Coupling and pathway control of coenzyme Q redox state and respiration in isolated mitochondria

Redox states of the mitochondrial coenzyme Q pool, which reacts with the electron transfer system, reflect the balance between (1) reducing capacities of electron flow from fuel substrates converging at the Q-junction, (2) oxidative capacities downstream of Q to O2, and (3) the load on the OXPHOS system utilizing or dissipating the protonmotive force. A three-electrode sensor (Rich 1988; Moore et al 1988) was implemented into the NextGen-O2k to monitor continuously the redox state of CoQ2 added as a Q-mimetic simultaneously with O2 consumption. The Q-Module was optimized for high signal-to-noise ratio, minimum drift, and minimum oxygen diffusion. CoQ2 equilibrates in the same manner as Q at Complexes CI, CII and CIII. The CoQ2 redox state is monitored amperometrically with the working electrode, which is poised at CoQ2 redox peak potentials determined by cyclic voltammetry. The voltammogram also provides quality control of the Q-sensor and reveals chemical interferences. The CoQ2 redox state and O2 consumption were measured simultaneously in isolated mouse cardiac and brain mitochondria. CoQ2 ― and by implication mitochondrial Q ― was more oxidized when O2 flux was stimulated by coupling control: when energy demand increased from LEAK to OXPHOS and electron transfer capacities in the succinate pathway. In contrast, CoQ2 was more reduced when O2 flux was stimulated by pathway-control of electron input capacities, increasing from the NADH (N)- to succinate (S)-linked pathway which converge at the Q-junction, with CI-Q-CIII and CII-Q-CIII segments, respectively. N- and S- respiratory pathway capacities were not completely additive, compatible with partitioning of Q intermediary between the solid-state and liquid-state models of supercomplex organization. The direct proportionality of CoQ2 reduction and electron input capacities through the CI-Q-CIII and CII-Q-CIII segments suggests that CoQ2 is accurately mimicking mitochondrial Q-redox changes

Arsenic methylation patterns before and after changing from high to lower concentrations of arsenic in drinking water.

Inorganic arsenic (In-As), an occupational and environmental human carcinogen, undergoes biomethylation to monomethylarsonate (MMA) and dimethylarsinate (DMA). It has been proposed that saturation of methylation capacity at high exposure levels may lead to a threshold for the carcinogenicity of In-As. The relative distribution of urinary In-As, MMA, and DMA is used as a measure of human methylation capacity. The most common pathway for elevated environmental exposure to In-As worldwide is through drinking water. We conducted a biomarker study in northern Chile of a population chronically exposed to water naturally contaminated with high arsenic content (600 micrograms/l). In this paper we present the results of a prospective follow-up of 73 exposed individuals, who were provided with water of lower arsenic content (45 micrograms/l) for 2 months. The proportions of In-As, MMA, and DMA in urine were compared before and after intervention, and the effect of other factors on the distribution of arsenic metabolites was also analyzed. The findings of this study indicate that the decrease in arsenic exposure was associated with a small decrease in the percent In-As in urine (from 17.8% to 14.6%) and in the MMA/DMA ratio (from 0.23 to 0.18). Other factors such as smoking, gender, age, years of residence, and ethnicity were associated mainly with changes in the MMA/DMA ratio, with smoking having the strongest effect. Nevertheless, the factors investigated accounted for only about 20% of the large interindividual variability observed. Genetic polymorphisms in As-methylating enzymes and other co-factors are likely to contribute to some of the unexplained variation. The changes observed in the percent In-As and in the MMA/DMA ratio do not support an exposure-based threshold for arsenic methylation in humans

Methylation study of a population environmentally exposed to arsenic in drinking water.

Methylation is considered the detoxification pathway for inorganic arsenic (InAs), an established human carcinogen. Urinary speciation analysis is used to assess the distribution of metabolites [monomethylarsonate (MMA), dimethylarsinate (DMA), and unmethylated arsenic (InAs)], as indicators of methylation capacity. We conducted a large biomarker study in northern Chile of a population chronically exposed to high levels of arsenic in drinking water. We report the results of the methylation study, which focused on the effects of exposure and other variables on the percent InAs, MMA, DMA, and the ratio of MMA to DMA in urine. The study consisted of 122 people in a town with arsenic water levels around 600 micrograms/l and 98 participants in a neighboring town with arsenic levels in water of about 15 micrograms/l. The corresponding mean urinary arsenic levels were 580 micrograms/l and 60 micrograms/l, of which 18.4% and 14.9% were InAs, respectively. The main differences were found for MMA:DMA; exposure, smoking, and being male were associated with higher MMA:DMA, while longer residence, Atacameño ethnicity, and being female were associated with lower MMA:DMA. Together, these variables explained about 30% of the variability in MMA:DMA. Overall, there was no evidence of a threshold for methylation capacity, even at very high exposures, and the interindividual differences were within a much wider range than those attributed to the variables investigated. The differences in percent InAs were small and within the ranges of other studies of background exposure levels. The biological significance of MMA:DMA, which was more than 1.5 times greater in the exposed group, and its relationship to sex, length of exposure, and ethnicity need further investigation because its relevance to health risk is not clear

