Coenzyme Q10 deficiencies: pathways in yeast and humans.

Coenzyme Q (ubiquinone or CoQ) is an essential lipid that plays a role in mitochondrial respiratory electron transport and serves as an important antioxidant. In human and yeast cells, CoQ synthesis derives from aromatic ring precursors and the isoprene biosynthetic pathway. Saccharomyces cerevisiae coq mutants provide a powerful model for our understanding of CoQ biosynthesis. This review focusses on the biosynthesis of CoQ in yeast and the relevance of this model to CoQ biosynthesis in human cells. The COQ1-COQ11 yeast genes are required for efficient biosynthesis of yeast CoQ. Expression of human homologs of yeast COQ1-COQ10 genes restore CoQ biosynthesis in the corresponding yeast coq mutants, indicating profound functional conservation. Thus, yeast provides a simple yet effective model to investigate and define the function and possible pathology of human COQ (yeast or human gene involved in CoQ biosynthesis) gene polymorphisms and mutations. Biosynthesis of CoQ in yeast and human cells depends on high molecular mass multisubunit complexes consisting of several of the COQ gene products, as well as CoQ itself and CoQ intermediates. The CoQ synthome in yeast or Complex Q in human cells, is essential for de novo biosynthesis of CoQ. Although some human CoQ deficiencies respond to dietary supplementation with CoQ, in general the uptake and assimilation of this very hydrophobic lipid is inefficient. Simple natural products may serve as alternate ring precursors in CoQ biosynthesis in both yeast and human cells, and these compounds may act to enhance biosynthesis of CoQ or may bypass certain deficient steps in the CoQ biosynthetic pathway

Incorporating climate change into invasive species management: insights from managers

Invasive alien species are likely to interact with climate change, thus necessitating management that proactively addresses both global changes. However, invasive species managers’ concerns about the effects of climate change, the degree to which they incorporate climate change into their management, and what stops them from doing so remain unknown. Therefore, we surveyed natural resource managers addressing invasive species across the U.S. about their priorities, concerns, and management strategies in a changing climate. Of the 211 managers we surveyed, most were very concerned about the influence of climate change on invasive species management, but their organizations were significantly less so. Managers reported that lack of funding and personnel limited their ability to effectively manage invasive species, while lack of information limited their consideration of climate change in decision-making. Additionally, managers prioritized research that identifies range-shifting invasive species and native communities resilient to invasions and climate change. Managers also reported that this information would be most effectively communicated through conversations, research summaries, and meetings/symposia. Despite the need for more information, 65% of managers incorporate climate change into their invasive species management through strategic planning, preventative management, changing treatment and control, and increasing education and outreach. These results show the potential for incorporating climate change into management, but also highlight a clear and pressing need for more targeted research, accessible science communication, and two-way dialogue between researchers and managers focused on invasive species and climate change

Functional desensitization of the β 2 adrenoceptor is not dependent on agonist efficacy

© 2015 John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. Chronic treatment with β2 adrenoceptor agonists is recommended as a first-line maintenance therapy for chronic obstructive pulmonary disease (COPD). However, a potential consequence of long-term treatment may be the loss of functional response (tachyphylaxis) over time. In this study, we have investigated the tendency of such agonists, with a range of efficacies, to develop functional desensitization to cAMP responses in primary human bronchial smooth muscle cells following prolonged agonist exposure. The data show that upon repeat exposure, all agonists produced functional desensitization to the same degree and rate. In addition, β2 adrenoceptor internalization and β-arrestin-2 recruitment were monitored using β2·eGFP visualization and the PathHunter™ β-arrestin-2 assay, respectively. All agonists were capable of causing robust receptor internalization and β-arrestin-2 recruitment, the rate of which was influenced by agonist efficacy, as measured in those assays. In summary, although a relationship exists between agonist efficacy and the rate of both receptor internalization and β-arrestin-2 recruitment, there is no correlation between agonist efficacy and the rate or extent of functional desensitization

{N,N-Bis 2-(Diphenylphosphanyl)Ethyl Aniline}(Eta(2)-Dibenzylideneaceton E)Palladium(0)

In the title complex, [Pd(C34H33NP2)(C17H14O)], the Pd-0 atom is coordinated in a trigonal planar geometry formed by two P atoms of a bis[(diphenylphosphino)ethyl] aniline ligand and a C=C (eta(2)) bond involving the C atoms that are in the alpha,beta positions relative to the central ketone of the dibenzylideneacetone ligand.Robert A. Welch Foundation F-1631National Science Foundation CHE-0741973, CHE-0847763Texas Higher Education Coordinating Board 01916-090-2010American Heart Association 0765078YUT-AustinICDDSigma-Xi, the Scientific Research SocietyChemistryBiochemistr

Vector competence of Aedes aegypti, Culex tarsalis, and Culex quinquefasciatus from California for Zika virus.

