Acyl-CoA dehydrogenase substrate promiscuity: Challenges and opportunities for development of substrate reduction therapy in disorders of valine and isoleucine metabolism.

Toxicity of accumulating substrates is a significant problem in several disorders of valine and isoleucine degradation notably short-chain enoyl-CoA hydratase (ECHS1 or crotonase) deficiency, 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, propionic acidemia (PA), and methylmalonic aciduria (MMA). Isobutyryl-CoA dehydrogenase (ACAD8) and short/branched-chain acyl-CoA dehydrogenase (SBCAD, ACADSB) function in the valine and isoleucine degradation pathways, respectively. Deficiencies of these acyl-CoA dehydrogenase (ACAD) enzymes are considered biochemical abnormalities with limited or no clinical consequences. We investigated whether substrate reduction therapy through inhibition of ACAD8 and SBCAD can limit the accumulation of toxic metabolic intermediates in disorders of valine and isoleucine metabolism. Using analysis of acylcarnitine isomers, we show that 2-methylenecyclopropaneacetic acid (MCPA) inhibited SBCAD, isovaleryl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase and medium-chain acyl-CoA dehydrogenase, but not ACAD8. MCPA treatment of wild-type and PA HEK-293 cells caused a pronounced decrease in C3-carnitine. Furthermore, deletion of ACADSB in HEK-293 cells led to an equally strong decrease in C3-carnitine when compared to wild-type cells. Deletion of ECHS1 in HEK-293 cells caused a defect in lipoylation of the E2 component of the pyruvate dehydrogenase complex, which was not rescued by ACAD8 deletion. MCPA was able to rescue lipoylation in ECHS1 KO cells, but only in cells with prior ACAD8 deletion. SBCAD was not the sole ACAD responsible for this compensation, which indicates substantial promiscuity of ACADs in HEK-293 cells for the isobutyryl-CoA substrate. Substrate promiscuity appeared less prominent for 2-methylbutyryl-CoA at least in HEK-293 cells. We suggest that pharmacological inhibition of SBCAD to treat PA should be investigated further.

Plant Metabolic Network 15: A resource of genome-wide metabolism databases for 126 plants and algae.

To understand and engineer plant metabolism, we need a comprehensive and accurate annotation of all metabolic information across plant species. As a step towards this goal, we generated genome-scale metabolic pathway databases of 126 algal and plant genomes, ranging from model organisms to crops to medicinal plants (https://plantcyc.org). Of these, 104 have not been reported before. We systematically evaluated the quality of the databases, which revealed that our semi-automated validation pipeline dramatically improves the quality. We then compared the metabolic content across the 126 organisms using multiple correspondence analysis and found that Brassicaceae, Poaceae, and Chlorophyta appeared as metabolically distinct groups. To demonstrate the utility of this resource, we used recently published sorghum transcriptomics data to discover previously unreported trends of metabolism underlying drought tolerance. We also used single-cell transcriptomics data from the Arabidopsis root to infer cell type-specific metabolic pathways. This work shows the quality and quantity of our resource and demonstrates its wide-ranging utility in integrating metabolism with other areas of plant biology.

Renaming Indigenous crops and addressing colonial bias in scientific language.

Indigenous crops, commonly known as orphan, forgotten, or neglected crops, are understudied, but have important roles in the diet and economy of the communities that cultivate them. Here, we review potential benefits of Indigenous crop research and highlight the importance of an anticolonial framework to prevent exploitation of these unique resources.

Policing the drunk driver: measuring law enforcement involvement in reducing alcohol-impaired driving.

INTRODUCTION: With many thousands of deaths still annually attributable to driving under the influence (DUI), it remains imperative that we continually address the problem of producing and sustaining effective countermeasures, and that we subject these efforts to empirical scrutiny. This article presents relevant findings from state-wide datasets. RESULTS: A formula generating a potentially useful metric for assessing aspects of the DUI prosecutorial chain is presented, focusing on the rate of proactive DUI arrests. While in need of cautious interpretation due to issues of inherent inaccuracies in large databases, small numbers of crashes and/or arrests in multiple jurisdictions, and the lack of replication in other states, the analyses show no relationship between the level of DUI arrest activity and DUI-related crashes. This finding brings into question the efficacy of the many millions of dollars devoted each year to targeted DUI enforcement, as it is currently being implemented. CONCLUSIONS: Results are discussed in terms of developing adequate disincentives to DUI so as to raise general deterrence via dramatic increases in proactive DUI enforcement and then engaging in pervasive and persistent social marketing of such efforts to maximize the perception that arrest and punishment for DUI is always imminent, that penalties will be swift, certain, and severe. It is echoed that accurate data need to be collected at all levels of the DUI arrest and prosecution process in every jurisdiction within a state, so as to facilitate the empirical assessment of countermeasure efficacy in reducing alcohol-related crashes. IMPACT ON INDUSTRY: Given that this work needs to be replicated, the impact on the traffic safety industry is potentially huge. The present data indicate that law enforcement efforts to further abate DUI-related crashes are apparently ineffective, though likely necessary to maintain reductions achieved in the 80s and early 90s. Thus, to attain additional systematic reductions, a dramatic increase in enforcement will be necessary as will a diversification of abatement efforts, including an increase in aggressive social marketing tactics to positively impact our traffic safety culture by making DUI universally unacceptable (for a discussion of this latter issue and on the use of positive reinforcement to change driver behavior, see Dula & Geller, 2007).

