Increased urine IgM excretion predicts cardiovascular events in patients with type 1 diabetes nephropathy

<p>Abstract</p> <p>Background</p> <p>Diabetic nephropathy, a major complication of diabetes, is characterized by progressive renal injury and increased cardiovascular mortality. An increased urinary albumin excretion due dysfunction of the glomerular barrier is an early sign of diabetic nephropathy. An increased urinary excretion of higher molecular weight proteins such as IgM appears with progression of glomerular injury. We aim here to study the prognostic significance of urine IgM excretion in patients with type 1 diabetes mellitus (type 1 diabetic nephropathy).</p> <p>Methods</p> <p>This is an observational study of 139 patients with type1 diabetes mellitus (79 males and 60 females) under routine care at the diabetic outpatient clinic at the Lund University Hospital. The median follow-up time was 18 years (1 to 22) years. Urine albumin and urine IgM concentration were measured at time of recruitment.</p> <p>Results</p> <p>Overall 32 (14 male and 18 female) patients died in a cardiovascular event and 20 (11 male and 9 female) patients reached end-stage renal disease. Univariate analysis indicated that patient survival and renal survival were inversely associated with urine albumin excretion (RR = 2.9 and 5.8, respectively) and urine IgM excretion (RR = 4.6 and 5.7, respectively). Stratified analysis demonstrated that in patients with different degrees of albuminuria, the cardiovascular mortality rate and the incidence of end-stage renal disease was approximately three times higher in patients with increased urine IgM excretion.</p> <p>Conclusion</p> <p>An increase in urinary IgM excretion in patients with type 1 diabetes is associated with an increased risk for cardiovascular mortality and renal failure, regardless of the degree of albuminuria.</p

Statistical-mechanical lattice models for protein-DNA binding in chromatin

Statistical-mechanical lattice models for protein-DNA binding are well established as a method to describe complex ligand binding equilibriums measured in vitro with purified DNA and protein components. Recently, a new field of applications has opened up for this approach since it has become possible to experimentally quantify genome-wide protein occupancies in relation to the DNA sequence. In particular, the organization of the eukaryotic genome by histone proteins into a nucleoprotein complex termed chromatin has been recognized as a key parameter that controls the access of transcription factors to the DNA sequence. New approaches have to be developed to derive statistical mechanical lattice descriptions of chromatin-associated protein-DNA interactions. Here, we present the theoretical framework for lattice models of histone-DNA interactions in chromatin and investigate the (competitive) DNA binding of other chromosomal proteins and transcription factors. The results have a number of applications for quantitative models for the regulation of gene expression.Comment: 19 pages, 7 figures, accepted author manuscript, to appear in J. Phys.: Cond. Mat

Myocardin regulates exon usage in smooth muscle cells through induction of splicing regulatory factors

Differentiation of smooth muscle cells (SMCs) depends on serum response factor (SRF) and its co-activator myocardin (MYOCD). The role of MYOCD for the SMC program of gene transcription is well established. In contrast, the role of MYOCD in control of SMC-specific alternative exon usage, including exon splicing, has not been explored. In the current work we identified four splicing factors (MBNL1, RBPMS, RBPMS2, and RBFOX2) that correlate with MYOCD across human SMC tissues. Forced expression of MYOCD family members in human coronary artery SMCs in vitro upregulated expression of these splicing factors. For global profiling of transcript diversity, we performed RNA-sequencing after MYOCD transduction. We analyzed alternative transcripts with three different methods. Exon-based analysis identified 1637 features with differential exon usage. For example, usage of 3 ' exons in MYLK that encode telokin increased relative to 5 ' exons, as did the 17 kDa telokin to 130 kDa MYLK protein ratio. Dedicated event-based analysis identified 239 MYOCD-driven splicing events. Events involving MBNL1, MCAM, and ACTN1 were among the most prominent, and this was confirmed using variant-specific PCR analyses. In support of a role for RBPMS and RBFOX2 in MYOCD-driven splicing we found enrichment of their binding motifs around differentially spliced exons. Moreover, knockdown of either RBPMS or RBFOX2 antagonized splicing events stimulated by MYOCD, including those involving ACTN1, VCL, and MBNL1. Supporting an in vivo role of MYOCD-SRF-driven splicing, we demonstrate altered Rbpms expression and splicing in inducible and SMC-specific Srf knockout mice. We conclude that MYOCD-SRF, in part via RBPMS and RBFOX2, induce a program of differential exon usage and alternative splicing as part of the broader program of SMC differentiation.Peer reviewe

