Miracle-dz/UniFAR-FTUs huggingface dataset:
Angiotensin II‐dependent loss of cardiac function: Mechanisms and pharmacological targets attenuating this effect

Pharmacological inhibition of components of the renin‐angiotensin‐system is one of the major therapeutically options to treat patients with heart failure. This study hypothesized that angiotensin II (Ang II) directly depresses contractile function (cell shortening) by activation of transforming growth factor‐β1 (TGF‐β1). Moreover, we hypothesized that an inhibition of glycogen synthase kinase 3‐βGSK will compensate for this depressive effect by increasing SERCA2 expression. Isolated adult ventricular rat cardiomyocytes were used and cultured in the presence of Ang II (100 nM) for 24 h. Cell shortening and contractile dynamics were recorded at 2 Hz. Immunoblot techniques and gel mobility shift assays were used to demonstrate NFAT activation caused by inhibition of GSK and to demonstrate increases in the expression of SERCA2. Ang‐II caused a nearly 20% decrease in cell shortening. This Ang II‐dependent effect was mimicked by TGF‐β1 (10 ng/ml), attenuated by addition of aprotinin, that was used to block the proteolytic activation of TGF‐β1, or by application of a neutralizing antibody directed against TGF‐β1. Inhibition of GSK activated NFAT, increased SERCA2 expression and improved cell function. In conclusion, the study identified a paracrine mechanism for the Ang II‐dependent loss of cardiac function that occurs independently of hemodynamic changes. Furthermore, it characterized the differences between Ang II and α‐adrenoceptor stimulation with respect to the maintenance of cellular function explaining cellular events contributing to the difference between adaptive (physiological) and mal‐adaptive (patho‐physiological) hypertrophy. J. Cell. Physiol. 217: 242–249, 2008. © 2008 Wiley‐Liss, Inc.
Efficacy and safety of rituximab in neuromyelitis optica: Review of evidence

Neuromyelitis optica (NMO) is an autoimmune inflammatory disease of the central nervous system with preferential involvement in the optic nerve and spinal cord with a widespread spectrum of clinical features; multiple therapeutic agents have been used with different results. Recent evidence points to B-cell-mediated humoral immunity in the pathogenesis of NMO. Rituximab targets the CD20 antigen on B-cells. Treatment leads to profound B-cell depletion, principally over an antibody-dependent cell cytotoxicity mechanism. The aim of our study was to review clinical trials to elucidate the impact of rituximab on the relapse rate, Expanded Disability Status Scale (EDSS), and progression of disability in NMO. We performed a comprehensive review of all studies that evaluated clinical and paraclinical effects of rituximab on NMO. MEDLINE-PubMed, Web of Sciences, EMBASE, and Cochrane databases up to June 2016 included in our searches. In addition, reference lists from articles identified by search as well as a key review article to identify additional articles included in the study. Rituximab targets the CD20 antigen on B-cells and decreases attack frequency and severity in patients with NMO; however, it does not remove attacks, even when modifying treatment to achieve B-cell depletion. Most of the investigations revealed that EDSS significantly in all patients with rituximab treatment will be decreased after treatment with rituximab. No new or enlarged lesions or pathological gadolinium enhancement was observed in serial brain and spinal cord magnetic resonance imaging, except for those observed concomitantly with clinical relapses and the median length of spinal cord lesions was significantly reduced after therapy. Rituximab targets the CD20 antigen and decreases attack frequency and severity in patients with NMO.
The nature and extent of contributions by defective ribosome products to the HLA peptidome

