Association between Inflammation and Cardiac Geometry in Chronic Kidney Disease: Findings from the CRIC Study.

Background Left ventricular hypertrophy (LVH) and myocardial contractile dysfunction are independent predictors of mortality in patients with chronic kidney disease (CKD). The association between inflammatory biomarkers and cardiac geometry has not yet been studied in a large cohort of CKD patients with a wide range of kidney function. Methods Plasma levels of interleukin (IL)-1β, IL-1 receptor antagonist (IL-1RA), IL-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, high-sensitivity C-Reactive protein (hs-CRP), fibrinogen and serum albumin were measured in 3,939 Chronic Renal Insufficiency Cohort study participants. Echocardiography was performed according to the recommendations of the American Society of Echocardiography and interpreted at a centralized core laboratory. Results LVH, systolic dysfunction and diastolic dysfunction were present in 52.3%, 11.8% and 76.3% of the study subjects, respectively. In logistic regression analysis adjusted for age, sex, race/ethnicity, diabetic status, current smoking status, systolic blood pressure, urinary albumin- creatinine ratio and estimated glomerular filtration rate, hs-CRP (OR 1.26 [95% CI 1.16, 1.37], p Conclusion In patients with CKD, elevated plasma levels of hs-CRP and IL-6 are associated with LVH and systolic dysfunction

Carbon nanotube-based quantum pump in the presence of superconducting lead

Parametric electron pump through superconductor-carbon-nanotube based molecular devices was investigated. It is found that a dc current, which is assisted by resonant Andreev reflection, can be pumped out from such molecular device by a cyclic variation of two gate voltages near the nanotube. The pumped current can be either positive or negative under different system parameters. Due to the Andreev reflection, the pumped current has the double peak structure around the resonant point. The ratio of pumped current of N-SWNT-S system to that of N-SWNT-N system (I^{NS}/I^N) is found to approach four in the weak pumping regime near the resonance when there is exactly one resonant level at Fermi energy inside the energy gap. Numerical results confirm that in the weak pumping regime the pumped current is proportional to the square of the pumping amplitude V_p, but in the strong pumping regime the pumped current has the linear relation with V_p. Our numerical results also predict that pumped current can be obtained more easily by using zigzag tube than by using armchair tube

Non-adiabatic charge pump: an exact solution

We derived a general and exact expression of current for quantum parametric charge pumps in the non-adiabatic regime at finite pumping frequency and finite driving amplitude. The non-perturbative theory predicts a remarkable plateau structure in the pumped current due to multi-photon assisted processes in a double-barrier quantum well pump involving only a {\it single} pumping potential. It also predicts a current reversal as the resonant level of the pump crosses the Fermi energy of the leads

Bias associated with delayed verification in test accuracy studies: accuracy of tests for endometrial hyperplasia may be much higher than we think!

BACKGROUND: To empirically evaluate bias in estimation of accuracy associated with delay in verification of diagnosis among studies evaluating tests for predicting endometrial hyperplasia. METHODS: Systematic reviews of all published research on accuracy of miniature endometrial biopsy and endometr ial ultrasonography for diagnosing endometrial hyperplasia identified 27 test accuracy studies (2,982 subjects). Of these, 16 had immediate histological verification of diagnosis while 11 had verification delayed > 24 hrs after testing. The effect of delay in verification of diagnosis on estimates of accuracy was evaluated using meta-regression with diagnostic odds ratio (dOR) as the accuracy measure. This analysis was adjusted for study quality and type of test (miniature endometrial biopsy or endometrial ultrasound). RESULTS: Compared to studies with immediate verification of diagnosis (dOR 67.2, 95% CI 21.7–208.8), those with delayed verification (dOR 16.2, 95% CI 8.6–30.5) underestimated the diagnostic accuracy by 74% (95% CI 7%–99%; P value = 0.048). CONCLUSION: Among studies of miniature endometrial biopsy and endometrial ultrasound, diagnostic accuracy is considerably underestimated if there is a delay in histological verification of diagnosis

Successful Inhibition of Tumor Development by Specific Class-3 Semaphorins Is Associated with Expression of Appropriate Semaphorin Receptors by Tumor Cells

