Chemical preservatives in foodstuffs. V. The effect of benzoic acid on the sporulation of Bacillus megaterium

In Bacillus megaterium, benzoic acid does not inhibit the reproduction or germination of already-formed spores when the concentration of undissociated benzoic acid is 10-5-m, but it prevents the formation of new spores in this concentration. It was not possible to eliminate this sporulation-inhibiting effect of benzoic acid by the addition of nutrients containing nitrogen or various metal ions. Ethyl ester of p-hydroxybenzoic acid in the concentration 3 X 10-3-m showed an effect on the sporulation of B. megaterium similar to that of benzoic acid

Chemical preservatives in foodstuffs VI. The effect of silver ions on microbes, in particular on the flora of fresh fish

A study has been made of the effect of silver ions upon microbes in water, in rinsing and washing experiments, and in the storage of fresh Baltic herring in ice containing silver ions. It was observed that silver ions were microbicidic in all experiments except in those with stored fish. Even in this case, silver ions were effective in killing bacteria when they were isolated and kept in an aqueous solution. In all the experiments the pure cultures were less resistant than the natural mixed cultures

BRD4 facilitates replication stress-induced DNA damage response.

Previous reports have demonstrated that select cancers depend on BRD4 to regulate oncogenic gene transcriptional programs. Here we describe a novel role for BRD4 in DNA damage response (DDR). BRD4 associates with and regulates the function of pre-replication factor CDC6 and plays an indispensable part in DNA replication checkpoint signaling. Inhibition of BRD4 by JQ1 or AZD5153 resulted in a rapid, time-dependent reduction in CHK1 phosphorylation and aberrant DNA replication re-initiation. Furthermore, BRD4 inhibition sensitized cancer cells to various replication stress-inducing agents, and synergized with ATR inhibitor AZD6738 to induce cell killing across a number of cancer cell lines. The synergistic interaction between AZD5153 and AZD6738 is translatable to in vivo ovarian cell-line and patient-derived xenograft models. Taken together, our study uncovers a new biological function of BRD4 and provides mechanistic rationale for combining BET inhibitors with DDR-targeted agents for cancer therapy

Simple integrative preprocessing preserves what is shared in data sources

<p>Abstract</p> <p>Background</p> <p>Bioinformatics data analysis toolbox needs general-purpose, fast and easily interpretable preprocessing tools that perform data integration during exploratory data analysis. Our focus is on vector-valued data sources, each consisting of measurements of the same entity but on different variables, and on tasks where source-specific variation is considered noisy or not interesting. Principal components analysis of all sources combined together is an obvious choice if it is not important to distinguish between data source-specific and shared variation. Canonical Correlation Analysis (CCA) focuses on mutual dependencies and discards source-specific "noise" but it produces a separate set of components for each source.</p> <p>Results</p> <p>It turns out that components given by CCA can be combined easily to produce a linear and hence fast and easily interpretable feature extraction method. The method fuses together several sources, such that the properties they share are preserved. Source-specific variation is discarded as uninteresting. We give the details and implement them in a software tool. The method is demonstrated on gene expression measurements in three case studies: classification of cell cycle regulated genes in yeast, identification of differentially expressed genes in leukemia, and defining stress response in yeast. The software package is available at <url>http://www.cis.hut.fi/projects/mi/software/drCCA/</url>.</p> <p>Conclusion</p> <p>We introduced a method for the task of data fusion for exploratory data analysis, when statistical dependencies between the sources and not within a source are interesting. The method uses canonical correlation analysis in a new way for dimensionality reduction, and inherits its good properties of being simple, fast, and easily interpretable as a linear projection.</p

Discovery of Sexual Dimorphisms in Metabolic and Genetic Biomarkers

Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values<3.8 x 10(-4); Bonferroni-corrected threshold). Sex-specific genome-wide association studies (GWAS) showed genome-wide significant differences in beta-estimates for SNPs in the CPS1 locus (carbamoyl-phosphate synthase 1, significance level: p<3.8 x 10(-10); Bonferroni-corrected threshold) for glycine. We showed that the metabolite profiles of males and females are significantly different and, furthermore, that specific genetic variants in metabolism-related genes depict sexual dimorphism. Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider sex-specific effects in design and interpretation

Psychiatric (Axis I) and personality (Axis II) disorders and subjective psychiatric symptoms in chronic tinnitus

Objective: Chronic tinnitus has been associated with several psychiatric disorders. Only few studies have investigated these disorders using validated diagnostic interviews. The aims were to diagnose psychiatric and personality disorders with structured interviews, to assess self-rated psychiatric symptoms and elucidate temporal relations between psychiatric disorders and tinnitus. Design: Current and lifetime DSM-IV diagnoses of axis-I (psychiatric disorders) and axis-II (personality disorders) were assessed using structured clinical interviews (SCID-I and -II). Current subjective psychiatric symptoms were evaluated via self-rating instruments: the Symptom Check List-90 (SCL-90), the Beck Depression Inventory, and the Dissociative Experiences Scale (DES). Study sample: 83 patients (mean age 51.7, 59% men) with chronic, disturbing tinnitus and a median Tinnitus Handicap Inventory score of 32. Results: The rates of lifetime and current major depression were 26.5% and 2.4%. The lifetime rate of obsessive-compulsive personality disorder (type C) was 8.4%. None of the patients had cluster B personality disorder or psychotic symptoms. The SCL-90 subscales did not differ from the general population, and median DES score was low, 2.4. Conclusions: Tinnitus patients are prone to episodes of major depression and often also have obsessive-compulsive personality features. Psychiatric disorders seem to be comorbid or predisposing conditions rather than consequences of tinnitus.Clinical trial reference: ClinicalTrials.gov (ID NCT 01929837).</p

Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells.

