bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel Benzodiazepine Compound Inhibits Yellow Fever Virus Infection by Specifically Targeting NS4B Protein
Authors: Guo Fang , Wu Shuo , Julander Justin , Ma Julia , Zhang Xuexiang , Kulp John , Cuconati Andrea , Block Timothy M. , Du Yanming , Guo Ju-Tao , Chang Jinhong 
Published: September 2016

ABSTRACT
Although a highly effective vaccine is available, the number of yellow fever cases has increased over the past 2 decades, which highlights the pressing need for antiviral therapeutics. In a high-throughput screening campaign, we identified an acetic acid benzodiazepine (BDAA) compound which potently inhibits yellow fever virus (YFV). Interestingly, while treatment of YFV-infected cultures with 2 μM BDAA reduced the virion production by greater than 2 logs, the compound was not active against 21 other viruses from 14 different viral families. Selection and genetic analysis of drug-resistant viruses revealed that replacement of the proline at amino acid 219 (P219) of the nonstructural protein 4B (NS4B) with serine, threonine, or alanine conferred YFV with resistance to BDAA without apparent loss of replication fitness in cultured mammalian cells. However, replacement of P219 with glycine conferred BDAA resistance with significant loss of replication ability. Bioinformatics analysis predicts that the P219 amino acid is localized at the endoplasmic reticulum lumen side of the fifth putative transmembrane domain of NS4B, and the mutation may render the viral protein incapable of interacting with BDAA. Our studies thus revealed an important role and the structural basis for the NS4B protein in supporting YFV replication. Moreover, in YFV-infected hamsters, oral administration of BDAA protected 90% of the animals from death, significantly reduced viral load by greater than 2 logs, and attenuated virus infection-induced liver injury and body weight loss. The encouraging preclinical results thus warrant further development of BDAA or its derivatives as antiviral agents to treat yellow fever.

IMPORTANCE
Yellow fever is an acute viral hemorrhagic disease which threatens approximately 1 billion people living in tropical areas of Africa and Latin America. Although a highly effective yellow fever vaccine has been available for more than 7 decades, the low vaccination rate fails to prevent outbreaks in at-risk regions. It has been estimated that up to 1.7 million YFV infections occur in Africa each year, resulting in 29,000 to 60,000 deaths. Thus far, there is no specific antiviral treatment for yellow fever. To cope with this medical challenge, we identified a benzodiazepine compound that selectively inhibits YFV by targeting the viral NS4B protein. To our knowledge, this is the first report demonstrating
in vivo
safety and antiviral efficacy of a YFV NS4B inhibitor in an animal model. We have thus reached a critical milestone toward the development of specific antiviral therapeutics for clinical management of yellow fever.
HIV-1 Escape from a Peptidic Anchor Inhibitor through Stabilization of the Envelope Glycoprotein Spike
Authors: Eggink Dirk , de Taeye Steven W. , Bontjer Ilja , Klasse Per Johan , Langedijk Johannes P. M. , Berkhout Ben , Sanders Rogier W. 
Published: September 2016

ABSTRACT
The trimeric HIV-1 envelope glycoprotein spike (Env) mediates viral entry into cells by using a spring-loaded mechanism that allows for the controlled insertion of the Env fusion peptide into the target membrane, followed by membrane fusion. Env is the focus of vaccine research aimed at inducing protective immunity by antibodies as well as efforts to develop drugs that inhibit the viral entry process. The molecular factors contributing to Env stability and decay need to be understood better in order to optimally design vaccines and therapeutics. We generated viruses with resistance to VIR165, a peptidic inhibitor that binds the fusion peptide of the gp41 subunit and prevents its insertion into the target membrane. Interestingly, a number of escape viruses acquired substitutions in the C1 domain of the gp120 subunit (A60E, E64K, and H66R) that rendered these viruses dependent on the inhibitor. These viruses could infect target cells only when VIR165 was present after CD4 binding. Furthermore, the VIR165-dependent viruses were resistant to soluble CD4-induced Env destabilization and decay. These data suggest that VIR165-dependent Env proteins are kinetically trapped in the unliganded state and require the drug to negotiate CD4-induced conformational changes. These studies provide mechanistic insight into the action of the gp41 fusion peptide and its inhibitors and provide new ways to stabilize Env trimer vaccines.

