Aptamer-based multiplexed proteomic technology for biomarker discovery

Interrogation of the human proteome in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 [mu]L of serum or plasma). Our current assay allows us to measure ~800 proteins with very low limits of detection (1 pM average), 7 logs of overall dynamic range, and 5% average coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding DNA aptamer concentration signature, which is then quantified with a DNA microarray. In essence, our assay takes advantage of the dual nature of aptamers as both folded binding entities with defined shapes and unique sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to discover unique protein signatures characteristic of various disease states. More generally, we describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine

Effects of autologous bone marrow stem cell transplantation on beta-adrenoceptor density and electrical activation pattern in a rabbit model of non-ischemic heart failure

BACKGROUND: Since only little is known on stem cell therapy in non-ischemic heart failure we wanted to know whether a long-term improvement of cardiac function in non-ischemic heart failure can be achieved by stem cell transplantation. METHODS: White male New Zealand rabbits were treated with doxorubicine (3 mg/kg/week; 6 weeks) to induce dilative non-ischemic cardiomyopathy. Thereafter, we obtained autologous bone marrow stem cells (BMSC) and injected 1.5–2.0 Mio cells in 1 ml medium by infiltrating the myocardium via a left anterolateral thoracotomy in comparison to sham-operated rabbits. 4 weeks later intracardiac contractility was determined in-vivo using a Millar catheter. Thereafter, the heart was excised and processed for radioligand binding assays to detect β(1)- and β(2)-adrenoceptor density. In addition, catecholamine plasma levels were determined via HPLC. In a subgroup we investigated cardiac electrophysiology by use of 256 channel mapping. RESULTS: In doxorubicine-treated animals β-adrenoceptor density was significantly down-regulated in left ventricle and septum, but not in right ventricle, thereby indicating a typical left ventricular heart failure. Sham-operated rabbits exhibited the same down-regulation. In contrast, BMSC transplantation led to significantly less β-adrenoceptor down-regulation in septum and left ventricle. Cardiac contractility was significantly decreased in heart failure and sham-operated rabbits, but was significantly higher in BMSC-transplanted hearts. Norepinephrine and epinephrine plasma levels were enhanced in heart failure and sham-operated animals, while these were not different from normal in BMSC-transplanted animals. Electrophysiological mapping revealed unaltered electrophysiology and did not show signs of arrhythmogeneity. CONCLUSION: BMSC transplantation improves sympathoadrenal dysregualtion in non-ischemic heart failure

The Role of Anorexia in Resistance and Tolerance to Infections in Drosophila

Infections initiate a signaling loop in which sick animals become anorexic, and the resulting change in diet alters the body's ability to fight infections in good and bad ways

Separation – integration – and now …? - An historical perspective on the relationship between German management accounting and financial accounting

German accounting has traditionally followed a dual ledger approach with strictly separated internal cost accounting, as the basis for management information, and external financial accounting focusing on creditor protection and based on the commercial law. However, the increased adoption of integrated accounting system implies a significant change in the relationship between financial and management accounting systems. We use Hegelian dialectic to trace the historical development of German accounting from separated systems towards antithetical propositions of full integration, and the emergence of partial integration as the synthesis of this transformation process. For this reason, our paper provides a comprehensive analysis of the literature on the relationship between financial and management accounting in Germany. On this basis, we elaborate how financial accounting in Germany has been shaped by its economic context and legislation, and how financial accounting – accompanied by institutional pressures – in turn influenced management accounting. We argue that the changing relationship between management and financial accounting in the German context illustrates how current accounting practice is shaped not only by its environment, but also by its historical path. Based on this reasoning, we discuss several avenues for future research

How a Diverse Research Ecosystem Has Generated New Rehabilitation Technologies: Review of NIDILRR’s Rehabilitation Engineering Research Centers

Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a “total approach to rehabilitation”, combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970’s, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program

Multisensory body representation in autoimmune diseases

Body representation has been linked to the processing and integration of multisensory signals. An outstanding example of the pivotal role played by multisensory mechanisms in body representation is the Rubber Hand Illusion (RHI). In this paradigm, multisensory stimulation induces a sense of ownership over a fake limb. Previous work has shown high interindividual differences in the susceptibility to the RHI. The origin of this variability remains largely unknown. Given the tight and bidirectional communication between the brain and the immune system, we predicted that the origin of this variability could be traced, in part, to the immune system's functioning, which is altered by several clinical conditions, including Coeliac Disease (CD). Consistent with this prediction, we found that the Rubber Hand Illusion is stronger in CD patients as compared to healthy controls. We propose a biochemical mechanism accounting for the dependency of multisensory body representation upon the Immune system. Our finding has direct implications for a range of neurological, psychiatric and immunological conditions where alterations of multisensory integration, body representation and dysfunction of the immune system co-exist

X-Ray Spectroscopy of Stars

(abridged) Non-degenerate stars of essentially all spectral classes are soft X-ray sources. Low-mass stars on the cooler part of the main sequence and their pre-main sequence predecessors define the dominant stellar population in the galaxy by number. Their X-ray spectra are reminiscent, in the broadest sense, of X-ray spectra from the solar corona. X-ray emission from cool stars is indeed ascribed to magnetically trapped hot gas analogous to the solar coronal plasma. Coronal structure, its thermal stratification and geometric extent can be interpreted based on various spectral diagnostics. New features have been identified in pre-main sequence stars; some of these may be related to accretion shocks on the stellar surface, fluorescence on circumstellar disks due to X-ray irradiation, or shock heating in stellar outflows. Massive, hot stars clearly dominate the interaction with the galactic interstellar medium: they are the main sources of ionizing radiation, mechanical energy and chemical enrichment in galaxies. High-energy emission permits to probe some of the most important processes at work in these stars, and put constraints on their most peculiar feature: the stellar wind. Here, we review recent advances in our understanding of cool and hot stars through the study of X-ray spectra, in particular high-resolution spectra now available from XMM-Newton and Chandra. We address issues related to coronal structure, flares, the composition of coronal plasma, X-ray production in accretion streams and outflows, X-rays from single OB-type stars, massive binaries, magnetic hot objects and evolved WR stars.Comment: accepted for Astron. Astrophys. Rev., 98 journal pages, 30 figures (partly multiple); some corrections made after proof stag

A Histone Map of Human Chromosome 20q13.12

We present a systematic search for regulatory elements in a 3.5 Mb region on human chromosome 20q13.12, a region associated with a number of medical conditions such as type II diabetes and obesity.We profiled six histone modifications alongside RNA polymerase II (PolII) and CTCF in two cell lines, HeLa S3 and NTERA-2 clone D1 (NT2/D1), by chromatin immunoprecipitation using an in-house spotted DNA array, constructed with 1.8 kb overlapping plasmid clones. In both cells, more than 90% of transcription start sites (TSSs) of expressed genes showed enrichments with PolII, di-methylated lysine 4 of histone H3 (H3K4me2), tri-methylated lysine 4 of histone H3 (H3K4me3) or acetylated H3 (H3Ac), whereas mono-methylated lysine 4 of histone H3 (H3K4me1) signals did not correlate with expression. No TSSs were enriched with tri-methylated lysine 27 of histone H3 (H3K27me3) in HeLa S3, while eight TSSs (4 expressed) showed enrichments in NT2/D1. We have also located several CTCF binding sites that are potential insulator elements.In summary, we annotated a number of putative regulatory elements in 20q13.12 and went on to verify experimentally a subset of them using dual luciferase reporter assays. Correlating this data to sequence variation can aid identification of disease causing variants