Influenza virus infection exacerbates gene expression related to neurocognitive dysfunction in brains of old mice.

BACKGROUND: Age > 65 years is a key risk factor for poor outcomes after human influenza infection. Specifically, in addition to respiratory disease, non-neurotropic influenza A virus (IAV) causes neuro-cognitive complications, e.g. new onset depression and increases the risk of dementia after hospitalization. This study aimed to identify potential mechanisms of these effects by determining differences between young and old mice in brain gene expression in a mouse model of non-neurotropic IAV infection. METHODS: Young (12 weeks) and old (70 weeks) C57Bl/6J mice were inoculated intranasally with 200 PFU H1N1 A/PR/34/8 (PR8) or sterile PBS (mock). Gene expression in lung and brain was measured by qRT-PCR and normalized to ß-actin. Findings were confirmed using the nCounter Mouse Neuroinflammation Array (NanoString) and analyzed with nSolver 4.0 and Ingenuity Pathway Analysis (IPA, Qiagen). RESULTS: IAV PR8 did not invade the central nervous system. Young and old mice differed significantly in brain gene expression at baseline and during non-neurotropic IAV infection. Expression of brain Ifnl, Irf7, and Tnf mRNAs was upregulated over baseline control at 3 days post-infection (p.i.) only in young mice, but old mice expressed more Ifnl than young mice 7 days p.i. Gene arrays showed down-regulation of the Epigenetic Regulation, Insulin Signaling, and Neurons and Neurotransmission pathways in old mice 3 days p.i. while young mice demonstrated no change or induction of these pathways at the same time point. IPA revealed marked baseline differences between old and young mice. Gene expression related to Cognitive Impairment, Memory Deficits and Learning worsened in old mice relative to young mice during IAV infection. Aged mice demonstrate more severe changes in gene expression related to memory loss and cognitive dysfunction by IPA. CONCLUSIONS: These data suggest the genes and pathways related to learning and cognitive performance that were worse at baseline in old mice were further worsened by IAV infection, similar to old patients. Early events in the brain triggered by IAV infection portend downstream neurocognitive pathology in old adults.

Bacillus anthracis spores are internalized in human lung epithelial cells by Rab GTPase-supported macropinocytosis.

Inhalation anthrax, the deadliest form of the disease, requires inhaled B. anthracis spores to escape from the alveolar space and travel to the mediastinal lymph nodes, from where the vegetative form of the pathogen disseminates, resulting in a rapidly fatal outcome. The role of epithelia in alveolar escape is unclear, but previous work suggests these epithelial cells are involved in this process. Using confocal microscopy, we found that B. anthracis spores are internalized more rapidly by A549 type II alveolar epithelial cells compared to hAELVi type I alveolar epithelial cells. Internalization of spores by alveolar epithelial cells requires cytoskeletal rearrangement evidenced by significant inhibition by cytochalasin D, an actin inhibitor. Chemical inhibitors of macropinocytosis significantly downregulated B. anthracis spore internalization in human alveolar cells, while inhibitors of other endocytosis pathways had minimal effects. Additional studies using a macropinosome marker and electron microscopy confirmed the role of macropinocytosis in spore uptake. By colocalization of B. anthracis spores with four endocytic Rab proteins, we demonstrated that Rab31 played a role in B. anthracis spore macropinocytosis. Finally, we confirmed that Rab31 is involved in B. anthracis spore internalization by enhanced spore uptake in Rab31-overexpressing A549 cells. This is the first report that shows B. anthracis spore internalization by macropinocytosis in human epithelial cells. Several Rab GTPases are involved in the process.

Diel oxygen fluctuation drives the thermal response and metabolic performance of coastal marine ectotherms.

