Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential Requirement of SAGA Components for Recruitment of TATA-Box-Binding Protein to Promoters In Vivo

ABSTRACT The multisubunit Saccharomyces cerevisiae SAGA (Spt-Ada-Gcn5-acetyltransferase) complex is required to activate transcription of a subset of RNA polymerase II-dependent genes. However, the contribution of each SAGA component to transcription activation is relatively unknown. Here, using a formaldehyde-based in vivo cross-linking and chromatin immunoprecipitation assay, we have systematically analyzed the role of SAGA components in the recruitment of TATA-box binding protein (TBP) to SAGA-dependent promoters. We show that recruitment of TBP is diminished at a number of SAGA-dependent promoters in ada1Δ, spt7Δ, and spt20Δ null mutants, consistent with previous biochemical data suggesting that these components maintain the integrity of the SAGA complex. We also find that Spt3p is generally required for TBP binding to SAGA-dependent promoters, consistent with biochemical and genetic experiments, suggesting that Spt3p interacts with and recruits TBP to the core promoter. By contrast, Spt8p, which has been proposed to be required for the interaction between Spt3p and TBP, is required for TBP binding at only a subset of SAGA-dependent promoters. Ada2p and Ada3p are both required for TBP recruitment to Gcn5p-dependent promoters, supporting previous biochemical data that Ada2p and Ada3p are required for the histone acetyltransferase activity of Gcn5p. Finally, our results suggest that TBP-associated-factor components of SAGA are differentially required for TBP binding to SAGA-dependent promoters. In summary, we show that SAGA-dependent promoters require different combinations of SAGA components for TBP recruitment, revealing a complex combinatorial network for transcription activation in vivo.
Iron lung vs mask ventilation in the treatment of acute on chronic respiratory failure in COPD patients: a multicenter study.

STUDY OBJECTIVES Evaluation of the effectiveness of negative-pressure ventilation (NPV) with the use of the iron lung vs noninvasive positive-pressure ventilation (NIPPV) in the treatment of COPD patients with acute on chronic respiratory failure. DESIGN A retrospective case-control study. SETTING Four Italian respiratory intermediate ICUs. PATIENTS Of a total of 393 COPD patients admitted to the ICU in 1996, 53 pairs were treated with the iron lung (NPV group). Patients treated with NIPPV (NIPPV group) were matched according to mean (+/- SD) age (70.3 +/- 7.1 vs 70.3 +/- 6.9 years, respectively), sex, causes of acute respiratory failure (ARF), APACHE (acute physiology and chronic health evaluation) II score (22.4 +/- 5.3 vs 22.1 +/- 4.6, respectively), pH (7.26 +/- 0.05 vs 7.27 +/- 0.04, respectively), and PaCO(2) (88.1 +/- 11.5 vs 85.1 +/- 13.5 mm Hg, respectively) on admission to the ICU. The effectiveness of matching was 98.4%. RESULTS Five patients from the NPV group (9.4%) and seven patients from the NIPPV group (13.2%) needed endotracheal intubation (EI). The treatment failure rate (ie, death and/or need of EI) was 20.7% in the NPV group and 24.5% in the NIPPV group (difference was not significant). The mean duration of mechanical ventilation (29.6 +/- 28.6 vs 62.3 +/- 35.7 h, respectively) and length of hospital stay (10.4 +/- 4.3 vs 15 +/- 5.2 d, respectively) among the 35 concordant surviving pairs were significantly lower in the NPV group than in the NIPPV group (p = 0.001 and p = 0.001, respectively). CONCLUSIONS These data suggest that both ventilatory techniques are equally effective in avoiding EI and death in COPD patients with ARF. Prospective trials are needed to confirm these preliminary results.
Protocol renal allograft biopsies and the design of clinical trials aimed to prevent or treat chronic allograft nephropathy.

