Computational Exploration of Potential CFTR Binding Sites for Type I Corrector Drugs.

Cystic fibrosis (CF) is a recessive genetic disease that is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The recent development of a class of drugs called "correctors", which repair the structure and function of mutant CFTR, has greatly enhanced the life expectancy of CF patients. These correctors target the most common disease causing CFTR mutant F508del and are exemplified by the FDA-approved VX-809.

Antitumor T-cell Immunity Contributes to Pancreatic Cancer Immune Resistance.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Pancreatic tumors are minimally infiltrated by T cells and are largely refractory to immunotherapy. Accordingly, the role of T-cell immunity in pancreatic cancer has been somewhat overlooked.

Carotenoids promote lateral packing and condensation of lipid membranes.

Carotenoids are pigment molecules that protect biomembranes against degradation and may be involved in the formation of functional bacterial membrane microdomains. Little is known on whether different types of carotenoids have different effects on the membrane or if there is any concentration dependence of these effects. In this work, we present results from molecular dynamics simulations of phospholipid bilayers containing different amounts of either β-carotene or zeaxanthin.

Improving Rural Access to Opioid Treatment Programs.

This article explores challenges to accessing opioid treatment programs in rural areas, and offers solutions that would ease these problems.

Case Study: County-Level Responses to the Opioid Crisis in Northern Kentucky.

This article highlights local government responses to the opioid crisis in Northern Kentucky through a series of interviews with county-level officials. The author's discussions with civic leaders reflect the challenges faced by local communities and the new approaches implemented to stem the epidemic.

A 2017 global update on folic acid-preventable spina bifida and anencephaly.

Background: Spina bifida and anencephaly are largely preventable birth defects through mandatory folic acid fortification. Our objective was to estimate the proportion of folic acid-preventable spina bifida and anencephaly (FAP SBA) prevented worldwide through mandatory fortification of wheat and/or maize flour with folic acid during the year 2017.

Methods: Using existing data, we identified countries with mandatory fortification policies that added at least 1.

CAMERRA: An analysis tool for the computation of conformational dynamics by evaluating residue-residue associations.

A computational method which extracts the dominant motions from an ensemble of biomolecular conformations via a correlation analysis of residue-residue contacts is presented. The algorithm first renders the structural information into contact matrices, then constructs the collective modes based on the correlated dynamics of a selected set of dynamic contacts. Associated programs can bridge the results for further visualization using graphics software.

Effects of carotenoids on lipid bilayers.

Carotenoids have been found to be important in improving the integrity of biomembranes in eukaryotes. However, the molecular details of how carotenoids modulate the physical properties of biomembranes are unknown. To this end, we have conducted a series of molecular dynamics simulations of different biologically-relevant membranes in the presence of carotenoids.

Characterizing protein conformations by correlation analysis of coarse-grained contact matrices.

We have developed a method to capture the essential conformational dynamics of folded biopolymers using statistical analysis of coarse-grained segment-segment contacts. Previously, the residue-residue contact analysis of simulation trajectories was successfully applied to the detection of conformational switching motions in biomolecular complexes. However, the application to large protein systems (larger than 1000 amino acid residues) is challenging using the description of residue contacts.

DMSO enhanced conformational switch of an interfacial enzyme.

Interfacial proteins function in unique heterogeneous solvent environments, such as water-oil interfaces. One important example is microbial lipase, which is activated in an oil-water emulsion phase and has many important enzymatic functions. A unique aprotic dipolar organic solvent, dimethyl sulfoxide (DMSO), has been shown to increase the activity of lipases, but the mechanism behind this enhancement is still unknown.

A 2015 global update on folic acid-preventable spina bifida and anencephaly.

Background: Spina bifida and anencephaly are two major neural tube defects. They contribute substantially to perinatal, neonatal, infant, and under-five mortality and life-long disability. To monitor the progress toward the total prevention of folic acid-preventable spina bifida and anencephaly (FAP SBA), we examined their global status in 2015.

The Promiscuity of Allosteric Regulation of Nuclear Receptors by Retinoid X Receptor.

The promiscuous protein retinoid X receptor (RXR) displays essential allosteric regulation of several members in the nuclear hormone receptor superfamily via heterodimerization and (anti)cooperative binding of cognate ligands. Here, the structural basis of the positive allostery of RXR and constitutive androstane receptor (CAR) is revealed. In contrast, a similar computational approach had previously revealed the mechanism for negative allostery in the complex of RXR and thyroid receptor (TR).

Pressure-induced conformational switch of an interfacial protein.

A special class of proteins adopts an inactive conformation in aqueous solution and activates at an interface (such as the surface of lipid droplet) by switching their conformations. Lipase, an essential enzyme for breaking down lipids, serves as a model system for studying such interfacial proteins. The underlying conformational switch of lipase induced by solvent condition is achieved through changing the status of the gated substrate-access channel.

