148 research outputs found
Base pair interactions and hybridization isotherms of matched and mismatched oligonucleotide probes on microarrays
The lack of specificity in microarray experiments due to non-specific
hybridization raises a serious problem for the analysis of microarray data
because the residual chemical background intensity is not related to the
expression degree of the gene of interest. We analyzed the concentration
dependence of the signal intensity of perfect match (PM) and mismatch (MM)
probes in terms using a microscopic binding model using a combination of mean
hybridization isotherms and single base related affinity terms. The signal
intensities of the PM and MM probes and their difference are assessed with
regard to their sensitivity, specificity and resolution for gene expression
measures. The presented theory implies the refinement of existing algorithms of
probe level analysis to correct microarray data for non-specific background
intensities.Comment: 32 pages, 12 figures, 3 table
The Human Blood Transcriptome in a Large Population Cohort and Its Relation to Aging and Health
Background: The blood transcriptome is expected to provide a detailed picture of
an organism’s physiological state with potential outcomes for applications in medical
diagnostics and molecular and epidemiological research.We here present the analysis of
blood specimens of 3,388 adult individuals, together with phenotype characteristics such
as disease history, medication status, lifestyle factors, and body mass index (BMI). The
size and heterogeneity of this data challenges analytics in terms of dimension reduction,
knowledge mining, feature extraction, and data integration.
Methods: Self-organizing maps (SOM)-machine learning was applied to study
transcriptional states on a population-wide scale. This method permits a detailed
description and visualization of the molecular heterogeneity of transcriptomes and of
their association with different phenotypic features.
Results: The diversity of transcriptomes is described by personalized SOM-portraits,
which specify the samples in terms of modules of co-expressed genes of different
functional context. We identified two major blood transcriptome types where type
1 was found more in men, the elderly, and overweight people and it upregulated
genes associated with inflammation and increased heme metabolism, while type 2 was
predominantly found in women, younger, and normal weight participants and it was
associated with activated immune responses, transcriptional, ribosomal, mitochondrial,
and telomere-maintenance cell-functions. We find a striking overlap of signatures shared
by multiple diseases, aging, and obesity driven by an underlying common pattern, which
was associated with the immune response and the increase of inflammatory processes.
Conclusions: Machine learning applications for large and heterogeneous omics data
provide a holistic view on the diversity of the human blood transcriptome. It provides a
tool for comparative analyses of transcriptional signatures and of associated phenotypes
in population studies and medical applications
Datenmanagement und Qualitätssicherung im Verkehrswasserbau 2.0. FuE-Abschlussbericht B3954.07.04.70006
Investigating the retention of intermediate-mass black holes in star clusters using N-body simulations
Contrary to supermassive and stellar-mass black holes (SBHs), the existence
of intermediate-mass black holes (IMBHs) with masses ranging between 10^{2-5}
Msun has not yet been confirmed. The main problem in the detection is that the
innermost stellar kinematics of globular clusters (GCs) or small galaxies, the
possible natural loci to IMBHs, are very difficult to resolve. However, if
IMBHs reside in the centre of GCs, a possibility is that they interact
dynamically with their environment. A binary formed with the IMBH and a compact
object of the GC would naturally lead to a prominent source of gravitational
radiation, detectable with future observatories. We use N-body simulations to
study the evolution of GCs containing an IMBH and calculate the gravitational
radiation emitted from dynamically formed IMBH-SBH binaries and the possibility
that the IMBH escapes the GC after an IMBH-SBH merger. We run for the first
time direct-summation integrations of GCs with an IMBH including the dynamical
evolution of the IMBH with the stellar system and relativistic effects, such as
energy loss in gravitational waves (GWs) and periapsis shift, and gravitational
recoil. We find in one of our models an intermediate mass-ratio inspiral
(IMRI), which leads to a merger with a recoiling velocity higher than the
escape velocity of the GC. The GWs emitted fall in the range of frequencies
that a LISA-like observatory could detect, like the European eLISA or in
mission options considered in the recent preliminary mission study conducted in
China. The merger has an impact on the global dynamics of the cluster, as an
important heating source is removed when the merged system leaves the GC. The
detection of one IMRI would constitute a test of GR, as well as an irrefutable
proof of the existence of IMBHs.Comment: Accepted for publication by A&A, minor modification
Cell division and death inhibit glassy behaviour of confluent tissues
We investigate the effects of cell division and apopotosis on collective
dynamics in two-dimensional epithelial tissues. Our model includes three key
ingredients observed across many epithelia, namely cell-cell adhesion, cell
death and a cell division process that depends on the surrounding environment.
We show a rich non-equilibrium phase diagram depending on the ratio of cell
death to cell division and on the adhesion strength. For large apopotosis
rates, cells die out and the tissue disintegrates. As the death rate decreases,
however, we show, consecutively, the existence of a gas-like phase, a gel-like
phase, and a dense confluent (tissue) phase. Most striking is the observation
that the tissue is self-melting through its own internal activity, ruling out
the existence of any glassy phase.Comment: 9 pages, 10 figure
Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01
Background: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing. Methods: We analyzed the association between COVID-19 severity and HLAs in 435 individuals from Germany (n = 135), Spain (n = 133), Switzerland (n = 20) and the United States (n = 147), who had been enrolled from March 2020 to August 2020. This study included patients older than 18 years, diagnosed with COVID19 and representing the full spectrum of the disease. Finally, we tested our results by meta-analysing data from prior genome-wide association studies (GWAS). Findings: We describe a potential association of HLA-C*04:01 with severe clinical course of COVID-19. Carriers of HLA-C*04:01 had twice the risk of intubation when infected with SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1-2.1], odds ratio 3.5 [95% CI 1.9-6.6], adjusted p-value = 0.0074). These findings are based on data from four countries and corroborated by independent results from GWAS. Our findings are biologically plausible, as HLA-C*04:01 has fewer predicted bindings sites for relevant SARS-CoV-2 peptides compared to other HLA alleles. Interpretation: HLA-C*04:01 carrier state is associated with severe clinical course in SARS-CoV-2. Our findings suggest that HLA class I alleles have a relevant role in immune defense against SARS-CoV-2. Funding: Funded by Roche Sequencing Solutions, Inc
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