Benzoic acid and specific 2-oxo acids activate hepatic efflux of glutamate at OAT2

The liver is the principal source of glutamate in blood plasma. Recently we have discovered that efflux of glutamate from hepatocytes is catalyzed by the transporter OAT2 (human gene symbol SLC22A7). Organic anion transporter 2 (OAT2) is an integral membrane protein of the sinusoidal membrane domain; it is primarily expressed in liver and much less in kidney, both in rats and humans. Many years ago, Häussinger and coworkers have demonstrated in isolated perfused rat liver that benzoic acid or specific 2-oxo acid analogs of amino acids like e.g. 2-oxo-4-methyl-pentanoate (‘2-oxo-leucine’) strongly stimulate release of glutamate (up to 7-fold); ‘2-oxo-valine’ and the corresponding amino acids were without effect. The molecular mechanism of efflux stimulation has remained unclear. In the present study, OAT2 from human and rat were heterologously expressed in 293 cells. Addition of 1 mmol/l benzoic acid to the external medium increased OAT2-specific efflux of glutamate up to 20-fold; ‘2-oxo-leucine’ was also effective, but not ‘2-oxo-valine’. Similar effects were seen for efflux of radiolabeled orotic acid. Expression of OAT2 did not increase uptake of benzoic acid; thus, benzoic acid is no substrate, and trans-stimulation can be excluded. Instead, further experiments suggest that increased efflux of glutamate is caused by direct interaction of benzoic acid and specific 2-oxo acids with OAT2. We propose that stimulators bind to a distinct extracellular site and thereby accelerate relocation of the empty substrate binding site to the intracellular face. Increased glutamate efflux at OAT2 could be the main benefit of benzoate treatment in patients with urea cycle defects.     

A Recurrent PDGFRB Mutation Causes Familial Infantile Myofibromatosis

Infantile myofibromatosis (IM) is the most common benign fibrous tumor of soft tissues affecting young children. By using whole-exome sequencing, RNA sequencing, and targeted sequencing, we investigated germline and tumor DNA in individuals from four distinct families with the familial form of IM and in five simplex IM cases with no previous family history of this disease. We identified a germline mutation c.1681C>T (p.Arg561Cys) in platelet-derived growth factor receptor β (PDGFRB) in all 11 affected individuals with familial IM, although none of the five individuals with nonfamilial IM had mutations in this gene. We further identified a second heterozygous mutation in PDGFRB in two myofibromas from one of the affected familial cases, indicative of a potential second hit in this gene in the tumor. PDGFR-β promotes growth of mesenchymal cells, including blood vessels and smooth muscles, which are affected in IM. Our findings indicate p.Arg561Cys substitution in PDGFR-β as a cause of the dominant form of this disease. They provide a rationale for further investigations of this specific mutation and gene to assess the benefits of targeted therapies against PDGFR-β in aggressive life-threatening familial forms of the disease.     

Short‐distance migration of Wrynecks Jynx torquilla from Central European populations

European Wrynecks Jynx torquilla torquilla have generally been considered to be long‐distance Palaearctic–African migrants that spend the non‐breeding season in Sahelian Africa, where they have been reported regularly. Results from tracking individual birds showed that Wrynecks from two Central European populations migrated only relatively short distances to the Iberian Peninsula and northwestern Africa (c. 1500 km and 3000 km, respectively), compared with a minimum distance of about 4500 km to Sahelian Africa. Additionally, differences in wing lengths of populations from Central and Northern Europe support the idea of leap‐frog migration, populations from Northern Europe being long‐distance migrants with a non‐breeding distribution in Sahelian Africa.     

Baseline time accounting: Considering global land use dynamics when estimating the climate impact of indirect land use change caused by biofuels

Purpose

Current estimations of the climate impact from indirect land use change (ILUC) caused by biofuels are heavily influenced by assumptions regarding the biofuel production period. The purpose of this paper is to propose a new method (baseline time accounting) that takes global land use dynamics into account that is consistent with the global warming potential, that is applicable to any phenomenon causing land use change, and that is independent of production period assumptions.