Significance Rapid degradation of newly synthesized proteins, followed by presentation of the resulting peptides by the MHC molecules, serves as an early alert for the immune system during pathogen infection. This study defines the relative contribution to the MHC peptidome of defective ribosome products (DRiPs), which are newly synthesized and rapidly degraded proteins, vs. mature proteins, degraded at the end of their functional lifetimes (retirees). The rates of synthesis of the individual MHC peptides and their source proteins were followed using stable isotope labeling and quantitative proteomics and peptidomics analyses. We conclude that DRiPs are a significant source of MHC peptides. Many of these DRiPs are misassembled surplus subunits of protein complexes and therefore are degraded soon after synthesis. MHC class I peptides are products of endogenous cellular protein degradation. Their prompt presentation, after rapid degradation of their newly synthesized source proteins, is needed to alert the immune system during pathogen infection. A possible source for such rapidly degrading proteins can be defective ribosome products (DRiPs), which include polypeptides produced as part of the pioneer round of translation, premature translation termination, and proteins failing to fold properly or to assemble into their multisubunit protein complexes. However, the identities and relative contribution to the MHC peptidome of these mature or newly synthesized and rapidly degraded cellular proteins is not well understood. To clarify these issues, we used dynamic stable isotope labeling by amino acids in cell culture to define the relative rates of synthesis of the HLA class I peptidomes and the source proteomes of three cultured human hematopoietic cell lines. Large numbers of HLA class I peptides were observed to be derived from DRiPs, defined here as HLA peptides that shift from their light to heavy isotope forms faster than their source proteins. Specific groups of proteins, such as ribosomal and T-complex protein 1 (TCP-1), contributed a disproportionately large number of DRiPs to the HLA peptidomes. Furthermore, no significant preference was observed for HLA peptides derived from the amino terminal regions of the proteins, suggesting that the contribution of products of premature translation termination was minimal. Thus, the most likely sources of DRiPs-derived HLA peptides are full-sized, misassembled, and surplus subunits of large protein complexes.
Bacterial protein meal produced on natural gas replacing soybean meal or fish meal in broiler chicken diets

Abstract The effects of replacing soybean meal or fish meal with 2, 4 or 6% bacterial protein meal (BPM) on growth performance, ileal digestibility of amino acids and sensory quality of meat, were examined using 630 broiler chickens. Weight gain from 7 – 32 days of age did not differ significantly among the treatments. Efficiency of feed conversion was increased when BPM replaced soybean meal, and abdominal fat deposition tended to decline. Feed conversion was not affected when BPM replaced fish meal. Amino acid digestibility was unaffected or improved when BPM replaced soybean meal, whereas replacement of fishmeal with BPM resulted in similar digestibility. Sensory quality of fresh thigh meat was similar among treatments, but for freeze-stored chest meat replacement of fish meal with BPM reduced off-odour and off-flavour and increased juiciness. It was concluded that 6% BPM can replace soybean meal or fish meal protein in broiler chicken diets.
Evolutionarily Assembled cis-Regulatory Module at a Human Ciliopathy Locus

Distinguishing Ciliopathy Cilia were once thought to be evolutionary remnants, but structural defects reveal their importance in signaling pathways and human disease, such as Joubert syndrome. Either of the genes TMEM138 and TMEM216 can be found mutated in phenotypically indistinguishable ciliopathy patients. Interestingly, despite their lack of sequence homology, these genes have always been aligned in head-to-tail configuration during vertebrate evolution. The proteins expressed by these genes mark distinct tethered vesicles, which differentially carry ciliary proteins for assembly. Lee et al. (p. 966, published online 26 January; see the Perspective by Chakravarti and Kapoor) show that the coordinated expression of these adjacent genes depends upon a coevolved regulatory element in the noncoding intergenic region, which thus integrates the roles of both gene products. This discovery explains not only the indistinguishable pathogenesis of the patients' genotypes but also how the evolutionary clustering of genes unrelated in sequence may correlate with coordinated control of expression and function. Mutation in either of a pair of neighboring, coordinately expressed genes causes indistinguishable human disease. Neighboring genes are often coordinately expressed within cis-regulatory modules, but evidence that nonparalogous genes share functions in mammals is lacking. Here, we report that mutation of either TMEM138 or TMEM216 causes a phenotypically indistinguishable human ciliopathy, Joubert syndrome. Despite a lack of sequence homology, the genes are aligned in a head-to-tail configuration and joined by chromosomal rearrangement at the amphibian-to-reptile evolutionary transition. Expression of the two genes is mediated by a conserved regulatory element in the noncoding intergenic region. Coordinated expression is important for their interdependent cellular role in vesicular transport to primary cilia. Hence, during vertebrate evolution of genes involved in ciliogenesis, nonparalogous genes were arranged to a functional gene cluster with shared regulatory elements.
The STIMS Trial: The Ticlopidine Experience and its Clinical Applications

