Chronic pain is highly prevalent worldwide and represents a significant socioeconomic and public health burden. Several aspects of chronic pain, for example back pain and a severity-related phenotype ...'chronic pain grade', have been shown previously to be complex heritable traits with a polygenic component. Additional pain-related phenotypes capturing aspects of an individual's overall sensitivity to experiencing and reporting chronic pain have also been suggested as a focus for investigation. We made use of a measure of the number of sites of chronic pain in individuals within the UK general population. This measure, termed Multisite Chronic Pain (MCP), is a complex trait and its genetic architecture has not previously been investigated. To address this, we carried out a large-scale genome-wide association study (GWAS) of MCP in ~380,000 UK Biobank participants. Our findings were consistent with MCP having a significant polygenic component, with a Single Nucleotide Polymorphism (SNP) heritability of 10.2%. In total 76 independent lead SNPs at 39 risk loci were associated with MCP. Additional gene-level association analyses identified neurogenesis, synaptic plasticity, nervous system development, cell-cycle progression and apoptosis genes as enriched for genetic association with MCP. Genetic correlations were observed between MCP and a range of psychiatric, autoimmune and anthropometric traits, including major depressive disorder (MDD), asthma and Body Mass Index (BMI). Furthermore, in Mendelian randomisation (MR) analyses a causal effect of MCP on MDD was observed. Additionally, a polygenic risk score (PRS) for MCP was found to significantly predict chronic widespread pain (pain all over the body), indicating the existence of genetic variants contributing to both of these pain phenotypes. Overall, our findings support the proposition that chronic pain involves a strong nervous system component with implications for our understanding of the physiology of chronic pain. These discoveries may also inform the future development of novel treatment approaches.
Microbial mercury (Hg) methylation transforms a toxic trace metal into the highly bioaccumulated neurotoxin methylmercury (MeHg). The lack of a genetic marker for microbial MeHg production has ...prevented a clear understanding of Hg-methylating organism distribution in nature. Recently, a specific gene cluster (hgcAB) was linked to Hg methylation in two bacteria. Here we test if the presence of hgcAB orthologues is a reliable predictor of Hg methylation capability in microorganisms, a necessary confirmation for the development of molecular probes for Hg-methylation in nature. Although hgcAB orthologues are rare among all available microbial genomes, organisms are much more phylogenetically and environmentally diverse than previously thought. By directly measuring MeHg production in several bacterial and archaeal strains encoding hgcAB, we confirmed that possessing hgcAB predicts Hg methylation capability. For the first time, we demonstrated Hg methylation in a number of species other than sulfate- (SRB) and iron- (FeRB) reducing bacteria, including methanogens, and syntrophic, acetogenic, and fermentative Firmicutes. Several of these species occupy novel environmental niches for Hg methylation, including methanogenic habitats such as rice paddies, the animal gut, and extremes of pH and salinity. Identification of these organisms as Hg methylators now links methylation to discrete gene markers in microbial communities.
Dietary supplementation with beetroot juice (BR), containing approximately 5-8 mmol inorganic nitrate (NO3(-)), increases plasma nitrite concentration (NO2(-)), reduces blood pressure, and may ...positively influence the physiological responses to exercise. However, the dose-response relationship between the volume of BR ingested and the physiological effects invoked has not been investigated. In a balanced crossover design, 10 healthy men ingested 70, 140, or 280 ml concentrated BR (containing 4.2, 8.4, and 16.8 mmol NO3(-), respectively) or no supplement to establish the effects of BR on resting plasma NO3(-) and NO2(-) over 24 h. Subsequently, on six separate occasions, 10 subjects completed moderate-intensity and severe-intensity cycle exercise tests, 2.5 h postingestion of 70, 140, and 280 ml BR or NO3(-)-depleted BR as placebo (PL). Following acute BR ingestion, plasma NO2(-) increased in a dose-dependent manner, with the peak changes occurring at approximately 2-3 h. Compared with PL, 70 ml BR did not alter the physiological responses to exercise. However, 140 and 280 ml BR reduced the steady-state oxygen (O2) uptake during moderate-intensity exercise by 1.7% (P = 0.06) and 3.0% (P < 0.05), whereas time-to-task failure was extended by 14% and 12% (both P < 0.05), respectively, compared with PL. The results indicate that whereas plasma NO2(-) and the O2 cost of moderate-intensity exercise are altered dose dependently with NO3(-)-rich BR, there is no additional improvement in exercise tolerance after ingesting BR containing 16.8 compared with 8.4 mmol NO3(-). These findings have important implications for the use of BR to enhance cardiovascular health and exercise performance in young adults.
