bluuebunny/crossref_metadata_2025_split huggingface dataset:
MicroRNA 373 Facilitates the Replication of Porcine Reproductive and Respiratory Syndrome Virus by Its Negative Regulation of Type I Interferon Induction
Authors: Chen Jing , Shi Xibao , Zhang Xiaozhuan , Wang Aiping , Wang Li , Yang Yanyan , Deng Ruiguang , Zhang Gai-Ping 
Published: November 2016

ABSTRACTMicroRNAs (miRNAs) play an important role in the regulation of immune responses. Previous studies have indicated that dysregulating the miRNAs leads to the immunosuppression of porcine reproductive and respiratory syndrome virus (PRRSV). However, it is not clear how PRRSV regulates the expression of host miRNA, which may lead to immune escape or promote the replication of the virus. The present work suggests that PRRSV upregulated the expression of miR-373 through elevating the expression of specificity protein 1 (Sp1) in MARC-145 cells. Furthermore, this work demonstrated that miR-373 promoted the replication of PRRSV, since miR-373 was a novel negative miRNA for the production of beta interferon (IFN-β) by targeting nuclear factor IA (NFIA), NFIB, interleukin-1 receptor-associated kinase 1 (IRAK1), IRAK4, and interferon regulatory factor 1 (IRF1). We also found that both NFIA and NFIB were novel proteins for inducing the production of IFN-β, and both of them could inhibit the replication of PRRSV. In conclusion, PRRSV upregulated the expression of miR-373 by elevating the expression of Sp1 and hijacked the host miR-373 to promote the replication of PRRSV by negatively regulating the production of IFN-β.IMPORTANCEPRRSV causes one of the most economically devastating diseases of swine, and there is no effective method for controlling PRRSV. It is not clear how PRRSV inhibits the host's immune response and induces persistent infection. Previous studies have shown that PRRSV inhibited the production of type I IFN, and the treatment of type I IFN could efficiently inhibit the replication of PRRSV, so it will be helpful to design new methods of controlling PRRSV by understanding the molecular mechanism by which PRRSV modulated the production of IFN. The current work shows that miR-373, upregulated by PRRSV, promotes PRRSV replication, since miR-373 impaired the production of IFN-β by targeting NFIA, NFIB, IRAK1, IRAK4, and IRF1, and both NFIA and NFIB were antiviral proteins to PRRSV. In conclusion, this paper revealed a novel mechanism of PRRSV that impaired the production of type I IFN by upregulating miR-373 expression in MARC-145 cells.
Inclusion Body Fusion of Human Parainfluenza Virus Type 3 Regulated by Acetylated α-Tubulin Enhances Viral Replication
Authors: Zhang Shengwei , Jiang Yanliang , Cheng Qi , Zhong Yi , Qin Yali , Chen Mingzhou 
Published: November 2016

ABSTRACT
Viral inclusion bodies (IBs), or replication factories, are unique structures generated by viral proteins together with some cellular proteins as a platform for efficient viral replication, but little is known about the mechanism underlying IB formation and fusion. Our previous study demonstrated that the interaction between the nucleoprotein (N) and phosphoprotein (P) of human parainfluenza virus type 3 (HPIV3), an enveloped virus with great medical impact, can form IBs. In this study, we found that small IBs can fuse with each other to form large IBs that enhance viral replication. Furthermore, we found that acetylated α-tubulin interacts with the N-P complex and colocalizes with IBs of HPIV3 but does not interact with the N-P complex of human respiratory syncytial virus or vesicular stomatitis virus and does not colocalize with IBs of human respiratory syncytial virus. Most importantly, enhancement of α-tubulin acetylation using the pharmacological inhibitor trichostatin A (TSA), RNA interference (RNAi) knockdown of the deacetylase enzymes histone deacetylase 6 (HDAC6) and sirtuin 2 (SIRT2), or expression of α-tubulin acetyltransferase 1 (α-TAT1) resulted in the fusion of small IBs into large IBs and effective viral replication. In contrast, suppression of acetylation of α-tubulin by overexpressing HDAC6 and SIRT2 profoundly inhibited the fusion of small IBs and viral replication. Our findings offer previously unidentified mechanistic insights into the regulation of viral IB fusion by acetylated α-tubulin, which is critical for viral replication.

