Miracle-dz/UniFAR-FTUs huggingface dataset:
Evidence for a role of IL-17 in organ allograft rejection: IL-17 promotes the functional differentiation of dendritic cell progenitors.

IL-17 is a T cell-derived cytokine that stimulates stromal cells and macrophages to secrete proinflammatory cytokines. We hypothesized that IL-17 might play a role in alloimmune responses, and that interference with its activity might suppress allograft rejection. IL-17R:Fc or control IgG was added at the start of mouse MLR or was administered i.p. (100-500 microg/day) for different durations post-transplant to murine recipients of MHC-mismatched cardiac allografts. IL-17R:Fc (50-200 microg/ml) markedly inhibited T cell proliferation in vitro and significantly prolonged nonvascularized cardiac allograft median survival time from 13 to 20 days (100 microg/day; days 0 and 1) or to 19 days (100-300 microg/day; days 0-4). Survival of vascularized grafts was also extended significantly from 10.5 to 19 days by IL-17R:Fc (500 microg/day; days 0-6). To address a possible mechanism by which IL-17 may promote alloreactivity, we examined the influence of IL-17 on the differentiation and function of bone marrow-derived cells propagated in granulocyte-macrophage CSF with or without IL-4 to promote dendritic cell (DC) growth. A minor proportion of CD11c+ DC expressed the IL-17R. IL-17 promoted the maturation of DC progenitors, as evidenced by increased cell surface expression of CD11c, costimulatory molecules (CD40, CD80, CD86), and MHC class II Ag, and allostimulatory capacity. IL-17 had a lesser effect on the phenotype and function of more fully differentiated myeloid DC. These findings suggest a role for IL-17 in allogeneic T cell proliferation that may be mediated in part via a maturation-inducing effect on DC. IL-17 appears to be a novel target for therapeutic intervention in allograft rejection.
THE EFFECTS OF FENOLDOPAM ON RENAL FUNCTION AND METABOLISM IN AN OVINE MODEL OF SEPTIC SHOCK

Introduction: The importance of renal perfusion and metabolism in septic acute kidney injury (AKI) remains unclear. Prophylactic administration of the dopaminergic agent, fenoldopam, has been suggested to reduce the occurrence of AKI, but its effects in septic shock are poorly defined. Methods: Sepsis was induced in 15 adult female sheep by injecting autologous feces into the abdominal cavity. Two hours later, the animals were randomized to one of three groups: low-dose fenoldopam (1.0 &mgr;g/kg/min, n = 5), high-dose fenoldopam (5.0 &mgr;g/kg/min, n = 5), or placebo (control, n = 5). A perivascular flow probe was placed around the renal artery and a catheter in the renal vein for measurement of renal blood flow index (RBFI) and oxygen consumption (VO2renI). Metabolism in the renal cortex was evaluated using microdialysis. Serum creatinine was measured 6-hourly and the sublingual microcirculation assessed using sidestream dark-field videomicroscopy. Results: High-dose fenoldopam was associated with a lower RBFI at 18 h (P = 0.032) than in the control group, but VO2renI was maintained by a higher oxygen extraction (P < 0.05 vs. baseline). Sublingual microcirculatory alterations at 18 h were more severe in the high-dose than in the control and low-dose groups (P = 0.021 and P = 0.032). Renal cortex lactate and pyruvate levels increased earlier in the high-dose group than in the other two groups (P < 0.001 vs. baseline). Fenoldopam did not affect creatinine clearance or urine output. Conclusions: In this model of septic shock, fenoldopam did not improve renal blood flow, worsened microcirculatory alterations, and induced metabolic changes that were indicative of increased glycolysis.
Validation study of the lambda model for predicting the BRCA1 or BRCA2 mutation carrier status of North American Ashkenazi Jewish women

