A novel cause of -related bone marrow failure: Partial deletion of the 3' untranslated region.

Telomere biology disorders (TBDs), including dyskeratosis congenita (DC), are a group of rare inherited diseases characterized by very short telomeres. Mutations in the components of the enzyme telomerase can lead to insufficient telomere maintenance in hematopoietic stem cells, resulting in the bone marrow failure that is characteristic of these disorders. While an increasing number of genes are being linked to TBDs, the causative mutation remains unidentified in 30-40% of patients with DC.

Telomerase promotes formation of a telomere protective complex in cancer cells.

Telomerase is a ribonucleoprotein complex that catalyzes addition of telomeric DNA repeats to maintain telomeres in replicating cells. Here, we demonstrate that the telomerase protein hTERT performs an additional role at telomeres that is independent of telomerase catalytic activity yet essential for telomere integrity and cell proliferation. Short-term depletion of endogenous hTERT reduced the levels of heat shock protein 70 (Hsp70-1) and the telomere protective protein Apollo at telomeres, and induced telomere deprotection and cell cycle arrest, in the absence of telomere shortening.

Delayed recruiting of TPD52 to lipid droplets - evidence for a "second wave" of lipid droplet-associated proteins that respond to altered lipid storage induced by Brefeldin A treatment.

Tumor protein D52 (TPD52) is amplified and overexpressed in breast and prostate cancers which are frequently characterised by dysregulated lipid storage and metabolism. TPD52 expression increases lipid storage in mouse 3T3 fibroblasts, and co-distributes with the Golgi marker GM130 and lipid droplets (LDs). We examined the effects of Brefeldin A (BFA), a fungal metabolite known to disrupt the Golgi structure, in TPD52-expressing 3T3 cells, and in human AU565 and HMC-1-8 breast cancer cells that endogenously express TPD52.

The temporal profile of activity-dependent presynaptic phospho-signalling reveals long-lasting patterns of poststimulus regulation.

Depolarization of presynaptic terminals stimulates calcium influx, which evokes neurotransmitter release and activates phosphorylation-based signalling. Here, we present the first global temporal profile of presynaptic activity-dependent phospho-signalling, which includes two KCl stimulation levels and analysis of the poststimulus period. We profiled 1,917 regulated phosphopeptides and bioinformatically identified six temporal patterns of co-regulated proteins.

Telomere sequence content can be used to determine ALT activity in tumours.

The replicative immortality of human cancer cells is achieved by activation of a telomere maintenance mechanism (TMM). To achieve this, cancer cells utilise either the enzyme telomerase, or the Alternative Lengthening of Telomeres (ALT) pathway. These distinct molecular pathways are incompletely understood with respect to activation and propagation, as well as their associations with clinical outcomes.

Differential proteomic analysis of actinic keratosis, Bowen's disease and cutaneous squamous cell carcinoma by label-free LC-MS/MS.

Background: The boundaries between actinic keratosis (AK), Bowen's disease (BD), and cutaneous squamous cell carcinoma (cSCC) are sometimes not clear. Large-scale proteomic profiling studies of these lesions are also non-existent.

Objective: To evaluate proteomic changes between normal epidermis, AK, BD and cSCC that could support a molecular classification and improve our understanding of disease progression.

Automated classification and characterization of the mitotic spindle following knockdown of a mitosis-related protein.

Background: Cell division (mitosis) results in the equal segregation of chromosomes between two daughter cells. The mitotic spindle plays a pivotal role in chromosome alignment and segregation during metaphase and anaphase. Structural or functional errors of this spindle can cause aneuploidy, a hallmark of many cancers.

MatCol: a tool to measure fluorescence signal colocalisation in biological systems.

Protein colocalisation is often studied using pixel intensity-based coefficients such as Pearson, Manders, Li or Costes. However, these methods cannot be used to study object-based colocalisations in biological systems. Therefore, a novel method is required to automatically identify regions of fluorescent signal in two channels, identify the co-located parts of these regions, and calculate the statistical significance of the colocalisation.

Extensive Proliferation of Human Cancer Cells with Ever-Shorter Telomeres.

Acquisition of replicative immortality is currently regarded as essential for malignant transformation. This is achieved by activating a telomere lengthening mechanism (TLM), either telomerase or alternative lengthening of telomeres, to counter normal telomere attrition. However, a substantial proportion of some cancer types, including glioblastomas, liposarcomas, retinoblastomas, and osteosarcomas, are reportedly TLM-negative.

Limiting Thymic Precursor Supply Increases the Risk of Lymphoid Malignancy in Murine X-Linked Severe Combined Immunodeficiency.

In early gene therapy trials for SCID-X1, using γ-retroviral vectors, T cell leukemias developed in a subset of patients secondary to insertional proto-oncogene activation. In contrast, we have reported development of T cell leukemias in SCID-X1 mice following lentivirus-mediated gene therapy independent of insertional mutagenesis. A distinguishing feature in our study was that only a proportion of transplanted γc-deficient progenitors were transduced and therefore competent for reconstitution.

An Exploratory Study Identifying a Possible Response Shift Phenomena of the .

A then-test technique was used to investigate the possibility of a response shift in the (GHABP). Following completion of part 1 of the GHABP, 16 adults were invited for hearing-aid follow up appointments. In accordance with then-test technique, participants were asked to think back to before they had their hearing-aids fitted and the GHABP part 1 was completed again to re-establish the disability and handicap scores.

Comparative analysis of whole genome sequencing-based telomere length measurement techniques.

