bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene variants encoding proteins involved in antioxidant defense system and the clinical expression of Wilson disease
Authors: Gromadzka Grażyna , Kruszyńska Monika , Wierzbicka Diana , Litwin Tomasz , Dzieżyc Karolina , Wierzchowska‐Ciok Agata , Chabik Grzegorz , Członkowska Anna 
Published: February 2014

AbstractBackground & AimsWilson disease (WD) is an autosomal recessive disorder of copper metabolism resulting from pathogenic mutations of the ATP7B gene. The basis of phenotypic variability of the disease is not understood. The main mechanism of copper toxicity is probably related to generation of intracellular oxidative stress. To evaluate whether interindividual variability within genes encoding proteins involved in antioxidant defense system may modulate phenotypic expressions of WD.MethodsVariability within genes encoding the cytosolic enzymes: glutathione peroxidase (GPX1 rs1050450) and manganese superoxide dismutase (SOD2 rs4880), and peroxisomal enzyme: catalase (CAT rs1001179) were analysed in 435 patients. Individual genotypes were tested for their relationship with phenotypic features of WD.ResultsGPX1 genotypes were not related to phenotypic manifestations of WD. Among males homozygocity for the SOD2 rs4880 T allele was related to earlier onset of WD. Patients homozygous for the CAT rs1001179 T allele characterized with later onset of WD [median (interquartile range) age: 29.0 (14.0) years vs. 22.0 (12.0) years, respectively, P < 0.004], later manifestation of hepatic symptoms [34.5 (14.0) years vs. 22.0 (12.0) years, P < 0.0009], and later presentation of neurological symptoms [37.0 (16.0) years vs. 28.0 (13.0) years, P < 0.03] than those having one or two C alleles.ConclusionVariability within the CAT gene may be an important modifier of the clinical course of WD. SOD2 genotype may influence WD phenotype among males. These observations indirectly confirm a role of oxidative stress in the pathogenesis of WD, as well as indirectly suggest that peroxisomes impairment may be involved in WD pathophysiology.
Lack of efficacy of mTOR inhibitors and ACE pathway inhibitors as antifibrotic agents in evolving and established fibrosis in Mdr2−/− mice
Authors: Bridle Kim R. , Sobbe Amy L. , de Guzman C. Erika , Santrampurwala Nishreen , Jaskowski Lesley A. , Clouston Andrew D. , Campbell Catherine M. , Nathan Subramaniam V. , Crawford Darrell HG 
Published: February 2014

AbstractBackground & AimsMammalian target of rapamycin and angiotensin‐converting enzyme inhibition has been shown to have antifibrotic activity in models of liver fibrosis. The aim of our study was to determine the efficacy of rapamycin, everolimus, irbesartan and captopril, alone and in combination, as antifibrotic agents in the Mdr2−/− model of cholestasis both in early injury and established disease.MethodsMdr2−/− mice were treated for 4 weeks with vehicle, rapamycin (1 mg/kg) or everolimus (5 mg/kg) every second day or with captopril (30 mg/kg/day), irbesartan (10 mg/kg/day) or vehicle. Further groups of 3‐week‐old Mdr2−/− mice were treated with rapamycin and irbesartan in combination (1 mg/kg/day and 10 mg/kg/day) or with rapamycin (2 mg/kg/day) for 4 weeks. Liver injury and fibrosis were compared between treated and untreated animals.ResultsThere were no significant improvements in liver injury, histology, hepatic hydroxyproline or profibrogenic gene expression following treatment with rapamycin, everolimus, captopril or irbesartan at any time point studied. Likewise, there were no improvements in liver histology or profibrogenic gene expression following combination therapy or high‐dose rapamycin treatment.ConclusionsThe antifibrotic effects of rapamycin, everolimus, captopril and irbesartan seen in other models of fibrosis were not replicated in the Mdr2−/− model in this study. This highlights the clear need to test specific antifibrotic agents in a number of different animal models. We believe this animal model is ideal to study usefulness of antifibrotic agents in cholestatic liver disease because of the similarity in genetics and hepatic histopathology to human cholestatic liver disease.
Results of salvage liver transplantation
Authors: Guerrini Gian Piero , Gerunda Giorgio E. , Montalti Roberto , Ballarin Roberto , Cautero Nicola , De Ruvo Nicola , Spaggiari Mario , Di Benedetto Fabrizio 
Published: February 2014