lambda is a model that estimates the probability an Ashkenazi Jewish (AJ) woman carries an ancestral BRCA1 or BRCA2 mutation from her personal and family cancer history. lambda is relevant to clinical practice, and its implementation does not require a computer. It was developed principally from Australian and UK data. We conducted a validation study using 1286 North American AJ women tested for the mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. Most had a personal or family history of breast cancer. We observed 197 carriers. The area under the receiver operator characteristic (ROC) curve (a measure of ranking) was 0.79 [95% confidence interval (CI) = 0.77–0.81], similar to that for the model‐generating data (0.78; 95% CI = 0.75–0.82). lambda predicted 232 carriers (18% more than observed; p = 0.002) and was overdispersed (p = 0.009). The Bayesian computer program brcapro gave a similar area under the ROC curve (0.78; 95% CI = 0.76–0.80), but predicted 367 carriers (86% more than observed; p < 0.0001), and was substantially overdispersed (p < 0.0001). Therefore, lambda is comparable to brcapro for ranking AJ women according to their probability of being a BRCA1 or BRCA2 mutation carrier and is more accurate than brcapro which substantially overpredicts carriers in this population.
Relationships linking emotional, motor, cognitive and GABAergic dysfunctions in dystrophin-deficient mdx mice

Alterations in the Duchenne muscular dystrophy (DMD) gene have been associated with enhanced stress reactivity in vertebrate species, suggesting a role for brain dystrophin in fear-related behavioral and cognitive processes. Because the loss of dystrophin (Dp427) reduces clustering of central γ-aminobutyric acid (GABAA) receptors, it is suspected that local inhibitory tuning and modulation of neuronal excitability are perturbed in a distributed brain circuit that normally controls such critical behavioral functions. In this study, we undertook a large-scale behavioral study to evaluate fear-related behavioral disturbances in dystrophin-deficient mdx mice. We first characterized the behavioral determinants of the enhanced fearfulness displayed by mdx mice following mild acute stress and its association with increased anxiety and altered fear memories. We further demonstrated that this enhanced fearfulness induces long-lasting motor inhibition, suggesting that neurobehavioral dysfunctions significantly influence motor outcome measures in this model. We also found that mdx mice are more sensitive to the sedative and hypnotic effects of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochlorid (THIP), a selective pharmacological activator of extrasynaptic GABAA receptors involved in central tonic inhibition. Our results highlight that information on the emotional aspects of mdx mice are important to better understand the bases of intellectual and neuropsychiatric defects in DMD and to better define valuable functional readouts for preclinical studies. Our data also support the hypothesis that altered spatial localization of GABAA receptors due to Dp427 loss is a pathological mechanism associated with brain dysfunction in DMD, suggesting that extrasynaptic GABAA receptors might be candidate targets for future therapeutic developments.
Evidence-based practice and research utilization activities among rural nurses.

PURPOSE To identify the extent to which rural nurses utilize evidence-based practice guidelines from scientific research in their practice; to describe both previous and current research utilization activities in which they have participated, and to identify the specific barriers they face in their practice settings. DESIGN AND METHODS Data for this descriptive study were collected through questionnaires with open-ended questions focused on (a) current utilization of nursing research findings, (b) previous involvement in nursing research activities, and (c) participation in medical research activities. The participants were 106 nurses from various practice areas in six rural counties of a southwestern state in the United States. FINDINGS Results revealed that only 20.8% of the participants stated they were currently involved in research utilization, and they were mostly nurses with bachelor's degrees. The two most common areas of current research utilization were pain management and pressure ulcer prevention and management. Barriers to research utilization, such as rural isolation and lack of nursing research consultants, were identified. CONCLUSIONS The types of research utilization activities identified by these nurses indicate how much the facilities in which these nurses work in the rural areas are striving with the utilization of available scientific evidence. Rural nurses face unique barriers related to situational and geographic factors, with implications for nursing administrators, researchers, and educators.
Heme oxygenase‐1 could mediate the protective effects of hyperbaric oxygen preconditioning against hepatic ischemia–reperfusion injury in rats

1. Heme oxygenase 1 (HO‐1) has been shown to play a pivotal role in the maintenance of cellular homeostasis when the liver undergoes sublethal stress, such as ischaemia–reperfusion (I/R) injury. In the present study, we investigated the protective role of HO‐1 in hyperbaric oxygen (HBO) preconditioning against liver injury after I/R.
Preventing low Birthweight through Maternal Multiple Micronutrient Supplementation: A Cluster-Randomized, Controlled Trial in Indramayu, West Java