Coastal marine systems are characterized by high levels of primary production that result in diel oxygen fluctuations from undersaturation to supersaturation. Constant normoxia, or 100% oxygen saturation, is therefore rare. Since the thermal sensitivity of invertebrates is directly linked to oxygen availability, we hypothesized that (i) the metabolic response of coastal marine invertebrates would be more sensitive to thermal stress when exposed to oxygen supersaturation rather than 100% oxygen saturation and (ii) natural diel fluctuation in oxygen availability rather than constant 100% oxygen saturation is a main driver of the thermal response. We tested the effects of oxygen regime on the metabolic rate, and haemocyanin and lactate levels, of velvet crabs (Necora puber) and blue mussels (Mytilus edulis), under rising temperatures (up to 24°C) in the laboratory. Oxygen supersaturation and photosynthetically induced diel oxygen fluctuation amplified animal metabolic thermal response significantly in both species, demonstrating that the natural variability of oxygen in coastal environments can provide considerable physiological benefits under ocean warming. Our study highlights the significance of integrating ecologically relevant oxygen variability into experimental assessments of animal physiology and thermal response, and predictions of metabolic performance under climate warming. Given the escalating intensity and frequency of climate anomalies, oxygen variation caused by coastal vegetation will likely become increasingly important in mitigating the effects of higher temperatures on coastal fauna.

The use of continuous electronic prescribing data to infer trends in antimicrobial consumption and estimate the impact of stewardship interventions in hospitalized children.

BACKGROUND: Understanding antimicrobial consumption is essential to mitigate the development of antimicrobial resistance, yet robust data in children are sparse and methodologically limited. Electronic prescribing systems provide an important opportunity to analyse and report antimicrobial consumption in detail. OBJECTIVES: We investigated the value of electronic prescribing data from a tertiary children's hospital to report temporal trends in antimicrobial consumption in hospitalized children and compare commonly used metrics of antimicrobial consumption. METHODS: Daily measures of antimicrobial consumption [days of therapy (DOT) and DDDs] were derived from the electronic prescribing system between 2010 and 2018. Autoregressive moving-average models were used to infer trends and the estimates were compared with simulated point prevalence surveys (PPSs). RESULTS: More than 1.3 million antimicrobial administrations were analysed. There was significant daily and seasonal variation in overall consumption, which reduced annually by 1.77% (95% CI 0.50% to 3.02%). Relative consumption of meropenem decreased by 6.6% annually (95% CI -3.5% to 15.8%) following the expansion of the hospital antimicrobial stewardship programme. DOT and DDDs exhibited similar trends for most antimicrobials, though inconsistencies were observed where changes to dosage guidelines altered consumption calculation by DDDs, but not DOT. PPS simulations resulted in estimates of change over time, which converged on the model estimates, but with much less precision. CONCLUSIONS: Electronic prescribing systems offer significant opportunities to better understand and report antimicrobial consumption in children. This approach to modelling administration data overcomes the limitations of using interval data and dispensary data. It provides substantially more detailed inferences on prescribing patterns and the potential impact of stewardship interventions.

Long-term cigarette smoke exposure dysregulates pulmonary T cell response and IFN-γ protection to influenza virus in mouse.

BACKGROUND: Influenza is a highly contagious, acute, febrile respiratory infection caused by a negative-sense, single-stranded RNA virus, which belongs in the Orthomyxoviridae family. Cigarette smoke (CS) exposure worsens influenza infection in terms of frequency and severity in both human and animal models. METHODS: C57BL/6 mice with or without CS exposure for 6 weeks were inoculated intranasally with a single, non-lethal dose of the influenza A virus (IAV) A/Puerto Rico/8/1934 (PR8) strain. At 7 and 10 days after infection, lung and mediastinal lymph nodes (MLN) cells were collected to determine the numbers of total CD4 + and CD8 + T cells, and IAV-specific CD4 + and CD8 + T cells, using flow cytometry. Bronchoalveolar lavage fluid (BALF) was also collected to determine IFN-γ levels and total protein concentration. RESULTS: Although long-term CS exposure suppressed early pulmonary IAV-antigen specific CD8 + and CD4 + T cell numbers and IFN-γ production in response to IAV infection on day 7 post-infection, CS enhanced numbers of these cells and IFN-γ production on day 10. The changes of total protein concentration in BALF are consistent with the changes in the IFN-γ amounts between day 7 and 10, which suggested that excessive IFN-γ impaired barrier function and caused lung injury at the later stage of infection. CONCLUSIONS: Our results demonstrated that prior CS exposure caused a biphasic T cell and IFN-γ response to subsequent infection with influenza in the lung. Specifically, the number of IAV antigen-specific T cells on day 10 was greatly increased by CS exposure even though CS decreased the number of the same group of cells on day 7. The result suggested that CS affected the kinetics of the T cell response to IAV, which was suppressed at an early stage and exaggerated at a later stage. This study is the first to describe the different effect of long-term CS on T cell responses to IAV at early and late stages of infection in vivo.

