Miracle-dz/UniFAR-FTUs huggingface dataset:
Type IV pilus biogenesis in Neisseria meningitidis: PilW is involved in a step occurring after pilus assembly, essential for fibre stability and function

Type IV pili (Tfp) play a critical role in the pathogenic lifestyle of Neisseria meningitidis and N. gonorrhoeae, notably by facilitating bacterial attachment to human cells, but our understanding of their biogenesis, during which the fibres are assembled in the periplasm, then emerge onto the cell surface and are stabilized, remains fragmentary. We therefore sought to identify the genes required for Tfp formation in N. meningitidis by screening a genome‐wide collection of mutants for those that were unable to form aggregates, another phenotype mediated by these organelles. Fifteen proteins, of which only seven were previously characterized, were found to be essential for Tfp biogenesis. One novel component, named PilW, was studied in more detail. We found that PilW is an outer‐membrane protein necessary for the stabilization of the fibres but not for their assembly or surface localization, because Tfp could be restored on the surface in a pilW mutant by a mutation in the twitching motility gene pilT. However, Tfp‐linked properties, including adherence to human cells, were not restored in a pilW/T mutant, which suggests that PilW is also essential for the functionality of the fibres. Together with the finding that PilW is important for the stability of PilQ multimers, our results extend the current model for Tfp biogenesis by suggesting that a multiprotein machinery in the outer‐membrane is involved in the terminal stage of Tfp biogenesis during which growing fibres are not only stabilized, but also become perfectly functional.
Susceptibility of MHC class I expressing extravillous trophoblast cell lines to killing by natural killer cells.

Purified human first trimester extravillous trophoblast (EVT) cell lines HTR-8 and HT-116 were examined for susceptibility to natural killer (NK) cell-mediated lysis. Based upon nucleic acid sequencing of an amplified fragment of cDNA, Western blot analysis and immunostaining of fixed and live cells, it was shown that both EVT cell lines expressed HLA-G mRNA and protein within the cytoplasm when cultured on laminin-coated plates. Very weak HLA-G expression was detectable on the cell surface under these conditions. However, strong cell surface expression of a classical MHC class I molecule (most likely HLA-C) was exhibited by these EVT cell lines when grown on laminin, as indicated by W6/32 FACS analysis (Ab recognizing pan MHC class I), and Western immunoblotting with HC10 (Ab recognizing HLA-B/C). When these EVT cells, cultured on laminin, were used as targets for peripheral blood natural killer (NK) cells in a standard chromium release assay, both HTR-8 and HT-116 cells were lysed by NK cells in a dose-dependent manner. The respective percentage specific lysis at an effector to target (E/T) ratio of 100 was 28+/-7, and 48+/-14. The choriocarcinoma cell lines JAR and JEG-3 which were respectively MHC class I negative and HLA-G positive were resistant to NK cell lysis. Thus, there was no clear relationship between the MHC class I expression and NK cell resistance or susceptibility among the EVT cell lines and choriocarcinoma cells. These findings raise the possibility that NK cells may take part in the surveillance of the invasive EVT cells during normal placentation.
The predictors of adopting a health-promoting lifestyle among work site adults with prediabetes.