IMPORTANCE
Because of the rapid development of HIV-1 drug resistance, new drug targets need to be explored continuously. The fusion peptide of the envelope glycoprotein can be targeted by anchor inhibitors. Here we describe virus escape from the anchor inhibitor VIR165. Interestingly, some escape viruses became dependent on the inhibitor for cell entry. We show that the identified escape mutations stabilize the ground state of the envelope glycoprotein and should thus be useful in the design of stabilized envelope-based HIV vaccines.
Hepacivirus NS3/4A Proteases Interfere with MAVS Signaling in both Their Cognate Animal Hosts and Humans: Implications for Zoonotic Transmission
Authors: Anggakusuma  , Brown Richard J. P. , Banda Dominic H. , Todt Daniel , Vieyres Gabrielle , Steinmann Eike , Pietschmann Thomas 
Published: September 2016

ABSTRACT

Multiple novel members of the genus
Hepacivirus
have recently been discovered in diverse mammalian species. However, to date, their replication mechanisms and zoonotic potential have not been explored in detail. The NS3/4A serine protease of hepatitis C virus (HCV) is critical for cleavage of the viral polyprotein. It also cleaves the cellular innate immune adaptor MAVS, thus decreasing interferon (IFN) production and contributing to HCV persistence in the human host. To investigate the conservation of fundamental aspects of the hepaciviral life cycle, we explored if MAVS cleavage and suppression of innate immune signaling represent a common mechanism employed across different clades of the genus
Hepacivirus
to enhance viral replication. To estimate the zoonotic potential of these nonhuman hepaciviruses, we assessed if their NS3/4A proteases were capable of cleaving human MAVS. NS3/4A proteases of viruses infecting colobus monkeys, rodents, horses, and cows cleaved the MAVS proteins of their cognate hosts and interfered with the ability of MAVS to induce the IFN-β promoter. All NS3/4A proteases from nonhuman viruses readily cleaved human MAVS. Thus, NS3/4A-dependent cleavage of MAVS is a conserved replication strategy across multiple clades within the genus
Hepacivirus
. Human MAVS is susceptible to cleavage by these nonhuman viral proteases, indicating that it does not pose a barrier for zoonotic transmission of these viruses to humans.

IMPORTANCE
Virus infection is recognized by cellular sensor proteins triggering innate immune signaling and antiviral defenses. While viruses have evolved strategies to thwart these antiviral programs in their cognate host species, these evasion mechanisms are often ineffective in a novel host, thus limiting viral transmission across species. HCV, the best-characterized member of the genus
Hepacivirus
within the family
Flaviviridae
, uses its NS3/4A protease to disrupt innate immune signaling by cleaving the cellular adaptor protein MAVS. Recently, a large number of HCV-related viruses have been discovered in various animal species, including wild, livestock, and companion animals. We show that the NS3/4A proteases of these hepaciviruses from different animals and representing various clades of the genus cleave their cognate host MAVS proteins in addition to human MAVS. Therefore, cleavage of MAVS is a common strategy of hepaciviruses, and human MAVS is likely unable to limit replication of these nonhuman viruses upon zoonotic exposure.
Arthritis in children: comparison of clinical and biological characteristics of septic arthritis and juvenile idiopathic arthritis
Authors: Aupiais Camille , Basmaci Romain , Ilharreborde Brice , Blachier Audrey , Desmarest Marie , Job-Deslandre Chantal , Faye Albert , Bonacorsi Stéphane , Alberti Corinne , Lorrot Mathie 
Published: September 2016

AimChildhood arthritis arises from several causes. The aim of this observational study is to compare the clinical and biological features and short-term outcome of different types of arthritis because they have different treatment and prognoses.MethodsChildren <16 years of age hospitalised in a French tertiary care centre for a first episode of arthritis lasting for less than 6 weeks who underwent joint aspiration were retrospectively included. We performed non-parametrical tests to compare groups (septic arthritis (SA), juvenile idiopathic arthritis (JIA) and arthritis with no definitive diagnosis). The time before apyrexia or C reactive protein (CRP) <10 mg/L was analysed using the Kaplan-Meier method.ResultsWe studied 125 children with a sex ratio (M/F) of 1.1 and a median age of 2.2 years (range 0.3 to 14.6). SA was associated with a lower age at onset (1.5 years, IQR 1.2–3.0 vs 3.6 years, IQR 2.2–5.6), shorter duration of symptoms before diagnosis (2 days, IQR 1–4 vs 7 days, IQR 1–19) and higher synovial white blood cell count (147 cells ×103/mm3, IQR 71–227, vs 51 cells ×103/mm3, IQR 12–113), than JIA. Apyrexia occurred later in children with JIA (40% after 2 days, 95% CI 17% to 75%) than children with SA (82%, 95% CI 68% to 92%), as did CRP<10 mg/L (18% at 7 days, 95% CI 6.3% to 29.6% vs 82.1%, 95% CI 76.1% to 89.7%, p=0.01).ConclusionsThere were no sufficiently reliable predictors for differentiating between SA and JIA at onset. The outcomes were different; JIA should be considered in cases of poor disease evolution after antibiotic treatment and joint aspiration.
Can vestibular rehabilitation exercises help patients with concussion? A systematic review of efficacy, prescription and progression patterns
Authors: Murray Drew A , Meldrum Dara , Lennon Olive 
Published: September 2016