Background Micronutrient deficiencies may contribute to a higher incidence of low birthweight (LBW). UNICEF/United Nations University/World Health Organization jointly proposed a formulation for a multiple micronutrient supplement for pregnant women, and several effectiveness trials were conducted to assess its impact. Objective To evaluate the efficacy of prenatal multiple micronutrient supplementation for improving birth size, pregnancy outcome, and maternal micronutrient status in comparison with iron–folic acid supplementation. Methods We carried out a cluster-randomized, controlled trial in Indramayu, Indonesia, involving 843 pregnant women. Of these, 432 received multiple micronutrients and 411 received iron–folic acid. Fieldworkers visited the women daily to observe supplement consumption and record fetal loss and mortality. Results The mean number of supplements consumed during pregnancy and 30 days postpartum was high (136 in the group receiving multiple micronutrients and 140 in the iron–folic acid group). The women consumed the supplements on average 5 days per week. Although there were no significant differences between the groups in the percentage of infants with LBW, there was a trend toward a lower incidence of LBW in the group receiving multiple micronutrients (6.3% vs. 7.3%), and the mean birthweight was 40 g higher in the group receiving multiple micronutrients than in the iron–folic acid group, although the difference was not significant. Among those who consumed 90 or more supplements during pregnancy, women taking multiple micronutrients had a 3.3% combined rate of miscarriage, stillbirth, or neonatal death, as compared with 6.9% for those taking iron–folic acid only (p < .049). The anemia rates in the two groups were similar after supplementation, even though the amount of iron in the multiple micronutrient supplement was half that in the iron–folic acid supplement. Serum retinol was higher in the group receiving multiple micronutrients. Conclusions Multivitamin supplementation use among pregnant women is as effective as iron–folic acid in improving anemia status and appears to have other benefits for maternal and child nutritional status.
Visible lasers were better than invisible lasers in accelerating burn healing on diabetic rats.

OBJECTIVE This study was designed to assess and compare the efficacy of accelerating burn healing in diabetic rats using low-power visible and invisible lasers. BACKGROUND DATA Low-level laser therapy (LLLT) has been used in a number of diabetic animal and human studies, with both positive and no effects. MATERIALS AND METHODS Male Sprague-Dawley rats were used in the study. Streptozotocin (70 mg/kg) was given for diabetes induction. A burn wound was created on the shaved back of the animals using a metal rod heated to 600 degrees C. The study was performed using 532-, 633-, 670-, 810-, and 980-nm diode lasers. Incident doses of 5, 10, 20, and 30 J/cm(2) and a treatment schedule of three times per week were used in the experiments. The burned areas on all rats were measured and plotted on a chart, and the slope values (mm(2)/d) and the percentages of burn healing were compared. RESULTS The percentage of burn healing on diabetic rats after LLLT was 78.37% for the visible lasers and 50.68% for the invisible lasers. There was a significant difference (p < 0.005) between visible lasers and invisible lasers in the percentage of burn healing on diabetic rats after laser therapy. CONCLUSION LLLT at the appropriate treatment parameters can accelerate burn healing on diabetic rats using both visible and invisible lasers. The effects of visible lasers were better than those of invisible lasers in accelerating burn healing on diabetic rats in this study.
Atg4 recycles inappropriately lipidated Atg8 to promote autophagosome biogenesis

Atg8 is a ubiquitin-like protein required for autophagy in the budding yeast Saccharomyces cerevisiae. A ubiquitin-like system mediates the conjugation of the C terminus of Atg8 to the lipid phosphatidylethanolamine (PE), and this conjugate (Atg8–PE) plays a crucial role in autophagosome formation at the phagophore assembly site/pre-autophagosomal structure (PAS). The cysteine protease Atg4 processes the C terminus of newly synthesized Atg8 and also delipidates Atg8 to release the protein from membranes. While the former is a prerequisite for lipidation of Atg8, the significance of the latter in autophagy has remained unclear. Here, we show that autophagosome formation is significantly retarded in cells deficient for Atg4-mediated delipidation of Atg8. We find that Atg8–PE accumulates on various organelle membranes including the vacuole, the endosome and the ER in these cells, which depletes unlipidated Atg8 and thereby attenuates its localization to the PAS. Our results suggest that the Atg8–PE that accumulates on organelle membranes is erroneously produced by lipidation system components independently of the normal autophagic process. It is also suggested that delipidation of Atg8 by Atg4 on different organelle membranes promotes autophagosome formation. Considered together with other results, we propose that Atg4 acts to compensate for the intrinsic defect in the lipidation system; it recycles Atg8–PE generated on inappropriate membranes to maintain a reservoir of unlipidated Atg8 that is required for autophagosome formation at the PAS.
Characterization of ExsC and ExsD Self-Association and Heterocomplex Formation