The class-3 semaphorins (sema3s) include seven family members. Six of them bind to neuropilin-1 (np1) or neuropilin-2 (np2) receptors or to both, while the seventh, sema3E, binds to the plexin-D1 receptor. Sema3B and sema3F were previously characterized as tumor suppressors and as inhibitors of tumor angiogenesis. To determine if additional class-3 semaphorins such as sema3A, sema3D, sema3E and sema3G possess anti-angiogenic and anti-tumorigenic properties, we expressed the recombinant full length semaphorins in four different tumorigenic cell lines expressing different combinations of class-3 semaphorin receptors. We show for the first time that sema3A, sema3D, sema3E and sema3G can function as potent anti-tumorigenic agents. All the semaphorins we examined were also able to reduce the concentration of tumor associated blood vessels although the potencies of the anti-angiogenic effects varied depending on the tumor cell type. Surprisingly, there was little correlation between the ability to inhibit tumor angiogenesis and their anti-tumorigenic activity. None of the semaphorins inhibited the adhesion of the tumor cells to plastic or fibronectin nor did they modulate the proliferation of tumor cells cultured in cell culture dishes. However, various semaphorins were able to inhibit the formation of soft agar colonies from tumor cells expressing appropriate semaphorin receptors, although in this case too the inhibitory effect was not always correlated with the anti-tumorigenic effect. In contrast, the anti-tumorigenic effect of each of the semaphorins correlated very well with tumor cell expression of specific signal transducing receptors for particular semaphorins. This correlation was not broken even in cases in which the tumor cells expressed significant concentrations of endogenous semaphorins. Our results suggest that combinations of different class-3 semaphorins may be more effective than single semaphorins in cases in which tumor cells express more than one type of semaphorin receptors

Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk

Coding variants represent many of the strongest associations between genotype and phenotype; however, they exhibit interindividual differences in effect, termed 'variable penetrance'. Here, we study how cis-regulatory variation modifies the penetrance of coding variants. Using functional genomic and genetic data from the Genotype-Tissue Expression Project (GTEx), we observed that in the general population, purifying selection has depleted haplotype combinations predicted to increase pathogenic coding variant penetrance. Conversely, in cancer and autism patients, we observed an enrichment of penetrance increasing haplotype configurations for pathogenic variants in disease-implicated genes, providing evidence that regulatory haplotype configuration of coding variants affects disease risk. Finally, we experimentally validated this model by editing a Mendelian single-nucleotide polymorphism (SNP) using CRISPR/Cas9 on distinct expression haplotypes with the transcriptome as a phenotypic readout. Our results demonstrate that joint regulatory and coding variant effects are an important part of the genetic architecture of human traits and contribute to modified penetrance of disease-causing variants.Peer reviewe

Scale-dependent perspectives on the geomorphology and evolution of beachdune systems

Despite widespread recognition that landforms are complex Earth systems with process-response linkages that span temporal scales from seconds to millennia and spatial scales from sand grains to landscapes, research that integrates knowledge across these scales is fairly uncommon. As a result, understanding of geomorphic systems is often scale-constrained due to a host of methodological, logistical, and theoretical factors that limit the scope of how Earth scientists study landforms and broader landscapes. This paper reviews recent advances in understanding of the geomorphology of beach-dune systems derived from over a decade of collaborative research from Prince Edward Island (PEI), Canada. A comprehensive summary of key findings is provided from short-term experiments embedded within a decade-long monitoring program and a multi-decadal reconstruction of coastal landscape change. Specific attention is paid to the challenges of scale integration and the contextual limitations research at specific spatial and/or temporal scales imposes. A conceptual framework is presented that integrates across key scales of investigation in geomorphology and is grounded in classic ideas in Earth surface sciences on the effectiveness of formative events at different scales. The paper uses this framework to organize the review of this body of research in a 'scale aware' way and, thereby, identifies many new advances in knowledge on the form and function of subaerial beach-dune systems. Finally, the paper offers a synopsis of how greater understanding of the complexities at different scales can be used to inform the development of predictive models, especially those at a temporal scale of decades to centuries, which are most relevant to coastal management issues. Models at this (landform) scale require an understanding of controls that exist at both ‘landscape’ and ‘plot’ scales. Landscape scale controls such as sea level change, regional climate, and the underlying geologic framework essentially provide bounding conditions for independent variables such as winds, waves, water levels, and littoral sediment supply. Similarly, an holistic understanding of the range of processes, feedbacks, and linkages at the finer plot scale is required to inform and verify the assumptions that underly the physical modelling of beach-dune interaction at the landform scale