Primates have adapted to numerous environments and lifestyles but very few species are native to high elevations. Here we investigated high-altitude adaptations in the gelada (Theropithecus gelada), ...a monkey endemic to the Ethiopian Plateau. We examined genome-wide variation in conjunction with measurements of haematological and morphological traits. Our new gelada reference genome is highly intact and assembled at chromosome-length levels. Unexpectedly, we identified a chromosomal polymorphism in geladas that could potentially contribute to reproductive barriers between populations. Compared with baboons at low altitude, we found that high-altitude geladas exhibit significantly expanded chest circumferences, potentially allowing for greater lung surface area for increased oxygen diffusion. We identified gelada-specific amino acid substitutions in the alpha-chain subunit of adult haemoglobin but found that gelada haemoglobin does not exhibit markedly altered oxygenation properties compared with lowland primates. We also found that geladas at high altitude do not exhibit elevated blood haemoglobin concentrations, in contrast to the normal acclimatization response to hypoxia in lowland primates. The absence of altitude-related polycythaemia suggests that geladas are able to sustain adequate tissue-oxygen delivery despite environmental hypoxia. Finally, we identified numerous genes and genomic regions exhibiting accelerated rates of evolution, as well as gene families exhibiting expansions in the gelada lineage, potentially reflecting altitude-related selection. Our findings lend insight into putative mechanisms of high-altitude adaptation while suggesting promising avenues for functional hypoxia research.
Systemic acquired resistance is an important component of the disease resistance repertoire of plants. In this study, a novel synthetic chemical, benzo(1,2,3)thiadiazole-7-carbothioic acid S-methyl ...ester (BTH), was shown to induce acquired resistance in wheat. BTH protected wheat systemically against powdery mildew infection by affecting multiple steps in the life cycle of the pathogen. The onset of resistance was accompanied by the induction of a number of newly described wheat chemically induced (WCI) genes, including genes encoding a lipoxygenase and a sulfur-rich protein. With respect to both timing and effectiveness, a tight correlation existed between the onset of resistance and the induction of the WCI genes. Compared with other plant activators, such as 2,6-dichloroisonicotinic acid and salicylic acid, BTH was the most potent inducer of both resistance and gene induction. BTH is being developed commercially as a novel type of plant protection compound that works by inducing the plant's inherent disease resistance mechanisms.
Skeletal muscle plays a central role in the regulation of systemic metabolism during lifespan. With aging, this function is perturbed, initiating multiple chronic diseases. Our knowledge of ...mechanisms responsible for this decline is limited. Glycerophosphocholine phosphodiesterase 1 (Gpcpd1) is a highly abundant muscle enzyme that hydrolyzes glycerophosphocholine (GPC). The physiological functions of Gpcpd1 remain largely unknown. Here we show, in mice, that the Gpcpd1-GPC metabolic pathway is perturbed in aged muscles. Further, muscle-specific, but not liver- or fat-specific, inactivation of Gpcpd1 resulted in severely impaired glucose metabolism. Western-type diets markedly worsened this condition. Mechanistically, Gpcpd1 muscle deficiency resulted in accumulation of GPC, causing an 'aged-like' transcriptomic signature and impaired insulin signaling in young Gpcpd1-deficient muscles. Finally, we report that the muscle GPC levels are markedly altered in both aged humans and patients with type 2 diabetes, displaying a high positive correlation between GPC levels and chronological age. Our findings reveal that the muscle GPCPD1-GPC metabolic pathway has an important role in the regulation of glucose homeostasis and that it is impaired during aging, which may contribute to glucose intolerance in aging.
Background:
Use of acid suppressant medications has increased in both frequency and breadth in recent years. Data have indicated that questionable use of acid suppressants for non-accepted ...indications is common.
Objective:
To assess the indications and prevalence of acid suppressants used by inpatients on admission and at discharge.
Methods:
A retrospective chart review of 213 patients admitted to the University of Michigan Hospital non-critical care general medical service was conducted. Relevant medical history, acid suppressant drug used, and indications were collected from both inpatient medical records and discharge medication lists.
Results:
Of the 213 patients reviewed, 29% were taking acid suppressants prior to admission, with 33% being proton pump inhibitors (PPIs). Once patients were admitted, acid suppressant use increased to 71% (152 of 213), with 84% PPIs, 11% histamine2-receptor antagonists, and 5% combination therapy. Based upon our criteria, only 10% (15 of 152) of those on acid suppressants were found to have an acceptable indication. In patients where any history of gastroesophageal reflux disorder (GERD) was deemed as an acceptable indication (32 other patients), 31% (47 of 152) had an acceptable indication. For the 137 patients with non-accepted indications, 29% had no discernable indication and 38% were prescribed acid suppressants for corticosteroid-associated or stress ulcer prophylaxis. A history of gastrointestinal bleeds or peptic ulcer disease of more than 3 months since initial diagnosis or documented exacerbation of symptoms comprised 8% of the population. The aforementioned group of GERD patients made up 23% of this group. Compared to the 29% of patients taking acid suppressants prior to admission, 54% (115 of 213) of patients were prescribed acid suppressants at discharge. If only recent exacerbations of GERD were deemed as long-term indications, 10% (12 of 115) of these patients were found to have accepted indications. If all GERDs were acceptable long-term indications, 27% (31 of 115) would have met criteria for acceptable outpatient use.