Reducing emergency department (ED) computed tomography (CT) utilization in women treated for gynecologic cancers.

OBJECTIVES: The objective of this quality improvement (QI) project was to decrease the rate of low-value computed tomography (CT) imaging in established gynecologic oncology patients presenting to the emergency department (ED). METHODS: This was a cohort study with a before and after design that evaluated implementation of a QI project designed to decrease CT utilization in established gynecologic oncology patients in the ED. The pre-intervention cohort included patients admitted through the ED from 4/1/17 to 5/31/18, while the post-intervention cohort was from 6/1/18 to 5/31/19. The intervention included gynecologic oncology consultation before CT on patients who had imaging within the prior 3 weeks. Details regarding CT, ED length of stay (LOS), and oncologic history were abstracted. The value of CT was determined by consensus from 2 reviewers. Prospective data monitoring evaluated for patient safety. RESULTS: Prior to intervention, there were 129 unique ED encounters in gynecologic oncology patients leading to admission. CT scans were performed in 101 (78.3%) encounters, 57.7% of which were deemed to be of low-value. Following implementation, the CT utilization rate decreased significantly from median monthly rate of 75.2% to 49.1% (p < 0.00001), and the ED LOS decreased from 8.1 to 6.9 h (p = 0.0102). The number of CT scans deemed to be low-value in the post-intervention group decreased to 2 (3.8%). CONCLUSIONS: Implementation of an early consultation policy and imaging guidelines led to a significant decrease in unnecessary CT utilization and shorter ED LOS in gynecologic oncology patients presenting to the ED.

Synthetic Biology of Cannabinoids and Cannabinoid Glucosides in Nicotiana benthamiana and Saccharomyces cerevisiae.

Phytocannabinoids are a group of plant-derived metabolites that display a wide range of psychoactive as well as health-promoting effects. The production of pharmaceutically relevant cannabinoids relies on extraction and purification from cannabis (Cannabis sativa) plants yielding the major constituents, Δ9-tetrahydrocannabinol and cannabidiol. Heterologous biosynthesis of cannabinoids in Nicotiana benthamiana or Saccharomyces cerevisiae may provide cost-efficient and rapid future production platforms to acquire pure and high quantities of both the major and the rare cannabinoids as well as novel derivatives. Here, we used a meta-transcriptomic analysis of cannabis to identify genes for aromatic prenyltransferases of the UbiA superfamily and chalcone isomerase-like (CHIL) proteins. Among the aromatic prenyltransferases, CsaPT4 showed CBGAS activity in both N. benthamiana and S. cerevisiae. Coexpression of selected CsaPT pairs and of CHIL proteins encoding genes with CsaPT4 did not affect CBGAS catalytic efficiency. In a screen of different plant UDP-glycosyltransferases, Stevia rebaudiana SrUGT71E1 and Oryza sativa OsUGT5 were found to glucosylate olivetolic acid, cannabigerolic acid, and Δ9-tetrahydrocannabinolic acid. Metabolic engineering of N. benthamiana for production of cannabinoids revealed intrinsic glucosylation of olivetolic acid and cannabigerolic acid. S. cerevisiae was engineered to produce olivetolic acid glucoside and cannabigerolic acid glucoside.

Transcriptional Classification and Functional Characterization of Human Airway Macrophage and Dendritic Cell Subsets.

