bluuebunny/crossref_metadata_2025_split huggingface dataset:
UNDERSTANDING VARIATIONS IN RELATIVE EFFECTIVENESS: A HEALTH PRODUCTION APPROACH
Authors: Towse Adrian , Jonsson Bengt , McGrath Clare , Mason Anne , Puig-Peiro Ruth , Mestre-Ferrandiz Jorge , Pistollato Michele , Devlin Nancy 
Published: February 2016

Background: Relative effectiveness has become a key concern of health policy. In Europe, this is because of the need for early information to guide reimbursement and funding decisions about new medical technologies. However, ways that effectiveness (does it work?) and efficacy (can it work?) might differ across health systems are poorly understood.Methods: This study proposes an analytical framework, drawing on production function theory, to systematically identify and quantify the determinants of relative effectiveness and sources of variation between populations and healthcare systems. We consider how methods such as stochastic frontier analysis and data envelopment analysis using a Malmquist productivity index could in principle be used to generate evidence on, and improve understanding about, the sources of variation in relative effectiveness between countries and over time.Results: Better evidence on factors driving relative effectiveness could: inform decisions on how to best use a new technology to maximum effectiveness; establish the need if any for follow-up post-launch studies, and provide evidence of the impact of new health technologies on outcomes in different healthcare systems.Conclusions: The health production function approach for assessment of relative effectiveness is complementary to traditional experimental and observational studies, focusing on identifying, collecting, and analyzing data at the national level, enabling comparisons to take place. There is a strong case for exploring the use of this approach to better understand the impact of new medicines and devices for improvements in health outcomes.
Exposure to viral and bacterial pathogens among Soay sheep (Ovis aries) of the St Kilda archipelago
Authors: GRAHAM A. L. , NUSSEY D. H. , LLOYD-SMITH J. O. , LONGBOTTOM D. , MALEY M. , PEMBERTON J. M. , PILKINGTON J. G. , PRAGER K. C. , SMITH L. , WATT K. A. , WILSON K. , McNEILLY T. N. , BRÜLISAUER F. 
Published: February 2016

SUMMARYWe assessed evidence of exposure to viruses and bacteria in an unmanaged and long-isolated population of Soay sheep (Ovis aries) inhabiting Hirta, in the St Kilda archipelago, 65 km west of Benbecula in the Outer Hebrides of Scotland. The sheep harbour many metazoan and protozoan parasites but their exposure to viral and bacterial pathogens is unknown. We tested for herpes viral DNA in leucocytes and found that 21 of 42 tested sheep were infected with ovine herpesvirus 2 (OHV-2). We also tested 750 plasma samples collected between 1997 and 2010 for evidence of exposure to seven other viral and bacterial agents common in domestic Scottish sheep. We found evidence of exposure toLeptospiraspp., with overall seroprevalence of 6·5%. However, serological evidence indicated that the population had not been exposed to border disease, parainfluenza, maedi-visna, or orf viruses, nor toChlamydia abortus. Some sheep tested positive for antibodies againstMycobacterium aviumsubsp.paratuberculosis(MAP) but, in the absence of retrospective faecal samples, the presence of this infection could not be confirmed. The roles of importation, the pathogen–host interaction, nematode co-infection and local transmission warrant future investigation, to elucidate the transmission ecology and fitness effects of the few viral and bacterial pathogens on Hirta.
Constitutive p53 heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors of BCL-xL
Authors: Le Pen J , Laurent M , Sarosiek K , Vuillier C , Gautier F , Montessuit S , Martinou J C , Letaï A , Braun F , Juin P P 
Published: February 2016

AbstractProapoptotic molecules directly targeting the BCL-2 family network are promising anticancer therapeutics, but an understanding of the cellular stress signals that render them effective is still elusive. We show here that the tumor suppressor p53, at least in part by transcription independent mechanisms, contributes to cell death induction and full activation of BAX by BH3 mimetic inhibitors of BCL-xL. In addition to mildly facilitating the ability of compounds to derepress BAX from BCL-xL, p53 also provides a death signal downstream of anti-apoptotic proteins inhibition. This death signal cooperates with BH3-induced activation of BAX and it is independent from PUMA, as enhanced p53 can substitute for PUMA to promote BAX activation in response to BH3 mimetics. The acute sensitivity of mitochondrial priming to p53 revealed here is likely to be critical for the clinical use of BH3 mimetics.
Humans and seasonal climate variability threaten large-bodied coral reef fish with small ranges
Authors: Mellin C. , Mouillot D. , Kulbicki M. , McClanahan T. R. , Vigliola L. , Bradshaw C. J. A. , Brainard R. E. , Chabanet P. , Edgar G. J. , Fordham D. A. , Friedlander A. M. , Parravicini V. , Sequeira A. M. M. , Stuart-Smith R. D. , Wantiez L. , Caley M. J. 
Published: February 2016

