Tunneling dynamics of side chains and defects in proteins, polymer glasses, and OH-doped network glasses

Simulations on a Lennard-Jones computer glass are performed to study effects arising from defects in glasses at low temperatures. The numerical analysis reveals that already a low concentration of defects may dramatically change the low temperature properties by giving rise to extrinsic double-well potentials (DWP's). The main characteristics of these extrinsic DWP's are (i) high barrier heights, (ii) high probability that a defect is indeed connected with an extrinsic DWP, (iii) highly localized dynamics around this defect, and (iv) smaller deformation potential coupling to phonons. Designing an extension of the Standard Tunneling Model (STM) which parametrizes this picture and comparing with ultrasound experiments on the wet network glass $a$-B$_2$O$_3$ shows that effects of OH-impurities are accurately accounted for. This model is then applied to organic polymer glasses and proteins. It is suggested that side groups may act similarly like doped impurities inasmuch as extrinsic DWP's are induced, which possess a distribution of barriers peaked around a high barrier height. This compares with the structurlessly distributed barrier heights of the intrinsic DWP's, which are associated with the backbone dynamics. It is shown that this picture is consistent with elastic measurements on polymers, and can explain anomalous nonlogarithmic line broadening recently observed in hole burning experiments in PMMA.Comment: 34 pages, Revtex, 9 eps-figures, accepted for publication in J. Chem. Phy

BAFF Index and CXCL13 levels in the cerebrospinal fluid associate respectively with intrathecal IgG synthesis and cortical atrophy in multiple sclerosis at clinical onset

Abstract Background B lymphocytes are thought to play a relevant role in multiple sclerosis (MS) pathology. The in vivo analysis of intrathecally produced B cell-related cytokines may help to clarify the mechanisms of B cell recruitment and immunoglobulin production within the central nervous system (CNS) in MS. Methods Paired cerebrospinal fluid (CSF) and serum specimens from 40 clinically isolated syndrome suggestive of MS or early-onset relapsing-remitting MS patients (CIS/eRRMS) and 17 healthy controls (HC) were analyzed for the intrathecal synthesis of IgG (quantitative formulae and IgG oligoclonal bands, IgGOB), CXCL13, BAFF, and IL-21. 3D-FLAIR, 3D-DIR, and 3D-T1 MRI sequences were applied to evaluate white matter (WM) and gray matter (GM) lesions and global cortical thickness (gCTh). Results Compared to HC, CIS/eRRMS having IgGOB (IgGOB+, 26 patients) had higher intrathecal IgG indexes ( p \u2009<\u20090.01), lower values of BAFF Index (11.9\u2009\ub1\u20096.1 vs 17.5\u2009\ub1\u20095.2, p \u2009<\u20090.01), and higher CSF CXCL13 levels (27.7\u2009\ub1\u200933.5 vs 0.9\u2009\ub1\u20091.5, p \u2009<\u20090.005). In these patients, BAFF Index but not CSF CXCL13 levels inversely correlated with the intrathecal IgG synthesis ( r \u2009>\u20090.5 and p \u2009<\u20090.05 for all correlations). CSF leukocyte counts were significantly higher in IgGOB+ compared to IgGOB\u2212 ( p \u2009<\u20090.05) and HC ( p \u2009<\u20090.01), and correlated to CSF CXCL13 concentrations ( r 0.77, p \u2009<\u20090.001). The gCTh was significantly lower in patients with higher CSF CXCL13 levels (2.41\u2009\ub1\u20090.1 vs 2.49\u2009\ub1\u20090.1\ua0mm, p \u2009<\u20090.05), while no difference in MRI parameters of WM and GM pathology was observed between IgGOB+ and IgGOB\u2212. Conclusions The intrathecal IgG synthesis inversely correlated with BAFF Index and showed no correlation with CSF CXCL13. These findings seem to indicate that intrathecally synthesized IgG are produced by long-term PCs that have entered the CNS from the peripheral blood, rather than produced by PCs developed in the meningeal follicle-like structures (FLS). In this study, CXCL13 identifies a subgroup of MS patients characterized by ..

