Intraluminal Pressure Modulates Vascular Contractility of Perfused Mesenteric Resistance Arteries: Altered Response in Hypertension

Intraluminal pressure may affect vascular contractility in both normotension and hypertension. To test this hypothesis, we studied mesenteric resistance arteries from normotensive humans as well as normotensive (WKY) and spontaneously hypertensive (SHR) rats (internal diameter 214 ± 27, 201 ± 6, and 172 ± 6 μm, mean ± SEM at 10 mm Hg). Vessels were mounted on glass cannulas and perfused in organ chambers filled with buffer solution at intraluminal pressures of 10 to 120 mm Hg; vasomotion was measured using a video dimension analyzer. Under baseline conditions (10 mm Hg), wall thickness was 36 ± 4 μm in humans, 32 ± 4 μm in WKY, and 47 ± 2 μm in SHR (P < .001). With increasing pressure, the diameter of human vessels increased up to 25 mm Hg and remained constant at higher pressures. In contrast, resistance arteries of normotensive and hypertensive rats exhibited an almost linear increase in diameter over the whole pressure range. In SHR, the pressure-diameter relationship was much flatter than that of WKY, indicating reduced compliance. In human arteries, the contraction to KCl was maximal at 25 mm Hg and averaged 40 ± 6%. Both above and below 25 mm Hg, the response declined to a minimum of 17 ± 2% at 120 mm Hg (P < .01). Similar results were obtained in WKY rats. In contrast, the contractile response in SHR remained maximal over the entire pressure range studied (65 ± 5%). Thus, intraluminal pressure profoundly affects vascular reactivity of resistance arteries; low pressure augments and high pressure reduces the contractile response in normotensive human and rat resistance arteries, whereas this pressure-dependent modulation of vascular reactivity is lost in the SHR. Am J Hypertens 1992;5:542-54

Purpose in life in patients with rheumatoid arthritis

To evaluate the role of purpose in life among people with rheumatoid arthritis (RA), a questionnaire comprising the Purpose in Life test (PIL) and the purpose in life dimension of the Psychological Well-Being test (PWB-pil) was sent to a random sample of 300 patients with RA. Additional questions comprised sociodemographic and disease characteristics, physical, mental and social functioning, coping (Coping with rheumatic stressors questionnaire), and quality of life (RAND-36). Associations between sociodemographic and disease characteristics, physical, mental and social functioning, and coping on the one side and the two measures of purpose in life on the other side and associations between the two purpose of life measures and physical and mental dimensions of quality of life were assessed by means of univariate and multivariate regression analyses. The response rate was 156 of 300 (52%). The median PIL and PWB-pil scores were 103 (range 63–131) and 82 (41–110), respectively. A lower age, a better mental health status, and an optimistic coping style were significantly associated with both higher PIL and PWB-pil scores, whereas more participation in leisure and/or social activities was associated with a higher PIL score. It was found that the PIL and PWB-pil contributed independently and significantly to the mental component summary scale of the RAND-36. In RA patients, lower age, a better mental health status, an optimistic coping style, and participation in leisure and/or social activities were significantly associated with more sense of purpose in life. Purpose in life pays a significant and independent contribution to the mental component of quality of life. These findings highlight the significance of the concept of purpose in life in patients with RA

Architecture and Advanced Electronics Pathways Toward Highly Adaptive Energy- Efficient Computing

With the explosion of the number of compute nodes, the bottleneck of future computing systems lies in the network architecture connecting the nodes. Addressing the bottleneck requires replacing current backplane-based network topologies. We propose to revolutionize computing electronics by realizing embedded optical waveguides for onboard networking and wireless chip-to-chip links at 200-GHz carrier frequency connecting neighboring boards in a rack. The control of novel rate-adaptive optical and mm-wave transceivers needs tight interlinking with the system software for runtime resource management

Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers

Comparison of sequencing-based methods to profile DNA methylation and identification of monoallelic epigenetic modifications.

