bluuebunny/crossref_metadata_2025 huggingface dataset:
Misperception of body weight and associated factors
Authors: Boo Sunjoo
Published: June 2014

The prevalence of obesity is increasing. In Korea, this is especially true of men in general, and women of low socioeconomic status. Misperception of body weight poses a barrier to the prevention of obesity. In this study, the misperception of body weight in relation to actual body weight and associated factors in Korean adults was evaluated. Data from 7162 adults who participated in the 2009 Korean National Health and Nutrition Examination Survey were analyzed. Misperception of body weight was substantial in Koreans, with 48.9% underestimating and 6.8% overestimating their weight status. More men than women underestimated their weight status. Weight perception in women was affected more by sociodemographic characteristics. Women's underestimation was positively associated with older age, marital status, and lower socioeconomic status. This suggests that increasing public awareness of healthy weight will be helpful to counteract the current obesity epidemic in Korea.
Reduced peroxisomal citrate synthase activity increases substrate availability for polyhydroxyalkanoate biosynthesis in plant peroxisomes
Authors: Tilbrook Kimberley , Poirier Yves , Gebbie Leigh , Schenk Peer M. , McQualter Richard B. , Brumbley Stevens M.
Published: June 2014

Polyhydroxyalkanoates (PHAs) are bacterial carbon storage polymers used as renewable, biodegradable plastics. PHA production in plants may be a way to reduce industrial PHA production costs. We recently demonstrated a promising level of peroxisomal PHA production in the high biomass crop species sugarcane. However, further production strategies are needed to boost PHA accumulation closer to commercial targets. Through exogenous fatty acid feeding of Arabidopsis thaliana plants that contain peroxisome‐targeted PhaA, PhaB and PhaC enzymes from Cupriavidus necator, we show here that the availability of substrates derived from the β‐oxidation cycle limits peroxisomal polyhydroxybutyrate (PHB) biosynthesis. Knockdown of peroxisomal citrate synthase activity using artificial microRNA increased PHB production levels approximately threefold. This work demonstrates that reduction of peroxisomal citrate synthase activity may be a valid metabolic engineering strategy for increasing PHA production in other plant species.
Differences in MAT gene distribution and expression between Rhynchosporium species on grasses
Authors: King K. M. , West J. S. , Fitt B. D. L. , Dyer P. S.
Published: June 2014

Leaf blotch is a globally important disease of barley crops and other grasses that is caused by at least five host‐specialized species in the fungal genus Rhynchosporium. The pathogen R. commune (specialized to barley, brome‐grass and Italian ryegrass) has long been considered to reproduce only by asexual means, but there has been accumulating evidence for recombination and gene flow from population genetic studies and the detection of complementary MAT1‐1 and MAT1‐2 isolates in a c. 1:1 ratio in the field. Here, it is demonstrated that 28 isolates of the closely related species R. agropyri (on couch‐grass) and R. secalis (on rye and triticale), collected from Europe, were also either of MAT1‐1 or MAT1‐2 genotype and that the distribution of mating types did not deviate significantly from a 1:1 ratio. Evidence is then provided for MAT1‐1‐1 and MAT1‐2‐1 gene expression during mycelial growth for all three species. By contrast, 27 isolates of the more distantly related R. orthosporum (on cocksfoot) and R. lolii (on Italian and perennial ryegrasses) from Europe were exclusively of the MAT1‐1 genotype, and expression of the MAT1‐1‐1 gene could not be detected during mycelial growth. These data suggest that cryptic sexual cycles are more likely to exist for R. commune, R. agropyri and R. secalis than for either R. orthosporum or R. lolii. A phylogenetic analysis of partial MAT1‐1 idiomorph sequences resolved these five species into two distinct groups (R. commune, R. agropyri and R. secalis versus R. orthosporum and R. lolii) but provided only limited resolution within each group.
Chilling‐related cell damage of apple (Malus × domestica Borkh.) fruit cortical tissue impacts antioxidant, lipid and phenolic metabolism
Authors: Leisso Rachel S. , Buchanan David A. , Lee Jinwook , Mattheis James P. , Sater Chris , Hanrahan Ines , Watkins Christopher B. , Gapper Nigel , Johnston Jason W. , Schaffer Robert J. , Hertog Maarten L.A.T.M. , Nicolaï Bart M. , Rudell David R.
Published: June 2014

‘Soggy breakdown’ (SB) is an internal flesh disorder of ‘Honeycrisp’ apple (Malus × domestica Borkh.) fruit that occurs during low temperature storage. The disorder is a chilling injury (CI) in which visible symptoms typically appear after several weeks of storage, but information about the underlying metabolism associated with its induction and development is lacking. The metabolic profile of flesh tissue from wholly healthy fruit and brown and healthy tissues from fruit with SB was characterized using gas chromatography‐mass spectrometry (GC‐MS) and liquid chromatograph‐mass spectrometry (LC‐MS). Partial least squares discriminant analysis (PLS‐DA) and correlation networks revealed correlation among ester volatile compounds by composition and differences in phytosterol, phenolic and putative triacylglycerides (TAGs) metabolism among the tissues. anova‐simultaneous component analysis (ASCA) was used to test the significance of metabolic changes linked with tissue health status. ASCA‐significant components included antioxidant compounds, TAGs, and phytosterol conjugates. Relative to entirely healthy tissues, elevated metabolite levels in symptomatic tissue included γ‐amino butyric acid, glycerol, sitosteryl (6′‐O‐palmitoyl) β‐d‐glucoside and sitosteryl (6′‐O‐stearate) β‐d‐glucoside, and TAGs containing combinations of 16:0, 18:3, 18:2 and 18:1 fatty acids. Reduced metabolite levels in SB tissue included 5‐caffeoyl quinate, β‐carotene, catechin, epicatechin, α‐tocopherol, violaxanthin and sitosteryl β‐d glucoside. Pathway analysis indicated aspects of primary metabolism differed according to tissue condition, although differences in metabolites involved were more subtle than those of some secondary metabolites. The results implicate oxidative stress and membrane disruption processes in SB development and constitute a diagnostic metabolic profile for the disorder.
Emotional content modulates response inhibition and perceptual processing
Authors: Yang Suyong , Luo Wenbo , Zhu Xiangru , Broster Lucas S. , Chen Taolin , Li Jinzhen , Luo Yuejia
Published: June 2014

