bluuebunny/crossref_metadata_2025_split huggingface dataset:
Do clinical features of Lesch‐Nyhan disease correlate more closely with hypoxanthine or guanine recycling?
Authors: Schretlen David J. , Callon Wynne , Ward Rebecca E. , Fu Rong , Ho Tiffany , Gordon Barry , Harris James C. , Jinnah H. A. 
Published: June 2015

AbstractLesch‐Nyhan disease (LND) is a rare, X‐linked recessive neurodevelopmental disorder caused by deficiency of hypoxanthine‐guanine phosphoribosyltransferase (HGprt), an enzyme in the purine salvage pathway. HGprt has two functions; it recycles hypoxanthine and guanine. Which of these two functions is more relevant for pathogenesis is unclear because some evidence points to hypoxanthine recycling, but other evidence points to guanine recycling. In this study, we selectively assayed hypoxanthine (Hprt) and guanine (Gprt) recycling in skin fibroblasts from 17 persons with LND, 11 with an attenuated variant of the disease (LNV), and 19 age‐, sex‐, and race‐matched healthy controls (HC). Activity levels of both enzymes differed across groups (p < 0.0001), but only Gprt distinguished patients with LND from those with LNV (p < 0.05). Gprt also showed slightly stronger correlations than Hprt with 13 of 14 measures of the clinical phenotype, including the severity of dystonia, cognitive impairment, and behavioral abnormalities. These findings suggest that loss of guanine recycling might be more closely linked to the LND/LNV phenotype than loss of hypoxanthine recycling.
Stereotactic Radiosurgery for Metastases in Eloquent Central Brain Locations
Authors: Hsu Fred , Nichol Alan , Ma Roy , Kouhestani Para , Toyota Brian , McKenzie Michael 
Published: June 2015

AbstractBackground: To examine stereotactic radiosurgery (SRS) following whole brain radiotherapy for metastases in eloquent, central brain locations: brainstem, thalamus, and basal ganglia. Methods: We conducted a retrospective review of patients with metastases in eloquent, central brain locations who were treated with SRS between January 2000 and April 2012. All patients had whole brain radiotherapy. Patients eligible for SRS had one to three brain metastases, metastasis size ≤4 cm, and Karnofsky performance status ≥70. Local progression-free survival and overall survival were calculated using the Kaplan-Meier method. Results: For 24 patients, the median age was 50 years (range, 36-73). Metastases by location were: 11 brainstem, 9 thalamus, and 5 basal ganglia. The median metastasis size was 15 mm (range, 2-33) and the median SRS dose prescription was 15 Gy (range, 12-24). The median local progression-free survival was 13.7 months and median overall survival was 16.4 months. Compared with a cohort of 188 patients with noneloquent brain metastases receiving a median dose of 24 Gy, overall survival of 10.8 months was not significantly different (p=0.16). The only symptomatic complication was grade 2 headache in 8.3%. Asymptomatic adverse radiologic events were radionecrosis in two (8.3%), peritumoural edema in four (16.7%), and hemorrhage in one patient (4.2%). Conclusions: Lower SRS marginal doses do not appear to compromise survival in patients with eloquently located brain metastases compared with higher doses for other brain metastases, with minimal symptomatic complications.
Law, Regulation, and Safety Crime: Exploring the Boundaries of Criminalizing Powerful Corporate Actors
Authors: Bittle Steven , Snider Laureen 
Published: June 2015

AbstractThis article interrogates the laws that govern safety crimes, harmful but typically unintentional acts of negligence that occur in the production of goods and services. Acts that injure employees at work are commonly depicted in legal discourses as accidents and penalized through administrative laws, although other negligent acts such as driving offences causing injury or death are treated as potentially criminal events. Through a discourse analysis of legal and regulatory texts and documents, the authors argue that the constitution of workplace safety crime is rooted in complex historical factors that shape state responses to corporate wrongdoing. This article documents the roots of this “common sense” view of workplace crime, empirically focusing on Canadian corporate negligence law, and concludes with tentative strategies of resistance and change.
EVALUATION OF PATIENT INVOLVEMENT IN A HEALTH TECHNOLOGY ASSESSMENT
Authors: Dipankui Mylène Tantchou , Gagnon Marie-Pierre , Desmartis Marie , Légaré France , Piron Florence , Gagnon Johanne , Rhiands Marc , Coulombe Martin 
Published: June 2015

