Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of antihypertensive treatment on small artery remodelling

Although it is recognized that the cause of hypertension can be various, once blood pressure has become established structural changes emerge in the systemic vasculature. In medium- and large-sized vessels, as in the left ventricle, there is clear histological evidence of hypertrophy of the medial smooth muscle layers but, downstream in small arteries, which modulate vascular resistance, other changes occur. In essential hypertension, the smooth muscle cells of small vessels are restructured around a smaller lumen, but there is no evidence of hypertrophy or hyperplasia of the vascular wall. In secondary forms of hypertension, which tend to be representative of severer forms of the disease, hypertrophic remodelling is observed. Similarly, in non-insulin-dependent diabetes mellitus, irrespective of whether blood pressure accompanies this disorder or not, hypertrophy is also seen. The presence of architectural alterations in the vascular wall of small arteries may have a strong prognostic significance in patients, and this may be over and above all other known cardiovascular risk factors. Although it is yet to be established whether regression of such changes should be a goal of effective antihypertensive therapy, there is a body of evidence emerging indicating that different classes of antihypertensive drug have a varied effect on reversing vascular structure both in humans and animal models of genetic and experimental hypertension. However, at present, there are no data available concerning the prognostic impact of regressing vascular structural alterations in hypertension, and this must be an urgent research priority.
Systematic Review and Meta-Analysis of Pancreatic Amylase Value on Postoperative Day 1 After Pancreatic Resection to Predict Postoperative Pancreatic Fistula

Abstract Early detection of postoperative pancreatic fistula (POPF) may help to improve the outcome following pancreatic surgery, and exclusion of POPF may allow early drain removal which can accelerate recovery. The aim of this study was to evaluate the diagnostic accuracy of drain/plasma pancreatic amylase values on postoperative day 1 (DPA1/PPA1) in POPF by means of a systemic review and meta-analysis. Online journal databases and a manual search up to March 2015 were used. Studies clearly documenting DPA1 or PPA1 in predicting overall POPF (Grade 0 vs A+B+C) or clinically relevant POPF (Grade 0+A vs B+C) following pancreatic surgery were selected. Pooled predictive parameters were performed using STATA 12.0. Fifteen studies were finally identified with a total of 4331 patients. The pooled sensitivity and specificity of DPA1 were 0.92 (95% confidence interval (CI) 0.81–0.96) and 0.77 (95% CI 0.64–0.86) for predicting overall POPF and 0.79 (95% CI 0.61–0.90) and 0.83 (95% CI 0.74–0.89) for predicting clinically relevant POPF. The pooled sensitivity and specificity of PPA1 were 0.74 (95% CI 0.63–0.82) and 0.62 (95% CI 0.55–0.70) for overall POPF. After the DPA1 at/over cutoff values for overall POPF or clinically relevant POPF, corresponding post-test probability (Post-test (+)) (if pretest probability was 50%) was 80% and 82% respectively, while, if values were below the cutoff values, the post-test probability (Post-test (−)) was 10% and 20% respectively. Post-test (+) and Post-test (−) of PPA1 for overall POPF were 66% and 30% respectively. In subgroup analysis, the summary sensitivities of cutoff <1000 group and cutoff >1000 group were 0.96 (0.92–0.98) and 0.85 (0.64–0.95), respectively; the summary specificities were 0.59 (0.44–0.72) and 0.86 (0.80–0.91) respectively. Positive LR were 2.3 (1.7–3.3) and 6.2 (3.7–10.2) respectively. Negative LR were 0.06 (0.03–0.14) and 0.18 (0.07–0.47) respectively. DPA1 is a useful predictive test for overall POPF and clinically relevant POPF which has good sensitivity and specificity based on the current studies. Meanwhile, it should be cautiously applied to clinical practice because cutoffs had a wide range between studies.
Phosphoproteomic Analysis of Salmonella-Infected Cells Identifies Key Kinase Regulators and SopB-Dependent Host Phosphorylation Events