AbstractCoral reefs are among the most species-rich and threatened ecosystems on Earth, yet the extent to which human stressors determine species occurrences, compared with biogeography or environmental conditions, remains largely unknown. With ever-increasing human-mediated disturbances on these ecosystems, an important question is not only how many species can inhabit local communities, but also which biological traits determine species that can persist (or not) above particular disturbance thresholds. Here we show that human pressure and seasonal climate variability are disproportionately and negatively associated with the occurrence of large-bodied and geographically small-ranging fishes within local coral reef communities. These species are 67% less likely to occur where human impact and temperature seasonality exceed critical thresholds, such as in the marine biodiversity hotspot: the Coral Triangle. Our results identify the most sensitive species and critical thresholds of human and climatic stressors, providing opportunity for targeted conservation intervention to prevent local extinctions.
Marine mammals harbor unique microbiotas shaped by and yet distinct from the sea
Authors: Bik Elisabeth M. , Costello Elizabeth K. , Switzer Alexandra D. , Callahan Benjamin J. , Holmes Susan P. , Wells Randall S. , Carlin Kevin P. , Jensen Eric D. , Venn-Watson Stephanie , Relman David A. 
Published: February 2016

AbstractMarine mammals play crucial ecological roles in the oceans, but little is known about their microbiotas. Here we study the bacterial communities in 337 samples from 5 body sites in 48 healthy dolphins and 18 healthy sea lions, as well as those of adjacent seawater and other hosts. The bacterial taxonomic compositions are distinct from those of other mammals, dietary fish and seawater, are highly diverse and vary according to body site and host species. Dolphins harbour 30 bacterial phyla, with 25 of them in the mouth, several abundant but poorly characterized Tenericutes species in gastric fluid and a surprisingly paucity of Bacteroidetes in distal gut. About 70% of near-full length bacterial 16S ribosomal RNA sequences from dolphins are unique. Host habitat, diet and phylogeny all contribute to variation in marine mammal distal gut microbiota composition. Our findings help elucidate the factors structuring marine mammal microbiotas and may enhance monitoring of marine mammal health.
Epidermal β-catenin activation remodels the dermis via paracrine signalling to distinct fibroblast lineages
Authors: Lichtenberger Beate M. , Mastrogiannaki Maria , Watt Fiona M. 
Published: February 2016

AbstractSustained epidermal Wnt/β-catenin signalling expands the stem cell compartment and induces ectopic hair follicles (EFs). This is accompanied by extensive fibroblast proliferation and extracellular matrix (ECM) remodelling in the underlying dermis. Here we show that epidermal Hedgehog (Hh) and Transforming growth factor-beta (TGF-β) signalling mediate the dermal changes. Pharmacological inhibition or genetic deletion of these pathways prevents β-catenin-induced dermal reprogramming and EF formation. Epidermal Shh stimulates proliferation of the papillary fibroblast lineage, whereas TGF-β2 controls proliferation, differentiation and ECM production by reticular fibroblasts. Hh inhibitors do not affect TGF-β target gene expression in reticular fibroblasts, and TGF-β inhibition does not prevent Hh target gene induction in papillary fibroblasts. However, when Hh signalling is inhibited the reticular dermis does not respond to epidermal β-catenin activation. We conclude that the dermal response to epidermal Wnt/β-catenin signalling depends on distinct fibroblast lineages responding to different paracrine signals.
Diapause is associated with a change in the polarity of secretion of insulin-like peptides
Authors: Matsunaga Yohei , Honda Yoko , Honda Shuji , Iwasaki Takashi , Qadota Hiroshi , Benian Guy M. , Kawano Tsuyoshi 
Published: February 2016