A solid state light-matter interface at the single photon level

Coherent and reversible mapping of quantum information between light and matter is an important experimental challenge in quantum information science. In particular, it is a decisive milestone for the implementation of quantum networks and quantum repeaters. So far, quantum interfaces between light and atoms have been demonstrated with atomic gases, and with single trapped atoms in cavities. Here we demonstrate the coherent and reversible mapping of a light field with less than one photon per pulse onto an ensemble of 10 millions atoms naturally trapped in a solid. This is achieved by coherently absorbing the light field in a suitably prepared solid state atomic medium. The state of the light is mapped onto collective atomic excitations on an optical transition and stored for a pre-programmed time up of to 1 mu s before being released in a well defined spatio-temporal mode as a result of a collective interference. The coherence of the process is verified by performing an interference experiment with two stored weak pulses with a variable phase relation. Visibilities of more than 95% are obtained, which demonstrates the high coherence of the mapping process at the single photon level. In addition, we show experimentally that our interface allows one to store and retrieve light fields in multiple temporal modes. Our results represent the first observation of collective enhancement at the single photon level in a solid and open the way to multimode solid state quantum memories as a promising alternative to atomic gases.Comment: 5 pages, 5 figures, version submitted on June 27 200

Protein Localization with Flexible DNA or RNA

Localization of activity is ubiquitous in life, and also within sub-cellular compartments. Localization provides potential advantages as different proteins involved in the same cellular process may supplement each other on a fast timescale. It might also prevent proteins from being active in other regions of the cell. However localization is at odds with the spreading of unbound molecules by diffusion. We model the cost and gain for specific enzyme activity using localization strategies based on binding to sites of intermediate specificity. While such bindings in themselves decrease the activity of the protein on its target site, they may increase protein activity if stochastic motion allows the acting protein to touch both the intermediate binding site and the specific site simultaneously. We discuss this strategy in view of recent suggestions on long non-coding RNA as a facilitator of localized activity of chromatin modifiers

Impact of metabolic comorbidity on the association between body mass index and heatlh-related quality of life: a Scotland-wide cross-sectional study of 5,608 participants

&lt;p/&gt;Background: The prevalence of obesity is rising in Scotland and globally. Overall, obesity is associated with increased morbidity, mortality and reduced health-related quality of life. Studies suggest that "healthy obesity" (obesity without metabolic comorbidity) may not be associated with morbidity or mortality. Its impact on health-related quality of life is unknown. &lt;p/&gt;Methods: We extracted data from the Scottish Health Survey on self-reported health-related quality of life, body mass index (BMI), demographic information and comorbidity. SF-12 responses were converted into an overall health utility score. Linear regression analyses were used to explore the association between BMI and health utility, stratified by the presence or absence of metabolic comorbidity (diabetes, hypertension, hypercholesterolemia or cardiovascular disease), and adjusted for potential confounders (age, sex and deprivation quintile). &lt;p/&gt;Results: Of the 5,608 individuals, 3,744 (66.8%) were either overweight or obese and 921 (16.4%) had metabolic comorbidity. There was an inverted U-shaped relationship whereby health utility was highest among overweight individuals and fell with increasing BMI. There was a significant interaction with metabolic comorbidity (p = 0.007). Individuals with metabolic comorbidty had lower utility scores and a steeper decline in utility with increasing BMI (morbidly obese, adjusted coefficient: -0.064, 95% CI -0.115, -0.012, p = 0.015 for metabolic comorbidity versus -0.042, 95% CI -0.067, -0.018, p = 0.001 for no metabolic comorbidity). &lt;p/&gt;Conclusions: The adverse impact of obesity on health-related quality of life is greater among individuals with metabolic comorbidity. However, increased BMI is associated with reduced health-related quality of life even in the absence of metabolic comorbidity, casting doubt on the notion of "healthy obesity"