The foodborne pathogen Salmonella triggers distinct phosphorylation events in host cells to promote infection. Profiling Pathogen-Induced Phosphorylation Contamination of food with the pathogenic bacterium Salmonella enterica is a leading source of food poisoning. Salmonella induces inflammation in the intestine, a process that requires the bacterial enzyme SopB. Rogers et al. provide a temporal profile of sites in Salmonella-infected host cell proteins with increased or decreased phosphorylation, many of which were predicted to be targeted by the kinases Akt and Pim. Deficiency in members of the Pim family in host cells attenuated release of the proinflammatory cytokine interleukin-8. Many of these changes in the phosphorylation of host cell proteins were reduced in cells infected with Salmonella lacking SopB, which activates Akt in host cells. Activation of Akt by Salmonella was originally shown to promote survival of host cells, but some of the predicted Akt-mediated phosphorylation events may promote invasion by Salmonella as well. This work provides a map of the phosphorylation events that occur in Salmonella-infected cells and identifies the host cell kinases that the pathogen manipulates during the initial stages of infection. Salmonella enterica is a bacterial pathogen that causes gastroenteritis and typhoid fever. Virulence is achieved by two type III secretion systems that translocate effector proteins into host cells, where they mimic or block host protein function. Effectors translocated into host cells by the first type III secretion system facilitate invasion and stimulate intracellular signaling cascades leading to inflammation. Here, we performed global temporal analysis of host signaling events induced during the initial stages of Salmonella infection and identified the dynamics of host protein phosphorylation as well as differences between growth factor–stimulated and bacteria-induced signaling. Informatics analysis predicted that sites with altered phosphorylation in infected cells were targeted by the serine-threonine kinases Akt, protein kinase C, and Pim and that up to half of the host phosphorylation events detected after Salmonella infection required the effector protein SopB. Our data reveal extensive manipulation of host phosphorylation cascades by this Salmonella effector and provide a detailed map of the events leading to intestinal inflammation, which is the crucial host response that enables Salmonella to proliferate in the intestine.
Diverse Chemical Scaffolds Support Direct Inhibition of the Membrane-bound O-Acyltransferase Porcupine*

Background: The acyltransferase Porcupine (Porcn) is essential for active Wnt ligand production and is chemically tractable. Results: Novel small molecules targeting Porcn enables interrogation of Wnt signaling in vitro and in vivo. Conclusion: Porcn is highly druggable and supports diverse cellular responses in embryonic development and regeneration. Significance: Porcn inhibitors represent versatile chemical probes for Wnt signaling in vivo and are potential anti-cancer therapeutic agents. Secreted Wnt proteins constitute one of the largest families of intercellular signaling molecules in vertebrates with essential roles in embryonic development and adult tissue homeostasis. The functional redundancy of Wnt genes and the many forms of cellular responses they elicit, including some utilizing the transcriptional co-activator β-catenin, has limited the ability of classical genetic strategies to uncover their roles in vivo. We had previously identified a chemical compound class termed Inhibitor of Wnt Production (or IWP) that targets Porcupine (Porcn), an acyltransferase catalyzing the addition of fatty acid adducts onto Wnt proteins. Here we demonstrate that diverse chemical structures are able to inhibit Porcn by targeting its putative active site. When deployed in concert with small molecules that modulate the activity of Tankyrase enzymes and glycogen synthase kinase 3 β (GSK3β), additional transducers of Wnt/β-catenin signaling, the IWP compounds reveal an essential role for Wnt protein fatty acylation in eliciting β-catenin-dependent and -independent forms of Wnt signaling during zebrafish development. This collection of small molecules facilitates rapid dissection of Wnt gene function in vivo by limiting the influence of redundant Wnt gene functions on phenotypic outcomes and enables temporal manipulation of Wnt-mediated signaling in vertebrates.
Nitric oxide increases persistent sodium current in rat hippocampal neurons