The mortality in patients with intermittent claudication can be reduced by treatment with ticlopidine. This is the clinically most significant result from STIMS, the Swedish Ticlopidine Multicenter Study. During an average treatment period of 5.6 years, 153 of the 687 patients died, 26.1% in the placebo group and 18.5% in the ticlopidine group (RR0.7, p=0.015). The incidence of fatal vascular events in the two groups was 12% and 6%. In terms of lives saved per years of treatment, STIMS showed that by treating 200 claudicants for 5 years one can save 13 from a cardiovascular death, not merely dying from something else as treatment was associated with a reduced total mortality as well. The interpretation of the on-treatment analysis is that for those who tolerate the drug the combined vascular morbidity and mortality rate is lowered from 24% to 14%. The disadvantage is that many patients do not tolerate ticlopidine. In STIMS, 22% (2.5 times as many as in the control group) had to stop medication because of gastrointestinal side-effects. Although ticlopidine is associated with an increased risk of leukopenia, the risk in absolute numbers is small: according to STIMS, 4% during 5.6 years. All events were reversible. The 1.4% incidence of thrombocytopenia did not seem to be associated with ticlopidine treatment.
Landscapes Synthesis Achieved through Erosion and Deposition Process Simulation

This paper describes an original approach to terrain evolution in landscapes synthesis. In order to create some realistic landforms, we simulate geologically contrasted terrains and apply to them deterministic erosion processes. This allows us to relate the erosion on any point of the landsurface to local geological parameters. Any height field may be chosen as an initial topographic surface. Small perturbations may be introduced to avoid unpleasant regularities. A 3D model defines the geological parameters of each point according to its elevation. Our method is iterative: at each step, rock removal and possible alluvial deposition are computed at each point of the landsurface. The available erosion laws simulate mechanical erosion, chemical dissolution and alluvial deposition. At the end of each iteration, a new landsurface and the corresponding river network are created. Landsurfaces can be visualized at the final stage by two rendering algorithms including natural textures mapping. The stream network and the ridges may also be visualized.
Re-establishing Conversational Skills in Overtly Psychotic, Chronic Schizophrenic Patients

A discrete trials procedure incorporating graduated prompts, social and consumable reinforcement, corrective feedback, delay of reinforcement, and a chaining procedure was used to teach four actively psychotic, chronic schizophrenic patients rudimentary conversational skills. In a multiple-baseline design, training was sequentially applied to the target conversational skills of giving a salutation, addressing the trainer by his or her name, making a personal inquiry, and asking a conversational question. Results showed systematic training effects in three of the four subjects. Training gains were reliable but slow, requiring over 70 trials to reach acquisition criterion on certain skills. The fourth subject exhibited only unstable gains on the first target response and minor improvements on the second target response, the latter of which disappeared when training procedures were withdrawn. All subjects displayed spontaneous recovery on the generalization measure of answering a personal inquiry.
Characterization of Pneumococcal Genes Involved in Bloodstream Invasion in a Mouse Model

