OBJECTIVES: Recent evidence suggests that occupational physical activity (OPA) is associated with adverse cardiovascular health, whereas leisure time physical activity is protective. This study explored explanatory physiological mechanisms. METHODS: Nineteen males (68% white, age=46.6±7.9 years, body mass index=27.9±5.1 kg/m(2)) with high self-reported OPA wore activity (ActiGraph and activPAL) and heart rate (HR) monitors for 7 days and an ambulatory blood pressure (BP) monitor on one workday and one non-workday. Mixed effects models compared cardiovascular variables (24-hour, nocturnal, waking and non-work time HR and BP) and nocturnal HR variability (HRV) on workdays versus non-workdays. Additional models examined associations of daily activity (steps, light physical activity (LPA) and moderate-to-vigorous physical activity (MVPA)) with cardiovascular variables. Workday by daily activity interactions were examined. RESULTS: 24-hour and waking HR and diastolic BP as well as non-work diastolic BP were significantly higher on workdays versus non-workdays (p<0.05 for all). However, no difference in systolic BP or nocturnal HR or BP was observed between work and non-workdays (p>0.05 for all). Low-frequency and high-frequency power indices of nocturnal HRV were lower on workdays (p<0.05 for both). Daily steps and LPA were positively associated with 24-hour and waking HR on work and non-workdays. Significant interactions suggested MVPA increases HR and lowers nocturnal HRV during workdays, with the opposite effect on non-workdays. CONCLUSIONS: Cardiovascular load was higher on workdays versus non-workdays with no compensatory hypotensive response following workdays. Daily MVPA may differentially affect ambulatory cardiovascular load and nocturnal HRV on workdays versus non-workdays, supporting the physical activity health paradox hypothesis.

Marburg virus (MARV) is among the most virulent pathogens of primates, including humans. Contributors to severe MARV disease include immune response suppression and inflammatory gene dysregulation ("cytokine storm"), leading to systemic damage and often death. Conversely, MARV causes little to no clinical disease in its reservoir host, the Egyptian rousette bat (ERB). Previous genomic and in vitro data suggest that a tolerant ERB immune response may underlie MARV avirulence, but no significant examination of this response in vivo yet exists. Here, using colony-bred ERBs inoculated with a bat isolate of MARV, we use species-specific antibodies and an immune gene probe array (NanoString) to temporally characterize the transcriptional host response at sites of MARV replication relevant to primate pathogenesis and immunity, including CD14(+) monocytes/macrophages, critical immune response mediators, primary MARV targets, and skin at the inoculation site, where highest viral loads and initial engagement of antiviral defenses are expected. Our analysis shows that ERBs upregulate canonical antiviral genes typical of mammalian systems, such as ISG15, IFIT1, and OAS3, yet demonstrate a remarkable lack of significant induction of proinflammatory genes classically implicated in primate filoviral pathogenesis, including CCL8, FAS, and IL6. Together, these findings offer the first in vivo functional evidence for disease tolerance as an immunological mechanism by which the bat reservoir asymptomatically hosts MARV. More broadly, these data highlight factors determining disparate outcomes between reservoir and spillover hosts and defensive strategies likely utilized by bat hosts of other emerging pathogens, knowledge that may guide development of effective antiviral therapies.

The Egyptian rousette bat (ERB) is the only known Marburg virus (MARV) reservoir host. ERBs develop a productive MARV infection with low viremia and shedding but no overt disease, suggesting this virus is efficiently controlled by ERB antiviral responses. This dynamic would contrast with humans, where MARV-mediated interferon (IFN) antagonism early in infection is thought to contribute to the severe, often fatal disease. The newly-annotated ERB genome and transcriptome have now enabled us to use a custom-designed NanoString nCounter ERB CodeSet in conjunction with RNA-seq to investigate responses in a MARV-infected ERB cell line. Both transcriptomic platforms correlated well and showed that MARV inhibited the antiviral program in ERB cells, while an IFN antagonism-impaired MARV was less efficient at suppressing the response gene induction, phenotypes previously reported for primate cells. Interestingly, and despite the expansion of IFN loci in the ERB genome, neither MARV showed specific induction of almost any IFN gene. However, we detected an upregulation of putative, unannotated ERB antiviral paralogs, as well as an elevated basal expression in uninfected ERB cells of key antiviral genes.

