bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficient Vpu-Mediated Tetherin Antagonism by an HIV-1 Group O Strain
Authors: Mack Katharina , Starz Kathrin , Sauter Daniel , Langer Simon , Bibollet-Ruche Frederic , Learn Gerald H. , Stürzel Christina M. , Leoz Marie , Plantier Jean-Christophe , Geyer Matthias , Hahn Beatrice H. , Kirchhoff Frank 
Published: January 2017

ABSTRACT

Simian immunodeficiency viruses (SIVs) use their Nef proteins to counteract the restriction factor tetherin. However, a deletion in human tetherin prevents antagonism by the Nef proteins of SIVcpz and SIVgor, which represent the ape precursors of human immunodeficiency virus type 1 (HIV-1). To promote virus release from infected cells, pandemic HIV-1 group M strains evolved Vpu as a tetherin antagonist, while the Nef protein of less widespread HIV-1 group O strains acquired the ability to target a region adjacent to this deletion. In this study, we identified an unusual HIV-1 group O strain (RBF206) that evolved Vpu as an effective antagonist of human tetherin. While both RBF206 Vpu and Nef exert anti-tetherin activity in transient-transfection assays, mainly Vpu promotes RBF206 release in infected CD4
+
T cells. Although mutations distinct from the adaptive changes observed in group M Vpus (M-Vpus) were critical for the acquisition of its anti-tetherin activity, RBF206 O-Vpu potently suppresses NF-κB activation and reduces CD4 cell surface expression. Interestingly, RBF206 Vpu counteracts tetherin in a largely species-independent manner, degrading both the long and short isoforms of human tetherin. Downmodulation of CD4, but not counteraction of tetherin, by RBF206 Vpu was dependent on the cellular ubiquitin ligase machinery. Our data present the first example of an HIV-1 group O Vpu that efficiently antagonizes human tetherin and suggest that counteraction by O-Nefs may be suboptimal.

IMPORTANCE
Previous studies showed that HIV-1 groups M and O evolved two alternative strategies to counteract the human ortholog of the restriction factor tetherin. While HIV-1 group M switched from Nef to Vpu due to a deletion in the cytoplasmic domain of human tetherin, HIV-1 group O, which lacks Vpu-mediated anti-tetherin activity, acquired a Nef protein that is able to target a region adjacent to the deletion. Here we report an unusual exception, identifying a strain of HIV-1 group O (RBF206) whose Vpu protein evolved an effective antagonism of human tetherin. Interestingly, the adaptive changes in RBF206 Vpu are distinct from those found in M-Vpus and mediate efficient counteraction of both the long and short isoforms of this restriction factor. Our results further illustrate the enormous flexibility of HIV-1 in counteracting human defense mechanisms.
Viral RNA at Two Stages of Reovirus Infection Is Required for the Induction of Necroptosis
Authors: Berger Angela K. , Hiller Bradley E. , Thete Deepti , Snyder Anthony J. , Perez Encarnacion , Upton Jason W. , Danthi Pranav 
Published: January 2017

ABSTRACT

Necroptosis, a regulated form of necrotic cell death, requires the activation of the RIP3 kinase. Here, we identify that infection of host cells with reovirus can result in necroptosis. We find that necroptosis requires sensing of the genomic RNA within incoming virus particles via cytoplasmic RNA sensors to produce type I interferon (IFN). While these events that occur prior to the
de novo
synthesis of viral RNA are required for the induction of necroptosis, they are not sufficient. The induction of necroptosis also requires late stages of reovirus infection. Specifically, efficient synthesis of double-stranded RNA (dsRNA) within infected cells is required for necroptosis. These data indicate that viral RNA interfaces with host components at two different stages of infection to induce necroptosis. This work provides new molecular details about events in the viral replication cycle that contribute to the induction of necroptosis following infection with an RNA virus.