BACKGROUND The minimum sample size to perform a clinical trial aimed to modify the natural history of chronic allograft nephropathy (CAN) is very large. Since the presence of chronic tubulointerstitial damage in renal protocol biopsy specimens is an independent predictor of late outcome, we evaluated whether protocol biopsies could facilitate the design of trials aimed to prevent or treat CAN. METHODS Two hundred eighty-two protocol biopsy specimens were obtained 3 months after transplantation in 280 patients with serum creatinine levels <300 micromol/L, proteinuria <1000 mg/day, and stable function. The specimens were evaluated according to the Banff criteria. RESULTS Graft survival depended on the presence of CAN and renal transplant vasculopathy (RTV). Thus, biopsy specimens were classified as: (a) no CAN (n=174); (b) CAN without RTV (n=87); and (c) CAN with RTV (n=21). Graft survival at 10 years was 95%, 82%, and 41%, respectively (P=0.001). Total serum cholesterol before transplantation was 4.5+/-1.1, 4.6+/-1.1, and 5.3+/-1.6 mmol/L, respectively (P=0.009) and it was the only predictor of RTV. Power analysis (beta=20%, alpha=5%) was done to evaluate whether protocol biopsies can facilitate the design of clinical trials aimed either to prevent or treat CAN. We showed that the most feasible approach would be to use the presence of CAN as the primary efficacy end point in a prevention trial. To demonstrate a 50% reduction in the incidence of CAN at 3 months, 570 patients would be required. CONCLUSIONS Protocol biopsies may allow a reduction of sample size and especially the time of follow-up in a trial aimed to prevent CAN.
Further assessment of exome‐wide UVR footprints in melanoma and their possible relevance

C>T substitutions at dipyrimidine sites dominate the melanoma genome. We recently analyzed the exomes of spontaneous and neonatal UVR‐induced murine melanomas, noting a dramatic change in the genomic footprint at C>T substitutions in the latter. Here we re‐analyzed published exome‐wide footprints in human melanomas stratified in terms of likely previous sun exposure. Acral and mucosal melanomas were heterogeneous in terms of base substitution types, but most C>Ts occurred in the context of 3′G, probably resulting from spontaneous deamination of the cytosine. C>Ts in sun‐exposed melanomas were statistically different from acral/mucosal lesions only in preferring an adjacent 5′T and 3′C. Pyrimidine dimer adducts can form between any pyrimidine (TT, TC, CT, CC). Hence in melanoma C>Ts are overwhelmingly induced at TC or CC photoproducts, or, there are peculiarities in DNA repair that favor the mutation of cytosines with these two pyrimidines adjacent. If melanoma UVR footprints at C>Ts reflect a specific dimer type (eg, 6–4 photoproduct or cyclobutane pyrimidine dimer), these could be removed post UVR, for instance using photolyases, to potentially reduce melanoma risk. If specific modes of DNA repair and/or replication cause these footprints, methodically downregulating selected DNA polymerases in UVR‐induced animal models of melanoma, combined with exome sequencing, could begin to assess this. Finally, a preponderance of TpCpC as opposed to NpCpG at C>Ts exome‐wide is likely to be a good indicator of whether a melanoma has incurred even a small amount of sun damage. This information will assist epidemiological studies in predicting individual levels of sun exposure.
Spectral efficiency analysis for downlink massive MIMO systems with MRT precoding

As an important part of the channel fading, large scale fading should be considered in downlink massive multiple-input multiple-output (MIMO) systems. This paper investigates the downlink massive MIMO system over a large scale fading channel, when the base station takes advantage of maximum-radio transmission (MRT) precoding. The cases when the base station has perfect and imperfect channel state information (CSI) are considered respectively. Specially, through the analysis of single user's ergodic achievable rate, some novel and approximate expressions for the spectral efficiency (SE) are derived. Based on the approximate SE, the effect of the channel estimation error is analyzed intuitively. In addition, the average SE of all the users with different large-scale fading parameters is carefully investigated. Simulations validate that all the theoretical results coincide with numerical results and the large scale fading factors have little influence on SE reduction resulted from channel estimation.
Development of self-inflicted injury: Comorbidities and continuities with borderline and antisocial personality traits

Abstract Self-inflicted injury (SII) is a continuum of intentionally self-destructive behaviors, including nonsuicidal self-injuries, suicide attempts, and death by suicide. These behaviors are among the most pressing yet perplexing clinical problems, affecting males and females of every race, ethnicity, culture, socioeconomic status, and nearly every age. The complexity of these behaviors has spurred an immense literature documenting risk and vulnerability factors ranging from individual to societal levels of analysis. However, there have been relatively few attempts to articulate a life span developmental model that integrates ontogenenic processes across these diverse systems. The objective of this review is to outline such a model with a focus on how observed patterns of comorbidity and continuity can inform developmental theories, early prevention efforts, and intervention across traditional diagnostic boundaries. Specifically, when SII is viewed through the developmental psychopathology lens, it becomes apparent that early temperamental risk factors are associated with risk for SII and a range of highly comorbid conditions, such as borderline and antisocial personality disorders. Prevention efforts focused on early-emerging biological and temperamental contributors to psychopathology have great potential to reduce risk for many presumably distinct clinical problems. Such work requires identification of early biological vulnerabilities, behaviorally conditioned social mechanisms, as well as societal inequities that contribute to self-injury and underlie intergenerational transmission of risk.
Dietary n-3 and n-6 fatty acids alter avian glucose metabolism

