Explore the vast range of titles available.

Urine specific gravity (USG) is frequently utilized in sports practice and research to assess hydration status. Prior research suggests that individuals with large amounts of fat-free mass (FFM) and muscle have elevated USG, but little is known about whether the time of collection (first-morning vs. spot sampling) and various nutritional factors influence these relationships. This cross-sectional, observational study assessed fasted first-morning (n = 55) and non-fasted spot USG (n = 51) samples in adults and evaluated relationships of USG with body composition and nutrition intake. The InBody 770 was used to estimate FFM, skeletal muscle mass (SMM), and total body water (TBW). Protein, water, and sodium intakes from the 24-hour period before USG assessments were generated based on the Automated Self-Administered 24-hour Recall. Median USG was higher for fasted first-morning samples than non-fasted spot samples (1.018 vs. 1.011, Z = −5.2, p < 0.001). Based on fasted first-morning samples, 41.8% of participants had a USG ≥ 1.020 while the prevalence of USG ≥ 1.020 was 21.6% using non-fasted spot samples. None of the body composition variables (FFM, SMM, TBW) significantly associated with fasted first-morning USG (Spearman ρ < 0.10), while all three variables showed significant, positive associations with non-fasted spot USG (Spearman ρ = 0.32–0.36, p < 0.05). None of the dietary variables were significantly associated with either fasted first-morning or non-fasted spot USG. Although previous research has shown the FFM positively associates with USG, this investigation provides evidence that this relationship could depend on sampling time. Non-fasted spot samples, in comparison to fasted first-morning samples, may be impacted by FFM to a greater degree.

Lactate (La−) has long been at the center of controversy in research, clinical, and athletic settings. Since its discovery in 1780, La− has often been erroneously viewed as simply a hypoxic waste product with multiple deleterious effects. Not until the 1980s, with the introduction of the cell-to-cell lactate shuttle did a paradigm shift in our understanding of the role of La− in metabolism begin. The evidence for La− as a major player in the coordination of whole-body metabolism has since grown rapidly. La− is a readily combusted fuel that is shuttled throughout the body, and it is a potent signal for angiogenesis irrespective of oxygen tension. Despite this, many fundamental discoveries about La− are still working their way into mainstream research, clinical care, and practice. The purpose of this review is to synthesize current understanding of La− metabolism via an appraisal of its robust experimental history, particularly in exercise physiology. That La− production increases during dysoxia is beyond debate, but this condition is the exception rather than the rule. Fluctuations in blood [La−] in health and disease are not typically due to low oxygen tension, a principle first demonstrated with exercise and now understood to varying degrees across disciplines. From its role in coordinating whole-body metabolism as a fuel to its role as a signaling molecule in tumors, the study of La− metabolism continues to expand and holds potential for multiple clinical applications. This review highlights La−’s central role in metabolism and amplifies our understanding of past research.

Through much of the history of metabolism, lactate (La(-)) has been considered merely a dead-end waste product during periods of dysoxia. Congruently, the end product of glycolysis has been viewed dichotomously: pyruvate in the presence of adequate oxygenation, La(-) in the absence of adequate oxygenation. In contrast, given the near-equilibrium nature of the lactate dehydrogenase (LDH) reaction and that LDH has a much higher activity than the putative regulatory enzymes of the glycolytic and oxidative pathways, we contend that La(-) is always the end product of glycolysis. Cellular La(-) accumulation, as opposed to flux, is dependent on (1) the rate of glycolysis, (2) oxidative enzyme activity, (3) cellular O2 level, and (4) the net rate of La(-) transport into (influx) or out of (efflux) the cell. For intracellular metabolism, we reintroduce the Cytosol-to-Mitochondria Lactate Shuttle. Our proposition, analogous to the phosphocreatine shuttle, purports that pyruvate, NAD(+), NADH, and La(-) are held uniformly near equilibrium throughout the cell cytosol due to the high activity of LDH. La(-) is always the end product of glycolysis and represents the primary diffusing species capable of spatially linking glycolysis to oxidative phosphorylation.

This paper reviews the evidence for the effectiveness and cost-effectiveness of policies to reduce alcohol-related harm. Policies focus on price, marketing, availability, information and education, the drinking environment, drink-driving, and brief interventions and treatment. Although there is variability in research design and measured outcomes, evidence supports the effectiveness and cost-effectiveness of policies that address affordability and marketing. An adequate reduction in temporal availability, particularly late night on-sale availability, is effective and cost-effective. Individually-directed interventions delivered to at-risk drinkers and enforced legislative measures are also effective. Providing information and education increases awareness, but is not sufficient to produce long-lasting changes in behaviour. At best, interventions enacted in and around the drinking environment lead to small reductions in acute alcohol-related harm. Overall, there is a rich evidence base to support the decisions of policy makers in implementing the most effective and cost-effective policies to reduce alcohol-related harm.