Elevated APOBEC3B expression in tumours correlates with a kataegic pattern of localised hypermutation. We assessed the cellular phenotypes associated with high-level APOBEC3B expression and the influence of p53 status on these phenotypes using an isogenic system.We used RNA interference of p53 in cells with inducible APOBEC3B and assessed DNA damage response (DDR) biomarkers. The mutational effects of APOBEC3B were assessed using whole-genome sequencing. In vitro small-molecule inhibitor sensitivity profiling was used to identify candidate therapeutic vulnerabilities.Although APOBEC3B expression increased the incorporation of genomic uracil, invoked DDR biomarkers and caused cell cycle arrest, inactivation of p53 circumvented APOBEC3B-induced cell cycle arrest without reversing the increase in genomic uracil or DDR biomarkers. The continued expression of APOBEC3B in p53-defective cells not only caused a kataegic mutational signature but also caused hypersensitivity to small-molecule DDR inhibitors (ATR, CHEK1, CHEK2, PARP, WEE1 inhibitors) as well as cisplatin/ATR inhibitor and ATR/PARP inhibitor combinations.Although loss of p53 might allow tumour cells to tolerate elevated APOBEC3B expression, continued expression of this enzyme might impart a number of therapeutic vulnerabilities upon tumour cells

Parents' experiences of an abnormal ultrasound examination - vacillating between emotional confusion and sense of reality

<p>Abstract</p> <p>Background</p> <p>An ultrasound examination is an important confirmation of the pregnancy and is accepted without reflection to any prenatal diagnostic aspects. An abnormal finding often comes unexpectedly and is a shock for the parents. The aim was to generate a theoretical understanding of parents' experiences of the situation when their fetus is found to have an abnormality at a routine ultrasound examination.</p> <p>Methods</p> <p>Sixteen parents, mothers and fathers, whose fetus had been diagnosed with an abnormality during an ultrasound scan in the second or third trimester, were interviewed. The study employed a grounded theory approach.</p> <p>Results</p> <p>The core category <it>vacillating between the emotional confusion and sense of reality </it>is related to the main concern <it>assessment of the diagnosis impact on the well-being of the fetus</it>. Two other categories <it>Entering uncertainty </it>and <it>Involved in an ongoing change and adaptation </it>have each five sub-categories.</p> <p>Conclusions</p> <p>Parents are aware of that ultrasound examination is a tool for identifying abnormalities prenatally. The information about the abnormality initially results in broken expectations and anxiety. Parents become involved in ongoing change and adaptation. They need information about the ultrasound findings and the treatment without prolonged delay and in a suitable environment. The examiner who performs the ultrasound examination must be aware of how anxiety can be intensified by environmental factors. All parents should to be offered a professional person to give them <it>s</it>upport as a part of the routine management of this situation.</p

Mutation screening of the RNF8, UBC13 and MMS2 genes in Northern Finnish breast cancer families

<p>Abstract</p> <p>Background</p> <p>Currently known susceptibility genes such as <it>BRCA1 </it>and <it>BRCA2 </it>explain less than 25% of familial aggregation of breast cancer, which suggests the involvement of additional susceptibility genes. RNF8, UBC13 and MMS2 are involved in the DNA damage response pathway and play important roles in BRCA1-mediated DNA damage recognition. Based on the evidence that several players in the ubiquitin-mediated BRCA1-dependent DDR seem to contribute to breast cancer predisposition, <it>RNF8, UBC13 </it>and <it>MMS2 </it>were considered plausible candidate genes for susceptibility to breast cancer.</p> <p>Methods</p> <p>The entire coding region and splice junctions of <it>RNF8, UBC13 </it>and <it>MMS2 </it>genes were screened for mutations in affected index cases from 123 Northern Finnish breast cancer families by using conformation sensitive gel electrophoresis, high resolution melting (HRM) analysis and direct sequencing.</p> <p>Results</p> <p>Mutation analysis revealed several changes in <it>RNF8 </it>and <it>UBC13</it>, whereas no aberrations were observed in <it>MMS2</it>. None of the found sequence changes appeared to associate with breast cancer susceptibility.</p> <p>Conclusions</p> <p>The present data suggest that mutations in <it>RNF8, UBC13 </it>and <it>MMS2 </it>genes unlikely make any sizeable contribution to breast cancer predisposition in Northern Finland.</p