Miracle-dz/UniFAR-FTUs huggingface dataset:
Novel histone deacetylase inhibitor AR-42 exhibits antitumor activity in pancreatic cancer cells by affecting multiple biochemical pathways

Objective Pancreatic cancer is one of the most lethal types of cancer with a 5-year survival rate of ~5%. Histone deacetylases (HDACs) participate in many cellular processes, including carcinogenesis, and pharmacological inhibition of HDACs has emerged as a potential therapeutic strategy. In this study, we explored antitumor activity of the novel HDAC inhibitor AR-42 in pancreatic cancer. Methods Human pancreatic cancer cell lines BxPC-3 and PANC-1 were used in this study. Real-time PCR, RT-PCR, and western blotting were employed to investigate expression of specific genes and proteins, respectively. Translocation of apoptosis-inducing factor was investigated by immunofluorescence and subcellular fractionation. The number of apoptotic cells, cell cycle stages, and reactive oxygen species (ROS) generation levels were determined by flow cytometry. Cell invasiveness was examined by the Matrigel invasion assay. Efficacy of AR-42 in vivo was evaluated by utilizing BxPC-3 xenograft mouse model. Results AR-42 inhibited pancreatic cancer cell proliferation by causing G2/M cell cycle arrest via regulating expression levels of genes and proteins involved in cell cycle. AR-42 also induced ROS generation and DNA damage, triggering apoptosis of pancreatic cancer cells via both caspase-3-dependent and caspase-3-independent pathways. In addition, AR-42 increased expression levels of negative regulators of p53 (miR-125b, miR-30d, and miR33), which could contribute to lower expression level of mutant p53 in pancreatic cancer cells. Cell invasion assay showed that AR-42 reduced cancer cell aggressiveness and significantly diminished BxPC-3 xenograft tumor growth in vivo. Conclusion AR-42, a novel HDAC inhibitor, inhibited pancreatic cancer cells by regulating p53 expression, inducing cell cycle arrest, particularly at the G2/M stage, and activating multiple apoptosis pathways. Additionally, AR-42 inhibited cell invasiveness and potently suppressed pancreatic cancer tumors in vivo. We conclude that by virtue of its multiple mechanisms of action, AR-42 possesses a considerable potential as an antitumor agent in pancreatic cancer.
Nϵ-(3-Methylpyridinium)lysine, a Major Antigenic Adduct Generated in Acrolein-modified Protein*

Acrolein, a representative carcinogenic aldehyde, that could be ubiquitously generated in biological systems under oxidative stress shows facile reactivity with a nucleophile such as a protein. In this study, to gain a better understanding of the molecular basis of acrolein modification of protein, we characterized the acrolein modification of a model peptide (the oxidized B chain of insulin) by electrospray ionization-liquid chromatography/mass spectrometry method and established a novel acrolein-lysine condensation reaction. In addition, we found that this condensation adduct represented the major antigenic adduct generated in acrolein-modified protein. To identify the modification site and structures of adducts generated in the acrolein-modified insulin B chain, both the acrolein-pretreated and untreated peptides were digested with V8 protease and the resulting peptides were subjected to electrospray ionization-liquid chromatography/mass spectrometry. This technique identified nine peptides, which contained the acrolein adducts at Lys-29 and the N terminus, and revealed that the reaction of the insulin B chain with acrolein gave multiple adducts, including an unknown adduct containing two molecules of acrolein per lysine. To identify this adduct, we incubated Nα-acetyllysine with acrolein and isolated a product having the same molecular mass as the unknown acrolein-lysine adduct. On the basis of the chemical and spectroscopic evidence, the adduct was determined to be a novel pyridinium-type lysine adduct, Nϵ-(3-methylpyridinium)lysine (MP-lysine). The formation of MP-lysine was confirmed by amino acid analysis of proteins treated with acrolein. More notably, this condensation adduct appeared to be an intrinsic epitope of a monoclonal antibody 5F6 that had been raised against acrolein-modified protein.
Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis.

