Genetic determinants of metabolism in health and disease: from biochemical genetics to genome-wide associations

Increasingly sophisticated measurement technologies have allowed the fields of metabolomics and genomics to identify, in parallel, risk factors of disease; predict drug metabolism; and study metabolic and genetic diversity in large human populations. Yet the complementarity of these fields and the utility of studying genes and metabolites together is belied by the frequent separate, parallel applications of genomic and metabolomic analysis. Early attempts at identifying co-variation and interaction between genetic variants and downstream metabolic changes, including metabolic profiling of human Mendelian diseases and quantitative trait locus mapping of individual metabolite concentrations, have recently been extended by new experimental designs that search for a large number of gene-metabolite associations. These approaches, including metabolomic quantitiative trait locus mapping and metabolomic genome-wide association studies, involve the concurrent collection of both genomic and metabolomic data and a subsequent search for statistical associations between genetic polymorphisms and metabolite concentrations across a broad range of genes and metabolites. These new data-fusion techniques will have important consequences in functional genomics, microbial metagenomics and disease modeling, the early results and implications of which are reviewed

Acoustic flow sensor using a passive bell transducer

Sensing based on a passive transducer that is wirelessly linked to a nearby data collection node can offer an attractive solution for use in remote, inaccessible, or harsh environments. Here we report a pipe flow sensor based on this principle. A transducer mounted inside the pipe generates an acoustic signal that is picked up by an external microphone. The passive transducer comprises a cavity with a trapped ball that can oscillate in response to flow. Its collisions generate an acoustic signal correlated to the flow speed. The transducer is implemented on a 6 mm diameter probe and characterized as a water flow meter. The time - average microphone voltage output is calculated by an analogue circuit, without any further signal processing. With the microphone mounted on the probe, and for flow rates in the range 0.35 m/s to 6.5 m/s, correlation between the sensor voltage output and flow rate data from a commercial flow meter is demonstrated with a worst-case accuracy of 2%. This was achieved by simple averaging of the acoustic pulse train over a 5-second time interval. Consistent correlation with the microphone mounted on the pipe wall at distances up to 150 mm from the probe location is also reported. These results demonstrate the viability of remote acoustic flow sensing using passive structures and offer a simple and minimally invasive flow monitoring method

Antimicrobial resistance in human populations: challenges and opportunities.

Antimicrobial resistance (AMR) is a global public health threat. Emergence of AMR occurs naturally, but can also be selected for by antimicrobial exposure in clinical and veterinary medicine. Despite growing worldwide attention to AMR, there are substantial limitations in our understanding of the burden, distribution and determinants of AMR at the population level. We highlight the importance of population-based approaches to assess the association between antimicrobial use and AMR in humans and animals. Such approaches are needed to improve our understanding of the development and spread of AMR in order to inform strategies for the prevention, detection and management of AMR, and to support the sustainable use of antimicrobials in healthcare

Miniaturized wet-wet differential pressure sensor

We report a miniaturized wet-wet differential pressure sensor with applications in pressure and flow sensing in water networks and other harsh environments. The device is similar in concept to a conventional wet-wet differential pressure sensor in that the sensing element is protected from the external environment by oil-filled cavities closed off by corrugated diaphragms. However, with a package envelope of 11.0 x 4.8 x 3.4 mm 3 , corresponding to a volume of only 0.18 cm 3 , the device is considerably smaller than commercially available wet-wet differential pressure sensors. A high degree of miniaturization has been achieved by using micromachining to fabricate the corrugated diaphragms. Preliminary experimental results are presented showing operation of the device as a delta-pressure flow speed sensor in a water flow test rig

Talking a team into being in online workplace collaborations: the discourse of virtual work

Digital communication technologies led to a revolution in how people interact at work: relying on computer-mediated communication technologies is now a must, rather than an alternative. This empirical study investigates how colleagues in a virtual team use synchronous online communication platform in the workplace. Inspired by the conceptualisation of web-based communication platforms as tool, place or context of social construction, we explore the discursive strategies that contribute to the construction of the team’s shared sense of purpose and identity, a collegial atmosphere and consequently lead to effective collaboration. The close analyses of real-life data from a multinational workplace provide insights into the everyday communication practices of virtual team members. Our findings supplement organisational literature based on etic observations of the effectiveness of virtual work and provide a basis for further theorisations about how communication technologies affect the ecology of and discourse practices in computer-mediated communication at work

