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Muscle activation as well as changes in peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) following high-intensity interval exercise (HIIE) were examined in young healthy men (n  = 8; age, 21.9±2.2 yrs; VO2peak, 53.1±6.4 ml/min/kg; peak work rate, 317±23.5 watts). On each of 3 visits HIIE was performed on a cycle ergometer at a target intensity of 73, 100, or 133% of peak work rate. Muscle biopsies were taken at rest and three hours after each exercise condition. Total work was not different between conditions (∼730 kJ) while average power output (73%, 237±21; 100%, 323±26; 133%, 384±35 watts) and EMG derived muscle activation (73%, 1262±605; 100%, 2089±737; 133%, 3029±1206 total integrated EMG per interval) increased in an intensity dependent fashion. PGC-1α mRNA was elevated after all three conditions (p<0.05), with a greater increase observed following the 100% condition (∼9 fold, p<0.05) compared to both the 73 and 133% conditions (∼4 fold). When expressed relative to muscle activation, the increase in PGC-1α mRNA for the 133% condition was less than that for the 73 and 100% conditions (p<0.05). SIRT1 mRNA was also elevated after all three conditions (∼1.4 fold, p<0.05), with no difference between conditions. These findings suggest that intensity-dependent increases in PGC-1α mRNA following submaximal exercise are largely due to increases in muscle recruitment. As well, the blunted response of PGC-1α mRNA expression following supramaximal exercise may indicate that signalling mediated activation of PGC-1α may also be blunted. We also indentify that increases in PDK4, SIRT1, and RIP140 mRNA following acute exercise are dissociated from exercise intensity and muscle activation, while increases in EGR1 are augmented with supramaximal HIIE (p<0.05).

Purpose The present study examined the effect of reducing sprint interval training (SIT) work-interval duration on increases in maximal and submaximal performance. Methods Subjects ( n  = 36) were assigned to one of three training groups: endurance training (ET; 60 min per session for weeks 1–2, increasing to 75 min per session for weeks 3–4), or sprint interval training consisting of either repeated 30 (SIT 30) or 15 (SIT 15) second all-out intervals (starting with 4 bouts per session for weeks 1–2, increasing to 6 intervals per session for weeks 3–4). Training consisted of cycling 3 times per week for 4 weeks. Results While there was a significant main effect of training on V ˙ O 2peak such that V ˙ O 2peak was elevated post-training, no significant difference was observed in the improvements observed between groups (ET ~13 %, SIT 30–4 %, SIT 15–8 %). A significant main effect of training was observed such that lactate threshold and critical power were higher during post-testing across all groups ( p  < 0.05). There was a main effect of training ( p  < 0.05) on Wingate peak power with no differences observed between groups at post-training. Conclusions Together, these results indicate that reducing SIT work-interval duration from 30 to 15 s had no impact on training-induced increases in aerobic or anaerobic power, or on increases in lactate threshold (absolute) and critical power.

Muscle activation as well as changes in peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1[alpha]) following high-intensity interval exercise (HIIE) were examined in young healthy men (n = 8; age, 21.9±2.2 yrs; VO.sub.2 peak, 53.1±6.4 ml/min/kg; peak work rate, 317±23.5 watts). On each of 3 visits HIIE was performed on a cycle ergometer at a target intensity of 73, 100, or 133% of peak work rate. Muscle biopsies were taken at rest and three hours after each exercise condition. Total work was not different between conditions (~730 kJ) while average power output (73%, 237±21; 100%, 323±26; 133%, 384±35 watts) and EMG derived muscle activation (73%, 1262±605; 100%, 2089±737; 133%, 3029±1206 total integrated EMG per interval) increased in an intensity dependent fashion. PGC-1[alpha] mRNA was elevated after all three conditions (p<0.05), with a greater increase observed following the 100% condition (~9 fold, p<0.05) compared to both the 73 and 133% conditions (~4 fold). When expressed relative to muscle activation, the increase in PGC-1[alpha] mRNA for the 133% condition was less than that for the 73 and 100% conditions (p<0.05). SIRT1 mRNA was also elevated after all three conditions (~1.4 fold, p<0.05), with no difference between conditions. These findings suggest that intensity-dependent increases in PGC-1[alpha] mRNA following submaximal exercise are largely due to increases in muscle recruitment. As well, the blunted response of PGC-1[alpha] mRNA expression following supramaximal exercise may indicate that signalling mediated activation of PGC-1[alpha] may also be blunted. We also indentify that increases in PDK4, SIRT1, and RIP140 mRNA following acute exercise are dissociated from exercise intensity and muscle activation, while increases in EGR1 are augmented with supramaximal HIIE (p<0.05).

