Germline Genetic Findings Which May Impact Therapeutic Decisions in Families with a Presumed Predisposition for Hereditary Breast and Ovarian Cancer

In this study, we aim to gain insight in the germline mutation spectrum of ATM, BARD1, BRIP1, ERCC4, PALB2, RAD51C and RAD51D in breast and ovarian cancer families from Spain. We have selected 180 index cases in whom a germline mutation in BRCA1 and BRCA2 was previously ruled out. The importance of disease-causing variants in these genes lies in the fact that they may have possible therapeutic implications according to clinical guidelines. All variants were assessed by combined annotation dependent depletion (CADD) for scoring their deleteriousness. In addition, we used the cancer genome interpreter to explore the implications of some variants in drug response. Finally, we compiled and evaluated the family history to assess whether carrying a pathogenic mutation was associated with age at diagnosis, tumour diversity of the pedigree and total number of cancer cases in the family. Eight unequivocal pathogenic mutations were found and another fourteen were prioritized as possible causal variants. Some of these molecular results could contribute to cancer diagnosis, treatment selection and prevention. We found a statistically significant association between tumour diversity in the family and carrying a variant with a high score predicting pathogenicity (p = 0.0003)

Public administration in an age of austerity:the future of the discipline

Reflecting changes in the nature of governance, some have questioned whether Public Administration is now an historical anachronism. While a legitimate debate exists between sceptics and optimists, this special issue demonstrates grounds for optimism by indicating the continuing diversity and adaptability of the field of Public Administration. In this introduction, we first sketch the variety of intellectual traditions which comprise the field of modern Public Administration. We then consider institutional challenges facing the subject given considerable pressures towards disciplinary fragmentation, and ideological challenges arising from a new distrust of public provision in the UK. Despite these challenges, Public Administration continues to provide a framework to analyse the practice of government and governance, governing institutions and traditions, and their wider sociological context. It can also directly inform policy reform - even if this endeavour can have its own pitfalls and pratfalls for the 'engaged' academic. We further suggest that, rather than lacking theoretical rigour, new approaches are developing that recognise the structural and political nature of the determinants of public administration. Finally, we highlight the richness of modern comparative work in Public Administration. Researchers can usefully look beyond the Atlantic relationship for theoretical enhancement and also consider more seriously the recursive and complex nature of international pressures on public administration

Brain energy metabolism: A roadmap for future research

Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD+, as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation. It describes our current level of understanding of these facets of brain energy metabolism as well as a roadmap for future research

Understanding childhood asthma in focus groups: perspectives from mothers of different ethnic backgrounds

BACKGROUND: Diagnosing childhood asthma is dependent upon parental symptom reporting but there are problems in the use of words and terms. The purpose of this study was to describe and compare understandings of childhood 'asthma' by mothers from three different ethnic backgrounds who have no personal experience of diagnosing asthma. A better understanding of parents' perceptions of an illness by clinicians should improve communication and management of the illness. METHOD: Sixty-six mothers living in east London describing their ethnic backgrounds as Bangladeshi, white English and black Caribbean were recruited to 9 focus groups. Discussion was semi-structured. Three sessions were conducted with each ethnic group. Mothers were shown a video clip of a boy with audible wheeze and cough and then addressed 6 questions. Sessions were recorded and transcribed verbatim. Responses were compared within and between ethnic groups. RESULTS: Each session, and ethnic group overall, developed a particular orientation to the discussion. Some mothers described the problem using single signs, while others imitated the sound or made comparisons to other illnesses. Hereditary factors were recognised by some, although all groups were concerned with environmental triggers. Responses about what to do included 'normal illness' strategies, use of health services and calls for complementary treatment. All groups were concerned about using medication every day. Expectations about the quality of life were varied, with recognition that restrictions may be based on parental beliefs about asthma, rather than asthma itself. CONCLUSION: Information from these focus groups suggests mothers know a great deal about childhood asthma even though they have no personal experience of it. Knowledge of how mothers from these ethnic backgrounds perceive asthma may facilitate doctor – patient communication with parents of children experiencing breathing difficulties