Telomeres are regions of repetitive DNA at the ends of human chromosomes that function to maintain the integrity of the genome. Telomere attrition is associated with cellular ageing, whilst telomere maintenance is a prerequisite for malignant transformation. Whole genome sequencing (WGS) captures sequence information from the entire genome, including the telomeres, and is increasingly being applied in research and in the clinic.

Does Hearing Aid Use Increase the Likelihood of Cerumen Impaction?

Background And Objectives: Impacted cerumen is a common condition in adults. It is commonly believed that wearing hearing aids may increase the cerumen impaction, although no empirical evidence exist. The current study was aimed at studying if the use of hearing aids increase the likelihood of impaction of cerumen.

Reactive Oxygen Species (ROS)-Activated ATM-Dependent Phosphorylation of Cytoplasmic Substrates Identified by Large-Scale Phosphoproteomics Screen.

Ataxia-telangiectasia, mutated (ATM) protein plays a central role in phosphorylating a network of proteins in response to DNA damage. These proteins function in signaling pathways designed to maintain the stability of the genome and minimize the risk of disease by controlling cell cycle checkpoints, initiating DNA repair, and regulating gene expression. ATM kinase can be activated by a variety of stimuli, including oxidative stress.

Is cell culture a risky business? Risk analysis based on scientist survey data.

Cell culture is a technique that requires vigilance from the researcher. Common cell culture problems, including contamination with microorganisms or cells from other cultures, can place the reliability and reproducibility of cell culture work at risk. Here we use survey data, contributed by research scientists based in Australia and New Zealand, to assess common cell culture risks and how these risks are managed in practice.

Single nucleotide differences (SNDs) continue to contaminate the dbSNP database with consequences for human genomics and health.

It has been established that up to 8.3% of the biallelic coding SNPs present in dbSNP are actually artefactual polymorphism-like errors, previously termed single nucleotide differences, or SNDs. In this study, a previous analysis of SNPs in dbSNP was extended and updated to examine how the incidence of SNDs has changed over an intervening five year period.

Predicting peptide binding affinities to MHC molecules using a modified semi-empirical scoring function.

The Major Histocompatibility Complex (MHC) plays an important role in the human immune system. The MHC is involved in the antigen presentation system assisting T cells to identify foreign or pathogenic proteins. However, an MHC molecule binding a self-peptide may incorrectly trigger an immune response and cause an autoimmune disease, such as multiple sclerosis.

Predicting peptide binding to Major Histocompatibility Complex molecules.

The Major Histocompatibility Complex (MHC) constitutes an important part of the human immune system. During infection, pathogenic proteins are processed into peptide fragments by the antigen processing machinery. These peptides bind to MHC molecules and the MHC-peptide complex is then transported to the cell membrane where it elicits an immune response via T-cell binding.

Modeling single nucleotide polymorphisms in the human AKR1C1 and AKR1C2 genes: implications for functional and genotyping analyses.

Enzymes encoded by the AKR1C1 and AKR1C2 genes are responsible for the metabolism of progesterone and 5α-dihydrotestosterone (DHT), respectively. The effect of amino acid substitutions, resulting from single nucleotide polymorphisms (SNPs) in the AKR1C2 gene, on the enzyme kinetics of the AKR1C2 gene product were determined experimentally by Takashi et al. In this paper, we used homology modeling to predict and analyze the structure of AKR1C1 and AKR1C2 genetic variants.

Harvest: an open-source tool for the validation and improvement of peptide identification metrics and fragmentation exploration.

Background: Protein identification using mass spectrometry is an important tool in many areas of the life sciences, and in proteomics research in particular. Increasing the number of proteins correctly identified is dependent on the ability to include new knowledge about the mass spectrometry fragmentation process, into computational algorithms designed to separate true matches of peptides to unidentified mass spectra from spurious matches. This discrimination is achieved by computing a function of the various features of the potential match between the observed and theoretical spectra to give a numerical approximation of their similarity.

A dynamic wavelet-based algorithm for pre-processing tandem mass spectrometry data.

Motivation: Mass spectrometry (MS)-based proteomics is one of the most commonly used research techniques for identifying and characterizing proteins in biological and medical research. The identification of a protein is the critical first step in elucidating its biological function. Successful protein identification depends on various interrelated factors, including effective analysis of MS data generated in a proteomic experiment.

Gene expression of Pseudomonas aeruginosa in a mucin-containing synthetic growth medium mimicking cystic fibrosis lung sputum.

Pseudomonas aeruginosa airway infection is the leading cause of morbidity and mortality in cystic fibrosis (CF) patients. Various in vitro models have been developed to study P. aeruginosa pathobiology in the CF lung.

Novel approaches to detect serum biomarkers for clinical response to interferon-beta treatment in multiple sclerosis.

Interferon beta (IFNbeta) is the most common immunomodulatory treatment for relapsing-remitting multiple sclerosis (RRMS). However, some patients fail to respond to treatment. In this study, we identified putative clinical response markers in the serum and plasma of people with multiple sclerosis (MS) treated with IFNbeta.

Single nucleotide differences (SNDs) in the dbSNP database may lead to errors in genotyping and haplotyping studies.

The creation of single nucleotide polymorphism (SNP) databases (such as NCBI dbSNP) has facilitated scientific research in many fields. SNP discovery and detection has improved to the extent that there are over 17 million human reference (rs) SNPs reported to date (Build 129 of dbSNP). SNP databases are unfortunately not always complete and/or accurate.

Differential protein expression profiling of myocardial tissue in a mouse model of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in genes encoding sarcomere proteins. The mechanisms involved in the development of cardiac hypertrophy and heart failure remain poorly understood. Global proteomic profiling was used to study the cardiac proteome of mice predisposed to developing HCM.