AbstractBackground & AimsSalvage liver transplantation (SLT) is an attractive sequential strategy which combines liver resection (LR) for hepatocellular carcinoma (HCC), followed by liver transplant (LT) in the event of HCC recurrence or progressive liver deterioration. To compare the long‐term results of SLT with primary liver transplant (PLT).MethodsBetween 2000 and 2011, 125 patients (72 transplantable) underwent LR and 226 underwent LT in our unit. The outcome of SLT was analysed in a two‐step fashion: firstly, SLT (n = 28) was compared with PLT (n = 198), secondly an intention‐to‐treat analysis was performed on all transplantable HCC patients who underwent LR (LRT group = 72) compared to PLT (n = 198).ResultsThe five‐year overall survival (OS) was 65.4% vs. 49.2% (P = 0.63), and disease‐free survival (DFS) was 89.7% vs. 80.6% (P = 0.31) for PLT and SLT respectively.Predictive factors for DFS after LT included HCC total diameter [hazard ratio (HR) 1.29 P = 0.003], alpha‐foetoprotein (HR 1.002 P < 0.001) and number of HCC nodules (HR 1.317 P = 0.035), whereas viral hepatitis C positivity (HR 1.911 P = 0.03) and outside Up‐to‐seven criteria (HR 2.652 P < 0.001) were negative independent prediction factors of OS. Intention‐to‐treat analysis showed that OS at 5 years was improved in PLT vs. LRT (LRT n = 72 including SLT plus LR group) and was 69.4% vs. 42.2% (P < 0.004), with an additional increase in DFS (89.2% vs. 54.5% respectively P < 0.001).ConclusionSalvage liver transplantation is a safe treatment strategy, as it does not impair long‐term survival. At intention‐to‐treat analysis, PLT showed improved survival compared with LRT.
Low‐dose anti‐CD3 antibody induces remission of active autoimmune hepatitis in xenoimmunized mice
Authors: Marceau Gabriel , Yang Roland , Lapierre Pascal , Béland Kathie , Alvarez Fernando 
Published: February 2014

AbstractBackgroundSome patients with autoimmune hepatitis (AIH), despite appropriate treatment, progress towards cirrhosis and liver failure, requiring transplantation. New biological agents targeting immune cell subtypes have been developed, with better specificity and longer‐lasting effects than conventional wide‐spectrum immunosuppressive drugs.AimsThe goal of this study was to evaluate the effectiveness of low dose of αCD3 targeting therapy in a model of type 2 AIH.MethodsThis experimental model is based on xenoimmunization of C57BL/6 mice with DNA coding for human liver autoantigens. Mice with AIH were treated with five daily injections of low dose of αCD3 monoclonal antibody, before disease onset (5.5 months post‐xenoimmunization) or during AIH (7 months post‐xenoimmunization). Along with serum aminotransferases, autoantibody levels and end‐point liver histology, spleen and liver‐infiltrating lymphocytes were phenotyped by flow cytometry and immune response measured by lymphoproliferative assays.ResultsBefore onset of AIH, treatment prevented the development of liver inflammation and tissue injury. During active AIH, low dose of αCD3 antibody therapy resulted in a resorption of liver inflammatory infiltrates, normalization of serum aminotransferas levels, reduced autoantibody titres, increased regulatory T cells and lowered proliferation of autoreactive liver lymphocytes.ConclusionsWe report that low dose αCD3 antibody administration is an effective treatment for AIH in an experimental model of type 2 AIH. These data suggest that αCD3 antibody therapy could be tested in clinical trials as a rescue therapy for patients with uncontrolled AIH.
N‐cadherin, A Vascular Smooth Muscle Cell–Cell Adhesion Molecule: Function and Signaling for Vasomotor Control
Authors: Sun Zhe , Parrish Alan R. , Hill Michael A. , Meininger Gerald A. 
Published: February 2014

