Biochemical and structural characterization of Fapy•dG replication by Human DNA polymerase ß.

N6-(2-deoxy-α,ß-d-erythro-pentofuranosyl)-2,6-diamino-4-hydroxy-5-formamido-pyrimidine (Fapy•dG) is formed from a common intermediate and in comparable amounts to the well-studied mutagenic DNA lesion 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OxodGuo). Fapy•dG preferentially gives rise to G → T transversions and G → A transitions. However, the molecular basis by which Fapy•dG is processed by DNA polymerases during this mutagenic process remains poorly understood. To address this we investigated how DNA polymerase ß (Pol ß), a model mammalian polymerase, bypasses a templating Fapy•dG, inserts Fapy•dGTP, and extends from Fapy•dG at the primer terminus. When Fapy•dG is present in the template, Pol ß incorporates TMP less efficiently than either dCMP or dAMP. Kinetic analysis revealed that Fapy•dGTP is a poor substrate but is incorporated ∼3-times more efficiently opposite dA than dC. Extension from Fapy•dG at the 3'-terminus of a nascent primer is inefficient due to the primer terminus being poorly positioned for catalysis. Together these data indicate that mutagenic bypass of Fapy•dG is likely to be the source of the mutagenic effects of the lesion and not Fapy•dGTP. These experiments increase our understanding of the promutagenic effects of Fapy•dG.

Human performance augmentation: the importance of integrative physiological quantification.

In recent years, there has been an explosion of new approaches (technological, methodological, pharmacological, etc.) designed to improve physical performance for athletes, the military and in other applications. The goal of the present discussion is to review and quantify several ways in which physiology can provide important insights about which tools may lead to improved performance (and may therefore be worth resource investment) and which tools are less likely to provide meaningful enhancement. To address these objectives, we review examples of technological solutions/approaches in terms of the magnitude of their potential (or actual) influences: transformational, moderate, ineffective or undetermined. As one example, if there were a technology which significantly increased arterial oxygen partial pressure by 10%, this would be relatively meaningless in healthy people resting at sea level, where it would have a minimal effect on arterial oxygen content. However, there might be specific situations where such an effect would be very helpful, including at high altitude or in some patient populations. We discuss the importance of quantitative evaluation of putative approaches to performance enhancement and highlight the important role of integrative physiologists in the development and critical appraisal of these approaches.

Both moderate- and high-intensity exercise training increase intramyocellular lipid droplet abundance and modify myocellular distribution in adults with obesity.

Exercise training modifies lipid metabolism in skeletal muscle, but the effect of exercise training on intramyocellular lipid droplet (LD) abundance, size, and intracellular distribution in adults with obesity remains elusive. This study compared high-intensity interval training (HIIT) with more conventional moderate-intensity continuous training (MICT) on intramyocellular lipid content, as well as LD characteristics (size and number) and abundance within the intramyofibrillar (IMF) and subsarcolemmal (SS) regions of type I and type II skeletal muscle fibers in adults with obesity. Thirty-six adults with obesity [body mass index (BMI) = 33 ± 3 kg/m2] completed 12 wk (4 days/wk) of either HIIT (10 × 1 min, 90% HRmax + 1-min active recovery; n = 19) or MICT (45-min steady-state exercise, 70% HRmax; n = 17), while on a weight-maintaining diet throughout training. Skeletal muscle biopsies were collected from the vastus lateralis before and after training, and intramyocellular lipid content and intracellular LD distribution were measured by immunofluorescence microscopy. Both MICT and HIIT increased total intramyocellular lipid content by more than 50% (P < 0.01), which was attributed to a greater LD number per µm2 in the IMF region of both type I and type II muscle fibers (P < 0.01). Our findings also suggest that LD lipophagy (autophagy-mediated LD degradation) may be transiently upregulated the day after the last exercise training session (P < 0.02 for both MICT and HIIT). In summary, exercise programs for adults with obesity involving either MICT or HIIT increased skeletal muscle LD abundance via a greater number of LDs in the IMF region of the myocyte, thereby providing more lipid in close proximity to the site of energy production during exercise.NEW & NOTEWORTHY In this study, 12 wk of either moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT) enhanced skeletal muscle lipid abundance by increasing lipid droplet number within the intramyofibrillar (IMF) region of muscle. Because the IMF associates with high energy production during muscle contraction, this adaptation may enhance lipid oxidation during exercise. Despite differences in training intensity and energy expenditure between MICT and HIIT, their effects on muscle lipid abundance and metabolism were remarkably similar.

