Understanding how community assembly processes drive biodiversity patterns is a central goal of community ecology. While it is generally accepted that ecological communities are assembled by both ...stochastic and deterministic processes, quantifying their relative importance remains challenging. Few studies have investigated how the relative importance of stochastic and deterministic community assembly processes vary among taxa and along gradients of habitat degradation. Using data on 1645 arthropod species across seven taxonomic groups in Malaysian Borneo, we quantified the importance of ecological stochasticity and of a suite of community assembly processes across a gradient of logging intensity. The relationship between logging and community assembly varied depending on the specific combination of taxa and stochasticity metric used, but, in general, the processes that govern invertebrate community assembly were remarkably robust to changes in land use intensity.
Transmembrane Protein 41B (TMEM41B) and Vacuole Membrane Protein 1 (VMP1) are two ER-associated lipid scramblases that play a role in autophagosome formation and cellular lipid metabolism. TMEM41B is ...also a recently validated host factor required by flaviviruses and coronaviruses. However, the exact underlying mechanism of TMEM41B in promoting viral infections remains an open question. Here, we validated that both TMEM41B and VMP1 are essential host dependency factors for all four serotypes of dengue virus (DENV) and human coronavirus OC43 (HCoV-OC43), but not chikungunya virus (CHIKV). While HCoV-OC43 failed to replicate entirely in both TMEM41B- and VMP1-deficient cells, we detected diminished levels of DENV infections in these cell lines, which were accompanied by upregulation of the innate immune dsRNA sensors, RIG-I and MDA5. Nonetheless, this upregulation did not correspondingly induce the downstream effector TBK1 activation and Interferon-beta expression. Despite low levels of DENV replication, classical DENV replication organelles were undetectable in the infected TMEM41B-deficient cells, suggesting that the upregulation of the dsRNA sensors is likely a consequence of aberrant viral replication rather than a causal factor for reduced DENV infection. Intriguingly, we uncovered that the inhibitory effect of TMEM41B deficiency on DENV replication, but not HCoV-OC43, can be partially reversed using exogenous fatty acid supplements. In contrast, VMP1 deficiency cannot be rescued using the metabolite treatment. In line with the observed phenotypes, we found that both TMEM41B- and VMP1-deficient cells harbor higher levels of compromised mitochondria, especially in VMP1 deficiency which results in severe dysregulations of mitochondrial beta-oxidation. Using a metabolomic profiling approach, we revealed distinctive global dysregulations of the cellular metabolome, particularly lipidome, in TMEM41B- and VMP1-deficient cells. Our findings highlight a central role for TMEM41B and VMP1 in modulating multiple cellular pathways, including lipid mobilization, mitochondrial beta-oxidation, and global metabolic regulations, to facilitate the replication of flaviviruses and coronaviruses.
•Tai Chi is a safe and feasible exercise intervention for Chinese adults with metabolic syndrome.•A 3-month Tai Chi intervention was effective in reducing systolic blood pressure in Chinese adults ...with metabolic syndrome.•The potential benefits of Tai Chi in reducing cardiometabolic risk factors suggest the need for a full-scale randomized controlled trial.
To determine the feasibility, acceptability and effects of a 12-week Tai Chi exercise program on cardiometabolic risk factors and quality of life in community-dwelling Chinese adults with metabolic syndrome.
A single blind, pilot randomized controlled trial.
A general outpatient clinic of a community-based hospital in Hong Kong.
Ethnic Chinese, 18 years and older, who had at least three of the five criteria of metabolic syndrome defined by the National Cholesterol Education– Adult Treatment Panel III.
The Tai Chi group attended a 1 -h Tai Chi class, twice a week for 12 weeks, plus 30-minutes home practice three-times per week. The control group maintained their usual daily activities.
Primary outcomes were feasibility and acceptability of the Tai Chi intervention. Secondary outcome measures were cardiometabolic risk factors, quality of life, stress and Tai Chi exercise self-efficacy.
Study retention rate was 65% (n = 35). Overall satisfaction of completers with the Tai Chi intervention was 4.5 ± 0.63 (possible range = 1–5). When compared to controls, the Tai Chi group had significantly lower systolic blood pressure (p = 0.037) at 12-weeks. Significant within group changes for the Tai Chi group included lower diastolic blood pressure (p = 0.015), higher fasting blood glucose (p = 0.009), higher waist circumference (females only, p = 0.007), and better perceived mental health (p = 0.046); while controls had significantly higher fasting blood glucose (p = 0.031), and higher waist circumference (females only, p = 0.003).