IMPORTANCE
An appreciation of how cell death pathways are regulated following viral infection may reveal strategies to limit tissue destruction and prevent the onset of disease. Cell death following virus infection can occur by apoptosis or a regulated form of necrosis known as necroptosis. Apoptotic cells are typically disposed of without activating the immune system. In contrast, necroptotic cells alert the immune system, resulting in inflammation and tissue damage. While apoptosis following virus infection has been extensively investigated, how necroptosis is unleashed following virus infection is understood for only a small group of viruses. Here, using mammalian reovirus, we highlight the molecular mechanism by which infection with a dsRNA virus results in necroptosis.
Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor
Authors: Mori Seiichiro , Takeuchi Takamasa , Ishii Yoshiyuki , Yugawa Takashi , Kiyono Tohru , Nishina Hiroshi , Kukimoto Iwao 
Published: January 2017

ABSTRACT
The cytidine deaminase APOBEC3B (A3B) underlies the genetic heterogeneity of several human cancers, including cervical cancer, which is caused by human papillomavirus (HPV) infection. We previously identified a region within the A3B promoter that is activated by the viral protein HPV16 E6 in human keratinocytes. Here, we discovered three sites recognized by the TEAD family of transcription factors within this region of the A3B promoter. Reporter assays in HEK293 cells showed that exogenously expressed TEAD4 induced A3B promoter activation through binding to these sites. Normal immortalized human keratinocytes expressing E6 (NIKS-E6) displayed increased levels of TEAD1/4 protein compared to parental NIKS. A series of E6 mutants revealed that E6-mediated degradation of p53 was important for increasing TEAD4 levels. Knockdown of TEADs in NIKS-E6 significantly reduced A3B mRNA levels, whereas ectopic expression of TEAD4 in NIKS increased A3B mRNA levels. Finally, chromatin immunoprecipitation assays demonstrated increased levels of TEAD4 binding to the A3B promoter in NIKS-E6 compared to NIKS. Collectively, these results indicate that E6 induces upregulation of A3B through increased levels of TEADs, highlighting the importance of the TEAD-A3B axis in carcinogenesis.

IMPORTANCE
The expression of APOBEC3B (A3B), a cellular DNA cytidine deaminase, is upregulated in various human cancers and leaves characteristic, signature mutations in cancer genomes, suggesting that it plays a prominent role in carcinogenesis. Viral oncoproteins encoded by human papillomavirus (HPV) and polyomavirus have been reported to induce A3B expression, implying the involvement of A3B upregulation in virus-associated carcinogenesis. However, the molecular mechanisms causing A3B upregulation remain unclear. Here, we demonstrate that exogenous expression of the cellular transcription factor TEAD activates the A3B promoter. Further, the HPV oncoprotein E6 increases the levels of endogenous TEAD1/4 protein, thereby leading to A3B upregulation. Since increased levels of TEAD4 are frequently observed in many cancers, an understanding of the direct link between TEAD and A3B upregulation is of broad oncological interest.
Herpes Simplex Virus 1 Abrogates the cGAS/STING-Mediated Cytosolic DNA-Sensing Pathway via Its Virion Host Shutoff Protein, UL41
Authors: Su Chenhe , Zheng Chunfu 
Published: January 2017

ABSTRACT
Cyclic GMP-AMP synthase (cGAS) is a key DNA sensor capable of detecting microbial DNA and activating the adaptor protein stimulator of interferon genes (STING), leading to interferon (IFN) production and host antiviral responses. Cells exhibited reduced type I IFN production in response to cytosolic DNA in the absence of cGAS. Although the cGAS/STING-mediated DNA-sensing signal is crucial for host defense against many viruses, especially for DNA viruses, few viral components have been identified to specifically target this signaling pathway. Herpes simplex virus 1 (HSV-1) is a DNA virus that has evolved multiple strategies to evade host immune responses. In the present study, we found that HSV-1 tegument protein UL41 was involved in counteracting the cGAS/STING-mediated DNA-sensing pathway. Our results showed that wild-type (WT) HSV-1 infection could inhibit immunostimulatory DNA-induced activation of the IFN signaling pathway compared with the UL41-null mutant virus (R2621), and ectopic expression of UL41 decreased cGAS/STING-mediated IFN-β promoter activation and IFN-β production. Further study indicated that UL41 reduced the accumulation of cGAS to abrogate host recognition of viral DNA. In addition, stable knockdown of cGAS facilitated the replication of R2621 but not WT HSV-1. For the first time, HSV-1 UL41 was demonstrated to evade the cGAS/STING-mediated DNA-sensing pathway by degrading cGAS via its RNase activity.

