bluuebunny/crossref_metadata_2025 huggingface dataset:
The Green Prescription Active Families programme in Taranaki, New Zealand 2007–2009: Did it reach children in need?
Authors: Anderson Yvonne , Taylor Greg , Grant Cameron , Fulton Ross , Hofman Paul
Published: November 2018

INTRODUCTION: The Green Prescription Active Families (GRxAF) programme focuses on overweight/ obese children and adolescents, and is family/whanau based. It is an intervention supporting lifestyle changes through weekly sessions (nutrition advice and/or physical activity), and goal setting for the family/whanau for up to 12 months. AIMS: To describe the GRxAF programme in Taranaki and evaluate its reach and engagement, especially for those most at risk of obesity. METHODS: Participant files for each referred child from May 2007 to December 2009 were reviewed. Baseline demographic data, programme graduation information, and weekly activity session attendance were collected. RESULTS: Of the 109 participants during the audit period, 39% were Maori, 57% New Zealand European (NZE), 3% Pacific, and 1% Other ethnicity. Mean age at entry was 10 (range 4–17) years. Mean duration of programme involvement was five (range 0–12) months. Overall, 33/60 (55%) of the participants completing the programme during the audit period graduated, having made steps towards healthy lifestyle change. In comparison with NZE (68%), a smaller proportion of Maori (40%) graduated (p=0.04). In comparison with those who attended no sessions, participants who attended any sessions were more likely to make positive changes (OR=3.65, 95% CI 1.24–10.8). DISCUSSION: GRxAF in Taranaki met a need for some obese/overweight children, but not for all families/whanau, especially those over-represented in childhood obesity statistics. Programme delivery for Maori requires improvement, and assessment of readiness to make lifestyle change as an enrolment criteria for all participants is recommended. KEYWORDS: Adolescent; child; nutrition; obesity; physical activity; treatment
General practitioner awareness of sexual orientation among a community and internet sample of gay and bisexual men in New Zealand
Authors: Ludlam Adrian , Saxton Peter , Dickson Nigel , Hughes Anthony
Published: November 2018

INTRODUCTION: General practitioners (GPs) can improve HIV and sexually transmitted infection (STI) screening, vaccination and wellbeing among gay, bisexual and other men who have sex with men (GBM) if they are aware of a patient?s sexual orientation. AIM: To estimate GP awareness of their GBM patients' sexual orientation and examine whether HIV and STI screening was associated with this. METHODS: We analysed anonymous, self-completed data from 3168 GBM who participated in the community-based Gay Auckland Periodic Sex Survey (GAPSS) and internet-based Gay men's Online Sex Survey (GOSS) in 2014. Participants were asked if their usual GP was aware of their sexual orientation or that they had sex with men. RESULTS: Half (50.5%) believed their usual GP was aware of their sexual orientation/behaviour, 17.0% were unsure, and 32.6% believed he/she was unaware. In multivariate analysis, GP awareness was significantly lower if the respondent was younger, Asian or an 'Other' ethnicity, bisexual-identified, had never had anal intercourse or had first done so very recently or later in life, and had fewer recent male sexual partners. GBM whose GP was aware of their sexual orientation were more likely to have ever had an HIV test (91.5% vs 57.9%; p<0.001), specific STI tests (91.7% vs 68.9%; p<0.001), and were twice as likely to have had an STI diagnosed. DISCUSSION: Lack of sexual orientation disclosure is resulting in missed opportunities to reduce health inequalities for GBM. More proactive, inclusive and safe environments surrounding the care of sexual orientation minorities are needed in general practice to encourage disclosure. KEYWORDS: Culturally competent care; general practice; HIV; HPV; sexual health; sexual orientation
Molecular structure of the ATP-bound, phosphorylated human CFTR
Authors: Zhang Zhe , Liu Fangyu , Chen Jue
Published: November 2018

The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel important in maintaining proper functions of the lung, pancreas, and intestine. The activity of CFTR is regulated by ATP and protein kinase A-dependent phosphorylation. To understand the conformational changes elicited by phosphorylation and ATP binding, we present here the structure of phosphorylated, ATP-bound human CFTR, determined by cryoelectron microscopy to 3.2-Å resolution. This structure reveals the position of the R domain after phosphorylation. By comparing the structures of human CFTR and zebrafish CFTR determined under the same condition, we identified common features essential to channel gating. The differences in their structures indicate plasticity permitted in evolution to achieve the same function. Finally, the structure of CFTR provides a better understanding of why the G178R, R352Q, L927P, and G970R/D mutations would impede conformational changes of CFTR and lead to cystic fibrosis.
Spaces of international gender justice: a reply to Baldez and DeLaet
Authors: Bunting Annie
Published: November 2018

In assessing the effectiveness of international human rights law to achieve meaningful gender equality, Lisa Baldez and Debra DeLaet offer two complementary yet different case studies. De Laet argues that despite the rhetoric and promise of international women's rights law, such codification has yet to achieve ‘systemic progress’ to address gender inequality. DeLaet concludes that progress is most often attributable to national law reform and enforcement rather than global legalism. Picking up on the importance of national context, Baldez comes to a different conclusion in examining the case of Cuba's submissions to Convention on the Elimination of All Forms of Discrimination Against Women. Both papers point not only to the limitations and potential of international law but also to the limitations of feminist strategies that emphasize law reform at the exclusion of other non-juridical strategies for social change. As I read the papers together, I am reminded of the need to see global legal strategies as embedded in and alongside other strategies for social change. I argue that, despite its frailties, international law remains a useful resource for national or grass-roots feminist strategies for positive social change.
Tacking between the global and the local: a reply to DeLaet and Bunting
Authors: Baldez Lisa
Published: November 2018