In this study, event‐related potentials were used to investigate the effect of emotion on response inhibition. Participants performed an emotional go/no‐go task that required responses to human faces associated with a “go” valence (i.e., emotional, neutral) and response inhibition to human faces associated with a “no‐go” valence. Emotional content impaired response inhibition, as evidenced by decreased response accuracy and N2 amplitudes in no‐go trials. More importantly, emotional expressions elicited larger N170 amplitudes than neutral expressions, and this effect was larger in no‐go than in go trials, indicating that the perceptual processing of emotional expression had priority in inhibitory trials. In no‐go trials, correlation analysis showed that increased N170 amplitudes were associated with decreased N2 amplitudes. Taken together, our findings suggest that emotional content impairs response inhibition due to the prioritization of emotional content processing.
Enhancing the Characterization of Epistemic Uncertainties in PM2.5 Risk Analyses
Authors: Smith Anne E. , Gans Will
Published: June 2014

The Environmental Benefits Mapping and Analysis Program (BenMAP) is a software tool developed by the U.S. Environmental Protection Agency (EPA) that is widely used inside and outside of EPA to produce quantitative estimates of public health risks from fine particulate matter (PM2.5). This article discusses the purpose and appropriate role of a risk analysis tool to support risk management deliberations, and evaluates the functions of BenMAP in this context. It highlights the importance in quantitative risk analyses of characterization of epistemic uncertainty, or outright lack of knowledge, about the true risk relationships being quantified. This article describes and quantitatively illustrates sensitivities of PM2.5 risk estimates to several key forms of epistemic uncertainty that pervade those calculations: the risk coefficient, shape of the risk function, and the relative toxicity of individual PM2.5 constituents. It also summarizes findings from a review of U.S.‐based epidemiological evidence regarding the PM2.5 risk coefficient for mortality from long‐term exposure. That review shows that the set of risk coefficients embedded in BenMAP substantially understates the range in the literature. We conclude that BenMAP would more usefully fulfill its role as a risk analysis support tool if its functions were extended to better enable and prompt its users to characterize the epistemic uncertainties in their risk calculations. This requires expanded automatic sensitivity analysis functions and more recognition of the full range of uncertainty in risk coefficients.
Mild Renal Artery Stenosis Can Induce Renovascular Hypertension and is Associated with Elevated Renal Vein Renin Secretion
Authors: Balamuthusamy Saravanan , Kannan Arun , Thajudeen Bijin , Ottley Dean , Jalandhara Nishant
Published: June 2014

Renovascular hypertension is a syndrome which encompasses the physiological response of the kidney to changes in renal blood flow and renal perfusion pressure. Such physiological changes can occur with renal artery occlusion irrespective of the severity of the lesion. We have analyzed hypertensive patients with mild renal artery stenosis and compared them to patients with no stenosis. Renal vein renin sampling from catheterization of the renal vein was performed in all these patients. Patients with mild stenosis had higher renal vein renin ratio (3.01 ± 1.5) than the patients with no stenosis (1.10 ± 0.29; p = 0.002). Patients with mild stenosis were also found to have higher diastolic blood pressure and renal artery resistive indices when compared to patients with no stenosis. We therefore conclude that mild stenosis can precipitate renin‐mediated hypertension in renovascular stenosis and also emphasis that parameters pertinent to renal physiology need to be evaluated before considering treatment options in patients with renal artery stenosis and medical management with RAAS blockade is the preferred modality of therapy for patients with renin‐mediated hypertension.
Football training improves lean body mass in men with prostate cancer undergoing androgen deprivation therapy
Authors: Uth J. , Hornstrup T. , Schmidt J. F. , Christensen J. F. , Frandsen C. , Christensen K. B. , Helge E. W. , Brasso K. , Rørth M. , Midtgaard J. , Krustrup P.
Published: June 2014