Systems Biological Determination of the Epi-Genomic Structure Function Relation:

Despite our knowledge of the sequence of the human genome, the relation of its three-dimensional dynamic architecture with its function – the storage and expression of genetic information – remains one of the central unresolved issues of our age. It became very clear meanwhile that this link is crucial for the entire holistic function of the genome on all genomic coding levels from the DNA sequence to the entire chromosomes. To fulfil the dreams for better diagnostics and treatment in the 21st century (e.g. by gene therapy by inserting a gene into a new global context), we propose here in a unique interdisciplinary project to combine experiment with theory to analyze the (epi-)genomic structure function relationships within the dynamic organization of the -Globin locus, the Immuno Globin loci, and the Tumor Necrosis Factor Alpha regulated SAMD4 region in mouse and human active and inactive cell states, and their global genomic context. The project consists of five work packages (WP1-WP5) and corresponding tasks connected in a system biological approach with iterative use of data, modelling, simulation and experiments via a unique data sharing and visualization platform: In WP1 (Längst, Rippe, Wedemann, Knoch/Grosfeld; T1-T5) to investigate nucleosomal association changes in relation to the DNA sequence and the activity of ATP-driven chromatin remodelling complexes, nucleosome positions will be determined by high-throughput sequencing. The resulting nucleosomal localization probability maps will be evaluated by a novel combination of analysis tools and innovative generic data ontologies. The relation to epigenetic modifications, to the activity of ATP-driven remodelling complexes and compaction degree of nucleosomes will be analysed to understand chromatin morphogenesis and fiber formation. In parallel, in WP2 (Grosveld/Knoch, Cook, Rippe, Längst; T1-T3) we determine by high-throughput monitoring of intra/inter chromosomal contacts and architecture absolute DNA-DNA interaction probability maps for the individual loci and their global context using a novel chromosome conformation capture approach based on deep sequencing. From these the 3D conformation of the chromatin fiber and its higher-order folding into loops and loop clusters can be derived using algorithms recently developed by us. WP3 (Cook, Grosveld/Knoch, Längst; T1-T5) focuses on the determination of transcription rates and structure by qRT-PCR, DNA and RNA fluorescence in situ hybridization using intronic probes and high-resolution laser-scanning and single molecule imaging with advanced image analysis tools. Transcription-dependent changes of active and inactive loci as well as rapid synchronous transcription alteration against the unchanged background is one main interest here. This will yield results in a detailed cartography of the structure-transcription-function dependency and its importance. To rationalize the experimental results theoretically, in WP4 (Wedemann Knoch/Grosveld, Rippe; T1-T3) simulations are made of nucleosomal structure, chromatin fiber conformation and chromosomal architecture using parallel and grid super-computers with ~10.000 CPUs. The impact of different nucleosomal positions and epigenetic modifications on the nucleosomal structure and the chromatin fiber conformation will be assessed by novel Monte Carlo approaches. To understand the higher-order architecture Brownian Dynamics simulations of entire cell nuclei with molecular re

No preconscious attentional bias towards itch in healthy individuals

Education and Child Studie

TNFα is required for cholestasis-induced liver fibrosis in the mouse

TNFα, a mediator of hepatotoxicity in several animal models, is elevated in acute and chronic liver diseases. Therefore, we investigated whether hepatic injury and fibrosis due to bile duct ligation (BDL) would be reduced in TNFα knockout mice (TNFα−/−). Survival after BDL was 60% in wild-type mice (TNFα+/+) and 90% in TNFα−/− mice. Body weight loss and liver to body weight ratios were reduced in TNFα−/− mice compared to TNFα+/+ mice. Following BDL, serum alanine transaminases (ALT) levels were elevated in TNFα+/+ mice (268.6 ± 28.2 U/L) compared to TNFα−/− mice (105.9 U/L ± 24.4). TNFα −/− mice revealed lower hepatic collagen expression and less liver fibrosis in the histology. Further, α-smooth muscle actin, an indicator for activated myofibroblasts, and TGF-β mRNA, a profibrogenic cytokine, were markedly reduced in TNFα−/− mice compared to TNFα+/+ mice. Thus, our data indicate that TNFα induces hepatotoxicity and promotes fibrogenesis in the BDL model