Objectives: We sought to evaluate patient involvement (consultation and direct participation) in the assessment of alternative measures to restraint and seclusion among adults in short-term hospital wards (in psychiatry) and long-term care facilities for the elderly.Methods: We conducted individual semi-structured interviews with thirteen stakeholders: caregivers, healthcare managers, patient representatives, health technology assessment (HTA) unit members, researchers, and members of the local HTA scientific committee. Data were collected until saturation. We carried out content analysis of two HTA reports and four other documents that were produced in relation with this HTA. We also used field notes taken during formal meetings and informal discussions with stakeholders. We performed thematic analysis based on a framework for assessing patient involvement in HTA. We then triangulated data.Results: For the majority of interviewees, patient consultation enriched the content of the HTA report and its recommendations. This also made it possible to suggest other alternatives that could reduce the use of restraint and seclusion and helped confirm some views and comments from healthcare professionals consulted in this HTA. The direct participation of patient representatives enabled rephrasing of some findings so as to bring the patient perspective to the HTA report.Conclusions: Patient consultation was seen as having directly influenced the content of the HTA report while direct participation made it possible to rephrase some findings. This is one of few studies to assess the impact of patient involvement in HTA and more such studies are needed to identify the best ways to improve the input of such involvement.
INTEGRATING ETHICS IN HEALTH TECHNOLOGY ASSESSMENT: MANY WAYS TO ROME
Authors: Hofmann Björn , Oortwijn Wija , Bakke Lysdahl Kristin , Refolo Pietro , Sacchini Dario , van der Wilt Gert Jan , Gerhardus Ansgar 
Published: June 2015

Objectives: The aim of this study was to identify and discuss appropriate approaches to integrate ethical inquiry in health technology assessment (HTA).Methods: The key question is how ethics can be integrated in HTA. This is addressed in two steps: by investigating what it means to integrate ethics in HTA, and by assessing how suitable the various methods in ethics are to be integrated in HTA according to these meanings of integration.Results: In the first step, we found that integrating ethics can mean that ethics is (a) subsumed under or (b) combined with other parts of the HTA process; that it can be (c) coordinated with other parts; or that (d) ethics actively interacts and changes other parts of the HTA process. For the second step, we found that the various methods in ethics have different merits with respect to the four conceptions of integration in HTA.Conclusions: Traditional approaches in moral philosophy tend to be most suited to be subsumed or combined, while processual approaches being close to the HTA or implementation process appear to be most suited to coordinated and interactive types of integration. The article provides a guide for choosing the ethics approach that appears most appropriate for the goals and process of a particular HTA.
Prevalent high-risk HPV infection and vaginal microbiota in Nigerian women
Authors: DARENG E. O. , MA B. , FAMOOTO A. O. , AKAROLO-ANTHONY S. N. , OFFIONG R. A. , OLANIYAN O. , DAKUM P. S. , WHEELER C. M. , FADROSH D. , YANG H. , GAJER P. , BROTMAN R. M. , RAVEL J. , ADEBAMOWO C. A. 
Published: June 2015

SUMMARYIn this study, we evaluated the association between high-risk human papillomavirus (hrHPV) and the vaginal microbiome. Participants were recruited in Nigeria between April and August 2012. Vaginal bacterial composition was characterized by deep sequencing of barcoded 16S rRNA gene fragments (V4) on Illumina MiSeq and HPV was identified using the Roche Linear Array®HPV genotyping test. We used exact logistic regression models to evaluate the association between community state types (CSTs) of vaginal microbiota and hrHPV infection, weighted UniFrac distances to compare the vaginal microbiota of individuals with prevalent hrHPV to those without prevalent hrHPV infection, and the Linear Discriminant Analysis effect size (LEfSe) algorithm to characterize bacteria associated with prevalent hrHPV infection. We observed four CSTs: CST IV-B with a low relative abundance ofLactobacillusspp. in 50% of participants; CST III (dominated byL. iners) in 39·2%; CST I (dominated byL. crispatus) in 7·9%; and CST VI (dominated by proteobacteria) in 2·9% of participants. LEfSe analysis suggested an association between prevalent hrHPV infection and a decreased abundance ofLactobacillussp. with increased abundance of anaerobes particularly of the generaPrevotellaandLeptotrichiain HIV-negative women (P< 0·05). These results are hypothesis generating and further studies are required.
Aspirin delays mesothelioma growth by inhibiting HMGB1-mediated tumor progression
Authors: Yang H , Pellegrini L , Napolitano A , Giorgi C , Jube S , Preti A , Jennings C J , De Marchis F , Flores E G , Larson D , Pagano I , Tanji M , Powers A , Kanodia S , Gaudino G , Pastorino S , Pass H I , Pinton P , Bianchi M E , Carbone M 
Published: June 2015