BACKGROUND & AIMS Inflammatory bowel disease (IBD) is a multifactorial disease thought to be caused by alterations in epithelial function, innate and adaptive immunity, and luminal microbiota. The specific role of epithelial barrier function remains undefined, although increased activity of intestinal epithelial myosin light chain kinase (MLCK), which is the primary mechanism of tumor necrosis factor-induced barrier dysfunction, occurs in human IBD. Our aim was to determine whether, in an intact epithelium, primary dysregulation of the intestinal epithelial barrier by pathophysiologically relevant mechanisms can contribute to development of colitis. METHODS We developed transgenic (Tg) mice that express constitutively active MLCK (CA-MLCK) specifically within intestinal epithelia. Their physiology, immune status, and susceptibility to disease were assessed and compared with non-Tg littermate controls. RESULTS CA-MLCK Tg mice demonstrated significant barrier loss but grew and gained weight normally and did not develop spontaneous disease. CA-MLCK Tg mice did, however, develop mucosal immune activation demonstrated by increased numbers of lamina propria CD4(+)lymphocytes, redistribution of CD11c+cells, increased production of interferon-gamma and tumor necrosis factor, as well as increased expression of epithelial major histocompatibility complex class I. When challenged with CD4+CD45+Rb(hi) lymphocytes, Tg mice developed an accelerated and more severe form of colitis and had shorter survival times than non-Tg littermates. CONCLUSIONS Primary pathophysiologically relevant intestinal epithelial barrier dysfunction is insufficient to cause experimental intestinal disease but can broadly activate mucosal immune responses and accelerate the onset and severity of immune-mediated colitis.
Science, Technology, Engineering and Mathematics (STEM)

Research indicates that there is likely to be an increasing demand for graduates qualified in STEM within the growing sectors of the Northern Ireland economy in the coming years. In addition, an Independent Review of Economic Policy in 2009 highlighted the important role of skills in raising productivity and competitiveness, and recommended that the local education system should make preparations to meet increased demand for STEM graduates.
Beclin 1 mRNA Strongly Correlates with Bcl-XLmRNA Expression in Human Hepatocellular Carcinoma

Beclin 1 physically associates with Bcl-xL and is considered as a haploinsufficient tumor suppressor. As the role of Beclin 1 in hepatocellular carcinoma (HCC) is unknown, we determined Beclin 1 mRNA expression in 27 pairs of tumoral/nontumoral (T/NT) liver samples. The Beclin 1 mRNA T/NT ratio was less than 0.5 in 2 tumors and more than 2 in 1 tumor, and was positively correlated with the Bcl-XL mRNA T/NT ratio (P < 0.001), but not with the proliferating cell nuclear antigen mRNA T/NT ratio. Coregulation of Beclin 1 and Bcl-XL expression in HCC may suggest cooperation in the regulation of apoptosis.
Urinary Equol Excretion with a Soy Challenge: Influence of Habitual Diet

Abstract Equol is an isoflavonoid phytoestrogen produced from the soy isoflavone daidzein by gut microflora. Not all humans produce equol from daidzein, presumably due to differences in colonic bacterial populations among individuals. Previously, smaller studies reported that approximately 30% of participants excreted equol when consuming soy. The purpose of our study was to determine the prevalence of equol excreters in a larger sample and to examine what dietary components might influence the tendency to be an equol excreter. Thirty men and thirty women consumed a soy protein beverage containing 22 mg genistein and 8 mg daidzein for 4 days as a supplement to their habitual diets. The mean daily nutrient content of their habitual intakes was determined from 4-day food records. On Day 4, participants provided a 24-hour urine collection. Urinary isoflavonoid (genistein, daidzein, equol, and O-desmethy-langolensin) excretion was measured by gas chromatography-mass spectrometry. Twenty-one of the 60 participants (35%) excreted equol (> 2000 nmol/day) after 3 days of consuming the soy supplement. Daily equol excretion ranged from 2,134–20,301 nmol/day in the excreters and 21–233 nmol/day in the nonexcreters. There was no difference in equol excreter prevalence between men (43%) and women (27%). Daily excretion of daidzein, genistein, and O-desmethylangolensin was similar between equol excreters and nonexcreters and between men and women. Among the women, equol excreters consumed a significantly higher percentage of energy as carbohydrate and greater amounts of plant protein and dietary fiber, both as soluble and insoluble fiber compared to nonexcreters. Such differences were not observed in the men, who overall had significantly higher fiber intakes than the women. These data suggest that, among women, dietary fiber or other components of a high-fiber diet may promote the growth and/or the activity of bacterial populations responsible for equol production in the colon.
Importance of interferons in recovery from mousepox