Exercise training remodels subcutaneous adipose tissue in adults with obesity even without weight loss.

Excessive adipose tissue mass underlies much of the metabolic health complications in obesity. Although exercise training is known to improve metabolic health in individuals with obesity, the effects of exercise training without weight loss on adipose tissue structure and metabolic function remain unclear. Thirty-six adults with obesity (body mass index = 33 ± 3 kg · m-2 ) were assigned to 12 weeks (4 days week-1 ) of either moderate-intensity continuous training (MICT; 70% maximal heart rate, 45 min; n = 17) or high-intensity interval training (HIIT; 90% maximal heart rate, 10 × 1 min; n = 19), maintaining their body weight throughout. Abdominal subcutaneous adipose tissue (aSAT) biopsy samples were collected once before and twice after training (1 day after last exercise and again 4 days later). Exercise training modified aSAT morphology (i.e. reduced fat cell size, increased collagen type 5a3, both P ≤ 0.05, increased capillary density, P = 0.05) and altered protein abundance of factors that regulate aSAT remodelling (i.e. reduced matrix metallopeptidase 9; P = 0.02; increased angiopoietin-2; P < 0.01). Exercise training also increased protein abundance of factors that regulate lipid metabolism (e.g. hormone sensitive lipase and fatty acid translocase; P ≤ 0.03) and key proteins involved in the mitogen-activated protein kinase pathway when measured the day after the last exercise session. However, most of these exercise-mediated changes were no longer significant 4 days after exercise. Importantly, MICT and HIIT induced remarkably similar adaptations in aSAT. Collectively, even in the absence of weight loss, 12 weeks of exercise training induced changes in aSAT structure, as well as factors that regulate metabolism and the inflammatory signal pathway in adults with obesity. KEY POINTS: Exercise training is well-known to improve metabolic health in obesity, although how exercise modifies the structure and metabolic function of adipose tissue, in the absence of weight loss, remains unclear. We report that both 12 weeks of moderate-intensity continuous training (MICT) and 12 weeks of high-intensity interval training (HIIT) induced modifications in adipose tissue structure and factors that regulate adipose tissue remodelling, metabolism and the inflammatory signal pathway in adults with obesity, even without weight loss (with no meaningful differences between MICT and HIIT). The modest modifications in adipose tissue structure in response to 12 weeks of MICT or HIIT did not lead to changes in the rate of fatty acid release from adipose tissue. These results expand our understanding about the effects of two commonly used exercise training prescriptions (MICT and HIIT) on adipose tissue remodelling that may lead to advanced strategies for improving metabolic health outcomes in adults with obesity.

Structural Dynamics of a Common Mutagenic Oxidative DNA Lesion in Duplex DNA and during DNA Replication.

N6-(2-Deoxy-α,ß-d-erythro-pentofuranosyl)-2,6-diamino-4-hydroxy-5-formamido pyrimidine (Fapy•dG) is a prevalent form of genomic DNA damage. Fapy•dG is formed in greater amounts under anoxic conditions than the well-studied, chemically related 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-oxodGuo). Fapy•dG is more mutagenic in mammalian cells than 8-oxodGuo. A distinctive property of Fapy•dG is facile epimerization, but prior works with Fapy•dG analogues have precluded determining its effect on chemistry. We present crystallographic characterization of natural Fapy•dG in duplex DNA and as the template base for DNA polymerase ß (Pol ß). Fapy•dG adopts the ß-anomer when base paired with cytosine but exists as a mixture of α- and ß-anomers when promutagenically base paired with adenine. Rotation about the bond between the glycosidic nitrogen atom and the pyrimidine ring is also affected by the opposing nucleotide. Sodium cyanoborohydride soaking experiments trap the ring-opened Fapy•dG, demonstrating that ring opening and epimerization occur in the crystalline state. Ring opening and epimerization are facilitated by propitious water molecules that are observed in the structures. Determination of Fapy•dG mutagenicity in wild type and Pol ß knockdown HEK 293T cells indicates that Pol ß contributes to G → T transversions but also suppresses G → A transitions. Complementary kinetic studies have determined that Fapy•dG promotes mutagenesis by decreasing the catalytic efficiency of dCMP insertion opposite Fapy•dG, thus reducing polymerase fidelity. Kinetic studies have determined that dCMP incorporation opposite the ß-anomer is ∼90 times faster than the α-anomer. This research identifies the importance of anomer dynamics, a feature unique to formamidopyrimidines, when considering the incorporation of nucleotides opposite Fapy•dG and potentially the repair of this structurally unusual lesion.