ObjectiveConcussion symptoms normally resolve within 7–10 days but vertigo, dizziness and balance dysfunction persist in 10–30% of cases causing significant morbidity. This study systematically evaluated the evidence supporting the efficacy, prescription and progression patterns of vestibular rehabilitation therapy (VRT) in patients with concussion.DesignSystematic Review, guided by PRISMA guidelines and presenting a best evidence synthesis.Data sourcesElectronic databases PubMed (1949 to May 2015), CINAHL (1982 to May 2015), EMBASE (1947 to May 2015), SPORTDiscus (1985 to May 2015), Web of Science (1945 to May 2015) and PEDRO (1999 to May 2015), supplemented by manual searches and grey literature.Eligibility criteria for study selectionArticle or abstract of original research, population of patients with concussion/mild traumatic brain injury (mTBI) with vestibular symptoms, interventions detailing VRT, measurement of outcomes pre-VRT/post-VRT. Study type was not specified.ResultsFollowing a double review of abstract and full-text articles, 10 studies met the inclusion criteria: randomised controlled trial (n=2), uncontrolled studies (n=3) and case studies (n=5). 4 studies evaluated VRT as a single intervention. 6 studies incorporated VRT in multimodal interventions (including manual therapy, strength training, occupational tasks, counselling or medication). 9 studies reported improvement in outcomes but level I evidence from only 1 study was found that demonstrated increased rates (OR 3.91; 95% CI 1.34 to 11.34; p=0.002) of medical clearance for return to sport within 8 weeks, when VRT (combined with cervical therapy) was compared with usual care. Heterogeneity in study type and outcomes precluded meta-analysis. Habituation and adaptation exercises were employed in 8 studies and balance exercises in 9 studies. Prescription and progression patterns lacked standardisation.ConclusionsCurrent evidence for optimal prescription and efficacy of VRT in patients with mTBI/concussion is limited. Available evidence, although weak, shows promise in this population. Further high-level studies evaluating the effects of VRT in patients with mTBI/concussion with vestibular and/or balance dysfunction are required.
Sodium intake and blood pressure in children and adolescents: protocol for a systematic review and meta-analysis
Authors: Leyvraz Magali , Taffé Patrick , Chatelan Angeline , Paradis Gilles , Tabin René , Bovet Pascal , Bochud Murielle , Chiolero Arnaud 
Published: September 2016

IntroductionHypertension is a major risk factor for cardiovascular diseases. In adults, high sodium intake is associated with elevated blood pressure. In children, experimental studies have shown that reducing sodium intake can reduce blood pressure. However, their external validity is limited, notably because the sodium reduction was substantial and not applicable in a real-life setting. Observational studies, on the other hand, allow assess the association between blood pressure and sodium intake across usual levels of consumption. There is also evidence that the association differs between subgroups of children according to age and body weight. Our objective is to conduct a systematic review and meta-analysis of experimental and observational studies on the association between sodium intake and blood pressure in children and adolescents and to assess whether the association differs according to age and body weight.Methods and analysisA systematic search of the MEDLINE, EMBASE, CINAHL and CENTRAL databases will be conducted and supplemented by a manual search of bibliographies and unpublished studies. Experimental and observational studies involving children or adolescents between 0 and 18 years of age will be included. The exposure will be dietary sodium intake, estimated using different methods including urinary sodium excretion. The outcomes will be systolic and diastolic blood pressure, elevated blood pressure and hypertension. If appropriate, meta-analyses will be performed by pooling data across all studies together and separately for experimental and observational studies. Subgroup meta-analyses by age and body weight will be also conducted. Moreover, separate meta-analyses for different sodium intake levels will be conducted to investigate the dose–response relationship.Ethics and disseminationThis systematic review and meta-analysis will be published in a peer-reviewed journal. A report will be prepared for national authorities and other stakeholders in the domains of nutrition, public health, and child health in Switzerland.Trial registration numberCRD42016038245.
Capillary and Venous Lactate Agreement: a pilot prospective observational study
Authors: Datta Deepankar , Grahamslaw Julia , Gray Alasdair James , Graham Catriona 
Published: September 2016