Androgen deprivation therapy (ADT) remains a cornerstone in the management of patients with prostate cancer (PCa) despite adverse effects on body composition and functional parameters. We compared the effects of football training with standard care in PCa patients managed with ADT (> 6 months). Fifty‐seven men aged 67 (range: 43–74) were randomly assigned to a football group (FG, n = 29) or a usual care control group (CON, n = 28). The primary outcome was change in lean body mass (LBM) assessed by dual‐energy X‐ray absorptiometry scanning. Secondary outcomes included changes in knee‐extensor muscle strength (one repetition maximum), fat percentage, and maximal oxygen uptake (VO2max). Mean heart rate during training was 137.7 (standard deviation 13.7) bpm or 84.6 (3.9)% HRmax. In FG, LBM increased by 0.5 kg [95% confidence interval (CI) 0.1–0.9; P = 0.02] with no change in CON (mean group difference 0.7 kg; 95% CI 0.1–1.2; P = 0.02). Also, muscle strength increased in FG (8.9 kg; 95% CI 6.0–11.8; P < 0.001) with no change in CON (mean group difference 6.7 kg; 95% CI 2.8–10.7; P < 0.001). In FG, VO2max increased (1.0 mL/kg/min; 95% CI 0.2–1.9; P = 0.02) and fat percentage tended to decrease (0.7%; 95%CI 1.3–0.0; P = 0.06), but these changes were not significantly different from CON. In conclusion, football training over 12 weeks improved LBM and muscle strength compared with usual care in men with prostate cancer receiving ADT.
Executive summary: Football for health – prevention and treatment of non‐communicable diseases across the lifespan through football
Authors: Bangsbo J. , Junge A. , Dvorak J. , Krustrup P.
Published: June 2014

This supplement contains 16 original articles describing how football conducted as small sided games affects fitness and health of untrained individuals across the lifespan. The intermittent nature of football and high exercise intensity result in a broad range of effects. The heart changes its structure and improves its function. Blood pressure is markedly reduced with the mean arterial blood pressure being lowered by ~10 mmHg for hypertensive men and women training 2–3 times/week for 12–26 weeks. Triglycerides and cholesterol are lowered and body fat declines, especially in middle‐aged men and women with type 2 diabetes. Furthermore, muscle mass and bone mineral density increases in a number of participant groups, including 65–75‐year‐old men. The functional capacity is elevated with increases in VO2max of 10–15%, and 50–100% improvements in the capacity to perform intermittent work within 16 weeks. These effects apply irrespective of whether the participants are young, overweight, elderly or suffering from a disease. The studies clearly show that the participants enjoy playing football and form special relationships with their team mates. Thus, football is a healthy activity, providing a unique opportunity to increase recruitment and adherence to physical activity in a hitherto underserved population, and to treat and rehabilitate patients with hypertension, type 2 diabetes and prostate cancer.
Football Fitness – a new version of football? A concept for adult players in Danish football clubs
Authors: Bennike S. , Wikman J. M. , Ottesen L. S.
Published: June 2014

This article explores a new Danish football‐based activity for health called Football Fitness (FF). Data are from quantitative and qualitative methods, and the theoretical framework for the analysis of the organizational form of FF is the theory of path dependency (Mahoney) and first‐ and second‐order change (Watzlawick et al.). Theories of Pestoff concerning differences between state, market, and the civil society and theories of voluntary associations in a Danish context (Kaspersen & Ottesen; Ibsen & Seippel) are applied. This article indicates how FF is a result of the changing landscape of sport and argues that it can be beneficial to target sports organizations and include the expertise of non‐profit sports clubs if the goal is to raise the physical activity level of the local community and make these long lasting. But the organizations need to consider how this is to be done. FF, established by the Danish Football Association (FA) and managed by the voluntary clubs, is one example in a Danish context. Data indicate that FF is beneficial to the clubs involved in a number of ways. Among other things, it attracts new user groups and improves the club environment, including social activities and parental environment.
Globalization and the Question of Social Justice
Authors: Agartan Kaan
Published: June 2014

Previous conceptions of social justice presupposed a closed political community in which nation‐states were to be in full control of policy instruments that reinforced mechanisms of social justice. States’ governing capacity to deliver social justice to their citizens has been challenged in the face of deepening transnational interactions and interdependencies in economic, political, and cultural realms, as these interactions and interdependencies directly affect the lives of millions of people. This paper revisits an ongoing debate on Global Social Justice and aims to introduce two clashing views – namely, Minimalist and Cosmopolitan approaches – on whether or not people in affluent societies have distinctive duties of concern for people in less developed countries. After outlining the main contours of the arguments on both sides, the paper concludes by suggesting that the debate can inform different areas of sociological inquiry that are directly related to issues such as power, inequality, and social exclusion.
Capturing Capital to Negotiate the Intersections of Motherhood and Work
Authors: Brooks Jane E. , Rogalin Christabel L.
Published: June 2014

Women are judged and judge themselves in response to cultural norms about motherhood and employment. While much has been written in sociology and other disciplines about the intersections of motherhood and work, there is not much on their ideals and the enactment of the ideals of womanhood and worker in connection to various forms of capital. In this paper, we review the literature on motherhood to explore the ways in which these ideals are related to the meanings of mother and worker. Further, we highlight how differential access to economic and non‐economic capital due to one's social location influences a woman's ability to be viewed successful simultaneously as mother and worker.
Residue incorporation mitigates tillage‐induced loss of soil carbon in laboratory microcosms
Authors: Bajgai Y. , Hulugalle N. , Kristiansen P. , McHenry M. , Cowie A.
Published: June 2014