Streptococcus pneumoniae (the pneumococcus) continues to account for significant morbidity and mortality worldwide, causing life-threatening diseases such as pneumonia, bacteremia and meningitis, as well as less serious infections such as sinusitis, conjunctivitis and otitis media. Current polysaccharide vaccines are strictly serotype-specific and also drive the emergence of non-vaccine serotype strains. In this study, we used microarray analysis to compare gene expression patterns of either serotype 4 or serotype 6A pneumococci in the nasopharynx and blood of mice, as a model to identify genes involved in invasion of blood in the context of occult bacteremia in humans. In this manner, we identified 26 genes that were significantly up-regulated in the nasopharynx and 36 genes that were significantly up-regulated in the blood that were common to both strains. Gene Ontology classification revealed that transporter and DNA binding (transcription factor) activities constitute the significantly different molecular functional categories for genes up-regulated in the nasopharynx and blood. Targeted mutagenesis of selected genes from both niches and subsequent virulence and pathogenesis studies identified the manganese-dependent superoxide dismutase (SodA) as most likely to be essential for colonization, and the cell wall-associated serine protease (PrtA) as important for invasion of blood. This work extends our previous analyses and suggests that both PrtA and SodA warrant examination in future studies aimed at prevention and/or control of pneumococcal disease.
Clinical outcomes of HIV care delivery models in the US: a systematic review

ABSTRACT With over 1 million people living with HIV, the US faces national challenges in HIV care delivery due to an inadequate HIV specialist workforce and the increasing role of non-communicable chronic diseases in driving morbidity and mortality in HIV-infected patients. Alternative HIV care delivery models, which include substantial roles for advanced practitioners and/or coordination between specialty and primary care settings in managing HIV-infected patients, may address these needs. We aimed to systematically review the evidence on patient-level HIV-specific and primary care health outcomes for HIV-infected adults receiving outpatient care across HIV care delivery models. We identified randomized trials and observational studies from bibliographic and other databases through March 2016. Eligible studies met pre-specified eligibility criteria including on care delivery models and patient-level health outcomes. We considered all available evidence, including non-experimental studies, and evaluated studies for risk of bias. We identified 3605 studies, of which 13 met eligibility criteria. Of the 13 eligible studies, the majority evaluated specialty-based care (9 studies). Across all studies and care delivery models, eligible studies primarily reported mortality and antiretroviral use, with specialty-based care associated with mortality reductions at the clinician and practice levels and with increased antiretroviral initiation or use at the clinician level but not the practice level. Limited and heterogeneous outcomes were reported for other patient-level HIV-specific outcomes (e.g., viral suppression) as well as for primary care health outcomes across all care delivery models. No studies addressed chronic care outcomes related to aging. Limited evidence was available across geographic settings and key populations. As re-design of care delivery in the US continues to evolve, better understanding of patient-level HIV-related and primary care health outcomes, especially across different staffing models and among different patient populations and geographic locations, is urgently needed to improve HIV disease management.
Optimal code and data layout in embedded systems

Efficient layout of code and data sections in various types/levels of memory in an embedded system is very critical not only for achieving real-time performance, but also for reducing its cost and power consumption. In this paper we formulate the optimal code and data section layout problem as an integer linear programming (ILP) problem. The proposed formulation can handle: (i) on-chip and off-chip memory, (ii) multiple on-chip memory banks, (iii) single and dual ported on-chip RAMS, (iv) overlay of data sections, and (v) swapping of code and data (from/to external memory). Our experiments demonstrate that, for a moderately complex embedded system, the optimal results produced by our formulation took only a few minutes on a PC, and it matches, in terms of performance and on-chip memory size, with a hand-optimized code/data layout which took 1 man-month.
Predictors of PTSD and Delayed PTSD After Disaster: The Impact of Exposure and Psychosocial Resources

In the present study we sought to identify factors associated with posttraumatic stress disorder (PTSD) following the World Trade Center Disaster (WTCD) and examine changes in PTSD status over time. Our data come from a two-wave, prospective cohort study of New York City adults who were living in the city on September 11, 2001. We conducted a baseline survey 1 year after the attacks (year 1), followed by a survey 1 year later (year 2). Overall, 2368 individuals completed the year 1 survey, and 1681 were interviewed at year 2. Analyses for year 1 indicated that being younger, being female, experiencing more WTCD events, reporting more traumatic events other than the WTCD, experiencing more negative life events, having low social support, and having low self-esteem increased the likelihood of PTSD. For year 2, being middle-aged, being Latino, experiencing more negative life events and traumas since the WTCD, and having low self-esteem increased the likelihood of PTSD. Exposure to WTCD events was not related to year 2 PTSD once other factors were controlled. Following previous research, we divided study respondents into four categories: resilient cases (no PTSD years 1 or 2), remitted cases (PTSD year 1 but not year 2), delayed cases (no PTSD year 1 but PTSD year 2), and acute cases (PTSD both years 1 and 2). Factors predicting changes in PTSD between year 1 and year 2 suggested that delayed PTSD cases were more likely to have been Latino, to have experienced more negative life events, and to have had a decline in self-esteem. In contrast, remitted cases experienced fewer negative life events and had an increase in self-esteem. We discuss these findings in light of the psychosocial context associated with community disasters and traumatic stress exposures.
Prospective analysis of serious cardiorespiratory events in children during ophthalmic artery chemotherapy for retinoblastoma under a deep standardized anesthesia