Influence of graded hypercapnia on endurance exercise performance in healthy humans.

Military and/or emergency services personnel may be required to perform high-intensity physical activity during exposure to elevated inspired carbon dioxide (CO2). Although many of the physiological consequences of hypercapnia are well characterized, the effects of graded increases in inspired CO2 on self-paced endurance performance have not been determined. The aim of this study was to compare the effects of 0%, 2%, and 4% inspired CO2 on 2-mile run performance, as well as physiological and perceptual responses during time trial exercise. Twelve physically active volunteers (peak oxygen uptake = 49 ± 5 mL·kg-1·min-1; 3 women) performed three experimental trials in a randomized, single-blind, crossover manner, breathing 21% oxygen with either 0%, 2%, or 4% CO2. During each trial, participants completed 10 min of walking at ∼40% peak oxygen uptake followed by a self-paced 2-mile treadmill time trial. One participant was unable to complete the 4% CO2 trial due to lightheadedness during the run. Compared with the 0% CO2 trial, run performance was 5 ± 3% and 7 ± 3% slower in the 2% and 4% CO2 trials, respectively (both P < 0.001). Run performance was significantly slower with 4% versus 2% CO2 (P = 0.046). The dose-dependent performance impairments were accompanied by stepwise increases in mean ventilation, despite significant reductions in running speed. Dyspnea and headache were significantly elevated during the 4% CO2 trial compared with both the 0% and 2% trials. Overall, our findings show that graded increases in inspired CO2 impair endurance performance in a stepwise manner in healthy humans.

Exercise training decreases whole-body and tissue iron storage in adults with obesity.

NEW FINDINGS: What is the central question of this study? Does exercise training modify tissue iron storage in adults with obesity? What is the main finding and its importance? Twelve weeks of moderate-intensity exercise or high-intensity interval training lowered whole-body iron stores, decreased the abundance of the key iron storage protein in skeletal muscle (ferritin) and tended to lower hepatic iron content. These findings show that exercise training can reduce tissue iron storage in adults with obesity and might have important implications for obese individuals with dysregulated iron homeostasis. ABSTRACT: The regulation of iron storage is crucial to human health, because both excess and deficient iron storage have adverse consequences. Recent studies suggest altered iron storage in adults with obesity, with increased iron accumulation in their liver and skeletal muscle. Exercise training increases iron use for processes such as red blood cell production and can lower whole-body iron stores in humans. However, the effects of exercise training on liver and muscle iron stores in adults with obesity have not been assessed. The aim of this study was to determine the effects of 12 weeks of exercise training on whole-body iron stores, liver iron content and the abundance of ferritin (the key iron storage protein) in skeletal muscle in adults with obesity. Twenty-two inactive adults (11 women and 11 men; age, 31 ± 6 years; body mass index, 33 ± 3 kg/m2 ) completed 12 weeks (four sessions/week) of either moderate-intensity continuous training (MICT; 45 min at 70% of maximal heart rate; n = 11) or high-intensity interval training (HIIT; 10 × 1 min at 90% of maximal heart rate, interspersed with 1 min active recovery; n = 11). Whole-body iron stores were lower after training, as indicated by decreased plasma concentrations of ferritin (P = 3 × 10-5 ) and hepcidin (P = 0.02), without any change in C-reactive protein. Hepatic R2*, an index of liver iron content, was 6% lower after training (P = 0.06). Training reduced the skeletal muscle abundance of ferritin by 10% (P = 0.03), suggesting lower muscle iron storage. Interestingly, these adaptations were similar in MICT and HIIT groups. Our findings indicate that exercise training decreased iron storage in adults with obesity, which might have important implications for obese individuals with dysregulated iron homeostasis.

Skeletal muscle ferritin abundance is tightly related to plasma ferritin concentration in adults with obesity.