ABSTRACT Expression of the Pseudomonas aeruginosa type III secretion system (T3SS) is induced by calcium depletion and is positively regulated by the ExsA transcriptional activator and negatively regulated by the ExsD antiactivator. Under conditions permissive for expression of the T3SS, the negative regulatory activity of ExsD is antagonized by a direct binding interaction with ExsC. In the present study, the ExsC-ExsD binding interaction was characterized. Individually, both ExsC and ExsD form self-associated complexes, as judged by bacterial monohybrid and gel filtration experiments. A mixture of purified ExsC and ExsD readily formed a complex that elutes from gel filtration medium as a single included peak. The calculated molecular weight of the ExsC-ExsD complex is consistent with a complex containing multiple copies of ExsC and ExsD. Isothermic titration calorimetry experiments found formation of the ExsC-ExsD complex to be thermodynamically favorable, with a Kd of ∼18 nM and a likely binding ratio of 1:1. To identify amino acid residues important for the regulatory activities of ExsC and ExsD, self-association, and complex formation, charged-cluster mutagenesis was performed. Two of the resulting ExsD charged-cluster mutants (DM2 and DM3) demonstrated a hyperrepressive phenotype for expression of the T3SS. By two-hybrid and copurification assays, the DM3 mutant was found to be impaired in its interaction with ExsC. This finding demonstrates that the binding of ExsC to ExsD is required for transcriptional induction of the T3SS under calcium-limiting growth conditions.
Topological Predictions for Integral Membrane Permeases of the Phosphoenolpyruvate:Sugar Phosphotransferase System

We report bioinformatic analyses of the largest superfamily of integral membrane permeases of the bacterial phosphotransferase system (PTS), the Enzyme IIC constituents of the Glc superfamily. Phylogenetic analyses reveal that this superfamily consists of five equally distant families, the Glucose (Glc), β-Glucoside (Bgl), Fructose (Fru), Mannitol (Mtl) and Lactose (Lac) families. Average hydropathy, amphipathicity and similarity plots were generated for these five families as well as for the entire superfamily. Charged residue distribution was analyzed, and the most conserved sequence motif, common to all five families, was identified. The results show that the members of all five families exhibit similar average hydropathy plots with regions of average amphipathicity and relative conservation also being similar. Evidence is presented suggesting that the Glucitol (Gut) family of Enzyme IIC constituents is a distant member of the Glc superfamily. Based on our analyses we offer a topological model that resembles, but differs in detail from the two previously proposed models.
A performance counter-based control flow checking technique for multi-core processors

Today, both the rapid improvement of process technology and the arrival of new embedded systems with highperformance requirements, have led to making the current trend in processors manufacturing shift from single-core processors to multi-core processors. This trend has raised several challenges for reliability in safety-critical systems that operate in high-risk environments, making them more vulnerable to soft errors. Hence, using additional methods to satisfy the strict system requirements in terms of safety and reliability is unavoidable. In this paper, an efficient hybrid method to detect control flow errors in multi-core processors has been proposed and evaluated. About 36,000 software faults have been injected into three well-known multi-threaded benchmarks at run-time. The experiment results show that the fault coverage is 100%. The results also show that the execution time overhead varies between 31.25% and 51.02%, and the program size overhead varies between 20.23% and 67.64% with respect to the employed benchmark.
Torque teno virus (TTV): current status