Lactate or gas exchange threshold (GET) and critical power (CP) are closely associated with human exercise performance. We tested the hypothesis that the limit of tolerance (T
) during cycle exercise ...performed within the exercise intensity domains demarcated by GET and CP is linked to discrete muscle metabolic and neuromuscular responses. Eleven men performed a ramp incremental exercise test, 4-5 severe-intensity (SEV; >CP) constant-work-rate (CWR) tests until T
, a heavy-intensity (HVY; <CP but >GET) CWR test until T
, and a moderate-intensity (MOD; <GET) CWR test until T
Muscle biopsies revealed that a similar (
> 0.05) muscle metabolic milieu (i.e., low pH and PCr and high lactate) was attained at T
(approximately 2-14 min) for all SEV exercise bouts. The muscle metabolic perturbation was greater at T
following SEV compared with HVY, and also following SEV and HVY compared with MOD (all
< 0.05). The normalized M-wave amplitude for the vastus lateralis (VL) muscle decreased to a similar extent following SEV (-38 ± 15%), HVY (-68 ± 24%), and MOD (-53 ± 29%), (
> 0.05). Neural drive to the VL increased during SEV (4 ± 4%;
< 0.05) but did not change during HVY or MOD (
> 0.05). During SEV and HVY, but not MOD, the rates of change in M-wave amplitude and neural drive were correlated with changes in muscle metabolic (PCr, lactate) and blood ionic/acid-base status (lactate, K
) (
< 0.05). The results of this study indicate that the metabolic and neuromuscular determinants of fatigue development differ according to the intensity domain in which the exercise is performed.
The gas exchange threshold and the critical power demarcate discrete exercise intensity domains. For the first time, we show that the limit of tolerance during whole-body exercise within these domains is characterized by distinct metabolic and neuromuscular responses. Fatigue development during exercise greater than critical power is associated with the attainment of consistent "limiting" values of muscle metabolites, whereas substrate availability and limitations to muscle activation may constrain performance at lower intensities.
Dietary nitrate supplementation increases circulating nitrite concentration, and the subsequent reduction of nitrite to nitric oxide is promoted in hypoxic environments. Given that PO2 is lower in ...Type II compared with Type I muscle, this article examines the hypothesis that the ergogenicity of nitrate supplementation is linked to specific effects on vascular, metabolic, and contractile function in Type II muscle.
Dietary nitrate supplementation has been shown to reduce the O2 cost of submaximal exercise and to improve high-intensity exercise tolerance. However, it is presently unknown whether it may enhance ...performance during simulated competition. The present study investigated the effects of acute dietary nitrate supplementation on power output (PO), VO2, and performance during 4- and 16.1-km cycling time trials (TT).
After familiarization, nine club-level competitive male cyclists were assigned in a randomized, crossover design to consume 0.5 L of beetroot juice (BR; containing ∼ 6.2 mmol of nitrate) or 0.5 L of nitrate-depleted BR (placebo, PL; containing ∼ 0.0047 mmol of nitrate), ∼ 2.5 h before the completion of a 4- and a 16.1-km TT.
BR supplementation elevated plasma nitrite (PL = 241 ± 125 vs BR = 575 ± 199 nM, P < 0.05). The VO2 values during the TT were not significantly different between the BR and PL conditions at any elapsed distance (P > 0.05), but BR significantly increased mean PO during the 4-km (PL = 279 ± 51 vs BR = 292 ± 44 W, P < 0.05) and 16.1-km TT (PL = 233 ± 43 vs BR = 247 ± 44 W, P < 0.01). Consequently, BR improved 4-km performance by 2.8% (PL = 6.45 ± 0.42 vs BR = 6.27 ± 0.35 min, P < 0.05) and 16.1-km performance by 2.7% (PL = 27.7 ± 2.1 vs BR = 26.9 ± 1.8 min, P < 0.01).
These results suggest that acute dietary nitrate supplementation with 0.5 L of BR improves cycling economy, as demonstrated by a higher PO for the same VO2 and enhances both 4- and 16.1-km cycling TT performance.