NEW FINDINGS: What is the central question of this study? Obesity is associated with complex perturbations to iron homeostasis: is plasma ferritin concentration (a biomarker of whole-body iron stores) related to the abundance of ferritin (the key tissue iron storage protein) in skeletal muscle in adults with obesity? What is the main finding and its importance? Plasma ferritin concentration was tightly correlated with the abundance of ferritin in skeletal muscle, and this relationship persisted when accounting for sex, age, body mass index and plasma C-reactive protein concentration. Our findings suggest that skeletal muscle may be an important iron store. ABSTRACT: Obesity is associated with complex perturbations to whole-body and tissue iron homeostasis. Recent evidence suggests a potentially important influence of iron storage in skeletal muscle on whole-body iron homeostasis, but this association is not clearly resolved. The primary aim of this study was to assess the relationship between whole-body and skeletal muscle iron stores by measuring the abundance of the key iron storage (ferritin) and import (transferrin receptor) proteins in skeletal muscle, as well as markers of whole-body iron homeostasis in men (n = 19) and women (n = 43) with obesity. Plasma ferritin concentration (a marker of whole-body iron stores) was highly correlated with muscle ferritin abundance (r = 0.77, P = 2 × 10-13 ) and negatively associated with muscle transferrin receptor abundance (r = -0.76, P = 1 × 10-12 ). These relationships persisted when accounting for sex, age, BMI and plasma C-reactive protein concentration. In parallel with higher whole-body iron stores in our male versus female participants, men had 2.2-fold higher muscle ferritin abundance (P = 1 × 10-4 ) compared with women. In accordance with lower muscle iron storage, women had 2.7-fold higher transferrin receptor abundance (P = 7 × 10-10 ) compared with men. We conclude that muscle iron storage and import proteins are tightly and independently related to plasma ferritin concentration in adults with obesity, suggesting that skeletal muscle may be an underappreciated iron store.

Plasma ferritin concentration is positively associated with in vivo fatty acid mobilization and insulin resistance in obese women.

NEW FINDINGS: What is the central question of this study? Do obese women with relatively high whole-body iron stores exhibit elevated in vivo rates of fatty acid (FA) release from adipose tissue compared with a well-matched cohort of obese women with relatively low iron stores? What is the main finding and its importance? Obese women with high plasma [ferritin] (a marker of whole-body iron stores) had greater FA mobilization, lipolytic activation in adipose tissue and insulin resistance (IR) compared with obese women with lower plasma [ferritin]. Given that elevated FA mobilization is intimately linked with the development of IR, these findings suggest that elevated iron stores might contribute to IR in obesity by increasing systemic FA availability. ABSTRACT: High rates of fatty acid (FA) mobilization from adipose tissue are associated with insulin resistance (IR) in obesity. In vitro evidence suggests that iron stimulates lipolysis in adipocytes, but whether iron is related to in vivo FA mobilization is unknown. We hypothesized that plasma ferritin concentration ([ferritin]), a marker of body iron stores, would be positively associated with FA mobilization. We measured [ferritin], the rate of appearance of FA in the systemic circulation (FA Ra; stable isotope dilution), key adipose tissue lipolytic proteins and IR (hyperinsulinaemic-euglycaemic clamp) in 20 obese, premenopausal women. [Ferritin] was correlated with FA Ra (r = 0.65; P = 0.002) and IR (r = 0.57; P = 0.008); these relationships remained significant after controlling for body mass index and plasma [C-reactive protein] (a marker of systemic inflammation) in multiple regression analyses. We then stratified subjects into tertiles based on [ferritin] to compare subjects with 'High-ferritin' versus 'Low-ferritin'. Plasma [hepcidin] was more than fivefold greater (P < 0.05) in the High-ferritin versus Low-ferritin group, but there was no difference in plasma [C-reactive protein] between groups, indicating that the large difference in plasma [ferritin] reflects a difference in iron stores, not systemic inflammation. We found that FA Ra, adipose protein abundance of hormone-sensitive lipase and adipose triglyceride lipase, and IR were significantly greater in subjects with High-ferritin versus Low-ferritin (all P < 0.05). These data provide the first evidence linking iron and in vivo FA mobilization and suggest that elevated iron stores might contribute to IR in obesity by increasing systemic FA availability.

Beneficial Effects of Cooling during Constant Power Non-steady State Cycling.