Annual horticultural systems rely on frequent and intensive tillage to prepare beds, manage weeds and control insects. But this practice reduces soil organic carbon (SOC) through accelerated CO2 emission. Crop residue incorporation could counteract this loss. We investigated whether vegetable systems could be made more resilient by including a high‐residue grain crop such as sweet corn (Zea mays L. var. rugosa), in the rotation through the use of conventional (no residue, no soil sieving) and organic (residue incorporated and soil sieved) soil management scenarios. We evaluated short‐term emission of CO2‐C and soil C content in incubated Chromosol and Vertosol soils (Australian Classification) with and without sieving (simulated tillage) or the incorporation of ground sweet corn residue. Residue treatment emitted 2.3 times more CO2‐C compared to the no‐residue treatment, and furthermore, sieved soil emitted 1.5 times more CO2‐C than the unsieved across the two soil types. The residue incorporation had a greater effect on CO2‐C flux than simulated tillage, suggesting that C availability and form can be more important than physical disturbance in cropping soils. The organic scenario (with residue and sieved) emitted more CO2‐C, but had 13% more SOC compared with the conventional scenario (without residue and unsieved), indicating that organic systems may retain more SOC than a conventional system. The SOC lost by soil disturbance was more than offset by the incorporation of residue in the laboratory conditions. Therefore, the possible SOC loss by tillage for weed control under organic management may be offset by organic residue input.
Sur les rapprochements par conjugaison en dimension 1 et classe
Authors: Navas Andrés
Published: June 2014

We show that the space of actions of every finitely generated, nilpotent group by $C^1$ orientation-preserving diffeomorphisms of the circle is path-connected. This is done via a general result that allows any given action on the interval to be connected to the trivial one by a continuous path of topological conjugates.
Single Versus Combined Cognitive and Physical Activity Effects on Fluid Cognitive Abilities of Healthy Older Adults: A 4-Month Randomized Controlled Trial With Follow-Up
Authors: Linde Katja , Alfermann Dorothee
Published: June 2014

Background:

Physical and cognitive activity seems to be an effective strategy by which to promote age-sensitive fluid cognitive abilities in older adults.

Method:

In this randomized controlled trial, 70 healthy senior citizens (age 60–75) were allocated to a physical, cognitive, combined physical plus cognitive, and waiting control group. The trial assessed information processing speed, short-term memory, spatial relations, concentration, reasoning, and cognitive speed.

Results:

In contrast to the control group, the physical, cognitive, and combined training groups enhanced their concentration immediately after intervention. Only the physical training group showed improved concentration 3 months later. The combined training group displayed improved cognitive speed both immediately and three months after intervention. The cognitive training group displayed improved cognitive speed 3 months after intervention.

Conclusions:

Physical, cognitive, and combined physical plus cognitive activity can be seen as cognition-enrichment behaviors in healthy older adults that show different rather than equal intervention effects.
Validation of the Human Activity Profile Questionnaire as a Measure of Physical Activity Levels in Older Community-Dwelling Women
Authors: Bastone Alessandra de Carvalho , Moreira Bruno de Souza , Vieira Renata Alvarenga , Kirkwood Renata Noce , Dias João Marcos Domingues , Dias Rosângela Corrêa
Published: June 2014

The purpose of this study was to assess the validity of the Human Activity Profile (HAP) by comparing scores with accelerometer data and by objectively testing its cutoff points. This study included 120 older women (age 60–90 years). Average daily time spent in sedentary, moderate, and hard activity; counts; number of steps; and energy expenditure were measured using an accelerometer. Spearman rank order correlations were used to evaluate the correlation between the HAP scores and accelerometer variables. Significant relationships were detected (rho = .47−.75, p < .001), indicating that the HAP estimates physical activity at a group level well; however, scatterplots showed individual errors. Receiver operating characteristic curves were constructed to determine HAP cutoff points on the basis of physical activity level recommendations, and the cutoff points found were similar to the original HAP cutoff points. The HAP is a useful indicator of physical activity levels in older women.
Community-Based Exergaming Program Increases Physical Activity and Perceived Wellness in Older Adults
Authors: Strand Kara A. , Francis Sarah L. , Margrett Jennifer A. , Franke Warren D. , Peterson Marc J.
Published: June 2014

Exergaming may be an effective strategy to increase physical activity participation among rural older adults. This pilot project examined the effects of a 24-wk exergaming and wellness program (8 wk onsite exergaming, 16-wk wellness newsletter intervention) on physical activity participation and subjective health in 46 rural older adults. Sociodemographic data and self-reported physical activity were analyzed using descriptive statistics and Cochran’s Q, respectively. Qualitative data were reviewed, categorized on the basis of theme, and tabulated for frequency. Increased physical activity and perceived health were the most reported perceived positive changes. Significant increases in physical activity participation were maintained among participants who were physically inactive at baseline. Best-liked features were physical activity and socialization. Findings suggest that this pilot exergaming and wellness program is effective in increasing physical activity in sedentary rural older adults, increasing socialization, and increasing subjective physical health among rural older adults.
Accelerometer-Determined Sedentary and Physical Activity Estimates Among Older Adults With Diabetes: Considerations by Demographic and Comorbidity Characteristics
Authors: Loprinzi Paul D.
Published: June 2014

Understanding of the objectively measured physical activity (PA) and sedentary patterns of adults with diabetes at the population level is currently limited. Therefore, the purpose of this study was to report accelerometer-determined PA and sedentary patterns among a national sample of U.S. adults with and without evidence of diabetes and to also explore differences across other comorbidity characteristics. Data from the 2003–2006 National Health and Nutrition Examination Survey were used. Four hundred seven participants had evidence of diabetes (mean age = 73.4 years), and 1,346 did not have diabetes (mean age = 74.3 years). Results showed that few older adults meet PA guidelines; the majority of their time is spent in sedentary activities; very few engage in more light-intensity PA than sedentary behavior; and older adults with multiple comorbidities engage in less PA and more sedentary behavior than their counterparts. The development and implementation of feasible, effective PA programs for older adults with multiple comorbidities are warranted.
Evaluation of Bio-Rad Geenius HIV-1 and -2 Assay as a Confirmatory Assay for Detection of HIV-1 and -2 Antibodies
Authors: Hawthorne Hallen Anne , Samuelson Agneta , Nordin Margareta , Albert Jan , Bogdanovic Gordana
Published: June 2014