The respiratory system is a complex network of many cell types, including subsets of macrophages and dendritic cells that work together to maintain steady-state respiration. Owing to limitations in acquiring cells from healthy human lung, these subsets remain poorly characterized transcriptionally and phenotypically. We set out to systematically identify these subsets in human airways by developing a schema of isolating large numbers of cells by whole-lung bronchoalveolar lavage. Six subsets of phagocytic APC (HLA-DR+) were consistently observed. Aside from alveolar macrophages, subsets of Langerin+, BDCA1-CD14+, BDCA1+CD14+, BDCA1+CD14-, and BDCA1-CD14- cells were identified. These subsets varied in their ability to internalize Escherichia coli, Staphylococcus aureus, and Bacillus anthracis particles. All subsets were more efficient at internalizing S. aureus and B. anthracis compared with E. coli Alveolar macrophages and CD14+ cells were overall more efficient at particle internalization compared with the four other populations. Subsets were further separated into two groups based on their inherent capacities to upregulate surface CD83, CD86, and CCR7 expression levels. Whole-genome transcriptional profiling revealed a clade of "true dendritic cells" consisting of Langerin+, BDCA1+CD14+, and BDCA1+CD14- cells. The dendritic cell clade was distinct from a macrophage/monocyte clade, as supported by higher mRNA expression levels of several dendritic cell-associated genes, including CD1, FLT3, CX3CR1, and CCR6 Each clade, and each member of both clades, was discerned by specific upregulated genes, which can serve as markers for future studies in healthy and diseased states.

Gene expression profiling of primary human type I alveolar epithelial cells exposed to Bacillus anthracis spores reveals induction of neutrophil and monocyte chemokines.

The lung is the entry site for Bacillus anthracis in inhalation anthrax, the most deadly form of the disease. Spores must escape through the alveolar epithelial cell (AEC) barrier and migrate to regional lymph nodes, germinate and enter the circulatory system to cause disease. Several mechanisms to explain alveolar escape have been postulated, and all these tacitly involve the AEC barrier. In this study, we incorporate our primary human type I AEC model, microarray and gene enrichment analysis, qRT-PCR, multiplex ELISA, and neutrophil and monocyte chemotaxis assays to study the response of AEC to B. anthracis, (Sterne) spores at 4 and 24 h post-exposure. Spore exposure altered gene expression in AEC after 4 and 24 h and differentially expressed genes (±1.3 fold, p ≤ 0.05) included CCL4/MIP-1ß (4 h), CXCL8/IL-8 (4 and 24 h) and CXCL5/ENA-78 (24 h). Gene enrichment analysis revealed that pathways involving cytokine or chemokine activity, receptor binding, and innate immune responses to infection were prominent. Microarray results were confirmed by qRT-PCR and multiplex ELISA assays. Chemotaxis assays demonstrated that spores induced the release of biologically active neutrophil and monocyte chemokines, and that CXCL8/IL-8 was the major neutrophil chemokine. The small or sub-chemotactic doses of CXCL5/ENA-78, CXCL2/GROß and CCL20/MIP-3α may contribute to chemotaxis by priming effects. These data provide the first whole transcriptomic description of the human type I AEC initial response to B. anthracis spore exposure. Taken together, our findings contribute to an increased understanding of the role of AEC in the pathogenesis of inhalational anthrax.

Pharmacokinetic modelling and validation of the half-life extension needed to reduce the burden of infusions compared with standard factor VIII.