AIM AND OBJECTIVE To examine how prediabetes knowledge, health beliefs and self-efficacy of health behaviour contribute to work site adults adopting a health-promoting lifestyle and to analyse these three factors as independent variables to identify key predictors of adopting health-promoting lifestyles. BACKGROUND Health providers use health-promoting lifestyle interventions as the primary approach in preventing diabetes. However, many influential factors make it difficult for individuals to adopt a health-promoting lifestyle. Furthermore, no previous study has examined prediabetes knowledge, health beliefs, self-efficacy of health behaviour and health-promoting lifestyle in work site adults with prediabetes, especially among Asians. DESIGN This was a cross-sectional study of 260 adults at four work sites in southern Taiwan. METHOD Patients with prediabetes were given a cross-sectional questionnaire about prediabetes knowledge, health beliefs, self-efficacy of health behaviour and health-promoting lifestyle. Multiple stepwise regression analysis was used to determine predictors of implementing health-promoting lifestyles. RESULTS In general, this study found that over age 45 and a BMI above 25 kg/m(2) are risk factors for prediabetes. A 47.5% variance in implementing health-promoting lifestyle was explained by a model that included self-efficacy of health behaviour (beta = 0.519, p < 0.001), perceived action barrier (beta = -0.207, p = 0.001) and perceived action benefits (beta = 0.129, p = 0.023). CONCLUSIONS Work site health care units should identify prediabetes cases and teach diet control strategies for reducing body weight. By designing behaviour self-regulation protocol to promote self-management for prediabetic individuals, organisations could enhance self-efficacy and delay further development of diabetes. RELEVANCE TO CLINICAL PRACTICE Findings guide the clinical assessment (e.g. self-efficacy) of prediabetic adults regarding their health-promoting lifestyles and provide effective guidelines for designing lifestyle interventions to prevent prediabetes in high-risk groups.
Porcine von Willebrand disease: implications for the pathophysiology of atherosclerosis and thrombosis.

A role of von Willebrand factor-mediated platelet function in porcine atherogenesis is strongly suggested by these studies. This influence of platelet function is probably most important in experimental systems that involve long-term observation and low or moderately elevated levels of serum cholesterol. On the other hand, effects of platelet function on development of atherosclerosis in animals with extremely high serum cholesterol levels are difficult to demonstrate and may be of relatively less importance. These observations are consistent with the results of numbers of recent studies describing the relationship of vascular injury to intimal smooth muscle cell proliferation. There is considerable evidence that lipid-rich intimal lesions occur in hypercholesterolemic animals with no antecedent denudation of endothelium or platelet adherence. It is difficult to ascribe intimal proliferation to platelet effects in this setting. On the other hand, endothelial cells, smooth muscle cells, and monocytes, which are all known to be involved in the atherosclerotic process, can produce mitogenic and chemotactic proteins, including platelet-derived growth factor. Therefore, metabolic aberrations of various kinds, including those initiated by mechanical injury or hypercholesterolemia, may promote proliferation in the vascular wall and resultant lesion development. Data from studies of pigs with vWD suggest a contribution of platelets to this process, but the effects of this contribution are modulated by numbers of variables, most of which are yet to be identified. The control of these multiple variables will be necessary before a clear understanding of the magnitude of the platelet-mediated effects can be gained. This will require carefully defined conditions of hypercholesterolemia, special attention to the immunologic variables and study of properly selected vascular segments under known conditions of flow. This later element will be especially important in the study of vWF-mediated platelet function, since shear forces are a critical determinant of vWF function. Systems that model flow conditions in various segments of the aorta, carotid, and coronary arteries are presently under development for this purpose. Finally, studies examining the molecular basis of vWF-mediated and other platelet functions will probably guide the most productive use of these models. Platelet membrane glycoprotein (GP) receptor Ib and the complex GP IIb and IIIa have been shown in ex vivo studies to be binding sites for vWF molecules. (ABSTRACT TRUNCATED AT 400 WORDS)
Effects of denosumab on fracture and bone mineral density by level of kidney function

The incidences of osteoporosis and chronic kidney disease (CKD) both increase with increasing age, yet there is a paucity of data on treatments for osteoporosis in the setting of impaired kidney function. We examined the efficacy and safety of denosumab (DMAb) among subjects participating in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Study. We estimated creatinine clearance (eGFR) using Cockcroft‐Gault and classified levels of kidney function using the modified National Kidney Foundation classification of CKD. We examined incident fracture rates; changes in bone mineral density (BMD), serum calcium, and creatinine; and the incidence of adverse events after 36 months of follow‐up in subjects receiving DMAb or placebo, stratified by level of kidney function. We used a subgroup interaction term to determine if there were differences in treatment effect by eGFR. Most (93%) women were white, and the mean age was 72.3 ± 5.2 years; 73 women had an eGFR of 15 to 29 mL/min; 2817, between 30 to 59 mL/min; 4069, between 60 to 89 mL/min, and 842 had an eGFR of 90 mL/min or greater. None had stage 5 CKD. Fracture risk reduction and changes in BMD at all sites were in favor of DMAb. The test for treatment by subgroup interaction was not statistically significant, indicating that treatment efficacy did not differ by kidney function. Changes in creatinine and calcium and the incidence of adverse events were similar between groups and did not differ by level of kidney function. It is concluded that DMAb is effective at reducing fracture risk and is not associated with an increase in adverse events among patients with impaired kidney function. © 2011 American Society for Bone and Mineral Research
Correlation of serum opsonins with in vitro phagocytosis of Streptococcus pneumoniae