Mechanotransduction: use the force(s).

Mechanotransduction - how cells sense physical forces and translate them into biochemical and biological responses - is a vibrant and rapidly-progressing field, and is important for a broad range of biological phenomena. This forum explores the role of mechanotransduction in a variety of cellular activities and highlights intriguing questions that deserve further attention

Focal nodular hyperplasia: morphologic and functional information from MR imaging with gadobenate dimeglumine.

PURPOSE: To determine whether gadobenate dimeglumine (Gd-BOPTA) is able to provide morphologic and functional information for characterization of focal nodular hyperplasia (FNH). MATERIALS AND METHODS: Sixty-three consecutive patients with proved FNH were retrospectively examined. Magnetic resonance (MR) imaging with T2-weighted turbo spin-echo and T1-weighted gradient-echo sequences was performed. Images were acquired prior to and during the dynamic phase of contrast-material enhancement and 1-3 hours after administration of 0.1 mmol/kg Gd-BOPTA. Qualitative analysis of signal intensity and homogeneity on images in the various phases of the MR study and examination for the presence of central scar or atypical features were performed. On the basis of features observed in the precontrast and dynamic phases, lesions were defined as typical or atypical. Intensity and enhancement patterns of the lesions and scars were also evaluated in the delayed phase. RESULTS: One hundred FNHs were depicted on MR images. Seventy-nine of 100 lesions demonstrated typical morphologic and enhancement characteristics. On delayed phase images, 72% of 100 FNHs appeared hyperintense; 21%, isointense; and 7%, slightly hypointense. The delayed pattern of enhancement was homogeneous, heterogeneous, and peripheral in 58%, 22%, and 20% of 100 FNHs, respectively. Atypical morphologic features and lesion and/or scar enhancement were observed in 21 of 100 FNHs. On delayed phase images, 76% of 100 atypical FNHs appeared hyperintense, 14% isointense, and 10% slightly hypointense. Hyperintensity and isointensity allowed the correct characterization in 90% of atypical FNHs. CONCLUSION: Gd-BOPTA during both dynamic and delayed phases provides morphologic and functional information for the characterization of FNH

Transcriptional Regulation of the Capsular Polysaccharide Biosynthesis Locus of Streptococcus Pneumoniae: a Bioinformatic Analysis

The polysaccharide capsule of Streptococcus pneumoniae is the main virulence factor, which makes the bacterium resistant to phagocytosis. Expression of capsular polysaccharide must be adjusted at different stages of pneumococcal infection, thus, their transcriptional regulation appears to be crucial. To get insight into the existence of regulatory mechanisms common to most serotypes, a bioinformatic analysis of the DNA region located upstream of the capsular locus was performed. With the exception of serotype 37, the capsular locus is located between dexB and aliA on the pneumococcal chromosome. Up to 26 different sequence organizations were found among pneumococci synthesizing their capsule through a Wzy-polymerase-dependent mechanism, mostly varying according to the presence/absence of distinct insertion elements. As a consequence, only ∼250 bp (including a 107 bp RUP_A element) was conserved in 86 sequences, although only a short (ca. 87 bp) region located immediately upstream of cpsA was strictly conserved in all the sequences analyzed. An exhaustive search for possible operator sequences was done. Interestingly, although the promoter region of serotype 3 isolates completely differs from that of other serotypes, most of the proteins proposed to regulate transcription in serotype 3 pneumococci were also predicted to function as possible regulators in non-serotype 3 S. pneumoniae isolates

The effect of four-phasic versus three-phasic contrast media injection protocols on extravasation rate in coronary CT angiography: a randomized controlled trial.