AbstractCell–cell adhesion complexes are increasingly recognized as an important cell‐signaling site, similar to integrin‐extracellular matrix FA. Furthermore, cell–cell adhesions are involved in the regulation of multi‐cellular/tissue organization and organ, tissue, and cellular level functional behavior. Although N‐cadherin is the major cell–cell adhesion molecule in VSM, only limited studies have been undertaken to understand its function in VSM. In contrast, N‐cadherin signaling and functions have been extensively studied in neurons, fibroblasts, and myocytes, as well as in the context of epithelial‐mesenchymal‐transitions. Increasing evidence has indicated that N‐cadherin‐mediated cell–cell adhesions are important for tissue integrity and cell proliferation. Relevant to VSM, N‐cadherin's role in actin cytoskeleton organization and contraction, as well as its role in regulation of Rho family GTPases are of particular interest. This article briefly reviews the fundamentals of N‐cadherin biology that help shape our current understanding of its function and signaling mechanisms. In particular, attention is given to applications of this knowledge to VSM. The review points to the need for more research effort that is directed at understanding the role of N‐cadherins in the regulation of vascular function.
Neuropilin Regulation of Angiogenesis, Arteriogenesis, and Vascular Permeability
Authors: Plein Alice , Fantin Alessandro , Ruhrberg Christiana 
Published: February 2014

AbstractThe formation of the cardiovasculature, consisting of both the heart and blood vessels, is a critical step in embryonic development and relies on three processes termed vasculogenesis, angiogenesis, and vascular remodeling. The transmembrane protein NRP1 is an essential modulator of embryonic angiogenesis with additional roles in vessel remodeling and arteriogenesis. NRP1 also enhances arteriogenesis in adults to alleviate pathological tissue ischemia. However, in certain circumstances, vascular NRP1 signaling can be detrimental, as it may promote cancer by enhancing tumor angiogenesis or contribute to tissue edema by increasing vascular permeability. Understanding the mechanisms of NRP1 signaling is, therefore, of profound importance for the design of therapies aiming to control vascular functions. Previous work has shown that vascular NRP1 can variably serve as a receptor for two secreted glycoproteins, the VEGF‐A and SEMA3A, but it also has a poorly understood role as an adhesion receptor. Here, we review current knowledge of NRP1 function during blood vessel growth and homeostasis, with special emphasis on the vascular roles of its multiple ligands and signaling partners.
A Sparsity‐Inducing Optimization‐Based Algorithm for Planar Patches Extraction from Noisy Point‐Cloud Data
Authors: Zhang Guangcong , Vela Patricio A. , Karasev Peter , Brilakis Ioannis 
Published: February 2014

AbstractCurrently, much of the manual labor needed to generate as‐built building information models (BIMs) of existing facilities is spent converting raw point cloud data sets (PCDs) to BIM descriptions. Automating the PCD conversion process can drastically reduce the cost of generating as‐built BIMs. Due to the widespread existence of planar structures in civil infrastructures, detecting and extracting planar patches from raw PCDs is a fundamental step in the conversion pipeline from PCDs to BIMs. However, existing methods cannot effectively address both automatically detecting and extracting planar patches from infrastructure PCDs. The existing methods cannot resolve the problem due to the large scale and model complexity of civil infrastructure, or due to the requirements of extra constraints or known information. To address the problem, this article presents a novel framework for automatically detecting and extracting planar patches from large‐scale and noisy raw PCDs. The proposed method automatically detects planar structures, estimates the parametric plane models, and determines the boundaries of the planar patches. The first step recovers existing linear dependence relationships amongst points in the PCD by solving a group‐sparsity inducing optimization problem. Next, a spectral clustering procedure based on the recovered linear dependence relationships segments the PCD. Then, for each segmented group, model parameters of the extracted planes are estimated via singular value decomposition (SVD) and maximum likelihood estimation sample consensus (MLESAC). Finally, the α‐shape algorithm detects the boundaries of planar structures based on a projection of the data to the planar model. The proposed approach is evaluated comprehensively by experiments on two types of PCDs from real‐world infrastructures, one captured directly by laser scanners and the other reconstructed from video using structure‐from‐motion techniques. To evaluate the performance comprehensively, five evaluation metrics are proposed which measure different aspects of performance. Experimental results reveal that the proposed method outperforms the existing methods, in the sense that the method automatically and accurately extracts planar patches from large‐scaled raw PCDs without any extra constraints nor user assistance.
Activation of phenotypic subpopulations in response to ciprofloxacin treatment in Acinetobacter baumannii
Authors: MacGuire Ashley E. , Ching Meining Carly , Diamond Brett H. , Kazakov Alexey , Novichkov Pavel , Godoy Veronica G. 
Published: February 2014