C-reactive protein (CRP), an acute-phase reactant which binds to phosphocholine (PC) in the pneumococcal cell wall, and anti-PC antibodies are protective against experimental pneumococcal bacteremia in mice. To determine the relative opsonic capacities of CRP and anti-PC compared with those of antibodies against pneumococcal capsular polysaccharides (anti-PCP), we correlated in vitro opsonic activity for serotype 7F Streptococcus pneumoniae with concentrations of CRP, anti-PC, and anti-type 7F PCP in human sera from 10 normal subjects and 38 patients with sickle cell (SS) disease, a high-risk group for pneumococcal infection. Opsonic activity, measured by a radiolabeled bacterial uptake assay, correlated with anti-PCP levels but not with CRP or anti-PC in both the normal subjects and patients with SS disease. Addition of CRP to normal sera did not increase opsonic activity for serotypes 4 and 7F S. pneumoniae, although it did so for serotype 27, a nonpathogenic strain unique for having PC in its capsule. CRP and anti-PC were not effective opsonins when they bound to the pneumococcal cell wall rather than the capsule. The protective effects of CRP or anti-PC against these serotypes may be produced by means other than complement-dependent opsonization.
Mechanisms of tendon injury and repair

Tendon disorders are common and lead to significant disability, pain, healthcare cost, and lost productivity. A wide range of injury mechanisms exist leading to tendinopathy or tendon rupture. Tears can occur in healthy tendons that are acutely overloaded (e.g., during a high speed or high impact event) or lacerated (e.g., a knife injury). Tendinitis or tendinosis can occur in tendons exposed to overuse conditions (e.g., an elite swimmer's training regimen) or intrinsic tissue degeneration (e.g., age‐related degeneration). The healing potential of a torn or pathologic tendon varies depending on anatomic location (e.g., Achilles vs. rotator cuff) and local environment (e.g., intrasynovial vs. extrasynovial). Although healing occurs to varying degrees, in general healing of repaired tendons follows the typical wound healing course, including an early inflammatory phase, followed by proliferative and remodeling phases. Numerous treatment approaches have been attempted to improve tendon healing, including growth factor‐ and cell‐based therapies and rehabilitation protocols. This review will describe the current state of knowledge of injury and repair of the three most common tendinopathies—flexor tendon lacerations, Achilles tendon rupture, and rotator cuff disorders—with a particular focus on the use of animal models for understanding tendon healing. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:832–839, 2015.
Differential phosphorylation of vertebrate p34cdc2 kinase at the G1/S and G2/M transitions of the cell cycle: identification of major phosphorylation sites.

The cdc2 kinase is a key regulator of the eukaryotic cell cycle. The activity of its catalytic subunit, p34cdc2, is controlled by cell cycle dependent interactions with other proteins as well as by phosphorylation–dephosphorylation reactions. In this paper, we examine the phosphorylation state of chicken p34cdc2 at various stages of the cell cycle. By peptide mapping, we detect four major phosphopeptides in chicken p34cdc2; three phosphorylation sites are identified as threonine (Thr) 14, tyrosine (Tyr) 15 and serine (Ser) 277. Analysis of synchronized cells demonstrates that phosphorylation of all four sites is cell cycle regulated. Thr 14 and Tyr 15 are phosphorylated maximally during G2 phase but dephosphorylated abruptly at the G2/M transition, concomitant with activation of p34cdc2 kinase. This result suggests that phosphorylation of Thr 14 and/or Tyr 15 inhibits p34cdc2 kinase activity, in line with the location of these residues within the putative ATP binding site of the kinase. During M phase, p34cdc2 is also phosphorylated, but phosphorylation occurs on a threonine residue distinct from Thr 14. Finally, phosphorylation of Ser 277 peaks during G1 phase and drops markedly as cells progress through S phase, raising the possibility that this modification may contribute to control the proposed G1/S function of the vertebrate p34cdc2 kinase.
Chemopreventive Effects of Dietary Eicosapentaenoic Acid Supplementation in Experimental Myeloid Leukemia