BackgroundBlood lactate is a marker of patient illness severity. Capillary lactate (CAP-LACT) measurement can potentially improve patient screening; however, it has poor evidence of clinical utility.AimWe aimed to investigate agreement between CAP-LACT and peripheral venous lactate (PV-LACT).MethodsWe performed a prospective observational pilot study of 99 patients requiring lactate measurement. Paired CAP-LACT and PV-LACT was recorded. Agreement was determined by Bland-Altman analysis.ResultsBias was 0.2 mmol/L, with 95% limits of agreement from −1.9 to 2.3.ConclusionsCAP-LACT has poor agreement with PV-LACT. Further research is needed to improve its potential clinical utility.
Life-course partnership history and midlife health behaviours in a population-based birth cohort
Authors: Keenan Katherine , Ploubidis George B , Silverwood Richard J , Grundy Emily 
Published: September 2016

BackgroundMarital and partnership history is strongly associated with health in midlife and later life. However, the role of health behaviours as an explanatory mechanism remains unclear. The aim of this study was to investigate prospective associations between life-course partnership trajectories (taking into account timing, non-marital cohabitation, remarriage and marital transitions) and health behaviours measured in midlife.MethodsWe analysed data from the British National Child Development Study, a prospective cohort study that includes all people born in 1 week of March 1958 (N=10 226). This study included men and women with prospective data on partnership history from age 23 to 42–44 and health behaviours collected at ages 42–46 (2000–2004). Latent class analysis was used to derive longitudinal trajectories of partnership history. We used multivariable regression models to estimate the association between midlife health behaviours and partnership trajectory, adjusting for various early and young adult characteristics.ResultsAfter adjustment for a range of potential selection factors in childhood and early adulthood, we found that problem drinking, heavy drinking and smoking were more common in men and women who experienced divorce or who had never married or cohabited. Women who married later had a lower prevalence of smoking and were less likely to be overweight than those who married earlier. Overall marriage was associated with a higher body mass index. Individuals who never married or cohabited spent less time exercising.ConclusionsSome aspects of partnership history such as remaining unpartnered and experiencing divorce are associated with more smoking and drinking in midlife, whereas marriage is associated with midlife weight gain. Despite these offsetting influences, differences in health behaviours probably account for much of the association between partnership trajectories and health found in previous studies.
Importance of length and external diameter in left ventricular geometry. Normal values from the HUNT Study
Authors: Støylen Asbjørn , Mølmen Harald E , Dalen Håvard 
Published: September 2016

BackgroundWe aimed to study left ventricular (LV) geometry assessed by length (LVWL), external diameter (LVEDD) and relative wall thickness (RWT) in relation to age, body size and gender in healthy individuals.Methods1266 individuals underwent echocardiography in the Nord-Trøndelag Health Study (HUNT3), Norway. Septum thickness (IVS), posterior wall thickness (LVPWd) and end-diastolic internal diameter (LVIDD) were measured in M-mode, and LVEDD was calculated as the sum. Myocardial wall lengths were measured in a straight line from apex to the mitral ring in apical views at end diastole and averaged to LVWL. RWT ([IVSd+LVPWd]/LVIDD) and the ratio between length and diameter (L/D) were calculated.ResultsNormal age-related and gender-related values are provided. Conventional measures conform to previous studies. All measures correlated with body surface area (BSA) (r 0.29–0.60), and BSA indexed values were higher in women. Wall thickness (WT) and LVEDD, but not LVIDD, were higher with higher age. LVWL and L/D were lower with increasing age, but L/D was independent of BSA and similar in women and men (1.41 vs 1.40). RWT correlated with BSA and age (r 0.17 and 0.34).ConclusionsLV WT increases and LVWL decreases with higher age. Excluding length in LV mass calculations increasingly overestimates mass with ageing. L/D is a BSA independent measure of LV age-related geometry and may be useful as a body size independent measure in LV hypertrophy. RWT depends on body size and age, and a single cut-off value is not warranted.
Alkaline-rich quartz syenite intrusions of the Western Karelia subprovince
Authors: Heilimo Esa , Mikkola Perttu , Huhma Hannu , Halla Jaana 
Published: September 2016