SummaryThe multidrug‐resistant, opportunistic pathogen, Acinetobacter baumannii, has spread swiftly through hospitals worldwide. Previously, we demonstrated that A. baumannii regulates the expression of various genes in response to DNA damage. Some of these regulated genes, especially those encoding the multiple error‐prone DNA polymerases, can be implicated in induced mutagenesis, leading to antibiotic resistance. Here, we further explore the DNA damage‐inducible system at the single cell level using chromosomal transcriptional reporters for selected DNA damage response genes. We found the genes examined respond in a bimodal fashion to ciprofloxacin treatment, forming two phenotypic subpopulations: induced and uninduced. This bimodal response to ciprofloxacin treatment in A. baumannii is unique and quite different than the Escherichia coli paradigm. The subpopulations are not genetically different, with each subpopulation returning to a starting state and differentiating with repeated treatment. We then identified a palindromic motif upstream of certain DNA damage response genes, and have shown alterations to this sequence to diminish the bimodal induction in response to DNA damaging treatment. Lastly, we are able to show a biological advantage for a bimodal response, finding that one subpopulation survives ciprofloxacin treatment better than the other.
Assessing the essentiality of the decaprenyl‐phospho‐d‐arabinofuranose pathway in Mycobacterium tuberculosis using conditional mutants
Authors: Kolly Gaëlle S. , Boldrin Francesca , Sala Claudia , Dhar Neeraj , Hartkoorn Ruben C. , Ventura Marcello , Serafini Agnese , McKinney John D. , Manganelli Riccardo , Cole Stewart T. 
Published: February 2014

SummaryIn Mycobacterium tuberculosis the decaprenyl‐phospho‐d‐arabinofuranose (DPA) pathway is a validated target for the drugs ethambutol and benzothiazinones. To identify other potential drug targets in the pathway, we generated conditional knock‐down mutants of each gene involved using the TET‐PIP OFF system. dprE1, dprE2, ubiA, prsA, rv2361c, tkt and rpiB were confirmed to be essential under non‐permissive conditions, whereas rv3807c was not required for survival. In the most vulnerable group, DprE1‐depleted cells died faster in vitro and intracellularly than those lacking UbiA and PrsA. Downregulation of DprE1 and UbiA resulted in similar phenotypes, namely swelling of the bacteria, cell wall damage and lysis as observed at the single cell level, by real time microscopy and electron microscopy. By contrast, depletion of PrsA led to cell elongation and implosion, which was suggestive of a more pleiotropic effect. Drug sensitivity assays with known DPA‐inhibitors supported the use of conditional knock‐down strains for target‐based whole‐cell screens. Together, our work provides strong evidence for the vulnerability of all but one of the enzymes in the DPA pathway and generates valuable tools for the identification of lead compounds targeting the different biosynthetic steps. PrsA, phosphoribosyl‐pyrophosphate synthetase, appears to be a particularly attractive new target for drug discovery.
Economic and physical determinants of the global distributions of crop pests and pathogens
Authors: Bebber Daniel P. , Holmes Timothy , Smith David , Gurr Sarah J. 
Published: February 2014

Summary

Crop pests and pathogens pose a significant and growing threat to food security, but their geographical distributions are poorly understood. We present a global analysis of pest and pathogen distributions, to determine the roles of socioeconomic and biophysical factors in determining pest diversity, controlling for variation in observational capacity among countries.

Known distributions of 1901 pests and pathogens were obtained from CABI. Linear models were used to partition the variation in pest species per country amongst predictors.