IMPORTANCE
HSV-1 is well known for its ability to evade host antiviral responses and establish a lifelong latent infection while triggering reactivation and lytic infection under stress. Currently, whether HSV-1 evades the cytosolic DNA sensing and signaling is still poorly understood. In the present study, we found that tegument protein UL41 targeted the cGAS/STING-mediated cellular DNA-sensing pathway by selectively degrading cGAS mRNA. Knockdown of endogenous cGAS could facilitate the replication of R2621 but not WT HSV-1. Furthermore, UL41 was shown for the first time to act directly on cGAS. Findings in this study could provide new insights into the host-virus interaction and help develop new approaches against HSV-1.
Hierarchical and Redundant Roles of Activating FcγRs in Protection against Influenza Disease by M2e-Specific IgG1 and IgG2a Antibodies
Authors: Van den Hoecke Silvie , Ehrhardt Katrin , Kolpe Annasaheb , El Bakkouri Karim , Deng Lei , Grootaert Hendrik , Schoonooghe Steve , Smet Anouk , Bentahir Mostafa , Roose Kenny , Schotsaert Michael , Schepens Bert , Callewaert Nico , Nimmerjahn Falk , Staeheli Peter , Hengel Hartmut , Saelens Xavier 
Published: January 2017

ABSTRACT

The ectodomain of matrix protein 2 is a universal influenza A virus vaccine candidate that provides protection through antibody-dependent effector mechanisms. Here we compared the functional engagement of Fcγ receptor (FcγR) family members by two M2e-specific monoclonal antibodies (MAbs), MAb 37 (IgG1) and MAb 65 (IgG2a), which recognize a similar epitope in M2e with similar affinities. The binding of MAb 65 to influenza A virus-infected cells triggered all three activating mouse Fcγ receptors
in vitro
, whereas MAb 37 activated only FcγRIII. The passive transfer of MAb 37 or MAb 65 in wild-type,
Fcer1g
−/−
,
Fcgr3
−/−
, and
Fcgr1
−/−
Fcgr3
−/−
BALB/c mice revealed the importance of these receptors for protection against influenza A virus challenge, with a clear requirement of FcγRIII for IgG1 MAb 37 being found. We also report that FcγRIV contributes to protection by M2e-specific IgG2a antibodies.

IMPORTANCE
There is increased awareness that protection by antibodies directed against viral antigens is also mediated by the Fc domain of these antibodies. These Fc-mediated effector functions are often missed in clinical assays, which are used, for example, to define correlates of protection induced by vaccines. The use of antibodies to prevent and treat infectious diseases is on the rise and has proven to be a promising approach in our battle against newly emerging viral infections. It is now also realized that Fcγ receptors significantly enhance the
in vivo
protective effect of broadly neutralizing antibodies directed against the conserved parts of the influenza virus hemagglutinin. We show here that two M2e-specific monoclonal antibodies with close to identical antigen-binding specificities and affinities have a very different
in vivo
protective potential that is controlled by their capacity to interact with activating Fcγ receptors.
Genome-Wide Approaches to Defining Macrophage Identity and Function
Authors: Fonseca Gregory J. , Seidman Jason S. , Glass Christopher K. 
Published: January 2017

ABSTRACT
Macrophages play essential roles in the response to injury and infection and contribute to the development and/or homeostasis of the various tissues they reside in. Conversely, macrophages also influence the pathogenesis of metabolic, neurodegenerative, and neoplastic diseases. Mechanisms that contribute to the phenotypic diversity of macrophages in health and disease remain poorly understood. Here we review the recent application of genome-wide approaches to characterize the transcriptomes and epigenetic landscapes of tissue-resident macrophages. These studies are beginning to provide insights into how distinct tissue environments are interpreted by transcriptional regulatory elements to drive specialized programs of gene expression.
Myeloid Cell Phenotypes in Susceptibility and Resistance to Helminth Parasite Infections
Authors: Maizels Rick M. , Hewitson James P. 
Published: January 2017

ABSTRACTMany major tropical diseases are caused by long-lived helminth parasites that are able to survive by modulation of the host immune system, including the innate compartment of myeloid cells. In particular, dendritic cells and macrophages show markedly altered phenotypes during parasite infections. In addition, many specialized subsets such as eosinophils and basophils expand dramatically in response to these pathogens. The changes in phenotype and function, and their effects on both immunity to infection and reactivity to bystander antigens such as allergens, are discussed.
Laboratory Diagnosis and Susceptibility Testing for
Mycobacterium tuberculosis
Authors: Procop Gary W. 
Published: January 2017