IMPORTANCE
Inclusion bodies (IBs) are unique structures generated by viral proteins and some cellular proteins as a platform for efficient viral replication. Human parainfluenza virus type 3 (HPIV3) is a nonsegmented single-stranded RNA virus that mainly causes lower respiratory tract disease in infants and young children. However, no vaccines or antiviral drugs for HPIV3 are available. Therefore, understanding virus-host interactions and developing new antiviral strategies are increasingly important. Acetylation on lysine (K) 40 of α-tubulin is an evolutionarily conserved modification and plays an important role in many cellular processes, but its role in viral IB dynamics has not been fully explored. To our knowledge, our findings are the first to show that acetylated α-tubulin enhances viral replication by regulating HPIV3 IB fusion.
Phylogenetic Diversity of Koala Retrovirus within a Wild Koala Population
Authors: Chappell K. J. , Brealey J. C. , Amarilla A. A. , Watterson D. , Hulse L. , Palmieri C. , Johnston S. D. , Holmes E. C. , Meers J. , Young P. R. 
Published: November 2016

ABSTRACT
Koala populations are in serious decline across many areas of mainland Australia, with infectious disease a contributing factor. Koala retrovirus (KoRV) is a gammaretrovirus present in most wild koala populations and captive colonies. Five subtypes of KoRV (A to E) have been identified based on amino acid sequence divergence in a hypervariable region of the receptor binding domain of the envelope protein. However, analysis of viral genetic diversity has been conducted primarily on KoRV in captive koalas housed in zoos in Japan, the United States, and Germany. Wild koalas within Australia have not been comparably assessed. Here we report a detailed analysis of KoRV genetic diversity in samples collected from 18 wild koalas from southeast Queensland. By employing deep sequencing we identified 108 novel KoRV envelope sequences and determined their phylogenetic diversity. Genetic diversity in KoRV was abundant and fell into three major groups; two comprised the previously identified subtypes A and B, while the third contained the remaining hypervariable region subtypes (C, D, and E) as well as four hypervariable region subtypes that we newly define here (F, G, H, and I). In addition to the ubiquitous presence of KoRV-A, which may represent an exclusively endogenous variant, subtypes B, D, and F were found to be at high prevalence, while subtypes G, H, and I were present in a smaller number of animals.

IMPORTANCE
Koala retrovirus (KoRV) is thought to be a significant contributor to koala disease and population decline across mainland Australia. This study is the first to determine KoRV subtype prevalence among a wild koala population, and it significantly expands the total number of KoRV sequences available, providing a more precise picture of genetic diversity. This understanding of KoRV subtype prevalence and genetic diversity will be important for conservation efforts attempting to limit the spread of KoRV. Furthermore, KoRV is one of the only retroviruses shown to exist in both endogenous (transmitted vertically to offspring in the germ line DNA) and exogenous (horizontally transmitted between infected individuals) forms, a division of fundamental evolutionary importance.
Activation and Inactivation of Primary Human Immunodeficiency Virus Envelope Glycoprotein Trimers by CD4-Mimetic Compounds
Authors: Madani Navid , Princiotto Amy M. , Zhao Connie , Jahanbakhshsefidi Fatemeh , Mertens Max , Herschhorn Alon , Melillo Bruno , Smith Amos B. , Sodroski Joseph 
Published: November 2016

ABSTRACT
Human immunodeficiency virus type 1 (HIV-1) entry into cells is mediated by the viral envelope glycoproteins (Env), a trimer of three gp120 exterior glycoproteins, and three gp41 transmembrane glycoproteins. The metastable Env is triggered to undergo entry-related conformational changes when gp120 binds sequentially to the receptors, CD4 and CCR5, on the target cell. Small-molecule CD4-mimetic compounds (CD4mc) bind gp120 and act as competitive inhibitors of gp120-CD4 engagement. Some CD4mc have been shown to trigger Env prematurely, initially activating Env function, followed by rapid and irreversible inactivation. Here, we study CD4mc with a wide range of anti-HIV-1 potencies and demonstrate that all tested CD4mc are capable of activating as well as inactivating Env function. Biphasic dose-response curves indicated that the occupancy of the protomers in the Env trimer governs viral activation versus inactivation. One CD4mc bound per Env trimer activated HIV-1 infection. Envs with two CD4mc bound were activated for infection of CD4-negative, CCR5-positive cells, but the infection of CD4-positive, CCR5-positive cells was inhibited. Virus was inactivated when all three Env protomers were occupied by the CD4mc, and gp120 shedding from the Env trimer was increased in the presence of some CD4mc. Env reactivity and the on rates of CD4mc binding to the Env trimer were found to be important determinants of the potency of activation and entry inhibition. Cross-sensitization of Env protomers that do not bind the CD4mc to neutralization by an anti-V3 antibody was not evident. These insights into the mechanism of antiviral activity of CD4mc should assist efforts to optimize their potency and utility.