In these two pieces, DeLaet and Bunting express reservations about the potential for international law to have positive effects on the de facto status of the world's citizens—but point to activism on the local level as the most viable way to strengthen the human rights regime. In her thorough overview of the literature on the impact of international law, DeLaet focuses on the ability of local activists to domestic international treaties by mobilizing at the grassroots level to enact the provisions of international law. Bunting's analysis of the offers a different solution, one that involves tacking back and forth between the precepts of international law and the lived experiences of victims of human rights violations.
TGF-β–SMAD–miR-520e axis regulates NSCLC metastasis through a TGFBR2-mediated negative-feedback loop
Authors: Kucuksayan Hakan , Akgun Sakir , Ozes Osman Nidai , Alikanoglu Arsenal Sezgin , Yildiz Mustafa , Dal Egemen , Akca Hakan
Published: November 2018

Transforming growth factor-β (TGF-β) pathway plays crucial roles during the carcinogenesis and metastasis. TGF-β receptor 2 (TGFBR2) is a key molecule for the regulation of TGF-β pathway and frequently downregulated or lost in several cancer types including non-small cell lung cancer (NSCLC), and TGF-β pathway is often regulated by negative-feedback mechanisms, but little is known about the mechanism of TGFBR2 downregulation in NSCLC. Here, we found that the expression of miR-520e is upregulated in metastatic tumor tissues compared with non-metastatic ones, and its expression is inversely correlated with that of TGFBR2 in clinical samples. We also discovered that TGF-β dramatically increased the expression of miR-520e, which targeted and downregulated TGFBR2, and the suppression of miR-520e significantly impaired TGF-β-induced TGFBR2 downregulation. Chromatin immunoprecipitation–PCR experiments further showed that miR-520e is transcriptionally induced by SMAD2/3 in response to TGF-β. Our findings reveal a novel negative-feedback mechanism in TGF-β signaling and the expression level of miR-520e could be a predictive biomarker for NSCLC metastasis.
The Epidemiology of Herpes Zoster in the United States During the Era of Varicella and Herpes Zoster Vaccines: Changing Patterns Among Older Adults
Authors: Harpaz Rafael , Leung Jessica W
Published: November 2018

Historic herpes zoster incidence trends in US adults have been hard to interpret. Using administrative databases, we extended previous descriptions of these trends through 2016. We observed an age-specific transition, with ongoing increases among younger adults but deceleration in older adults. The patterns are not readily explained.
Dynamic transcriptomic analysis reveals suppression of PGC1α/ERRα drives perturbed myogenesis in facioscapulohumeral muscular dystrophy
Authors: Banerji Christopher R S , Panamarova Maryna , Pruller Johanna , Figeac Nicolas , Hebaishi Husam , Fidanis Efthymios , Saxena Alka , Contet Julian , Sacconi Sabrina , Severini Simone , Zammit Peter S
Published: November 2018

Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable myopathy, linked to epigenetic derepression of D4Z4 repeats on chromosome 4q, leading to ectopic DUX4 expression. FSHD patient myoblasts have defective myogenic differentiation, forming smaller myotubes with reduced myosin content. However, molecular mechanisms driving such disrupted myogenesis in FSHD are poorly understood. We performed high-throughput morphological analysis describing FSHD and control myogenesis, revealing altered myogenic differentiation results in hypotrophic myotubes. Employing polynomial models and an empirical Bayes approach, we established eight critical time points during which human healthy and FSHD myogenesis differ. RNA-sequencing at these eight nodal time points in triplicate, provided temporal depth for a multivariate regression analysis, allowing assessment of interaction between progression of differentiation and FSHD disease status. Importantly, the unique size and structure of our data permitted identification of many novel FSHD pathomechanisms undetectable by previous approaches. For further analysis here, we selected pathways that control mitochondria: of interest considering known alterations in mitochondrial structure and function in FSHD muscle, and sensitivity of FSHD cells to oxidative stress. Notably, we identified suppression of mitochondrial biogenesis, in particular via peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α), the cofactor and activator of oestrogen-related receptor α (ERRα). PGC1α knock-down caused hypotrophic myotubes to form from control myoblasts. Known ERRα agonists and safe food supplements biochanin A, daidzein or genistein, each rescued the hypotrophic FSHD myotube phenotype. Together our work describes transcriptomic changes in high resolution that occur during myogenesis in FSHD ex vivo, identifying suppression of the PGC1α-ERRα axis leading to perturbed myogenic differentiation, which can effectively be rescued by readily available food supplements.
Pattern Recognition Receptor Polymorphisms as Predictors of Oxaliplatin Benefit in Colorectal Cancer
Authors: Gray Victoria , Briggs Sarah , Palles Claire , Jaeger Emma , Iveson Timothy , Kerr Rachel , Saunders Mark P , Paul James , Harkin Andrea , McQueen John , Summers Matthew G , Johnstone Elaine , Wang Haitao , Gatcombe Laura , Maughan Timothy S , Kaplan Richard , Escott-Price Valentina , Al-Tassan Nada A , Meyer Brian F , Wakil Salma M , Houlston Richard S , Cheadle Jeremy P , Tomlinson Ian , Church David N
Published: November 2018

Background

Constitutional loss of function (LOF) single nucleotide polymorphisms (SNPs) in pattern recognition receptors FPR1, TLR3, and TLR4 have previously been reported to predict oxaliplatin benefit in colorectal cancer. Confirmation of this association could substantially improve patient stratification.