Reported pest numbers increased with per capita gross domestic product (GDP), research expenditure and research capacity, and the influence of economics was greater in micro‐organisms than in arthropods. Total crop production and crop diversity were the strongest physical predictors of pest numbers per country, but trade and tourism were insignificant once other factors were controlled. Islands reported more pests than mainland countries, but no latitudinal gradient in species richness was evident.

Country wealth is likely to be a strong indicator of observational capacity, not just trade flow, as has been interpreted in invasive species studies. If every country had US levels of per capita GDP, then 205 ± 9 additional pests per country would be reported, suggesting that enhanced investment in pest observations will reveal the hidden threat of crop pests and pathogens.
Sun‐induced freckling: ephelides and solar lentigines
Authors: Praetorius Christian , Sturm Richard A. , Steingrimsson Eirikur 
Published: February 2014

SummaryFreckles, the lay term for ephelides and lentigines, are important pigmentation characteristics observed in humans. Both are affected by sunlight; ephelides are largely genetically determined but induced by sunlight, whereas lentigines are induced by sun exposure and photodamage of the skin. However, despite being commonly observed, we know very little about them. Here, we review the current status of knowledge about freckles and propose a model for their formation.
Bilateral Congenital Entropion with Cutis Laxa
Authors: Al‐Faky Yasser H. , Salih Mustafa A. , Mubarak Mohammed , Al‐Rikabi Ammar C. 
Published: February 2014

AbstractCutis laxa is a rare connective tissue disorder characterized by redundant and pendulous skin due to a defect in the elastic fiber network. Two cases of entropion associated with cutis laxa have been reported, although entropion was due to elongation of the anterior lamella or horizontal lid laxity. Thorough systemic and ophthalmic evaluations were performed, as well as chart review for the perinatal period. Surgical correction of entropion through posterior tarsotomy was done. An infant boy with dysmorphic features and furrowing of the skin of the entire body without hyperelasticity, which is typical for cutis laxa, presented with bilateral congenital entropion. We report here for the first time a different etiology of congenital entropion with cutis laxa: the eyelashes were abnormally directed due to the unusual location of their roots, which were embedded within the tarsus. Moreover, this is the only case of cutis laxa with congenital entropion involving both upper and lower eyelids. Congenital entropion can be associated with cutis laxa. Although elongation of the anterior lamella and horizontal lid laxity predispose to such an entropion, abnormal location of the roots of the eyelashes might be encountered and marginal eyelid rotation surgery is indicated.
Differential accumulation of γ‐aminobutyric acid in elicited cells of two rice cultivars showing contrasting sensitivity to the blast pathogen
Authors: Forlani G. , Bertazzini M. , Giberti S. 
Published: February 2014

AbstractIntracellular free amino acid pools were quantified in suspension cultured cells of a blast‐sensitive and a blast‐resistant rice genotype at increasing times after treatment with Magnaporthe oryzae cell wall hydrolysates. Besides some expected variations in free phenylalanine, a remarkable early increase of γ‐aminobutyric acid (GABA) levels was evident in both cultivars. Glutamate decarboxylase activity and protein levels were unaffected. GABA homeostasis was recovered in the sensitive cultivar 48 h after the treatment. In contrast, a further GABA accumulation and a general increase of most amino acids was found at this later stage in the resistant genotype, which showed a larger decrease in cell viability as a consequence of elicitor addition. Data support a recently hypothesised role of GABA metabolism in the plant response to fungal pathogens.
Crowdsourcing and regulatory reviews: A new way of challenging red tape in British government?
Authors: Lodge Martin , Wegrich Kai 
Published: February 2014

AbstractMuch has been said about the appeal of digital government devices to enhance consultation on rulemaking. This paper explores the most ambitious attempt by the UK central government so far to draw on “crowdsourcing” to consult and act on regulatory reform, the “Red Tape Challenge.” We find that the results of this exercise do not represent any major change to traditional challenges to consultation processes. Instead, we suggest that the extensive institutional arrangements for crowdsourcing were hardly significant in informing actual policy responses: neither the tone of the crowdsourced comments, the direction of the majority views, nor specific comments were seen to matter. Instead, it was processes within the executive that shaped the overall governmental responses to this initiative. The findings, therefore, provoke wider debates about the use of social media in rulemaking and consultation exercises.