Current therapies for treatment of myeloid leukemia do not eliminate leukemia stem cells (LSC), leading to disease relapse. In this study, we supplemented mice with eicosapentaenoic acid (EPA, C20:5), a polyunsaturated omega-3 fatty acid, at pharmacologic levels, to examine whether the endogenous metabolite, cyclopentenone prostaglandin delta-12 PGJ3 (Δ12-PGJ3), was effective in targeting LSCs in experimental leukemia. EPA supplementation for 8 weeks resulted in enhanced endogenous production of Δ12-PGJ3 that was blocked by indomethacin, a cyclooxygenase (COX) inhibitor. Using a murine model of chronic myelogenous leukemia (CML) induced by bone marrow transplantation of BCR-ABL–expressing hematopoietic stem cells, mice supplemented with EPA showed a decrease in the LSC population, and reduced splenomegaly and leukocytosis, when compared with mice on an oleic acid diet. Supplementation of CML mice carrying the T315I mutation (in BCR-ABL) with EPA resulted in a similar effect. Indomethacin blocked the EPA effect and increased the severity of BCR-ABL–induced CML and decreased apoptosis. Δ12-PGJ3 rescued indomethacin-treated BCR-ABL mice and decreased LSCs. Inhibition of hematopoietic-prostaglandin D synthase (H-PGDS) by HQL-79 in EPA-supplemented CML mice also blocked the effect of EPA. In addition, EPA supplementation was effective in a murine model of acute myeloid leukemia. EPA-supplemented mice exhibited a decrease in leukemia burden and a decrease in the LSC colony-forming unit (LSC-CFU). The decrease in LSCs was confirmed through serial transplantation assays in all disease models. The results support a chemopreventive role for EPA in myeloid leukemia, which is dependent on the ability to efficiently convert EPA to endogenous COX-derived prostanoids, including Δ12-PGJ3. Cancer Prev Res; 8(10); 989–99. ©2015 AACR.
Impact of biased mislabeling on learning with deep networks

The aim of machine learning is to obtain a good model to correctly predict unseen data. In order to train such models, one needs a sufficient number of clean examples of the ground truth. However, some applications' datasets are not guaranteed to consist entirely of pure examples and might contain mislabeled data. Handling mislabeled data is a domain of outlier statistics and have been studied to some extent in the context of machine learning. Here we ask how does mislabeled data in a training set effect classification performance in deep neural networks. More specifically, motivated by an industrial application, we consider the case where the probability of the class mislabeling in the training set varies considerably between each class. We hence contrast in this paper the case of systematic mislabeling of one class to the more commonly studied situation of a uniform mislabeling between all classes. We demonstrate that the non-uniform mislabeling is more challenging than the more commonly studied uniform case. We also explicitly explore the dependence of our findings to the size of the training data which is not only a common limiting factor in industrial applications but which also has a large effect on the results. We demonstrate that deep networks have an inherent robustness when large datasets are available.
Assessment of whole brain white matter integrity in youths and young adults with a family history of substance‐use disorders