ABSTRACT

The laboratory, which utilizes some of the most sophisticated and rapidly changing technologies, plays a critical role in the diagnosis of tuberculosis. Some of these tools are being employed in resource-challenged countries for the rapid detection and characterization of
Mycobacterium tuberculosis
. Foremost, the laboratory defines appropriate specimen criteria for optimal test performance. The direct detection of mycobacteria in the clinical specimen, predominantly done by acid-fast staining, may eventually be replaced by rapid-cycle PCR. The widespread use of the Xpert MTB/RIF (Cepheid) assay, which detects both
M. tuberculosis
and key genetic determinants of rifampin resistance, is important for the early detection of multidrug-resistant strains. Culture, using both broth and solid media, remains the standard for establishing the laboratory-based diagnosis of tuberculosis. Cultured isolates are identified far less commonly by traditional biochemical profiling and more commonly by molecular methods, such as DNA probes and broad-range PCR with DNA sequencing. Non-nucleic acid-based methods of identification, such as high-performance liquid chromatography and, more recently, matrix-assisted laser desorption/ionization–time of flight mass spectrometry, may also be used for identification. Cultured isolates of
M. tuberculosis
should be submitted for susceptibility testing according to standard guidelines. The use of broth-based susceptibility testing is recommended to significantly decrease the time to result. Cultured isolates may also be submitted for strain typing for epidemiologic purposes. The use of massive parallel sequencing, also known as next-generation sequencing, promises to continue to this molecular revolution in mycobacteriology, as whole-genome sequencing provides identification, susceptibility, and typing information simultaneously.
No evidence for the use of stem cell therapy for tendon disorders: a systematic review
Authors: Pas Haiko I M F L , Moen Maarten H , Haisma Hidde J , Winters Marinus 
Published: January 2017

IntroductionStem cells have emerged as a new treatment option for tendon disorders. We systematically reviewed the current evidence for stem cell therapy in tendon disorders.MethodsRandomised and non-randomised controlled trials, cohort studies and case series with a minimum of 5 cases were searched in MEDLINE, CENTRAL, EMBASE, CINAHL, PEDro and SPORTDiscus. In addition, we searched grey literature databases and trial registers. Only human studies were included and no time or language restrictions were applied to our search. All references of included trials were checked for possibly eligible trials. Risk of bias assessment was performed using the Cochrane risk of bias tool for controlled trials and the Newcastle-Ottawa scale for case series. Levels of evidence were assigned according to the Oxford levels of evidence.Results4 published and three unpublished/pending trials were found with a total of 79 patients. No unpublished data were available. Two trials evaluated bone marrow-derived stem cells in rotator cuff repair surgery and found lower retear rates compared with historical controls or the literature. One trial used allogenic adipose-derived stem cells to treat lateral epicondylar tendinopathy. Improved Mayo Elbow Performance Index, Visual Analogue Pain scale and ultrasound findings after 1-year follow-up compared with baseline were found. Bone marrow-derived stem cell-treated patellar tendinopathy showed improved International Knee Documentation Committee, Knee injury and Osteoarthritis Outcome Score subscales and Tegner scores after 5-year follow-up. One trial reported adverse events and found them to be mild (eg, swelling, effusion). All trials were at high risk of bias and only level 4 evidence was available.ConclusionsNo evidence (level 4) was found for the therapeutic use of stem cells for tendon disorders. The use of stem cell therapy for tendon disorders in clinical practice is currently not advised.
The effect of generalised joint hypermobility on rate, risk and frequency of injury in male university-level rugby league players: a prospective cohort study
Authors: Oddy Cassie , Johnson Mark I , Jones Gareth 
Published: January 2017