This study compared the effects of cooling on the energetic and associated physiological and perceptual responses to constant power, non-steady state cycling. Twelve males cycled at their lactate threshold power for 60 min or until exhaustion under 3 conditions: wearing a cooling vest and sleeves (COOL), a synthetic shirt embedded with an active particle technology claimed to facilitate evaporative heat loss (EVAP), and a standard synthetic shirt (CON). When adjusted for time, the increase in gastrointestinal temperature from baseline was reduced during COOL and EVAP compared to CON (1.44±0.45 and 1.52±0.43 vs. 1.66±0.45°C, p<0.05). Sweat rate was reduced during COOL compared to EVAP and CON (1 312±331 vs. 1 525±393 and 1 550±548 mL·h-1, p<0.01). Gross efficiency decreased over time across conditions (p<0.01), but COOL attenuated this decrease by 22% compared to CON (p<0.05). The rating of perceived exertion was reduced during COOL and EVAP compared to CON (p<0.01). In conclusion, cooling using a vest and sleeves or wearing an active particle technology shirt reduced the rise in gastrointestinal temperature and rating of perceived exertion compared to a standard synthetic shirt. Cooling using a vest and sleeves also reduced the decrease in gross efficiency and sweat rate compared to wearing the standard synthetic shirt.

Decreased arterial PO2, not O2 content, increases blood flow through intrapulmonary arteriovenous anastomoses at rest.

KEY POINTS: The mechanism(s) that regulate hypoxia-induced blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA ) are currently unknown. Our previous work has demonstrated that the mechanism of hypoxia-induced QIPAVA is not simply increased cardiac output, pulmonary artery systolic pressure or sympathetic nervous system activity and, instead, it may be a result of hypoxaemia directly. To determine whether it is reduced arterial PO2 (PaO2) or O2 content (CaO2) that causes hypoxia-induced QIPAVA , individuals were instructed to breathe room air and three levels of hypoxic gas at rest before (control) and after CaO2 was reduced by 10% by lowering the haemoglobin concentration (isovolaemic haemodilution; Low [Hb]). QIPAVA , assessed by transthoracic saline contrast echocardiography, significantly increased as PaO2 decreased and, despite reduced CaO2 (via isovolaemic haemodilution), was similar at iso-PaO2. These data suggest that, with alveolar hypoxia, low PaO2 causes the hypoxia-induced increase in QIPAVA , although where and how this is detected remains unknown. ABSTRACT: Alveolar hypoxia causes increased blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA ) in healthy humans at rest. However, it is unknown whether the stimulus regulating hypoxia-induced QIPAVA is decreased arterial PO2 (PaO2) or O2 content (CaO2). CaO2 is known to regulate blood flow in the systemic circulation and it is suggested that IPAVA may be regulated similar to the systemic vasculature. Thus, we hypothesized that reduced CaO2 would be the stimulus for hypoxia-induced QIPAVA . Blood volume (BV) was measured using the optimized carbon monoxide rebreathing method in 10 individuals. Less than 5 days later, subjects breathed room air, as well as 18%, 14% and 12.5% O2 , for 30 min each, in a randomized order, before (CON) and after isovolaemic haemodilution (10% of BV withdrawn and replaced with an equal volume of 5% human serum albumin-saline mixture) to reduce [Hb] (Low [Hb]). PaO2 was measured at the end of each condition and QIPAVA was assessed using transthoracic saline contrast echocardiography. [Hb] was reduced from 14.2 ± 0.8 to 12.8 ± 0.7 g dl(-1) (10 ± 2% reduction) from CON to Low [Hb] conditions. PaO2 was no different between CON and Low [Hb], although CaO2 was 10.4%, 9.2% and 9.8% lower at 18%, 14% and 12.5% O2 , respectively. QIPAVA significantly increased as PaO2 decreased and, despite reduced CaO2, was similar at iso-PaO2. These data suggest that, with alveolar hypoxia, low PaO2 causes the hypoxia-induced increase in QIPAVA . Whether the low PO2 is detected at the carotid body, airway and/or the vasculature remains unknown.

Haemoglobin mass alterations in healthy humans following four-day head-down tilt bed rest.

