STAG2 Promotes Error Correction in Mitosis by Regulating Kinetochore–Microtubule Attachments

Mutations in the STAG2 gene are present in ∼20% of tumors from different tissues of origin. STAG2 encodes a subunit of the cohesin complex, and tumors with loss-of-function mutations are usually aneuploid and display elevated frequencies of lagging chromosomes during anaphase. Lagging chromosomes are a hallmark of chromosomal instability (CIN) arising from persistent errors in kinetochore-microtubule (kMT) attachment. To determine whether the loss of STAG2 increases the rate of formation of kMT attachment errors or decreases the rate of their correction, we examined mitosis in STAG2-deficient cells. STAG2 depletion does not impair bipolar spindle formation or delay mitotic progression. Instead, loss of STAG2 permits excessive centromere stretch along with hyperstabilization of kMT attachments. STAG2-deficient cells display mislocalization of Bub1 kinase, Bub3 and the chromosome passenger complex. Importantly, strategically destabilizing kMT attachments in tumor cells harboring STAG2 mutations by overexpression of the microtubule-destabilizing enzymes MCAK (also known as KIF2C) and Kif2B decreased the rate of lagging chromosomes and reduced the rate of chromosome missegregation. These data demonstrate that STAG2 promotes the correction of kMT attachment errors to ensure faithful chromosome segregation during mitosis

The epithelial sodium channel in inflammation and blood pressure modulation

A major regulator of blood pressure and volume homeostasis in the kidney is the epithelial sodium channel (ENaC). ENaC is composed of alpha(α)/beta(β)/gamma(γ) or delta(δ)/beta(β)/gamma(γ) subunits. The δ subunit is functional in the guinea pig, but not in routinely used experimental rodent models including rat or mouse, and thus remains the least understood of the four subunits. While the δ subunit is poorly expressed in the human kidney, we recently found that its gene variants are associated with blood pressure and kidney function. The δ subunit is expressed in the human vasculature where it may influence vascular function. Moreover, we recently found that the δ subunit is also expressed human antigen presenting cells (APCs). Our studies indicate that extracellular Na+ enters APCs via ENaC leading to inflammation and salt-induced hypertension. In this review, we highlight recent findings on the role of extra-renal ENaC in inflammation, vascular dysfunction, and blood pressure modulation. Targeting extra-renal ENaC may provide new drug therapies for salt-induced hypertension

State and parameter estimation for model-based retinal laser treatment

We present an approach for state and parameter estimation in retinal laser treatment by a novel setup where both measurement and heating is performed by a single laser. In this medical application, the temperature that is induced by the laser in the patient's eye is critical for a successful and safe treatment. To this end, we pursue a model-based approach using a model given by a heat diffusion equation on a cylindrical domain, where the source term is given by the absorbed laser power. The model is parametric in the sense that it involves an absorption coefficient, which depends on the treatment spot and plays a central role in the input-output behavior of the system. After discretization, we apply a particularly suited parametric model order reduction to ensure real-time tractability while retaining parameter dependence. We augment known state estimation techniques, i.e., extended Kalman filtering and moving horizon estimation, with parameter estimation to estimate the absorption coefficient and the current state of the system. Eventually, we show first results for simulated and experimental data from porcine eyes. We find that, regarding convergence speed, the moving horizon estimation slightly outperforms the extended Kalman filter on measurement data in terms of parameter and state estimation, however, on simulated data the results are very similar

Towards model-based temperature-control for retinal laser therapies

Sophisticated control designs for retinal laser therapies, such as model predictive control, allow for safer treatment and a uniform outcome irrespective of spatially varying parameters such as the absorption coefficient. To enable model-based control, the internal states and unknown parameters need to be estimated, which can be done using non-invasive temperature measurements. We present experimental results for joint state and parameter estimation using an extended Kalman filter and a moving horizon estimator. The experiments were conducted on ex vivo porcine eye's explants

Association Between Hypocholesterolemia and Mortality in Critically Ill Patients With Sepsis: A Systematic Review and Meta-Analysis

