Miracle-dz/UniFAR-FTUs huggingface dataset:
Integrated Sequence Analysis Pipeline Provides One‐Stop Solution for Identifying Disease‐Causing Mutations

Next‐generation sequencing has greatly accelerated the search for disease‐causing defects, but even for experts the data analysis can be a major challenge. To facilitate the data processing in a clinical setting, we have developed a novel medical resequencing analysis pipeline (MERAP). MERAP assesses the quality of sequencing, and has optimized capacity for calling variants, including single‐nucleotide variants, insertions and deletions, copy‐number variation, and other structural variants. MERAP identifies polymorphic and known causal variants by filtering against public domain databases, and flags nonsynonymous and splice‐site changes. MERAP uses a logistic model to estimate the causal likelihood of a given missense variant. MERAP considers the relevant information such as phenotype and interaction with known disease‐causing genes. MERAP compares favorably with GATK, one of the widely used tools, because of its higher sensitivity for detecting indels, its easy installation, and its economical use of computational resources. Upon testing more than 1,200 individuals with mutations in known and novel disease genes, MERAP proved highly reliable, as illustrated here for five families with disease‐causing variants. We believe that the clinical implementation of MERAP will expedite the diagnostic process of many disease‐causing defects.
Role of CCL 11 in Eosinophilic Lung Disease during Respiratory Syncytial Virus Infection

Respiratory syncytial virus (RSV) is a major viral pathogen of infants and the elderly. Significant morbidity is caused by an overexuberant mixed lung cell infiltrate, which is thought to be driven by chemokines. One of the main chemotactic mediators responsible for the movement of eosinophils is CCL11 (eotaxin). Using a mouse model of eosinophilic bronchiolitis induced by RSV, we show here that treatment in vivo with a blocking antibody to CCL11 greatly reduces lung eosinophilia and disease severity. In addition, anti-CCL11 caused a striking inhibition of CD4-T-cell influx and shifted cytokine production away from interleukin-5 without reducing the resistance to viral replication. These results suggest that in addition to influencing eosinophil diapedesis and survival, anti-CCL11 has an action on T cells. These studies strengthen the case for anti-CCL11 treatment of Th2-driven diseases.
The H-Impairment Index (HII): a standardized assessment of alcohol-induced impairment in the Emergency Department

Abstract Background: Emergency Departments (EDs) care for thousands of alcohol-intoxicated patients annually. No clinically relevant bedside measures currently exist to describe degree of impairment. Objectives: To assess a group of bedside tests (“Hack's Impairment Index [HII] score”) that applies a numerical value to the degree of alcohol-induced impairment in ED patients. Methods: A six-month retrospective review of HII score data was performed in a convenience sample of 293 intoxicated ED patients. Patients were scored 0–4 on five tasks, divided by the maximum score (20 if all tasks completed), every 2 hours; and classified by the number of visits: Low-frequency (1 visit); Medium-frequency (2 visits); High-frequency (≥3 visits). Correlations were assessed between HII score, healthcare provider judgment of intoxication, and measured alcohol levels. Results: Study patients had 513 visits; 236 were low-frequency, 26 middle-frequency and 31 high-frequency. Clinical assessment and HII score were strongly correlated (Spearman’s rho = 0.82, p << 0.001); clinical assessment and alcohol level less strongly so (rho = 0.49, p << 0.001). Among low-frequency patients, HII score and alcohol level were weakly correlated (r = 0.324, p < 0.001), with no such correlation among high-frequency visitors (r = −0.04, p = 0.89). The mean decline between serial HII scores was 0.126 (95% CI: 0.098–0.154). Conclusion: This pilot study shows the HII score can be performed at the bedside of alcohol-intoxicated patients. The HII declines in a reasonably predictable manner over time; and applies a quantitative, objective assessment of alcohol impairment.
Variations in hypertension awareness, treatment, and control among Ghanaian migrants living in Amsterdam, Berlin, London, and nonmigrant Ghanaians living in rural and urban Ghana – the RODAM study

Objectives: Hypertension is a major burden among African migrants, but the extent of the differences in prevalence, treatment, and control among similar African migrants and nonmigrants living in different contexts in high-income countries and rural and urban Africa has not yet been assessed. We assessed differences in hypertension prevalence and its management among relatively homogenous African migrants (Ghanaians) living in three European cities (Amsterdam, London, and Berlin) and nonmigrants living in rural and urban Ghana. Methods: A multicenter cross-sectional study was conducted among Ghanaian adults (n = 5659) aged 25–70 years. Comparisons between sites were made using prevalence ratios with adjustment for age, education, and BMI. Results: The age-standardised prevalence of hypertension was 22 and 28% in rural Ghanaian men and women. The prevalence was higher in urban Ghana [men, 34%; adjusted prevalence ratio = 1.37, 95% confidence interval (CI), 1.10–1.70]; and much higher in migrants in Europe, especially in Berlin (men, 57%; prevalence ratio = 2.21, 1.78–2.73; women, 51%; prevalence ratio = 1.74, 1.45–2.09) than in rural Ghana. Hypertension awareness and treatment levels were higher in Ghanaian migrants than in nonmigrant Ghanaians. However, adequate hypertension control was lower in Ghanaian migrant men in Berlin (20%; prevalence ratio = 0.43 95%, 0.23–0.82), Amsterdam (29%; prevalence ratio = 0.59, 0.35–0.99), and London (36%; prevalence ratio = 0.86, 0.49–1.51) than rural Ghanaians (59%). Among women, no differences in hypertension control were observed. About 50% of migrants to 85% of rural Ghanaians with severe hypertension (Blood pressure > 180/110) were untreated. Antihypertensive medication prescription patterns varied considerably by site. Conclusion: Hypertension prevalence, awareness, and treatment levels were generally higher in African migrants, but blood pressure control level was lower in Ghanaian migrant men compared with their nonmigrant peers. Further work is needed to identify key underlying factors to support prevention and management efforts. Supplement Figure 1, http://links.lww. com/HJH/A831.
Arrhythmia disease classification using a higher-order neural unit

This paper presents a quadratic neural unit with error backpropagation learning algorithm to classify electrocardiogram arrhythmia disease. The electrocardiogram arrhythmia classification scheme consists of data acquisition, feature extraction, feature reduction, and a quadratic neural unit classifier to discriminate three different types of arrhythmia. A total of 44 records were obtained from MIT-BIH arrhythmia database to test the efficiency of arrhythmia disease classification method, the obtained results were a specificity of 97.60 % and a sensitivity of 97.05 %. The best accuracy classification rate obtained using the presented approach has been of 98.16 %.
Methyl green-pyronin staining: effects of fixation; use in routine pathology.

After formalin fixation and paraffin embedding, plasma cells and other py-roninophilic cells may be demonstrated as follows: The staining solution contains 4 ml of a 2% aqueous solution of methyl green, 6 ml of a 2% aqueous solution of pyronin Y, 2 ml of absolute ethanol, and Walpole's HCl-sodium acetate buffer at pH 3.8 to make a final volume of 100 ml. Staining is for 15–30 sec, differentiation by dipping twice, 1–2 sec each, in 2 changes of distilled water, next by keeping the slides in 2 changes of 96% ethanol for 30 sec each and finally by dipping them 6 times in each of 2 changes of absolute ethanol before clearing in xylene and covering in Canada balsam. Both the methyl green (Merck, C.I. No. 42585) and pyronin Y (National Aniline, C.I. No. 45005, Cert. No. NPy-20) stock solutions should be well extracted with chloroform. Sections of freeze-substituted tissues, frozen sections and smears are stained for 5 min or more in a similar solution made up with 0.1 M sodium acetate-acetic acid at pH 4.8, nex.
Cooperative Behavior of Artificial Neural Agents Based on Evolutionary Architectures

Artificial agents modeled by evolutionary neural networks have been diffusely described in the specific case of static architectures and synaptic weights coded in genetic strings. At present, more attractive theories devoted to a general theory of mind consider the biological and structural levels as necessary elements for an appropriate natural information processing. In this paper, an evolutionary approach has been taken into account for the selection of neural architectures of agents embedded in an artificial environment. Several correspondences between natural and artificial neural behavior has been detected (perception, multimodal integration, memory). Moreover, a cooperative social behavior emerged among the agents for a suitable exploration of the environment and the exploitation of the resources.
Correlative Fluorescence and Electron Microscopy on Ultrathin Cryosections: Bridging the Resolution Gap

Microscopy has become increasingly important for analysis of cells and cell function in recent years. This is due in large part to advances in light microscopy that facilitate quantitative studies and improve imaging of living cells. Analysis of fluorescence signals has often been a key feature in these advances. Such studies involve a number of techniques, including imaging of fluorescently labeled proteins in living cells, single-cell physiological experiments using fluorescent indicator probes, and immunofluorescence localization. The importance of fluorescence microscopy notwithstanding, there are instances in which electron microscopy provides unique information about cell structure and function. Correlative microscopy in which a fluorescence signal is reconciled with a signal from the electron microscope is an additional tool that can provide powerful information for cellular analysis. Here we review two different methodologies for correlative fluorescence and electron microscopy using ultrathin cryosections and the advantages attendant on this approach.
Gender differences in psychological effect of the August 1999 earthquake in Turkey

Disasters traumatically expose normal populations to severe threats to life, deaths of relatives and massive environmental destruction. Epidemiological studies found that women would be more vulnerable to disaster than men. In this study, we examined gender differences in short-term psychological effect of the 1999 earthquake in Turkey on adult survivors. A total of 184 subjects (79 males and 105 females) who used a psychiatric service were interviewed within 6–10 weeks after the earthquake. All subjects were assessed using a modified version of the Mississippi Scale for Posttraumatic Stress Disorder, the Beck Depression Inventory, the Beck Hopelessness Scale, and four subscales (depression, anxiety, hostility and somatization) of the Symptom Check List (SCL-90-R). Women had higher mean total Mississippi Scale scores than men (84.29 vs. 78.72; P<0.05). Women scored higher on the Beck Depression Inventory and the Beck Hopelessness Scale than men (respectively 16.3 vs. 10.4; P<0.001 and 7.5 vs. 6.0; P<0.05). Women had significantly higher depression (1.40 vs. 0.94; P<0.001), anxiety (1.46 vs. 1.12; P<0.05) and somatization (1.31 vs. 0.84; P<0.001) subscale scores of the SCL-90-R than men. These findings indicate that women may experience more severe psychological reactions than men after a disastrous earthquake.
Membrane introduction mass spectrometry: trends and applications.

Recent advances in membrane introduction mass spectrometry (MIMS) are reviewed. On-line monitoring is treated by focusing on critical variables, including the nature and dimensions of the membrane, and the analyte vapor pressure, diffusivity, and solubility in the membrane barrier. Sample introduction by MIMS is applied in (i) on-line monitoring of chemical and biological reactors, (ii) analysis of volatile organic compounds in environmental matrices, including air, water and soil, and (iii) in more fundamental studies, such as measurements of thermochemical properties, reaction mechanisms, and kinetics. New semipermeable membranes are discussed, including those consisting of thin polymers, low vapor pressure liquids, and zeolites. These membranes have been used to monitor polar compounds, selectively differentiate compounds through affinity-binding, and provide isomer differentiation based on molecular size. Measurements at high spatial resolution, for example, using silicone-capped hypodermic needle inlets, are also covered, as is electrically driven sampling through microporous membranes. Other variations on the basic MIMS experiment include analyte preconcentration through cryotrapping (CT-MIMS) or trapping in the membrane (trap-and-release), as well as differential thermal release methods and reverse phase (i.e., organic solvent) MIMS. Method limitations center on semivolatile compounds and complex mixture analysis, and novel solutions are discussed. Semivolatile compounds have been monitored with thermally assisted desorption, ultrathin membranes and derivatization techniques. Taking advantage of the differences in time of membrane permeation, mixtures of structurally similar compounds have been differentiated by using sample modulation techniques and by temperature-programmed desorption from a membrane interface. Selective ionization techniques that increase instrument sensitivity towards polar compounds are also described, and comparisons are made with other direct sampling (nonchromatographic) methods that are useful in mixture analysis.
TNF-alpha induces endothelial dysfunction in diabetic adults, an effect reversible by the PPAR-gamma agonist pioglitazone.

