin plus muscle conductance decreased similarly.
A permanent magnet generator for small scale wind and water turbines

This paper describes the design and development of a 5 kW, 150 rpm, air-cored, axial flux generator for use as a direct drive generator with small wind and water turbines. The generator uses trapezoidal shaped magnets to obtain a greater active length than that provided by circular magnets. The armature coils are also trapezoidal. A prototype generator has been tested and produces up to 5000 W at 150 rpm with an electrical efficiency substantially greater than 90%. The generator performs as predicted by the design process. The paper also describes how the generator can be used to control turbine speed in strong winds. This is achieved by introducing an additional resistive dump load on the electrical output of the generator; this stalls the turbine as it approaches rated speed. If the dumps load is applied and then released, the generator can be kept within its rated power limit. A vertical axis wind turbine and axial flux generator are modeled to examine the speed control system. It is found that when the turbine is subjected to a turbulent wind, the speed control mechanism performs as expected. Practical test has verified the simulation.
Crystalline phase differentiation in urinary calcium phosphate and magnesium phosphate calculi.

UNLABELLED Phosphates are encountered as the main components in about 15% of urinary calculi. Except for struvite, no specific correlations have been found between the crystalline phase of the phosphates and the cause of nephrolithiasis. OBJECTIVE The relationship between aetiological factors and crystalline phases or carbonate rate in calcium phosphate stones were assessed. MATERIAL AND METHODS From a series of 1148 phosphate calculi, we investigated the relationship between composition and aetiological factors. RESULTS Carbapatite was the most frequent crystalline phase (74.0%). It was associated with many possible causes, including hypercalciuria, hypocitraturia, primary hyperparathyroidism, tubular acidosis, medullary sponge kidney and chronic urinary tract infection. The carbonate rate of carbapatite may be of clinical interest because carbonate rates above 15% are frequently related to urinary tract infection with urea-splitting bacteria. Conversely, the carbonate rate was commonly less than 10% in cases of carbapatite induced by metabolic disorders. Among other phosphates, brushite was found in hypercalciuric states and primary hyperparathyroidism and whitlockite in cases of urinary tract infection by non-urease-producing bacteria. CONCLUSION Identification of crystalline phases and measurement of carbonate rate in calcium phosphate calculi is of clinical interest for identifying stone aetiology.
Clinical and procedural predictors of no-reflow in patients with acute myocardial infarction after primary percutaneous coronary intervention.

BACKGROUND The treatment of acute myocardial infarction (AMI) is thought to restore antegrade blood flow in the infarct-related artery (IRA) and minimize ischemic damage to the myocardium as soon as possible. The present study aimed to identify possible clinical predictors for no-reflow in patients with AMI after primary percutaneous coronary intervention (PCI). METHODS A total of 312 consecutive patients with AMI who had been treated from January 2008 to December 2010 at the Cardiology Department of East Hospital, Tongji University School of Medicine were enrolled in this study. Inclusion criteria were: (i) patients underwent successfully primary PCI within 12 hours after the appearance of symptoms; or (ii) patients with ischemic chest pain for more than 12 hours after a successful primary PCI within 24 hours after appearance of symptoms. Exculsion criteria were: (i) coronary artery spasm; (ii) diameter stenosis of the culprit lesion was <50% and coronary blood flow was normal; (iii) patients with severe left main coronary or multivessel disease, who had to require emergency revascularization. According to thrombolysis in myocardial infarction (TIMI), the patients were divided into a reflow group and a no-reflow group. The clinical data, angiography findings and surgical data were compared between the two groups. Univariate and multivariate logistic regressions were used to determine the predictors for no-reflow. RESULTS Fifty-four (17.3%) of the patients developed NR phenomenon after primary PCI. Univariate analysis showed that age, time from onset to reperfusion, systolic blood pressure (SBP) on admission, Killip class of myocardial infarction, intra-aortic balloon pump (IABP) use before primary PCI, TIMI flow grade before primary PCI, type of occlusion, thrombus burden on baseline angiography, target lesion length, reference luminal diameter and method of reperfusion were correlated with no-reflow (P<0.05 for all). Multiple logistic regression analysis identified that age >65 years [OR=1.470, 95% confidence interval (CI) 1.460-1.490, P=0.007], long time from onset to reperfusion >6 hours (OR=1.270, 95%CI 1.160-1.400, P=0.001), low SBP on admission <100 mmHg (OR=1.910, 95%CI 1.018-3.896, P=0.004), IABP use before PCI (OR= 1.949, 95%CI 1.168-3.253, P=0.011), low (≤1) TIMI flow grade before primary PCI (OR=1.100, 95%CI 1.080-1.250, P<0.001), high thrombus burden (OR=1.600, 95%CI 1.470-2.760, P=0.030), and long target lesion (OR=1.948, 95%CI 1.908-1.990, P=0.019) on angiography were independent predictors of no-reflow. CONCLUSION The occurrence of no-reflow after primary PCI for acute myocardial infarction can predict clinical, angiographic and procedural features.
The Effect of Changes in Cervical Cancer Screening Guidelines on Chlamydia Testing