OBJECTIVE: To ascertain the association between cholesterol and triglyceride levels on ICU admission and mortality in patients with sepsis. DATA SOURCES: Systematic review and meta-analysis of published studies on PubMed and Embase. STUDY SELECTION: All observational studies reporting ICU admission cholesterol and triglyceride levels in critically ill patients with sepsis were included. Authors were contacted for further data. DATA EXTRACTION: Eighteen observational studies were identified, including 1,283 patients with a crude overall mortality of 33.3%. Data were assessed using Revman (Version 5.1, Cochrane Collaboration, Oxford, United Kingdom) and presented as mean difference (MD) with 95% CIs, p values, and I2 values. DATA SYNTHESIS: Admission levels of total cholesterol (17 studies, 1,204 patients; MD = 0.52 mmol/L [0.27–0.77 mmol/L]; p < 0.001; I2 = 91%), high-density lipoprotein (HDL)-cholesterol (14 studies, 991 patients; MD = 0.08 mmol/L [0.01–0.15 mmol/L]; p = 0.02; I2 = 61%), and low-density lipoprotein (LDL) cholesterol (15 studies, 1,017 patients; MD = 0.18 mmol/L [0.04–0.32 mmol/L]; p = 0.01; I2 = 71%) were significantly lower in eventual nonsurvivors compared with survivors. No association was seen between admission triglyceride levels and mortality (15 studies, 1,070 patients; MD = 0.00 mmol/L [–0.16 to 0.15 mmol/L]; p = –0.95; I2 = 79%). CONCLUSIONS: Mortality was associated with lower levels of total cholesterol, HDL-cholesterol, and LDL-cholesterol, but not triglyceride levels, in patients admitted to ICU with sepsis. The impact of cholesterol replacement on patient outcomes in sepsis, particularly in at-risk groups, merits investigation. KEYWORDS: cholesterol levels; intensive care unit; lipids; sepsis; triglyceride

Modeling complex genetic and environmental influences on comorbid bipolar disorder with tobacco use disorder

Abstract Background Comorbidity of psychiatric and substance use disorders represents a significant complication in the clinical course of both disorders. Bipolar Disorder (BD) is a psychiatric disorder characterized by severe mood swings, ranging from mania to depression, and up to a 70% rate of comorbid Tobacco Use Disorder (TUD). We found epidemiological evidence consistent with a common underlying etiology for BD and TUD, as well as evidence of both genetic and environmental influences on BD and TUD. Therefore, we hypothesized a common underlying genetic etiology, interacting with nicotine exposure, influencing susceptibility to both BD and TUD. Methods Using meta-analysis, we compared TUD rates for BD patients and the general population. We identified candidate genes showing statistically significant, replicated, evidence of association with both BD and TUD. We assessed commonality among these candidate genes and hypothesized broader, multi-gene network influences on the comorbidity. Using Fisher Exact tests we tested our hypothesized genetic networks for association with the comorbidity, then compared the inferences drawn with those derived from the commonality assessment. Finally, we prioritized candidate SNPs for validation. Results We estimate risk for TUD among BD patients at 2.4 times that of the general population. We found three candidate genes associated with both BD and TUD (COMT, SLC6A3, and SLC6A4) and commonality analysis suggests that these genes interact in predisposing psychiatric and substance use disorders. We identified a 69 gene network that influences neurotransmitter signaling and shows significant over-representation of genes associated with BD and TUD, as well as genes differentially expressed with exposure to tobacco smoke. Twenty four of these genes are known drug targets. Conclusions This work highlights novel bioinformatics resources and demonstrates the effectiveness of using an integrated bioinformatics approach to improve our understanding of complex disease etiology. We illustrate the development and testing of hypotheses for a comorbidity predisposed by both genetic and environmental influences. Consistent with our hypothesis, the selected network models multiple interacting genetic influences on comorbid BD with TUD, as well as the environmental influence of nicotine. This network nominates candidate genes for validation and drug testing, and we offer a panel of SNPs prioritized for follow-up.http://deepblue.lib.umich.edu/bitstream/2027.42/112449/1/12881_2009_Article_575.pd

Hyaluronan Export through Plasma Membranes Depends on Concurrent K+ Efflux by Kir Channels

Hyaluronan is synthesized within the cytoplasm and exported into the extracellular matrix through the cell membrane of fibroblasts by the MRP5 transporter. In order to meet the law of electroneutrality, a cation is required to neutralize the emerging negative hyaluronan charges. As we previously observed an inhibiting of hyaluronan export by inhibitors of K+ channels, hyaluronan export was now analysed by simultaneously measuring membrane potential in the presence of drugs. This was done by both hyaluronan import into inside-out vesicles and by inhibition with antisense siRNA. Hyaluronan export from fibroblast was particularly inhibited by glibenclamide, ropivacain and BaCl2 which all belong to ATP-sensitive inwardly-rectifying Kir channel inhibitors. Import of hyaluronan into vesicles was activated by 150 mM KCl and this activation was abolished by ATP. siRNA for the K+ channels Kir3.4 and Kir6.2 inhibited hyaluronan export. Collectively, these results indicated that hyaluronan export depends on concurrent K+ efflux