INTRODUCTION: Currently, no universally accepted definition of extended half-life (EHL) recombinant FVIII (rFVIII) exists. Identifying the minimum half-life extension ratio required for a reduction in dosing frequency compared with standard rFVIII could enable a more practical approach to decisions around prophylaxis with EHL rFVIII. AIM: To identify the half-life extension ratio required to decrease rFVIII dosing frequency by at least 1 day while maintaining the proportion of patients with plasma rFVIII levels above 1 IU/dL and without increasing the total weekly dose. METHODS: A previously published population pharmacokinetic model for standard rFVIII was used to estimate the percentage of patients with factor VIII (FVIII) levels always >1 IU/dL using various benchmark regimens. Using modelling, dosing frequency was reduced while rFVIII half-life was extended until the percentage of patients with FVIII >1 IU/dL equalled that of the benchmark regimen. RESULTS: Benchmark 3×/wk dosing totalling 100 IU/kg/wk of rFVIII resulted in 56.6% of patients with FVIII levels always >1 IU/dL. With 2×/wk dosing, totalling 80 or 90 IU/kg/wk, half-life extensions required to maintain 56.6% of patients at FVIII levels >1 IU/dL were 1.30 and 1.26, respectively. A half-life extension ratio of 1.33 was required to change dosing from every 48 hours to every 72 hours (both at 105 IU/kg/wk) while maintaining 92.8% of patients with FVIII >1 IU/dL. CONCLUSION: Based on this investigation, EHL rFVIII products should have a minimum half-life extension ratio of 1.3 to provide a reduction in dosing frequency from 3× to 2×/wk compared with standard rFVIII products while maintaining the same minimum FVIII trough level.

Phenotypical resistance correlation networks for 10 non-typhoidal Salmonella subpopulations in an active antimicrobial surveillance programme.

Antimicrobials play a critical role in treating cases of invasive non-typhoidal salmonellosis (iNTS) and other diseases, but efficacy is hindered by resistant pathogens. Selection for phenotypical resistance may occur via several mechanisms. The current study aims to identify correlations that would allow indirect selection of increased resistance to ceftriaxone, ciprofloxacin and azithromycin to improve antimicrobial stewardship. These are medically important antibiotics for treating iNTS, but these resistances persist in non-Typhi Salmonella serotypes even though they are not licensed for use in US food animals. A set of 2875 Salmonella enterica isolates collected from animal sources by the National Antimicrobial Resistance Monitoring System were stratified in to 10 subpopulations based on serotype and host species. Collateral resistances in each subpopulation were estimated as network models of minimum inhibitory concentration partial correlations. Ceftriaxone sensitivity was correlated with other ß-lactam resistances, and less commonly resistances to tetracycline, trimethoprim-sulfamethoxazole or kanamycin. Azithromycin resistance was frequently correlated with chloramphenicol resistance. Indirect selection for ciprofloxacin resistance via collateral selection appears unlikely. Density of the ACSSuT subgraph resistance aligned well with the phenotypical frequency. The current study identifies several important resistances in iNTS serotypes and further research is needed to identify the causative genetic correlations.

RIG-I Signaling via MAVS Is Dispensable for Survival in Lethal Influenza Infection In Vivo.

Retinoic acid-inducible gene I (RIG-I) is an important regulator of virus-induced antiviral interferons (IFNs) and proinflammatory cytokines. It requires interaction with an adaptor molecule, mitochondrial antiviral-signaling protein (MAVS), to activate downstream signaling pathways. To elucidate the mechanism(s) by which RIG-I-dependent recognition of IAV infection in vivo triggers innate immune responses, we infected mutant mice lacking RIG-I or MAVS with influenza A virus (IAV) and measured their innate immune responses. As has previously been demonstrated with isolated deletion of the virus recognition receptors TLR3, TLR7, and NOD2, RIG-I or MAVS knockout (KO) did not result in higher mortality and did not reduce IAV-induced cytokine responses in mice. Infected RIG-I KO animals displayed similar lung inflammation profiles as did WT mice, in terms of the protein concentration, total cell count, and inflammatory cell composition in the bronchoalveolar lavage fluid. RNA-Seq results demonstrated that all types of mice exhibited equivalent antiviral and inflammatory gene responses following IAV infection. Together, the results indicated that although RIG-I is important in innate cytokine responses in vitro, individual deletion of the genes encoding RIG-I or MAVS did not change survival or innate responses in vivo after IAV infection in mice.

