De novo protein fold design through sequence-independent fragment assembly simulations.

De novo protein design generally consists of two steps, including structure and sequence design. Many protein design studies have focused on sequence design with scaffolds adapted from native structures in the PDB, which renders novel areas of protein structure and function space unexplored. We developed FoldDesign to create novel protein folds from specific secondary structure (SS) assignments through sequence-independent replica-exchange Monte Carlo (REMC) simulations. The method was tested on 354 non-redundant topologies, where FoldDesign consistently created stable structural folds, while recapitulating on average 87.7% of the SS elements. Meanwhile, the FoldDesign scaffolds had well-formed structures with buried residues and solvent-exposed areas closely matching their native counterparts. Despite the high fidelity to the input SS restraints and local structural characteristics of native proteins, a large portion of the designed scaffolds possessed global folds completely different from natural proteins in the PDB, highlighting the ability of FoldDesign to explore novel areas of protein fold space. Detailed data analyses revealed that the major contributions to the successful structure design lay in the optimal energy force field, which contains a balanced set of SS packing terms, and REMC simulations, which were coupled with multiple auxiliary movements to efficiently search the conformational space. Additionally, the ability to recognize and assemble uncommon super-SS geometries, rather than the unique arrangement of common SS motifs, was the key to generating novel folds. These results demonstrate a strong potential to explore both structural and functional spaces through computational design simulations that natural proteins have not reached through evolution.

Improving Health Risk Assessment as a Basis for Public Health Decisions in the 21st Century.

One-fifth of the way through the 21st century, a commonality of factors with those of the last 50 years may offer the opportunity to address unfinished business and current challenges. The recommendations include: (1) Resisting the tendency to oversimplify scientific assessments by reliance on single disciplines in lieu of clear weight-of-evidence expressions, and on single quantitative point estimates of health protective values for policy decisions; (2) Improving the separation of science and judgment in risk assessment through the use of clear expressions of the range of judgments that bracket protective quantitative levels for public health protection; (3) Use of comparative risk to achieve the greatest gains in health and the environment; and (4) Where applicable, reversal of the risk assessment and risk management steps to facilitate timely and substantive improvements in public health and the environment. Lessons learned and improvements in the risk assessment process are applied to the unprecedented challenges of the 21st century such as, pandemics and climate change. The beneficial application of the risk assessment and risk management paradigm to ensure timely research with consistency and transparency of assessments is presented. Institutions with mandated stability and leadership roles at the national and international levels are essential to ensure timely interdisciplinary scientific assessment at the interface with public policy as a basis for organized policy decisions, to meet time sensitive goals, and to inform the public.

The Impact of Alternative Payment Models on Oncology Innovation and Patient Care.

Oncology care is in a time of major transformation. Scientific discovery is driving breakthroughs in prevention, diagnostics, and treatment, resulting in tremendous gains for patients as the number of cancer survivors continues to grow on an annual basis. At the same time, there is mounting pressure across the healthcare system to contain costs while improving the quality of cancer care. In response to this pressure, private and government payers are increasingly turning to tools such as alternative payment models (APM) and clinical pathways to improve the efficiency of care, inform coverage decisions, and support shared decision-making. As APMs, clinical pathways and other tools are utilized more broadly, it will be critical that these models support the evidence-based use of innovative biomedical advances, including personalized medicine, and deliver patient-centered, high-value care. Clin Cancer Res; 22(10); 2335-41. ©2016 AACR.

Epigenetics: relevance and implications for public health.

Improved understanding of the multilayer regulation of the human genome has led to a greater appreciation of environmental, nutritional, and epigenetic risk factors for human disease. Chromatin remodeling, histone tail modifications, and DNA methylation are dynamic epigenetic changes responsive to external stimuli. Careful interpretation can provide insights for actionable public health through collaboration between population and basic scientists and through integration of multiple data sources. We review key findings in environmental epigenetics both in human population studies and in animal models, and discuss the implications of these results for risk assessment and public health protection. To ultimately succeed in identifying epigenetic mechanisms leading to complex phenotypes and disease, researchers must integrate the various animal models, human clinical approaches, and human population approaches while paying attention to life-stage sensitivity, to generate effective prescriptions for human health evaluation and disease prevention.

Healthcare information technology and economics.

At the 2011 American College of Medical Informatics (ACMI) Winter Symposium we studied the overlap between health IT and economics and what leading healthcare delivery organizations are achieving today using IT that might offer paths for the nation to follow for using health IT in healthcare reform. We recognized that health IT by itself can improve health value, but its main contribution to health value may be that it can make possible new care delivery models to achieve much larger value. Health IT is a critically important enabler to fundamental healthcare system changes that may be a way out of our current, severe problem of rising costs and national deficit. We review the current state of healthcare costs, federal health IT stimulus programs, and experiences of several leading organizations, and offer a model for how health IT fits into our health economic future.

New and improved proteomics technologies for understanding complex biological systems: addressing a grand challenge in the life sciences.

This White Paper sets out a Life Sciences Grand Challenge for Proteomics Technologies to enhance our understanding of complex biological systems, link genomes with phenotypes, and bring broad benefits to the biosciences and the US economy. The paper is based on a workshop hosted by the National Institute of Standards and Technology (NIST) in Gaithersburg, MD, 14-15 February 2011, with participants from many federal R&D agencies and research communities, under the aegis of the US National Science and Technology Council (NSTC). Opportunities are identified for a coordinated R&D effort to achieve major technology-based goals and address societal challenges in health, agriculture, nutrition, energy, environment, national security, and economic development.