Methods

We performed a retrospective biomarker analysis of the Short Course in Oncology Therapy (SCOT) and COIN/COIN-B trials. Participant status for LOF variants in FPR1 (rs867228), TLR3 (rs3775291), and TLR4 (rs4986790/rs4986791) was determined by genotyping array or genotype imputation. Associations between LOF variants and disease-free survival (DFS) and overall survival (OS) were analyzed by Cox regression, adjusted for confounders, using additive, dominant, and recessive genetic models. All statistical tests were two-sided.

Results

Our validation study populations included 2929 and 1948 patients in the SCOT and COIN/COIN-B cohorts, respectively, of whom 2728 and 1672 patients had functional status of all three SNPs determined. We found no evidence of an association between any SNP and DFS in the SCOT cohort, or with OS in either cohort, irrespective of the type of model used. This included models for which an association was previously reported for rs867228 (recessive model, multivariable-adjusted hazard ratio [HR] for DFS in SCOT = 1.19, 95% confidence interval [CI] = 0.99 to 1.45, P = .07; HR for OS in COIN/COIN-B = 0.92, 95% CI = 0.63 to 1.34, P = .66), and rs4986790 (dominant model, multivariable-adjusted HR for DFS in SCOT = 0.86, 95% CI = 0.65 to 1.13, P = .27; HR for OS in COIN/COIN-B = 1.08, 95% CI = 0.90 to 1.31, P = .40).

Conclusion

In this prespecified analysis of two large clinical trials, we found no evidence that constitutional LOF SNPs in FPR1, TLR3, or TLR4 are associated with differential benefit from oxaliplatin. Our results suggest these SNPs are unlikely to be clinically useful biomarkers.
Effects of the Refugee Crisis on Perceptions of Asylum Seekers in Recipient Populations
Authors: Bjånesøy Lise Lund
Published: November 2018

This article examines the effects of the refugee crisis on perceptions of asylum seekers. Previous research has demonstrated that asylum seekers are perceived in terms of deservingness—either as deserving refugees in need of help or as undeserving and unwelcome exploiters. The article uses unique panel data from a representative sample drawn directly from the Norwegian population registry. Through Structural Topic Modelling (STM) of open-ended survey responses fielded before and after the refugee crisis, this article analyses, first, how ordinary citizens perceive asylum seekers and, second, the article documents that these perceptions of asylum seekers changed. They did, however, not change from perceiving asylum seekers as deserving to perceiving them as undeserving. The change was more subtle. Responses that characterize asylum seekers as deserving prior to the crisis tended to reflect a sense of responsibility to help—of involvement. Responses after the crisis were more distanced, even as they characterized the asylum seekers as deserving. All in all, these findings improve our knowledge about how the refugee crisis affected public opinion in recipient populations.
Mapping museum ‘Soft Power’: Adding geo-visualization to the methodological framework
Authors: Grincheva Natalia
Published: November 2018

The article proposes, justifies, and tests a new methodological framework to measure museum ‘soft power’ by employing geo-visualization as a new method empowered by the rapid development of digital humanities. This research not only demystifies the buzz term of ‘soft power’ that is frequently applied in relation to contemporary museums and their international cultural engagements but also develops an evaluation framework to assess museum capacities to exert global impacts. Specifically, the article draws on the academic scholarship outlining a plethora of approaches for ‘soft power’ evaluation, including Resources, Outputs, Perceptions, and Networks evaluation models. It argues for a new integrative approach that can comprehensively combine different methods to construct a more advanced tool to measure museum ‘soft power’. The article draws on preliminary results of developing a digital mapping system to assess museum soft power. It shares findings from the pilot project, Australian Center of the Moving Image (ACMI) on the Global Map, designed in collaboration with the ACMI in Melbourne.
Generalized Update Semantics
Authors: Goldstein Simon
Published: November 2018

This paper explores the relationship between dynamic and truth conditional semantics for epistemic modals. It provides a generalization of a standard dynamic update semantics for modals. This new semantics derives a Kripke semantics for modals and a standard dynamic semantics for modals as special cases. The semantics allows for new characterizations of a variety of principles in modal logic, including the inconsistency of ‘p and might not p’. Finally, the semantics provides a construction procedure for transforming any truth conditional semantics for modals into a dynamic semantics for modals with similar properties.
Baseline graft status is a critical predictor of kidney graft failure after diarrhoea
Authors: Devresse Arnaud , Morin Lise , Aulagnon Florence , Taupin Jean-Luc , Scemla Anne , Lanternier Fanny , Aubert Olivier , Aidoud Adel A , Lebreton Xavier , Sberro-Soussan Rebecca , Snanoudj Renaud , Amrouche Lucile , Tinel Claire , Martinez Frank , Bererhi Lynda , Anglicheau Dany , Lortholary Olivier , Legendre Christophe , Avettand-Fenoel Véronique , Zuber Julien
Published: November 2018

Background

Diarrhoea is one of the most frequent complications after kidney transplantation (KT). Non-infectious diarrhoea has been associated with reduced graft survival in kidney transplant recipients. However, the risk factors for renal allograft loss following diarrhoea remain largely unknown.

