188 research outputs found
Extended microsatellite analysis in microsatellite stable, MSH2 and MLH1 mutation-negative HNPCC patients: Genetic reclassification and correlation with clinical features
Background: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder predisposing to predominantly colorectal cancer (CRC) and endometrial cancer frequently due to germline mutations in DNA mismatch repair (MMR) genes, mainly MLH1, MSH2 and also MSH6 in families seen to demonstrate an excess of endometrial cancer. As a consequence, tumors in HNPCC reveal alterations in the length of simple repetitive genomic sequences like poly-A, poly-T, CA or GT repeats (microsatellites) in at least 90% of the cases. Aim of the Study: The study cohort consisted of 25 HNPCC index patients ( 19 Amsterdam positive, 6 Bethesda positive) who revealed a microsatellite stable (MSS) - or low instable (MSI-L) - tumor phenotype with negative mutation analysis for the MMR genes MLH1 and MSH2. An extended marker panel (BAT40, D10S197, D13S153, D18S58, MYCL1) was analyzed for the tumors of these patients with regard to three aspects. First, to reconfirm the MSI-L phenotype found by the standard panel; second, to find minor MSIs which might point towards an MSH6 mutation, and third, to reconfirm the MSS status of hereditary tumors. The reconfirmation of the MSS status of tumors not caused by mutations in the MMR genes should allow one to define another entity of hereditary CRC. Their clinical features were compared with those of 150 patients with sporadic CRCs. Results: In this way, 17 MSS and 8 MSI-L tumors were reclassified as 5 MSS, 18 MSI-L and even 2 MSI-H ( high instability) tumors, the last being seen to demonstrate at least 4 instable markers out of 10. Among all family members, 87 malignancies were documented. The mean age of onset for CRCs was the lowest in the MSI-H-phenotyped patients with 40.5 +/- 4.9 years (vs. 47.0 +/- 14.6 and 49.8 +/- 11.9 years in MSI-L- and MSS-phenotyped patients, respectively). The percentage of CRC was the highest in families with MSS-phenotyped tumors (88%), followed by MSI-L-phenotyped ( 78%) and then by MSI-H-phenotyped (67%) tumors. MSS tumors were preferentially localized in the distal colon supposing a similar biologic behavior like sporadic CRC. MSH6 mutation analysis for the MSI-L and MSI-H patients revealed one truncating mutation for a patient initially with an MSS tumor, which was reclassified as MSI-L by analyzing the extended marker panel. Conclusion: Extended microsatellite analysis serves to evaluate the sensitivity of the reference panel for HNPCC detection and permits phenotype confirmation or upgrading. Additionally, it confirms the MSS status of hereditary CRCs not caused by the common mutations in the MMR genes and provides hints to another entity of hereditary CRC. Copyright (C) 2004 S. Karger AG, Basel
Self-gravitating elastic bodies
Extended objects in GR are often modelled using distributional solutions of
the Einstein equations with point-like sources, or as the limit of
infinitesimally small "test" objects. In this note, I will consider models of
finite self-gravitating extended objects, which make it possible to give a
rigorous treatment of the initial value problem for (finite) extended objects.Comment: 16 pages. Based on a talk given at the 2013 WE-Heraeus seminar on
"Equations of motion in relativistic gravity
Expression and Function of Serotonin 2A and 2B Receptors in the Mammalian Respiratory Network
Neurons of the respiratory network in the lower brainstem express a variety of serotonin receptors (5-HTRs) that act primarily through adenylyl cyclase. However, there is one receptor family including 5-HT2A, 5-HT2B, and 5-HT2C receptors that are directed towards protein kinase C (PKC). In contrast to 5-HT2ARs, expression and function of 5-HT2BRs within the respiratory network are still unclear. 5-HT2BR utilizes a Gq-mediated signaling cascade involving calcium and leading to activation of phospholipase C and IP3/DAG pathways. Based on previous studies, this signal pathway appears to mediate excitatory actions on respiration. In the present study, we analyzed receptor expression in pontine and medullary regions of the respiratory network both at the transcriptional and translational level using quantitative RT-PCR and self-made as well as commercially available antibodies, respectively. In addition we measured effects of selective agonists and antagonists for 5-HT2ARs and 5-HT2BRs given intra-arterially on phrenic nerve discharges in juvenile rats using the perfused brainstem preparation. The drugs caused significant changes in discharge activity. Co-administration of both agonists revealed a dominance of the 5-HT2BR. Given the nature of the signaling pathways, we investigated whether intracellular calcium may explain effects observed in the respiratory network. Taken together, the results of this study suggest a significant role of both receptors in respiratory network modulation
Putting prevention into practice: qualitative study of factors that inhibit and promote preventive care by general practitioners, with a focus on elderly patients