Zika virus (ZIKV) has emerged since 2013 as a significant global human health threat following outbreaks in the Pacific Islands and rapid spread throughout South and Central America. Severe congenital and neurological sequelae have been linked to ZIKV infections. Assessing the ability of common mosquito species to transmit ZIKV and characterizing variation in mosquito transmission of different ZIKV strains is important for estimating regional outbreak potential and for prioritizing local mosquito control strategies for Aedes and Culex species. In this study, we evaluated the laboratory vector competence of Aedes aegypti, Culex quinquefasciatus, and Culex tarsalis that originated in areas of California where ZIKV cases in travelers since 2015 were frequent. We compared infection, dissemination, and transmission rates by measuring ZIKV RNA levels in cohorts of mosquitoes that ingested blood meals from type I interferon-deficient mice infected with either a Puerto Rican ZIKV strain from 2015 (PR15), a Brazilian ZIKV strain from 2015 (BR15), or an ancestral Asian-lineage Malaysian ZIKV strain from 1966 (MA66). With PR15, Cx. quinquefasciatus was refractory to infection (0%, N = 42) and Cx. tarsalis was infected at 4% (N = 46). No ZIKV RNA was detected in saliva from either Culex species 14 or 21 days post feeding (dpf). In contrast, Ae. aegypti developed infection rates of 85% (PR15; N = 46), 90% (BR15; N = 20), and 81% (MA66; N = 85) 14 or 15 dpf. Although MA66-infected Ae. aegypti showed higher levels of ZIKV RNA in mosquito bodies and legs, transmission rates were not significantly different across virus strains (P = 0.13, Fisher's exact test). To confirm infectivity and measure the transmitted ZIKV dose, we enumerated infectious ZIKV in Ae. aegypti saliva using Vero cell plaque assays. The expectorated plaque forming units PFU varied by viral strain: MA66-infected expectorated 13±4 PFU (mean±SE, N = 13) compared to 29±6 PFU for PR15-infected (N = 13) and 35±8 PFU for BR15-infected (N = 6; ANOVA, df = 2, F = 3.8, P = 0.035). These laboratory vector competence results support an emerging consensus that Cx. tarsalis and Cx. quinquefasciatus are not vectors of ZIKV. These results also indicate that Ae. aegypti from California are efficient laboratory vectors of ancestral and contemporary Asian lineage ZIKV

Evaluation of a Brief Sodium Screener in Two Samples

The Sodium Screener© (SS©), as developed by NutritionQuest (Berkeley, CA, USA), was designed to reduce the burden of repeated dietary or urinary sodium measurements, but the accuracy of daily sodium intake estimates has not been reported. Associations were examined between sodium intakes derived from the SS© scores and repeated 24-h recalls (24DR) in two studies with different administration modes. In one study, 102 registered dietitians (RD) completed three Automated Self-Administered 24DRs (ASA24©), version 2014, followed by the SS©; both were self-administered and web-based. In the second sample, (the Study of Household Purchasing Patterns, Eating, and Recreation or SHoPPER), trained dietitians conducted 24DR interviews with 69 community-dwelling adults in their homes; all the community adults then completed a paper-based SS© at the final visit. In the RD study, SS©-predicted sodium intakes were 2604 ± 990 (mean ± Standard deviation (SD)), and ASA24© sodium intakes were 3193 ± 907 mg/day. In the SHoPPER sample, corresponding values were 3338 ± 1310 mg/day and 2939 ± 1231 mg/day, respectively. SS© -predicted and recall sodium estimates were correlated in the RD study (r = 0.381, p = 0.0001) and in the SHoPPER (r = 0.430, p = 0.0002). Agreement between the SS© and 24-h recalls was poor when classifying individuals as meeting the dietary sodium guidelines of 2300 mg/day or not (RD study: kappa = 0.080, p = 0.32; SHoPPER: kappa = 0.207, p = 0.08). Based on repeated 24DR either in person or self-reported online as the criterion for estimating daily sodium intakes, the SS© may require additional modifications

Scholarly Concentrations Program: A PRIME Approach to Addressing Care for the Medically Underserved and Vulnerable Populations

Examine how well the structure of the Scholarly Concentrations Program and content of each concentration relates to the goals of the federal Health Resources and Services Administration grant received to create more interest and prepare more medical school graduates to care for medically underserved and vulnerable populations. The grant funds the Primary Care Reaffirmation for Indiana Medical Education, or PRIME. project. A review of how concentrations align with the grant was conducted by reviewing program, concentration and course learning objectives and mapping to the grant objectives. Numerous concentrations were found to be an excellent fit, creating a PRIME opportunity to enhance the SC Program and move the needle on the grant objectives