The study intervention was feasible and acceptable for Chinese adults with metabolic syndrome. While not powered to find statistically significant differences, positive and negative changes were observed in some cardiometabolic risk factors and quality of life. Further investigation with a larger sample size and longer study period is needed to explore potential environmental factors that may have influenced the study results.
22q11.2 Deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans, estimated to affect up to 1 in 2,000 live births. Major features of this multisystem condition include ...congenital anomalies, developmental delay, and an array of early- and later-onset medical and psychiatric disorders. Advances in pediatric care ensure a growing population of adults with 22q11.2DS. Informed by an international panel of multidisciplinary experts and a comprehensive review of the existing literature concerning adults, we present the first set of guidelines focused on managing the neuropsychiatric, endocrine, cardiovascular, reproductive, psychosocial, genetic counseling, and other issues that are the focus of attention in adults with 22q11.2DS. We propose practical strategies for the recognition, evaluation, surveillance, and management of the associated morbidities.Genet Med 17 8, 599-609.
A number of genes in the 9q34.11 region may be haploinsufficient. However, studies analyzing genotype–phenotype correlations of deletions encompassing multiple dosage-sensitive genes in the region ...are lacking.
We mapped breakpoints of 10 patients with 9q34.11 deletions using high-resolution 9q34-specific array comparative genomic hybridization (CGH) to determine deletion size and gene content.
The 9q34.11 deletions range in size from 67kb to 2.8Mb. Six patients exhibit intellectual disability and share a common deleted region including STXBP1; four manifest variable epilepsy. In five subjects, deletions include SPTAN1, previously associated with early infantile epileptic encephalopathy, infantile spasms, intellectual disability, and hypomyelination. In four patients, the deletion includes endoglin (ENG), causative of hereditary hemorrhagic telangiectasia. Finally, in four patients, deletions involve TOR1A, of which molecular defects lead to early-onset primary dystonia. Ninety-four other RefSeq genes also map to the genomic intervals investigated.
STXBP1 haploinsufficiency results in progressive encephalopathy characterized by intellectual disability and may be accompanied by epilepsy, movement disorders, and autism. We propose that 9q34.11 genomic deletions involving ENG, TOR1A, STXBP1, and SPTAN1 are responsible for multisystemic vascular dysplasia, early-onset primary dystonia, epilepsy, and intellectual disability, therefore revealing cis-genetic effects leading to complex phenotypes.
Genet Med 2012:14(10):868–876
l-asparaginase (ASNase) is a metabolism-targeted anti-neoplastic agent used to treat acute lymphoblastic leukemia (ALL). ASNase's anticancer activity results from the enzymatic depletion of ...asparagine (Asn) and glutamine (Gln), which are converted to aspartic acid (Asp) and glutamic acid (Glu), respectively, in the blood. Unfortunately, accurate assessment of the in vivo pharmacodynamics (PD) of ASNase is challenging because of the following reasons: (i) ASNase is resilient to deactivation; (ii) ASNase catalytic efficiency is very high; and (iii) the PD markers Asn and Gln are depleted ex vivo in blood samples containing ASNase. To address those issues and facilitate longitudinal studies in individual mice for ASNase PD studies, we present here a new LC-MS/MS bioanalytical method that incorporates rapid quenching of ASNase for measurement of Asn, Asp, Gln, and Glu in just 10 µL of whole blood, with limits of detection (s:n ≥ 10:1) estimated to be 2.3, 3.5, 0.8, and 0.5 µM, respectively. We tested the suitability of the method in a 5-day, longitudinal PD study in mice and found the method to be simple to perform with sufficient accuracy and precision for whole blood measurements. Overall, the method increases the density of data that can be acquired from a single animal and will facilitate optimization of novel ASNase treatment regimens and/or the development of new ASNase variants with desired kinetic properties.
L-asparaginase (L-ASP) is an enzyme-drug that has been used for decades to treat acute lymphoblastic leukemia (ALL). The red blood cell (RBC)-encapsulated L-ASP product GRASPA (eryaspase) was ...introduced recently with the goal of reducing L-ASP side effects without compromising efficacy. We previously showed in a Phase 2/3 trial that none of the patients treated with GRASPA had evidence of allergic reactions during induction compared to 46% of patients treated with non-encapsulated L-ASP (Baruchel et al., ASH, 2015). Similarly, evidence of pancreatic or hepatic toxicities were substantially lower with GRASPA compared to native L-ASP. Hence, GRASPA exhibits a clear benefit over L-ASP in terms of toxicity profile.