RIG-I overexpression decreases mortality of cigarette smoke exposed mice during influenza A virus infection.

BACKGROUND: Retinoic acid-inducible gene I (RIG-I) is an important regulator of virus-induced antiviral interferons (IFNs) and proinflammatory cytokines which participate in clearing viral infections. Cigarette smoke (CS) exposure increases the frequency and severity of respiratory tract infections. METHODS: We generated a RIG-I transgenic (TG) mouse strain that expresses the RIG-I gene product under the control of the human lung specific surfactant protein C promoter. We compared the mortality and host immune responses of RIG-I TG mice and their litter-matched wild type (WT) mice following challenge with influenza A virus (IAV). RESULTS: RIG-I overexpression increased survival of IAV-infected mice. CS exposure increased mortality in WT mice infected with IAV. Remarkably, the effect of RIG-I overexpression on survival during IAV infection was enhanced in CS-exposed animals. CS-exposed IAV-infected WT mice had a suppressed innate response profile in the lung compared to sham-exposed IAV-infected WT mice in terms of the protein concentration, total cell count and inflammatory cell composition in the bronchoalveolar lavage fluid. RIG-I overexpression restored the innate immune response in CS-exposed mice to that seen in sham-exposed WT mice during IAV infection, and is likely responsible for enhanced survival in RIG-I TG mice as restoration preceded death of the animals. CONCLUSIONS: Our results demonstrate that RIG-I overexpression in mice is protective for CS enhanced susceptibility of smokers to influenza infection, and that CS mediated RIG-I suppression may be partially responsible for the increased morbidity and mortality of the mice exposed to IAV. Thus, optimizing the RIG-I response may be an important treatment strategy for CS-enhanced lung infections, particularly those due to IAV.

Human primary airway epithelial cells isolated from active smokers have epigenetically impaired antiviral responses.

BACKGROUND: Cigarette smoking (CS) is the main risk factor for the development of chronic obstructive pulmonary disease (COPD) and most COPD exacerbations are caused by respiratory infections including influenza. Influenza infections are more severe in smokers. The mechanism of the increased risk and severity of infections in smokers is likely multifactorial, but certainly includes changes in immunologic host defenses. METHODS: We investigated retinoic acid-inducible protein I (RIG-I) and interferon (IFN) induction by influenza A virus (IAV) in human bronchial epithelial cells (HBEC) isolated from smokers or nonsmokers. Subcultured HBEC cells were infected with A/Puerto Rico/8/1934 (PR8) IAV at an MOI of 1. After 24 h of infection, cells and supernatants were collected for qRT-PCR, immunoblot or ELISA to determine RIG-I, Toll-like receptor3 (TLR3) and IFN expression levels. RESULTS: IAV exposure induced a vigorous IFN-ß, IFN-λ 1 and IFN-λ 2/3 antiviral response in HBEC from nonsmokers and significant induction of RIG-I and TLR3. In cells from smokers, viral RIG-I and TLR3 mRNA induction was reduced 87 and 79 % compared to the response from nonsmokers. CS exposure history was associated with inhibition of viral induction of the IFN-ß, IFN-λ1 and IFN-λ 2/3 mRNA response by 85, 96 and 95 %, respectively, from that seen in HBEC from nonsmokers. The demethylating agent 5-Aza-2-deoxycytidine reversed the immunosuppressive effects of CS exposure in HBEC since viral induction of all three IFNs was restored. IFN-ß induction of RIG-I and TLR3 was also suppressed in the cells from smokers. CONCLUSION: Our results suggest that active smoking reduces expression of antiviral cytokines in primary HBEC cells. This effect likely occurs via downregulation of RIG-I and TLR3 due to smoke-induced epigenetic modifications. Reduction in lung epithelial cell RIG-I and TLR3 responses may be a major mechanism contributing to the increased risk and severity of viral respiratory infections in smokers and to viral-mediated acute exacerbations of COPD.

Hubbard physics in the PAW GW approximation.