Investigation of Carbohydrate Recognition via Computer Simulation.

Carbohydrate recognition by proteins, such as lectins and other (bio)molecules, can be essential for many biological functions. Recently, interest has arisen due to potential protein and drug design and future bioengineering applications. A quantitative measurement of carbohydrate-protein interaction is thus important for the full characterization of sugar recognition.

Mapping allostery through computational glycine scanning and correlation analysis of residue-residue contacts.

Understanding allosteric mechanisms is essential for the physical control of molecular switches and downstream cellular responses. However, it is difficult to decode essential allosteric motions in a high-throughput scheme. A general two-pronged approach to performing automatic data reduction of simulation trajectories is presented here.

Effects of branched O-glycosylation on a semiflexible peptide linker.

Glycosylation is an essential modification of proteins and lipids by the addition of carbohydrate residues. These attached carbohydrates range from single monomers to elaborate branched glycans. Here, we examine how the level of glycosylation affects the conformation of a semiflexible peptide linker using the example of the hinge peptide from immunoglobulin A.

External mill monitoring of wheat flour fortification programs: an approach for program managers using experiences from Jordan.

The fortification of wheat flour with micronutrients is a common strategy to increase vitamin and mineral intake. While wheat flour mills are often inspected by agencies affiliated with national ministries to ensure compliance with national fortification standards, few countries use data derived from these inspections to construct an external monitoring system for use in program management and evaluation. The primary objective of this paper is to assess the performance of the external monitoring system utilized in Jordan according to the US Centers for Disease Control and Prevention's Updated Guidelines for Evaluating Public Health Surveillance Systems.

Solvent-induced α- to 3(10)-helix transition of an amphiphilic peptide.

The amphiphilic peptide of the triacylglycerol lipase derived from Pseudomonas aeruginosa plays a critical role in guarding the gate for ligand access. Conformations of this peptide at several water-oil interfaces and in protein environments were compared using atomistic simulations with explicit solvents. In oil-containing solvents, this peptide is able to retain a folded structure.

Regulatory monitoring systems of fortified salt and wheat flour in selected ASEAN countries.

Background: Considerable efforts have been made over the past decade to address vitamin and mineral deficiencies. An increasing number of countries in the Association of Southeast Asian Nations (ASEAN) are adopting mandatory food fortification as one of the primary strategies to overcome these deficiencies. Experience shows that fortified foods can reach large parts of the population, including the poor, if the fortification is done on a mandatory rather than a voluntary basis and if the food vehicle is widely consumed.

2012 Update on global prevention of folic acid-preventable spina bifida and anencephaly.

Background: Folic acid was proven in 1991 to prevent most cases of spina bifida and anencephaly. In 2008, less than 10% of folic acid-preventable spina bifida and anencephaly (FAPSBA) was prevented through folic acid fortification programs. This study updates the global estimates of the proportion of FAPSBA prevented with various types of folic acid fortification as of 2012.

Fortification of wheat flour and maize meal with different iron compounds: results of a series of baking trials.

Background: Wheat and maize flour fortification is a preventive food-based approach to improve the micronutrient status of populations. In 2009, the World Health Organization (WHO) released recommendations for such fortification, with guidelines on the addition levels for iron, folic acid, vitamin B12, vitamin A, and zinc at various levels of average daily consumption. Iron is the micronutrient of greatest concern to the food industry, as some believe there may be some adverse interaction(s) in some or all of the finished products produced from wheat flour and maize meal.

Solvent-dependent gating motions of an extremophilic lipase from Pseudomonas aeruginosa.

Understanding how organic solvent-stable proteins can function in anhydrous and often complex solutions is essential for the study of the interaction of protein and molecular immiscible interfaces and the design of efficient industrial enzymes in nonaqueous solvents. Using an extremophilic lipase from Pseudomonas aeruginosa as an example, we investigated the conformational dynamics of an organic solvent-tolerant enzyme in complex solvent milieux. Four 100-ns molecular dynamics simulations of the lipase were performed in solvent systems: water, hexane, and two mixtures of hexane and water, 5% and 95% (w/w) hexane.

Enhancing processes for introduction, production, quality assurance, and delivery of US Title II food aid products.

Background: Enacted in 1950, Public Law 480 (PL480) dramatically increased the volume of U.S.food aid and the scope of interventions it supports.

Water's Contribution to the Energetic Roughness from Peptide Dynamics.

Water plays a very important role in the dynamics and function of proteins. Apart from protein-protein and protein-water interactions, protein motions are accompanied by the formation and breakage of hydrogen-bonding network of the surrounding water molecules. This ordering and reordering of water also adds to the underlying roughness of the energy landscape of proteins and thereby alters their dynamics.