Gamma interferon is shown to be critical in recovery of C57BL/6 mice from mousepox. Anti-gamma interferon treatment of mice infected in the footpad with ectromelia virus resulted in enhanced spread to and efficient virus replication in the spleen, lungs, ovaries, and, especially, liver. All treated, infected mice died within a mean of 7 days, 2.5 days earlier than mice with severe combined immunodeficiency that were given a comparable infection. On the other hand, alpha interferon appeared not to have a major role in controlling virus replication in tissues examined, and beta interferon was important for virus clearance in the liver and ovaries but not the spleen. Either anti-alpha, beta interferon or anti-beta interferon antibody therapy resulted in only 25% mortality. Infected control mice survived but showed persistence of ectromelia virus at the site of infection (the footpad) and transient presence of the virus in the spleen, liver, lungs, and ovaries and in the fibroreticular but not lymphoid cells of the draining popliteal lymph node. Depletion of gamma interferon but not alpha and/or beta interferon resulted in a significant reduction in the numbers of splenic T (especially gamma delta-TCR+), B, and Mac-1+ cells, although the proportion of Mac-1+ cells in the spleen increased compared with control values. Depletion of alpha, beta, or gamma interferons did not severely affect the generation of virus-specific cytotoxic T-lymphocyte responses or natural killer cell cytolytic activity. This study, in which a natural virus disease model was used, underscores the crucial importance of gamma interferon in virus clearance at all stages of infection and in all tissues tested except the primary site of infection, where virus clearance appears to be delayed.
Pavement Condition and Residential Property Values: A Spatial Hedonic Price Model for Solano County, California

Transportation agencies invest billions of dollars every year in resurfacing roadways, ostensibly to improve the travel experience. When locally funded, one justification for increased expenditure on the pavement surface is that it could increase property values. We evaluated this approach directly, using hedonic regression to estimate the relationship between pavement condition and residential property value in Solano County, California. We hypothesized that improving pavement condition would positively affect property values in two ways: directly as an indicator of neighborhood blight and indirectly through its effect on traffic conditions and noise. We estimated this relationship for the County as a whole and for each city within the County, controlling for spatial autocorrelation. The estimated relationship is small in magnitude and often not statistically significant. Although there are certainly reasons to improve pavement condition, our results suggest that increasing property value may not be one of them.
An Intelligent Multi-Restart Memetic Algorithm for Box Constrained Global Optimisation

In this paper, we propose a multi-restart memetic algorithm framework for box constrained global continuous optimisation. In this framework, an evolutionary algorithm (EA) and a local optimizer are employed as separated building blocks. The EA is used to explore the search space for very promising solutions (e.g., solutions in the attraction basin of the global optimum) through its exploration capability and previous EA search history, and local search is used to improve these promising solutions to local optima. An estimation of distribution algorithm (EDA) combined with a derivative free local optimizer, called NEWUOA (M. Powell, Developments of NEWUOA for minimization without derivatives. Journal of Numerical Analysis, 28:649–664, 2008), is developed based on this framework and empirically compared with several well-known EAs on a set of 40 commonly used test functions. The main components of the specific algorithm include: (1) an adaptive multivariate probability model, (2) a multiple sampling strategy, (3) decoupling of the hybridisation strategy, and (4) a restart mechanism. The adaptive multivariate probability model and multiple sampling strategy are designed to enhance the exploration capability. The restart mechanism attempts to make the search escape from local optima, resorting to previous search history. Comparison results show that the algorithm is comparable with the best known EAs, including the winner of the 2005 IEEE Congress on Evolutionary Computation (CEC2005), and significantly better than the others in terms of both the solution quality and computational cost.
A generalized technique for the reconstruction of permittivity profiles with a controllable resolution in an arbitrary coordinate system