The next critical question is whether GRASPA can maintain asparagine depletion. Since plasma asparagine must be transported into the RBC to be degraded by GRASPA, the RBC membrane could limit the efficacy of GRASPA. Therefore, we sought to characterize the transport and degradation of amino acids between the plasma and RBC cytoplasm in the presence of L-ASP or GRASPA. To that end, we used a bioanalytical method for the simultaneous analysis of the metabolites asparagine, aspartic acid, glutamine, and glutamic acid. Notably, the method completely quenches L-ASP and GRASPA and uses liquid chromatography-tandem mass spectrometry (LC-MS/MS) to achieve high sensitivity, accuracy, and precision. The method also involves correction for ex vivo (post-sampling) depletion of target amino acids, which occurs, for example, during centrifugation of whole blood to separate RBCs and plasma. Specifically, we added two stable isotope-labeled amino acids, 13C4-asparagine and 13C5-glutamine, to the sample at the point of collection. After centrifugation, samples were quenched by addition of 10% formic acid. Concentrations of all 12C- amino acids and their 13C- counterparts were then determined by LC-MS/MS. The difference between the nominal concentrations of the 13C amino acid substrates and their L-ASP-generated products were used to correct for the actual concentrations of the 12C amino acids. In that manner, measuring ex vivo conversion of 13C4-asparagine to 13C4-aspartate and conversion of 13C5-glutamine to 13C5-glutamate provided correction factors to calculate the original concentrations of the endogenous metabolites (unlabeled asparagine and glutamine) present in the sample at the time of collection.
In whole blood test tube reactions containing L-ASP or GRASPA at matched overall asparaginase activities, the glutaminase activity of GRASPA was 10-fold lower than that of L-ASP, with initial rates of approximately 0.8 µM/min and 8.0 µM/min, respectively. Therefore, GRASPA exhibits significantly decreased glutaminase activity relative to L-ASP, resulting in an approximately 10-fold increase in selectivity for asparagine over glutamine, which may explain the observed decrease in frequency of adverse events in clinical trials with GRASPA compared to L-ASP. Notably, in the presence of GRASPA, asparagine was rapidly and extensively converted to aspartic acid inside the RBC of GRASPA, whereas no aspartic acid accumulated in the RBC following treatment of whole blood with L-ASP.
In conclusion, the RBC membrane of GRASPA imbues L-ASP with improved target selectivity, which may explain the better toxicity profile of GRASPA. Altered target selectivity has been added to a growing list of beneficial properties of the RBC membrane, including improved half-life and decreased immunogenicity.
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Lorenzi:Erytech Pharma: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties: NIH-held patent related to L-asparaginase. Weinstein:NIH: Patents & Royalties: patent related to L-asparaginase. Swart:Erytech Pharma: Employment, Membership on an entity’s Board of Directors or advisory committees. El-Hariry:Erytech Pharma: Employment.
From the year 2006 to 2008, 69 patients of symptomatic osteoarthritis of the knees were divided randomly and entered into three non-operative treatment protocols. It included 4 weeks of ...pharmacological treatment followed by 4 weeks of specific treatments (physiotherapy, acupuncture, and combined). The pretreatment and post-treatment physical and functional statuses were evaluated. Their body mass index (BMI) was measured. The patients with below-normal BMI did not benefit from all the three treatment protocols. However, all other groups of increased BMI did benefit from all three treatment protocols in terms of pain score, analgesic sparing, and knee scores.
由2006至2008年間，有69名膝關節退化性骨關節炎的患者，接受非手術治療。病人被隨機分為三組作非手術特定的治療，這項研究涉及以4週藥物治療後 再加上4週特定的治療方法: 乙酰氨基酚,物理治療及電針等。記錄他們的身體質量指數 (BMI), 治療開始和結束時的生理與功能狀況，並在第12個星期跟進評估。本研究發現，低於正常BMI的病人對所有三個治療方案並沒有獲益，但所有高於正常BMI的病人對三種治療方案皆有獲益，包括疼痛的強度分數、鎮痛藥物遺餘數量和膝關節分數等。
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