AbstractThe insulin/IGF-1 signalling (IIS) pathway plays an important role in the regulation of larval diapause, the long-lived growth arrest state called dauer arrest, in Caenorhabditis elegans. In this nematode, 40 insulin-like peptides (ILPs) have been identified as putative ligands of the IIS pathway; however, it remains unknown how ILPs modulate larval diapause. Here we show that the secretory polarity of INS-35 and INS-7, which suppress larval diapause, is changed in the intestinal epithelial cells at larval diapause. These ILPs are secreted from the intestine into the body cavity during larval stages. In contrast, they are secreted into the intestinal lumen and degraded during dauer arrest, only to be secreted into the body cavity again when the worms return to developmental growth. The process that determines the secretory polarity of INS-35 and INS-7, thus, has an important role in the modulation of larval diapause.
Liver-derived ketone bodies are necessary for food anticipation
Authors: Chavan Rohit , Feillet Céline , Costa Sara S. Fonseca , Delorme James E. , Okabe Takashi , Ripperger Jürgen A. , Albrecht Urs 
Published: February 2016

AbstractThe circadian system has endowed animals with the ability to anticipate recurring food availability at particular times of day. As daily food anticipation (FA) is independent of the suprachiasmatic nuclei, the central pacemaker of the circadian system, questions arise of where FA signals originate and what role components of the circadian clock might play. Here we show that liver-specific deletion ofPer2in mice abolishes FA, an effect that is rescued by viral overexpression ofPer2in the liver. RNA sequencing indicates thatPer2regulates β-hydroxybutyrate (βOHB) production to induce FA leading to the conclusion that liverPer2is important for this process. Unexpectedly, we show that FA originates in the liver and not in the brain. However, manifestation of FA involves processing of the liver-derived βOHB signal in the brain, indicating that the food-entrainable oscillator is not located in a single tissue but is of systemic nature.
Steric interactions lead to collective tilting motion in the ribosome during mRNA–tRNA translocation
Authors: Nguyen Kien , Whitford Paul C. 
Published: February 2016

AbstractTranslocation of mRNA and tRNA through the ribosome is associated with large-scale rearrangements of the head domain in the 30S ribosomal subunit. To elucidate the relationship between 30S head dynamics and mRNA–tRNA displacement, we apply molecular dynamics simulations using an all-atom structure-based model. Here we provide a statistical analysis of 250 spontaneous transitions between the A/P–P/E and P/P–E/E ensembles. Consistent with structural studies, the ribosome samples a chimeric ap/P–pe/E intermediate, where the 30S head is rotated ∼18°. It then transiently populates a previously unreported intermediate ensemble, which is characterized by a ∼10° tilt of the head. To identify the origins of head tilting, we analyse 781 additional simulations in which specific steric features are perturbed. These calculations show that head tilting may be attributed to specific steric interactions between tRNA and the 30S subunit (PE loop and protein S13). Taken together, this study demonstrates how molecular structure can give rise to large-scale collective rearrangements.
Seamless growth of a supramolecular carpet
Authors: Kim Ju-Hyung , Ribierre Jean-Charles , Yang Yu Seok , Adachi Chihaya , Kawai Maki , Jung Jaehoon , Fukushima Takanori , Kim Yousoo 
Published: February 2016

AbstractOrganic/metal interfaces play crucial roles in the formation of intermolecular networks on metal surfaces and the performance of organic devices. Although their purity and uniformity have profound effects on the operation of organic devices, the formation of organic thin films with high interfacial uniformity on metal surfaces has suffered from the intrinsic limitation of molecular ordering imposed by irregular surface structures. Here we demonstrate a supramolecular carpet with widely uniform interfacial structure and high adaptability on a metal surface via a one-step process. The high uniformity is achieved with well-balanced interfacial interactions and site-specific molecular rearrangements, even on a pre-annealed amorphous gold surface. Co-existing electronic structures show selective availability corresponding to the energy region and the local position of the system. These findings provide not only a deeper insight into organic thin films with high structural integrity, but also a new way to tailor interfacial geometric and electronic structures.
Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease
Authors: Hyötyläinen Tuulia , Jerby Livnat , Petäjä Elina M. , Mattila Ismo , Jäntti Sirkku , Auvinen Petri , Gastaldelli Amalia , Yki-Järvinen Hannele , Ruppin Eytan , Orešič Matej 
Published: February 2016

