bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alveolar Macrophages Are a Prominent but Nonessential Target for Murine Cytomegalovirus Infecting the Lungs
Authors: Farrell Helen E. , Lawler Clara , Oliveira Martha T. , Davis-Poynter Nick , Stevenson Philip G. 
Published: December 2015

ABSTRACT
Cytomegaloviruses (CMVs) infect the lungs and cause pathological damage there in immunocompromised hosts. How lung infection starts is unknown. Inhaled murine CMV (MCMV) directly infected alveolar macrophages (AMs) and type 2 alveolar epithelial cells (AEC2s) but not type 1 alveolar epithelial cells (AEC1s). In contrast, herpes simplex virus 1 infected AEC1s and murid herpesvirus 4 (MuHV-4) infected AEC1s via AMs. MCMV-infected AMs prominently expressed viral reporter genes from a human CMV IE1 promoter; but most IE1-positive cells were AEC2s, and CD11c-cre mice, which express cre in AMs, switched the fluorochrome expression of <5% of floxed MCMV in the lungs. In contrast, CD11C-cre mice exhibited fluorochrome switching in >90% of floxed MuHV-4 in the lungs and 50% of floxed MCMV in the blood. AM depletion increased MCMV titers in the lung during the acute phase of infection. Thus, the influence of AMs was more restrictive than permissive. Circulating monocytes entered infected lungs in large numbers and became infected, but not directly; infection occurred mainly via AEC2s. Mice infected with an MCMV mutant lacking its m131/m129 chemokine homolog, which promotes macrophage infection, showed levels of lung infection equivalent to those of wild-type MCMV-infected mice. The level of lung infiltration by Gr-1-positive cells infected with the MCMV m131/m129-null mutant was modestly different from that for wild-type MCMV-infected lungs. These results are consistent with myeloid cells mainly disseminating MCMV from the lungs, whereas AEC2s provide local amplification.

IMPORTANCE
Cytomegaloviruses (CMVs) chronically and systemically infect most mammals. Human CMV infection is usually asymptomatic but causes lung disease in people with poor immune function. As human infection is hard to analyze, studies with related animal viruses provide important insights. We show that murine CMV has two targets in the lungs: macrophages and surfactant-secreting epithelial cells. Acute virus replication occurred largely in epithelial cells. Macrophages had an important defensive role, as their removal increased the level of infection. These results establish the dual nature of lung infection, with local virus replication occurring in epithelial cells and spread occurring via quiescently infected macrophages. Distinct therapies may be needed to target these contrasting events.
Neuropeptide Y Negatively Influences Monocyte Recruitment to the Central Nervous System during Retrovirus Infection
Authors: Woods Tyson A. , Du Min , Carmody Aaron , Peterson Karin E. 
Published: December 2015

ABSTRACT

Monocyte infiltration into the CNS is a hallmark of several viral infections of the central nervous system (CNS), including retrovirus infection. Understanding the factors that mediate monocyte migration in the CNS is essential for the development of therapeutics that can alter the disease process. In the current study, we found that neuropeptide Y (NPY) suppressed monocyte recruitment to the CNS in a mouse model of polytropic retrovirus infection. NPY
−/−
mice had increased incidence and kinetics of retrovirus-induced neurological disease, which correlated with a significant increase in monocytes in the CNS compared to wild-type mice. Both Ly6C
hi
inflammatory and Ly6C
lo
alternatively activated monocytes were increased in the CNS of NPY
−/−
mice following virus infection, suggesting that NPY suppresses the infiltration of both cell types.
Ex vivo
analysis of myeloid cells from brain tissue demonstrated that infiltrating monocytes expressed high levels of the NPY receptor Y2R. Correlating with the expression of Y2R on monocytes, treatment of NPY
−/−
mice with a truncated, Y2R-specific NPY peptide suppressed the incidence of retrovirus-induced neurological disease. These data demonstrate a clear role for NPY as a negative regulator of monocyte recruitment into the CNS and provide a new mechanism for suppression of retrovirus-induced neurological disease.