OBJECTIVES: Contrast media (CM) extravasation is a well-known complication of CT angiography (CTA). Our prospective randomized control study aimed to assess whether a four-phasic CM administration protocol reduces the risk of extravasation compared to the routinely used three-phasic protocol in coronary CTA. METHODS: Patients referred to coronary CTA due to suspected coronary artery disease were included in the study. All patients received 400 mg/ml iomeprol CM injected with dual-syringe automated injector. Patients were randomized into a three-phasic injection-protocol group, with a CM bolus of 85 ml followed by 40 ml of 75%:25% saline/CM mixture and 30 ml saline chaser bolus; and a four-phasic injection-protocol group, with a saline pacer bolus of 10 ml injected at a lower flow rate before the three-phasic protocol. RESULTS: 2,445 consecutive patients were enrolled (mean age 60.6 +/- 12.1 years; females 43.6%). Overall rate of extravasation was 0.9% (23/2,445): 1.4% (17/1,229) in the three-phasic group and 0.5% (6/1,216) in the four-phasic group (p = 0.034). CONCLUSIONS: Four-phasic CM administration protocol is easy to implement in the clinical routine at no extra cost. The extravasation rate is reduced by 65% with the application of the four-phasic protocol compared to the three-phasic protocol in coronary CTA. KEY POINTS: * Four-phasic CM injection-protocol reduces extravasation rate by 65% compared to three-phasic. * The saline pacer bolus substantially reduces the risk of CM extravasation. * The implementation of four-phasic injection-protocol is at no cost

Safety of liver resection and effect on quality of life in patients with benign hepatic disease: Single center experience

<p>Abstract</p> <p>Background</p> <p>Although liver resection has long been established for selected patients with benign hepatic disease, the success of surgical treatment of these patients cannot be evaluated exclusively through postoperative morbidity and mortality. Therefore, the aim of the study was to prove the safety of liver resection in the treatment of benign liver tumors and to evaluate the effect of surgical treatment on the patients' qauality of life.</p> <p>Methods</p> <p>A total of 146 patients who underwent liver resection because of benign liver tumors were included in this study. Postoperative outcome was assessed and patients evaluated their quality of life before surgery and at the present time using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (QLQ C-30).</p> <p>Results</p> <p>The rate of serious (> grade 2) complications was 4.1% with no postoperative death. The quality of life assessment revealed an overall improvement of general health status after resection (0.7 vs. 0.56, p < 0.001) and additionally a significant reduction of 6 out of 9 symptoms. Furthermore, compelling benefits in the patients' social and emotional coping could be detected after surgery.</p> <p>Conclusions</p> <p>Liver resection for benign liver disease is a safe procedure and leads to a significant improvement of quality of life in selected patients.</p

CovR-Controlled Global Regulation of Gene Expression in Streptococcus mutans

CovR/S is a two-component signal transduction system (TCS) that controls the expression of various virulence related genes in many streptococci. However, in the dental pathogen Streptococcus mutans, the response regulator CovR appears to be an orphan since the cognate sensor kinase CovS is absent. In this study, we explored the global transcriptional regulation by CovR in S. mutans. Comparison of the transcriptome profiles of the wild-type strain UA159 with its isogenic covR deleted strain IBS10 indicated that at least 128 genes (∼6.5% of the genome) were differentially regulated. Among these genes, 69 were down regulated, while 59 were up regulated in the IBS10 strain. The S. mutans CovR regulon included competence genes, virulence related genes, and genes encoded within two genomic islands (GI). Genes encoded by the GI TnSmu2 were found to be dramatically reduced in IBS10, while genes encoded by the GI TnSmu1 were up regulated in the mutant. The microarray data were further confirmed by real-time RT-PCR analyses. Furthermore, direct regulation of some of the differentially expressed genes was demonstrated by electrophoretic mobility shift assays using purified CovR protein. A proteomic study was also carried out that showed a general perturbation of protein expression in the mutant strain. Our results indicate that CovR truly plays a significant role in the regulation of several virulence related traits in this pathogenic streptococcus