1. This investigation studied the effects of dietary saturated and polyunsaturated fatty acids (PUFAs) from the n-3 and n-6 series on insulin action and glucose uptake in broiler chickens. 2. One-day-old male chicks were fed on a commercial starter diet for 3 weeks, randomly divided into three groups (n = 6) and fed ad libitum on isonitrogenous experimental diets of equal energy density for a further 6 weeks. The diets contained 20·8 g/100 g protein and 80 g/kg of either edible tallow, fish oil or sunflower oil, giving diets high in saturated fatty acids, n-3 PUFAs or n-6 PUFAs, respectively. 3. Jugular catheterisation was performed under general anaesthesia during week 4 of the dietary treatments and the birds given 7 d post-surgery to recover. To estimate insulin action, a bolus glucose infusion (1 g/kg) was given to each chicken and sequential blood samples taken over a one-hour period. To estimate the disappearance rate of glucose from the plasma and its incorporation into tissues, 2-deoxy-D-3H glucose (2DG-3H glucose) was infused into each chicken (50 µCi) 2 d later. 4. Although there were no significant differences in glucose clearance rate following the glucose infusion, the maximal insulin release in response to the glucose infusion was higher in the tallow group than in either the n-3 or n-6 PUFA dietary groups. There were no significant differences in the clearance rate of 2DG-3H glucose. Labelled glucose incorporation into the breast muscle was greater in birds given fish oil than in birds given tallow and significantly greater than in birds given sunflower oil. 5. The data suggest that the type of dietary fat can influence glucose metabolism and that this change in glucose utilisation may alter the energy metabolism of the broiler.
Synergistic Parasite-Pathogen Interactions Mediated by Host Immunity Can Drive the Collapse of Honeybee Colonies

The health of the honeybee and, indirectly, global crop production are threatened by several biotic and abiotic factors, which play a poorly defined role in the induction of widespread colony losses. Recent descriptive studies suggest that colony losses are often related to the interaction between pathogens and other stress factors, including parasites. Through an integrated analysis of the population and molecular changes associated with the collapse of honeybee colonies infested by the parasitic mite Varroa destructor, we show that this parasite can de-stabilise the within-host dynamics of Deformed wing virus (DWV), transforming a cryptic and vertically transmitted virus into a rapidly replicating killer, which attains lethal levels late in the season. The de-stabilisation of DWV infection is associated with an immunosuppression syndrome, characterized by a strong down-regulation of the transcription factor NF-κB. The centrality of NF-κB in host responses to a range of environmental challenges suggests that this transcription factor can act as a common currency underlying colony collapse that may be triggered by different causes. Our results offer an integrated account for the multifactorial origin of honeybee losses and a new framework for assessing, and possibly mitigating, the impact of environmental challenges on honeybee health.
Differential Use of CCR5 by HIV-1 Clinical Isolates Resistant to Small-Molecule CCR5 Antagonists