A generalized technique for the reconstruction of permittivity profiles in an arbitrary coordinate system is presented. The resolution of the reconstructed permittivity profile can precisely be controlled by adjusting the ratio between the bandwidth and the midband frequency of frequency-dependent measured data, or equivalently the duration of a pulse modulated carrier used to produce time-dependent measurements. The proposed technique represents in fact a versatile relaxation of the well-known Fourier transformation method used to reconstruct one-dimensional profiles in half-spaces or slab-shaped media in Cartesian coordinate systems. Representative cases in the Cartesian coordinate system have been considered for validating the suggested technique. Excellent agreement between the original and reconstructed permittivity profiles has been achieved.
Impact of an antimicrobial dressing in reducing surgical site infections in cardiac surgery patients.

UNLABELLED xBxxaxcxkground. In addition to prevention guidelines already in place, the effectiveness of an antimicrobial dressing on the occurrence of surgical site infections (SSIs) among adult patients undergoing cardiac surgery was evaluated. METHODS A house-wide replacement of the plain postoperative gauze dressing with a sterile dressing impregnated with 0.2% polyhexamethylene biguanide directly on the incision after closure in the operation room was performed. From May 2005 to March 2007, 1658 patients were enrolled in this study. Surgical site infections were identified using the Centers for Disease Control and Prevention standard criteria. RESULTS Of the 1658 patients enrolled, 1399 patients were included in the analysis, 692 with the plain dressing and 707 with antimicrobial dressing. The overall and leg site infection rate was significantly higher in the plain dressing group compared to the antimicrobial group but similar in the sternal site. Overall, the antimicrobial dressings significantly reduced infection (OR 0.58 [0.38-0.89]). Obesity was also a strong independent predictor of SSI regardless of the site of surgery. Increasing age at surgery and left ventricular ejection fraction of 30%-49% were also independent predictors of infection. CONCLUSION The antimicrobial dressing had a positive effect by reducing the infection rate, especially for leg incisions using conventional open techniques, and could be a worthwhile addition in conjunction with a strategic program. ﻿﻿﻿.
In-Vitro Phosphorylation Activity by Recombinant α and β Subunits of Bombyx mori Casein Kinase 2

Abstract To clarify the control mechanism of the catalytic activity of casein kinase 2 (CK2) during early embryonic development in the silkworm, Bombyx mori, we attempted an in-vitro functional analysis by using the recombinant α and β subunits of B. mori CK2 (rBmCK2α and rBmCK2β) produced in a bacterial system. The renatured rBmCK2α possessed protein kinase activity. When rBmCK2α and rBmCK2β were reconstituted in an approximate 1:1 molar ratio, the catalytic activity was almost the same as that of rBmCK2α alone. The catalytic activity of rBmCK2α was inhibited by polylysine, which is one of the activators of CK2 activity. However, when using the reconstituted rBmCK2α and rBmCK2β (rBmCK2), activation by polylysine was observed. We examined the influence of sorbitol and 3-hydroxykynurenine (3-OHK), which are contained mainly in diapause eggs, on the phosphorylation activity of rBmCK2. Three-OHK inhibited rBmCK2 activity, but sorbitol had no effect on it. Furthermore, a functional analysis using rBmCK2α and β subunits of Drosophila melanogaster CK2 revealed that a difference in the C-terminal amino acid of the CK2β subunit influenced the phosphorylation activity of rBmCK2α. These results may provide new insights for clarifying the control mechanism of B. mori casein kinase 2 in eggs.
A comparison of the validity of different diagnostic tests in adults with asthma.