Methods

Between January 2010 and August 2011, 195 consecutive KT recipients who underwent standardized microbiological workups for diarrhoea at a single centre were enrolled in this retrospective study.

Results

An enteric pathogen was readily identified in 91 patients (47%), while extensive microbiological investigations failed to find any pathogen in the other 104. Norovirus was the leading cause of diarrhoea in these patients, accounting for 30% of the total diarrhoea episodes. The baseline characteristics were remarkably similar between non-infectious and infectious diarrhoea patients, with the exception that the non-infectious group had significantly lower graft function before diarrhoea (P = 0.039). Infectious diarrhoea was associated with a longer duration of symptoms (P = 0.001) and higher rates of acute kidney injury (P = 0.029) and hospitalization (P < 0.001) than non-infectious diarrhoea. However, the non-infectious group had lower death-censored graft survival than the infectious group (Gehan–Wilcoxon test, P = 0.038). Multivariate analysis retained three independent predictors of graft failure after diarrhoea: diarrhoea occurring ≥5 years after KT [hazard ratio (HR) 4.82; P < 0.001], re-transplantation (HR 2.38; P = 0.001) and baseline estimated glomerular filtration rate <30 mL/min/1.73 m2 (HR 11.02; P < 0.001).

Conclusion

Our study shows that pre-existing conditions (re-transplantation, chronic graft dysfunction and late occurrence) determine the primary functional long-term consequences of post-transplant diarrhoea.
Eliminating yellow fever epidemics in Africa: vaccine demand forecast and impact modelling
Authors: Jean Kévin , Hamlet Arran , Benzler Justus , Cibrelus Laurence , Gaythorpe Katy A. M. , Sall Amadou , Ferguson Neil M. , Garske Tini
Published: November 2018

Background

To counter the increasing global risk of Yellow fever (YF), the World Health Organisation initiated the Eliminate Yellow fever Epidemics (EYE) strategy. Estimating YF burden, as well as vaccine impact, while accounting for the features of urban YF transmission such as indirect benefits of vaccination, is key to informing this strategy.

Methods and Findings

We developed two model variants to estimate YF burden in sub-Saharan Africa, assuming all infections stem from either the sylvatic or the urban cycle of the disease. Both relied on an ecological niche model fitted to the local presence of any YF reported event in 34 African countries. We calibrated under-reporting using independent estimates of transmission intensity provided by 12 serological surveys performed in 11 countries. We calculated local numbers of YF infections, deaths and disability-adjusted life years (DALYs) lost based on estimated transmission intensity while accounting for time-varying vaccination coverage. We estimated vaccine demand and impact of future preventive mass vaccination campaigns (PMVCs) according to various vaccination scenarios.

Vaccination activities conducted in Africa between 2005 and 2017 were estimated to prevent from 3.3 (95% CI 1.2-7.7) to 6.1 (95% CI 2.4-13.2) millions of deaths over the lifetime of vaccinees, representing extreme scenarios of all transmission due to the sylvatic or the urban cycle, respectively. By prioritizing provinces based on the risk of urban YF transmission, an average of 37.7 million annual doses for PMVCs over eight years would avert an estimated 9,900,000 (95% CI 7,000,000-13,400,000) infections and 480,000 (180,000-1,140,000) deaths over the lifetime of vaccinees, corresponding to 1.7 (0.7-4.1) deaths averted per 1,000 vaccine doses.

Limitations include substantial uncertainty in the estimates arising from the scarcity of reliable data from surveillance and serological surveys.

Conclusions

By estimating YF burden and vaccine impact over a range of spatial and temporal scales, while accounting for the specificity of urban transmission, our model can be used to inform the current EYE strategy.
Strenuous occupational physical activity - potential association with esophageal squamous cell carcinoma risk
Authors: Shah Idrees Ayoub , Bhat Gulzar Ahmad , Rafiq Rumaisa , Nissa Najma , Muzaffar Mansha , Rasool Malik Tariq , Banday Abdul Rouf , Lone Mohd Maqbool , Lone Gulam Nabi , Boffetta Paolo , Dar Nazir Ahmad
Published: November 2018

The impact of leisure time or recreational physical activity (RPA) on cancer risk has been extensively studied. However, the association of the occupational physical activity (OPA), which differs in dose and intensity from RPA, with different cancers including esophageal squamous cell carcinoma (ESCC), has received less attention. Here, we present data from a case-control study which was conducted for assessing the risk factors for ESCC. Histopathologically confirmed 703 ESCC cases and 1664 controls, individually matched to the respective cases for age, sex and district of residence were recruited. Information on type, duration and intensity of physical activity was obtained in face-to-face interviews with participants using a structured questionnaire. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). A high level of occupational physical activity was associated with increased ESCC risk (OR = 2.17, 95% CI; 1.41 – 3.32), compared to subjects with moderate occupational physical activity. The association with ESCC risk was stronger in strenuous workers (OR = 3.64, 95% CI; 2.13 – 6.20). The association of strenuous OPA with ESCC risk persisted only in subjects that were involved in strenuous activities for equal to or greater than 5days/week. Our study suggests a possible association of strenuous occupational physical activity with ESCC risk. Although, our results were adjusted for multiple factors including indicators of socioeconomic status, more replicative occupational epidemiological studies are needed to rule out any residual confounding.
Age-related changes in social behaviours in the 5xFAD mouse model of Alzheimer’s disease
Authors: Kosel Filip , Munoz Paula Torres , Yang J. Renee , Wong Aimee A. , Franklin Tamara B.
Published: November 2018