AbstractNon-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switch from lactate to glycerol as substrate for gluconeogenesis, indicating an intricate balance of exacerbated opposite metabolic processes in glycemic regulation. These changes were associated with reduced metabolic adaptability on a network level in the sense that liver fat accumulation puts increasing demands on the liver to adaptively regulate metabolic responses to maintain basic liver functions. We propose that failure to meet excessive metabolic challenges coupled with reduced metabolic adaptability may lead to a vicious pathogenic cycle leading to the co-morbidities of NAFLD.
Reducing antibiotic prescriptions for respiratory tract infections in family practice: results of a cluster randomized controlled trial evaluating a multifaceted peer-group-based intervention
Authors: Vervloet Marcia , Meulepas Marianne A , Cals Jochen W L , Eimers Mariëtta , van der Hoek Lucas S , van Dijk Liset 
Published: February 2016

AbstractIrrational antibiotic use for respiratory tract infections (RTI) is a major driver of bacterial resistance. The aim of this study was to evaluate the effect of a multifaceted peer-group based intervention aiming to reduce RTI-related antibiotic prescriptions in family practice. This was a cluster randomized controlled trial with pre- and follow-up measurement. The intervention was implemented through PharmacoTherapy Audit Meetings (PTAM) in which family physicians (FPs) and pharmacists collaborate. Four PTAM groups received the intervention consisting of: (1) FP communication skills training, including communication about delayed prescribing; (2) implementation of antibiotic prescribing agreements in FPs’ Electronic Prescribing Systems; (3) quarterly feedback figures for FPs. Four other PTAM groups were matched controls. Primary outcome measure was the number of RTI-related antibiotic prescriptions after the intervention, assessed with multilevel linear regression analyses. Total number and number of prescriptions stratified by age (under/over 12 years) were analysed. At baseline, the average total number of RTI-related antibiotic prescriptions per 1,000 patients was 207.9 and 176.7 in the intervention and control PTAM groups, respectively. At follow-up, FPs in both the intervention and control groups prescribed significantly less antibiotics. For adolescents and adults, the drop in number of antibiotic prescription was significantly larger in the intervention groups (−27.8 per 1,000 patients) than the control groups (−7.2 per 1,000 patients; P<0.05). This multifaceted peer-group-based intervention was effective in reducing the number of RTI-related antibiotic prescriptions for adolescents and adults. To affect antibiotic prescribing in children other methods are needed.
Interpersonal interactions and empathy modulate perception of threat and defensive responses
Authors: Fossataro C. , Sambo C. F. , Garbarini F. , Iannetti G. D. 
Published: February 2016

AbstractThe defensive peripersonal space (DPPS) is a vital “safety margin” surrounding the body. When a threatening stimulus is delivered inside the DPPS, subcortical defensive responses like the hand-blink reflex (HBR) are adjusted depending on the perceived threat content. In three experiments, we explored whether and how defensive responses are affected by the interpersonal interaction within the DPPS of the face. In Experiment 1, we found that the HBR is enhanced when the threat is brought close to the face not only by one’s own stimulated hand, but also by another person’s hand, although to a significantly lesser extent. In Experiments 2 and 3, we found that the HBR is also enhanced when the hand of the participant enters the DPPS of another individual, either in egocentric or in allocentric perspective. This enhancement is larger in participants with strong empathic tendency when the other individual is in a third person perspective. These results indicate that interpersonal interactions shape perception of threat and defensive responses. These effects are particularly evident in individuals with greater tendency to having empathic concern to other people.
Curcumin Nanoformulation for Cervical Cancer Treatment
Authors: Zaman Mohd S. , Chauhan Neeraj , Yallapu Murali M. , Gara Rishi K. , Maher Diane M. , Kumari Sonam , Sikander Mohammed , Khan Sheema , Zafar Nadeem , Jaggi Meena , Chauhan Subhash C. 
Published: February 2016