The interaction between immune cells and virus-infected targets involves multiple plasma membrane (PM) proteins. A systematic study of PM protein modulation by vaccinia virus (VACV), the paradigm of host regulation, has the potential to reveal not only novel viral immune evasion mechanisms, but also novel factors critical in host immunity. Here, >1000 PM proteins were quantified throughout VACV infection, revealing selective downregulation of known T and NK cell ligands including HLA-C, downregulation of cytokine receptors including IFNAR2, IL-6ST and IL-10RB, and rapid inhibition of expression of certain protocadherins and ephrins, candidate activating immune ligands. Downregulation of most PM proteins occurred via a proteasome-independent mechanism. Upregulated proteins included a decoy receptor for TRAIL. Twenty VACV-encoded PM proteins were identified, of which five were not recognised previously as such. Collectively, this dataset constitutes a valuable resource for future studies on antiviral immunity, host-pathogen interaction, poxvirus biology, vector-based vaccine design and oncolytic therapy.

Innate immunity is the first immunological defence against pathogens. During virus infection detection of nucleic acids is crucial for the inflammatory response. Here we identify DNA-dependent protein kinase (DNA-PK) as a DNA sensor that activates innate immunity. We show that DNA-PK acts as a pattern recognition receptor, binding cytoplasmic DNA and triggering the transcription of type I interferon (IFN), cytokine and chemokine genes in a manner dependent on IFN regulatory factor 3 (IRF-3), TANK-binding kinase 1 (TBK1) and stimulator of interferon genes (STING). Both cells and mice lacking DNA-PKcs show attenuated cytokine responses to both DNA and DNA viruses but not to RNA or RNA virus infection. DNA-PK has well-established functions in the DNA repair and V(D)J recombination, hence loss of DNA-PK leads to severe combined immunodeficiency (SCID). However, we now define a novel anti-microbial function for DNA-PK, a finding with implications for host defence, vaccine development and autoimmunity. For multicellular organisms, the innate immune system is the first immunological defence against infection, rapidly recognizing and responding to the presence of any pathogen. Many different cell types contribute to the innate immunity, including fibroblasts, epithelial cells, dendritic cells and macrophages. Once alerted to injury or infection, these cells release proteins called cytokines, interferons and chemokines into the blood or directly into tissue. These proteins act as messengers and interact with receptors on the surfaces of other cells in the immune system, stimulating them to join the battle against the infection. Detecting nucleic acids such as DNA is an important part of recognizing pathogens and infectious agents, particularly viruses, and activating the innate immune system. However, while the presence of DNA in the cytoplasm is known to initiate an innate immune response, we do not fully understand how this foreign DNA is sensed, or how the innate immune system is activated once foreign DNA has been detected. Here Ferguson et al. report that a well-known complex of three proteins, collectively called DNA-dependent protein kinase, is able to activate an innate immune response when it detects foreign DNA. This enzyme, called DNA-PK for short, is best known for its ability to repair broken DNA inside the nucleus. Now Ferguson et al. have found that it is also present at high levels within fibroblasts, cells that are often primary targets of viral infection, and they go on to explain how the detection of DNA by DNA-PK triggers a sequence of events that leads to the innate immune response being activated. These events include the transcription of type I interferon, chemokines and cytokines in a manner that depends on the presence IRF-3, a transcription factor that has a central role in the response of the immune system to viral infection. By identifying a role for DNA-PK in the cytoplasm as a DNA sensor, the work of Ferguson et al. increases our understanding of innate immunity. It may also, in the future, lead to an improved understanding of autoimmunity, and might also assist in the development of more immunogenic vaccines based on DNA or microbes that contain DNA.

The innate immune system is critical in the response to infection by pathogens and it is activated by pattern recognition receptors (PRRs) binding to pathogen associated molecular patterns (PAMPs). During viral infection, the direct recognition of the viral nucleic acids, such as the genomes of DNA viruses, is very important for activation of innate immunity. Recently, DNA-dependent protein kinase (DNA-PK), a heterotrimeric complex consisting of the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs was identified as a cytoplasmic PRR for DNA that is important for the innate immune response to intracellular DNA and DNA virus infection. Here we show that vaccinia virus (VACV) has evolved to inhibit this function of DNA-PK by expression of a highly conserved protein called C16, which was known to contribute to virulence but by an unknown mechanism. Data presented show that C16 binds directly to the Ku heterodimer and thereby inhibits the innate immune response to DNA in fibroblasts, characterised by the decreased production of cytokines and chemokines. Mechanistically, C16 acts by blocking DNA-PK binding to DNA, which correlates with reduced DNA-PK-dependent DNA sensing. The C-terminal region of C16 is sufficient for binding Ku and this activity is conserved in the variola virus (VARV) orthologue of C16. In contrast, deletion of 5 amino acids in this domain is enough to knockout this function from the attenuated vaccine strain modified vaccinia virus Ankara (MVA). In vivo a VACV mutant lacking C16 induced higher levels of cytokines and chemokines early after infection compared to control viruses, confirming the role of this virulence factor in attenuating the innate immune response. Overall this study describes the inhibition of DNA-PK-dependent DNA sensing by a poxvirus protein, adding to the evidence that DNA-PK is a critical component of innate immunity to DNA viruses.