The performance of the new Bio-Rad Geenius HIV-1/2 confirmatory assay was compared with that of the Chiron RIBA HIV-1/HIV-2 strip immunoblot assay using 166 samples from HIV-1-, HIV-2-, or HIV-1/2-positive and HIV-negative individuals and two quality control panels. Our results indicate that the Geenius assay is a suitable alternative for confirmatory HIV testing.
Murine Cytomegalovirus Virion-Associated Protein M45 Mediates Rapid NF-κB Activation after Infection
Authors: Krause Eva , de Graaf Miranda , Fliss Patricia M. , Dölken Lars , Brune Wolfram
Published: June 2014

Murine cytomegalovirus (MCMV) rapidly induces activation of nuclear factor κB (NF-κB) upon infection of host cells. After a transient phase of activation, the MCMV M45 protein blocks all canonical NF-κB-activating pathways by inducing the degradation of the gamma subunit of the inhibitor of κB kinase complex (IKKγ; commonly referred to as the NF-κB essential modulator [NEMO]). Here we show that the viral M45 protein also mediates rapid NF-κB activation immediately after infection. MCMV mutants lacking M45 or expressing C-terminally truncated M45 proteins induced neither NF-κB activation nor transcription of NF-κB-dependent genes within the first 3 h of infection. Rapid NF-κB activation was absent in MCMV-infected NEMO-deficient fibroblasts, indicating that activation occurs at or upstream of the IKK complex. NF-κB activation was strongly reduced in murine fibroblasts lacking receptor-interacting protein 1 (RIP1), a known M45-interacting protein, but was restored upon complementation with murine RIP1. However, the ability of M45 to interact with RIP1 and NEMO was not sufficient to induce NF-κB activation upon infection. In addition, incorporation of the M45 protein into virions was required. This was dependent on a C-terminal region of M45, which is not required for interaction with RIP1 and NEMO. We propose a model in which M45 delivered by viral particles activates NF-κB, presumably involving an interaction with RIP1 and NEMO. Later in infection, expression of M45 induces the degradation of NEMO and the shutdown of canonical NF-κB activation.

IMPORTANCETranscription factor NF-κB is an important regulator of innate and adaptive immunity. Its activation can be beneficial or detrimental for viral pathogens. Therefore, many viruses interfere with NF-κB signaling by stimulating or inhibiting the activation of this transcription factor. Cytomegaloviruses, opportunistic pathogens that cause lifelong infections in their hosts, activate NF-κB rapidly and transiently upon infection but block NF-κB signaling soon thereafter. Here we report the surprising finding that the murine cytomegalovirus protein M45, a component of viral particles, plays a dual role in NF-κB signaling. It not only blocks NF-κB signaling later in infection but also triggers the rapid activation of NF-κB immediately following virus entry into host cells. Both activation and inhibition involve M45 interaction with the cellular signaling mediators RIP1 and NEMO. Similar dual functions in NF-κB signaling are likely to be found in other viral proteins.
Triggering TLR2, -3, -4, -5, and -8 Reinforces the Restrictive Nature of M1- and M2-Polarized Macrophages to HIV
Authors: Schlaepfer Erika , Rochat Mary-Aude , Duo Li , Speck Roberto F.
Published: June 2014

Macrophages must react to a large number of pathogens and their effects. In chronic HIV infection, the microenvironment changes with an influx of microbial products that trigger Toll-like receptors (TLRs). That dynamic nature can be replicated
ex vivo
by the proinflammatory (M1-polarized) and alternatively activated (M2-polarized) macrophages. Thus, we determined how polarized macrophages primed by various TLR agonists support HIV replication. Triggering of TLR2, -3, -4, -5, and -8 reinforced the low level of permissiveness in polarized macrophages. HIV was inhibited even more in M1-polarized macrophages than in macrophages activated only by TLR agonists. HIV was inhibited before its integration into the host chromosome. Polarization and triggering by various TLR agonists resulted in distinct cytokine profiles, endocytic activity, and distinct upregulation of restriction factors of HIV. Thus, different mechanisms likely contribute to the HIV-inhibitory effects. In chronic HIV infection, macrophages might become less permissive to HIV due to changes in the microenvironment. The high level of reactivity of polarized macrophages to TLR triggering may be exploited for immunotherapeutic strategies.