Bats harbor many viruses asymptomatically, including several notorious for causing extreme virulence in humans. To identify differences between antiviral mechanisms in humans and bats, we sequenced, assembled, and analyzed the genome of Rousettus aegyptiacus, a natural reservoir of Marburg virus and the only known reservoir for any filovirus. We found an expanded and diversified KLRC/KLRD family of natural killer cell receptors, MHC class I genes, and type I interferons, which dramatically differ from their functional counterparts in other mammals. Such concerted evolution of key components of bat immunity is strongly suggestive of novel modes of antiviral defense. An evaluation of the theoretical function of these genes suggests that an inhibitory immune state may exist in bats. Based on our findings, we hypothesize that tolerance of viral infection, rather than enhanced potency of antiviral defenses, may be a key mechanism by which bats asymptomatically host viruses that are pathogenic in humans.

The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg-1 GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.

BACKGROUND: The Egyptian Rousette bat (Rousettus aegyptiacus), a common fruit bat species found throughout Africa and the Middle East, was recently identified as a natural reservoir host of Marburg virus. With Ebola virus, Marburg virus is a member of the family Filoviridae that causes severe hemorrhagic fever disease in humans and nonhuman primates, but results in little to no pathological consequences in bats. Understanding host-pathogen interactions within reservoir host species and how it differs from hosts that experience severe disease is an important aspect of evaluating viral pathogenesis and developing novel therapeutics and methods of prevention. RESULTS: Progress in studying bat reservoir host responses to virus infection is hampered by the lack of host-specific reagents required for immunological studies. In order to establish a basis for the design of reagents, we sequenced, assembled, and annotated the R. aegyptiacus transcriptome. We performed de novo transcriptome assembly using deep RNA sequencing data from 11 distinct tissues from one male and one female bat. We observed high similarity between this transcriptome and those available from other bat species. Gene expression analysis demonstrated clustering of expression profiles by tissue, where we also identified enrichment of tissue-specific gene ontology terms. In addition, we identified and experimentally validated the expression of novel coding transcripts that may be specific to this species. CONCLUSION: We comprehensively characterized the R. aegyptiacus transcriptome de novo. This transcriptome will be an important resource for understanding bat immunology, physiology, disease pathogenesis, and virus transmission.

BACKGROUND: Rapidly rising childhood obesity rates constitute a public health priority in Latin America which makes it imperative to develop evidence-based strategies. Schools are a promising setting but to date it is unclear how many school-based obesity interventions have been documented in Latin America and what level of evidence can be gathered from such interventions. METHODS: We performed a systematic review of papers published between 1965 and December 2010. Interventions were considered eligible if they had a school-based component, were done in Latin America, evaluated an obesity related outcome (body mass index [BMI], weight, %body fat, waist circumference, BMI z-score), and compared youth exposed vs not exposed. RESULTS: Ten studies were identified as having a school-based component. Most interventions had a sample of normal and overweight children. The most successful interventions focused on prevention rather than treatment, had longer follow-ups, a multidisciplinary team, and fewer limitations in execution. Three prevention and 2 treatment interventions found sufficient improvements in obesity-related outcomes. CONCLUSIONS: We found sufficient evidence to recommend school-based interventions to prevent obesity among youth in Latin America. Evidence-based interventions in the school setting should be promoted as an important component for integrated programs, policies, and monitoring frameworks designed to reverse the childhood obesity in the region.

During the pandemic (H1N1) 2009 outbreak, Minnesota, New Mexico, and Oregon used several surveillance methods to detect associated deaths. Surveillance using unexplained death and medical examiner data allowed for detection of 34 (18%) pandemic (H1N1) 2009-associated deaths that were not detected by hospital-based surveillance.