Tile Number and Space-Efficient Knot Mosaics

In this paper we introduce the concept of a space-efficient knot mosaic. That is, we seek to determine how to create knot mosaics using the least number of non-blank tiles necessary to depict the knot. This least number is called the tile number of the knot. We determine strict bounds for the tile number of a knot in terms of the mosaic number of the knot. In particular, if $t$ is the tile number of a prime knot with mosaic number $m$, then $5m-8 \leq t \leq m^2-4$ if $m$ is even and $5m-8 \leq t \leq m^2-8$ if $m$ is odd. We also determine the tile number of several knots and provide space-efficient knot mosaics for each of them.Comment: The original version of this article was split into two articles during refereein

Projecting grassland sensitivity to climate change from an ensemble of models

The grassland biome covers about one-quarter of the earth’s land area and contributes to the livelihoods of ca. 800 million people. Increased aridity and persistent droughts are projected in the twenty-first century for most of Africa, southern Europe and the Middle East, most of the Americas, Australia and South East Asia. A number of these regions have a large fraction of their land use covered by grasslands and rangelands. Grasslands are the ecosystems that respond most rapidly to precipitation variability. However, global projections of climate change impacts on grasslands are still lacking in the scientific literature. Within AgMIP, based on the C3MP protocol initially developed for crops, we have explored the sensitivity of temperate grasslands to climate change drivers with an ensemble of models. Site calibrated models are used to provide projections under probabilistic climate change scenarios, which are defined by a combination of air temperature, precipitation and atmospheric CO2 changes resulting in 99 runs for each model times site combination. This design provides a test of grassland production, GHG (N2O and CH4) emissions and soil carbon sensitivity to climate change drivers. This integrated approach has been tested for 12 grassland simulation models applied to 19 sites over three continents. We show here that a single polynomial emulator can be fitted with high significance to the results of all models and sites, when these are expressed as relative changes from the optimal combination of climate drivers. This polynomial emulator shows that elevated atmospheric CO2 expands the thermal and hydric range which allows for the development of temperate grasslands. Moreover, we calculate the climatic response surface of GHG emissions per unit grassland production and we show that this surface varies with elevated CO2. From these results we provide first estimates of the impacts of climate change on temperate grasslands based on a range of climate scenarios

Efficacy and safety of endoscopic sleeve gastroplasty and laparoscopic sleeve gastrectomy with 12+ months of adjuvant multidisciplinary support

BACKGROUND: The laparoscopic sleeve gastrectomy (LSG) and the incisionless endoscopic sleeve gastroplasty (ESG) weight loss procedures require further investigation of their efficacy, safety and patient-centered outcomes in the Australian setting. METHODS: The aim was to examine the 6- and 12-month weight loss efficacy, safety, and weight-related quality of life (QoL) of adults with obesity who received the ESG or LSG bariatric procedure with 12+ months of adjuvant multidisciplinary pre- and postprocedural support. Data were from a two-arm prospective cohort study that followed patients from baseline to 12-months postprocedure from a medical center in Queensland. Percent excess weight loss (%EWL) was the primary outcome. Secondary outcomes were body composition (fat mass, fat-free mass, android:gynoid ratio, bone mineral content) via dual energy X-ray absorptiometry, weight-related QoL, lipid, glycemic, and hepatic biochemistry, and adverse events. RESULTS: 16 ESG (19% attrition; 81.2% female; aged:41.4 (SD: 10.4) years; BMI: 35.5 (SD: 5.2) kg/m(2)) and 45 LSG (9% attrition; 84.4% female; aged:40.4 (SD: 9.0) years; BMI: 40.7 (SD: 5.6) kg/m(2)) participants were recruited. At 12-months postprocedure, ESG %EWL was 57% (SD: 32%; p  0.05]; 48.1% in LSG [p  0.05]; − 0.4 mmol/L in LSG [P < 0.05]) at 12-months. Both cohorts reduced fat mass (p < 0.05). The ESG maintained but LSG decreased fat-free mass at 6-months (p < 0.05); and both cohorts lost fat-free mass at 12-months (p < 0.05). There were no adverse events directly related to the procedure. The ESG reported 25% mild-moderate adverse events possibly related to the procedure, and the LSG reported 27% mild-severe adverse events possibly related to the procedure. CONCLUSIONS: In this setting, the ESG and LSG were safe and effective weight loss treatments for obese adults alongside multidisciplinary support. Patients who elected the ESG maintained fat-free mass at 6-months but both cohorts lost fat-free mass at 12-months postprocedure. Patients who elected the LSG had large and significant improvements to weight-related quality of life. Further well-powered studies are required to confirm these findings. TRIAL REGISTRATION: This study was registered prospectively at the Australia New Zealand Clinical Trials Registry on 06/03/2018, Registration Number ACTRN12618000337279. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12875-022-01629-7