NEW FINDINGS: What is the central question of this study? Is haemoglobin mass (Hbmass) decreased following 4 days of head-down tilt bed rest (HDTBR), and does increased red blood cell (RBC) destruction mediate this adaptation? What is the main finding and its importance? Haemoglobin mass was increased immediately following HDTBR, before decreasing below baseline 5 days after return to normal living conditions. The transient increase in Hbmass might be the result of decreased RBC destruction, but it is also possible that spleen contraction after HDTBR contributed to this adaptation. Our data suggest that the decreased Hbmass 5 days following HDTBR resulted from decreased RBC production, not increased RBC destruction. Rapid decreases in haemoglobin mass (Hbmass) have been reported in healthy humans following spaceflight and descent from high altitude. It has been proposed that a selective increase in the destruction of young red blood cells (RBCs) mediates these decreases, but conclusive evidence demonstrating neocytolysis in humans is lacking. Based on the proposed triggers and time course of adaptation during spaceflight, we hypothesized that Hbmass would be reduced after 4 days of -6 deg head-down tilt bed rest (HDTBR) and that this would be associated with evidence for increased RBC destruction. We assessed Hbmass in seven healthy, recreationally active men before (PRE), 5 h after (POST) and 5 days after (POST5) 4 days of HDTBR. The concentration of erythropoietin decreased from 7.1 ± 1.8 mIU ml(-1) at PRE to 5.2 ± 2.8 mIU ml(-1) at POST (mean ± SD; P = 0.028). Contrary to our hypothesis, Hbmass was increased from 817 ± 135 g at PRE to 849 ± 141 g at POST (P = 0.014) before decreasing below PRE to 789 ± 139 g at POST5 (P = 0.027). From PRE to POST, the concentration of haptoglobin increased from 0.54 ± 0.32 to 0.68 ± 0.28 g l(-1) (P = 0.013) and the concentration of bilirubin decreased from 0.50 ± 0.24 to 0.32 ± 0.11 mg dl(-1) (P = 0.054), suggesting that decreased RBC destruction might have contributed to the increased Hbmass. However, it is possible that spleen contraction following HDTBR also played a role in the increase in Hbmass at POST, but as the transient increase in Hbmass was unexpected, we did not collect data that would provide direct evidence for or against spleen contraction. From PRE to POST5, the concentration of soluble transferrin receptor decreased from 20.7 ± 3.9 to 17.1 ± 3.3 nmol l(-1) (P = 0.018) but the concentrations of ferritin, haptoglobin and bilirubin were not significantly altered, suggesting that the decrease in Hbmass was mediated by decreased RBC production rather than increased RBC destruction. Peak oxygen uptake decreased by 0.31 ± 0.16 l min(-1) from PRE to POST (P = 2 × 10(-4) ) but was not significantly altered at POST5 compared with PRE. Overall, these findings indicate that 4 days of HDTBR does not increase RBC destruction and that re-examination of the time course and mechanisms of Hbmass alterations following short-term spaceflight and simulated microgravity is warranted.

Analyzing the impact of severe tropical cyclone Yasi on public health infrastructure and the management of noncommunicable diseases.

INTRODUCTION: Traditionally, post disaster response activities have focused on immediate trauma and communicable diseases. In developed countries such as Australia, the post disaster risk for communicable disease is low. However, a "disease transition" is now recognized at the population level where noncommunicable diseases (NCDs) are increasingly documented as a post disaster issue. This potentially places an extra burden on health care resources and may have implications for disaster-management systems. With increasing likelihood of major disasters for all sectors of global society, there is a need to ensure that health systems, including public health infrastructure (PHI), can respond properly. Problem There is limited peer-reviewed literature on the impact of disasters on NCDs. Research is required to better determine both the impact of NCDs post disaster and their impact on PHI and disaster-management systems. METHODS: A literature review was used to collect and analyze data on the impact of the index case event, Australia's Severe Tropical Cyclone Yasi (STC Yasi), on PHI and the management of NCDs. The findings were compared with data from other world cyclone events. The databases searched were MEDLINE, CINAHL, Google Scholar, and Google. The date range for the STC Yasi search was January 26, 2011 through May 2, 2013. No time limits were applied to the search from other cyclone events. The variables compared were tropical cyclones and their impacts on PHI and NCDs. The outcome of interest was to identify if there were trends across similar world events and to determine if this could be extrapolated for future crises. RESULTS: This research showed a tropical cyclone (including a hurricane and typhoon) can impact PHI, for instance, equipment (oxygen, syringes, and medications), services (treatment and care), and clean water availability/access that would impact both the treatment and management of NCDs. The comparison between STC Yasi and worldwide tropical cyclones found the challenges faced were linked closely. These relate to communication, equipment and services, evacuation, medication, planning, and water supplies. CONCLUSION: This research demonstrated that a negative trend pattern existed between the impact of STC Yasi and other similar world cyclone events on PHI and the management of NCDs. This research provides an insight for disaster planners to address concerns of people with NCDs. While further research is needed, this study provides an understanding of areas for improvement, specifically enhancing protective PHI and the development of strategies for maintaining treatment and alternative care options, such as maintaining safe water for dialysis patients.

