Description: BACKGROUND The cardio-renal interaction occurs via hemodynamic and humoral factors. Noninvasive assessment of renal hemodynamics is currently possible by assessment of renal resistive index (RRI) derived from intrarenal Doppler arterial waveforms as ((peak systolic velocity – end-diastolic velocity)/peak systolic velocity). Limited information is available regarding the relationship between RRI and cardiac hemodynamics. We investigated these associations in randomly recruited subjects from a general population. METHODS In 171 participants (48.5% women; mean age, 52.2 years), using pulsed wave Doppler, we measured RRI (mean, 0.60) and left ventricular outflow tract (LVOT) and transmitral (E and A) blood flow peak velocities and its velocity time integrals (VTI). Using carotid applanation tonometry, we measured central pulse pressure and arterial stiffness indexes such as augmentation pressure and carotid–femoral pulse wave velocity. RESULTS In stepwise regression analysis, RRI independently and significantly increased with female sex, age, body weight, brachial pulse pressure, and use of β-blockers, whereas it decreased with body height and mean arterial pressure. In multivariable-adjusted models with central pulse pressure and arterial stiffness indexes as the explanatory variables, we observed a significant and positive correlation of RRI only with central pulse pressure ( P 〈 0.0001). Among the Doppler indexes of left ventricular blood flow, RRI was significantly and positively associated with LVOT and E peak velocities ( P ≤ 0.012) and VTIs ( P ≤ 0.010). CONCLUSIONS We demonstrated that in unselected subjects RRI was significantly associated with central pulse pressure and left ventricular systolic and diastolic Doppler blood flow indexes. Our findings imply that in addition to the anthropometric characteristics, cardiac hemodynamic factors influence the intrarenal arterial Doppler waveform patterns.

Description: We analyse continuous recordings from 23 broadband seismic stations near Alberta, the southwestern sector of the Western Canada Sedimentary Basin. Noise correlation tomo-graphy based on vertical-component seismograms reveals below-average shear velocities at shallow and middle crustal depths in central Alberta, spanning across Proterozoic accreted terranes and Archean microcontinents. This observation likely results from extensive plate convergence and crustal melting during the Proterozoic eon. The overall correlation between the crustal velocities and presumed basement domains is lower than expected, however. In the lower crust, the main pattern of shear velocities is relatively concordant with the reported domain boundaries and key Precambrian structures appear to be intact. The shear velocities beneath the Loverna Block, the largest constituent of the Hearne craton, are 10 per cent higher than the regional average. This prominent northeast striking seismic anomaly is moderately correlated with the regional heat flow and potentially represents the remnant core of the Archean Hearne province. The associated high velocities extend into the western part of the Medicine Hat Block, a possible Archean microcontinent with a debatable origin, and contribute to a strong east–west structural gradient in the lower crust. The presence and the continuity of this anomalous structure imply extensive communications among the various basement domains in southern Alberta during the assembly of the North American continent.

Description: Telomeres maintain chromosomal stability and integrity and are crucial in carcinogenesis. Telomere length is implicated in multiple cancer risk, but the results are conflicting. Genome-wide association studies have identified several genetic loci associated with telomere length in Caucasians. However, the roles of telomere length and related variants on gastric cancer development are largely unknown. We conducted a case–control study including 1136 gastric cancer cases and 1012 controls to evaluate the associations between telomere length, eight telomere length-related variants identified in Caucasians and gastric cancer risk in Chinese population. We observed an obvious U-shaped association between telomere length and gastric cancer risk ( P 〈 0.001), with odds ratios (95% confidence intervals) being 3.81 (2.82–5.13), 1.65 (1.21–2.26), 1.28 (0.93–1.77) and 1.78 (1.30–2.44) for individuals in the first (the shortest), second, third and fifth (the longest) quintile as compared with those in the fourth quintile as reference group. The weighted genetic score (WGS) of eight variants was significantly associated with telomere length ( P 〈 0.001), and in particular, the G allele of rs2736100 in TERT at 5p15.33 exhibited a significant association with long telomeres ( P = 0.047). However, we did not observe significant associations between these genetic variants and gastric cancer risk for both single-variant and WGS analyses. These findings suggest that either short or extreme long telomeres may be risk factor for gastric cancer. Genetic variants identified in Caucasians may also contribute to the variation of telomere length in Chinese but seems not to gastric cancer susceptibility.