Methods

We consider ILUC in two forms. The first is called “accelerated expansion” and concerns ILUC in regions with an expanding agricultural area. The second is called “delayed reversion” and concerns ILUC in regions with a decreasing agricultural area. We use recent trends in international land use and projections of future land use change to assess how ILUC from biofuels will alter the development in global agricultural land use dynamics compared to the existing trend (i.e., the baseline development). We then use the definition of the global warming potential to determine the CO₂ equivalence of the change in land use dynamics.

Results and discussion

We apply baseline time accounting to two existing ILUC studies in the literature. With current trends in global agricultural land use, the method significantly reduces the estimated climate impact in the previous ILUC studies (by more than half). Sensitivity analyses show that results are somewhat sensitive to assumptions regarding carbon sequestration and assumptions regarding postreversion ecosystems.

Conclusions

The global dynamic development in land use has important implications for the time accounting step when estimating the climate impact of ILUC caused by biofuel production or other issues affecting land use. Ignoring this may lead to erroneous conclusions about the actual climate impact of ILUC. Several land use projections indicate that the global agricultural area will keep expanding up to and beyond 2050. We therefore recommend to apply the baseline time accounting concept as an integrated part of future ILUC studies and to update the results on a regular basis.     

A nonlinear autoregressive Volterra model of the Hodgkin–Huxley equations

We propose a new variant of Volterra-type model with a nonlinear auto-regressive (NAR) component that is a suitable framework for describing the process of AP generation by the neuron membrane potential, and we apply it to input-output data generated by the Hodgkin–Huxley (H–H) equations. Volterra models use a functional series expansion to describe the input-output relation for most nonlinear dynamic systems, and are applicable to a wide range of physiologic systems. It is difficult, however, to apply the Volterra methodology to the H–H model because is characterized by distinct subthreshold and suprathreshold dynamics. When threshold is crossed, an autonomous action potential (AP) is generated, the output becomes temporarily decoupled from the input, and the standard Volterra model fails. Therefore, in our framework, whenever membrane potential exceeds some threshold, it is taken as a second input to a dual-input Volterra model. This model correctly predicts membrane voltage deflection both within the subthreshold region and during APs. Moreover, the model naturally generates a post-AP afterpotential and refractory period. It is known that the H–H model converges to a limit cycle in response to a constant current injection. This behavior is correctly predicted by the proposed model, while the standard Volterra model is incapable of generating such limit cycle behavior. The inclusion of cross-kernels, which describe the nonlinear interactions between the exogenous and autoregressive inputs, is found to be absolutely necessary. The proposed model is general, non-parametric, and data-derived.     

Long-Term Prognostic Value of Restitution Slope in Patients with Ischemic and Dilated Cardiomyopathies

Background

An action potential duration (APD) restitution curve with a steep slope ≥1 has been associated with increased susceptibility for malignant ventricular arrhythmias. We aimed to evaluate the “restitution hypothesis” and tested ventricular APD restitution slope as well as effective refractory period (ERP)/APD ratio for long-term prognostic value in patients with ischemic (ICM) or dilated cardiomyopathy (DCM).

Methodology/Principal Findings

Monophasic action potentials were recorded in patients with ICM (n = 32) and DCM (n = 42) undergoing routine programmed ventricular stimulation (PVS). Left ventricular ejection fraction was 32±7% and 28±9%, respectively. APD and ERP were measured at baseline stimulation (S₁) and upon introduction of one to three extrastimuli (S₂–S₄). ERP/APD ratios and the APD restitution curve were calculated and the maximum restitution slope was determined. After a mean follow-up of 6.1±3.0 years, the combined end-point of mortality and and/or implantable cardioverter-defibrillator shock was not predicted by restitution slope or ERP/APD ratios. Comparing S₂ vs. S₃ vs. S₄ extrastimuli for restitution slope (1.5±0.6 vs. 1.4±0.4 vs. 1.3±0.5; p = NS), additional extrastimuli did not lead to a steepening restitution slope. ERP/APD ratio decreased with additional extrastimuli (0.98±0.09 [S₁] vs. 0.97±0.10 [S₂] vs. 0.93±0.11 [S₃]; p = 0.03 S₁ vs. S₃). Positive PVS was strongly predictive of outcome (p = 0.006).