<p>Abstract</p> <p>Background</p> <p>General practitioners (GPs) have a key role in providing preventive care, particularly for elderly patients. However, various factors can inhibit or promote the implementation of preventive care. In the present study, we identified and examined factors that inhibit and promote preventive care by German GPs, particularly for elderly patients, and assessed changes in physicians' attitudes toward preventive care throughout their careers.</p> <p>Methods</p> <p>A qualitative, explorative design was used to identify inhibitors and promoters of preventive care in German general medical practice. A total of 32 GPs in Berlin and Hannover were surveyed. Questions about factors that promote or inhibit implementation of preventive care and changes in physicians' perceptions of promoting and inhibiting factors throughout their careers were identified. Episodic interviews, which encouraged the reporting of anecdotes regarding daily knowledge and experiences, were analyzed using ATLAS/ti. Socio-demographic data of GPs and structural information about their offices were collected using short questionnaires. The factors identified as inhibitory or promoting were classified as being related to patients, physicians, or the healthcare system. The changes in GP attitudes toward preventive care throughout their careers were classified as personal transitions or as social and health policy transitions.</p> <p>Results</p> <p>Most of the identified barriers to preventive care were related to patients, such as a lack of motivation for making lifestyle changes and a lack of willingness to pay for preventive interventions. In addition, the healthcare system seemed to inadequately promote preventive care, mainly due to poor reimbursement for preventive care and fragmentation of care. GPs own attitudes and health habits seemed to influence the implementation of preventive care. GPs recognized their own lack of awareness of effective preventive interventions, particularly for elderly patients. GPs were motivated by positive preventive experiences, but often lacked the necessary training to counsel and support their patients.</p> <p>Conclusions</p> <p>German GPs had positive attitudes towards prevention, but the implementation of preventive care was neither systematic nor continuous. Identification and elimination of barriers to preventive care is crucial. Further research is needed to identify effective practice-based approaches to overcome these barriers.</p
Impairment of Immunoproteasome Function by ÎČ5i/LMP7 Subunit Deficiency Results in Severe Enterovirus Myocarditis
Proteasomes recognize and degrade poly-ubiquitinylated proteins. In infectious disease, cells activated by interferons (IFNs) express three unique catalytic subunits ÎČ1i/LMP2, ÎČ2i/MECL-1 and ÎČ5i/LMP7 forming an alternative proteasome isoform, the immunoproteasome (IP). The in vivo function of IPs in pathogen-induced inflammation is still a matter of controversy. IPs were mainly associated with MHC class I antigen processing. However, recent findings pointed to a more general function of IPs in response to cytokine stress. Here, we report on the role of IPs in acute coxsackievirus B3 (CVB3) myocarditis reflecting one of the most common viral disease entities among young people. Despite identical viral load in both control and IP-deficient mice, IP-deficiency was associated with severe acute heart muscle injury reflected by large foci of inflammatory lesions and severe myocardial tissue damage. Exacerbation of acute heart muscle injury in this host was ascribed to disequilibrium in protein homeostasis in viral heart disease as indicated by the detection of increased proteotoxic stress in cytokine-challenged cardiomyocytes and inflammatory cells from IP-deficient mice. In fact, due to IP-dependent removal of poly-ubiquitinylated protein aggregates in the injured myocardium IPs protected CVB3-challenged mice from oxidant-protein damage. Impaired NFÎșB activation in IP-deficient cardiomyocytes and inflammatory cells and proteotoxic stress in combination with severe inflammation in CVB3-challenged hearts from IP-deficient mice potentiated apoptotic cell death in this host, thus exacerbating acute tissue damage. Adoptive T cell transfer studies in IP-deficient mice are in agreement with data pointing towards an effective CD8 T cell immune. This study therefore demonstrates that IP formation primarily protects the target organ of CVB3 infection from excessive inflammatory tissue damage in a virus-induced proinflammatory cytokine milieu
Neuro-cognitive mechanisms of conscious and unconscious visual perception: From a plethora of phenomena to general principles
Psychological and neuroscience approaches have promoted much progress in
elucidating the cognitive and neural mechanisms that underlie phenomenal visual
awareness during the last decades. In this article, we provide an overview of
the latest research investigating important phenomena in conscious and
unconscious vision. We identify general principles to characterize conscious and
unconscious visual perception, which may serve as important building blocks for
a unified model to explain the plethora of findings. We argue that in particular
the integration of principles from both conscious and unconscious vision is
advantageous and provides critical constraints for developing adequate
theoretical models. Based on the principles identified in our review, we outline
essential components of a unified model of conscious and unconscious visual
perception. We propose that awareness refers to consolidated
visual representations, which are accessible to the entire brain and therefore
globally available. However, visual awareness not only depends
on consolidation within the visual system, but is additionally the result of a
post-sensory gating process, which is mediated by higher-level cognitive control
mechanisms. We further propose that amplification of visual representations by
attentional sensitization is not exclusive to the domain of conscious
perception, but also applies to visual stimuli, which remain unconscious.