Conclusions:
There is considerable excess usage of acid suppressants in both the inpatient and outpatient settings.
Patients with cystic fibrosis have an increased incidence of hyperoxaluria and calcium oxalate nephrolithiasis. Net intestinal absorption of dietary oxalate results from passive paracellular oxalate ...absorption as modified by oxalate back secretion mediated by the SLC26A6 oxalate transporter. We used mice deficient in the cystic fibrosis transmembrane conductance regulator gene (Cftr) to test the hypothesis that SLC26A6-mediated oxalate secretion is defective in cystic fibrosis. We mounted isolated intestinal tissue from C57BL/6 (wild-type) and Cftr
mice in Ussing chambers and measured transcellular secretion of
Coxalate. Intestinal tissue isolated from Cftr
mice exhibited significantly less transcellular oxalate secretion than intestinal tissue of wild-type mice. However, glucose absorption, another representative intestinal transport process, did not differ in Cftr
tissue. Compared with wild-type mice, Cftr
mice showed reduced expression of SLC26A6 in duodenum by immunofluorescence and Western blot analysis. Furthermore, coexpression of CFTR stimulated SLC26A6-mediated Cl
-oxalate exchange in Xenopus oocytes. In association with the profound defect in intestinal oxalate secretion, Cftr
mice had serum and urine oxalate levels 2.5-fold greater than those of wild-type mice. We conclude that defective intestinal oxalate secretion mediated by SLC26A6 may contribute to the hyperoxaluria observed in this mouse model of cystic fibrosis. Future studies are needed to address whether similar mechanisms contribute to the increased risk for calcium oxalate stone formation observed in patients with cystic fibrosis.
Molecular gene transfer techniques have been used to engineer the fatty acid composition of Brassica rapa and Brassica napus (canola) oil. Stearoyl-acyl carrier protein (stearoyl-ACP) desaturase (EC ...1.14.99.6) catalyzes the first desaturation step in seed oil biosynthesis, converting stearoyl-ACP to oleoyl-ACP. Seed-specific antisense gene constructs of B. rapa stearoyl-ACP desaturase were used to reduce the protein concentration and enzyme activity of stearoyl-ACP desaturase in developing rapeseed embryos during storage lipid biosynthesis. The resulting transgenic plants showed dramatically increased stearate levels in the seeds. A continuous distribution of stearate levels from 2% to 40% was observed in seeds of a transgenic B. napus plant, illustrating the potential to engineer specialized seed oil compositions
This phase III, open-label, randomized, controlled study aimed to evaluate the benefit of adding continuous low-dose oral cyclophosphamide to bortezomib-dexamethasone in patients with primary ...relapsed/refractory multiple myeloma. Patients were randomized 1:1 to receive up to eight 3-week cycles of bortezomib (1.3 mg/m
2
) and dexamethasone (20 mg; VD;
n
= 48) or bortezomib-dexamethasone plus oral cyclophosphamide (50 mg; VCD;
n
= 48). Median time to progression (primary endpoint) was slightly longer in the VD versus VCD group (12.6 vs 9.9 months,
P
= 0.192), and the hazard ratio for disease progression was in favor of VD (hazard ratio = 0.71, 95% confidence interval = 0.43–1.19,
P
= 0.196). The overall response rate was 74% with VD and 70% with VCD. Most adverse events were similar in frequency between arms; however, grade ≥ 3 peripheral neuropathy was more frequent in the VCD versus VD arm (15 vs 4%). Infection rate was higher in the VCD arm (64 vs 52%); however, grade ≥3 infection rates were comparable (19 vs 17%). Further trials are needed to determine whether addition of cyclophosphamide to VD at a different dose/schedule confers clinical benefit. This study was terminated prematurely, with insufficient sample size to adequately compare the arms; the results should, therefore, be considered descriptive. This trial is registered: EudraCT Number 2008-003213-27;
ClinicalTrials.gov
NCT00813150.
Muscle degeneration is the most prevalent cause for frailty and dependency in inherited diseases and ageing. Elucidation of pathophysiological mechanisms, as well as effective treatments for muscle ...diseases, represents an important goal in improving human health. Here, we show that the lipid synthesis enzyme phosphatidylethanolamine cytidyltransferase (PCYT2/ECT) is critical to muscle health. Human deficiency in PCYT2 causes a severe disease with failure to thrive and progressive weakness. pcyt2-mutant zebrafish and muscle-specific Pcyt2-knockout mice recapitulate the participant phenotypes, with failure to thrive, progressive muscle weakness and accelerated ageing. Mechanistically, muscle Pcyt2 deficiency affects cellular bioenergetics and membrane lipid bilayer structure and stability. PCYT2 activity declines in ageing muscles of mice and humans, and adeno-associated virus-based delivery of PCYT2 ameliorates muscle weakness in Pcyt2-knockout and old mice, offering a therapy for individuals with a rare disease and muscle ageing. Thus, PCYT2 plays a fundamental and conserved role in vertebrate muscle health, linking PCYT2 and PCYT2-synthesized lipids to severe muscle dystrophy and ageing.
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