In addition to memory impairments, patients with Alzheimer’s disease (AD) exhibit a number of behavioural and psychological symptoms that can affect social interactions over the course of the disease. While altered social interactions have been demonstrated in a number of mouse models of AD, many models only recapitulate the initial stages of the disease, and these behavioural changes have yet to be examined over the course of disease progression. By performing a longitudinal study using the 5xFAD mouse model, we have demonstrated that transgenic females exhibit progressive alterations in social investigation compared to wild-type controls. Transgenic females exhibited an age-related reduction in interest for social odours, as well as reduced investigative behaviours towards novel conspecifics in a novel environment. However, transgenic mice exhibited no obvious olfactory deficits, nor any changes in scent-marking behaviour compared to wild-type controls, indicating that changes in investigative behaviour were due to motivation to engage with a social stimulus. This evidence suggests that transgenic 5xFAD females exhibit increased social anxiety in novel environments compared to wildtype controls. Overall, transgenic 5xFAD female mice mimic some features of social withdrawal observed in human AD patients suggesting this strain may be suitable for modelling aspects of the social dysfunction observed in human patients.
Mechanisms of strain diversity of disease-associated in-register parallel β-sheet amyloids and implications about prion strains
Authors: Taguchi Yuzuru , Otaki Hiroki , Nishida Noriyuki
Published: November 2018

The mechanism of strain diversity of prions still remains unsolved, because the investigation of inheritance and diversification of the protein-based pathogenic information demands identification of the detailed structures of abnormal isoform of prion protein (PrPSc), while it is difficult to purify for analysis without affecting the infectious nature. On the other hand, the similar prion-like properties are recognized also in other disease-associated in-register parallel β-sheet amyloids including Tau and α-synuclein (αSyn) amyloids. Investigations into structures of those amyloids by solid-state nuclear magnetic resonance spectroscopy and cryo-electron microscopy recently made remarkable advances, because of their relatively small sizes and lack of post-translational modifications. We review the advances on those pathogenic amyloids, particularly Tau and αSyn, and discuss their implications about strain diversity mechanisms of prion/PrPSc from the viewpoint that PrPSc is an in-register parallel β-sheet amyloid. We also present our recent data of molecular dynamics simulations of αSyn amyloid, which suggest significance of compatibility between β-sheet propensities of the substrate and local structures of the template for stability of the amyloid structures. Detailed structures of the αSyn and Tau amyloids are good surrogate models of pathogenic amyloids including PrPSc to elucidate not only the strain diversity but also their pathogenic mechanisms.
Principles for enhancing virus capsid capacity and stability from a thermophilic virus capsid structure
Authors: Stone Nicholas P. , Demo Gabriel , Agnello Emily , Kelch Brian A.
Published: November 2018

The capsids of double-stranded DNA viruses protect the viral genome from the harsh extracellular environment, while maintaining stability against the high internal pressure of packaged DNA. To elucidate how capsids maintain stability in an extreme environment, we used cryoelectron microscopy to determine the capsid structure of the thermostable phage P74-26 to 2.8-Å resolution. We find the P74-26 capsid exhibits an overall architecture that is very similar to those of other tailed bacteriophages, allowing us to directly compare structures to derive the structural basis for enhanced stability. Our structure reveals ‘lasso’-like interactions that appear to function like catch bonds. This architecture allows the capsid to expand during genome packaging, yet maintain structural stability. The P74-26 capsid has T=7 geometry despite being twice as large as mesophilic homologs. Capsid capacity is increased through a novel mechanism with a larger, flatter major capsid protein. Our results suggest that decreased icosahedral complexity (i.e. lower T number) leads to a more stable capsid assembly.
Detecting and Correcting False Transients in Calcium Imaging
Authors: Gauthier Jeff L. , Koay Sue Ann , Nieh Edward H. , Tank David W. , Pillow Jonathan W. , Charles Adam S.
Published: November 2018

Population recordings of calcium activity are a major source of insight into neural function. Large dataset sizes often require automated methods, but automation can introduce errors that are difficult to detect. Here we show that automatic time course estimation can sometimes lead to significant misattribution errors, in which fluorescence is ascribed to the wrong cell. Misattribution arises when the shapes of overlapping cells are imperfectly defined, or when entire cells or processes are not identified, and misattribution can even be produced by methods specifically designed to handle overlap. To diagnose this problem, we develop a transient-by-transient metric and a visualization tool that allow users to quickly assess the degree of misattribution in large populations. To filter out misattribution, we also design a robust estimator that explicitly accounts for contaminating signals in a generative model. Our methods can be combined with essentially any cell finding technique, empowering users to diagnose and correct at large scale a problem that has the potential to significantly alter scientific conclusions.
Association between Apolipoprotein E genotype and the gut microbiome composition in humans and mice
Authors: Tran Tam T.T. , Corsini Simone , Kellingray Lee , Hegarty Claire , Gall Gwénaëlle Le , Narbad Arjan , Müller Michael , Tejera Noemi , O’Toole Paul W. , Minihane Anne-Marie , Vauzour David
Published: November 2018

