The Science Of Lipids And Cell Membranes In Health-Related Research

Presentation by Ronald Hills, Ph .D., describing the work of his laboratory at UNE. The Hills Lab is interested in the molecular mechanisms underlying biomedically relevant scientific problems. Having previously developed a suite of simulation tools for studying the molecular dynamics of membrane-protein systems, its research has since investigated the functional mechanisms of efflux transport proteins, of use for developing new therapies to overcome cellular multidrug resistance. The lab also investigates other aspects of health-related science. Student-centered scholarship in the group has included diverse topics from the development of POGIL learning activities for the classroom to reviewing health outcomes linked to nutrition and diet quality. Recent scholarship has explored the relationship between diet and the microbiome and reviewed evidence available for cardiovascular risk factors and lipid-lowering medications.https://dune.une.edu/pharmsci_facpres/1001/thumbnail.jp

Guide To Popular Diets, Food Choices, And Their Health Outcome

Integrative medicine is becoming increasingly important for a patient population afflicted with preventable illnesses such as cardiometabolic disease. Diet and nutrition are an under-tapped opportunity in health care for improving wellness and patient-centered health outcomes. Key nutritional principles are reviewed for alternate dietary strategies patients choose from in pursuit of healthy living or to alleviate chronic illness. Whole food eating plans are discussed including plant-based, Mediterranean, Paleo, and ketogenic diets as well as the specific carbohydrate and low FODMAP diets for colitis and irritable bowel syndrome. Opposed to the traditional categorization of diets by macronutrient composition, it is more useful to discuss the nutritional quality of specific foods and available micronutrients. Cardiovascular and other risk factors are reviewed for foods and food combinations, supporting a diet rich in vegetables, fruit, nuts/seeds, and seafood omega-3 fats.Nutrition and lifestyle education is needed to counsel patients on the best dietary strategy that ensures their adherence and improves long-term health outcomes

Multiscale coarse-graining of the protein energy landscape

Journal ArticleA variety of coarse-grained (CG) models exists for simulation of proteins. An outstanding problem is the construction of a CG model with physically accurate conformational energetics rivaling all-atom force fields. In the present work, atomistic simulations of peptide folding and aggregation equilibria are force-matched using multiscale coarse-graining to develop and test a CG interaction potential of general utility for the simulation of proteins of arbitrary sequence. The reduced representation relies on multiple interaction sites to maintain the anisotropic packing and polarity of individual sidechains. CG energy landscapes computed from replica exchange simulations of the folding of Trpzip, Trp-cage and adenylate kinase resemble those of other reduced representations; non-native structures are observed with energies similar to those of the native state. The artifactual stabilization of misfolded states implies that non-native interactions play a deciding role in deviations from ideal funnel-like cooperative folding. The role of surface tension, backbone hydrogen bonding and the smooth pairwise CG landscape is discussed. Ab initio folding aside, the improved treatment of sidechain rotamers results in stability of the native state in constant temperature simulations of Trpzip, Trp-cage, and the open to closed conformational transition of adenylate kinase, illustrating the potential value of the CG force field for simulating protein complexes and transitions between well-defined structural states

Multiscale Coarse-Graining of the Protein Energy Landscape

A variety of coarse-grained (CG) models exists for simulation of proteins. An outstanding problem is the construction of a CG model with physically accurate conformational energetics rivaling all-atom force fields. In the present work, atomistic simulations of peptide folding and aggregation equilibria are force-matched using multiscale coarse-graining to develop and test a CG interaction potential of general utility for the simulation of proteins of arbitrary sequence. The reduced representation relies on multiple interaction sites to maintain the anisotropic packing and polarity of individual sidechains. CG energy landscapes computed from replica exchange simulations of the folding of Trpzip, Trp-cage and adenylate kinase resemble those of other reduced representations; non-native structures are observed with energies similar to those of the native state. The artifactual stabilization of misfolded states implies that non-native interactions play a deciding role in deviations from ideal funnel-like cooperative folding. The role of surface tension, backbone hydrogen bonding and the smooth pairwise CG landscape is discussed. Ab initio folding aside, the improved treatment of sidechain rotamers results in stability of the native state in constant temperature simulations of Trpzip, Trp-cage, and the open to closed conformational transition of adenylate kinase, illustrating the potential value of the CG force field for simulating protein complexes and transitions between well-defined structural states.</p

Statin Treatment In Specific Patient Groups: Role For Improved Cardiovascular Risk Markers

Ample evidence supports the use of statin therapy for secondary prevention in patients with a history of atherosclerotic cardiovascular disease (ASCVD), but evidence is wanting in the case of primary prevention, low-risk individuals, and elderly adults 65+. Statins are effective in lowering low-density lipoprotein (LDL), which has long been a target for treatment decisions. We discuss the weakening dependence between cholesterol levels and mortality as a function of age and highlight recent findings on lipoprotein subfractions and other superior markers of ASCVD risk. The efficacy of statins is compared for distinct subsets of patients based on age, diabetes, ASCVD, and coronary artery calcium (CAC) status. Most cardiovascular risk calculators heavily weight age and overestimate one’s absolute risk of ASCVD, particularly in very old adults. Improvements in risk assessment enable the identification of specific patient populations that benefit most from statin treatment. Derisking is particularly important for adults over 75, in whom treatment benefits are reduced and adverse musculoskeletal effects are amplified. The CAC score stratifies the benefit effect size obtainable with statins, and forms of coenzyme Q are discussed for improving patient outcomes. Robust risk estimator tools and personalized, evidence-based approaches are needed to optimally reduce cardiovascular events and mortality rates through administration of cholesterol-lowering medications