Muscle activation as well as changes in peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha ) following high-intensity interval exercise (HIIE) were examined in young healthy men (n = 8; age, 21.9 plus or minus 2.2 yrs; VO2peak, 53.1 plus or minus 6.4 ml/min/kg; peak work rate, 317 plus or minus 23.5 watts). On each of 3 visits HIIE was performed on a cycle ergometer at a target intensity of 73, 100, or 133% of peak work rate. Muscle biopsies were taken at rest and three hours after each exercise condition. Total work was not different between conditions (~730 kJ) while average power output (73%, 237 plus or minus 21; 100%, 323 plus or minus 26; 133%, 384 plus or minus 35 watts) and EMG derived muscle activation (73%, 1262 plus or minus 605; 100%, 2089 plus or minus 737; 133%, 3029 plus or minus 1206 total integrated EMG per interval) increased in an intensity dependent fashion. PGC-1 alpha mRNA was elevated after all three conditions (p<0.05), with a greater increase observed following the 100% condition (~9 fold, p<0.05) compared to both the 73 and 133% conditions (~4 fold). When expressed relative to muscle activation, the increase in PGC-1 alpha mRNA for the 133% condition was less than that for the 73 and 100% conditions (p<0.05). SIRT1 mRNA was also elevated after all three conditions (~1.4 fold, p<0.05), with no difference between conditions. These findings suggest that intensity-dependent increases in PGC-1 alpha mRNA following submaximal exercise are largely due to increases in muscle recruitment. As well, the blunted response of PGC-1 alpha mRNA expression following supramaximal exercise may indicate that signalling mediated activation of PGC-1 alpha may also be blunted. We also indentify that increases in PDK4, SIRT1, and RIP140 mRNA following acute exercise are dissociated from exercise intensity and muscle activation, while increases in EGR1 are augmented with supramaximal HIIE (p<0.05).

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r 2  > 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer ( P  < 10 -7 ). Four of these contain plausible causative genes ( FGFR2 , TNRC9 , MAP3K1 and LSP1 ). At the second stage, 1,792 SNPs were significant at the P  < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach. Novel breast cancer genes Until the genome-wide association study on page 1087 was published online, known susceptibility genes — such as BRCA1 and BRCA2 — accounted for less than 25% of the familial risk of breast cancer. The new study, which involved 21,860 patients and 22,578 controls, has identified four genes positively associated with genetic susceptibility to breast cancer ( FGFR2 , TNRC9 , MAP3K1 and LSP1 ). Most previously identified breast cancer susceptibility genes are involved in DNA repair, but the newly discovered associations appear to relate more to the control of cell growth or to cell signalling. Only one of the genes — FGFR2 — had a clear prior relevance to breast cancer. The identification of these genes opens up new avenues of research into the causes of breast cancer. They may also become part of a new strategy to classify women's risk, paving the way for better disease prevention. Previous work has identified several genes where mutations lead to breast cancer, but other genetic and environmental factors must still be accounted for. A large study of genetic association with breast cancer points to four novel genes and many more genetic markers that should be pursued for their link to cancer susceptibility.

In epidemiologic studies, moderate consumption of alcohol is consistently associated with a reduced risk of myocardial infarction; however, the mechanism underlying this association is unclear. 1 – 6 Some have suggested that the apparent benefit may reflect socioeconomic or lifestyle factors correlated with alcohol consumption, or it may be due to constituents of alcoholic beverages other than ethanol. The pharmacokinetics of alcohol metabolism has been well studied. The class I alcohol dehydrogenase (ADH) isoenzymes, encoded by ADH1, ADH2, and ADH3 , oxidize ethanol and other small, aliphatic alcohols. 7 , 8 ADH2 and ADH3 have polymorphisms that produce isoenzymes with distinct kinetic properties; to . . .