It is demonstrated that the signatures of the Hubbard Model in the strongly interacting regime can be simulated by modifying the screening in the limit of zero wavevector in Projector-Augmented Wave GW calculations for systems without significant nesting. This modification, when applied to the Mott insulator CuO, results in the opening of the Mott gap by the splitting of states at the Fermi level into upper and lower Hubbard bands, and exhibits a giant transfer of spectral weight upon electron doping. The method is also employed to clearly illustrate that the M1 and M2 forms of vanadium dioxide are fundamentally different types of insulator. Standard GW calculations are sufficient to open a gap in M1 VO2, which arise from the Peierls pairing filling the valence band, creating homopolar bonds. The valence band wavefunctions are stabilized with respect to the conduction band, reducing polarizability and pushing the conduction band eigenvalues to higher energy. The M2 structure, however, opens a gap from strong on-site interactions; it is a Mott insulator.

How number line estimation skills relate to neural activations in single digit subtraction problems.

The Number Line (NL) task requires judging the relative numerical magnitude of a number and estimating its value spatially on a continuous line. Children's skill on this task has been shown to correlate with and predict future mathematical competence. Neurofunctionally, this task has been shown to rely on brain regions involved in numerical processing. However, there is no direct evidence that performance on the NL task is related to brain areas recruited during arithmetical processing and that these areas are domain-specific to numerical processing. In this study, we test whether 8- to 14-year-old's behavioral performance on the NL task is related to fMRI activation during small and large single-digit subtraction problems. Domain-specific areas for numerical processing were independently localized through a numerosity judgment task. Results show a direct relation between NL estimation performance and the amount of the activation in key areas for arithmetical processing. Better NL estimators showed a larger problem size effect than poorer NL estimators in numerical magnitude (i.e., intraparietal sulcus) and visuospatial areas (i.e., posterior superior parietal lobules), marked by less activation for small problems. In addition, the direction of the activation with problem size within the IPS was associated with differences in accuracies for small subtraction problems. This study is the first to show that performance in the NL task, i.e. estimating the spatial position of a number on an interval, correlates with brain activity observed during single-digit subtraction problem in regions thought to be involved in numerical magnitude and spatial processes.

Cigarette smoke attenuates the RIG-I-initiated innate antiviral response to influenza infection in two murine models.

Cigarette smoke (CS) exposure increases the frequency and severity of respiratory tract infections. Despite this association, the mechanisms underlying the increased susceptibility to respiratory virus infection are poorly understood. Retinoic acid-inducible gene I (RIG-I) is an important regulator of influenza virus-induced expression of antiviral cytokines, mainly interferons (IFNs), which are necessary to clear viral infections. In this study, we compared the innate cytokine responses of two mouse CS exposure models following a challenge with influenza A virus (IAV): 1) exposure of the mice to cigarette smoke extract (CSE) intratracheally and 2) exposure of the mice to CS in a whole body exposure chamber. Both intratracheal CSE treatment and whole body CS exposure caused antiviral immunosuppression in these mice, and both CS exposure methods inhibited RIG-I induction. CS attenuated influenza-induced antiviral IFNs and IP-10 expression in vivo. However, we did not find that CS inhibited induction of the proinflammatory cytokines IL-6 and TNF-α, whose expression was induced by IAV. Interestingly, IAV infection also increased Toll-like receptor 3 (TLR3) expression in mouse lung, but CS exposure did not impact TLR3 induction in these mice. Together, the results support our previous finding in a human lung organ culture model that the suppression of RIG-I induction and antiviral cytokine responses by CS are likely important in the enhanced susceptibility of smokers to influenza infection in the lung.

Obesity impairs academic attainment in adolescence: findings from ALSPAC, a UK cohort.