Suit Up: A Systematic Review of the Personal Protective Equipment (PPE) Recommended and Utilized by Various Classes of Responders to Nuclear Radiological Disasters at Nuclear Power Plants.

INTRODUCTION: Interest in nuclear power as a cleaner and alternative energy source is increasing in many countries. Despite the relative safety of nuclear power, large-scale disasters such as the Fukushima Daiichi (Japan) and Chernobyl (Ukraine) meltdowns are a reminder that emergency preparedness and safety should be a priority. In an emergency situation, there is a need to balance the tension between a rapid response, preventing harm, protecting communities, and safeguarding workers and responders. The first line of defense for workers and responders is personal protective equipment (PPE), but the needs vary by situation and location. Better understanding this is vital to inform PPE needs for workers and responders during nuclear and radiological power plant accidents and emergencies. STUDY OBJECTIVE: The aim of this study was to identify and describe the PPE used by different categories of workers and responders during nuclear and radiological power plant accidents and emergencies. METHODS: A systematic literature review format following the PRISMA 2020 guidelines was utilized. Databases SCOPUS, PubMed, EMBASE, INSPEC, and Web of Science were used to retrieve articles that examined the PPE recommended or utilized by responders to nuclear radiological disasters at nuclear power plants (NPPs). RESULTS: The search terms yielded 6,682 publications. After removal of duplicates, 5,587 sources continued through the systematic review process. This yielded 23 total articles for review, and five articles were added manually for a total of 28 articles reviewed in this study. Plant workers, decontamination or decommissioning workers, paramedics, Emergency Medical Services (EMS), emergency medical technicians, military, and support staff were the categories of responders identified for this type of disaster. Literature revealed that protective suits were the most common item of PPE required or recommended, followed by respirators and gloves (among others). However, adherence issues, human errors, and physiological factors frequently emerged as hinderances to the efficacy of these equipment in preventing contamination or efficiency of these responders. CONCLUSION: If worn correctly and consistently, PPE will reduce exposure to ionizing radiation during a nuclear and radiological accident or disaster. For the best results, standardization of equipment recommendations, clear guidelines, and adequate training in its use is paramount. As fields related to nuclear power and nuclear medicine expand, responder safety should be at the forefront of emergency preparedness and response planning.

'Super boots' for soldiers: theoretical ergogenic and thermoprotective benefits of energetically optimised military combat boots.

Soldiers typically perform physically demanding tasks while wearing military uniforms and tactical footwear. New research has revealed a substantial increase of ~10% in energetic cost of walking when wearing modern combat boots versus running shoes. One approach to mitigating these costs is to follow in the footsteps of recent innovations in athletic footwear that led to the development of 'super shoes', that is, running shoes designed to lower the energetic cost of locomotion and maximise performance. We modelled the theoretical effects of optimised combat boot construction on physical performance and heat strain with the intent of spurring similarly innovative research and development of 'super boots' for soldiers. We first assessed the theoretical benefits of super boots on 2-mile run performance in a typical US Army soldier using the model developed by Kipp and colleagues. We then used the Heat Strain Decision Aid thermoregulatory model to determine the metabolic savings required for a physiologically meaningful decrease in heat strain in various scenarios. Combat boots that impart a 10% improvement in running economy would result in 7.9%-15.1% improvement in 2-mile run time, for faster to slower runners, respectively. Our thermal modelling revealed that a 10% metabolic savings would more than suffice for a 0.25°C reduction in heat strain for the vast majority of work intensities and durations in both hot-dry and hot-humid environments. These findings highlight the impact that innovative military super boots would have on physical performance and heat strain in soldiers, which could potentially maximise the likelihood of mission success in real-world scenarios.

Biochemical and Structural Characterization of Fapy•dG Replication by Human DNA Polymerase ß.