IMPORTANCE
Monocyte recruitment to the brain is associated with multiple neurological diseases. However, the factors that influence the recruitment of these cells to the brain are still not well understood. In the current study, we found that neuropeptide Y, a protein produced by neurons, affected monocyte recruitment to the brain during retrovirus infection. We show that mice deficient in NPY have increased influx of monocytes into the brain and that this increase in monocytes correlates with neurological-disease development. These studies provide a mechanism by which the nervous system, through the production of NPY, can suppress monocyte trafficking to the brain and reduce retrovirus-induced neurological disease.
Animal Model of Sensorineural Hearing Loss Associated with Lassa Virus Infection
Authors: Yun Nadezhda E. , Ronca Shannon , Tamura Atsushi , Koma Takaaki , Seregin Alexey V. , Dineley Kelly T. , Miller Milagros , Cook Rebecca , Shimizu Naoki , Walker Aida G. , Smith Jeanon N. , Fair Joseph N. , Wauquier Nadia , Bockarie Bayon , Khan Sheik Humarr , Makishima Tomoko , Paessler Slobodan 
Published: December 2015

ABSTRACT
Approximately one-third of Lassa virus (LASV)-infected patients develop sensorineural hearing loss (SNHL) in the late stages of acute disease or in early convalescence. With 500,000 annual cases of Lassa fever (LF), LASV is a major cause of hearing loss in regions of West Africa where LF is endemic. To date, no animal models exist that depict the human pathology of LF with associated hearing loss. Here, we aimed to develop an animal model to study LASV-induced hearing loss using human isolates from a 2012 Sierra Leone outbreak. We have recently established a murine model for LF that closely mimics many features of human disease. In this model, LASV isolated from a lethal human case was highly virulent, while the virus isolated from a nonlethal case elicited mostly mild disease with moderate mortality. More importantly, both viruses were able to induce SNHL in surviving animals. However, utilization of the nonlethal, human LASV isolate allowed us to consistently produce large numbers of survivors with hearing loss. Surviving mice developed permanent hearing loss associated with mild damage to the cochlear hair cells and, strikingly, significant degeneration of the spiral ganglion cells of the auditory nerve. Therefore, the pathological changes in the inner ear of the mice with SNHL supported the phenotypic loss of hearing and provided further insights into the mechanistic cause of LF-associated hearing loss.

IMPORTANCE
Sensorineural hearing loss is a major complication for LF survivors. The development of a small-animal model of LASV infection that replicates hearing loss and the clinical and pathological features of LF will significantly increase knowledge of pathogenesis and vaccine studies. In addition, such a model will permit detailed characterization of the hearing loss mechanism and allow for the development of appropriate diagnostic approaches and medical care for LF patients with hearing impairment.
Alpha-Synuclein Expression Restricts RNA Viral Infections in the Brain
Authors: Beatman Erica L. , Massey Aaron , Shives Katherine D. , Burrack Kristina S. , Chamanian Mastooreh , Morrison Thomas E. , Beckham J. David 
Published: December 2015

ABSTRACT

We have discovered that native, neuronal expression of alpha-synuclein (Asyn) inhibits viral infection, injury, and disease in the central nervous system (CNS). Enveloped RNA viruses, such as West Nile virus (WNV), invade the CNS and cause encephalitis, yet little is known about the innate neuron-specific inhibitors of viral infections in the CNS. Following WNV infection of primary neurons, we found that Asyn protein expression is increased. The infectious titer of WNV and Venezuelan equine encephalitis virus (VEEV) TC83 in the brains of Asyn-knockout mice exhibited a mean increase of 10
4.5
infectious viral particles compared to the titers in wild-type and heterozygote littermates. Asyn-knockout mice also exhibited significantly increased virus-induced mortality compared to Asyn heterozygote or homozygote control mice. Virus-induced Asyn localized to perinuclear, neuronal regions expressing viral envelope protein and the endoplasmic reticulum (ER)-associated trafficking protein Rab1. In Asyn-knockout primary neuronal cultures, the levels of expression of ER signaling pathways, known to support WNV replication, were significantly elevated before and during viral infection compared to those in Asyn-expressing primary neuronal cultures. We propose a model in which virus-induced Asyn localizes to ER-derived membranes, modulates virus-induced ER stress signaling, and inhibits viral replication, growth, and injury in the CNS. These data provide a novel and important functional role for the expression of native alpha-synuclein, a protein that is closely associated with the development of Parkinson's disease.