BackgroundRugby league is a collision sport where musculoskeletal injuries are common. There has been little research on generalised joint hypermobility (GJH) as a risk factor for injury in rugby league. The aim of this study was to investigate the role of GJH on the incidence of injuries in first and second team rugby league players from one British university.MethodsWe conducted a prospective cohort study of 45 student players from one British university first and second team rugby league squads (mean age 20.93±1.57 years). At the beginning of the season, GJH was determined using a 9-point Beighton scale, and injury and exposure data were collected on a weekly basis throughout the 2013–2014 season.ResultsThe prevalence of GJH was 20%. There was no statistically significant difference in the frequency of injuries between GJH and non-GJH participants (p=0.938, Mann-Whitney U test).Participants categorised as having GJH did not experience a higher fequency of injury (p=0.722, Fisher's exact test) and there was no tendency to demonstrate a higher risk of injury for participants categorised as GJH (OR=0.64, 95% CI 0.15 to 2.78; relative risk (RR)=1.188, 95% CI 0.537 to 2.625). The most common site of injury was the ankle, but this was not statistically significant (OR=0.152, 95% CI 0.008 to 2.876; RR=0.195, CI 0.012 to 3.066).ConclusionBritish university rugby league players with GJH did not demonstrate a greater risk of injury than those without GJH.
The cerebrovascular response to lower-body negative pressure vs. head-up tilt
Authors: Bronzwaer Anne-Sophie G. T. , Verbree Jasper , Stok Wim J. , Daemen Mat J. A. P. , van Buchem Mark A. , van Osch Matthias J. P. , van Lieshout Johannes J. 
Published: January 2017

Lower-body negative pressure (LBNP) has been proposed as a MRI-compatible surrogate for orthostatic stress. Although the effects of LBNP on cerebral hemodynamic behavior have been considered to reflect those of orthostatic stress, a direct comparison with actual orthostasis is lacking. We assessed the effects of LBNP (−50 mmHg) vs. head-up tilt (HUT; at 70°) in 10 healthy subjects (5 female) on transcranial Doppler-determined cerebral blood flow velocity (CBF v) in the middle cerebral artery and cerebral perfusion pressure (CPP) as estimated from the blood pressure signal (finger plethysmography). CPP was maintained during LBNP but decreased after 2 min in response to HUT, leading to an ~15% difference in CPP between LBNP and HUT ( P ≤ 0.020). Mean CBF v initially decreased similarly in response to LBNP and for HUT, but, from minute 3 on, the decline became ~50% smaller ( P ≤ 0.029) during LBNP. The reduction in end-tidal Pco2 partial pressure (PetCO2) was comparable but with an earlier return toward baseline values in response to LBNP but not during HUT ( P = 0.008). We consider the larger decrease in CBF v during HUT vs. LBNP attributable to the pronounced reduction in PetCO2 and to gravitational influences on CPP, and this should be taken into account when applying LBNP as an MRI-compatible orthostatic stress modality. NEW & NOTEWORTHY Lower-body negative pressure (LBNP) has the potential to serve as a MRI-compatible surrogate of orthostatic stress but a comparison with actual orthostasis was lacking. This study showed that the pronounced reduction in end-tidal Pco2 together with gravitational effects on the brain circulation lead to a larger decline in cerebral blood flow velocity in response to head-up tilt than during lower-body negative pressure. This should be taken into account when employing lower-body negative pressure as MRI-compatible alternative to orthostatic stress.
Short-Term Phenological Predictions of Vegetation Abundance Using Multivariate Adaptive Regression Splines in the Upper Colorado River Basin
Authors: Zhang Yuan , Hepner George F. 
Published: January 2017

Abstract
The accurate prediction of plant phenology is of significant importance for more sustainable and effective land management. This research develops a framework of phenological modeling to estimate vegetation abundance [indicated by the normalized difference vegetation index (NDVI)] 7 days into the future in the geographically diverse Upper Colorado River basin (UCRB). This framework uses phenological regions (phenoregions) as the basic units of modeling to account for the spatially variant environment–vegetation relationships. The temporal variation of the relationships is accounted for via the identification of phenological phases. The modeling technique of Multivariate Adaptive Regression Splines (MARS) is employed and tested as an approach to construct enhanced predictive phenological models in each phenoregion using a comprehensive set of environmental drivers and factors. MARS has the ability to deal with a large number of independent variables and to approximate complex relationships. The R2 values of the models range from 91.62% to 97.22%. The root-mean-square error values of all models are close to their respective standard errors ranging from 0.016 to 0.035, as indicated by the results of cross and field validations. These demonstrate that the modeling framework ensures the accurate prediction of short-term vegetation abundance in regions with various environmental conditions.