Risk screening for ADHD in a college population: is there a relationship with academic performance?

OBJECTIVE: The present study examines the relationship between self-reported levels of ADHD and academic outcomes, as well as aptitude. METHOD: A total of 523 college students took the Adult Self-Report Scale-Version 1.1 (ASRS-V1.1), and their scores were compared with course performance and ACT (American College Test) composite scores. RESULTS: The measure identified 70 students (13.4%) as being in the "highly likely" category for an ADHD diagnosis. Course exam and ACT scores for the 70 "highly likely" students were statistically identical to the remaining 453 students in the sample and the 77 students identified as "highly unlikely" as well. Only 4 of the "highly likely" 70 students were registered with the university's Office of Student Disability Services as having been diagnosed with ADHD. CONCLUSIONS: The ASRS-V1.1 failed to discriminate academic performance and aptitude differences between ADHD "highly likely" and "highly unlikely" individuals. The use of self-report screeners of ADHD is questioned in contexts relating ADHD to academic performance.

Comparison of three ADHD screening instruments in college students of varying cognitive ability.

OBJECTIVE: To assess three of the better known screeners for Attention Deficit/Hyperactive Disorder (ADHD) and review the relationship between ADHD and cognitive ability. METHOD: The three ADHD screeners were administered to 111 college students enrolled in a college Introductory Psychology class, on whom ACT scores and total course performance were also available. As a measure of cognitive ability, the Wonderlic Personnel Test (Wonderlic, Inc., 2000) was also administered. Furthermore, self-report data were available from participants who had been diagnosed with ADHD. The three screeners were the Adult ADHD Self-Report Scale (ASRS) (Kessler et al., 2005), the Conners' Adult ADHD Rating Scale-Self-Report: Long Version (CAARS) (Conners, Erhardt, & Sparrow, 1999), and the Brown ADD Scales (Brown, 1996). RESULTS: The results are discussed in terms of the scales' reliability, as well as their relationship to academic aptitude, class performance, and their ability to identify self-reported ADHD diagnoses. CONCLUSION: All three screeners exhibited acceptable reliability levels. Criterion validity was demonstrated by the relationship between the CAARS's inattention subscale and self-reported cases of ADHD. Criterion validity was also seen in the relationship found between the CAARS's hyperactivity/restlessness subscale and the total course performance even after controlling for cognitive ability. Contrary to past research cognitive ability exhibited a weak but significant relationship with a few screeners and screener subscales.

Imbalance between cysteine proteases and inhibitors in a baboon model of bronchopulmonary dysplasia.

RATIONALE: Bronchopulmonary dysplasia (BPD) continues to be a major morbidity in preterm infants. The lung pathology in BPD is characterized by impaired alveolar and capillary development. An imbalance between proteases and protease inhibitors in association with changes in lung elastic fibers has been implicated in the pathogenesis of BPD. OBJECTIVE: To investigate the expression and activity levels of papain-like lysosomal cysteine proteases, cathepsins B, H, K, L, S, and their inhibitors, cystatins B and C, in a baboon model of BPD. METHODS: Real-time reverse transcriptase-polymerase chain reaction, immunohistochemistry, immunoblotting, active site labeling of cysteine proteases, and in situ hybridization were performed. MEASUREMENTS AND MAIN RESULTS: The steady-state mRNA and protein levels of all cathepsins were significantly increased in the lung tissue of baboons with BPD. In contrast, the steady-state mRNA and protein levels of two major cysteine protease inhibitors, cystatin B and C, were unchanged. Correlating with these alterations, the activity of cysteine proteases in lung tissue homogenates and bronchoalveolar lavage fluid was significantly higher in the BPD group. The levels of cathepsin B, H, and S increased and cathepsin K decreased with advancing gestation. All cathepsins, except for cat K, were immunolocalized to macrophages in BPD. In addition, cathepsin H and cystatin B were colocalized in type 2 alveolar epithelial cells. Cathepsin L was detected in some bronchial epithelial, endothelial, and interstitial cells. Cathepsin K was localized to some perivascular cells by in situ hybridization. CONCLUSIONS: Cumulatively, these findings demonstrate an imbalance between cysteine proteases and their inhibitors in BPD.

Falling asleep at the wheel: aclose look at 1,269 fatal and serious injury-producing crashes.

This article reviews the literature on the prevalence of sleep-related motor vehicle crashes and presents a detailed analysis of the driver and context variables associated with a sample of 1,269 sleepy-driver, fatal and injury-causing vehicle crashes that occurred over a 6-year period in Tennessee. The crash profiles and trends are discussed in terms of their implications for addressing this significant problem in highway safety. Findings suggest that younger drivers, ages 15-21, are more at-risk for sleep-related motor vehicle crashes. Also, there is some evidence for the effectiveness of rumble strips in reducing sleep-related, run-off-road, interstate crashes.