Description: Aims Nebulette is a 109 kDa modular protein localized in the sarcomeric Z-line of the heart. In vitro studies have suggested a role of nebulette in stabilizing the thin filament, and missense mutations in the nebulette gene were recently shown to be causative for dilated cardiomyopathy and endocardial fibroelastosis in human and mice. However, the role of nebulette in vivo has remained elusive. To provide insights into the function of nebulette in vivo , we generated and studied nebulette-deficient ( nebl – /– ) mice. Methods and results Nebl – /– mice were generated by replacement of exon 1 by Cre under the control of the endogenous nebulette promoter, allowing for lineage analysis using the ROSA26 Cre reporter strain. This revealed specific expression of nebulette in the heart, consistent with in situ hybridization results. Nebl – /– mice exhibited normal cardiac function both under basal conditions and in response to transaortic constriction as assessed by echocardiography and haemodynamic analyses. Furthermore, histological, IF, and western blot analysis showed no cardiac abnormalities in nebl – /– mice up to 8 months of age. In contrast, transmission electron microscopy showed Z-line widening starting from 5 months of age, suggesting that nebulette is important for the integrity of the Z-line. Furthermore, up-regulation of cardiac stress responsive genes suggests the presence of chronic cardiac stress in nebl – /– mice. Conclusion Nebulette is dispensable for normal cardiac function, although Z-line widening and up-regulation of cardiac stress markers were found in nebl – /– heart. These results suggest that the nebulette disease causing mutations have dominant gain-of-function effects.

Description: Most of current gene expression signatures for cancer prognosis are based on risk scores, usually calculated as some summaries of expression levels of the signature genes, whose applications require presetting risk score thresholds and data normalization. In this study, we demonstrate the critical limitations of such type of signatures that the risk scores of samples will change greatly when they are normalized together with different samples, which would induce spurious risk classification and difficulty in clinical settings, and the risk scores of independent samples are incomparable if data normalization is not adopted. To overcome these limitations, we propose a rank-based method to extract a prognostic gene pair signature for overall survival of stage I non-small-cell lung cancer. The prognostic gene pair signature is verified in three integrated data sets detected by different laboratories with different microarray platforms. We conclude that, different from the type of signatures based on risk scores summarized from gene expression levels, the rank-based signatures could be robustly applied at the individualized level to independent clinical samples assessed in different laboratories.

Description: Actin-like MreB paralogs play important roles in cell shape maintenance, cell wall synthesis and the regulation of the D,L-endopeptidases, CwlO and LytE. The gram-positive bacteria, Bacillus amyloliquefaciens LL3, is a poly--glutamic acid (-PGA) producing strain that contains three MreB paralogs: MreB, Mbl and MreBH. In B. amyloliquefaciens , CwlO and LytE can degrade -PGA. In this study, we aimed to test the hypothesis that modulating transcript levels of MreB paralogs would alter the synthesis and degradation of -PGA. The results showed that overexpression or inhibition of MreB, Mbl or MreBH had distinct effects on cell morphology and the molecular weight of the -PGA products. In fermentation medium, cells of mreB inhibition mutant were 50.2% longer than LL3, and the -PGA titer increased by 55.7%. However, changing the expression level of mbl showed only slight effects on the morphology, -PGA molecular weight and titer. In the mreBH inhibition mutant, -PGA production and its molecular weight increased by 56.7% and 19.4%, respectively. These results confirmed our hypothesis that suppressing the expression of MreB paralogs might reduce -PGA degradation, and that improving the cell size could strengthen -PGA synthesis. This is the first report of enhanced -PGA production via suppression of actin-like MreB paralogs.

Description: Clostridium acetobutylicum is an industrially important Gram-positive organism, which is capable of producing economically important chemicals in the ABE (Acetone, Butanol and Ethanol) fermentation process. Renewed interests in the ABE process necessitate the availability of additional genetics tools to facilitate the derivation of a greater understanding of the underlying metabolic and regulatory control processes in operation through forward genetic strategies. In this study, a xylose inducible, mariner -based, transposon system was developed and shown to allow high-efficient random mutagenesis in the model strain ATCC 824. Of the thiamphenicol resistant colonies obtained, 91.9% were shown to be due to successful transposition of the catP- based mini-transposon element. Phenotypic screening of 200 transposon clones revealed a sporulation-defective clone with an insertion in spo0A , thereby demonstrating that this inducible transposon system can be used for forward genetic studies in C. acetobutylicum .