IMPORTANCE
Neuroinvasive viruses such as West Nile virus are able to infect neurons and cause severe disease, such as encephalitis, or infection of brain tissue. Following viral infection in the central nervous system, only select neurons are infected, implying that neurons exhibit innate resistance to viral infections. We discovered that native neuronal expression of alpha-synuclein inhibited viral infection in the central nervous system. When the gene for alpha-synuclein was deleted, mice exhibited significantly decreased survival, markedly increased viral growth in the brain, and evidence of increased neuron injury. Virus-induced alpha-synuclein localized to intracellular neuron membranes, and in the absence of alpha-synuclein expression, specific endoplasmic reticulum stress signaling events were significantly increased. We describe a new neuron-specific inhibitor of viral infections in the central nervous system. Given the importance of alpha-synuclein as a cause of Parkinson's disease, these data also ascribe a novel functional role for the native expression of alpha-synuclein in the CNS.
Human Mucosal Mast Cells Capture HIV-1 and Mediate Viral
trans
-Infection of CD4
+
T Cells
Authors: Jiang Ai-Ping , Jiang Jin-Feng , Wei Ji-Fu , Guo Ming-Gao , Qin Yan , Guo Qian-Qian , Ma Li , Liu Bao-Chi , Wang Xiaolei , Veazey Ronald S. , Ding Yong-Bing , Wang Jian-Hua 
Published: December 2015

ABSTRACT

The gastrointestinal mucosa is the primary site where human immunodeficiency virus type 1 (HIV-1) invades, amplifies, and becomes persistently established, and cell-to-cell transmission of HIV-1 plays a pivotal role in mucosal viral dissemination. Mast cells are widely distributed in the gastrointestinal tract and are early targets for invasive pathogens, and they have been shown to have increased density in the genital mucosa in HIV-infected women. Intestinal mast cells express numerous pathogen-associated molecular patterns (PAMPs) and have been shown to combat various viral, parasitic, and bacterial infections. However, the role of mast cells in HIV-1 infection is poorly defined. In this study, we investigated their potential contributions to HIV-1 transmission. Mast cells isolated from gut mucosal tissues were found to express a variety of HIV-1 attachment factors (HAFs), such as DC-SIGN, heparan sulfate proteoglycan (HSPG), and α4β7 integrin, which mediate capture of HIV-1 on the cell surface. Intriguingly, following coculture with CD4
+
T cells, mast cell surface-bound viruses were efficiently transferred to target T cells. Prior blocking with anti-HAF antibody or mannan before coculture impaired viral
trans
-infection. Cell-cell conjunctions formed between mast cells and T cells, to which viral particles were recruited, and these were required for efficient cell-to-cell HIV-1 transmission. Our results reveal a potential function of gut mucosal mast cells in HIV-1 dissemination in tissues. Strategies aimed at preventing viral capture and transfer mediated by mast cells could be beneficial in combating primary HIV-1 infection.

IMPORTANCE
In this study, we demonstrate the role of human mast cells isolated from mucosal tissues in mediating HIV-1
trans
-infection of CD4
+
T cells. This finding facilitates our understanding of HIV-1 mucosal infection and will benefit the development of strategies to combat primary HIV-1 dissemination.
Subviral Hepatitis B Virus Filaments, like Infectious Viral Particles, Are Released via Multivesicular Bodies
Authors: Jiang Bingfu , Himmelsbach Kiyoshi , Ren Huimei , Boller Klaus , Hildt Eberhard 
Published: December 2015

ABSTRACT
In addition to infectious viral particles, hepatitis B virus-replicating cells secrete large amounts of subviral particles assembled by the surface proteins, but lacking any capsid and genome. Subviral particles form spheres (22-nm particles) and filaments. Filaments contain a much larger amount of the large surface protein (LHBs) compared to spheres. Spheres are released via the constitutive secretory pathway, while viral particles are ESCRT-dependently released via multivesicular bodies (MVBs). The interaction of virions with the ESCRT machinery is mediated by α-taxilin that connects the viral surface protein LHBs with the ESCRT component tsg101. Since filaments in contrast to spheres contain a significant amount of LHBs, it is unclear whether filaments are released like spheres or like virions. To study the release of subviral particles in the absence of virion formation, a core-deficient HBV mutant was generated. Confocal microscopy, immune electron microscopy of ultrathin sections and isolation of MVBs revealed that filaments enter MVBs. Inhibition of MVB biogenesis by the small-molecule inhibitor U18666A or inhibition of ESCRT functionality by coexpression of transdominant negative mutants (Vps4A, Vps4B, and CHMP3) abolishes the release of filaments while the secretion of spheres is not affected. These data indicate that in contrast to spheres which are secreted via the secretory pathway, filaments are released via ESCRT/MVB pathway like infectious viral particles.

