Using Health Care Utilization and Publication Patterns to Characterize the Research Portfolio and to Plan Future Research Investments

Objective: Government funders of biomedical research are under increasing pressure to demonstrate societal benefits of their investments. A number of published studies attempted to correlate research funding levels with the societal burden for various diseases, with mixed results. We examined whether research funded by the Department of Veterans Affairs (VA) is well aligned with current and projected veterans’ health needs. The organizational structure of the VA makes it a particularly suitable setting for examining these questions. Methods: We used the publication patterns and dollar expenditures of VA-funded researchers to characterize the VA research portfolio by disease. We used health care utilization data from the VA for the same diseases to define veterans’ health needs. We then measured the level of correlation between the two and identified disease groups that were under- or over-represented in the research portfolio relative to disease expenditures. Finally, we used historic health care utilization trends combined with demographic projections to identify diseases and conditions that are increasing in costs and/or patient volume and consequently represent potential targets for future research investments. Results: We found a significant correlation between research volume/expenditures and health utilization. Some disease groups were slightly under- or over-represented, but these deviations were relatively small. Diseases and conditions with the increasing utilization trend at the VA included hypertension, hypercholesterolemia, diabetes, hearing loss, sleeping disorders, complications of pregnancy, and several mental disorders. Conclusions: Research investments at the VA are well aligned with veteran health needs. The VA can continue to meet these needs by supporting research on the diseases and conditions with a growing number of patients, costs of care, or both. Our approach can be used by other funders of disease research to characterize their portfolios and to plan research investments

Discrete charging of metallic grains: Statistics of addition spectra

We analyze the statistics of electrostatic energies (and their differences) for a quantum dot system composed of a finite number $K$ of electron islands (metallic grains) with random capacitance-inductance matrix $C$, for which the total charge is discrete, $Q=Ne$ (where $e$ is the charge of an electron and $N$ is an integer). The analysis is based on a generalized charging model, where the electrons are distributed among the grains such that the electrostatic energy E(N) is minimal. Its second difference (inverse compressibility) $\chi_{N}=E(N+1)-2 E(N)+E(N-1)$ represents the spacing between adjacent Coulomb blockade peaks appearing when the conductance of the quantum dot is plotted against gate voltage. The statistics of this quantity has been the focus of experimental and theoretical investigations during the last two decades. We provide an algorithm for calculating the distribution function corresponding to $\chi_{N}$ and show that this function is piecewise polynomial.Comment: 21 pages, no figures, mathematical nomenclature (except for Abstract and Introduction

Modulation of reactivity in the cavity of liposomes promotes the formation of peptide bonds

In living cells reactions take place in membrane bound compartments, often in response to changes in the environment. Learning how the reactions are influenced by this compartmentalization will help us gain an optimal understanding of living organisms at the molecular level and, at the same time, will offer vital clues on the behavior of simple compartmentalized systems, such as prebiotic precursors of cells and cell-inspired artificial systems. In this work we show that a reactive building block (an activated amino acid derivative) trapped in the cavity of a liposome is protected against hydrolysis and reacts nearly quantitatively with another building block, which is membrane-permeable and free in solution, to form the dipeptide. By contrast, when found outside the liposome, the hydrolysis of the activated amino acid is the prevalent reaction, showing that the cavity of the liposomes promotes the formation of peptide bonds. We attribute this result to the large lipid concentration in small compartments from the point of view of a membrane-impermeable molecule. Based on this result we show how the outcome of the reaction can be predicted as a function of the size of the compartment. The implications of these results on the behavior of biomolecules in cell compartments, abiogenesis and the design of artificial cell-inspired systems are considere

Étude des marqueurs génétiques sanguins dans deux races de poneys de pologne

International audienc

Thermal stability of purified and reconstituted CFTR in a locked open channel conformation