Conscious and unconscious processing modes are highly interdependent with
influences in both directions. We therefore argue that exactly this
interdependence renders a unified model of conscious and unconscious visual
perception valuable. Computational modeling jointly with focused experimental
research could lead to a better understanding of the plethora of empirical
phenomena in consciousness research
Integrating Diverse Datasets Improves Developmental Enhancer Prediction
Gene-regulatory enhancers have been identified using various approaches, including evolutionary conservation, regulatory protein binding, chromatin modifications, and DNA sequence motifs. To integrate these different approaches, we developed EnhancerFinder, a two-step method for distinguishing developmental enhancers from the genomic background and then predicting their tissue specificity. EnhancerFinder uses a multiple kernel learning approach to integrate DNA sequence motifs, evolutionary patterns, and diverse functional genomics datasets from a variety of cell types. In contrast with prediction approaches that define enhancers based on histone marks or p300 sites from a single cell line, we trained EnhancerFinder on hundreds of experimentally verified human developmental enhancers from the VISTA Enhancer Browser. We comprehensively evaluated EnhancerFinder using cross validation and found that our integrative method improves the identification of enhancers over approaches that consider a single type of data, such as sequence motifs, evolutionary conservation, or the binding of enhancer-associated proteins. We find that VISTA enhancers active in embryonic heart are easier to identify than enhancers active in several other embryonic tissues, likely due to their uniquely high GC content. We applied EnhancerFinder to the entire human genome and predicted 84,301 developmental enhancers and their tissue specificity. These predictions provide specific functional annotations for large amounts of human non-coding DNA, and are significantly enriched near genes with annotated roles in their predicted tissues and lead SNPs from genome-wide association studies. We demonstrate the utility of EnhancerFinder predictions through in vivo validation of novel embryonic gene regulatory enhancers from three developmental transcription factor loci. Our genome-wide developmental enhancer predictions are freely available as a UCSC Genome Browser track, which we hope will enable researchers to further investigate questions in developmental biology. © 2014 Erwin et al
A ring-like accretion structure in M87 connecting its black hole and jet
The nearby radio galaxy M87 is a prime target for studying black hole
accretion and jet formation^{1,2}. Event Horizon Telescope observations of M87
in 2017, at a wavelength of 1.3 mm, revealed a ring-like structure, which was
interpreted as gravitationally lensed emission around a central black hole^3.
Here we report images of M87 obtained in 2018, at a wavelength of 3.5 mm,
showing that the compact radio core is spatially resolved. High-resolution
imaging shows a ring-like structure of 8.4_{-1.1}^{+0.5} Schwarzschild radii in
diameter, approximately 50% larger than that seen at 1.3 mm. The outer edge at
3.5 mm is also larger than that at 1.3 mm. This larger and thicker ring
indicates a substantial contribution from the accretion flow with absorption
effects in addition to the gravitationally lensed ring-like emission. The
images show that the edge-brightened jet connects to the accretion flow of the
black hole. Close to the black hole, the emission profile of the jet-launching
region is wider than the expected profile of a black-hole-driven jet,
suggesting the possible presence of a wind associated with the accretion flow.Comment: 50 pages, 18 figures, 3 tables, author's version of the paper
published in Natur
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