PURPOSE Many chlamydia infections are identified through screening, which is frequently offered to females concomitantly with cervical cancer screening. Recent cervical cancer screening guidelines recommend screening less frequently and starting later. We sought to evaluate the impact of the May 2012 Ontario, Canada, cervical cancer screening guideline change on Papanicolaou (Pap) and chlamydia trachomatis (chlamydia) testing and incidence. METHODS We extracted population-based physician billing claims data to identify Pap and chlamydia tests and public health surveillance data to identify chlamydia cases. We used interrupted time series analysis of quarterly data spanning 2 years before and after the guideline change and fitted segmented linear regression or rational functions to the outcomes using autoregressive integrated moving average models. Outcomes were stratified by sex and age group. RESULTS Two years after the guideline change, we observed reduced chlamydia testing in females, with the greatest relative reduction (25.5%) among those aged 15 to 19 years. We also observed decreases in reported chlamydia incidence for females aged 15 to 19 years and 20 to 24 years (relative reductions of 16.8% and 14.4%, respectively). Chlamydia incidence remained the same for males, despite increased chlamydia testing. CONCLUSIONS Recent cervical cancer screening guideline changes in Ontario were associated with reduced chlamydia testing and reported new cases of chlamydia in females. Females aged 15 to 19 years, who are at high risk for chlamydia if sexually active, and who no longer warrant cervical cancer screening, were disproportionately affected. Females should be tested for chlamydia based on risk, regardless of need for Pap testing.
Physical Exercise with Music Reduces Gray and White Matter Loss in the Frontal Cortex of Elderly People: The Mihama-Kiho Scan Project

Findings from previous studies suggest that physical exercise combined with cognitive training produces more positive effects on cognitive function in elderly people than physical exercise alone. However, the brain plasticity associated with these proposed benefits of combined therapy has not yet been investigated in elderly subjects. We hypothesized that the dual task group would experience greater benefits than the physical exercise alone and non-exercise control groups with regard to both cognitive function and brain plasticity. This study investigated the effect of physical exercise with musical accompaniment on structural brain changes in healthy elderly people. Fifty-one participants performed physical exercise (once a week for an hour with professional trainers) with musical accompaniment (ExM), 61 participants performed the same exercise without music (Ex), and 32 participants made up the non-exercise group (Cont). After the 1-year intervention, visuospatial functioning of the ExM but not the Ex group was significantly better than that of the Cont group. Voxel-based morphometry analyses revealed that the ExM group showed greater right superior frontal gyrus volume and preserved volumes of the right anterior cingulate gyrus, left superior temporal gyrus, and insula. These results indicate that compared with exercise alone, physical exercise with music induces greater positive effects on cognitive function and leads to subtle neuroanatomical changes in the brains of elderly people. Therefore, physical exercise with music may be a beneficial intervention to delay age-related cognitive decline.
Involvement of Endogenous Bone Morphogenetic Protein (BMP) 2 and BMP6 in Bone Formation*

Although accumulated evidence has shown the bone anabolic effects of bone morphogenetic proteins (BMPs) that were exogenously applied in vitro and in vivo, the roles of endogenous BMPs during bone formation remain to be clarified. This study initially investigated expression patterns of BMPs in the mouse long bone and found that BMP2 and BMP6 were the main subtypes expressed in hypertrophic chondrocytes that induce endochondral bone formation. We then examined the involvement of the combination of these BMPs in bone formation in vivo by generating the compound-deficient mice (Bmp2+/-;Bmp6-/-). Under physiological conditions, these mice exhibited moderate growth retardation compared with the wild-type (WT) littermates during the observation period up to 52 weeks of age. Both the fetal and adult compound-deficient mice showed a reduction in the trabecular bone volume with suppressed bone formation, but normal bone resorption, whereas the single deficient mice (Bmp2+/- or Bmp6-/-) did not. When a fracture was created at the femoral midshaft and the bone healing was analyzed, the endochondral bone formation, but not intramembranous bone formation, was impaired by the compound deficiency. In the cultures of bone marrow cells, however, there was no difference in osteogenic differentiation between WT and compound-deficient cells in the presence or absence of the exogenous BMP2. We thus concluded that endogenous BMP2 and BMP6 cooperatively play pivotal roles in bone formation under both physiological and pathological conditions.
Does Microfinance Empower Rural Women? Empirical Study in Udaipur District, Rajasthan

Microfinance has come to play a major role in many gender and development strategies because of its direct relationship to both poverty alleviation and to the empowerment of women. Women are the most crucial elements of the social fabric and are playing a pivotal role in the socio-economic scenario of Rajasthan. Microfinance programs like the SHGs in India have been promoted for their positive economic impact and the belief that they empower women. Microfinance programs like the SHGs in India have been promoted for their positive economic impact and belief that they empower women. The survey was conducted on around 100 respondents from various SHGs of Udaipur district, Rajasthan and the analysis was done to study the empowerment of women through microfinance. The results strongly demonstrate that on an average, there is a significant increase in women empowerment of the Self Help Groups members. However, social backwardness, indebtedness and presence of other microcredit programs in the same or nearby villages have a significant positive influence on women’s participation in this program.