An iterative block-shifting approach to retention time alignment that preserves the shape and area of gas chromatography-mass spectrometry peaks

<p>Abstract</p> <p>Background</p> <p>Metabolomics, petroleum and biodiesel chemistry, biomarker discovery, and other fields which rely on high-resolution profiling of complex chemical mixtures generate datasets which contain millions of detector intensity readings, each uniquely addressed along dimensions of <it>time </it>(<it>e.g.</it>, <it>retention time </it>of chemicals on a chromatographic column), a <it>spectral value </it>(<it>e.g., mass-to-charge ratio </it>of ions derived from chemicals), and the <it>analytical run number</it>. They also must rely on data preprocessing techniques. In particular, inter-run variance in the retention time of chemical species poses a significant hurdle that must be cleared before feature extraction, data reduction, and knowledge discovery can ensue. <it>Alignment methods</it>, for calibrating retention reportedly (and in our experience) can misalign matching chemicals, falsely align distinct ones, be unduly sensitive to chosen values of input parameters, and result in distortions of peak shape and area.</p> <p>Results</p> <p>We present an iterative block-shifting approach for retention-time calibration that detects chromatographic features and qualifies them by retention time, spectrum, and the effect of their inclusion on the quality of alignment itself. Mass chromatograms are aligned pairwise to one selected as a reference. In tests using a 45-run GC-MS experiment, block-shifting reduced the absolute deviation of retention by greater than 30-fold. It compared favourably to COW and XCMS with respect to alignment, and was markedly superior in preservation of peak area.</p> <p>Conclusion</p> <p>Iterative block-shifting is an attractive method to align GC-MS mass chromatograms that is also generalizable to other two-dimensional techniques such as HPLC-MS.</p

Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment

We report on three patients (two siblings and one unrelated) presenting in infancy with progressive muscle weakness and paralysis of the diaphragm. Metabolic studies revealed a profile of plasma acylcarnitines and urine organic acids suggestive of a mild form of the multiple acyl-CoA dehydrogenation defect (MADD, ethylmalonic/adipic acid syndrome). Subsequently, a profound flavin deficiency in spite of a normal dietary riboflavin intake was established in the plasma of all three children, suggesting a riboflavin transporter defect. Genetic analysis of these patients demonstrated mutations in the C20orf54 gene which encodes the human homolog of a rat riboflavin transporter. This gene was recently implicated in the Brown-Vialetto-Van Laere syndrome, a rare neurological disorder which may either present in infancy with neurological deterioration with hypotonia, respiratory insufficiency and early death, or later in life with deafness and progressive ponto-bulbar palsy. Supplementation of riboflavin rapidly improved the clinical symptoms as well as the biochemical abnormalities in our patients, demonstrating that high dose riboflavin is a potential treatment for the Brown-Vialetto-Van Laere syndrome as well as for the Fazio Londe syndrome which is considered to be the same disease entity without the deafnes

The MetabolomeExpress Project: enabling web-based processing, analysis and transparent dissemination of GC/MS metabolomics datasets

<p>Abstract</p> <p>Background</p> <p>Standardization of analytical approaches and reporting methods via community-wide collaboration can work synergistically with web-tool development to result in rapid community-driven expansion of online data repositories suitable for data mining and meta-analysis. In metabolomics, the inter-laboratory reproducibility of gas-chromatography/mass-spectrometry (GC/MS) makes it an obvious target for such development. While a number of web-tools offer access to datasets and/or tools for raw data processing and statistical analysis, none of these systems are currently set up to act as a public repository by easily accepting, processing and presenting publicly submitted GC/MS metabolomics datasets for public re-analysis.</p> <p>Description</p> <p>Here, we present MetabolomeExpress, a new File Transfer Protocol (FTP) server and web-tool for the online storage, processing, visualisation and statistical re-analysis of publicly submitted GC/MS metabolomics datasets. Users may search a quality-controlled database of metabolite response statistics from publicly submitted datasets by a number of parameters (eg. metabolite, species, organ/biofluid etc.). Users may also perform meta-analysis comparisons of multiple independent experiments or re-analyse public primary datasets via user-friendly tools for t-test, principal components analysis, hierarchical cluster analysis and correlation analysis. They may interact with chromatograms, mass spectra and peak detection results via an integrated raw data viewer. Researchers who register for a free account may upload (via FTP) their own data to the server for online processing via a novel raw data processing pipeline.</p> <p>Conclusions</p> <p>MetabolomeExpress <url>https://www.metabolome-express.org</url> provides a new opportunity for the general metabolomics community to transparently present online the raw and processed GC/MS data underlying their metabolomics publications. Transparent sharing of these data will allow researchers to assess data quality and draw their own insights from published metabolomics datasets.</p