1 The effects of nitric oxide (NO) donors on whole‐cell, TTX‐sensitive sodium currents and single sodium channels in excised patches were examined in rat hippocampal neurons. The whole‐cell sodium current consisted of a large transient component (INa,t) and a smaller, inactivation‐resistant, persistent component (INa,p). 2 In acutely dissociated neurons, the amplitude of the whole‐cell INa,p increased by 60–80% within a few minutes of exposure to either of two NO donors, sodium nitroprusside (SNP, 100 μm) or S‐nitroso‐N‐acetyl‐DL‐penicillamine (SNAP, 100 μm). 3 The amplitude of INa,t was not changed significantly by the same concentrations of SNP and SNAP, indicating that NO had a selective effect on INa,p. 4 Both NO donors significantly increased the mean persistent current in excised inside‐out patches from cultured hippocampal neurons. SNP at 10m100 μm increased average mean persistent current at a pipette potential (Vp) of +30 mV from −0.010 ± 0.014 pA (control) to −2.91 ± 1.41 pA (n= 10). SNAP at 3–100 μm increased the average mean inward current in six inside‐out patches from −0.07 ± 0.02 to −0.30 ± 0.08 pA (Vp=+30 mV). 5 The increase in persistent Na+ channel activity recorded in inside‐out patches in the presence of SNP or SNAP could be reversed by the reducing agent dithiothreitol (DTT, 2−5 mm) or by lidocaine (1–10 μm). 6 The average mean current recorded in the presence of SNP was 10‐fold higher than that elicited by SNAP. The time delay before an increase was observed was shorter with SNP (4.0 ± 0.8 min, n= 8) than with SNAP (8.4 ± 1.6 min, n= 7). 7 A component of the SNP molecule added on its own, 5 mm sodium cyanide (NaCN), increased mean current in excised inside‐out patches (Vp=+30 mV) from −0.06 ± 0.04 to −0.58 ± 0.21 pA (n= 19). This increase in channel activity could be blocked by 10 μm lidocaine and 2–5 mm DTT. 8 These results suggest that NO may directly increase the activity of neuronal persistent Na+ channels, but not transient Na+ channels, through an oxidizing action directly on the channel protein or on a closely associated regulatory protein in the plasma membrane.
Anti‐proliferative and anti‐remodelling effect of beclomethasone dipropionate, formoterol and salbutamol alone or in combination in primary human bronchial fibroblasts

Background: Bronchial asthma is characterized by lower airway inflammation and remodelling. Anti‐inflammatory treatment with inhaled corticosteroids (ICS) provides the mainstay of asthma therapy together with bronchodilation induced by short‐ and long‐acting inhaled β2‐agonists. Lower airway fibroblasts may play a critical role in airway inflammation and remodelling, suggesting that they might represent an important target for the major anti‐asthmatic drugs. The aim of our study was to investigate the effects of beclomethasone dipropionate (BDP), salbutamol and formoterol either alone or in combination on in vitro cultures of human bronchial fibroblasts.
Erythropoiesis-stimulating agent responsiveness and mortality in hemodialysis patients: results from a cohort study from the dialysis registry in Japan.

BACKGROUND Patient responsiveness to erythropoiesis-stimulating agents (ESAs), notoriously difficult to measure, has attracted attention for its association with mortality. We defined categories of ESA responsiveness and attempted to clarify their association with mortality. STUDY DESIGN Cohort study. SETTING & PARTICIPANTS Data from Japan's dialysis registry (2005-2006), including 95,460 adult hemodialysis patients who received ESAs. PREDICTOR We defined 6 categories of ESA responsiveness based on a combination of ESA dosage (low [<6,000 U/wk] or high [≥6,000 U/wk]) and hemoglobin level (low [<10 g/dL], medium [10-11.9 g/dL], or high [≥12 g/dL]), with medium hemoglobin level and low-dose ESA therapy as the reference category. OUTCOMES All-cause and cardiovascular mortality during 1-year follow-up. MEASUREMENTS HRs were estimated using a Cox model for the association between responsiveness categories and mortality, adjusting for potential confounders such as age, sex, postdialysis weight, dialysis duration, comorbid conditions, serum albumin level, and transferrin saturation. RESULTS Median ESA dosage (4,500-5,999 U/wk) was used as a cutoff point, and mean hemoglobin level was 10.1 g/dL in our cohort. Of 95,460 patients during follow-up, 7,205 (7.5%) died of all causes, including 5,586 (5.9%) cardiovascular deaths. Low hemoglobin levels and high-dose ESA therapy were both associated with all-cause mortality (adjusted HRs, 1.18 [95% CI, 1.09-1.27] for low hemoglobin level with low-dose ESA and 1.44 [95% CI, 1.34-1.55] for medium hemoglobin level with high-dose ESA). Adjusted HRs for high-dose ESA with low hemoglobin level (hyporesponsiveness) were 1.94 (95% CI, 1.82-2.07) for all-cause and 2.02 (95% CI, 1.88-2.17) for cardiovascular mortality. We also noted the interaction between ESA dosage and hemoglobin level on all-cause mortality (likelihood ratio test, P = 0.002). LIMITATIONS Potential residual confounding from unmeasured factors and single measurement of predictors. CONCLUSIONS Mortality can be affected by ESA responsiveness, which may include independent and interactive effects of ESA dose and hemoglobin level. Responsiveness category has prognostic importance and clinical relevance in anemia management.
Incidence of Methicillin Resistant Staphylococcus aureus in Burn Patients Admitted to Burn Unit, Dhaka Medical