AbstractHigh-mobility group box 1 (HMGB1) is an inflammatory molecule that has a critical role in the initiation and progression of malignant mesothelioma (MM). Aspirin (acetylsalicylic acid, ASA) is the most widely used nonsteroidal anti-inflammatory drug that reduces the incidence, metastatic potential and mortality of many inflammation-induced cancers. We hypothesized that ASA may exert anticancer properties in MM by abrogating the carcinogenic effects of HMGB1. Using HMGB1-secreting and -non-secreting human MM cell lines, we determined whether aspirin inhibited the hallmarks of HMGB1-induced MM cell growth in vitro and in vivo. Our data demonstrated that ASA and its metabolite, salicylic acid (SA), inhibit motility, migration, invasion and anchorage-independent colony formation of MM cells via a novel HMGB1-mediated mechanism. ASA/SA, at serum concentrations comparable to those achieved in humans taking therapeutic doses of aspirin, and BoxA, a specific inhibitor of HMGB1, markedly reduced MM growth in xenograft mice and significantly improved survival of treated animals. The effects of ASA and BoxA were cyclooxygenase-2 independent and were not additive, consistent with both acting via inhibition of HMGB1 activity. Our findings provide a rationale for the well documented, yet poorly understood antitumorigenic activity of aspirin, which we show proceeds via HMGB1 inhibition. Moreover, the use of BoxA appears to allow a more efficient HMGB1 targeting while eluding the known gastrointestinal side effects of ASA. Our findings are directly relevant to MM. Given the emerging importance of HMGB1 and its tumor-promoting functions in many cancer types, and of aspirin in cancer prevention and therapy, our investigation is poised to provide broadly applicable information.
Auditory cortex controls sound-driven innate defense behaviour through corticofugal projections to inferior colliculus
Authors: Xiong Xiaorui R. , Liang Feixue , Zingg Brian , Ji Xu-ying , Ibrahim Leena A. , Tao Huizhong W. , Zhang Li I. 
Published: June 2015

AbstractDefense against environmental threats is essential for animal survival. However, the neural circuits responsible for transforming unconditioned sensory stimuli and generating defensive behaviours remain largely unclear. Here, we show that corticofugal neurons in the auditory cortex (ACx) targeting the inferior colliculus (IC) mediate an innate, sound-induced flight behaviour. Optogenetic activation of these neurons, or their projection terminals in the IC, is sufficient for initiating flight responses, while the inhibition of these projections reduces sound-induced flight responses. Corticocollicular axons monosynaptically innervate neurons in the cortex of the IC (ICx), and optogenetic activation of the projections from the ICx to the dorsal periaqueductal gray is sufficient for provoking flight behaviours. Our results suggest that ACx can both amplify innate acoustic-motor responses and directly drive flight behaviours in the absence of sound input through corticocollicular projections to ICx. Such corticofugal control may be a general feature of innate defense circuits across sensory modalities.
AAV-mediated in vivo functional selection of tissue-protective factors against ischaemia
Authors: Ruozi Giulia , Bortolotti Francesca , Falcione Antonella , Dal Ferro Matteo , Ukovich Laura , Macedo Antero , Zentilin Lorena , Filigheddu Nicoletta , Cappellari Gianluca Gortan , Baldini Giovanna , Zweyer Marina , Barazzoni Rocco , Graziani Andrea , Zacchigna Serena , Giacca Mauro 
Published: June 2015