Apolipoprotein E (APOE) genotype is the strongest prevalent genetic risk factor for Alzheimer’s disease. Numerous studies have provided insights into the pathological mechanisms. However, a comprehensive understanding of the impact ofAPOEgenotype on microflora speciation and metabolism is completely lacking. The aim of this study was to investigate the association betweenAPOEgenotype and the gut microbiome composition in human andAPOE-targeted replacement (TR,APOE3andAPOE4) transgenic mice. Faecal microbiota amplicon sequencing from matched individuals with differentAPOEgenotypes revealed no significant differences in overall microbiota diversity (alpha or beta diversity) in group-aggregated humanAPOEgenotypes. However, several bacterial taxa showed significantly different relative abundance betweenAPOEgenotypes. Notably, we detected an association ofPrevotellaceaeandRuminococcaceaeand several butyrate-producing genera abundances withAPOEgenotypes. These findings were confirmed by comparing the gut microbiota ofAPOE-TR mice. Furthermore, metabolomic analysis of faecal water from murine samples detected significant differences in microbe-associated amino acids and short-chain fatty acids betweenAPOEgenotypes. Together, the findings indicate thatAPOEgenotype associated with specific gut microbiome profiles in both humans and inAPOE-TR mice. This suggests that the gut microbiome is worth further investigation as a potential therapeutic target to mitigate the deleterious impact of theAPOE4allele on cognitive decline and the prevention and treatment of AD.
The distribution of antibiotic use and its association with antibiotic resistance
Authors: Olesen Scott W. , Barnett Michael L. , MacFadden Derek R. , Brownstein John S. , Hernández-Díaz Sonia , Lipsitch Marc , Grad Yonatan H.
Published: November 2018

Antibiotic use is a primary driver of antibiotic resistance. However, antibiotic use can be distributed in different ways in a population, and the association between the distribution of use and antibiotic resistance has not been explored. Here we tested the hypothesis that repeated use of antibiotics has a stronger association with population-wide antibiotic resistance than broadly- distributed, low-intensity use. First, we characterized the distribution of outpatient antibiotic use across US states, finding that antibiotic use is uneven and that repeated use of antibiotics makes up a minority of antibiotic use. Second, we compared antibiotic use with resistance for 72 pathogen-antibiotic combinations across states. Finally, having partitioned total use into extensive and intensive margins, we found that intense use had a weaker association with resistance than extensive use. If the use-resistance relationship is causal, these results suggest that reducing total use and selection intensity will require reducing broadly-distributed, low- intensity use.
Tethered Bichromophoric Fluorophore Quencher Voltage Sensitive Dyes
Authors: Yan Ping , Acker Corey , Loew Leslie M.
Published: November 2018

Voltage sensitive dyes (VSDs) are used for in vitro drug screening and for in vivo imaging of patterns of electrical activity. However, wide application of this technology is limited by poor sensitivity. A promising approach uses a 2-component system consisting of charged membrane permeable quenchers together with fluorophores labeling one side of the membrane; this produces voltage-dependent fluorescence quenching. However, to achieve good sensitivity, the quencher compound must be used at high concentrations, which can perturb the membrane capacitance or have other pharmacological effects. By developing tethered bichromophoric fluorophore quencher (TBFQ) dyes, where the fluorophore and quencher are covalently connected by a long hydrophobic chain, the concentration required is minimized, and the sensitivity is maximized. A series of 13 TBFQ dyes based on the AminoNaphthylEthenylPyridinium (ANEP) fluorophore and the dipicrylamine anion (DPA) quencher have been synthesized and tested in an artificial lipid bilayer apparatus. The best one from the screening, TBFQ1, shows a 2.5 fold change in fluorescence per 100mV change in membrane potential, and the response kinetics is in 10-20 ms range. This sensitivity is an order of magnitude better than commonly used fluorescent voltage sensors. The design principles for TBFQ VSDs described here can be readily extended to other spectral regions and promise to greatly enhance our ability to monitor electrical activity in cells and tissues.
Chromatin Accessibility Plays a Key Role in Selective Targeting of Hox Proteins
Authors: Porcelli Damiano , Fischer Bettina , Russell Steven , White Robert
Published: November 2018

Hox protein transcription factors specify segmental diversity along the anterior-posterior body axis in metazoans. Understanding the basis of Hox function has long faced the problem that, while the different members of the Hox family show clear functional specificity in vivo, they all show very similar binding specificity in vitro. Based on in vitro studies, cofactors may increase Hox binding selectivity however a satisfactory understanding of in vivo Hox target selectivity is still lacking.

