Translational Research from an Informatics Perspective

Clinical and translational research (CTR) is an essential part of a sustainable global health system. Informatics is now recognized as an important en-abler of CTR and informaticians are increasingly called upon to help CTR efforts. The US National Institutes of Health mandated biomedical informatics activity as part of its new national CTR grant initiative, the Clinical and Translational Science Award (CTSA). Traditionally, translational re-search was defined as the translation of laboratory discoveries to patient care (bench to bedside). We argue, however, that there are many other kinds of translational research. Indeed, translational re-search requires the translation of knowledge dis-covered in one domain to another domain and is therefore an information-based activity. In this panel, we will expand upon this view of translational research and present three different examples of translation to illustrate the point: 1) bench to bedside, 2) Earth to space and 3) academia to community. We will conclude with a discussion of our local translational research efforts that draw on each of the three examples

From laboratory manipulations to Earth system models: scaling calcification impacts of ocean acidification

The observed variation in the calcification responses of coccolithophores to changes in carbonate chemistry paints a highly incoherent picture, particularly for the most commonly cultured "species", <i>Emiliania huxleyi</i>. The disparity between magnitude and potentially even sign of the calcification change under simulated end-of-century ocean surface chemical changes (higher <i>p</i>CO<sub>2</sub>, lower pH and carbonate saturation), raises challenges to quantifying future carbon cycle impacts and feedbacks because it introduces significant uncertainty in parameterizations used for global models. Here we compile the results of coccolithophore carbonate chemistry manipulation experiments and review how ocean carbon cycle models have attempted to bridge the gap from experiments to global impacts. Although we can rule out methodological differences in how carbonate chemistry is altered as introducing an experimental bias, the absence of a consistent calcification response implies that model parameterizations based on small and differing subsets of experimental observations will lead to varying estimates for the global carbon cycle impacts of ocean acidification. We highlight two pertinent observations that might help: (1) the degree of coccolith calcification varies substantially, both between species and within species across different genotypes, and (2) the calcification response across mesocosm and shipboard incubations has so-far been found to be relatively consistent. By analogy to descriptions of plankton growth rate vs. temperature, such as the "Eppley curve", which seek to encapsulate the net community response via progressive assemblage change rather than the response of any single species, we posit that progressive future ocean acidification may drive a transition in dominance from more to less heavily calcified coccolithophores. Assemblage shift may be more important to integrated community calcification response than species-specific response, highlighting the importance of whole community manipulation experiments to models in the absence of a complete physiological understanding of the underlying calcification process. However, on a century time-scale, regardless of the parameterization adopted, the atmospheric <i>p</i>CO<sub>2</sub> impact of ocean acidification is minor compared to other global carbon cycle feedbacks

The effect of inelastic processes on tunneling

We study an electron that interacts with phonons or other linear or nonlinear excitations as it resonantly tunnels. The method we use is based on mapping a many-body problem in a large variational space exactly onto a one-body problem. The method is conceptually simpler than previous Green's function approaches, and allows the essentially exact numerical solution of much more general problems. We solve tunneling problems with transverse channels, multiple sites coupled to phonons, and multiple phonon degrees of freedom and excitations.Comment: 12 pages, REVTex, 4 figures in compressed tar .ps forma

Hypoxia-inducible factor-1α and -2α are expressed in most rectal cancers but only hypoxia-inducible factor-1α is associated with prognosis