Conclusions/Significance

Neither ventricular APD restitution slope nor ERP/APD ratios predict outcome in patients with ICM or DCM.     

Aerobic exercise alone results in clinically significant weight loss for men and women: Midwest exercise trial 2

Exercise is recommended by public health agencies for weight management; however, the role of exercise is generally considered secondary to energy restriction. Few studies exist that have verified completion of exercise, measured the energy expenditure of exercise, and prescribed exercise with equivalent energy expenditure across individuals and genders.

Objective:

The objective of this study was to evaluate aerobic exercise, without energy restriction, on weight loss in sedentary overweight and obese men and women.

Design and Methods:

This investigation was a randomized, controlled, efficacy trial in 141 overweight and obese participants (body mass index, 31.0 ± 4.6 kg/m²; age 22.6 ± 3.9 years). Participants were randomized (2:2:1 ratio) to exercise at either 400 kcal/session or 600 kcal/session or to a nonexercise control. Exercise was supervised, 5 days/week, for 10 months. All participants were instructed to maintain usual ad libitum diets. Because of the efficacy design, completion of ≥90% of exercise sessions was an a priori definition of per protocol, and these participants were included in the analysis.

Results:

Weight loss from baseline to 10 months for the 400 and 600 kcal/session groups was 3.9 ± 4.9 kg (4.3%) and 5.2 ± 5.6 kg (5.7%), respectively, compared with weight gain for controls of 0.5 ± 3.5 kg (0.5%) (P < 0.05). Differences for weight loss from baseline to 10 months between the exercise groups and differences between men and women within groups were not statistically significant.

Conclusions:

Supervised exercise, with equivalent energy expenditure, results in clinically significant weight loss with no significant difference between men and women.     

Soil carbon sequestration and land use change associated with biofuel production: empirical evidence

Soil organic carbon (SOC) change can be a major impact of land use change (LUC) associated with biofuel feedstock production. By collecting and analyzing data from worldwide field observations of major LUCs from cropland, grassland, and forest to lands producing biofuel crops (i.e. corn, switchgrass, Miscanthus, poplar, and willow), we were able to estimate SOC response ratios and sequestration rates and evaluate the effects of soil depth and time scale on SOC change. Both the amount and rate of SOC change were highly dependent on the specific land transition. Irrespective of soil depth or time horizon, cropland conversions resulted in an overall SOC gain of 6–14% relative to initial SOC level, while conversion from grassland or forest to corn (without residue removal) or poplar caused significant carbon loss (9–35%). No significant SOC changes were observed in land converted from grasslands or forests to switchgrass, Miscanthus, or willow. The SOC response ratios were similar in both 0–30 and 0–100 cm soil depths in most cases, suggesting SOC changes in deep soil and that use of top soil only for SOC accounting in biofuel life cycle analysis (LCA) might underestimate total SOC changes. Soil carbon sequestration rates varied greatly among studies and land transition types. Generally, the rates of SOC change tended to be the greatest during the 10 years following land conversion and had declined to approach 0 within about 20 years for most LUCs. Observed trends in SOC change were generally consistent with previous reports. Soil depth and duration of study significantly influence SOC change rates and so should be considered in carbon emission accounting in biofuel LCA. High uncertainty remains for many perennial systems and forest transitions, additional field trials, and modeling efforts are needed to draw conclusions about the site‐ and system‐specific rates and direction of change.