IMPORTANCE
Macrophages are a major target of HIV-1 infection. Different cell types in this very heterogeneous cell population respond differently to stimuli.
In vitro
, the heterogeneity is mimicked by their polarization into proinflammatory and alternatively activated macrophages. Here we explored the extent to which agonists triggering the TLR family affect HIV replication in polarized macrophages. We found that a number of TLR agonists blocked HIV replication substantially when given before infection. We also report the mechanisms of how TLR agonists exert their inhibitory action. Our findings may advance our understanding of which and how TLR agonists block HIV infection in polarized macrophages and may facilitate the design of novel immunotherapeutic approaches.
Dendritic Cells Restore CD8+T Cell Reactivity to Autologous HIV-1
Authors: Smith Kellie N. , Mailliard Robbie B. , Larsen Brendan B. , Wong Kim , Gupta Phalguni , Mullins James I. , Rinaldo Charles R.
Published: June 2014

Recall T cell responses to HIV-1 antigens are used as a surrogate for endogenous cellular immune responses generated during infection. Current methods of identifying antigen-specific T cell reactivity in HIV-1 infection use bulk peripheral blood mononuclear cells (PBMC) yet ignore professional antigen-presenting cells (APC) that could reveal otherwise hidden responses. In the present study, peptides representing autologous variants of major histocompatibility complex (MHC) class I-restricted epitopes from HIV-1 Gag and Env were used as antigens in gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) and polyfunctional cytokine assays. Here we show that dendritic cells (DC) enhanced T cell reactivity at all stages of disease progression but specifically restored T cell reactivity after combination antiretroviral therapy (cART) to early infection levels. Type 1 cytokine secretion was also enhanced by DC and was most apparent late post-cART. We additionally show that DC reveal polyfunctional T cell responses after many years of treatment, when potential immunotherapies would be implemented. These data underscore the potential efficacy of DC immunotherapy that aims to awaken a dormant, autologous, HIV-1-specific CD8+T cell response.

IMPORTANCEAssessment of endogenous HIV-1-specific T cell responses is critical for generating immunotherapies for subjects on cART. Current assays ignore the ability of dendritic cells to reveal these responses and may therefore underestimate the breadth and magnitude of T cell reactivity. As DC do not prime new responses in these assays, it can be assumed that the observed responses are not detected without appropriate stimulation. This is important because dogma states that HIV-1 mutates to evade host recognition and that CD8+cytotoxic T lymphocyte (CTL) failure is due to the inability of T cells to recognize the autologous virus. The results presented here indicate that responses to autologous virus are generated during infection but may need additional stimulation to be effective. Detecting the breadth and magnitude of HIV-1-specific T cell reactivity generatedin vivois of the utmost importance for generating effective DC immunotherapies.
Intercontinental Dispersal of HIV-1 Subtype B Associated with Transmission among Men Who Have Sex with Men in Japan
Authors: Takebe Yutaka , Naito Yuki , Raghwani Jayna , Fearnhill Esther , Sano Takako , Kusagawa Shigeru , Mbisa Jean L. , Zhang Hongyi , Matano Tetsuro , Leigh Brown Andrew J. , Pybus Oliver G. , Dunn David , Kondo Makiko
Published: June 2014

Transmission clusters of HIV-1 subtype B uniquely associated with the epidemic among men who have sex with men (MSM) in East Asia have recently been identified. Using the Los Alamos HIV sequence database and the UK HIV drug resistance database, we explored possible links between HIV MSM epidemics in East Asia and the rest of the world by using phylogenetic and molecular clock analyses. We found that JP.MSM.B-1, a subtype B MSM variant that accounts for approximately one-third of the infections among Japanese MSM, was detected worldwide, in the United Kingdom (
n
= 13), mainland China (
n
= 3), the United States, Germany, Canada, and Taiwan (
n
= 1 each). Interestingly, 10 United Kingdom samples plus two from Germany and the United States formed a distinct monophyletic subgroup within JP.MSM.B-1. The estimated divergence times of JP.MSM.B-1 and the latter subgroup were ∼1989 and ∼1999, respectively. These dates suggest that JP.MSM.B-1 was circulating for many years in Japan among MSM before disseminating to other countries, most likely through global MSM networks. A significant number of other Asian MSM HIV lineages were also detected in the UK HIV drug resistance database. Our study provides insight into the regional and global dispersal of Asian MSM HIV lineages. Further study of these strains is warranted to elucidate viral migration and the interrelationship of HIV epidemics on a global scale.

IMPORTANCE
We previously identified several transmission clusters of HIV-1 subtype B uniquely associated with the epidemic among men who have sex with men (MSM) in East Asia. Using the Los Alamos HIV sequence database and the UK HIV drug resistance database, we explored the possible interplay of HIV MSM epidemics in the different geographic regions and found previously unrecognized interrelationships among the HIV-1 epidemics in East Asia, the United Kingdom, and the rest of the world. Our study provides insight into the regional and global dispersal of Asian MSM HIV lineages and highlights the importance of strengthening HIV monitoring efforts and the need for implementing effective control measures to reduce HIV transmission on a global scale.
TALEN Knockout of the
PSIP1
Gene in Human Cells: Analyses of HIV-1 Replication and Allosteric Integrase Inhibitor Mechanism
Authors: Fadel Hind J. , Morrison James H. , Saenz Dyana T. , Fuchs James R. , Kvaratskhelia Mamuka , Ekker Stephen C. , Poeschla Eric M.
Published: June 2014