The hypoxia-mediated response of tumours is a major determining factor in growth and metastasis. Understanding tumour biology under hypoxic conditions is crucial for the development of antiangiogenic therapy. Using one of the largest cohorts of rectal adenocarcinomas to date, this study investigated hypoxia-inducible factor-1α (HIF-1α) and HIF-2α protein expression in relation to rectal cancer recurrence and cancer-specific survival. Patients (n=90) who had undergone surgery for rectal adenocarcinoma, with no prior neoadjuvant therapy or metastatic disease, and for whom adequate follow-up data were available were selected. Microvessel density (MVD), HIF-1α and HIF-2α expressions were assessed immunohistologically with the CD34 antibody for vessel identification and the NB100-131B and NB100-132D3 antibodies for HIF-1α and HIF-2α, respectively. In a multifactorial analysis, results were correlated with tumour stage, recurrence rate and long-term survival. Microvessel density was higher across T and N stages (P<0.001) and associated with poor survival (hazard ratio (HR)=8.7, P<0.005) and decreased disease-free survival (HR=4.7, P<0.005). hypoxia-inducible factor-1α and -2α were expressed in >50% of rectal cancers (HIF-1α, 54%, 48/90; HIF-2α, 64%, 58/90). HIF-1α positivity was associated with both TNM stage (P<0.05) and vascular invasion (P<0.005). In contrast, no associations were shown between HIF-2α expression and any pathological features, and HIF-1α positivity had no effect on outcome. The study showed an independent association between HIF-1α expression and advanced TNM stage with poor outcome. Our results indicate that HIF-1α, but not HIF-2α, might be used as a marker of prognosis, in addition to methods currently used, to enhance patient management

MOF-associated complexes ensure stem cell identity and Xist repression

Histone acetyl transferases (HATs) play distinct roles in many cellular processes and are frequently misregulated in cancers. Here, we study the regulatory potential of MYST1-(MOF)-containing MSL and NSL complexes in mouse embryonic stem cells (ESCs) and neuronal progenitors. We find that both complexes influence transcription by targeting promoters and TSS-distal enhancers. In contrast to flies, the MSL complex is not exclusively enriched on the X chromosome, yet it is crucial for mammalian X chromosome regulation as it specifically regulates Tsix, the major repressor of Xist lncRNA. MSL depletion leads to decreased Tsix expression, reduced REX1 recruitment, and consequently, enhanced accumulation of Xist and variable numbers of inactivated X chromosomes during early differentiation. The NSL complex provides additional, Tsix-independent repression of Xist by maintaining pluripotency. MSL and NSL complexes therefore act synergistically by using distinct pathways to ensure a fail-safe mechanism for the repression of X inactivation in ESCs

Recent progress in understanding climate thresholds: ice sheets, the Atlantic meridional overturning circulation, tropical forests and responses to ocean acidification

This article reviews recent scientific progress, relating to four major systems that could exhibit threshold behaviour: ice sheets, the Atlantic meridional overturning circulation (AMOC), tropical forests and ecosystem responses to ocean acidification. The focus is on advances since the Intergovernmental Panel on Climate Change Fifth Assessment Report (IPCC AR5). The most significant developments in each component are identified by synthesizing input from multiple experts from each field. For ice sheets, some degree of irreversible loss (timescales of millennia) of part of the West Antarctic Ice Sheet (WAIS) may have already begun, but the rate and eventual magnitude of this irreversible loss is uncertain. The observed AMOC overturning has decreased from 2004–2014, but it is unclear at this stage whether this is forced or is internal variability. New evidence from experimental and natural droughts has given greater confidence that tropical forests are adversely affected by drought. The ecological and socio-economic impacts of ocean acidification are expected to greatly increase over the range from today’s annual value of around 400, up to 650 ppm CO2 in the atmosphere (reached around 2070 under RCP8.5), with the rapid development of aragonite undersaturation at high latitudes affecting calcifying organisms. Tropical coral reefs are vulnerable to the interaction of ocean acidification and temperature rise, and the rapidity of those changes, with severe losses and risks to survival at 2 °C warming above pre-industrial levels. Across the four systems studied, however, quantitative evidence for a difference in risk between 1.5 and 2 °C warming above pre-industrial levels is limited

Electronic Structure of the Complex Hydride NaAlH4

Density functional calculations of the electronic structure of the complex hydride NaAlH4 and the reference systems NaH and AlH3 are reported. We find a substantially ionic electronic structure for NaAlH4, which emphasizes the importance of solid state effects in this material. The relaxed hydrogen positions in NaAlH4 are in good agreement with recent experiment. The electronic structure of AlH3 is also ionic. Implications for the binding of complex hydrides are discussed.Comment: 4 pages, 5 figure

The Royal Society Climate Updates: What have we learnt since the IPCC 5th Assessment Report?

