The Dual Arrhenius and Michaelis–Menten kinetics model for decomposition of soil organic matter at hourly to seasonal time scales

Decomposition of soil carbon stocks is one of the largest potential biotic feedbacks to climate change. Models of decomposition of soil organic matter and of soil respiration rely on empirical functions that relate variation in temperature and soil water content to rates of microbial metabolism using soil‐C substrates. Here, we describe a unifying modeling framework to combine the effects of temperature, soil water content, and soluble substrate supply on decomposition of soluble soil‐C substrates using simple functions based on process concepts. The model's backbone is the Michaelis–Menten equation, which describes the relationship between reaction velocity and soluble organic‐C and O₂ substrate concentrations at an enzyme's reactive site, which are determined by diffusivity functions based on soil water content. Temperature sensitivity is simulated by allowing the maximum velocity of the reaction (V_max) to vary according to Arrhenius function. The Dual Arrhenius and Michaelis–Menten kinetics (DAMM) model core was able to predict effectively observations from of laboratory enzyme assays of β‐glucosidase and phenol‐oxidase across a range of substrate concentrations and incubation temperatures. The model also functioned as well or better than purely empirical models for simulating hourly and seasonal soil respiration data from a trenched plot in a deciduous forest at the Harvard Forest, in northeastern United States. The DAMM model demonstrates that enzymatic processes can be intrinsically temperature sensitive, but environmental constrains of substrate supply under soil moisture extremes can prevent that response to temperature from being observed. We discuss how DAMM could serve as a core module that is informed by other modules regarding microbial dynamics and supply of soluble‐C substrates from plant inputs and from desorption of physically stabilized soil‐C pools. Most importantly, it presents a way forward from purely empirical representation of temperature and moisture responses and integrates temperature‐sensitive enzymatic processes with constraints of substrate supply.     

Angiotensin-Converting Enzyme 2 Over-Expression in the Central Nervous System Reduces Angiotensin-II-Mediated Cardiac Hypertrophy

Angiotensin-converting enzyme type 2 (ACE2) has been shown to be an important member of the renin angiotensin system. Previously, we observed that central ACE2 reduces the development of hypertension following chronic angiotensin II (Ang-II) infusion in syn-hACE2 transgenic (SA) mice, in which the human ACE2 transgene is selectively targeted to neurons. To study the physiological consequences of central ACE2 over-expression on cardiac function and cardiac hypertrophy, SA and non-transgenic (NT) mice were infused with Ang-II (600 ng/kg/min, sc) for 14 days, and cardiac function was assessed by echocardiography. Blood pressure (BP), hemodynamic parameters, left ventricle (LV) mass/tibia length, relative ventricle wall thickness (2PW/LVD), cardiomyocyte diameters and collagen deposition were similar (P>0.05) between NT and SA mice during saline infusion. After a 2-week infusion, BP was elevated in NT but not in SA mice. Although ejection fraction and fractional shortening were not altered, Ang-II infusion increased 2PW/LVD compared to saline infusion in NT mice. Interestingly, the 2PW/LVD and LV mass/tibia ratios were significantly lower in SA compared to NT mice at the end of infusion. Moreover, Ang-II infusion significantly increased arterial collagen deposition and cardiomyocytes diameter in NT mice but not in transgenic animals (P<0.05). More importantly, ACE2 over expression significantly reduced the Ang-II-mediated increase in urine norepinephrine levels in SA compared to NT mice. The protective effect of ACE2 appears to involve reductions in Ang-II-mediated hypertension and sympathetic nerve activity.     

Association of Medical Students' Reports of Interactions with the Pharmaceutical and Medical Device Industries and Medical School Policies and Characteristics: A Cross-Sectional Study

Background

Professional societies use metrics to evaluate medical schools'' policies regarding interactions of students and faculty with the pharmaceutical and medical device industries. We compared these metrics and determined which US medical schools'' industry interaction policies were associated with student behaviors.