OBJECTIVE: While being overweight or obese in adolescence may have detrimental effects on academic attainment, the evidence base is limited by reliance on cross-sectional studies with small sample sizes, failure to take account of confounders and lack of consideration of potential mediators. The present study aimed to address these limitations and examine longitudinal associations between obesity in adolescence and academic attainment. DESIGN: Associations between weight status at 11 years old and academic attainment assessed by national tests at 11, 13 and 16 years were examined in the Avon Longitudinal Study of Parents and Children. Healthy weight was defined as body mass index (BMI) Z-score <1.04; overweight as BMI Z-score 1.04-1.63; obesity as BMI Z-score ⩾1.64. PARTICIPANTS: Data from 5966 participants with objectively measured weight status were examined: 71.4% were healthy weight (1935 males; 2325 females), 13.3% overweight (372 males; 420 females) and 15.3% obese (448 males; 466 females). RESULTS: Girls obese at 11 years had lower academic attainment at 11, 13 and 16 years compared with those of a healthy weight, even after controlling for a wide range of confounders. Associations between obesity and academic attainment were less clear in boys. The potential mediating effects of depressive symptoms, intelligence quotient (IQ) and age of menarche in girls were explored, but when confounders were included, there was no strong evidence for mediation. CONCLUSIONS: For girls, obesity in adolescence has a detrimental impact on academic attainment 5 years later. Mental health, IQ and age of menarche did not mediate this relationship, suggesting that further work is required to understand the underlying mechanisms. Parents, education and public health policy makers should consider the wide reaching detrimental impact of obesity on educational outcomes in this age group.

Acute resistance exercise and pressure pain sensitivity in knee osteoarthritis: a randomised crossover trial.

OBJECTIVE: To determine whether a single bout of resistance exercise produces an analgesic effect in individuals with knee osteoarthritis (OA). DESIGN: Eleven participants with knee OA (65.9 ± 10.4 yrs), and 11 old (61.3 ± 8.2 yrs) and 11 young (25.0 ± 4.9 yrs) healthy adults performed separate bouts of upper and lower body resistance exercise. Baseline and post-exercise pressure pain thresholds were measured at eight sites across the body and pressure pain tolerance was measured at the knee. RESULTS: Pressure pain thresholds increased following exercise for all three groups, indicating reduced pain sensitivity. For the young and old healthy groups this exercise-induced analgesia (EIA) occurred following upper or lower body resistance exercise. In contrast, only upper body exercise significantly raised pain thresholds in the knee OA group, with variable non-significant effects following lower body exercise. Pressure pain tolerance was unchanged in all groups following either upper or lower body exercise. CONCLUSION: An acute bout of upper or lower body exercise evoked a systemic decrease in pain sensitivity in healthy individuals irrespective of age. The decreased pain sensitivity following resistance exercise can be attributed to changes in pain thresholds, not pain tolerance. While individuals with knee OA experienced EIA, a systemic decrease in pain sensitivity was only evident following upper body exercise.

Associations between objectively measured physical activity and academic attainment in adolescents from a UK cohort.

BACKGROUND: To test for cross-sectional (at age 11) and longitudinal associations between objectively measured free-living physical activity (PA) and academic attainment in adolescents.Method Data from 4755 participants (45% male) with valid measurement of PA (total volume and intensity) by accelerometry at age 11 from the Avon Longitudinal Study of Parents and Children (ALSPAC) was examined. Data linkage was performed with nationally administered school assessments in English, Maths and Science at ages 11, 13 and 16. RESULTS: In unadjusted models, total volume of PA predicted decreased academic attainment. After controlling for total volume of PA, percentage of time spent in moderate-vigorous intensity PA (MVPA) predicted increased performance in English assessments in both sexes, taking into account confounding variables. In Maths at 16 years, percentage of time in MVPA predicted increased performance for males (standardised ß=0.11, 95% CI 0.00 to 0.22) and females (ß=0.08, 95% CI 0.00 to 0.16). For females the percentage of time spent in MVPA at 11 years predicted increased Science scores at 11 and 16 years (ß=0.14 (95% CI 0.03 to 0.25) and 0.14 (0.07 to 0.21), respectively). The correction for regression dilution approximately doubled the standardised ß coefficients. CONCLUSIONS: Findings suggest a long-term positive impact of MVPA on academic attainment in adolescence.