Analysis of DNA methylation patterns relies increasingly on sequencing-based profiling methods. The four most frequently used sequencing-based technologies are the bisulfite-based methods MethylC-seq and reduced representation bisulfite sequencing (RRBS), and the enrichment-based techniques methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylated DNA binding domain sequencing (MBD-seq). We applied all four methods to biological replicates of human embryonic stem cells to assess their genome-wide CpG coverage, resolution, cost, concordance and the influence of CpG density and genomic context. The methylation levels assessed by the two bisulfite methods were concordant (their difference did not exceed a given threshold) for 82% for CpGs and 99% of the non-CpG cytosines. Using binary methylation calls, the two enrichment methods were 99% concordant and regions assessed by all four methods were 97% concordant. We combined MeDIP-seq with methylation-sensitive restriction enzyme (MRE-seq) sequencing for comprehensive methylome coverage at lower cost. This, along with RNA-seq and ChIP-seq of the ES cells enabled us to detect regions with allele-specific epigenetic states, identifying most known imprinted regions and new loci with monoallelic epigenetic marks and monoallelic expression

Borrelia valaisiana resist complement-mediated killing independently of the recruitment of immune regulators and inactivation of complement components

Spirochetes belonging to the Borrelia (B.) burgdorferi sensu lato complex differ in their resistance to complement-mediated killing, particularly in regard to human serum. In the present study, we elucidate the serum and complement susceptibility of B. valaisiana, a genospecies with the potential to cause Lyme disease in Europe as well as in Asia. Among the investigated isolates, growth of ZWU3 Ny3 was not affected while growth of VS116 and Bv9 was strongly inhibited in the presence of 50% human serum. Analyzing complement activation, complement components C3, C4 and C6 were deposited on the surface of isolates VS116 and Bv9, and similarly the membrane attack complex was formed on their surface. In contrast, no surface-deposited components and no aberrations in cell morphology were detected for serum-resistant ZWU3 Ny3. While further investigating the protective role of bound complement regulators in mediating complement resistance, we discovered that none of the B. valaisiana isolates analyzed bound complement regulators Factor H, Factor H-like protein 1, C4b binding protein or C1 esterase inhibitor. In addition, B. valaisiana also lacked intrinsic proteolytic activity to degrade complement components C3, C3b, C4, C4b, and C5. Taken together, these findings suggest that certain B. valaisiana isolates differ in their capability to resist complement-mediating killing by human serum. The molecular mechanism utilized by B. valaisiana to inhibit bacteriolysis appears not to involve binding of the key host complement regulators of the alternative, classical, and lectin pathways as already known for serum-resistant Lyme disease or relapsing fever borreliae

Nucleosomes protect DNA from DNA methylation in vivo and in vitro

Positioned nucleosomes limit the access of proteins to DNA. However, the impact of nucleosomes on DNA methylation in vitro and in vivo is poorly understood. Here, we performed a detailed analysis of nucleosome binding and nucleosomal DNA methylation by the de novo methyltransferases. We show that compared to linker DNA, nucleosomal DNA is largely devoid of CpG methylation. ATP-dependent chromatin remodelling frees nucleosomal CpG dinucleotides and renders the remodelled nucleosome a 2-fold better substrate for Dnmt3a methyltransferase compared to free DNA. These results reflect the situation in vivo, as quantification of nucleosomal DNA methylation levels in HeLa cells shows a 2-fold decrease of nucleosomal DNA methylation levels compared to linker DNA. Our findings suggest that nucleosomal positions are stably maintained in vivo and nucleosomal occupancy is a major determinant of global DNA methylation patterns in vivo

X-ray radiation from ions with K-shell vacancies

Abstract New types of space resolved X-ray spectra produced in light matter experiments with high intensity lasers have been investigated experimentally and theoretically. This type of spectra is characterised by the disappearance of distinct resonance line emission and the appearance of very broad emission structures due to the dielectronic satellite transitions associated to the resonance lines. Atomic data calculations have shown, that rather exotic states with K-shell vacancies are involved. For quantitative spectra interpretation we developed a model for dielectronic satellite accumulation (DSA-model) in cold dense optically thick plasmas which are tested by rigorous comparison with space resolved spectra from ns-lasers. In experiments with laser intensities up to 10 19 W/cm 2 focused into nitrogen gas targets, hollow ion configurations are observed by means of soft X-ray spectroscopy. It is shown that transitions in hollow ions can be used for plasma diagnostic. The determination of the electron temperature in the long lasting recombining regime is demonstrated. In Light-matter interaction experiments with extremely high contrast (up to 10 10 ) short pulse (400 fs) lasers electron densities of n e ≈3×10 23 cm −3 at temperatures between kT e =200–300 eV have been determined by means of spectral simulations developed previously for ns-laser produced plasmas. Expansion velocities are determined analysing asymmetric optically thick line emission. Further, the results are checked by observing the spectral windows involving the region about the He α -line and the region from the He β -line to the He-like continuum. Finally, plasmas of solid density are characteristic in experiments with heavy ion beams heating massive targets. We report the first spectroscopic investigations in plasmas of this type with results on solid neon heated by Ar-ions. A spectroscopic method for the determination of the electron temperature in extreme optically thick plasmas is developed