CFTR is unique among ABC transporters as the only one functioning as an ion channel and from a human health perspective because mutations in its gene cause cystic fibrosis. Although considerable advances have been made towards understanding CFTR’s mechanism of action and the impact of mutations, the lack of a high-resolution 3D structure has hindered progress. The large multi-domain membrane glycoprotein is normally present at low copy number and when over expressed at high levels it aggregates strongly, limiting the production of stable mono-disperse preparations. While the reasons for the strong self-association are not fully understood, its relatively low thermal stability seems likely to be one. The major CF causing mutation, ΔF508, renders the protein very thermally unstable and therefore a great deal of attention has been paid to this property of CFTR. Multiple second site mutations of CFTR in NBD1 where F508 normally resides and small molecule binders of the domain increase the thermal stability of the mutant. These manipulations also stabilize the wild-type protein. Here we have applied ΔF508-stabilizing changes and other modifications to generate wild-type constructs that express at much higher levels in scaled-up suspension cultures of mammalian cells. After purification and reconstitution into liposomes these proteins are active in a locked-open conformation at temperatures as high as 50°C and remain monodisperse at 4°C in detergent or lipid for at least a week. The availability of adequate amounts of these and related stable active preparations of homogeneous CFTR will enable stalled structural and ligand binding studies to proceed

Regulatory Insertion Removal Restores Maturation, Stability and Function of ΔF508 CFTR

The cystic fibrosis transmembrane conductance regulator (CFTR) epithelial anion channel is a large multi-domain membrane protein which matures inefficiently during biosynthesis. Its assembly is further perturbed by the deletion of F508 from the first nucleotide binding domain (NBD1) responsible for most cystic fibrosis. The mutant polypeptide is recognized by cellular quality control systems and is proteolyzed. CFTR NBD1 contains a 32 residue segment termed the regulatory insertion (RI) not present in other ABC transporters. We report here that RI deletion enabled ΔF508 CFTR to mature and traffic to the cell surface where it mediated regulated anion efflux and exhibited robust single chloride channel activity. Long term pulse-chase experiments showed that the mature ΔRI/ΔF508 had a T1/2 of ~14h in cells, similar to the wild-type. RI deletion restored ATP occlusion by NBD1 of ΔF508 CFTR and had a strong thermo-stabilizing influence on the channel with gating up to at least 40°C. None of these effects of RI removal were achieved by deletion of only portions of RI. Discrete molecular dynamics simulations of NBD1 indicated that RI might indirectly influence the interaction of NBD1 with the rest of the protein by attenuating the coupling of the F508 containing loop with the F1-like ATP-binding core subdomain so that RI removal overcame the perturbations caused by F508 deletion. Restriction of RI to a particular conformational state may ameliorate the impact of the disease-causing mutation

Allosteric Modulation Balances Thermodynamic Stability and Restores Function of ΔF508 CFTR

Most cystic fibrosis is caused by a deletion of a single residue (F508) in CFTR that disrupts the folding and biosynthetic maturation of the ion channel protein. Progress towards understanding the underlying mechanisms and overcoming the defect remain incomplete. Here we show that the thermal instability of human ΔF508 CFTR channel activity evident in both cell-attached membrane patches and planar phospholipid bilayers is not observed in corresponding mutant CFTRs of several non-mammalian species. These more stable orthologs are distinguished from their mammalian counterparts by the substitution of proline residues at several key dynamic locations in the first nucleotide domain (NBD1), including the structurally diverse region (SDR), the gamma phosphate switch loop and the Regulatory Insertion (RI). Molecular Dynamic analyses revealed that addition of the prolines could reduce flexibility at these locations and increase the temperatures of unfolding transitions of ΔF508 NBD1 to that of the wild-type. Introduction of these prolines experimentally into full-length human ΔF508 CFTR together with the already recognized I539T suppressor mutation, also in the SDR, restored channel function and thermodynamic stability as well as its trafficking to and lifetime at the cell surface. Thus, while cellular manipulations that circumvent its culling by quality control systems leave ΔF508 CFTR dysfunctional at physiological temperature, restoration of the delicate balance between the dynamic protein’s inherent stability and channel activity returns a near-normal state

Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Previous genome-wide association studies (GWAS) have identified 14 single nucleotide polymorphisms (SNPs) associated with cutaneous SCC. Here, we report the largest cutaneous SCC meta-analysis to date, representing six international cohorts and totaling 19,149 SCC cases and 680,049 controls. We discover eight novel loci associated with SCC, confirm all previously associated loci, and perform fine mapping of causal variants. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility