Miracle-dz/UniFAR-FTUs huggingface dataset:
Multicenter Evaluation of a Sequence-Based Protocol for Subtyping Shiga Toxins and Standardizing Stx Nomenclature

ABSTRACT When Shiga toxin-producing Escherichia coli (STEC) strains emerged as agents of human disease, two types of toxin were identified: Shiga toxin type 1 (Stx1) (almost identical to Shiga toxin produced by Shigella dysenteriae type 1) and the immunologically distinct type 2 (Stx2). Subsequently, numerous STEC strains have been characterized that express toxins with variations in amino acid sequence, some of which confer unique biological properties. These variants were grouped within the Stx1 or Stx2 type and often assigned names to indicate that they were not identical in sequence or phenotype to the main Stx1 or Stx2 type. A lack of specificity or consistency in toxin nomenclature has led to much confusion in the characterization of STEC strains. Because serious outcomes of infection have been attributed to certain Stx subtypes and less so with others, we sought to better define the toxin subtypes within the main Stx1 and Stx2 types. We compared the levels of relatedness of 285 valid sequence variants of Stx1 and Stx2 and identified common sequences characteristic of each of three Stx/Stx1 and seven Stx2 subtypes. A novel, simple PCR subtyping method was developed, independently tested on a battery of 48 prototypic STEC strains, and improved at six clinical and research centers to test the reproducibility, sensitivity, and specificity of the PCR. Using a consistent schema for nomenclature of the Stx toxins and stx genes by phylogenetic sequence-based relatedness of the holotoxin proteins, we developed a typing approach that should obviate the need to bioassay each newly described toxin and that predicts important biological characteristics.
A Molecular Taxonomy for Urothelial Carcinoma

Purpose: Even though urothelial cancer is the fourth most common tumor type among males, progress in treatment has been scarce. A problem in day-to-day clinical practice is that precise assessment of individual tumors is still fairly uncertain; consequently efforts have been undertaken to complement tumor evaluation with molecular biomarkers. An extension of this approach would be to base tumor classification primarily on molecular features. Here, we present a molecular taxonomy for urothelial carcinoma based on integrated genomics. Experimental Design: We use gene expression profiles from 308 tumor cases to define five major urothelial carcinoma subtypes: urobasal A, genomically unstable, urobasal B, squamous cell carcinoma like, and an infiltrated class of tumors. Tumor subtypes were validated in three independent publically available data sets. The expression of 11 key genes was validated at the protein level by immunohistochemistry. Results: The subtypes show distinct clinical outcomes and differ with respect to expression of cell-cycle genes, receptor tyrosine kinases particularly FGFR3, ERBB2, and EGFR, cytokeratins, and cell adhesion genes, as well as with respect to FGFR3, PIK3CA, and TP53 mutation frequency. The molecular subtypes cut across pathologic classification, and class-defining gene signatures show coordinated expression irrespective of pathologic stage and grade, suggesting the molecular phenotypes as intrinsic properties of the tumors. Available data indicate that susceptibility to specific drugs is more likely to be associated with the molecular stratification than with pathologic classification. Conclusions: We anticipate that the molecular taxonomy will be useful in future clinical investigations. Clin Cancer Res; 18(12); 3377–86. ©2012 AACR.
Minimum selection GSC in independent Rayleigh fading

We analyze the error performance of minimum selection generalized selection combining (MS-GSC), in which the minimum number of diversity branches are selected such that their combined signal-to-noise ratio (SNR) is above a given threshold. A flat Rayleigh fading channel with independent and distinctly distributed branch SNR is considered. By transforming the ordered instantaneous branch SNR to their differences, we derive the distribution of the number of selected branches in closed-form. We then modify the derivation of this distribution to get the characteristic function (c.f.) of the combiner output SNR. This c.f. is used to obtain the symbol error probability for different coherent digital modulation schemes.
The JAK1/2 Inhibitor Ruxolitinib Reverses Interleukin-6-Mediated Suppression of Drug-Detoxifying Proteins in Cultured Human Hepatocytes

The inflammatory cytokine interleukin (IL)-6, which basically activates the Janus kinase (JAK)/ signal transducer and activator of transcription (STAT) signaling pathway, is well known to repress expression of hepatic cytochromes P-450 (P450s) and transporters. Therapeutic proteins, like monoclonal antibodies targeting IL-6 or its receptor, have consequently been demonstrated to restore full hepatic detoxification capacity, which results in inflammatory disease-related drug-drug interactions (idDDIs). In the present study, we investigated whether ruxolitinib, a small drug acting as a JAK1/2 inhibitor and currently used in the treatment of myeloproliferative neoplasms, may also counteract the repressing effects of IL-6 toward hepatic detoxifying systems. Ruxolitinib was found to fully inhibit IL-6-mediated repression of P450 (CYP1A2, CYP2B6, and CYP3A4) and transporter (NTCP, OATP1B1, and OCT1) mRNA levels in primary human hepatocytes and differentiated hepatoma HepaRG cells. Such effects were dose-dependent, with ruxolitinib EC50 values around 1.0–1.2 μM and thus close to ruxolitinib plasma levels that can be reached in patients. Moreover, they were associated with concomitant restoration of P450 and drug transporter activities in IL-6-exposed HepaRG cells. By contrast, ruxolitinib failed to suppress the repression of drug-detoxifying protein mRNA levels caused by IL-1β. The JAK inhibitor and anti–rheumatoid arthritis compound tofacitinib was additionally found to reverse IL-6-mediated suppression of P450 and transporter mRNA expressions. Taken together, our results demonstrated that small drugs acting as JAK inhibitors, like ruxolitinib, counteract IL-6-mediated repression of drug-metabolizing enzymes and drug transporters in cultured human hepatocytes. These JAK inhibitors may consequently be hypothesized to restore hepatic detoxification capacity for patients suffering from inflammatory diseases, which may in turn cause idDDIs.
Genetically Diverse Coronaviruses in Wild Bird Populations of Northern England

Infectious bronchitis virus (IBV) causes a costly respiratory viral disease of chickens. The role of wild birds in the epidemiology of IBV is poorly understood. We detected diverse coronaviruses by PCR in wildfowl and wading birds in England. Sequence analysis showed some viruses to be related to IBV.
Quantitative structure‐pharmacokinetic relationship modelling: apparent volume of distribution

The purpose of this study was to develop a quantitative structure‐activity relationship (QSAR) for the prediction of the apparent volume of distribution (Vd) in man for a heterogeneous series of drugs. The relationship of many computed, and some experimental, structural descriptors with Vd, and the Vd corrected for protein binding (unbound Vd), was investigated. Models were constructed using stepwise regression analysis for all the 70 drugs in the dataset, as well as for acidic drugs and basic drugs separately. The predictive power of the models was assessed using half the chemicals as a test set, and revealed that the models for Vd yielded lower prediction errors than those constructed for the unbound Vd (mean fold error of 2.01 for Vd compared with 2.28 for unbound Vd). Moreover, the separation of the compounds into acids and bases did not reduce the prediction error significantly.
A prospective randomized comparison of cold vs hot snare polypectomy in the occurrence of postpolypectomy bleeding in small colonic polyps

Aim Polypectomy techniques in the removal of polyps in the 3–8 mm size range are inconsistent. The aim of our study was to compare cold (CSP) with hot snare polypectomy (HSP) in the occurrence of postpolypectomy bleeding in small colonic polyps 3–8 mm in size.
Wnt/β-catenin mediates radiation resistance of Sca1+ progenitors in an immortalized mammary gland cell line

The COMMA-Dβ-geo cell line has been shown to contain a permanent subpopulation of progenitor cells that are enriched in outgrowth potential. Using the COMMA-Dβ-geo cell line as a model, we sought to study the radioresistance of mammary progenitor cells. Using the putative progenitor cell marker stem cell antigen 1 (Sca1), we were able to isolate a discrete subpopulation of Sca1+ multipotent cells from the immortalized COMMA-Dβ-geo murine mammary cell line. At a clinically relevant dose, the Sca1+ cells were resistant to radiation (2 Gy). Sca1+ cells contained fewer γ-H2AX+ DNA damage foci following irradiation, displayed higher levels of endogenous β-catenin, and selectively upregulated survivin after radiation. Expression of active β-catenin enhanced self-renewal preferentially in the Sca1+ cells, whereas suppressing β-catenin with a dominant negative, β-engrailed, decreased self-renewal of the Sca1+ cells. Understanding the radioresistance of progenitor cells may be an important factor in improving the treatment of cancer. The COMMA-Dβ-geo cell line may provide a useful model to study the signaling pathways that control mammary progenitor cell regulation.
Evaluation of DementiaNet, a network-based primary care innovation for community-dwelling patients with dementia: protocol for a longitudinal mixed methods multiple case study

Introduction Primary healthcare professionals will increasingly be required to manage and optimise their treatment for patients with dementia. With DementiaNet, we aim to reduce the burden of dementia on healthcare services and society through implementation and facilitation of integrated network-based care with increased dementia expertise. DementiaNet is designed as a stepwise approach including clinical leadership, quality improvement cycles and interprofessional training, which are tailor-made to the local context. For example, the composition of the network and improvement goals are tailored to the local context and availability. Here, we describe the linked evaluation study which aims to provide insight in effectiveness, process and mechanism of the DementiaNet approach through an innovative evaluation design. Methods and analysis We designed a longitudinal, mixed methods, multiple case study. Study population consists of two levels: (i) local DementiaNet networks of primary care professionals and (ii) patients and informal caregivers who receive care from these networks. At the start and after 12 and 24 months, quantitative data are collected for each network on: level of network maturity, quality of care indicators and outcomes reported by informal caregivers of dementia patients. We assess changes in networks over time and the association with quality of care and informal caregiver-reported outcomes. Throughout the study, logs about each network are registered. Additionally, semi-structured interviews with network members and informal caregivers will provide insight in experiences and opinions regarding effects and mechanisms through which changes in quantitative outcomes are effectuated. Rich narratives will be constructed about the development of the local networks using collected data. Ethics and dissemination The study protocol was reviewed by the local medical ethics committee; formal judgement was not required (protocol number: 2015–2053). The findings of this study will be disseminated through peer-reviewed publications, conference presentations and presentations for healthcare professionals where appropriate.
Surfactant Replacement Therapy for Preterm and Term Neonates With Respiratory Distress

Respiratory failure secondary to surfactant deficiency is a major cause of morbidity and mortality in preterm infants. Surfactant therapy substantially reduces mortality and respiratory morbidity for this population. Secondary surfactant deficiency also contributes to acute respiratory morbidity in late-preterm and term neonates with meconium aspiration syndrome, pneumonia/sepsis, and perhaps pulmonary hemorrhage; surfactant replacement may be beneficial for these infants. This statement summarizes the evidence regarding indications, administration, formulations, and outcomes for surfactant-replacement therapy. The clinical strategy of intubation, surfactant administration, and extubation to continuous positive airway pressure and the effect of continuous positive airway pressure on outcomes and surfactant use in preterm infants are also reviewed.
Neurotransmitter properties of spinal interneurons in embryonic and larval zebrafish

Many classes of spinal interneurons in zebrafish have been described based on morphology, but their transmitter phenotypes are largely unknown. Here we combine back‐filling or genetic labeling of spinal interneurons with in situ staining for markers of neurotransmitter phenotypes, including the vesicular glutamate transporter (VGLUT) genes for glutamatergic neurons, the neuronal glycine transporter (GLYT2) for glycinergic neurons, and glutamic acid decarboxylase (GAD) for GABAergic neurons. Neurons positive for VGLUT include the commissural CoPA, MCoD, UCoD, and some of the CoSA neurons. The CiD interneurons, which have ipsilateral descending axons, were also VGLUT‐positive, as were the ventrally located VeMe interneurons, whose descending axonal trajectory has not been clearly revealed. Cells positive for GLYT2 include the commissural CoLAs as well as some of the CoBL and CoSA neurons. The CiA cells were the only GLYT2‐positive cells with an ipsilateral axon. Cells staining for GAD included, most notably, the dorsal longitudinal ascending (DoLA) and KA interneurons. Our approach allowed us to define the likely transmitter phenotypes of most of the known classes of spinal interneurons. These data provide a foundation for understanding the functional organization of the spinal networks in zebrafish. J. Comp. Neurol. 480:19–37, 2004. © 2004 Wiley‐Liss, Inc.
The Variable Metabolic Response to Dietary Isoflavones in Humans