Topological Analysis of Metabolic Networks Integrating Co-Segregating Transcriptomes and Metabolomes in Type 2 Diabetic Rat Congenic Series

Background: The genetic regulation of metabolic phenotypes (i.e., metabotypes) in type 2 diabetes mellitus is caused by complex organ-specific cellular mechanisms contributing to impaired insulin secretion and insulin resistance. Methods: We used systematic metabotyping by 1H NMR spectroscopy and genome-wide gene expression in white adipose tissue to map molecular phenotypes to genomic blocks associated with obesity and insulin secretion in a series of rat congenic strains derived from spontaneously diabetic Goto-Kakizaki (GK) and normoglycemic Brown-Norway (BN) rats. We implemented a network biology strategy approach to visualise shortest paths between metabolites and genes significantly associated with each genomic block. Results: Despite strong genomic similarities (95-99%) among congenics, each strain exhibited specific patterns of gene expression and metabotypes, reflecting metabolic consequences of series of linked genetic polymorphisms in the congenic intervals. We subsequently used the congenic panel to map quantitative trait loci underlying specific metabotypes (mQTL) and genome-wide expression traits (eQTL). Variation in key metabolites like glucose, succinate, lactate or 3-hydroxybutyrate, and second messenger precursors like inositol was associated with several independent genomic intervals, indicating functional redundancy in these regions. To navigate through the complexity of these association networks we mapped candidate genes and metabolites onto metabolic pathways and implemented a shortest path strategy to highlight potential mechanistic links between metabolites and transcripts at colocalized mQTLs and eQTLs. Minimizing shortest path length drove prioritization of biological validations by gene silencing. Conclusions: These results underline the importance of network-based integration of multilevel systems genetics datasets to improve understanding of the genetic architecture of metabotype and transcriptomic regulations and to characterize novel functional roles for genes determining tissue-specific metabolism

Increased SERCA2a sub-cellular heterogeneity in right-ventricular heart failure inhibits excitation-contraction coupling and modulates arrhythmogenic dynamics

The intracellular calcium handling system of cardiomyocytes is responsible for controlling excitation-contraction coupling (ECC) and has been linked to pro-arrhythmogenic cellular phenomena in conditions such as heart failure (HF). SERCA2a, responsible for intracellular uptake, is a primary regulator of calcium homeostasis, and remodelling of its function has been proposed as a causal factor underlying cellular and tissue dysfunction in disease. Whereas adaptations to the global (i.e. whole-cell) expression of SERCA2a have been previously investigated in the context of multiple diseases, the role of its spatial profile in the sub-cellular volume has yet to be elucidated. We present an approach to characterize the sub-cellular heterogeneity of SERCA2a and apply this approach to quantify adaptations to the length-scale of heterogeneity (the distance over which expression is correlated) associated with right-ventricular (RV)-HF. These characterizations informed simulations to predict the functional implications of this heterogeneity, and its remodelling in disease, on ECC, the dynamics of calcium-transient alternans and the emergence of spontaneous triggered activity. Image analysis reveals that RV-HF is associated with an increase in length-scale and its inter-cellular variability; simulations predict that this increase in length-scale can reduce ECC and critically modulate the vulnerability to both alternans and triggered activity

Developing and applying heterogeneous phylogenetic models with XRate

Modeling sequence evolution on phylogenetic trees is a useful technique in computational biology. Especially powerful are models which take account of the heterogeneous nature of sequence evolution according to the "grammar" of the encoded gene features. However, beyond a modest level of model complexity, manual coding of models becomes prohibitively labor-intensive. We demonstrate, via a set of case studies, the new built-in model-prototyping capabilities of XRate (macros and Scheme extensions). These features allow rapid implementation of phylogenetic models which would have previously been far more labor-intensive. XRate's new capabilities for lineage-specific models, ancestral sequence reconstruction, and improved annotation output are also discussed. XRate's flexible model-specification capabilities and computational efficiency make it well-suited to developing and prototyping phylogenetic grammar models. XRate is available as part of the DART software package: http://biowiki.org/DART .Comment: 34 pages, 3 figures, glossary of XRate model terminolog