STUDY OBJECTIVES Diagnosing asthma is not always easy, and there are times when objective tests can be helpful. The extent to which these tests alter the probability of asthma depends on how much more commonly the test result is positive in subjects with asthma compared to healthy subjects and particularly subjects with conditions that are commonly confused with asthma. We set out to compare the sensitivity and specificity of different tests in this setting. DESIGN Single-center, cross-sectional, observational study. SETTING Teaching hospital. PATIENTS Twenty-one healthy control subjects, 69 patients with asthma, and 20 subjects referred to the hospital with a diagnosis of asthma who were found to have alternative explanations for their symptoms (i.e., pseudoasthma). INTERVENTIONS We measured methacholine airway responsiveness, the maximum within-day peak expiratory flow amplitude mean percentage (derived from twice-daily readings for > 2 weeks), the FEV(1)/FVC ratio, the percentage change in FEV(1) 10 min after the administration of 200 microg inhaled albuterol, and the differential eosinophil count in blood and induced sputum. We derived normal ranges (from the 95% upper or lower limit for healthy subjects), sensitivity, and specificity (ie, the percentage of subjects with pseudoasthma who had negative test results). RESULTS Most tests were less specific when the reference population was composed of subjects with conditions that can be confused with asthma. Methacholine airway responsiveness and the sputum differential eosinophil count were the most sensitive (91% and 72%, respectively) and specific (90% and 80%, respectively) tests. CONCLUSION We conclude that methacholine airway responsiveness and the sputum differential eosinophil count are the most useful objective tests in patients with mild asthma.
HIV-1 gp120 Vaccine Induces Affinity Maturation in both New and Persistent Antibody Clonal Lineages

ABSTRACT Most antibodies that broadly neutralize HIV-1 are highly somatically mutated in antibody clonal lineages that persist over time. Here, we describe the analysis of human antibodies induced during an HIV-1 vaccine trial (GSK PRO HIV-002) that used the clade B envelope (Env) gp120 of clone W6.1D (gp120W6.1D). Using dual-color antigen-specific sorting, we isolated Env-specific human monoclonal antibodies (MAbs) and studied the clonal persistence of antibodies in the setting of HIV-1 Env vaccination. We found evidence of VH somatic mutation induced by the vaccine but only to a modest level (3.8% ± 0.5%; range 0 to 8.2%). Analysis of 34 HIV-1-reactive MAbs recovered over four immunizations revealed evidence of both sequential recruitment of naïve B cells and restimulation of previously recruited memory B cells. These recombinant antibodies recapitulated the anti-HIV-1 activity of participant serum including pseudovirus neutralization and antibody-dependent cell-mediated cytotoxicity (ADCC). One antibody (3491) demonstrated a change in specificity following somatic mutation with binding of the inferred unmutated ancestor to a linear C2 peptide while the mutated antibody reacted only with a conformational epitope in gp120 Env. Thus, gp120W6.1D was strongly immunogenic but over four immunizations induced levels of affinity maturation below that of broadly neutralizing MAbs. Improved vaccination strategies will be needed to drive persistent stimulation of antibody clonal lineages to induce affinity maturation that results in highly mutated HIV-1 Env-reactive antibodies.
Examination of Frontal and Parietal Tectocortical Attention Pathways in Spina Bifida Meningomyelocele Using Probabilistic Diffusion Tractography

Abnormalities of the midbrain tectum are common but variable malformations in spina bifida meningomyelocele (SBM) and have been linked to neuropsychological deficits in attention orienting. The degree to which variations in tectum structure influence white matter (WM) connectivity to cortical regions is unknown. To assess the relationship of tectal structure and connectivity to frontal and parietal cortical regions, probabilistic diffusion tractography was performed on 106 individuals (80 SBM, 26 typically developing [TD]) to isolate anterior versus posterior tectocortical WM pathways. Results showed that those with SBM exhibited significantly reduced tectal volume, along with decreased fractional anisotropy (FA) in posterior but not anterior tectocortical WM pathways when compared with TD individuals. The group with SBM also showed greater within-subject discrepancies between frontal and parietal WM integrity compared with the TD group. Of those with SBM, qualitative classification of tectal beaking based on radiological review was associated with increased axial diffusivity across both anterior and posterior tectocortical pathways, relative to individuals with SBM and a normal appearing tectum. These results support previous volumetric findings of greater impairment to posterior versus anterior brain regions in SBM, and quantifiably relate tectal volume, tectocortical WM integrity, and tectal malformations in this population.