Serious adverse cardiorespiratory events complicate super selective ophthalmic artery chemotherapy for retinoblastoma in anesthetized children. Their mechanism remains unclear but may be attributed to an autonomic nervous reflex induced by the catheter close to the ophthalmic artery. Inadequate depth of anesthesia during catheter stimulation might be an aggravating factor. Thus, we tested whether deep general anesthesia reduced the incidence of serious cardiorespiratory events.
Analysing search engine advertising research: synthesis of two decades of research

Search engine advertising SEA has attracted the attention of academic researchers from marketing, information systems, computer science, mathematics and other related fields. Aiming to provide a picture of the state of the art in this field, the present research systematically searches for and reviews the literature on SEA, analyses and structures them, and provides directions for future research. We searched extensively and collected 97 journal papers on SEA published in 64 journals from different disciplines and analysed them to answer our research questions. Using systematic mapping approach, this research has identified research topics ten categories of topics were identified and visualised in a graphical representation, research approaches, nature of research and the interdependencies between them. The research also has identified directions for future research.
Alternative Splicing of Vitamin D-24-Hydroxylase

Synthesis of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25-(OH)2D), by renal epithelial cells is tightly controlled during normal calcium homeostasis. By contrast, macrophage production of 1,25-(OH)2D is often dysregulated with potential hypercalcemic complications. We have postulated that this is due to abnormal catabolism of 1,25-(OH)2D by the feedback control enzyme, vitamin D-24-hydroxylase (CYP24). Using chick HD-11 and human THP-1 myelomonocytic cell lines, we have shown that macrophage-like cells express a splice variant of the CYP24 gene (CYP24-SV), which encodes a truncated protein. Compared with the holo-CYP24 gene product in chick and human cells (508 and 513 amino acids, respectively), the truncated CYP24-SV versions consisted of 351 and 372 amino acids. These CYP24-SV proteins retained intact substrate-binding domains but lacked mitochondrial targeting sequences and were therefore catalytically inactive. In common with CYP24, expression of the CYP24 variants was induced by 1,25-(OH)2D but without a concomitant rise in 24-hydroxylase activity. However, overexpression of CYP24-SV in HD-11 and THP-1 cells reduced synthesis of 1,25-(OH)2 D (40–50%), whereas antisense CYP24-SV expression increased 1,25-(OH)2D production by 2–7-fold. These data suggest that alternative splicing of CYP24 leads to the generation of a dominant negative-acting protein that is catalytically dysfunctional. We theorize that expression of the CYP24-SV may contribute to the extracellular accumulation of 1,25(OH)2D in human health and disease.
Incorporating Extra Information in Nonparametric Smoothing

Nonparametric estimation of conditional mean functions has been studied extensively in the literature. This paper addresses the question of how to use extra informations to improve the estimation. Particularly, we consider the situation that the conditional mean functionE(Z|X) is of interest and there is an auxiliary variable available which is correlated with bothXandZ. A two-stage kernel smoother is proposed to incorporate the extra information. We prove that the asymptotic optimal mean squared error of the proposed estimator is smaller than that obtained when using the Nadaraya? Watson estimator directly without the auxiliary variable. A simulation study is also carried out to illustrate the procedure.