Abstract The aim of this study was to better understand the metabolic fate of dietary estrogenic isoflavones in humans. Twelve volunteers were challenged with soya flour and urinary levels of the isoflavones daidzein (Da), genistein (Gen), and glycitein (Gly), and the isoflavonoid metabolites equol (Eq) and O-desmethylangolensin (O-Dma) determined by GC and GC-MS. Prior to challenge, Da, Gen, and Gly were present in the urine of all participants at low levels and Eq and O-Dma were present in 9/12 and 10/12 participants, respectively. Urinary levels of all five diphenols were increased in each individual on the day following challenge, returning to approximately prechallenge levels on the second or third day post-challenge. Mean post-challenge peak levels of the five diphenols compared with pre-challenge levels were Da (4x), Gen (8x), Gly (5x), Eq (45x), and O-Dma (66x). However, there was considerable individual variation in this metabolic response with peak levels of Eq showing the highest variation (1527x). An inverse relationship between Eq and O-Dma excretion was also found post-challenge suggesting individual variability in the preferred metabolic pathways of dietary isoflavones.
The nature of X-ray spectral variability in Seyfert Galaxies

Abstract In many Seyfert galaxies the 2-20 keV X-ray spectrum typically softens with increasing X-ray flux. This effect has been explained by two different models; either pivoting of a single spectral component or relative changes in the normalisations of two components (a hard and a soft) which each have constant shape. We present a model-independent technique to analyse spectral variability, the ‘flux-flux’ plot, which shows conclusively that the two-component model is correct for some Seyfert galaxies (including the well studied MCG–6-30-15 ) but in other Seyferts spectral pivoting applies (e.g. NGC 4051). The nature of each of the spectral components in MCG–6-30-15 are briefly examined.
Success Factors for Data Warehouse and Business Intelligence Systems

Data warehouse (DW) and business intelligence (BI) systems are among the most important IT-based systems in organizations. The decisions made using these systems can fundamentally affect an organization’s nature and performance. This paper reports the results of a case study that investigated the nature of DW/BI development. The theory lens used to frame and analyse the research was critical success factors (CSF). Ten CSF were identified from previous research on executive information systems, DW, and BI. This CSF set was used to analyse the failure of a corporate DW/BI project and the subsequent success of a smaller, functional BI system. To overcome previous criticism of the CSF approach, the CSF were analysed within the project’s organizational context and in terms of the dynamics of CSF over the life of the project. The case provides a number of lessons for organizations embarking on enterprise-scale DW/BI projects. The study shows that the augmented CSF approach is useful in understanding DW/BI development.
Social Network Collaborative Filtering

This paper demonstrates that "social network collaborative filtering" (SNCF), wherein user-selected like-minded alters are used to make predictions, can rival traditional user-to-user collaborative filtering (CF) in predictive accuracy. Us-ing a unique data set from an online community where users rated items and also created social networking links specifically intended to represent like-minded â¬Sallies,â¬? we use SNCF and traditional CF to predict ratings by net-worked users. We find that SNCF using generic "friend" alters is moderately worse than the better CF techniques, but outperforms benchmarks such as by-item or by-user average rating; generic friends often are not like-minded. However, SNCF using "ally" alters is competitive with CF. These results are significant because SNCF is tremendously more computationally efficient than traditional user-user CF and may be implemented in large-scale web commerce and social networking communities. It is notoriously difficult to distinguish the contributions of social influence (where allies influence users) and "socialâ¬? selection (where users are simply effective at selecting like-minded people as their allies). Nonetheless, comparing similarity over time, we do show no evi-dence of strong social influence among allies or friends.
Lipids in Health and Disease