Staphylococcus aureus infection remains an increasing problem for higher morbidity and mortality in burn patients. We sought to determine the frequency of methicillin-resistant S. aureus (MRSA) in burn wound patients and study their drug resistance genes. Samples were collected (August 2010 to October 2011) from burn unit of Dhaka Medical College Hospital (DMCH), Bangladesh. MRSA was identified by conventional culture based methods. S. aureus was confirmed in 44.44% burn wound samples and 22.5% of the isolates were oxacillin resistant. All the S. aureus isolates were resistant to commonly used drugs like amoxicillin, azactam, erythromycin, azithromycin etc. and were sensitive to imipenem. The isolates were devoid of plasmid and the gene mecA, femA and IS431 were detected in their chromosomal DNA. Computational analysis of mecA gene sequence showed homology to S. aureus “penicillin binding protein 2a” (PBP-2a). The higher association of MRSA is in burn unit of DMCH, Bangladesh is alarming and with inappropriate antibiotic use, and the situation gets even complicated to treat. Therefore, the detection system and control practices for MRSA in DMCH should be improved in the hospital settings.
Broiler chicks with slow-feathering (K) or rapid-feathering (k+) genes: Effects of environmental stressors on physiological adaptive indicators up to 56 h posthatch.

Two experiments were conducted to examine the effects on the physiological responses of slow-feathering (K) and rapid-feathering (k(+)) genes in neonate broiler chicks subjected to posthatch fasting (PHF). In the first experiment, 300 Ross 308 chicks were denied access to feed and water for 0, 7, 14, 21, 28, 35, 42, 49, and 56 h posthatch. In the second experiment, 625 Ross 308 chicks were subjected to PHF for 0, 12, 24, 36, and 48 h. In experiment 1, the weight loss rate increased over 56 h PHF and did not differ between fast- and slow-feathering chicks up to 28 h posthatch but was greater (P < 0.05) in fast-feathering birds from 28 to 56 h posthatch. The fast-feathering genotypes demonstrated greater serum K levels following 7, 21, and 56 h (P < 0.05) and serum uric acid (UA) levels after 7, 21, 28, 49, and 56 h PHF (P < 0.01). In experiment 2, weight loss increased linearly with no difference between fast- and slow-feathering chicks through 36 h PHF but increased in fast-feathering birds when PHF continued for 48 h. Neonatal fasting periods of 12 to 48 h decreased breast and thigh percentage (P < 0.01), with no difference between feathering genotypes. The fast-feathering genotypes showed greater serum HDL levels at 24 h (P < 0.05) and greater serum UA concentration following 12, 36, and 48 h PHF (P < 0.05). The mean frequency of jumping (P < 0.01) and active wakefulness (P > 0.01) was increased as PHF continued from 12 to 48 h across genotypes. At 48 h, the fast-feathering chicks showed greater frequency of escape attempts from the test field (P < 0.01). It was concluded that slow-feathering chicks are more capable of withstanding PHF periods lasting more than 28 h. This is important to consider when day-old chicks are transported for extended periods without access to feed.
Thermosonic-Adhesive flip-chip assembly

Thermosonic (TS) and Non Conductive Film (NCF) flipchip assembly are well known packaging techniques for fine-pitch electronics manufacturing. In this work a novel process combining TS bonding with NCF packaging was developed, termed Thermosonic-Adhesive (TA) flip-chip assembly. The aim was to introduce a TS bonding step into the NCF assembly process in order to replace the mechanical contacts by direct metal-metal TS bonds. A custom TA bonder was constructed for this purpose that can heat the assembly rapidly to the temperature required for TS bonding without causing thermal damage to organic substrates. Assemblies were produced on flexible polyimide substrates and subjected to Temperature and Humidity reliability testing. It was found that the interconnections of the TA flip-chip assemblies were more reliable than those of anisotropic adhesive and TS assemblies prepared using the same bonder. The results indicate that this novel bonding technique may have the potential to improve the reliability of chip-on-flex assemblies.
Culturas políticas monárquicas en la España liberal: Discursos, representaciones y prácticas (1808-1902)