IMPORTANCE
The trimeric envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) mediate virus entry into host cells. Binding to the host cell receptors, CD4 and CCR5, triggers changes in the conformation of the HIV-1 envelope glycoprotein trimer important for virus entry. Small-molecule CD4-mimetic compounds inhibit HIV-1 infection by multiple mechanisms: (i) direct blockade of the interaction between the gp120 exterior envelope glycoprotein and CD4; (ii) premature triggering of conformational changes in the envelope glycoproteins, leading to irreversible inactivation; and (iii) exposure of cryptic epitopes to antibodies, allowing virus neutralization. The consequences of the binding of the CD4-mimetic compound to the HIV-1 envelope glycoproteins depends upon how many of the three subunits of the trimer are bound and upon the propensity of the envelope glycoproteins to undergo conformational changes. Understanding the mechanistic factors that influence the activity of CD4-mimetic compounds can help to improve their potency and coverage of diverse HIV-1 strains.
Mechanism of Enhanced HIV Restriction by Virion Coencapsidated Cytidine Deaminases APOBEC3F and APOBEC3G
Authors: Ara Anjuman , Love Robin P. , Follack Tyson B. , Ahmed Khawaja A. , Adolph Madison B. , Chelico Linda 
Published: November 2016

ABSTRACT

The APOBEC3 (A3) enzymes, A3G and A3F, are coordinately expressed in CD4
+
T cells and can become coencapsidated into HIV-1 virions, primarily in the absence of the viral infectivity factor (Vif). A3F and A3G are deoxycytidine deaminases that inhibit HIV-1 replication by inducing guanine-to-adenine hypermutation through deamination of cytosine to form uracil in minus-strand DNA. The effect of the simultaneous presence of both A3G and A3F on HIV-1 restriction ability is not clear. Here, we used a single-cycle infectivity assay and biochemical analyses to determine if coencapsidated A3G and A3F differ in their restriction capacity from A3G or A3F alone. Proviral DNA sequencing demonstrated that compared to each A3 enzyme alone, A3G and A3F, when combined, had a coordinate effect on hypermutation. Using size exclusion chromatography, rotational anisotropy, and
in vitro
deamination assays, we demonstrate that A3F promotes A3G deamination activity by forming an A3F/G hetero-oligomer in the absence of RNA which is more efficient at deaminating cytosines. Further, A3F caused the accumulation of shorter reverse transcripts due to decreasing reverse transcriptase efficiency, which would leave single-stranded minus-strand DNA exposed for longer periods of time, enabling more deamination events to occur. Although A3G and A3F are known to function alongside each other, these data provide evidence for an A3F/G hetero-oligomeric A3 with unique properties compared to each individual counterpart.

IMPORTANCE
The APOBEC3 enzymes APOBEC3F and APOBEC3G act as a barrier to HIV-1 replication in the absence of the HIV-1 Vif protein. After APOBEC3 enzymes are encapsidated into virions, they deaminate cytosines in minus-strand DNA, which forms promutagenic uracils that induce transition mutations or proviral DNA degradation. Even in the presence of Vif, footprints of APOBEC3-catalyzed deaminations are found, demonstrating that APOBEC3s still have discernible activity against HIV-1 in infected individuals. We undertook a study to better understand the activity of coexpressed APOBEC3F and APOBEC3G. The data demonstrate that an APOBEC3F/APOBEC3G hetero-oligomer can form that has unique properties compared to each APOBEC3 alone. This hetero-oligomer has increased efficiency of virus hypermutation, raising the idea that we still may not fully realize the antiviral mechanisms of endogenous APOBEC3 enzymes. Hetero-oligomerization may be a mechanism to increase their antiviral activity in the presence of Vif.
Comparison of therapy persistence for fixed versus free combination antihypertensives: a retrospective cohort study
Authors: Grimmsmann Thomas , Himmel Wolfgang 
Published: November 2016