Regional Invasive Species & Climate Change Management Challenge: Why Native? Benefits of planting native species in a changing climate

Yards host a variety of native and non-native plants. It is easy to assume all plants play a similar role in supporting wildlife, but native plants dramatically increase the diversity of bees, butterflies, birds and other native animals. Additionally, non-native plants can become invasive or support invasive pests. Native plants increase biodiversity and reduce risks associated with invasive species, which supports resilient ecosystems in the face of climate change

Exposure and potential effects of pesticides and pharmaceuticals in protected streams of the US National park Service southeast region

Globally, protected areas offer refugia for a broad range of taxa including threatened and endangered species. In the United States (US), the National Park Service (NPS) manages public lands to preserve biodiversity, but increasing park visitation and development of surrounding landscapes increase exposure to and effects from bioactive contaminants. The risk (exposure and hazard) to NPS protected-stream ecosystems within the highly urbanized southeast region (SER) from bioactive contaminants was assessed in five systems based on 334 pesticide and pharmaceutical analytes in water and 119 pesticides in sediment. Contaminant mixtures were common across all sampled systems, with approximately 24% of the unique analytes (80/334) detected at least once and 15% (49/334) detected in half of the surface-water samples. Pharmaceuticals were observed more frequently than pesticides, consistent with riparian buffers and concomitant spatial separation from non-point pesticide sources in four of the systems. To extrapolate exposure data to biological effects space, site-specific cumulative exposure-activity ratios (REAR) were calculated for detected surface-water contaminants with available ToxCast data; common exceedances of a 0.001 REAR effects-screening threshold raise concerns for molecular toxicity and possible, sub-lethal effects to non-target, aquatic vertebrates. The results illustrate the need for continued management of protected resources to reduce contaminant exposure and preserve habitat quality, including prioritization of conservation practices (riparian buffers) near stream corridors and increased engagement with upstream/up-gradient property owners and municipal wastewater facilities

A Randomized, Phase III Trial to Evaluate Rucaparib Monotherapy as Maintenance Treatment in Patients With Newly Diagnosed Ovarian Cancer (ATHENA–MONO/GOG-3020/ENGOT-ov45)

Cáncer de ovarios; MonoterapiaCàncer d'ovaris; MonoteràpiaOvarian cancer; MonotherapyPURPOSE ATHENA (ClinicalTrials.gov identifier: NCT03522246) was designed to evaluate rucaparib first-line maintenance treatment in a broad patient population, including those without BRCA1 or BRCA2 (BRCA) mutations or other evidence of homologous recombination deficiency (HRD), or high-risk clinical characteristics such as residual disease. We report the results from the ATHENA–MONO comparison of rucaparib versus placebo. METHODS Patients with stage III-IV high-grade ovarian cancer undergoing surgical cytoreduction (R0/complete resection permitted) and responding to first-line platinum-doublet chemotherapy were randomly assigned 4:1 to oral rucaparib 600 mg twice a day or placebo. Stratification factors were HRD test status, residual disease after chemotherapy, and timing of surgery. The primary end point of investigator-assessed progression-free survival was assessed in a step-down procedure, first in the HRD population (BRCA-mutant or BRCA wild-type/loss of heterozygosity high tumor), and then in the intent-to-treat population. RESULTS As of March 23, 2022 (data cutoff), 427 and 111 patients were randomly assigned to rucaparib or placebo, respectively (HRD population: 185 v 49). Median progression-free survival (95% CI) was 28.7 months (23.0 to not reached) with rucaparib versus 11.3 months (9.1 to 22.1) with placebo in the HRD population (log-rank P = .0004; hazard ratio [HR], 0.47; 95% CI, 0.31 to 0.72); 20.2 months (15.2 to 24.7) versus 9.2 months (8.3 to 12.2) in the intent-to-treat population (log-rank P < .0001; HR, 0.52; 95% CI, 0.40 to 0.68); and 12.1 months (11.1 to 17.7) versus 9.1 months (4.0 to 12.2) in the HRD-negative population (HR, 0.65; 95% CI, 0.45 to 0.95). The most common grade ≥ 3 treatment-emergent adverse events were anemia (rucaparib, 28.7% v placebo, 0%) and neutropenia (14.6% v 0.9%). CONCLUSION Rucaparib monotherapy is effective as first-line maintenance, conferring significant benefit versus placebo in patients with advanced ovarian cancer with and without HRD