Torque teno virus (TTV), currently classified into the family Circoviridae, genus Anellovirus, was first found in a patient with non‐A‐E hepatitis. TTV has a single stranded circular DNA of ∼3.8 kb. TTVs are extraordinarily diverse, spanning five groups including SANBAN and SEN viruses. Torque teno mini virus (TTMV) with ∼2.9 kb genome also has wide variants. Recently, two related 2.2‐ and 2.6‐kb species joined this community. Recombinations between variants are frequent. This extensive TTV diversity remains unexplained; it is unclear how TTVs could be viable, and why they require such genetic variation. An unequivocal culture system is still not available. TTVs are ubiquitous in > 90% of adults worldwide but no human pathogenicity of TTV has been fully established. Epidemiological surveys need to specify the variants being studied and clinical targets, and must calibrate the sensitivity of the assay used. Potentially interesting observations include a higher viral load in patients with severe idiopathic inflammatory myopathies, cancer and lupus. Active replication was also found in infants with acute respiratory diseases. TTV/TTMV‐related viruses were found in chimpanzees, apes, African monkeys and tupaias, and also in chickens, pigs, cows, sheep and dogs. Experimentally, rhesus monkeys were persistently infected by TTV, but only 1/53 chimpanzees. TTV transcribes three species of mRNAs, 3.0‐, 1.2‐ and 1.0‐kb in the ratio of 60:5:35. Recently, at least three mRNAs were shown in chicken anaemia virus. The genomic region −154/−76 contains a critical promoter. TTV seems to have at least three proteins; however, the definite functions of these proteins await further research work. Copyright © 2006 John Wiley & Sons, Ltd.
Identification of Two Legionella pneumophila Effectors that Manipulate Host Phospholipids Biosynthesis

The intracellular pathogen Legionella pneumophila translocates a large number of effector proteins into host cells via the Icm/Dot type-IVB secretion system. Some of these effectors were shown to cause lethal effect on yeast growth. Here we characterized one such effector (LecE) and identified yeast suppressors that reduced its lethal effect. The LecE lethal effect was found to be suppressed by the over expression of the yeast protein Dgk1 a diacylglycerol (DAG) kinase enzyme and by a deletion of the gene encoding for Pah1 a phosphatidic acid (PA) phosphatase that counteracts the activity of Dgk1. Genetic analysis using yeast deletion mutants, strains expressing relevant yeast genes and point mutations constructed in the Dgk1 and Pah1 conserved domains indicated that LecE functions similarly to the Nem1-Spo7 phosphatase complex that activates Pah1 in yeast. In addition, by using relevant yeast genetic backgrounds we examined several L. pneumophila effectors expected to be involved in phospholipids biosynthesis and identified an effector (LpdA) that contains a phospholipase-D (PLD) domain which caused lethal effect only in a dgk1 deletion mutant of yeast. Additionally, LpdA was found to enhance the lethal effect of LecE in yeast cells, a phenomenon which was found to be dependent on its PLD activity. Furthermore, to determine whether LecE and LpdA affect the levels or distribution of DAG and PA in-vivo in mammalian cells, we utilized fluorescent DAG and PA biosensors and validated the notion that LecE and LpdA affect the in-vivo levels and distribution of DAG and PA, respectively. Finally, we examined the intracellular localization of both LecE and LpdA in human macrophages during L. pneumophila infection and found that both effectors are localized to the bacterial phagosome. Our results suggest that L. pneumophila utilize at least two effectors to manipulate important steps in phospholipids biosynthesis.
The Endoplasmic Reticulum-resident Heat Shock Protein Gp96 Activates Dendritic Cells via the Toll-like Receptor 2/4 Pathway*

The heat shock protein Gp96 has been shown to induce specific immune responses. On one hand, this phenomenon is based on the specific interaction with CD91 that mediates endocytosis and results in major histocompatibility complex class I-restricted representation of the Gp96-associated peptides. On the other hand, Gp96 induces activation of professional antigen-presenting cells, resulting in the production of pro-inflammatory cytokines and up-regulation of costimulatory molecules by unknown mechanisms. In this study, we have analyzed the consequences of Gp96 interaction with cells expressing different Toll-like receptors (TLRs) and with bone marrow-derived dendritic cells from mice lacking functional TLR2 and/or TLR4 molecules. We find that the Gp96-TLR2/4 interaction results in activation of nuclear factor κB-driven reporter genes and mitogen- and stress-activated protein kinases and induces IκBα degradation. Bone marrow-derived dendritic cells of C3H/HeJ and more pronounced C3H/HeJ/TLR2−/− mice fail to respond to Gp96. Interestingly, activation of bone marrow-derived dendritic cells depends on endocytosis of Gp96 molecules. Our results provide, for the first time, the molecular basis for understanding the Gp96-mediated activation of antigen-presenting cells by describing the simultaneous stimulation of the innate and adaptive immune system. This feature explains the remarkable ability of Gp96 to induce specific immune responses against tumors and pathogens.