ObjectivesThe aim of the study was to compare therapy persistence among patients who started with one of three drug regimens: a monotherapy, or combination therapy either as a fixed combination (ie, ‘single pill’) or as a free combination (ie, two separate antihypertensive agents).DesignIn a secondary data analysis, we used descriptive statistics and multivariate logistic regression to measure the effect of the three therapy regimens on therapy persistence over 4 years.SettingPrescription data from a large German statutory health insurance provider.ParticipantsAll patients who started with a new antihypertensive therapy in 2007 or 2008 (n=8032) were included and followed for 4 years.Primary outcome measureTherapy persistence, defined as receiving a refill prescription no later than within 180 days.ResultsThe persistence rates after 4 years were nearly identical among patients who started with a monotherapy (40.3%) or a fixed combination of two drugs (39.8%). However, significantly more patients who started with free-drug combinations remained therapy persistent (56.4%), resulting in an OR of 2.00 (95% CI 1.6 to 2.5; p<0.0001) for free combinations versus fixed combinations. This trend was observed in all age groups and for men and women. At the end of the study period, the number of different antihypertensive agents was still similar between patients who started with a fixed combination (2.41) and patients who started with a free combination (2.28).ConclusionsWhile single-pill combinations make it easier to take different drugs at once, the risk is high that these several substances are stopped at once. Therapy persistence was significantly better for patients who started with a free-drug combination without taking much fewer different antihypertensive drugs as those with a fixed combination.
Rationale and protocol for using a smartphone application to study autism spectrum disorders: SMARTAUTISM
Authors: Bonnot Olivier , Bonneau Dominique , Doudard Aude , Duverger Philippe 
Published: November 2016

IntroductionLongitudinal studies on the evolution of autism spectrum disorder (ASD) symptoms are limited and have primarily used repeated measurements performed several months apart. However, measurements of changes in everyday life should more closely reflect the ‘real life’ of the patient and his or her family. We propose to study the child's ASD symptoms and their effect on the quality of life, psychological status and anxiety of the child's parents over a 6-month period using SMARTAUTISM, a smartphone application.Method and analysisThis is a prospective, longitudinal, exploratory, open study with a 6-month follow-up period. Data will be recorded longitudinally over multiple weeks under natural conditions. The factors affecting the quality of life and anxiety of parents of children with ASD and the children's functional symptoms will be examined, and the feasibility of using a smartphone application designed for parents of ASD patients will be assessed.Primary objective: Explore the evolution of a child's behaviour over 6 months and the (psychological and social) effects of these changes on the family.Secondary objective: Assess the feasibility of our application by examining the filling rate and application usage by parents for 6 months. 100 families containing 1 child diagnosed with ASD will be included. At baseline, sociodemographic, psychiatric and medical data will be recorded. The correlations of the general epidemiological variables (primary outcome measure) will be evaluated via multivariate analysis. The application filling rate (relative to the ideal filling rate) will be used to assess the feasibility of the application (secondary outcome measure).Ethics and disseminationThe SMARTAUTISM study has the approval of the local ethics committee, and data security will be ensured via the use of encryption and a secure medical server. The use of this application will be proposed at autism resource centres across France.
Clinicopathological features of neoplasms with neuroendocrine differentiation occurring in the liver
Authors: Nomura Yoriko , Nakashima Osamu , Akiba Jun , Ogasawara Sachiko , Fukutomi Shogo , Yamaguchi Rin , Kusano Hironori , Kage Masayoshi , Okuda Koji , Yano Hirohisa 
Published: November 2016