HIV-1 utilizes the cellular protein LEDGF/p75 as a chromosome docking and integration cofactor. The LEDGF/p75 gene,
PSIP1
, is a potential therapeutic target because, like CCR5, depletion of LEDGF/p75 is tolerated well by human CD4
+
T cells, and knockout mice have normal immune systems. RNA interference (RNAi) has been useful for studying LEDGF/p75, but the potent cofactor activity of small protein residua can be confounding. Here, in human cells with utility for HIV research (293T and Jurkat), we used transcription activator-like effector nucleases (TALENs) to completely eradicate all LEDGF/p75 expression. We performed two kinds of
PSIP1
knockouts: whole-gene deletion and deletion of the integrase binding domain (IBD)-encoding exons. HIV-1 integration was inhibited, and spreading viral replication was severely impaired in
PSIP1
−/−
Jurkat cells infected at high multiplicity. Furthermore, frameshifting the gene in the first coding exon with a single TALEN pair yielded trace LEDGF/p75 levels that were virologically active, affirming the cofactor's potency and the value of definitive gene or IBD exon segment deletion. Some recent studies have suggested that LEDGF/p75 may participate in HIV-1 assembly. However, we determined that assembly of infectious viral particles is normal in
PSIP1
−/−
cells. The potency of an allosteric integrase inhibitor, ALLINI-2, for rendering produced virions noninfectious was also unaffected by total eradication of cellular LEDGF/p75. We conclude that HIV-1 particle assembly and the main ALLINI mechanism are LEDGF/p75 independent. The block to HIV-1 propagation in
PSIP1
−/−
human CD4
+
T cells raises the possibility of gene targeting
PSIP1
combinatorially with
CCR5
for HIV-1 cure.

IMPORTANCE
LEDGF/p75 dependence is universally conserved in the retroviral genus
Lentivirus
. Once inside the nucleus, lentiviral preintegration complexes are thought to attach to the chromosome when integrase binds to LEDGF/p75. This tethering process is largely responsible for the 2-fold preference for integration into active genes, but the cofactor's full role in the lentiviral life cycle is not yet clear. Effective knockdowns are difficult because even trace residua of this tightly chromatin-bound protein can support integration cofactor function. Here, in experimentally useful human cell lines, we used TALENs to definitively eradicate LEDGF/p75 by deleting either all of
PSIP1
or the exons that code for the integrase binding domain. HIV-1 replication was severely impaired in these
PSIP1
knockout cells. Experiments in these cells also excluded a role for LEDGF/p75 in HIV-1 assembly and showed that the main ALLINI mechanism is LEDGF/p75 independent. Site-specific gene targeting of
PSIP1
may have therapeutic potential for HIV-1 disease.
Enterovirus 71 3C Inhibits Cytokine Expression through Cleavage of the TAK1/TAB1/TAB2/TAB3 Complex
Authors: Lei Xiaobo , Han Ning , Xiao Xia , Jin Qi , He Bin , Wang Jianwei
Published: June 2014

Enterovirus 71 (EV71) causes hand, foot, and mouth disease in young children and infants. Severe infection with EV71 can lead to various neurological complications or fatal diseases. However, the mechanism of EV71 pathogenesis is poorly understood. Emerging evidence suggests that EV71 modulates type I interferon (IFN) and cytokine responses. Here, we show that EV71 disables components of the TAB2 complex through the 3C protein. When expressed in mammalian cells, EV71 3C interacts with TAB2 and TAK1, which inhibits NF-κB activation. Furthermore, 3C mediates cleavage of TAB2 and its partners, which requires the protease activity. H40D or C147S substitution in the 3C active sites abolishes its activity, whereas R84Q or V154S substitution in the RNA binding domain has no effect. The 3C protein targets TAB2 at Q113-S114, TAK1 at Q360-S361, TAB1 both at Q414-G415 and Q451-S452, and TAB3 at Q173-G174 and Q343-G344. Importantly, overexpression of TAB2 inhibits EV71 replication, whereas addition of cleaved fragments has no effect. Thus, an equilibrium between the TAB2 complex and EV71 3C represents a control point of viral infection. These results suggest that TAK1/TAB1/TAB2/TAB3 cleavage mediated by EV71 may be a mechanism to interfere with inflammatory responses.

IMPORTANCE
The TAK1 complex plays a critical role in the activation of NF-κB and cytokine production. However, little is known about its connection to enterovirus 71 (EV71). We demonstrate that EV71 3C suppresses cytokine expression via cleavage of the TAK1 complex proteins. EV71 3C interacts with TAB2 and TAK1. Furthermore, overexpression of TAB2 inhibits EV71 replication, whereas addition of cleaved fragment has no effect. These results suggest that the interplay of EV71 and the TAK1 complex influences the outcome of viral infection.
Intrinsic Innate Immunity Fails To Control Herpes Simplex Virus and Vesicular Stomatitis Virus Replication in Sensory Neurons and Fibroblasts
Authors: Rosato Pamela C. , Leib David A.
Published: June 2014

Herpes simplex virus 1 (HSV-1) establishes lifelong latent infections in the sensory neurons of the trigeminal ganglia (TG), wherein it retains the capacity to reactivate. The interferon (IFN)-driven antiviral response is critical for the control of HSV-1 acute replication. We therefore sought to further investigate this response in TG neurons cultured from adult mice deficient in a variety of IFN signaling components. Parallel experiments were also performed in fibroblasts isolated concurrently. We showed that HSV-1 replication was comparable in wild-type (WT) and IFN signaling-deficient neurons and fibroblasts. Unexpectedly, a similar pattern was observed for the IFN-sensitive vesicular stomatitis virus (VSV). Despite these findings, TG neurons responded to IFN-β pretreatment with STAT1 nuclear localization and restricted replication of both VSV and an HSV-1 strain deficient in γ34.5, while wild-type HSV-1 replication was unaffected. This was in contrast to fibroblasts in which all viruses were restricted by the addition of IFN-β. Taken together, these data show that adult TG neurons can mount an effective antiviral response only if provided with an exogenous source of IFN-β, and HSV-1 combats this response through γ34.5. These results further our understanding of the antiviral response of neurons and highlight the importance of paracrine IFN-β signaling in establishing an antiviral state.