The mechanisms by which flaviviruses use non-canonical translation to support their replication in host cells are largely unknown. Here, we investigated how the integrated stress response (ISR), which promotes translational arrest by eIF2ɑ phosphorylation (p-eIF2ɑ), regulates flavivirus replication. During dengue virus (DENV) and Zika virus (ZIKV) infection, eIF2ɑ phosphorylation peaked at 24 hours post-infection and was dependent on protein kinase RNA-activated (PKR) but not type I interferon. The ISR is activated downstream of p-eIF2α during infection with either virus, but translation arrest only occurred following DENV4 infection. Despite this difference, both DENV4 and ZIKV replications were impaired in cells lacking PKR, independent of type I interferon/NF-kB signaling or cell viability. By using a ZIKV 5′-untranslated region (UTR) reporter system as a model, we found that this region of the genome is sufficient to promote an enhancement of viral mRNA translation in the presence of an active ISR. Together, we provide evidence that flaviviruses escape ISR translational arrest and co-opt this response to increase viral replication. One of the fundamental features that make viruses intracellular parasites is the necessity to use cellular translational machinery. Hence, this is a crucial checkpoint for controlling infections. Here, we show that dengue and Zika viruses, responsible for nearly 400 million infections every year worldwide, explore such control for optimal replication. Using immunocompetent cells, we demonstrate that arrest of protein translations happens after sensing of dsRNA and that the information required to avoid this blocking is contained in viral 5′-UTR. Our work, therefore, suggests that the non-canonical translation described for these viruses is engaged when the intracellular stress response is activated.

Air pollution damages health by promoting the onset of some non-communicable diseases (NCDs), putting additional strain on the National Health Service (NHS) and social care. This study quantifies the total health and related NHS and social care cost burden due to fine particulate matter (PM2.5) and nitrogen dioxide (NO2) in England. Air pollutant concentration surfaces from land use regression models and cost data from hospital admissions data and a literature review were fed into a microsimulation model, that was run from 2015 to 2035. Different scenarios were modelled: (1) baseline 'no change' scenario; (2) individuals' pollutant exposure is reduced to natural (non-anthropogenic) levels to compute the disease cases attributable to PM2.5 and NO2; (3) PM2.5 and NO2 concentrations reduced by 1 μg/m3; and (4) NO2 annual European Union limit values reached (40 μg/m3). For the 18 years after baseline, the total cumulative cost to the NHS and social care is estimated at £5.37 billion for PM2.5 and NO2 combined, rising to £18.57 billion when costs for diseases for which there is less robust evidence are included. These costs are due to the cumulative incidence of air-pollution-related NCDs, such as 348,878 coronary heart disease cases estimated to be attributable to PM2.5 and 573,363 diabetes cases estimated to be attributable to NO2 by 2035. Findings from modelling studies are limited by the conceptual model, assumptions, and the availability and quality of input data. Approximately 2.5 million cases of NCDs attributable to air pollution are predicted by 2035 if PM2.5 and NO2 stay at current levels, making air pollution an important public health priority. In future work, the modelling framework should be updated to include multi-pollutant exposure-response functions, as well as to disaggregate results by socioeconomic status.

Interactions between pathogens, host microbiota and the immune system influence many physiological and pathological processes. In the 20 th century, widespread dermal vaccination with vaccinia virus (VACV) led to the eradication of smallpox but how VACV interacts with the microbiota and whether this influences the efficacy of vaccination are largely unknown. Here we report that intradermal vaccination with VACV induces a large increase in the number of commensal bacteria in infected tissue, which enhance recruitment of inflammatory cells, promote tissue damage and influence the host response. Treatment of vaccinated specific-pathogen-free (SPF) mice with antibiotic, or infection of genetically-matched germ-free (GF) animals caused smaller lesions without alteration in virus titre. Tissue damage correlated with enhanced neutrophil and T cell infiltration and levels of pro-inflammatory tissue cytokines and chemokines. One month after vaccination, GF and both groups of SPF mice had equal numbers of VACV-specific CD8 + T cells and were protected from disease induced by VACV challenge, despite lower levels of VACV-neutralising antibodies observed in GF animals. Thus, skin microbiota may provide an adjuvant-like stimulus during vaccination with VACV and influence the host response to vaccination.