Background/aimsWe investigated the clinicopathological features of hepatic neuroendocrine tumours (NET) and neuroendocrine carcinoma (NEC), which remain largely unknown.Material and methodsWe examined 1235 tumours from 1048 patients who had undergone curative hepatectomy for liver neoplasms at Kurume University Hospital. Pathological diagnoses were based on the 2010 WHO Classification of Tumours of the Digestive System. We performed immunostaining for hepatocyte markers (eg, hepatocyte paraffin (HepPar)-1), neuroendocrine markers (eg, chromogranin A (CGA)) and the proliferation marker (Ki-67).ResultsThere were four cases of NET G2 (0.38%) and five of hepatic malignant tumours with an NEC component (HNEC) (0.48%). HNEC cases were classified into three types, that is, transitional, intermediate and separate types, according to their histological and immunohistochemical features. In the former two types, the NEC component intermingled with the moderately to poorly differentiated hepatocellular carcinoma (HCC) component or intermediate component consisting of tumour cells showing the colocalisation of CGA and HepPar-1. In the separate type, the NEC and poorly differentiated HCC components were present separately, whereas the sarcomatous HCC component was detected in the vicinity of the NEC component. Ki-67 labelling indices of the NET G2, HCC and NEC components of HNEC were 6.8%, 14.9% and 58.9%, respectively.ConclusionsPrimary hepatic NET and NEC are very rare tumours. The NEC component in HNEC showed high proliferative activity and influenced patient prognoses.
From Type II string theory toward BSM/dark sector physics
Authors: Honecker Gabriele 
Published: November 2016

Four-dimensional compactifications of string theory provide a controlled set of possible gauge representations accounting for BSM particles and dark sector components. In this review, constraints from perturbative Type II string compactifications in the geometric regime are discussed in detail and then compared to results from heterotic string compactifications and nonperturbative/nongeometric corners. As a prominent example, an open string realization of the QCD axion is presented. The status of deriving the associated low-energy effective action in four dimensions is discussed and open avenues of major phenomenological importance are highlighted. As examples, a mechanism of closed string moduli stabilization by D-brane backreaction as well as one-loop threshold corrections to the gauge couplings and balancing a low string scale [Formula: see text] with unisotropic compact dimensions are discussed together with implications on potential future new physics observations. For illustrative purposes, an explicit example of a globally consistent D6-brane model with MSSM-like spectrum on [Formula: see text] is presented.
Alterations of colonic function in theWinniemouse model of spontaneous chronic colitis
Authors: Robinson Ainsley M. , Rahman Ahmed A. , Carbone Simona E. , Randall-Demllo Sarron , Filippone Rhiannon , Bornstein Joel C. , Eri Rajaraman , Nurgali Kulmira 
Published: November 2016

The Winnie mouse, carrying a missense mutation in Muc2, is a model for chronic intestinal inflammation demonstrating symptoms closely resembling inflammatory bowel disease (IBD). Alterations to the immune environment, morphological structure, and innervation of Winnie mouse colon have been identified; however, analyses of intestinal transit and colonic functions have not been conducted. In this study, we investigated in vivo intestinal transit in radiographic studies and in vitro motility of the isolated colon in organ bath experiments. We compared neuromuscular transmission using conventional intracellular recording between distal colon of Winnie and C57BL/6 mice and smooth muscle contractions using force displacement transducers. Chronic inflammation in Winnie mice was confirmed by detection of lipocalin-2 in fecal samples over 4 wk and gross morphological damage to the colon. Colonic transit was faster in Winnie mice. Motility was altered including decreased frequency and increased speed of colonic migrating motor complexes and increased occurrence of short and fragmented contractions. The mechanisms underlying colon dysfunctions in Winnie mice included inhibition of excitatory and fast inhibitory junction potentials, diminished smooth muscle responses to cholinergic and nitrergic stimulation, and increased number of α-smooth muscle actin-immunoreactive cells. We conclude that diminished excitatory responses occur both prejunctionally and postjunctionally and reduced inhibitory purinergic responses are potentially a prejunctional event, while diminished nitrergic inhibitory responses are probably due to a postjunction mechanism in the Winnie mouse colon. Many of these changes are similar to disturbed motor functions in IBD patients indicating that the Winnie mouse is a model highly representative of human IBD.NEW & NOTEWORTHY This is the first study to provide analyses of intestinal transit and whole colon motility in an animal model of spontaneous chronic colitis. We found that cholinergic and purinergic neuromuscular transmission, as well as the smooth muscle cell responses to cholinergic and nitrergic stimulation, is altered in the chronically inflamed Winnie mouse colon. The changes to intestinal transit and colonic function we identified in the Winnie mouse are similar to those seen in inflammatory bowel disease patients.