IMPORTANCE
Herpes simplex virus 1 (HSV-1) is a ubiquitous virus that establishes a lifelong latent infection in neurons. Reactivation from latency can cause cold sores, blindness, and death from encephalitis. Humans with deficiencies in innate immunity have significant problems controlling HSV infections. In this study, we therefore sought to elucidate the role of neuronal innate immunity in the control of viral infection. Using neurons isolated from mice, we found that the intrinsic capacity of neurons to restrict virus replication was unaffected by the presence or absence of innate immunity. In contrast, neurons were able to mount a robust antiviral response when provided with beta interferon, a molecule that strongly stimulates innate immunity, and that HSV-1 can combat this response through the γ34.5 viral gene. Our results have important implications for understanding how the nervous system defends itself against virus infections.
Activation of NF-κB via Endosomal Toll-Like Receptor 7 (TLR7) or TLR9 Suppresses Murine Herpesvirus 68 Reactivation
Authors: Haas Florian , Yamauchi Kazuma , Murat Monika , Bernasconi Michele , Yamanaka Noboru , Speck Roberto F. , Nadal David
Published: June 2014

In order to understand and possibly treat B-cell malignancies associated with latent gammaherpesvirus infection, it is vital to understand the factors that control the balance between the two transcriptional states of gammaherpesviruses: latency and lytic replication. We used murine gammaherpesvirus 68 (MHV 68) as a model system to investigate how engagement of endosomal Toll-like receptors (TLRs) impacts reactivation from latency
in vitro
and establishment of latent infection
in vivo
. We found that treatment with TLR7 ligand R848 or TLR9 ligand CpG oligodeoxynucleotide (ODN) suppresses reactivation of MHV 68
in vitro
. These suppressive effects correlated with the ability to activate cellular transcription factor NF-κB. Downregulation of TLR9 by RNA interference
in vitro
led to a reduction of nuclear levels of NF-κB p65 and consequently to an increase of spontaneous reactivation in cells latently infected with MHV 68, indicating that the TLR9 pathway suppresses spontaneous reactivation events.
In vivo
, sustained stimulation of TLR7 by repeated R848 treatment led to an increased frequency of infected splenocytes compared to mock-treated control results. Frequencies of infected splenic B cells in
tlr7
−/−
or
tlr9
−/−
mice after establishment of latency did not differ from those seen with their wild-type counterparts. Nevertheless, MHV 68-infected B cells from
tlr9
−/−
mice showed a higher frequency of reactivation than B cells from wild-type or
tlr7
−/−
mice in
ex vivo
reactivation assays. Thus, we show a suppressive effect of TLR7 or TLR9 triggering on MHV 68 reactivation that correlates with NF-κB activation and that the mere presence of a functional TLR9 signaling pathway contributes to dampen lytic gammaherpesvirus reactivation in infected cells.

IMPORTANCE
A hallmark of gammaherpesviruses is their establishment of latency in B cells that is reversible through lytic reactivation. Latency can result in B-cell malignancies. Activation of the innate immune system is thought to contribute to controlling the switch between the transcriptional states of latency and reactivation. Nevertheless, the mechanisms involved are not clear. Here, we show that engagement of Toll-like receptor 7 (TLR7) and TLR9 suppresses reactivation of murine gammaherpesvirus MHV 68
in vitro
and that stimulation of TLR7
in vivo
increases the frequency of infected cells. TLR7 and TLR9 are innate immunity sensors of nucleic acids localized in endosomes. Additionally, we demonstrate that impairment of TLR9 signaling in latently infected B cells leads to increased reactivation. Thus, activated endosomal TLR7 and TLR9 pathways play an important role in promoting establishment of latent gammaherpesvirus infection. Counteracting signaling of these pathways allows reactivation and could represent treatment targets in gammaherpesvirus-associated malignancies.
Northern African Strains of Human T-Lymphotropic Virus Type 1 Arose from a Recombination Event
Authors: Desrames Alexandra , Cassar Olivier , Gout Olivier , Hermine Olivier , Taylor Graham P. , Afonso Philippe V. , Gessain Antoine
Published: June 2014

Although recombination is a major source of genetic variability in retroviruses, no recombinant strain had been observed for human T-lymphotropic virus type 1 (HTLV-1), the first isolated human-pathogenic retrovirus. Different genotypes exist for HTLV-1: Genotypes b and d to g are restricted to central Africa, while genotype c is only endemic in Australo-Melanesia. In contrast, the cosmopolitan genotype a is widely distributed. We applied a combination of phylogenetics and recombination analysis approaches to a set of new HTLV-1 sequences, which we collected from 19 countries throughout Africa, the continent where the virus has the largest endemic presence. This led us to demonstrate the presence of recombinants in HTLV-1. Indeed, the HTLV-1 strains currently present in North Africa have originated from a recombinant event between strains from Senegal and West Africa. This recombination is estimated to have occurred around 4,000 years ago. This recombination seems to have been generated during reverse transcription. In conclusion, we demonstrate that, albeit rare, recombination can occur in HTLV-1 and may play a role in the evolution of this retrovirus.

IMPORTANCE
A number of HTLV-1 subtypes have been described in different populations, but none of the genetic differences between these subtypes have been ascribed to recombination events. Here we report an HTLV-1 recombinant virus among infected individuals in North Africa. This demonstrates that, contrary to what was thought, recombination can occur and could play a role in the evolution of HTLV-1.