N6-(2-deoxy-α,ß-D-erythro-pentofuranosyl)-2,6-diamino-4-hydroxy-5-formamido-pyrimidine (Fapy•dG) is formed from a common intermediate and in comparable amounts to the well-studied mutagenic DNA lesion 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-OxodGuo). Fapy•dG preferentially gives rise to G → T transversions and G → A transitions. However, the molecular basis by which Fapy•dG is processed by DNA polymerases during this mutagenic process remains poorly understood. To address this we investigated how DNA polymerase ß (Pol ß), a model mammalian polymerase, bypasses a templating Fapy•dG, inserts Fapy•dGTP, and extends from Fapy•dG at the primer terminus. When Fapy•dG is present in the template, Pol ß incorporates TMP less efficiently than either dCMP or dAMP. Kinetic analysis revealed that Fapy•dGTP is a poor substrate but is incorporated ∼3-times more efficiently opposite dA than dC. Extension from Fapy•dG at the 3'-terminus of a nascent primer is inefficient due to the primer terminus being poorly positioned for catalysis. Together these data indicate that mutagenic bypass of Fapy•dG is likely to be the source of the mutagenic effects of the lesion and not Fapy•dGTP. These experiments increase our understanding of the promutagenic effects of Fapy•dG.

Molecular basis for the activation of the Fatty Acid Kinase complex of Staphylococcus aureus.

Gram-positive bacteria utilize a Fatty Acid Kinase (FAK) complex to harvest fatty acids from the environment. The complex, consisting of the fatty acid kinase, FakA, and an acyl carrier protein, FakB, is known to impact virulence and disease outcomes. However, FAK's structure and enzymatic mechanism remain poorly understood. Here, we used a combination of modeling, biochemical, and cell-based approaches to establish critical details of FAK activity. Solved structures of the apo and ligand-bound FakA kinase domain captured the protein state through ATP hydrolysis. Additionally, targeted mutagenesis of an understudied FakA Middle domain identified critical residues within a metal-binding pocket that contribute to FakA dimer stability and protein function. Regarding the complex, we demonstrated nanomolar affinity between FakA and FakB and generated computational models of the complex's quaternary structure. Together, these data provide critical insight into the structure and function of the FAK complex which is essential for understanding its mechanism.

Exogenous erythropoietin increases hematological status, fat oxidation, and aerobic performance in males following prolonged strenuous training.

This study investigated the effects of EPO on hemoglobin (Hgb) and hematocrit (Hct), time trial (TT) performance, substrate oxidation, and skeletal muscle phenotype throughout 28 days of strenuous exercise. Eight males completed this longitudinal controlled exercise and feeding study using EPO (50 IU/kg body mass) 3×/week for 28 days. Hgb, Hct, and TT performance were assessed PRE and on Days 7, 14, 21, and 27 of EPO. Rested/fasted muscle obtained PRE and POST EPO were analyzed for gene expression, protein signaling, fiber type, and capillarization. Substrate oxidation and glucose turnover were assessed during 90-min of treadmill load carriage (LC; 30% body mass; 55 ± 5% V̇O2peak) exercise using indirect calorimetry, and 6-6-[2H2]-glucose PRE and POST. Hgb and Hct increased, and TT performance improved on Days 21 and 27 compared to PRE (p < 0.05). Energy expenditure, fat oxidation, and metabolic clearance rate during LC increased (p < 0.05) from PRE to POST. Myofiber type, protein markers of mitochondrial biogenesis, and capillarization were unchanged PRE to POST. Transcriptional regulation of mitochondrial activity and fat metabolism increased from PRE to POST (p < 0.05). These data indicate EPO administration during 28 days of strenuous exercise can enhance aerobic performance through improved oxygen carrying capacity, whole-body and skeletal muscle fat metabolism.

Survey of COVID-19 isolation cases at a major university campus in the United States.

Objective: Baylor University established a surveillance system to assess the needs of students and faculty in isolation from SARS-CoV-2 as well as any longer-term symptoms. Participants: Overall, there were 309 responses between March 20 and May 19, 2021. Methods: A survey covering experience in isolation, symptoms, vaccination, and demographic characteristics was emailed to individuals on Day 7 of isolation; a follow-up health survey was sent 30 days later. Results: Only 9.6% of respondents reported needing assistance while in isolation. Nearly 75% of respondents experienced COVID-19 symptoms in isolation, and 31.9% had remaining symptoms after isolation. Older age, being male, and more severe symptoms were associated with longer symptom duration. Those vaccinated had lower odds of developing symptoms and having symptoms remaining post-isolation. Conclusions: The present study adds to our understanding of long-COVID in young adult populations, while providing a framework for similar institutions to sustain operations during a global pandemic.