espanolDurante el siglo XIX, los Estados-nacion europeos se construyeron en su gran mayoria contando con la monarquia como forma de gobierno, y Espana no fue una excepcion. Los nuevos marcos constitucionales, tras la ruptura con el Antiguo Regimen, abrieron el camino a una cambiante relacion entre la vieja institucion y el moderno sujeto soberano, la nacion. Los cambios abiertos por la nueva legalidad obligaron a las monarquias a «reinventarse», a buscar nuevas formas de legitimacion y de representacion, a discernir entre el ambito de lo publico y lo privado. Este volumen reflexiona sobre la monarquia en la Espana del siglo XIX, y aparece como resultado de las investigaciones de un nutrido grupo de estudiosos de diversas universidades espanolas, que se adentran en una problematica actual desde un punto de vista historiografico, social y politico: el de las culturas politicas monarquicas catalaDurant el segle XIX, els Estats-nacio europeus es van construir en la seua majoria comptant amb la monarquia com a forma de govern, i Espanya no va ser una excepcio. Els nous marcs constitucionals, despres de la ruptura amb l'Antic Regim, van obrir el cami a una relacio canviant entre la vella institucio i el modern subjecte sobira, la nacio. Els canvis oberts per la nova legalitat van obligar a les monarquies a «reinventar-se», a cercar noves formes de legitimacio i de representacio, a destriar entre l'ambit del public i el privat. Aquest volum reflexiona sobre la monarquia en l'Espanya del segle XIX, i apareix com a resultat de les recerques d'un nodrit grup d'estudiosos de diverses universitats espanyoles, que s'endinsen en una problematica actual des d'un punt de vista historiografic, social i politic: el de les cultures politiques monarquiques.
Examination of single and multiple mutations involved in resistance to quinolones in Staphylococcus aureus by a combination of PCR and denaturing high-performance liquid chromatography (DHPLC).

Detection of DNA sequence variation is fundamental to the identification of the genomic basis of phenotypic variability. Denaturing high-performance liquid chromatography (DHPLC) is a novel technique that has been used to detect mutations in human DNA. We report on the first study to use this technique as a tool to detect mutations in genes encoding antibiotic resistance in bacteria. Three methicillin-sensitive and three methicillin-resistant clinical Staphylococcus aureus isolates, susceptible to ciprofloxacin (MIC <or= 0.4 mg/L), were used to derive mutants resistant to ciprofloxacin, levofloxacin, sparfloxacin, trovafloxacin and moxifloxacin. Genomic DNA from each strain was subjected to PCR amplification of 225-500 bp regions spanning the quinolone resistance determining regions of the gyrA, gyrB, grlA and grlB genes. Following DNA sequencing of these amplicons and identification of resistance mutations, DHPLC was undertaken to correlate the distinctive chromatogram with DNA sequence. The mutations detected by DHPLC resulted in the following amino acid substitutions: Ser-84-->Leu, Ser-112-->Pro, Glu-88-->Lys in GyrA, Glu-84-->Val, Ser-80-->Phe in GrlA, Pro-456-->Ser in GyrB and Glu-422-->Asp, Pro-451-->Ser, Asp-432-->Gly in GrlB. Mutations could be rapidly and reproducibly identified from the PCR products using DHPLC, producing specific peak patterns that correlate with genotypes. This system facilitates the detection of resistance alleles, providing a rapid (5 min per sample), economic (96 sample per run) and reliable technique for characterizing antibiotic resistance in bacteria.
Vitamin D Depletion Induces RANKL‐Mediated Osteoclastogenesis and Bone Loss in a Rodent Model

The association between increased risk of hip fracture and low vitamin D status has long been recognized. However, the level of vitamin D required to maintain bone strength is controversial. We used a rodent model of vitamin D depletion to quantify the 25‐hydroxyvitamin D (25D) levels required for normal mineralization. Six groups of 10‐wk‐old male Sprague‐Dawley rats (n = 42) were fed a diet containing 0.4% calcium and various levels of dietary vitamin D3 for 4 mo to achieve stable mean serum 25D levels ranging between 10 and 115 nM. At 7 mo of age, animals were killed, and the histomorphometry of distal and proximal femora and L2 vertebra was analyzed. Total RNA was extracted from whole femora for real‐time RT‐PCR analyses. In the distal femoral metaphysis, trabecular bone mineral volume (BV/TV) showed a significant positive association with circulating 25D levels (r2 = 0.42, p < 0.01) in the animals with serum 25D levels between 20 and 115 nM. Osteoclast surface (Oc.S) levels were positively associated with RANKL:OPG mRNA ratio, higher in groups with lower serum 25D levels, and were independent of serum 1,25D levels. Serum 25D levels <80 nM gave rise to osteopenia as a result of increased osteoclastogenesis, suggesting that levels of 25D >80 nM are needed for optimal bone volume. These data indicate that serum 25D levels are a major determinant of osteoclastogenesis and bone mineral volume and are consistent with the levels of 25D recommended to reduce the risk of fracture in humans.