Background: Hypercholesterolemia is one of the most important factors causing cardiovascular disease (CVD). The aim of the present work was to evaluate the relationships between socio-demographic, clinical, lifestyle and depression status and the presence of hypercholesterolemia, among elderly individuals without known CVD. Methods: During 2005–2007, 1190 elderly (aged 65 to 100 years) men and women (from Cyprus, Mitilini, Samothraki, Cephalonia, Crete, Lemnos, Corfu and Zakynthos) were enrolled. Socio-demographic, clinical and lifestyle factors were assessed through standard procedures. Symptoms of depression were evaluated using the short-form of the Geriatric Depression Scale (GDS, range 0–15). Dietary habits were assessed through a semi-quantitative food frequency questionnaire. Hypercholesterolemia was defined as total serum cholesterol > 200 mg/dL or use of lipids lowering medication. Results: 44.6% of males and 61.9% of females had hypercholesterolemia (p < 0.001). Only, 63% of hypercholesterolemic participants were under special diet or pharmaceutical treatment. Hypercholisterolemic individuals had higher prevalence of obesity (43% vs. 25%), hypertension (76% vs. 57%) and diabetes (25% vs. 17%) compared with normal participants (p < 0.001). Furthermore, hypercholisterolemic participants showed higher depression levels (p = 0.002). After adjusting for various confounders, GDS score and BMI correlated with 13% (95%CI 0.98–1.30) and 14% (95%CI 0.99–1.31) higher likelihood of having hypercholesterolemia. Conclusion: A considerable proportion of our elderly sample had hypercholesterolemia, while 1/3 of them were untreated. Furthermore, presence of hypercholesterolemia was correlated with depressive symptomatology and increased BMI. Published: 30 March 2009 Lipids in Health and Disease 2009, 8:10 doi:10.1186/1476-511X-8-10 Received: 24 February 2009 Accepted: 30 March 2009 This article is available from: http://www.lipidworld. com/content/8/1/10 © 2009 Tyrovolas et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
MF63 [2-(6-Chloro-1H-phenanthro[9,10-d]imidazol-2-yl)-isophthalonitrile], a Selective Microsomal Prostaglandin E Synthase-1 Inhibitor, Relieves Pyresis and Pain in Preclinical Models of Inflammation

Microsomal prostaglandin E synthase-1 (mPGES-1) is a terminal prostaglandin E2 (PGE2) synthase in the cyclooxygenase pathway. Inhibitors of mPGES-1 may block PGE2 production and relieve inflammatory symptoms. To test the hypothesis, we evaluated the antipyretic and analgesic properties of a novel and selective mPGES-1 inhibitor, MF63 [2-(6-chloro-1H-phenanthro-[9,10-d]imidazol-2-yl)isophthalonitrile], in animal models of inflammation. MF63 potently inhibited the human mPGES-1 enzyme (IC50 = 1.3 nM), with a high degree (>1000-fold) of selectivity over other prostanoid synthases. In rodent species, MF63 strongly inhibited guinea pig mPGES-1 (IC50 = 0.9 nM) but not the mouse or rat enzyme. When tested in the guinea pig and a knock-in (KI) mouse expressing human mPGES-1, the compound selectively suppressed the synthesis of PGE2, but not other prostaglandins inhibitable by nonsteroidal anti-inflammatory drugs (NSAIDs), yet retained NSAID-like efficacy at inhibiting lipopolysaccharide-induced pyresis, hyperalgesia, and iodoacetate-induced osteoarthritic pain. In addition, MF63 did not cause NSAID-like gastrointestinal toxic effects, such as mucosal erosions or leakage in the KI mice or nonhuman primates, although it markedly inhibited PGE2 synthesis in the KI mouse stomach. Our data demonstrate that mPGES-1 inhibition leads to effective relief of both pyresis and inflammatory pain in preclinical models of inflammation and may be a useful approach for treating inflammatory diseases.
Phase Field Dynamic Modelling of Shape Memory Alloys Based on Isogeometric Analysis

Shape Memory Alloys (SMAs) exhibit complex behaviors as a result of their constituent phases and microstructure evolution. In this paper, we focus on the numerical simulations of microstructure evolution in SMAs using a phase-field model for the two dimensional square-to-rectangular martensitic phase transformations. The phase-field model, based on the Ginzburg-Landau theory, has strong non-linearity, thermo-mechanical coupling, and higher-order differential terms and presents substantial challenges for numerical simulations. The isogeometric analysis, developed in this paper using the rich NURBS basis functions, offers several advantages in solving such complex problems with higher-order partial differential equations as the problem at hand. To our best knowledge, we report here for the first time the use of the new method in the study of microstructure evolution in SMAs. The numerical experiments of microstructure evolution have been carried out on the FePd SMA specimen. The results are in good agreement with those previously reported in the literature.