The human proteome project: current state and future direction.

After the successful completion of the Human Genome Project, the Human Proteome Organization has recently officially launched a global Human Proteome Project (HPP), which is designed to map the entire human protein set. Given the lack of protein-level evidence for about 30% of the estimated 20,300 protein-coding genes, a systematic global effort will be necessary to achieve this goal with respect to protein abundance, distribution, subcellular localization, interaction with other biomolecules, and functions at specific time points. As a general experimental strategy, HPP research groups will use the three working pillars for HPP: mass spectrometry, antibody capture, and bioinformatics tools and knowledge bases. The HPP participants will take advantage of the output and cross-analyses from the ongoing Human Proteome Organization initiatives and a chromosome-centric protein mapping strategy, termed C-HPP, with which many national teams are currently engaged. In addition, numerous biologically driven and disease-oriented projects will be stimulated and facilitated by the HPP. Timely planning with proper governance of HPP will deliver a protein parts list, reagents, and tools for protein studies and analyses, and a stronger basis for personalized medicine. The Human Proteome Organization urges each national research funding agency and the scientific community at large to identify their preferred pathways to participate in aspects of this highly promising project in a HPP consortium of funders and investigators.

Evolution in health and medicine Sackler colloquium: Evolution and public health.

Evolution and its elements of natural selection, population migration, genetic drift, and founder effects have shaped the world in which we practice public health. Human cultures and technologies have modified life on this planet and have coevolved with myriad other species, including microorganisms; plant and animal sources of food; invertebrate vectors of disease; and intermediate hosts among birds, mammals, and nonhuman primates. Molecular mechanisms of differential resistance or susceptibility to infectious agents or diets have evolved and are being discovered with modern methods. Some of these evolutionary relations require a perspective of tens of thousands of years, whereas other changes are observable in real time. The implications and applications of evolutionary understanding are important to our current programs and policies for infectious disease surveillance, gene-environment interactions, and health disparities globally.

Meeting report: hazard assessment for nanoparticles--report from an interdisciplinary workshop.

In this report we present the findings from a nanotoxicology workshop held 6-7 April 2006 at the Woodrow Wilson International Center for Scholars in Washington, DC. Over 2 days, 26 scientists from government, academia, industry, and nonprofit organizations addressed two specific questions: what information is needed to understand the human health impact of engineered nanoparticles and how is this information best obtained? To assess hazards of nanoparticles in the near-term, most participants noted the need to use existing in vivo toxicologic tests because of their greater familiarity and interpretability. For all types of toxicology tests, the best measures of nanoparticle dose need to be determined. Most participants agreed that a standard set of nanoparticles should be validated by laboratories worldwide and made available for benchmarking tests of other newly created nanoparticles. The group concluded that a battery of tests should be developed to uncover particularly hazardous properties. Given the large number of diverse materials, most participants favored a tiered approach. Over the long term, research aimed at developing a mechanistic understanding of the numerous characteristics that influence nanoparticle toxicity was deemed essential. Predicting the potential toxicity of emerging nanoparticles will require hypothesis-driven research that elucidates how physicochemical parameters influence toxic effects on biological systems. Research needs should be determined in the context of the current availability of testing methods for nanoscale particles. Finally, the group identified general policy and strategic opportunities to accelerate the development and implementation of testing protocols and ensure that the information generated is translated effectively for all stakeholders.

Standards for plasma and serum proteomics in early cancer detection: a needs assessment report from the national institute of standards and technology--National Cancer Institute Standards, Methods, Assays, Reagents and Technologies Workshop, August 18-19, 2005.

NIST and the National Cancer Institute cosponsored a workshop on August 18-19, 2005, to examine needs for reference materials for early cancer detection. This meeting focused on standards, methods, assays, reagents, and technologies. Needs for plasma and serum proteomics, DNA methylation, and specimen reference collections were discussed, and recommendations from participants were solicited. This report summarizes the discussion and recommendations for proteomics reference materials.

Homocyst(e)ine and coronary heart disease: pharmacoeconomic support for interventions to lower hyperhomocyst(e)inaemia.

Homocyst(e)ine, a sulphur-containing amino acid, is an intermediate formed during the metabolism of the essential amino acid methionine. Biological and epidemiological evidence suggest that elevated plasma levels of homocyst(e)ine are a risk factor for atherosclerosis and coronary heart disease (CHD). In the general US population, hyperhomocyst(e)inaemia is common and most often due to mild nutritional deficiencies in the B vitamins (folic acid, vitamin B(12) and vitamin B(6)). While high homocyst(e)ine levels can be effectively lowered using folic acid and other B vitamins, it is unknown whether such vitamin therapy will lead to clinical benefits. Given that strategies for homocyst(e)ine-lowering are safe and inexpensive, however, even small reductions in CHD risk will be highly cost effective. Thus, it may be prudent for patients to ensure an adequate daily intake of dietary folic acid and other B vitamins and for physicians to screen high-risk adults such as those with established CHD as we await definitive results from ongoing clinical trials.