Individuals with a family history of substance use disorders (FH+) are at a greater risk of developing substance use disorders than their peers with no such family histories (FH−) and this vulnerability is proportional to the number of affected relatives (FH density). The risk for developing substance use disorders peaks during adolescence to early adulthood in the general population, and that is thought to be related to delayed maturation of frontocortical and frontostriatal functional circuits. We hypothesized that FH+ youth and young adults have impaired myelination of frontocortical and frontostriatal white matter tracts. We examined fractional anisotropy (FA) data in 80 FH+ and 34 FH− youths (12.9 ± 1.0 years) and in 25 FH+ and 30 FH− young adults (24.3 ± 3.4 years). FH+ youths had lower FA values in both frontocortical and frontostriatal tracts as well as parietocortical tracts including the anterior, superior and posterior corona radiata and the superior frontal‐occipital fasciculus. Moreover, FA values in these tracts were negatively correlated with FH density. FH+ adults had lower FA values in two frontocortical tracts: the genu of the corpus callosum and anterior corona radiata and also significant negative correlations between FA and FH density in these same tracts. In both groups, lower FA values corresponded to higher radial diffusivity suggesting reduced axonal myelination. We interpreted our findings as evidence for impaired myelination of frontal white matter that was proportional to FH density. Our data suggest that deficits may partially resolve with age, paralleling an age‐related decline in risk for developing substance use disorders. Hum Brain Mapp 35:5401–5413, 2014. © 2014 Wiley Periodicals, Inc.
Rapid mobilization of intracellular Mg2+ by bombesin in Swiss 3T3 cells: mobilization through external Ca(2+)- and tyrosine kinase-dependent mechanisms.

We examined the effects of growth factors on intracellular free Mg2+ concentrations ([Mg2+]i) in single Swiss 3T3 fibroblasts, using microfluorometry of a Mg(2+)-sensitive dye mag-fura-2. We had already noted an increase in [Mg2+]i after exposure to bombesin for 30-60 min [Ishijima, S. , Sonoda, T. , & Tatibana, M. (1991) Am. J. Physiol. 261 (Cell Physiol. 30), C1074-C1080]. In the present work, we found that bombesin also induced early changes in [Mg2+]i. The [Mg2+]i reached peak values within 15 s in most cells, and the significant rise lasted only for 1-2 min. The extent of the increase varied from cell to cell (0-600 microM above basal). On the average, the [Mg2+]i was increased from basal 0.33 to 0.54 mM. Since the time course was similar to that of [Ca2+]i changes, and the dye mag-fura-2 also binds Ca2+, we evaluated Ca2+ interference with measurement of [Mg2+]i. The contribution of Ca2+ binding would be below 20% of the mag-fura-2 signal. The bombesin-induced [Mg2+]i increase was not dependent on external Mg2+, but the omission of external Ca2+ decreased by 60% the [Mg2+]i increase, and the Ca2+ channel blocker, nicardipine inhibited by 90% the [Mg2+]i response. This inhibition was partially reversed by raising the concentration of external Ca2+. Two structurally distinct tyrosine kinase inhibitors, genistein and lavendustin A, almost completely inhibited the [Mg2+]i response. These results suggest that bombesin rapidly induces Mg2+ mobilization from the intracellular pool, through external Ca(2+)- and tyrosine kinase-dependent mechanisms.
Long-term nitrate therapy after acute myocardial infarction does not improve or aggravate prognosis.

BACKGROUND There is conflicting information about whether nitrate treatment aggravates long-term prognosis, so the present retrospective study was designed to determine the effects of long-term nitrate therapy on major adverse events after acute myocardial infarction (AMI) in the coronary interventional era. METHODS AND RESULTS Using the Japanese Acute Coronary Syndrome Study database, 1,236 consecutive patients who were hospitalized within 48 h of onset of symptoms of AMI from January to December 2003 were evaluated. All-cause mortality, cardiac events and cardiovascular events were lower in patients treated with nitrates than in the untreated controls. However, these crude comparisons included several confounding factors on nitrate prescription. To minimize the effect of selection bias on outcomes, the technique of propensity score matching for clinical characteristics was used and distortion of effective nitrate treatment was excluded as much as possible. The results of propensity score matching showed that nitrate therapy had no impact on all-cause mortality, cardiac events and cardiovascular events at 30, 60 or 90 days, 6 months, 1 year, and 2 years follow-up. CONCLUSIONS Long-term nitrate therapy after AMI neither improves nor aggravates prognosis. Prospective randomized clinical trials are warranted to determine the effects of long-term nitrate therapy for secondary prevention of AMI.