Three novel dimeric xanthones, cryptosporioptides A-C were isolated from
Cryptosporiopsis
sp. 8999 and their structures elucidated. Methylation of cryptosporioptide A gave a methyl ester with ...identical NMR data to cryptosporioptide, a compound previously reported to have been isolated from the same fungus. However, HRMS analysis revealed that cryptosporioptide is a symmetrical dimer, not a monomer as previously proposed, and the revised structure was elucidated by extensive NMR analysis. The genome of
Cryptosporiopsis
sp. 8999 was sequenced and the dimeric xanthone (
dmx
) biosynthetic gene cluster responsible for the production of the cryptosporioptides was identified. Gene disruption experiments identified a gene (
dmxR5
) encoding a cytochrome P450 oxygenase as being responsible for the dimerisation step late in the biosynthetic pathway. Disruption of
dmxR5
led to the isolation of novel monomeric xanthones. Cryptosporioptide B and C feature an unusual ethylmalonate subunit: a hrPKS and acyl CoA carboxylase are responsible for its formation. Bioinformatic analysis of the genomes of several fungi producing related xanthones,
e.g.
the widely occurring ergochromes, and related metabolites allows detailed annotation of the biosynthetic genes, and a rational overall biosynthetic scheme for the production of fungal dimeric xanthones to be proposed.
Three novel dimeric xanthones, cryptosporioptides A-C were isolated from
Cryptosporiopsis
sp. 8999 and their structures elucidated.
Strobilurins from fungi are the inspiration for the creation of the β-methoxyacrylate class of agricultural fungicides. However, molecular details of the biosynthesis of strobilurins have remained ...cryptic. Here we report the sequence of genomes of two fungi that produce strobilurins and show that each contains a biosynthetic gene cluster, which encodes a highly reducing polyketide synthase with very unusual C-terminal hydrolase and methyltransferase domains. Expression of stpks1 in Aspergillus oryzae leads to the production of prestrobilurin A when the fermentation is supplemented with a benzoyl coenzyme A (CoA) analogue. This enables the discovery of a previously unobserved route to benzoyl CoA. Reconstruction of the gene cluster in A. oryzae leads to the formation of prestrobilurin A, and addition of the gene str9 encoding an FAD-dependent oxygenase leads to the key oxidative rearrangement responsible for the creation of the β-methoxyacrylate toxophore. Finally, two methyltransferases are required to complete the synthesis.
Azaphilones are a family of polyketide‐based fungal natural products that exhibit interesting and useful bioactivities. This minireview explores the literature on various characterised azaphilone ...biosynthetic pathways, which allows for a proposed consensus scheme for the production of the core azaphilone structure, as well as identifying early diversification steps during azaphilone biosynthesis. A consensus understanding of the core enzymatic steps towards a particular family of fungal natural products can aid in genome‐mining experiments. Genome mining for novel fungal natural products is a powerful technique for both exploring chemical space and providing new insights into fungal natural product pathways.
Azaphilones are a polyketide‐based family of fungal natural products with a highly oxygenated bicyclic pyrone‐quinone structure, many of which have useful and interesting bioactivities. This minireview reveals the common steps in azaphilone biosynthetic pathways to aid the use of genome mining to identify orphan azaphilone biosynthetic gene clusters.
Dietary nitrate supplementation has been reported to improve short distance time trial (TT) performance by 1–3 % in club-level cyclists. It is not known if these ergogenic effects persist in longer ...endurance events or if dietary nitrate supplementation can enhance performance to the same extent in better trained individuals. Eight well-trained male cyclists performed two laboratory-based 50 mile TTs: (1) 2.5 h after consuming 0.5 L of nitrate-rich beetroot juice (BR) and (2) 2.5 h after consuming 0.5 L of nitrate-depleted BR as a placebo (PL). BR significantly elevated plasma NO
2
−
(BR: 472 ± 96 vs. PL: 379 ± 94 nM;
P
< 0.05) and reduced completion time for the 50 mile TT by 0.8 % (BR: 136.7 ± 5.6 vs. PL: 137.9 ± 6.4 min), which was not statistically significant (
P
> 0.05). There was a significant correlation between the increased post-beverage plasma NO
2
−
with BR and the reduction in TT completion time (
r
= −0.83,
P
= 0.01). Power output (PO) was not different between the conditions at any point (
P
> 0.05) but oxygen uptake (
O
2
) tended to be lower in BR (
P
= 0.06), resulting in a significantly greater PO/
O
2
ratio (BR: 67.4 ± 5.5 vs. PL: 65.3 ± 4.8 W L min
−1
;
P
< 0.05). In conclusion, acute dietary supplementation with beetroot juice did not significantly improve 50 mile TT performance in well-trained cyclists. It is possible that the better training status of the cyclists in this study might reduce the physiological and performance response to NO
3
−
supplementation compared with the moderately trained cyclists tested in earlier studies.
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