AIMS Inflammation contributes to the pathogenesis of cardiovascular disease. Tumour necrosis factor (TNF)-alpha, in particular, is a key mediator of inflammation and vascular dysfunction and progression of atherosclerotic disease. Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, not only improves insulin sensitivity, but may also have anti-inflammatory effects. The aims of this study were to investigate the acute effects of local intra-arterial infusion with low-dose TNF-alpha on resistance vessel endothelial function in type 2 diabetes and to determine whether short-term pioglitazone treatment protects against vascular dysfunction induced by this inflammatory stimulus. METHODS AND RESULTS A randomized, parallel, placebo-controlled, double blind trial with 30 mg pioglitazone once daily for 4 weeks was performed in 16 male patients with recently diagnosed type 2 diabetes. Forearm plethysmography (FBF) was used to evaluate the effect on resistance vessel responses of intra-arterial administration of serotonin (NO-dependent vasodilation) and nitroprusside (endothelium-independent vasodilation) followed by another FBF-measurement during the second hour of intra-arterial infusion with TNF-alpha (10 ng/100 mL forearm volume/min for 2 h). Endothelial-dependent FBF of type 2 diabetic patients was significantly impaired (25.4%) by intra-arterial TNF-alpha infusion (P = 0.01), whereas nitroprusside-induced vasodilation did not change. Treatment with pioglitazone for 4 weeks completely blocked TNF-alpha-induced impairment of endothelial-dependent FBF compared with placebo. No significant changes in plasma concentrations of TNF-alpha, interleukin-6, soluble TNF-alpha-receptors, or CD40L were observed. CONCLUSION Pioglitazone treatment can convey direct protection against cytokine (TNF-alpha)-induced endothelial dysfunction in humans with an increased cardiovascular risk due to type 2 diabetes.
The effect of post-natal mental distress amongst Indian and Pakistani mothers living in England on children's behavioural outcomes.

BACKGROUND Low socio-economic status (SES), post-natal mental distress and parenting impact child mental health and future well-being. There are unexplained differences in child mental health between South Asian ethnic minority groups living in the UK that may be due to variation in, and differential mediation of, these factors. METHODS We used multivariate multiple regression analysis of the effect of symptoms of mental distress, socio-demographic variables and warmth of parenting on child internalizing and externalizing scores at age seven (measured in 2010) in a population cohort of English children whose mothers were of Indian (n = 211) and Pakistani (n = 260) origin. RESULTS In the fully adjusted models the legacy of mental distress was visible for both internalizing (β coefficient 1.52, P = 0.04) and externalizing (1.68, P = 0.01) behaviour in the Pakistani children, and on the Indian children's internalizing (2.08, P = 0.008) but not externalizing (0.84, P = 0.204) behaviour. Lower SES was associated with worse behavioural scores for the Pakistani children, and warmth of parenting on Indian children's externalizing scores. CONCLUSIONS Symptoms of post-natal mental distress are associated with Indian and Pakistani child outcomes at age seven. The finding that warmth of parenting had a stronger association on Indian children's externalizing scores than mental distress might be explained by differences in the expression of SES on family characteristics and functioning between the two ethnic groups.
G protein-coupled receptors sense fluid shear stress in endothelial cells