An Ultra-Fast Metabolite Prediction Algorithm

Small molecules are central to all biological processes and metabolomics becoming an increasingly important discovery tool. Robust, accurate and efficient experimental approaches are critical to supporting and validating predictions from post-genomic studies. To accurately predict metabolic changes and dynamics, experimental design requires multiple biological replicates and usually multiple treatments. Mass spectra from each run are processed and metabolite features are extracted. Because of machine resolution and variation in replicates, one metabolite may have different implementations (values) of retention time and mass in different spectra. A major impediment to effectively utilizing untargeted metabolomics data is ensuring accurate spectral alignment, enabling precise recognition of features (metabolites) across spectra. Existing alignment algorithms use either a global merge strategy or a local merge strategy. The former delivers an accurate alignment, but lacks efficiency. The latter is fast, but often inaccurate. Here we document a new algorithm employing a technique known as quicksort. The results on both simulated data and real data show that this algorithm provides a dramatic increase in alignment speed and also improves alignment accuracy

Temperature Anomalies and Mortality Events in Marine Communities: Insights on Factors behind Differential Mortality Impacts in the NW Mediterranean

Two large-scale mass mortality events (MMEs) of unprecedented extent and severity affecting rocky benthic communities occurred during the summers of 1999 and 2003 along the coasts of the NW Mediterranean Sea. These mortality outbreaks were associated with positive thermal anomalies. In this study, we performed an analysis of inter-regional and inter-annual differences in temperature (T) conditions associated with MMEs of the red gorgonian Paramuricea clavata by analyzing high resolution T time series (hourly records for 3 to 8 years) from four regions of the NW Mediterranean with differing hydrological conditions and biological impacts. High resolution records allowed a detailed analysis using classical and new descriptors to characterize T anomalies. We were able to determine that the MMEs were triggered by two main types of positive thermal anomalies, with the first type being characterized by short periods (2 to 5 days) with high Mean T reaching more than 27°C in some regions and being associated with high intra-day and intra-period variability, while the second type of anomaly presented long duration (near one month) at warm T (24°C) with low intra-period variability. Inter-regional patterns arose; some regions displayed both types of anomalies, while others exhibited only one type. The results showed that T conditions should be considered as the main factor that explains the observed inter-regional and inter-annual differences in mortality impacts. In explaining these differences, the late timing of T anomalies, in addition to their magnitude was found to be determinant. Finally, by combining thermotolerance experimental data with the maximal T stress conditions observed in the four regions, we were able to determine the differential risk of mass mortality across regions. We conclude that expanding high resolution T series is important for the development of sound management and conservation plans to protect Mediterranean marine biodiversity in the face of climate change

The use and limits of ITS data in the analysis of intraspecific variation in Passiflora L. (Passifloraceae)

The discovery and characterization of informative intraspecific genetic markers is fundamental for evolutionary and conservation genetics studies. Here, we used nuclear ribosomal ITS sequences to access intraspecific genetic diversity in 23 species of the genus Passiflora L. Some degree of variation was detected in 21 of these. The Passiflora and Decaloba (DC.) Rchb. subgenera showed significant differences in the sizes of the two ITS regions and in GC content, which can be related to reproductive characteristics of species in these subgenera. Furthermore, clear geographical patterns in the spatial distribution of sequence types were identified in six species. The results indicate that ITS may be a useful tool for the evaluation of intraspecific genetic variation in Passiflora