ABSTRACT How HIV-1 resistant to small-molecule CCR5 antagonists uses the coreceptor for entry has been studied in a limited number of isolates. We characterized dependence on the N terminus (NT) and the second extracellular loop (ECL2) of CCR5 of three vicriviroc (VCV)-resistant clinical isolates broadly cross-resistant to other CCR5 antagonists. Pseudoviruses were constructed to assess CCR5 use by VCV-sensitive and -resistant envelopes of subtype B and C viruses. We determined the extent of entry inhibition by monoclonal antibodies (MAbs) directed against the NT and ECL2 in the presence and absence of VCV and the capacity of these pseudoviruses to use CCR5 mutants that contained scanning alanine substitutions in the CCR5 NT and ECL2 domains. Sensitive and resistant viruses were completely and competitively inhibited by the ECL2-specific MAb 2D7, whereas the NT-specific MAb CTC5 led to partial noncompetitive inhibition. VCV-resistant clones showed greater sensitivity to 2D7 than VCV-sensitive clones, but in the presence of saturating VCV concentrations, the 2D7 susceptibilities of two VCV-resistant viruses were similar to that of VCV-sensitive virus. The entry of VCV-sensitive and -resistant isolates was impaired to differing degrees by alanine mutations in CCR5; substitutions in NT had the greatest effect on viral entry. HIV-1 clinical isolates broadly resistant to CCR5 antagonists demonstrated significant heterogeneity in their use of CCR5. This heterogeneity makes it difficult to draw general conclusions about the relationship between patterns of CCR5 antagonist resistance and the use of specific CCR5 domains for entry.
Chronic hepatitis B in hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, and has a wide geographical variation. Eighty per cent of HCC is attributed to hepatitis B virus (HBV). The predominant carcinogenic mechanism of HBV associated HCC is through the process of liver cirrhosis, but direct oncogenic effects of HBV may also contribute. Prevention of HBV infections as well as effective treatment of chronic hepatitis B is still needed for the global control of HBV associated HCC. Continued investigation of the mechanisms of hepatocarcinogenesis will refine our current understanding of the molecular and cellular basis for neoplastic transformation in the liver.
Evaluation of the AutoMicrobic system for identification of glucose-nonfermenting gram-negative rods

With the Enterobacteriaceae Plus Biochemical Card, the AutoMicrobic system (Vitek Systems, Inc., Hazelwood, Mo.) is purported to identify members of the family Enterobacteriaceae and seven species of glucose-nonfermenting gram-negative rods: Pseudomonas aeruginosa, P. fluorescens, P. putida, P. maltophilia, P. cepacia, and Acinetobacter calcoaceticus (saccharolytic and non-saccharolytic). The latter capability was examined in this investigation. Of 410 glucose-nonfermenting rods included in the identification profile, the AutoMicrobic system correctly identified 366 (89.3%). Of 62 glucose-nonfermenting organisms not included in the identification profile, 41 (66%) were correctly reported as "unidentified organism. " The usefulness of the AutoMicrobic system-generated identification probability in establishing criteria for acceptance of identification is discussed.
Impact of distributed generation connection with distribution grids - two case-studies

Distributed generation (DG) can have an important impact over distribution grids, especially concerning voltage levels, reliability, line losses and planning methodologies. This paper presents two case-studies assessing the impact of the connection of significant amounts of DG with distribution networks. The first case-study shows a medium voltage (MV) 30 kV distribution grid connected with a substation located in a mainly industrial area of the North of Portugal, having several cogenerations plants in some industrial units (dispatchable DG). The second case-study is related with the high voltage (HV) 60 kV distribution grid that feeds two HV-MV substations located in the centre of Portugal, which has associated some wind farms (non-dispatchable DG). In both cases significant benefits can be observed
Secreted Respiratory Syncytial Virus G Glycoprotein Induces Interleukin-5 (IL-5), IL-13, and Eosinophilia by an IL-4-Independent Mechanism

ABSTRACT The attachment glycoprotein G of respiratory syncytial virus (RSV) is produced as both membrane-anchored and secreted forms by infected cells. Immunization with secreted RSV G (Gs) or formalin-inactivated alumprecipitated RSV (FI-RSV) predisposes mice to immune responses involving a Th2 cell phenotype which results in more severe illness and pathology, decreased viral clearance, and increased pulmonary eosinophilia upon subsequent RSV challenge. These responses are associated with increased interleukin-4 (IL-4) production in FI-RSV-primed mice, and the responses are IL-4 dependent. RNase protection assays demonstrated that similar levels of IL-4 mRNA were induced after RSV challenge in mice primed with vaccinia virus expressing Gs (vvGs) or a construct expressing only membrane-anchored G (vvGr). However, upon RSV challenge, vvGs-primed mice produced significantly greater levels of IL-5 and IL-13 mRNA and protein than vvGr-primed mice. Administration of neutralizing anti-IL-4 antibody 11.B11 during vaccinia virus priming did not alter the levels of vvGs-induced IL-5, IL-13, pulmonary eosinophilia, illness, or RSV titers upon RSV challenge, although immunoglobulin G (IgG) isotype profiles revealed that more IgG2a was produced. vvGs-priming of IL-4-deficient mice demonstrated that G-induced airway eosinophilia was not dependent on IL-4. In contrast, airway eosinophilia induced by FI-RSV priming was significantly reduced in IL-4-deficient mice. Thus we conclude that, in contrast to FI-RSV, the secreted form of RSV G can directly induce IL-5 and IL-13, producing pulmonary eosinophilia and enhanced illness in RSV-challenged mice by an IL-4-independent mechanism.
The Histopathology of the Iridocorneal‐Endothelial Syndrome