IMPORTANCE
This study revises the current model describing the release of subviral particles by showing that in contrast to spheres, which are secreted via the secretory pathway, filaments are released via the ESCRT/MVB pathway like infectious viral particles. These data significantly contribute to a better understanding of the viral morphogenesis and might be helpful for the design of novel antiviral strategies.
MxB Is Not Responsible for the Blocking of HIV-1 Infection Observed in Alpha Interferon-Treated Cells
Authors: Opp Silvana , Vieira Daniel A. S. A. , Schulte Bianca , Chanda Sumit K. , Diaz-Griffero Felipe 
Published: December 2015

ABSTRACT
MxB restricts HIV-1 infection by directly interacting with the HIV-1 core, which is made of viral capsid; however, the contribution of MxB to the HIV-1 restriction observed in alpha interferon (IFN-α)-treated human cells is unknown. To understand this contribution, we used HIV-1 bearing the G208R capsid mutant (HIV-1-G208R), which overcomes the restriction imposed by cells expressing MxB. Here we showed that the reason why MxB does not block HIV-1-G208R is that MxB does not interact with HIV-1 cores bearing the mutation G208R. To understand whether MxB contributes to the HIV-1 restriction imposed by IFN-α-treated human cells, we challenged IFN-α-treated cells with HIV-G208R and found that MxB does not contribute to the restriction imposed by IFN-α-treated cells. To more directly test the contribution of MxB, we challenged IFN-α-treated human cells that are knocked out for the expression of MxB with HIV-1. These experiments suggested that MxB does not contribute to the HIV-1 restriction observed in IFN-α-treated human cells.

IMPORTANCE
MxB is a restriction factor that blocks HIV-1 infection in human cells. Although it has been postulated that MxB is the factor that blocks HIV-1 infection in IFN-α-treated cells, this is a hard concept to grasp due to the great number of genes that are induced by IFN-α in cells from the immune system. The work presented here elegantly demonstrates that MxB has minimal or no contribution to the ability of IFN-α-treated human cells to block HIV-1 infection. Furthermore, this work suggests the presence of novel restriction factors in IFN-α-treated human cells that block HIV-1 infection.
Verum versus Sham Manual Acupuncture for Migraine: A Systematic Review of Randomised Controlled Trials
Authors: Yang Yan , Que Qinghui , Ye Xiaode , Zheng Guo hua 
Published: December 2015

Background Manual acupuncture (MA) is commonly used as a treatment for migraine in China. However, its specific clinical effects have been challenged on the basis that some of its effects may relate to psychological or ‘placebo’ mechanisms. Objective To identify the effectiveness of verum MA compared with sham acupuncture for the treatment of migraine. Methods Eight electronic databases were searched for randomised controlled trials (RCTs) evaluating the effect of verum versus sham MA on migraine. The quality of included trials was assessed using the ‘risk of bias’ tool provided by the Cochrane Handbook for Systematic Review of Intervention. RevMan 5.2 software was used for data analysis. Results Ten trials with 997 participants were included. Most trials had high methodological quality and were at low risk of bias. Meta-analysis showed superior effects of verum MA over sham acupuncture on the total effective rate, reflected by a reduction in the ‘not effective’ rate (relative risk (RR) 0.24, 95% CI 0.15 to 0.38; p<0.0001, four trials) and a reduced recurrence rate (RR 0.47, 95% CI 0.28 to 0.81; p=0.006, two trials), but no significant differences in headache intensity, frequency or duration, accompanying symptoms and use of medication. No severe adverse events related to acupuncture occurred during treatment with either verum or sham MA. Conclusions Current clinical evidence suggests that verum acupuncture is superior to sham acupuncture in migraine, reflected by a higher total effective rate and decreased recurrence rate. Nevertheless, further large-scale RCTs with a rigorous design are required to confirm these findings in view of the relative paucity of eligible RCTs and small sample sizes of those included.
Preterm birth and behavioural outcomes at 8 years of age: a nationwide survey in Japan
Authors: Higa Diez Midory , Yorifuji Takashi , Kado Yoko , Sanada Satoshi , Doi Hiroyuki 
Published: December 2015

