bluuebunny/crossref_metadata_2025_split huggingface dataset:
Palmitoylation Contributes to Membrane Curvature in Influenza A Virus Assembly and Hemagglutinin-Mediated Membrane Fusion
Authors: Chlanda Petr , Mekhedov Elena , Waters Hang , Sodt Alexander , Schwartz Cindi , Nair Vinod , Blank Paul S. , Zimmerberg Joshua 
Published: August 2017

ABSTRACTThe highly conserved cytoplasmic tail of influenza virus glycoprotein hemagglutinin (HA) contains three cysteines, posttranslationally modified by covalently bound fatty acids. While viral HA acylation is crucial in virus replication, its physico-chemical role is unknown. We used virus-like particles (VLP) to study the effect of acylation on morphology, protein incorporation, lipid composition, and membrane fusion. Deacylation interrupted HA-M1 interactions since deacylated mutant HA failed to incorporate an M1 layer within spheroidal VLP, and filamentous particles incorporated increased numbers of neuraminidase (NA). While HA acylation did not influence VLP shape, lipid composition, or HA lateral spacing, acylation significantly affected envelope curvature. Compared to wild-type HA, deacylated HA is correlated with released particles with flat envelope curvature in the absence of the matrix (M1) protein layer. The spontaneous curvature of palmitate was calculated by molecular dynamic simulations and was found to be comparable to the curvature values derived from VLP size distributions. Cell-cell fusion assays show a strain-independent failure of fusion pore enlargement among H2 (A/Japan/305/57), H3 (A/Aichi/2/68), and H3 (A/Udorn/72) viruses. In contradistinction, acylation made no difference in the low-pH-dependent fusion of isolated VLPs to liposomes: fusion pores formed and expanded, as demonstrated by the presence of complete fusion products observed using cryo-electron tomography (cryo-ET). We propose that the primary mechanism of action of acylation is to control membrane curvature and to modify HA's interaction with M1 protein, while the stunting of fusion by deacylated HA acting in isolation may be balanced by other viral proteins which help lower the energetic barrier to pore expansion.IMPORTANCEInfluenza A virus is an airborne pathogen causing seasonal epidemics and occasional pandemics. Hemagglutinin (HA), a glycoprotein abundant on the virion surface, is important in both influenza A virus assembly and entry. HA is modified by acylation whose removal abrogates viral replication. Here, we used cryo-electron tomography to obtain three-dimensional images to elucidate a role for HA acylation in VLP assembly. Our data indicate that HA acylation contributes to the capability of HA to bend membranes and to HA's interaction with the M1 scaffold protein during virus assembly. Furthermore, our data on VLP and, by hypothesis, virus suggests that HA acylation, while not critical to fusion pore formation, contributes to pore expansion in a target-dependent fashion.
Highly Pathogenic New World Arenavirus Infection Activates the Pattern Recognition Receptor Protein Kinase R without Attenuating Virus Replication in Human Cells
Authors: Huang Cheng , Kolokoltsova Olga A. , Mateer Elizabeth J. , Koma Takaaki , Paessler Slobodan 
Published: August 2017

ABSTRACT
The arenavirus family consists of several highly pathogenic viruses, including the Old World (OW) arenavirus Lassa fever virus (LASV) and the New World (NW) Junin virus (JUNV) and Machupo virus (MACV). Host response to infection by these pathogenic arenaviruses is distinct in many aspects. JUNV and MACV infections readily induce an interferon (IFN) response in human cells, while LASV infection usually triggers an undetectable or weak IFN response. JUNV induces an IFN response through RIG-I, suggesting that the host non-self RNA sensor readily detects JUNV viral RNAs (vRNAs) during infection and activates IFN response. Double-stranded-RNA (dsRNA)-activated protein kinase R (PKR) is another host non-self RNA sensor classically known for its vRNA recognition activity. Here we report that infection with NW arenaviruses JUNV and MACV, but not OW LASV, activated PKR, concomitant with elevated phosphorylation of the translation initiation factor α subunit of eukaryotic initiation factor 2 (eIF2α). Host protein synthesis was substantially suppressed in MACV- and JUNV-infected cells but was only marginally reduced in LASV-infected cells. Despite the antiviral activity known for PKR against many other viruses, the replication of JUNV and MACV was not impaired but was slightly augmented in wild-type (wt) cells compared to that in PKR-deficient cells, suggesting that PKR or PKR activation did not negatively affect JUNV and MACV infection. Additionally, we found an enhanced IFN response in JUNV- or MACV-infected PKR-deficient cells, which was inversely correlated with virus replication.