Climate has a huge influence on the way we live. For example, it affects the crops we can grow and the diseases we might encounter in particular locations. It also determines the physical infrastructure we need to build to survive comfortably in the face of extremes of heat, cold, drought and flood. Human emissions of carbon dioxide and other greenhouse gases have changed the composition of the atmosphere over the last two centuries. This is expected to take Earth’s climate out of the relatively stable range that has characterised the last few thousand years, during which human society has emerged. Measurements of ice cores and sea-floor sediments show that the current concentration of carbon dioxide, at just over 400 parts per million, has not been experienced for at least three million years. This causes more of the heat from the Sun to be retained on Earth, warming the atmosphere and ocean. The global average of atmospheric temperature has so far risen by about 1˚C compared to the late 19th century, with further increases expected dependent on the trajectory of carbon dioxide emissions in the next few decades. In 2013 and 2014 the Intergovernmental Panel on Climate Change (IPCC) published its fifth assessment report (AR5) assessing the evidence about climate change and its impacts. This assessment considered data from observations and records of the past. It then assessed future changes and impacts based on various scenarios for emissions of greenhouse gases and other anthropogenic factors. In 2015, almost every nation in the world agreed (in the so-called Paris Agreement) to the challenging goal of keeping global average warming to well below 2°C above pre-industrial temperatures while pursuing efforts to limit it to 1.5°C. With the next assessment report (AR6) not due until 2022, it is timely to consider how evidence presented since the publication of AR5 affects the assessments made then. The Earth’s climate is a complex system. To understand it, and the impact that climate change will have, requires many different kinds of study. Climate science consists of theory, observation and modelling. Theory begins with well-established scientific principles, seeks to understand processes occurring over a range of spatial and temporal scales and provides the basis for models. Observation includes long time series of careful measurements, recent data from satellites, and studies of past climate using archives such as tree rings, ice cores and marine sediments. It also encompasses laboratory and field experiments designed to test and enhance understanding of processes. Computer models of the Earth climate system use theory, calibrated and validated by the observations, to calculate the result of future changes. There are nevertheless uncertainties in estimating future climate. Firstly the course of climate change is dependent on what socioeconomic, political and energy paths society takes. Secondly there remain inevitable uncertainties induced for example by variability in the interactions between different parts of the Earth system and by processes, such as cloud formation, that occur at too small a scale to incorporate precisely in global models. Assessments such as those of the IPCC describe the state of knowledge at a particular time, and also highlight areas where more research is needed. We are still exploring and improving our understanding of many of the processes within the climate system, but, on the whole, new research confirms the main ideas underpinning climate research, while refining knowledge, so as to reduce the uncertainty in the magnitude and extent of crucial impacts

Impacts of Climate Change on indirect human exposure to pathogens and chemicals from agriculture

Objective: Climate change is likely to affect the nature of pathogens and chemicals in the environment and their fate and transport. Future risks of pathogens and chemicals could therefore be very different from those of today. In this review, we assess the implications of climate change for changes in human exposures to pathogens and chemicals in agricultural systems in the United Kingdom and discuss the subsequent effects on health impacts. Data sources: In this review, we used expert input and considered literature on climate change ; health effects resulting from exposure to pathogens and chemicals arising from agriculture ; inputs of chemicals and pathogens to agricultural systems ; and human exposure pathways for pathogens and chemicals in agricultural systems. Data synthesis: We established the current evidence base for health effects of chemicals and pathogens in the agricultural environment ; determined the potential implications of climate change on chemical and pathogen inputs in agricultural systems ; and explored the effects of climate change on environmental transport and fate of different contaminant types. We combined these data to assess the implications of climate change in terms of indirect human exposure to pathogens and chemicals in agricultural systems. We then developed recommendations on future research and policy changes to manage any adverse increases in risks. Conclusions: Overall, climate change is likely to increase human exposures to agricultural contaminants. The magnitude of the increases will be highly dependent on the contaminant type. Risks from many pathogens and particulate and particle-associated contaminants could increase significantly. These increases in exposure can, however, be managed for the most part through targeted research and policy changes