We have carried out a systematic analysis of the in vivo genomic binding profiles of all eight Drosophila Hox proteins using transient transfection in Kc167 cells to examine Hox protein targeting. We find that Hox proteins show considerable binding selectivity in vivo in the absence of the canonical Hox cofactors Extradenticle and Homothorax. Hox binding selectivity is strongly associated with chromatin accessibility; binding sites in less accessible chromatin show the highest selectivity and the different Hox proteins exhibit different propensities to bind less accessible chromatin. High Hox binding selectivity is also associated with high affinity binding regions, leading to a model where Hox proteins derive binding selectivity through an affinity-based competition with nucleosomes. Provision of the Extradenticle/Homothorax cofactors generally leads to an increase in the number of Hox binding regions and promotes the binding to regions in less accessible chromatin, however the provision of these cofactors has little effect on the overall selectivity of Hox targeting.

These studies indicate that chromatin accessibility plays a key role in Hox selectivity and we propose that relative chromatin accessibility provides a basis for subtle differences in binding specificity and affinity to generate significantly different sets of genomic targets for different Hox proteins. We suggest that this mechanism may also be relevant to other transcription factor families.
Impacts of thermal mismatches on chytrid fungusBatrachochytrium dendrobatidisprevalence are moderated by life stage, body size, elevation and latitude
Authors: Cohen Jeremy M. , McMahon Taegan A. , Ramsay Chloe , Roznik Elizabeth A. , Sauer Erin L. , Bessler Scott , Civitello David J. , Delius Bryan K. , Halstead Neal , Knutie Sarah A. , Nguyen Karena H. , Ortega Nicole , Sears Brittany , Venesky Matthew D. , Young Suzanne , Rohr Jason R.
Published: November 2018

Global climate change is increasing the frequency of unpredictable weather conditions; however, it remains unclear how species-level and geographic factors, including body size and latitude, moderate impacts of unusually warm or cool temperatures on disease. Because larger hosts and lower-latitude hosts generally have slower acclimation times, we hypothesized that their disease susceptibility increases under “thermal mismatches”, or differences between baseline climate and the temperature during surveying. Here, we examined how thermal mismatches interact with body size, life stage, habitat, latitude, elevation, phylogeny, and IUCN conservation status to predict infection prevalence of the chytrid fungusBatrachochytrium dendrobatidis(Bd) in a global analysis of 38,967 amphibian hosts. As hypothesized, we found that the susceptibility of larger hosts and hosts from lower latitudes was strongly influenced by thermal mismatches. Furthermore, hosts of conservation concern are more susceptible than others following thermal mismatches, suggesting that thermal mismatches might have contributed to recent amphibian declines.

Data Accessibility Statement

Should the manuscript be accepted, the data supporting the results will be archived in an appropriate public repository such as Dryad or Figshare and the data DOI will be included at the end of the article.
Improved TGIRT-seq methods for comprehensive transcriptome profiling with decreased adapter dimer formation and bias correction
Authors: Xu Hengyi , Yao Jun , Wu Douglas C. , Lambowitz Alan M.
Published: November 2018

Thermostable group II intron reverse transcriptases (TGIRTs) with high fidelity and processivity have been used for a variety of RNA sequencing (RNA-seq) applications, including comprehensive profiling of whole-cell, exosomal, and human plasma RNAs; quantitative tRNA-seq based on the ability of TGIRT enzymes to give full-length reads of tRNAs and other structured small ncRNAs; high-throughput mapping of post-transcriptional modifications; and RNA structure mapping. Here, we improved TGIRT-seq methods for comprehensive transcriptome profiling by (i) rationally designing RNA-seq adapters that minimize adapter dimer formation, and (ii) developing biochemical and computational methods that remediate 5’- and 3’-end biases. These improvements, some of which may be applicable to other RNA-seq methods, increase the efficiency of TGIRT-seq library construction and improve coverage of very small RNAs, such as miRNAs. Our findings provide insight into the biochemical basis of 5’- and 3’-end biases in RNA-seq and suggest general approaches for remediating biases and decreasing adapter dimer formation.
A kinesin Klp10A mediates cell cycle-dependent shuttling of Piwi between nucleus and nuage
Authors: Venkei Zsolt G. , Choi Charlotte , Feng Suhua , Jacobsen Steven E. , Kim John K. , Yamashita Yukiko M.
Published: November 2018

The piRNA pathway protects germline genomes through transcript cleavage of selfish genetic elements, such as transposons, in the cytoplasm and their transcriptional silencing in the nucleus. Here, we describe a mechanism by which the nuclear and cytoplasmic arms of the silencing mechanism are linked. During mitosis ofDrosophilaspermatogonia, nuclear Piwi interacts with nuage, the compartment that mediates the cytoplasmic arm of piRNA-mediated silencing. At the end of mitosis, Piwi leaves nuage to return to the nucleus. We found that dissociation of Piwi from nuage occurs at the depolymerizing microtubules of the central spindle, mediated by a microtubule-depolymerizing kinesin Klp10A. Depletion ofklp10Adelays Piwi’s return to the nucleus and affects piRNA production, suggesting the importance of nuclear-cytoplasmic communication in piRNA biogenesis. We propose that cell cycle-dependent communication between the nuclear and cytoplasmic arms of the piRNA pathway plays important roles in coordinated piRNA production.
Chronic pain with use of analgesics and mortality in the home healthcare elderly: a nationwide population-based study
Authors: Chen Hsuan-En , Tsay Wen-Ing , Her Shwu-Huey , Ho Chung-Han , Chen Yi-Chen , Tsai Kang-Ting , Hsu Chien-Chin , Wang Jhi-Joung , Huang Chien-Cheng
Published: November 2018

Background

Chronic pain may cause increased complications and all-cause mortality. However, nationwide data on elderly patients receiving home healthcare (HHC) remain unknown. Therefore, we conducted this study to address this issue.