IMPORTANCE
The detection of viral RNA by host non-self RNA sensors, including RIG-I and MDA5, is critical to the initiation of the innate immune response to RNA virus infection. Among pathogenic arenaviruses, the OW LASV usually does not elicit an interferon response. However, the NW arenaviruses JUNV and MACV readily trigger an IFN response in a RIG-I-dependent manner. Here, we demonstrate for the first time that pathogenic NW arenaviruses JUNV and MACV, but not the OW arenavirus LASV, activated the dsRNA-dependent PKR, another host non-self RNA sensor, during infection. Interestingly, the replication of JUNV and MACV was not restricted but was rather slightly augmented in the presence of PKR. Our data provide new evidence for a distinct interplay between host non-self RNA sensors and pathogenic arenaviruses, which also provides insights into the pathogenesis of arenaviruses and may facilitate the design of vaccines and treatments against arenavirus-caused diseases.
Hepatitis C Virus Core Protein Modulates Endoglin (CD105) Signaling Pathway for Liver Pathogenesis
Authors: Kwon Young-Chan , Sasaki Reina , Meyer Keith , Ray Ranjit 
Published: August 2017

ABSTRACT

Endoglin is part of the TGF-β receptor complex and has a crucial role in fibrogenesis and angiogenesis. It is also an important protein for tumor growth, survival, and cancer cell metastasis. In a previous study, we have shown that hepatitis C virus (HCV) infection induces epithelial-mesenchymal transition (EMT) state and cancer stem-like cell (CSC) properties in human hepatocytes. Our array data suggested that endoglin (CD105) mRNA is significantly upregulated in HCV-associated CSCs. In this study, we have observed increased endoglin expression on the cell surface of an HCV core-expressing hepatocellular carcinoma (HepG2) cell line or immortalized human hepatocytes (IHH) and activation of its downstream signaling molecules. The status of phospho-SMAD1/5 and the expression of inhibitor of DNA binding protein 1 (ID1) were upregulated in HCV-infected cells or viral core gene-transfected cells. Additionally, we observed upregulation of endoglin/ID1 mRNA expression in chronic HCV patient liver biopsy samples. CSC generation by HCV core protein was dependent on the endoglin signaling pathway using activin receptor-like kinase 1 (ALK1) Fc blocking peptide and endoglin small interfering RNA (siRNA). Further, follow-up from
in vitro
analysis suggested that the antiapoptosis Bcl2 protein, proliferation-related cyclin D1 protein, and CSC-associated Hes1, Notch1, Nanog, and Sox2 proteins are enhanced during infection or ectopic expression of HCV core protein.

IMPORTANCE
Endoglin plays a crucial role in fibrogenesis and angiogenesis and is an important protein for tumor growth, survival, and cancer cell metastasis. Endoglin enhances ALK1-SMAD1/5 signaling in different cell types, leading to increased proliferation and migration responses. We have observed endoglin expression on the HCV core-expressing cell surface of human hepatocyte origin and activation of phospho-SMAD1/5 and ID1 downstream signaling molecules. ID1 protein plays a role in CSC properties, and we found that this pathway is important for antiapoptotic and cell proliferation signaling. Blocking of endoglin-ALK1-SMAD1/5 might be a good candidate for therapy for liver cancer stem cells together with liver cirrhosis.
Malpractice claims related to diagnostic errors in the hospital
Authors: Gupta Ashwin , Snyder Ashley , Kachalia Allen , Flanders Scott , Saint Sanjay , Chopra Vineet 
Published: August 2017