Abstract

We have studied a group of granitoids from the Western Karelia subprovince of the Fennoscandian Shield. This group is referred to as quartz syenites, but shows compositional variation from syenites to quartz monzonites, with a small number of monzonites and granites. Compositionally studied rocks are alkali and alkali-calcic, and magnesian, mostly metaluminous. Characteristically, they have a high content of alkaline (Na, K), large ion lithophile elements (LILE) (Ba, Sr), high-field strength elements (HFSE) (TiO
2
, Zr, Ce), as well as a low content of Mg, Ni and Cr, by which they can be distinguished from sanukitoid and quartz diorite suites of the Karelia Province. These quartz syenites were emplaced between 2.74 and 2.66 Ga, representing late-phase intrusions overlapping in age with the sanukitoids, the quartz diorites and the leucogranitoids. Initial whole-rock ε
Nd
values of quartz syenites vary from 1.8 to −1.8, and do not indicate a significant contribution of considerably older crust. Oxygen-isotope data for zircon indicate a varying mantle source (δ
18
O 5.35–7.15‰), with a contribution from source(s) with elevated δ
18
O values. Our data provide constraints on compositionally diverse Neoarchaean magmatism in the Archaean Karelia Province. The late Archaean evolution of the Western Karelia subprovince resembles that of the Neoarchean domains worldwide with respect to granitoid composition and temporal distribution.

Supplementary material:
Tables detailing geochemical analyses, analytical data for the five age samples and oxygen-isotope analyses from this study are available at
https://doi.org/10.6084/m9.figshare.c.3459771
Adding art to STEM
Authors: Cook Perry R. 
Published: September 2016

The
Communications
Web site, http://cacm.acm.org, features more than a dozen bloggers in the BLOG@CACM community. In each issue of
Communications
, we'll publish selected posts or excerpts.

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Follow us on Twitter at http://twitter.com/blogCACM
http://cacm.acm.org/blogs/blog-cacm
Perry R. Cook considers the career path that led him to STEAM.
Baby Boomers and Birth Certificates: Early-Life Socioeconomic Status and Cancer Risk in Adulthood
Authors: Stroup Antoinette M. , Herget Kimberly A. , Hanson Heidi A. , Reed Diana Lane , Butler Jared T. , Henry Kevin A. , Harrell C. Janna , Sweeney Carol , Smith Ken R. 
Published: September 2016

Abstract
Background: Early-life socioeconomic status (SES) may play a role in cancer risk in adulthood. However, measuring SES retrospectively presents challenges. Parental occupation on the birth certificate is a novel method of ascertaining early-life SES that has not been applied in cancer epidemiology.
Methods: For a Baby-Boom cohort born from 1945–1959 in two Utah counties, individual-level Nam-Powers SES (Np-SES) was derived from parental industry/occupation reported on birth certificates. Neighborhood SES was estimated from average household income of census tract at birth. Cancer incidence was determined by linkage to Utah Cancer Registry records through the Utah Population Database. Hazard ratios (HR) for cancer risk by SES quartile were estimated using Cox proportional hazards regression.
Results: Females with low Np-SES at birth had lower risk of breast cancer compared with those in the highest Np-SES group [HRQ1/Q4 = 0.83; 95% confidence interval (CI), 0.72–0.97; HRQ2/Q4 = 0.81; 95% CI, 0.69–0.96]. Np-SES was inversely associated with melanoma (HRQ1/Q4 = 0.81; 95% CI, 0.67–0.98) and prostate cancer (HRQ1/Q4 = 0.70; 95% CI, 0.56–0.88). Women born into lower SES neighborhoods had significantly increased risk for invasive cervical cancer (HRQ1/Q4 = 1.44; 95% CI, 1.12–1.85; HRQ2/Q4 = 1.33; 95% CI, 1.04–1.72). Neighborhood SES had similar effects for melanoma and prostate cancers, but was not associated with female breast cancer. We found no association with SES for pancreas, lung, and colon and rectal cancers.
Conclusions: Individual SES derived from parental occupation at birth was associated with altered risk for several cancer sites.
Impact: This novel methodology can contribute to improved understanding of the role of early-life SES on cancer risk. Cancer Epidemiol Biomarkers Prev; 26(1); 75–84. ©2016 AACR.