AbstractFunctional screening of expression libraries in vivo would offer the possibility of identifying novel biotherapeutics without a priori knowledge of their biochemical function. Here we describe a procedure for the functional selection of tissue-protective factors based on the in vivo delivery of arrayed cDNA libraries from the mouse secretome using adeno-associated virus (AAV) vectors. Application of this technique, which we call FunSel, in the context of acute ischaemia, revealed that the peptide ghrelin protects skeletal muscle and heart from ischaemic damage. When delivered to the heart using an AAV9 vector, ghrelin markedly reduces infarct size and preserves cardiac function over time. This protective activity associates with the capacity of ghrelin to sustain autophagy and remove dysfunctional mitochondria after myocardial infarction. Our findings describe an innovative tool to identify biological therapeutics and reveal a novel role of ghrelin as an inducer of myoprotective autophagy.
Somatic CRISPR/Cas9-mediated tumour suppressor disruption enables versatile brain tumour modelling
Authors: Zuckermann Marc , Hovestadt Volker , Knobbe-Thomsen Christiane B. , Zapatka Marc , Northcott Paul A. , Schramm Kathrin , Belic Jelena , Jones David T. W. , Tschida Barbara , Moriarity Branden , Largaespada David , Roussel Martine F. , Korshunov Andrey , Reifenberger Guido , Pfister Stefan M. , Lichter Peter , Kawauchi Daisuke , Gronych Jan 
Published: June 2015

AbstractIn vivo functional investigation of oncogenes using somatic gene transfer has been successfully exploited to validate their role in tumorigenesis. For tumour suppressor genes this has proven more challenging due to technical aspects. To provide a flexible and effective method for investigating somatic loss-of-function alterations and their influence on tumorigenesis, we have established CRISPR/Cas9-mediated somatic gene disruption, allowing for in vivo targeting of TSGs. Here we demonstrate the utility of this approach by deleting single (Ptch1) or multiple genes (Trp53, Pten, Nf1) in the mouse brain, resulting in the development of medulloblastoma and glioblastoma, respectively. Using whole-genome sequencing (WGS) we characterized the medulloblastoma-driving Ptch1 deletions in detail and show that no off-targets were detected in these tumours. This method provides a fast and convenient system for validating the emerging wealth of novel candidate tumour suppressor genes and the generation of faithful animal models of human cancer.
The molecular size of the extra-membrane domain influences the diffusion of the GPI-anchored VSG on the trypanosome plasma membrane
Authors: Hartel Andreas J. W. , Glogger Marius , Guigas Gernot , Jones Nicola G. , Fenz Susanne F. , Weiss Matthias , Engstler Markus 
Published: June 2015

AbstractA plethora of proteins undergo random and passive diffusion in biological membranes. While the contribution of the membrane-embedded domain to diffusion is well established, the potential impact of the extra-membrane protein part has been largely neglected. Here, we show that the molecular length influences the diffusion coefficient of GPI-anchored proteins: smaller proteins diffuse faster than larger ones. The distinct diffusion properties of differently sized membrane proteins are biologically relevant. The variant surface glycoprotein (VSG) of African trypanosomes, for example, is sized for an effective diffusion-driven randomization on the cell surface, a process that is essential for parasite virulence. We propose that the molecular sizes of proteins dominating the cell surfaces of other eukaryotic pathogens may also be related to diffusion-limited functions.
Emergence of scale-free characteristics in socio-ecological systems with bounded rationality
Authors: Kasthurirathna Dharshana , Piraveenan Mahendra 
Published: June 2015

AbstractSocio–ecological systems are increasingly modelled by games played on complex networks. While the concept of Nash equilibrium assumes perfect rationality, in reality players display heterogeneous bounded rationality. Here we present a topological model of bounded rationality in socio-ecological systems, using the rationality parameter of the Quantal Response Equilibrium. We argue that system rationality could be measured by the average Kullback–-Leibler divergence between Nash and Quantal Response Equilibria and that the convergence towards Nash equilibria on average corresponds to increased system rationality. Using this model, we show that when a randomly connected socio-ecological system is topologically optimised to converge towards Nash equilibria, scale-free and small world features emerge. Therefore, optimising system rationality is an evolutionary reason for the emergence of scale-free and small-world features in socio-ecological systems. Further, we show that in games where multiple equilibria are possible, the correlation between the scale-freeness of the system and the fraction of links with multiple equilibria goes through a rapid transition when the average system rationality increases. Our results explain the influence of the topological structure of socio–ecological systems in shaping their collective cognitive behaviour and provide an explanation for the prevalence of scale-free and small-world characteristics in such systems.
Identification of the Conformational transition pathway in PIP2 Opening Kir Channels
Authors: Li Junwei , Lü Shouqin , Liu Yuzhi , Pang Chunli , Chen Yafei , Zhang Suhua , Yu Hui , Long Mian , Zhang Hailin , Logothetis Diomedes E. , Zhan Yong , An Hailong 
Published: June 2015