BackgroundLittle is known about the incidence or significance of diagnostic error in the inpatient setting. We used a malpractice claims database to examine incidence, predictors and consequences of diagnosis-related paid malpractice claims in hospitalised patients.MethodsThe US National Practitioner Database was used to identify paid malpractice claims occurring between 1 January 1999 and 31 December 2011. Patient and provider characteristics associated with paid claims were analysed using descriptive statistics. Differences between diagnosis-related paid claims and other paid claim types (eg, surgical, anaesthesia, medication) were assessed using Wilcoxon rank-sum and χ2 tests. Multivariable logistic regression was used to identify patient and provider factors associated with diagnosis-related paid claims. Trends for incidence of diagnosis-related paid claims and median annual payment were assessed using the Cochran-Armitage and non-parametric trend test.Results13 682 of 62 966 paid malpractice claims (22%) were diagnosis-related. Compared with other paid claim types, characteristics significantly associated with diagnosis-related paid claims were as follows: male patients, patient aged >50 years, provider aged <50 years and providers in the northeast region. Compared with other paid claim types, diagnosis-related paid claims were associated with 1.83 times more risk of disability (95% CI 1.75 to 1.91; p<0.001) and 2.33 times more risk of death (95% CI 2.23 to 2.43; p<0.001) than minor injury, after adjusting for patient and provider characteristics. Inpatient diagnostic error accounted for $5.7 billion in payments over the study period, and median diagnosis-related payments increased at a rate disproportionate to other types.ConclusionInpatient diagnosis-related malpractice payments are common and more often associated with disability and death than other claim types. Research focused on understanding and mitigating diagnostic errors in hospital settings is necessary.
Dog ownership supports the maintenance of physical activity during poor weather in older English adults: cross-sectional results from the EPIC Norfolk cohort
Authors: Wu Yu-Tzu , Luben Robert , Jones Andy 
Published: August 2017

BackgroundDog ownership has been suggested to encourage physical activity in older adults and may enhance resilience to poor environmental conditions. This study investigates the role of dog ownership and walking as a means of supporting the maintenance of physical activity in older adults during periods of inclement weather.MethodsThe analysis used data from the European Prospective Investigation into Cancer and Nutrition Norfolk cohort. Daily physical activity (counts per minute) and minutes of sedentary behaviour were measured using accelerometers over 7 days. Three types of environmental conditions, day length, precipitation and maximum temperature, were date matched with daily physical activity. A multilevel first-order autoregressive time-series model quantified the moderating effect of self-reported dog ownership and walking on the association between physical activity and weather factors.ResultsAmong the 3123 participants, 18% reported having a dog in their households and two-thirds of dog owners walked their dogs at least once a day. Regular dog walkers were more active and less sedentary on days with the poorest conditions than non-dog owners were on the days with the best conditions. In days with the worst conditions, those who walked their dogs had 20% higher activity levels than non-dog owners and spent 30 min/day less sedentary.ConclusionThose who walked dogs were consistently more physically active than those who did not regardless of environmental conditions. These large differences suggest that dog walking, where appropriate, can be a component of interventions to support physical activity in older adults.
Evaluation of the health impact of an urban regeneration policy: Neighbourhood Renewal in Northern Ireland
Authors: Mohan Gretta , Longo Alberto , Kee Frank 
Published: August 2017

BackgroundNeighbourhood Renewal (NR) was launched in Northern Ireland (NI) in 2003 to revive the social, economic and physical fabric of 36 deprived communities, characterised by a legacy of sectarian conflict. This study evaluates the impact of the policy on health over a decade.MethodsA merged panel of secondary data from the British Household Panel Survey (2001–2008) and Understanding Society (2009–2012) yields longitudinal information on respondents for 12 years.We conducted a controlled before and after investigation for NR intervention areas (NRAs) and three control groups—two groups of comparably deprived areas that did not receive assistance and the rest of NI. Linear difference-in-difference regression was used to identify the impact of NR on mental health, self-rated health, life satisfaction, smoking and exercise. Subgroup analysis was conducted for males and females, higher and lower educated, retired, unemployed and home owner groups.ResultsNR did not have a discernible impact on mental distress. A small, non-significant trend towards a reduction in the gap of good self-rated health and life satisfaction between NRAs and controls was observed. A 10% increase in probability of rating life as satisfying was uncovered for retirees in NRAs compared with the rest of NI. Smoking in NRAs declined on par with people from control areas, so a NR influence was not obvious. A steady rise in undertaking weekly exercise in NRAs compared with controls was not statistically significant.ConclusionsArea-based initiatives may not achieve health gains beyond mainstream service provision, though they may safeguard against widening of health disparities.
Compact static stars in minimal dilatonic gravity
Authors: Fiziev Plamen P. 
Published: August 2017