Methods and Findings

Using survey responses from a national sample of 1,610 US medical students, we compared their reported industry interactions with their schools'' American Medical Student Association (AMSA) PharmFree Scorecard and average Institute on Medicine as a Profession (IMAP) Conflicts of Interest Policy Database score. We used hierarchical logistic regression models to determine the association between policies and students'' gift acceptance, interactions with marketing representatives, and perceived adequacy of faculty–industry separation. We adjusted for year in training, medical school size, and level of US National Institutes of Health (NIH) funding. We used LASSO regression models to identify specific policies associated with the outcomes. We found that IMAP and AMSA scores had similar median values (1.75 [interquartile range 1.50–2.00] versus 1.77 [1.50–2.18], adjusted to compare scores on the same scale). Scores on AMSA and IMAP shared policy dimensions were not closely correlated (gift policies, r = 0.28, 95% CI 0.11–0.44; marketing representative access policies, r = 0.51, 95% CI 0.36–0.63). Students from schools with the most stringent industry interaction policies were less likely to report receiving gifts (AMSA score, odds ratio [OR]: 0.37, 95% CI 0.19–0.72; IMAP score, OR 0.45, 95% CI 0.19–1.04) and less likely to interact with marketing representatives (AMSA score, OR 0.33, 95% CI 0.15–0.69; IMAP score, OR 0.37, 95% CI 0.14–0.95) than students from schools with the lowest ranked policy scores. The association became nonsignificant when fully adjusted for NIH funding level, whereas adjusting for year of education, size of school, and publicly versus privately funded school did not alter the association. Policies limiting gifts, meals, and speaking bureaus were associated with students reporting having not received gifts and having not interacted with marketing representatives. Policy dimensions reflecting the regulation of industry involvement in educational activities (e.g., continuing medical education, travel compensation, and scholarships) were associated with perceived separation between faculty and industry. The study is limited by potential for recall bias and the cross-sectional nature of the survey, as school curricula and industry interaction policies may have changed since the time of the survey administration and study analysis.

Conclusions

As medical schools review policies regulating medical students'' industry interactions, limitations on receipt of gifts and meals and participation of faculty in speaking bureaus should be emphasized, and policy makers should pay greater attention to less research-intensive institutions. Please see later in the article for the Editors'' Summary     

The Sodium-Glucose Co-Transporter 2 Inhibitor Empagliflozin Improves Diabetes-Induced Vascular Dysfunction in the Streptozotocin Diabetes Rat Model by Interfering with Oxidative Stress and Glucotoxicity

Objective

In diabetes, vascular dysfunction is characterized by impaired endothelial function due to increased oxidative stress. Empagliflozin, as a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), offers a novel approach for the treatment of type 2 diabetes by enhancing urinary glucose excretion. The aim of the present study was to test whether treatment with empagliflozin improves endothelial dysfunction in type I diabetic rats via reduction of glucotoxicity and associated vascular oxidative stress.

Methods

Type I diabetes in Wistar rats was induced by an intravenous injection of streptozotocin (60 mg/kg). One week after injection empagliflozin (10 and 30 mg/kg/d) was administered via drinking water for 7 weeks. Vascular function was assessed by isometric tension recording, oxidative stress parameters by chemiluminescence and fluorescence techniques, protein expression by Western blot, mRNA expression by RT-PCR, and islet function by insulin ELISA in serum and immunohistochemical staining of pancreatic tissue. Advanced glycation end products (AGE) signaling was assessed by dot blot analysis and mRNA expression of the AGE-receptor (RAGE).

Results

Treatment with empagliflozin reduced blood glucose levels, normalized endothelial function (aortic rings) and reduced oxidative stress in aortic vessels (dihydroethidium staining) and in blood (phorbol ester/zymosan A-stimulated chemiluminescence) of diabetic rats. Additionally, the pro-inflammatory phenotype and glucotoxicity (AGE/RAGE signaling) in diabetic animals was reversed by SGLT2i therapy.

Conclusions

Empagliflozin improves hyperglycemia and prevents the development of endothelial dysfunction, reduces oxidative stress and improves the metabolic situation in type 1 diabetic rats. These preclinical observations illustrate the therapeutic potential of this new class of antidiabetic drugs.     

Cytologic diagnosis of a metastatic oligodendroglioma in a pleural effusion. A case report

BACKGROUND: Extraneural metastasis of oligodendroglioma is extremely rare and is diagnosed primarily by biopsy or autopsy and very occasionally by fine needle cytologic examination. We report a case of metastatic oligodendroglioma diagnosed by cytologic examination of a pleural effusion. Such a diagnosis has not been reported before. CASE: A 64-year-old woman developed anemia and bilateral pleural effusion 7 years after an operation for an oligodendroglioma over the left frontal lobe. Cytologic examination of the pleural effusion showed aggregates of atypical polygonal cells containing round, hyperchromatic nuclei and scanty, granular cytoplasm in Liu's and Papanicolaou stain and cell blocks. Immunohistochemical staining of the tumor cells revealed a positive reaction for antibodies to glial fibrillary acidic protein, S-100 and Olig2. Pleural biopsy confirmed the cytologic diagnosis of pleural effusion. A pathologic fracture of the right humeral and femoral bones was noted 1 month later, and the specimen also showed infiltrating oligodendroglioma cells in bone tissue. CONCLUSION: To the best of our knowledge, this is the first metastatic oligodendroglioma diagnosed by pleural cytology. Fine needle cytology can provide a reliable and rapid way to detect an extracranial metastatic oligodendroglioma in different organs.     