Methods

We identified elderly individuals (≥ 65 years) with chronic pain receiving HCC between 2002 and 2013 in the Taiwan National Health Insurance Research Database. The comparisons of the causes of chronic pain, comorbidities, follow-up mortality, and the use of analgesics between two sexes and among three age subgroups were performed.

Results

A total of 1435 participants were identified, with a mean age of 77.8 ± 7.1 years and male percentage of 46.7%. The prevalence of chronic pain was 5.8%. Chronic pain was most prevalent in the 75–84 years age group (46.5%). Malignancy was the most common cause of chronic pain (94.2%), followed by peripheral vascular diseases (6.0%), osteoarthritis (4.3%), pressure ulcer (3.9%), spine diseases (3.1%), osteoporosis (1.3%), and headache (1.3%). The follow-up mortality was 32.8% within 6 month, 64.1% within 1 year, 79.9% within 2 years, and 84.3% within 3 years without difference in two sexes and age subgroups. Acetaminophen was found to be the most common analgesics, followed by non-steroidal anti-inflammatory drugs and opioids. Morphine was the most commonly used opioid.

Conclusions

This study delineates the causes of chronic pain, use of analgesics, and follow-up mortality in the HHC elderly, clarifying the relationship between chronic pain and the HCC elderly. This will facilitate the further investigation of this issue in the future.
Sustaining yam yields amidst climate threat in the forest – savannah transition zone of Ghana
Authors: Frimpong F. , Owusu Danquah E. , Ennin S. A. , Asumadu H. , Aidoo A.K. , Maroya N.
Published: November 2018

With about 70% of yam tuber been water, yield is critically affected during bulking as a result of onset of temporal drought. As a consequence of climate change, farmers who are into Dioscorea rotundata (white yam) production for local and international market lose their investments mainly due to erratic precipitation, drought spells culminating into low yields of just 12t/ha compared to the potential of about 22-49t/ha depending on the variety. Innovative land uses technologies with higher and sustained productivity for yam production are imperative. This study verifies improved agronomic package for sustainable yam production in yam growing areas in the forest – savannah transition zone of Ghana during the 2015 and 2016 cropping seasons. The improved agronomic package included use of ridging as seedbed, seed treatment before planting, fertilizer application at a rate of 30:30:36 N:P205:K20 kg/ha plus 15 kg/ha Mg and 20 kg/ha S as MgSO4 and the use of minimum stakes (trellis; 30-50% less number of stakes used by farmers staking). This was compared with farmers’ practice which consisted of mounding, no fertilizer application and no seed treatment. The results revealed significant (P ≤ 0.01) yam yields of more than 60% difference between the improved agronomic practice and farmers’ practice from Ejura, Atebubu and Kintampo yam growing communities. Adoption of improved agronomic practices does not only sustain yam production and address deforestation but also provide higher returns on investments promoting climate resilience by small holders.
Effect of continuous compressive force on the expression of RANKL, OPG, and VEGF in MC3T3-E1 and MLO-Y4 cells
Authors: Yashima Yuka , Kaku Masato , Yamamoto Taeko , Izumino Jin , Kagawa Haruka , Tanimoto Kotaro
Published: November 2018

Osteocytes, known to have mechano-sensory functions, influence the regulation of bone remodeling. However, the mechanism by which osteocytes regulate bone metabolism when mechanical forces are being applied is still unclear. Osteoclastogenesis is mainly regulated by receptor activator of nuclear factor kappa-B ligand (RANKL); the protein osteoprotegerin (OPG) and angiogenesis also play important roles in osteogenesis. RANKL, OPG, and vascular endothelial growth factor (VEGF) are thought to be key factors for bone metabolism. In this study, we examined the effect of a continuous compressive force (CF) on the expression of RANKL, OPG, and VEGF in osteoblastic murine osteocytes (MLO-Y4) and osteoblastic (MC3T3-E1) cells. Gene and protein expression levels of RANKL, OPG, and VEGF in MLO-Y4 and MC3T3-E1 cells were quantitatively determined by real-time PCR and enzyme-linked immunosorbent assay (ELISA). Both cell types were also subjected to a CF of 1.0 g/cm2 for 1, 3, 6, and 12 hours. Furthermore, the effect of a stretch-activated (S-A) channel was examined by gadolinium (Gd3+) administration. The ratio of gene and protein expressions of RANKL, VEGF, and RANKL/OPG in MLO-Y4 cells were significantly higher than in MC3T3-E1 cells, while the expression of OPG was significantly lower. After CF application, both cell types showed significant increases in RANKL and VEGF expression as well as the RANKL/OPG ratio. Additionally, the upregulated gene and protein levels of these factors were reduced by Gd3+ administration.

These findings suggest that osteocytes play more important roles in bone metabolism and angiogenesis than osteoblasts. Osteocytes regulate the expression of RANKL, OPG, and VEGF via the S-A channel through the response to mechanical stress.