Description: Knowledge of the mantle reflectivity structure is highly dependent on our ability to efficiently extract, and properly interpret, small seismic arrivals. Among the various data types and techniques, long-period SS/PP precursors and high-frequency receiver functions are routinely utilized to increase the confidence of the recovered mantle stratifications at distinct spatial scales. However, low resolution and a complex Fresnel zone are glaring weaknesses of SS precursors, while over-reliance on receiver distribution is a formidable challenge for the analysis of converted waves from oceanic regions. A promising high frequency alternative to receiver functions is P ' P ' precursors, which are capable of resolving mantle structures at vertical and lateral resolution of ~5 and ~200 km, respectively, owing to their spectral content, shallow angle of incidence and near-symmetric Fresnel zones. This study presents a novel processing method for both SS (or PP) and P ' P ' precursors based on deconvolution, stacking, Radon transform and depth migration. A suite of synthetic tests is performed to quantify the fidelity and stability of this method under different data conditions. Our multiresolution survey of the mantle at targeted areas near Nazca-South America subduction zone reveal both olivine and garnet related transitions at depths below 400 km. We attribute a depressed 660 to thermal variations, whereas compositional variations atop the upper-mantle transition zone are needed to explain the diminished or highly complex reflected/scattered signals from the 410 km discontinuity. We also observe prominent P ' P ' reflections within the transition zone, and the anomalous amplitudes near the plate boundary zone indicate a sharp (~10 km thick) transition that likely resonates with the frequency content of P ' P ' precursors. The migration of SS precursors in this study shows no evidence of split 660 reflections, but potential majorite–ilmenite (590–640 km) and ilmenite–perovskite transitions (740–750 km) are identified based on similarly processed high-frequency P ' P ' precursors. Additional findings of severely scattered energy in the lithosphere and distinct lower mantle reflections at ~800 km could be potentially important but require further verifications. Overall, our improved imaging methods and the strong sensitivity of P ' P ' precursors to the existence, depth, sharpness and strength of reflective structures offer significant future promise for the understanding of mantle mineralogy and dynamics.

Description: Arrhythmogenic right ventricular cardiomyopathy (ARVC) termed a ‘disease of the desmosome’ is an inherited cardiomyopathy that recently underwent reclassification owing to the identification of left-dominant and biventricular disease forms. Homozygous loss-of-function mutations in the desmosomal component, desmoplakin, are found in patients exhibiting a biventricular form of ARVC; however, no models recapitulate the postnatal hallmarks of the disease as seen in these patients. To gain insights into the homozygous loss-of-function effects of desmoplakin in the heart, we generated cardiomyocyte-specific desmoplakin-deficient mice (DSP-cKO) using ventricular myosin light chain-2-Cre mice. Homozygous DSP-cKO mice are viable but display early ultrastructural defects in desmosomal integrity leading to a cardiomyopathy reminiscent of a biventricular form of ARVC, which includes cell death and fibro-fatty replacement within the ventricle leading to biventricular dysfunction, failure and premature death. DSP-cKO mice also exhibited ventricular arrhythmias that are exacerbated with exercise and catecholamine stimulation. Furthermore, DSP-cKO hearts exhibited right ventricular conduction defects associated with loss of connexin 40 expression and electrical wavefront propagation defects associated with loss of connexin 43 expression. Dose-dependent assessment of the effects of loss of desmoplakin in neonatal ventricular cardiomyocytes revealed primary loss of connexin 43 levels, phosphorylation and function independent of the molecular dissociation of the mechanical junction complex and fibro-fatty manifestation associated with ARVC, suggesting a role for desmoplakin as a primary stabilizer of connexin integrity. In summary, we provide evidence for a novel mouse model, which is reminiscent of the postnatal onset of ARVC while highlighting mechanisms underlying a biventricular form of human ARVC.