In the version1 of this paper we presented for the first time the basic equations and relations for relativistic static spherically symmetric stars (SSSS) in the model of minimal dilatonic gravity (MDG). This model is locally equivalent to the f(R) theory of gravity and gives an alternative description of the effects of dark matter and dark energy using the Brans–Dicke dilaton [Formula: see text]. To outline the basic properties of the MDG model of SSSS and to compare them with general relativistic results, in this paper we use the relativistic equation of state (EOS) of neutron matter as an ideal Fermi neutron gas at zero temperature. We overcome the well-known difficulties of the physics of SSSS in the f(R) theories of gravity[Formula: see text] applying novel highly nontrivial nonlinear boundary conditions, which depend on the global properties of the solution and on the EOS. We also introduce two pairs of new notions: cosmological–energy–pressure densities and dilaton–energy–pressure densities, as well as two new EOSs for them: cosmological EOS (CEOS) and dilaton EOS (DEOS). Special attention is paid to the dilatonic sphere (in brief — disphere) of SSSS, introduced in this paper for the first time. Using several realistic EOS for neutron star (NS): SLy, BSk19, BSk20 and BSk21, and current observational two-solar-masses-limit, we derive an estimate for scalar-field-mass [Formula: see text]. Thus, the present version of the paper reflects some of the recent developments of the topic.
Influence of nickel substitution on crystal structure and magnetic properties of strontium ferrite preparation via sol-gel auto-combustion route
Authors: Roohani Ebrahim , Arabi Hadi , Sarhaddi Reza 
Published: August 2017

In this research, SrFe[Formula: see text]Ni[Formula: see text]O[Formula: see text] (x [Formula: see text] 0 − 1) hexagonal ferrites were prepared by sol-gel auto-combustion method. Effect of Ni substitution on structural, morphological and magnetic properties of nanoparticles was investigated by X-ray diffraction (XRD), Fourier transform infrared (FT-IR), Transmission electron microscopy (TEM) and vibrating sample magnetometer (VSM), respectively. The XRD results confirmed that all samples with x [Formula: see text] 0.5 have single phase M-type strontium ferrite structure, whereas for the SrFe[Formula: see text]Ni[Formula: see text]O[Formula: see text] samples with x [Formula: see text] 0.5, the spinel NiFe2O4 phase has also appeared. The lattice parameters and crystallite sizes of the powders were concluded from the XRD data and Williamson–Hall method. Magnetic analyses showed that the coercivity of powders decreased from 5672 Oe to 639 Oe while the saturation magnetization increased from 74 emu/g to 81 emu/g with nickel substitution. The results of this study suggest that the strontium hexaferrites doped with Ni are suitable for applications in high density magnetic recording media as well as microwave devices because of their promising magnetic properties.
Aerobic exercise elevates markers of angiogenesis and macrophage IL-6 gene expression in the subcutaneous adipose tissue of overweight-to-obese adults
Authors: Van Pelt Douglas W. , Guth Lisa M. , Horowitz Jeffrey F. 
Published: August 2017

Alterations in the inflammatory state, metabolic function, and structure of subcutaneous adipose tissue (SAT) can impact the development of insulin resistance in obesity. Exercise can improve metabolic health in obesity, but the effects of exercise on SAT are not well known. The purpose of this study was to examine the effects of acute exercise and habitual exercise training on mRNA expression of markers of lipid metabolism, inflammation, fibrosis, and hypoxia/angiogenesis in SAT, as well as adipocyte cell size. We recruited overweight-to-obese adults who exercised regularly (ACTIVE: n = 8) or were sedentary (SED: n = 12). The groups were well matched for age (27 ± 1 vs. 24 ± 2 yr), body mass index (29 ± 1 vs. 27 ± 1 kg/m2), and body composition (30 ± 1 vs. 29 ± 1% body fat), but as expected, cardiorespiratory fitness was greater in ACTIVE vs. SED (V̇o2peak: 51 ± 3 vs. 42 ± 1 ml·kg fat-free mass−1·min−1; P = 0.01). Abdominal SAT biopsy samples were obtained before and 1 h after a single session of aerobic exercise (60 min at ~65% V̇o2peak). The exercise session increased SAT mRNA expression of VEGFA, an important regulator of angiogenic processes, in both groups. In addition, SAT from ACTIVE subjects had greater mRNA expression of the endothelial cell marker CD31 compared with SED, which may be a cumulative effect of the transient increases in VEGFA with regular exercise. We also magnetically sorted CD14+ immune cells from SAT samples and found that IL-6 expression was elevated in ACTIVE compared with SED. In conclusion, exercise initiates increases in factors related to angiogenic processes and may promote alterations in macrophage inflammation in SAT. NEW & NOTEWORTHY Acute exercise in overweight/obese adults increased subcutaneous adipose tissue (SAT) mRNA expression of VEGFA, an important regulator of angiogenesis and capillary growth. In addition, subjects that regularly exercise had elevated SAT CD31 mRNA expression and elevated IL-6 mRNA in adipose tissue macrophages compared with nonexercisers. This study demonstrates that aerobic exercise may alter processes related to whole body metabolic outcomes in obesity, such as angiogenesis and immune response, in the SAT of overweight/obese adults.
Imaging IGF-I uptake in growth plate cartilage using in vivo multiphoton microscopy
Authors: Serrat Maria A. , Ion Gabriela 
Published: August 2017