AbstractThe gating of Kir channels depends critically on phosphatidylinositol 4,5-bisphosphate (PIP2), but the detailed mechanism by which PIP2 regulates Kir channels remains obscure. Here, we performed a series of Targeted molecular dynamics simulations on the full-length Kir2.1 channel and, for the first time, were able to achieve the transition from the closed to the open state. Our data show that with the upward motion of the cytoplasmic domain (CTD) the structure of the C-Linker changes from a loop to a helix. The twisting of the C-linker triggers the rotation of the CTD, which induces a small downward movement of the CTD and an upward motion of the slide helix toward the membrane that pulls the inner helix gate open. At the same time, the rotation of the CTD breaks the interaction between the CD- and G-loops thus releasing the G-loop. The G-loop then bounces away from the CD-loop, which leads to the opening of the G-loop gate and the full opening of the pore. We identified a series of interaction networks, between the N-terminus, CD loop, C linker and G loop one by one, which exquisitely regulates the global conformational changes during the opening of Kir channels by PIP2.
Adiponectin exacerbates collagen-induced arthritis via enhancing Th17 response and prompting RANKL expression
Authors: Sun Xiaoxuan , Feng Xiaoke , Tan Wenfeng , Lin Na , Hua Minhui , Wei Yu , Wang Fang , Li Ningli , Zhang Miaojia 
Published: June 2015

AbstractWe previously reported adiponectin (AD) is highly expressed in the inflamed synovial joint tissue and correlates closely with progressive bone erosion in Rheumatoid arthritis (RA) patients. Here, we investigate the role of adiponectin in regulating Th17 response and the expression of receptor activator of nuclear factor-κB ligand (RANKL) in mice with CIA mice by intraarticularly injection of adiponectin into knee joints on day 17, day 20 and day 23 post first collagen immunization. The increased adiponectin expression was found in inflamed joint tissue of collagen-induced arthritis (CIA) mice. Adiponectin injection resulted in an earlier onset of arthritis, an aggravated arthritic progression, more severe synovial hyperplasia, bone erosion and osteoporosis in CIA mice. CD4+IL-17+ Th17 cells, IL-17 mRNA and RANKL mRNA expression were markedly increased in the joint tissue of adiponectin treated CIA mice. Moreover, adiponectin treatment markedly enhanced Th17 cell generation from naive CD4+ T cells in vitro, which accompanied by the high expression of Th17 transcription factor ROR-γt and Th17 cytokine genes included IL-22 and IL-23. This study reveals a novel effect of adiponectin in exacerbating CIA progression by enhancing Th17 cell response and RANKL expression.
Whole genome sequencing and analysis of Swarna, a widely cultivated indica rice variety with low glycemic index
Authors: Rathinasabapathi Pasupathi , Purushothaman Natarajan , VL Ramprasad , Parani Madasamy 
Published: June 2015

AbstractSwarna is a popular cultivated indica rice variety with low glycemic index (GI) but its genetic basis is not known. The whole genome of Swarna was sequenced using Illumina’s paired-end technology and the reads were mapped to the Nipponbare reference genome. Overall, 65,984 non-synonymous SNPs were identified in 20,350 genes and in silico analysis predicted that 4,847 of them in 2,214 genes may have deleterious effect on protein functions. Polymorphisms were found in all the starch biosynthesis genes, except the gene for branching enzyme IIa. It was found that T/G SNP at position 246, ‘A’ at position 2,386 and ‘C’ at position 3,378 in the granule bound starch synthase I gene and C/T SNP at position 1,188 in the glucose-6-phosphate translocator gene may contribute to the low GI phenotype in Swarna. All these variants were also found in the genome of another low GI indica rice variety from Columbia, Fedearroz 50. The whole genome analysis of Swarna helped to understand the genetic basis of GI in rice, which is a complex trait involving multiple factors.