Efficacy Of Statin Therapy In The Elderly

Statins are one of the most heavily prescribed medications. The 2018 ACC/AHA guidelines support statin therapy for most older adults, but recommendations are less clear for those over 75. The literature was systematically reviewed for evidence of the efficacy of statin treatment in different patient populations. Significant evidence was found supporting a decreasing association between low-density lipoprotein cholesterol (LDL-C) and mortality as well as decreasing statin efficacy with increasing age. The consequences of unnecessary statin therapy can be severe for older adults. Improved methods for evaluating atherosclerotic cardiovascular disease (ASCVD) risk, such as using negative markers to help identify those who may not benefit from statin therapy, should be more widely employed.https://dune.une.edu/pharm_studpost/1001/thumbnail.jp

Gut Microbiome: Profound Implications For Diet And Disease

The gut microbiome plays an important role in human health and influences the development of chronic diseases ranging from metabolic disease to gastrointestinal disorders and colorectal cancer. Of increasing prevalence in Western societies, these conditions carry a high burden of care. Dietary patterns and environmental factors have a profound effect on shaping gut microbiota in real time. Diverse populations of intestinal bacteria mediate their beneficial effects through the fermentation of dietary fiber to produce short-chain fatty acids, endogenous signals with important roles in lipid homeostasis and reducing inflammation. Recent progress shows that an individual’s starting microbial profile is a key determinant in predicting their response to intervention with live probiotics. The gut microbiota is complex and challenging to characterize. Enterotypes have been proposed using metrics such as alpha species diversity, the ratio of Firmicutes to Bacteroidetes phyla, and the relative abundance of beneficial genera (e.g., Bifidobacterium, Akkermansia) versus facultative anaerobes (E. coli), pro-inflammatory Ruminococcus, or nonbacterial microbes. Microbiota composition and relative populations of bacterial species are linked to physiologic health along different axes. We review the role of diet quality, carbohydrate intake, fermentable FODMAPs, and prebiotic fiber in maintaining healthy gut flora. The implications are discussed for various conditions including obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, depression, and cardiovascular disease

Multiscale Coarse-Graining of the Protein Energy Landscape

A variety of coarse-grained (CG) models exists for simulation of proteins. An outstanding problem is the construction of a CG model with physically accurate conformational energetics rivaling all-atom force fields. In the present work, atomistic simulations of peptide folding and aggregation equilibria are force-matched using multiscale coarse-graining to develop and test a CG interaction potential of general utility for the simulation of proteins of arbitrary sequence. The reduced representation relies on multiple interaction sites to maintain the anisotropic packing and polarity of individual sidechains. CG energy landscapes computed from replica exchange simulations of the folding of Trpzip, Trp-cage and adenylate kinase resemble those of other reduced representations; non-native structures are observed with energies similar to those of the native state. The artifactual stabilization of misfolded states implies that non-native interactions play a deciding role in deviations from ideal funnel-like cooperative folding. The role of surface tension, backbone hydrogen bonding and the smooth pairwise CG landscape is discussed. Ab initio folding aside, the improved treatment of sidechain rotamers results in stability of the native state in constant temperature simulations of Trpzip, Trp-cage, and the open to closed conformational transition of adenylate kinase, illustrating the potential value of the CG force field for simulating protein complexes and transitions between well-defined structural states

First demonstration of ionization cooling by the muon ionization cooling experiment

High-brightness muon beams of energy comparable to those produced by state-of-the-art electron, proton and ion accelerators have yet to be realised. Such beams have the potential to carry the search for new phenomena in lepton-antilepton collisions to extremely high energy and also to provide uniquely well-characterised neutrino beams. A muon beam may be created through the decay of pions produced in the interaction of a proton beam with a target. To produce a high-brightness beam from such a source requires that the phase space volume occupied by the muons be reduced (cooled). Ionization cooling is the novel technique by which it is proposed to cool the beam. The Muon Ionization Cooling Experiment collaboration has constructed a section of an ionization cooling cell and used it to provide the first demonstration of ionization cooling. We present these ground-breaking measurements

Lattice design and expected performance of the Muon Ionization Cooling Experiment demonstration of ionization cooling

Muon beams of low emittance provide the basis for the intense, well-characterized neutrino beams necessary to elucidate the physics of flavor at a neutrino factory and to provide lepton-antilepton collisions at energies of up to several TeV at a muon collider. The international Muon Ionization Cooling Experiment (MICE) aims to demonstrate ionization cooling, the technique by which it is proposed to reduce the phase-space volume occupied by the muon beam at such facilities. In an ionization-cooling channel, the muon beam passes through a material in which it loses energy. The energy lost is then replaced using rf cavities. The combined effect of energy loss and reacceleration is to reduce the transverse emittance of the beam (transverse cooling). A major revision of the scope of the project was carried out over the summer of 2014. The revised experiment can deliver a demonstration of ionization cooling. The design of the cooling demonstration experiment will be described together with its predicted cooling performance.The work described here was made possible by grants from the Science and Technology Facilities Council (UK), the Department of Energy and National Science Foundation (USA), the Instituto Nazionale di Fisica Nucleare (Italy), the Bulgarian Academy of Sciences, the Chinese Academy of Sciences, the Dutch National Science Foundation, the Ministry of Education, Science and Technological Development of the Republic of Serbia, the European Community under the European Commission Framework Programme 7 (AIDA project, Grant Agreement No. 262025, TIARA project, Grant Agreement No. 261905, and EuCARD), the Japan Society for the Promotion of Science and the Swiss National Science Foundation in the framework of the SCOPES programme. We gratefully acknowledge all sources of support. We are grateful to the support given to us by the staff of the STFC Rutherford Appleton and Daresbury Laboratories