Bones elongate through endochondral ossification in cartilaginous growth plates located at ends of primary long bones. Linear growth ensues from a cascade of biochemical signals initiated by actions of systemic and local regulators on growth plate chondrocytes. Although cellular processes are well defined, there is a fundamental gap in understanding how growth regulators are physically transported from surrounding blood vessels into and through dense, avascular cartilage matrix. Intravital imaging using in vivo multiphoton microscopy is one promising strategy to overcome this barrier by quantitatively tracking molecular delivery to cartilage from the vasculature in real time. We previously used in vivo multiphoton imaging to show that hindlimb heating increases vascular access of large molecules to growth plates using 10-, 40-, and 70-kDa dextran tracers. To comparatively evaluate transport of similarly sized physiological regulators, we developed and validated methods for measuring uptake of biologically active IGF-I into proximal tibial growth plates of live 5-wk-old mice. We demonstrate that fluorescently labeled IGF-I (8.2 kDa) is readily taken up in the growth plate and localizes to chondrocytes. Bioactivity tests performed on cultured metatarsal bones confirmed that the labeled protein is functional, assessed by phosphorylation of its signaling kinase, Akt. This methodology, which can be broadly applied to many different proteins and tissues, is relevant for understanding factors that affect delivery of biologically relevant molecules to the skeleton in real time. Results may lead to the development of drug-targeting strategies to treat a wide range of bone and cartilage pathologies. NEW & NOTEWORTHY This paper describes and validates a novel method for imaging transport of biologically active, fluorescently labeled IGF-I into skeletal growth plates of live mice using multiphoton microscopy. Cellular patterns of fluorescence in the growth plate were completely distinct from our prior publications using biologically inert probes, demonstrating for the first time in vivo localization of IGF-I in chondrocytes and perichondrium. These results form important groundwork for future studies aimed at targeting therapeutics into growth plates.
Cardiac output by pulse contour analysis does not match the increase measured by rebreathing during human spaceflight
Authors: Hughson Richard L. , Peterson Sean D. , Yee Nicholas J. , Greaves Danielle K. 
Published: August 2017

Pulse contour analysis of the noninvasive finger arterial pressure waveform provides a convenient means to estimate cardiac output (Q̇). The method has been compared with standard methods under a range of conditions but never before during spaceflight. We compared pulse contour analysis with the Modelflow algorithm to estimates of Q̇ obtained by rebreathing during preflight baseline testing and during the final month of long-duration spaceflight in nine healthy male astronauts. By Modelflow analysis, stroke volume was greater in supine baseline than seated baseline or inflight. Heart rate was reduced in supine baseline so that there were no differences in Q̇ by Modelflow estimate between the supine (7.02 ± 1.31 l/min, means ± SD), seated (6.60 ± 1.95 l/min), or inflight (5.91 ± 1.15 l/min) conditions. In contrast, rebreathing estimates of Q̇ increased from seated baseline (4.76 ± 0.67 l/min) to inflight (7.00 ± 1.39 l/min, significant interaction effect of method and spaceflight, P < 0.001). Pulse contour analysis utilizes a three-element Windkessel model that incorporates parameters dependent on aortic pressure-area relationships that are assumed to represent the entire circulation. We propose that a large increase in vascular compliance in the splanchnic circulation invalidates the model under conditions of spaceflight. Future spaceflight research measuring cardiac function needs to consider this important limitation for assessing absolute values of Q̇ and stroke volume. NEW & NOTEWORTHY Noninvasive assessment of cardiac function during human spaceflight is an important tool to monitor astronaut health. This study demonstrated that pulse contour analysis of finger arterial blood pressure to estimate cardiac output failed to track the 46% increase measured by a rebreathing method. These results strongly suggest that alternative methods not dependent on pulse contour analysis are required to track cardiac function in spaceflight.