ObjectiveTo analyse the effect of different preterm birth categories on behavioural outcomes.DesignProspective cohort design.SettingsThe Japanese Longitudinal Survey of Babies in the 21st Century was used for the study.SubjectsNeonates born in 2001 in Japan (n=34 163) and followed up at the age of 8 years. Post-term births were excluded and the sample was divided into four groups according to gestational age: <34 weeks, 34–36 weeks, 37–38 weeks and 39–41 weeks.Outcome measuresSeven behavioural outcomes were examined: three attention problems and four delinquent/aggressive behaviours.ResultsLogistic regression was used to estimate adjusted ORs and 95% CIs for each outcome. Positive associations were found between preterm birth (<37 weeks) and adverse behavioural outcomes compared with full-term birth (39–41 weeks). For attention problems, the OR for ‘inability to wait his/her turn’ was increased by 1.72 (95% CI 1.22 to 2.43) for gestational age <34 weeks and by 1.28 (95% CI 1.03 to 1.59) for 34–36 weeks’ gestation. For delinquent/aggressive behaviour, the OR for the outcome ‘destroying books/toys’ was increased by 1.46 (95% CI 1.07 to 1.99) for gestational age <34 weeks, while the outcome ‘disturbance in public’ was increased by 1.20 (95% CI 1.04 to 1.38) for 34–36 weeks’ gestation.ConclusionsChildren who are born <34 weeks, but also between 34 and 36 weeks, are at increased risk of behavioural problems related to attention and delinquent/aggressive behaviour when 8 years old.
Exercise improves quality of life in patients with cancer: a systematic review and meta-analysis of randomised controlled trials
Authors: Gerritsen Jasper K W , Vincent Arnaud J P E 
Published: December 2015

PurposeExercise may be associated with increased health-related quality of life (QoL) in patients with cancer, but it is not prescribed as standard care during or after cancer treatment. We systematically reviewed the methodological quality of, and summarised the evidence from, randomised controlled trials (RCTs). A meta-analysis was performed to examine the effectiveness of exercise in improving the QoL in patients with cancer, during and after medical treatment.MethodsRCTs that met the PICO (Patient Intervention Control Outcome) format were included in this study. 16 RCTs were identified through a search of Embase, Medline (OvidSP) and the Cochrane Library. These trials were reviewed for substantive results and the methodological quality was assessed using the Delphi criteria list.ResultsExercise interventions differed widely in content, frequency, duration and intensity. Based on the meta-analysis, exercise improved QoL significantly in patients with cancer as compared to usual care (mean difference 5.55, 95% CI (3.19 to 7.90), p<0.001). Other outcomes closely related to QoL, such as fatigue and physical functioning, also improved.ConclusionsExercise has a direct positive impact on QoL in patients with cancer, during and following medical intervention. Exercise is a clinically relevant treatment and should be an adjunct to disease therapy in oncology.
Epidemiology of National Collegiate Athletic Association men's and women's tennis injuries, 2009/2010–2014/2015
Authors: Lynall Robert C , Kerr Zachary Y , Djoko Aristarque , Pluim Babette M , Hainline Brian , Dompier Thomas P 
Published: December 2015

BackgroundThis study describes the epidemiology of men's and women's tennis injuries reported by the National Collegiate Athletic Association (NCAA) Injury Surveillance Program (ISP) during the 2009/2010–2014/2015 academic years.MethodsInjuries and athlete-exposure (AE) data originated from 19 varsity men's programmes (38 team-seasons); women's tennis data originated from 25 varsity programmes (52 team-seasons). Injury rates, injury rate ratios (IRRs) and injury proportions ratios (IPRs) were reported with 95% CIs.ResultsThe ISP captured 181 and 227 injuries for men's and women's tennis, respectively, for injury rates of 4.89 and 4.88/1000 AE for men and women, respectively. There were 32.2% and 63.9% reductions in men's and women's tennis practice injury rates between 2009/2010–2011/2012 and 2012/2013–2014/2015, but no reductions in competition injury rates. Competition injury rates were higher than practice injury rates in men's (IRR=2.32; 95% CI 1.72 to 3.13) and women's tennis (IRR=1.77; 95% CI 1.35 to 2.33). Most injuries in men's and women's tennis occurred to the lower extremities (47.0% and 52.4%, respectively), compared with the trunk (16.6% and 17.6%, respectively) and upper extremities (23.8 and 23.8, respectively).ConclusionsInjury rates in NCAA men's and women's tennis were similar overall. Practice injury rates in men's and women's tennis have declined, although competition rates have not changed. These findings may help inform injury prevention programmes in the future.