Endometriosis, polycystic ovary syndrome (PCOS) and uterine fibroids have been proposed as endometrial cancer risk factors; however, disentangling their relationships with endometrial cancer is complicated due to shared risk factors and comorbidities. Using genome-wide association study (GWAS) data, we explored the relationships between these non-cancerous gynecological diseases and endometrial cancer risk by assessing genetic correlation, causal relationships and shared risk loci. We found significant genetic correlation between endometrial cancer and PCOS, and uterine fibroids. Adjustment for genetically predicted body mass index (a risk factor for PCOS, uterine fibroids and endometrial cancer) substantially attenuated the genetic correlation between endometrial cancer and PCOS but did not affect the correlation with uterine fibroids. Mendelian randomization analyses suggested a causal relationship between only uterine fibroids and endometrial cancer. Gene-based analyses revealed risk regions shared between endometrial cancer and endometriosis, and uterine fibroids. Multi-trait GWAS analysis of endometrial cancer and the genetically correlated gynecological diseases identified a novel genome-wide significant endometrial cancer risk locus at 1p36.12, which replicated in an independent endometrial cancer dataset. Interrogation of functional genomic data at 1p36.12 revealed biologically relevant genes, including WNT4 which is necessary for the development of the female reproductive system. In summary, our study provides genetic evidence for a causal relationship between uterine fibroids and endometrial cancer. It further provides evidence that the comorbidity of endometrial cancer, PCOS and uterine fibroids may partly be due to shared genetic architecture. Notably, this shared architecture has revealed a novel genome-wide risk locus for endometrial cancer.

Endotoxin initiates a proinflammatory response from the innate immune system. Studies in children suggest that endotoxin exposure from house dust may be an important risk factor for asthma, but few studies have been conducted in adult populations. To investigate the association of house dust endotoxin levels with asthma and related phenotypes (wheeze, atopy, and pulmonary function) in a large U.S. farming population. Dust was collected from the bedrooms (n = 2,485) of participants enrolled in a case-control study of current asthma (927 cases) nested within the Agricultural Health Study. Dust endotoxin was measured by Limulus amebocyte lysate assay. Outcomes were measured by questionnaire, spirometry, and blood draw. We evaluated associations using linear and logistic regression. Endotoxin was significantly associated with current asthma (odds ratio [OR], 1.30; 95% confidence interval [CI], 1.14-1.47), and this relationship was modified by early-life farm exposure (born on a farm: OR, 1.18; 95% CI, 1.02-1.37; not born on a farm: OR, 1.67; 95% CI, 1.26-2.20; Interaction P = 0.05). Significant positive associations were seen with both atopic and nonatopic asthma. Endotoxin was not related to either atopy or wheeze. Higher endotoxin was related to lower FEV /FVC in asthma cases only (Interaction P = 0.01). For asthma, there was suggestive evidence of a gene-by-environment interaction for the CD14 variant rs2569190 (Interaction P = 0.16) but not for the TLR4 variants rs4986790 and rs4986791. House dust endotoxin was associated with current atopic and nonatopic asthma in a U.S. farming population. The degree of the association with asthma depended on early-life farm exposures. Furthermore, endotoxin was associated with lower pulmonary function in patients with asthma.

Background Genome-wide association studies (GWAS) have uncovered many genetic risk loci for psoriasis, yet many remain uncharacterised in terms of the causal gene and their biological mechanism in disease. This is largely a result of the findings that over 90% of GWAS variants map outside of protein-coding DNA and instead are enriched in cell type- and stimulation-specific gene regulatory regions. Results Here, we use a disease-focused Capture Hi-C (CHi-C) experiment to link psoriasis-associated variants with their target genes in psoriasis-relevant cell lines (HaCaT keratinocytes and My-La CD8+ T cells). We confirm previously assigned genes, suggest novel candidates and provide evidence for complexity at psoriasis GWAS loci. For one locus, uniquely, we combine further epigenomic evidence to demonstrate how a psoriasis-associated region forms a functional interaction with the distant (> 500 kb) KLF4 gene. This interaction occurs between the gene and active enhancers in HaCaT cells, but not in My-La cells. We go on to investigate this long-distance interaction further with Cas9 fusion protein-mediated chromatin modification (CRISPR activation) coupled with RNA-seq, demonstrating how activation of the psoriasis-associated enhancer upregulates KLF4 and its downstream targets, relevant to skin cells and apoptosis. Conclusions This approach utilises multiple functional genomic techniques to follow up GWAS-associated variants implicating relevant cell types and causal genes in each locus; these are vital next steps for the translation of genetic findings into clinical benefit.

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin ( LEP ) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P <10 −6 in 19,979 additional individuals. We identify five loci robustly associated ( P <5 × 10 −8 ) with leptin levels in/near LEP , SLC32A1 , GCKR , CCNL1 and FTO . Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin , a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health. This meta-analysis of genome-wide association studies identifies four genetic loci associated with circulating leptin levels independent of adiposity. Examination in mouse adipose tissue explants provides functional support for the leptin-associated loci.