Advances in structure elucidation of small molecules using mass spectrometry

The structural elucidation of small molecules using mass spectrometry plays an important role in modern life sciences and bioanalytical approaches. This review covers different soft and hard ionization techniques and figures of merit for modern mass spectrometers, such as mass resolving power, mass accuracy, isotopic abundance accuracy, accurate mass multiple-stage MS(n) capability, as well as hybrid mass spectrometric and orthogonal chromatographic approaches. The latter part discusses mass spectral data handling strategies, which includes background and noise subtraction, adduct formation and detection, charge state determination, accurate mass measurements, elemental composition determinations, and complex data-dependent setups with ion maps and ion trees. The importance of mass spectral library search algorithms for tandem mass spectra and multiple-stage MS(n) mass spectra as well as mass spectral tree libraries that combine multiple-stage mass spectra are outlined. The successive chapter discusses mass spectral fragmentation pathways, biotransformation reactions and drug metabolism studies, the mass spectral simulation and generation of in silico mass spectra, expert systems for mass spectral interpretation, and the use of computational chemistry to explain gas-phase phenomena. A single chapter discusses data handling for hyphenated approaches including mass spectral deconvolution for clean mass spectra, cheminformatics approaches and structure retention relationships, and retention index predictions for gas and liquid chromatography. The last section reviews the current state of electronic data sharing of mass spectra and discusses the importance of software development for the advancement of structure elucidation of small molecules

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Genetic and epigenetic mechanisms and their possible role in abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a common disease associated with significant cardiovascular morbidity and mortality. The pathogenesis of AAA is poorly defined, making targeting of new therapies problematic. Current evidence favours an interaction of multiple environmental and genetic factors in the initiation and progression of AAA. Epigenetics is the term used to define the properties of the genome that are not explained by the primary sequence, but are due to the modifications of DNA and/or associated proteins. Previous research indicates the association of gene specific promoter DNA hyper-methylation and global DNA hypo-methylation with atherosclerosis. Evidence also suggests an important role for epigenetic processes such as histone acetylation in cardiovascular diseases including atherosclerosis and restenosis. Altered DNA methylation or histone acetylation occur in inflammation, cellular proliferation and remodelling processes and therefore maybe relevant to the pathology of AAA. Important risk factors for AAA, including cigarette smoking, older age, male gender and hypertension, have been linked with epigenetic effects and thus could act in this way to promote AAA. In this review, we discuss the potential role of epigenetic mechanisms in AAA. Since epigenetic alterations are to some extent reversible, further study of this area may identify new treatment targets for AAA

Garnaut Climate Change Review: The Impacts of Climate Change on Three Health Outcomes: Temperature-Related Mortality and Hospitalisations, Salmonellosis and Other Bacterial Gastroenteritis, and Population at Risk From Dengue

Climate change will affect the health of Australians over this century in many ways. Some impacts will become evident before others. Some will occur via quite direct pathways (e.g. heatwaves and death); others will occur via indirect pathways entailing disturbances of natural ecological systems (e.g. mosquito population range and activity) or disruption to livelihoods and communities (e.g. mental health consequences of prolonged droughts and regional drying trends). Most health impacts will occur at different levels among regions and population sub-groups, reflecting the influence of environment, socioeconomic circumstances, infrastructural and institutional resources, and local preventive (adaptive) strategies on the patterns of disease. The likely health impacts are many and varied. The main health risks in Australia from climate change include: health impacts of weather disasters (floods, storms, cyclones, bushfires, etc.); health impacts of temperature extremes, including heatwaves; mosquito-borne infectious diseases (e.g. dengue fever, Ross River virus disease); food-borne infectious diseases (including those due to Salmonella, Campylobacter and many other microbes); water-borne infectious diseases, and other health risks from poor water quality; diminished food availability: yields, costs/affordability, nutritional consequences; increases in urban air pollution (e.g. ozone), and the interaction of this environmental health hazard with meteorological conditions; changes in aeroallergens (spores, pollens), potentially exacerbating asthma and other allergic respiratory diseases; mental health consequences of social, economic and demographic dislocations (e.g. in parts of rural Australia, and via disruptions to traditional ways of living in remote Indigenous communities) At this stage of research and understanding, and in context of available time and resources, it is only possible to include a minority of those anticipated health impacts in this quantitative modelling exercise

Association between osteopontin and human abdominal aortic aneurysm

Objectives—In vitro and animal studies have implicated osteopontin (OPN) in the pathogenesis of aortic aneurysm. The relationship between serum concentration of OPN and variants of the OPN gene with human abdominal aortic aneurysm(AAA) was investigated.\ud Methods and Results—OPN genotypes were examined in 4227 subjects in which aortic diameter and clinical risk factors\ud were measured. Serum OPN was measured by ELISA in two cohorts of 665 subjects. The concentration of serum OPN\ud was independently associated with the presence of AAA. Odds ratios (and 95% confidence intervals) for upper\ud compared with lower OPN tertiles in predicting presence of AAA were 2.23 (1.29 to 3.85, P0.004) for the population\ud cohort and 4.08 (1.67 to 10.00, P0.002) for the referral cohort after adjusting for other risk factors. In 198 patients with complete follow-up of aortic diameter at 3 years, initial serum OPN predicted AAA growth after adjustment for other risk factors (standardized coefficient 0.24, P0.001). The concentration of OPN in the aortic wall was greater in patients with small AAAs (30 to 50 mm) than those with aortic occlusive disease alone. There was no association between five single nucleotide polymorphisms or haplotypes of the OPN gene and aortic diameter or AAA expansion.\ud Conclusions—Serum and tissue concentrations of OPN are associated with human AAA. We found no relationship\ud between variation of the OPN gene and AAA. OPN may be a useful biomarker for AAA presence and growth