The influence of cultivation methods on Shewanella oneidensis physiology and proteome expression

High-throughput analyses that are central to microbial systems biology and ecophysiology research benefit from highly homogeneous and physiologically well-defined cell cultures. While attention has focused on the technical variation associated with high-throughput technologies, biological variation introduced as a function of cell cultivation methods has been largely overlooked. This study evaluated the impact of cultivation methods, controlled batch or continuous culture in bioreactors versus shake flasks, on the reproducibility of global proteome measurements in Shewanella oneidensis MR-1. Variability in dissolved oxygen concentration and consumption rate, metabolite profiles, and proteome was greater in shake flask than controlled batch or chemostat cultures. Proteins indicative of suboxic and anaerobic growth (e.g., fumarate reductase and decaheme c-type cytochromes) were more abundant in cells from shake flasks compared to bioreactor cultures, a finding consistent with data demonstrating that “aerobic” flask cultures were O₂ deficient due to poor mass transfer kinetics. The work described herein establishes the necessity of controlled cultivation for ensuring highly reproducible and homogenous microbial cultures. By decreasing cell to cell variability, higher quality samples will allow for the interpretive accuracy necessary for drawing conclusions relevant to microbial systems biology research.     

An apolipoprotein A-V gene SNP is associated with marked hypertriglyceridemia among Asian-American patients

Apolipoprotein A-V (apoA-V) is an important regulator of plasma levels of triglyceride (TG) in mice. In humans, APOA5 genetic variation is associated with TG in several populations. In this study, we determined the effects of the p.185Gly>Cys (c.553G>T; rs2075291) polymorphism on plasma TG levels in subjects of Chinese ancestry living in the United States and in a group of non-Chinese Asian ancestry. The frequency of the less common cysteine allele was 4-fold higher (15.1% vs. 3.7%) in Chinese high-TG subjects compared with a low-TG group (Chi-square = 20.2; P < 0.0001), corresponding with a 4.45 times higher risk of hypertriglyceridemia (95% confidence interval, 2.18-9.07; P < 0.001). These results were replicated in the non-Chinese Asians. Heterozygosity was associated, in the high-TG group, with a doubling of TG (P < 0.001), mainly VLDL TG (P = 0.014). All eleven TT homozygotes had severe hypertriglyceridemia, with mean TG of 2,292 +/- 447 mg/dl. Compared with controls, carriers of the T allele had lower postheparin lipoprotein lipase activity but not hepatic lipase activity. In Asian populations, this common polymorphism can lead to profound adverse effects on lipoprotein profiles, with homozygosity accounting for a significant number of cases of severe hypertriglyceridemia. This specific apoA-V variant has a pronounced effect on TG metabolism, the mechanism of which remains to be elucidated.     

Wdr5 is essential for osteoblast differentiation

Wdr5 is developmentally expressed in osteoblasts and accelerates osteoblast differentiation in vitro and in vivo. To address whether Wdr5 is essential for osteoblast differentiation, plasmid-based small interfering RNAs were used to stably suppress endogenous Wdr5 protein levels in MC3T3-E1 cells. Reduction of endogenous Wdr5 levels markedly inhibited osteoblast differentiation, evidenced by a significant decrease in alkaline phosphatase activity, Runx-2 and osteocalcin mRNAs, and absence of mineralized matrix formation. Wdr5 suppression also resulted in a reduction of histone H3 lysine 4 trimethylation, confirming its critical role in this modification. Because Wdr5 overexpression enhances canonical Wnt signaling in osteoblasts in vivo, the effects of Wdr5 silencing on this pathway were examined. The expression of the canonical Wnt target gene, c-myc, was decreased, whereas that of sfrp2, which is repressed by Wnt signaling, was increased with Wdr5 knockdown. Although only a minimal increase in apoptosis was observed, the antiapoptotic effect of Wnt signaling was also impaired with Wdr5 silencing. The expression of canonical Wnts was significantly decreased with Wdr5 knockdown, resulting in a decrease in nuclear beta-catenin protein levels. Activation of the canonical Wnt signaling pathway did not overcome the effects of Wdr5 knockdown on the expression of Wnt target genes. Chromatin immunoprecipitation demonstrated that Wdr5 is present on the Wnt1 promoter and on canonical Wnt response elements of the c-myc and Runx-2 promoters. These studies demonstrate that Wdr5 suppression interferes with the canonical Wnt signaling pathway at multiple stages and that optimal Wdr5 levels are required for induction of the osteoblast phenotype.