Hemodynamic shear stress stimulates a number of intracellular events that both regulate vessel structure and influence development of vascular pathologies. The precise molecular mechanisms by which endothelial cells transduce this mechanical stimulus into intracellular biochemical response have not been established. Here, we show that mechanical perturbation of the plasma membrane leads to ligand-independent conformational transitions in a G protein-coupled receptor (GPCR). By using time-resolved fluorescence microscopy and GPCR conformation-sensitive FRET we found that stimulation of endothelial cells with fluid shear stress, hypotonic stress, or membrane fluidizing agent leads to a significant increase in activity of bradykinin B2 GPCR in endothelial cells. The GPCR conformational dynamics was detected by monitoring redistribution of GPCRs between inactive and active conformations in a single endothelial cell under fluid shear stress in real time. We show that this response can be blocked by a B2-selective antagonist. Our data demonstrate that changes in cell membrane tension and membrane fluidity affect conformational dynamics of GPCRs. Therefore, we suggest that GPCRs are involved in mediating primary mechanochemical signal transduction in endothelial cells. We anticipate our experiments to be a starting point for more sophisticated studies of the effects of changes in lipid bilayer environment on GPCR conformational dynamics. Furthermore, because GPCRs are a major target of drug development, a detailed characterization of mechanochemical signaling via the GPCR pathway will be relevant for the development of new antiatherosclerosis drugs.
Inhibition of TGF-β Enhances the In Vivo Antitumor Efficacy of EGF Receptor–Targeted Therapy

EGF receptor (EGFR)–targeted monoclonal antibodies (mAb), such as cetuximab, execute their antitumor effect in vivo via blockade of receptor–ligand interactions and engagement of Fcγ receptors on immune effector cells that trigger antibody-dependent cell-mediated cytotoxicity (ADCC). We show that tumors counteract the in vivo antitumor activity of anti-EGFR mAbs by increasing tumor cell-autonomous expression of TGF-β. We show that TGF-β suppresses the expression of key molecular effectors of immune cell–mediated cytotoxicity, including Apo2L/TRAIL, CD95L/FasL, granzyme B, and IFN-γ. In addition to exerting an extrinsic inhibition of the cytotoxic function of immune effectors, TGF-β–mediated activation of AKT provides an intrinsic EGFR-independent survival signal that protects tumor cells from immune cell–mediated apoptosis. Treatment of mice-bearing xenografts of human head and neck squamous cell carcinoma with cetuximab resulted in emergence of resistant tumor cells that expressed relatively higher levels of TGF-β compared with untreated tumor-bearing mice. Although treatment with cetuximab alone forced the natural selection of TGF-β–overexpressing tumor cells in nonregressing tumors, combinatorial treatment with cetuximab and a TGF-β–blocking antibody prevented the emergence of such resistant tumor cells and induced complete tumor regression. Therefore, elevated levels of TGF-β in the tumor microenvironment enable tumor cells to evade ADCC and resist the antitumor activity of cetuximab in vivo. Our results show that TGF-β is a key molecular determinant of the de novo and acquired resistance of cancers to EGFR-targeted mAbs, and provide a rationale for combinatorial targeting of TGF-β to improve anti-EGFR–specific antibody therapy of EGFR-expressing cancers. Mol Cancer Ther; 11(11); 2429–39. ©2012 AACR.
Effect of Polyherbal Additives on Intake, Growth and Nutrient Digestibility in Yorkshire Male Pigs

Growth trial of thirteen weeks’ duration was carried out on 24 pigs (2 months age; 12.5 kg b. wt.) which were divided into four groups of 6 pigs each and were fed with control diet concentrated feed mixture (CFM) (T0), CFM plus polyherbal superliv (500 g/ton) (T1), CFM plus polyherbal Ruchamax (500g/ton) (T2) and CFM plus AV/AGP/10 polyherbal (500g/ton) (T3). The dry mater intake (DMI) (g/d) in T0, T1, T2 and T3 groups were 1152.80, 1277.59, 1204.73 and 1186.13 respectively where significantly (P<0.01) higher dry mater intake (DMI) was observed in T1 group. Significant (P<0.01) difference was observed among treatment groups in organic matter (OM), crude protein (CP), ether extract (EE), crude fibre (CF), nitrogen free extract (NFE), neutral detergent fibre (NDF), acid detergent fibre (ADF), cellulose and hemicellulose intake. Similarly, significantly higher (P<0.05) weight gain, feed conversion ratio (FCR) and feed efficiency ratio (FER) was noticed in T1 group when compared to other groups. The digestibility of DM, OM, NFE, NDF, Cellulose and Hemicellulose were significantly (P<0.01) different. It was concluded that superliv polyherbal supplemented group significantly improved weight gain, FCR and net profit than the other polyherbal supplemented and control group without any deleterious effect on pigs.