AbstractCervical cancer is one of the most common cancers among women worldwide. Current standards of care for cervical cancer includes surgery, radiation and chemotherapy. Conventional chemotherapy fails to elicit therapeutic responses and causes severe systemic toxicity. Thus, developing a natural product based, safe treatment modality would be a highly viable option. Curcumin (CUR) is a well-known natural compound, which exhibits excellent anti-cancer potential by regulating many proliferative, oncogenic and chemo-resistance associated genes/proteins. However, due to rapid degradation and poor bioavailability, its translational and clinical use has been limited. To improve these clinically relevant parameters, we report a poly(lactic-co-glycolic acid) based curcumin nanoparticle formulation (Nano-CUR). This study demonstrates that in comparison to free CUR, Nano-CUR effectively inhibits cell growth, induces apoptosis and arrests the cell cycle in cervical cancer cell lines. Nano-CUR treatment modulated entities such as miRNAs, transcription factors and proteins associated with carcinogenesis. Moreover, Nano-CUR effectively reduced the tumor burden in a pre-clinical orthotopic mouse model of cervical cancer by decreasing oncogenic miRNA-21, suppressing nuclear β-catenin and abrogating expression of E6/E7 HPV oncoproteins including smoking compound benzo[a]pyrene (BaP) induced E6/E7 and IL-6 expression. These superior pre-clinical data suggest that Nano-CUR may be an effective therapeutic modality for cervical cancer.
Exploring Carbon Nanomaterial Diversity for Nucleation of Protein Crystals
Authors: Govada Lata , Leese Hannah S. , Saridakis Emmanuel , Kassen Sean , Chain Benny , Khurshid Sahir , Menzel Robert , Hu Sheng , Shaffer Milo S. P. , Chayen Naomi E. 
Published: February 2016

AbstractControlling crystal nucleation is a crucial step in obtaining high quality protein crystals for structure determination by X-ray crystallography. Carbon nanomaterials (CNMs) including carbon nanotubes, graphene oxide and carbon black provide a range of surface topographies, porosities and length scales; functionalisation with two different approaches, gas phase radical grafting and liquid phase reductive grafting, provide routes to a range of oligomer functionalised products. These grafted materials, combined with a range of controls, were used in a large-scale assessment of the effectiveness for protein crystal nucleation of 20 different carbon nanomaterials on five proteins. This study has allowed a direct comparison of the key characteristics of carbon-based nucleants: appropriate surface chemistry, porosity and/or roughness are required. The most effective solid system tested in this study, carbon black nanoparticles functionalised with poly(ethylene glycol) methyl ether of mean molecular weight 5000, provides a novel highly effective nucleant, that was able to induce crystal nucleation of four out of the five proteins tested at metastable conditions.
The discriminatory capability of existing scores to predict advanced colorectal neoplasia: a prospective colonoscopy study of 5,899 screening participants
Authors: Wong Martin C. S. , Ching Jessica Y. L. , Ng Simpson , Lam Thomas Y. T. , Luk Arthur K. C. , Wong Sunny H. , Ng Siew C. , Ng Simon S. M. , Wu Justin C. Y. , Chan Francis K. L. , Sung Joseph J. Y. 
Published: February 2016

AbstractWe evaluated the performance of seven existing risk scoring systems in predicting advanced colorectal neoplasia in an asymptomatic Chinese cohort. We prospectively recruited 5,899 Chinese subjects aged 50–70 years in a colonoscopy screening programme(2008–2014). Scoring systems under evaluation included two scoring tools from the US; one each from Spain, Germany and Poland; the Korean Colorectal Screening(KCS) scores; and the modified Asia Pacific Colorectal Screening(APCS) scores. The c-statistics, sensitivity, specificity, positive predictive values(PPVs) and negative predictive values(NPVs) of these systems were evaluated. The resources required were estimated based on the Number Needed to Screen(NNS) and the Number Needed to Refer for colonoscopy(NNR). Advanced neoplasia was detected in 364 (6.2%) subjects. The German system referred the least proportion of subjects (11.2%) for colonoscopy, whilst the KCS scoring system referred the highest (27.4%). The c-statistics of all systems ranged from 0.56–0.65, with sensitivities ranging from 0.04–0.44 and specificities from 0.74–0.99. The modified APCS scoring system had the highest c-statistics (0.65, 95% C.I. 0.58–0.72). The NNS (12–19) and NNR (5-10) were similar among the scoring systems. The existing scoring systems have variable capability to predict advanced neoplasia among asymptomatic Chinese subjects and further external validation should be performed.