The iridocorneal-endothelial (ICE) syndrome is characterised clinically by a “hammered-silver” appearance of the corneal endothelium, corneal failure, glaucoma, and iris destruction. Specular photomicroscopic studies of the corneal endothelium have demonstrated a population of abnormal cells termed “ICE cells. ” The purpose of this study was to define the histological appearances typical of this disease and in particular the ultrastructural morphology of the ICE cell. Thirty-five corneas, 11 trabeculectomy specimens, and 3 failed corneal grafts taken from patients with the ICE syndrome were examined by transmission and scanning electron microscopy. Comparison was made with seven normal corneas. Ten corneas and two trabeculectomy specimens demonstrated a population of well-differentiated cells with epithelial features such as desmosomes, tonofilaments, and microvilli. Other cell types identified were cells that resembled those of normal corneal endothelium, inflammatory cells, and cells with a fibroblast-like morphology. It seems likely that the epithelial cells of our specimens are the histological equivalent of the ICE cell seen by specular photomicroscopy. The other cell types may be either residual normal endothelial cells or else arise from secondary phenenomena of various kinds.
Parentage analysis of Ansell's mole‐rat family groups indicates a high reproductive skew despite relatively relaxed ecological constraints on dispersal

To better understand evolutionary pathways leading to eusociality, interspecific comparisons are needed, which would use a common axis, such as that of reproductive skew, to array species. African mole‐rats (Bathyergidae, Rodentia) provide an outstanding model of social evolution because of a wide range of social organizations within a single family; however, their reproductive skew is difficult to estimate, due to their cryptic lifestyle. A maximum skew could theoretically be reached in groups where reproduction is monopolized by a stable breeding pair, but the value could be decreased by breeding‐male and breeding‐female turnover, shared reproduction and extra‐group mating. The frequency of such events should be higher in species or populations inhabiting mesic environments with relaxed ecological constraints on dispersal. To test this prediction, we studied patterns of parentage and relatedness within 16 groups of Ansell's mole‐rat (Fukomys anselli) in mesic miombo woodland. Contrary to expectation, there was no shared reproduction (more than one breeder of a particular sex) within the studied groups, and proportion of immigrants and offspring not assigned to current breeding males was low. The within‐group parentage and relatedness patterns observed resemble arid populations of ‘eusocial’ Fukomys damarensis, rather than a mesic population of ‘social’ Cryptomys hottentotus. As a possible explanation, we propose that the extent ecological conditions affect reproductive skew may be markedly affected by life history and natural history traits of the particular species and genera.
Specific dephosphorylation of Janus Kinase 2 by protein tyrosine phosphatases

Many protein kinases are activated through phosphorylation of an activation loop thereby turning on downstream signaling pathways. Activation of JAK2, a nonreceptor tyrosine kinase with an important role in growth factor and cytokine signaling, requires phosphorylation of the 1007 and 1008 tyrosyl residues. Dephosphorylation of these two sites by phosphatases presumably inactivates the enzyme, but the underlying mechanism is not known. In this study, we employed MALDI‐TOF/TOF and triple quadrupole mass spectrometers to analyze qualitatively and quantitatively the dephosphorylation process by using synthetic peptides derived from the tandem autophosphorylation sites (Y1007 and Y1008) of human JAK2. We found that tyrosine phosphatases catalyzed the dephosphorylation reaction sequentially, but different enzymes exhibited different selectivity. Protein tyrosine phosphatase 1B caused rapid dephosphorylation of Y1008 followed by Y1007, while SHP1 and SHP2 selectively dephosphorylated Y1008 only, and yet HePTP randomly removed a single phosphate from either Y1007 or Y1008, leaving behind mono‐phosphorylated peptides. The specificity of dephosphorylation was further confirmed by molecular modeling. The data reveal multiple modes of JAK2 regulation by tyrosine phosphatases, reflecting a complex, and intricate interplay between protein phosphorylation and dephosphorylation.