Showing papers by "David Eisenberg published in 2015"

Structure of the toxic core of α-synuclein from invisible crystals

Abstract: The protein α-synuclein is the main component of Lewy bodies, the neuron-associated aggregates seen in Parkinson disease and other neurodegenerative pathologies. An 11-residue segment, which we term NACore, appears to be responsible for amyloid formation and cytotoxicity of human α-synuclein. Here we describe crystals of NACore that have dimensions smaller than the wavelength of visible light and thus are invisible by optical microscopy. As the crystals are thousands of times too small for structure determination by synchrotron X-ray diffraction, we use micro-electron diffraction to determine the structure at atomic resolution. The 1.4 A resolution structure demonstrates that this method can determine previously unknown protein structures and here yields, to our knowledge, the highest resolution achieved by any cryo-electron microscopy method to date. The structure exhibits protofibrils built of pairs of face-to-face β-sheets. X-ray fibre diffraction patterns show the similarity of NACore to toxic fibrils of full-length α-synuclein. The NACore structure, together with that of a second segment, inspires a model for most of the ordered portion of the toxic, full-length α-synuclein fibril, presenting opportunities for the design of inhibitors of α-synuclein fibrils.

Insurance Coverage, Medical Conditions, and Visits to Alternative Medicine Providers

Abstract: Main Outcome Measure: The number of visits made to CAM providers. Results: An estimated 44% of the US population used at least 1 CAM therapy in 1997. Of those using CAM, 52% had seen at least 1 CAM provider in the last year. Among those who used a CAM therapy, factors independently associated with seeing a provider were having been in the upper quartile of visits to conventional providers in the last year (adjusted odds ratio [AOR], 2.00; 95% confidence interval [CI], 1.33-3.01), female sex (AOR, 1.67; 95% CI, 1.17-2.38), and having used the therapy to treat diabetes (AOR, 5.20; 95% CI, 1.40-19.40), cancer (AOR, 2.99; 95% CI, 1.04-8.62), or back or neck problems (AOR, 1.51; 95% CI, 1.02-2.23). Factors independently associated with frequent use (8 visits per year) of a CAM provider were full insurance coverage of the CAM provider (AOR, 5.06; 95% CI, 2.45-10.47), partial insurance coverage (AOR, 3.26; 95% CI, 1.72-6.19), having used the therapy for wellness (AOR, 2.85; 95% CI, 1.63-4.98), and having seen the provider for back or neck problems (AOR, 2.26; 95% CI, 1.29-3.94). Conservative extrapolation to national estimates suggests that 8.9% of the population (17.5 million adults) accounted for more than 75%ofthe629millionvisitsmadetoCAMprovidersin1997. Conclusions: A small minority of persons accounted for more than 75% of visits to CAM providers. Extent of insurance coverage for CAM providers and use for wellness are strong correlates of frequent use of CAM providers. Arch Intern Med. 2002;162:281-287

Human prion protein sequence elements impede cross-species chronic wasting disease transmission

Abstract: Chronic wasting disease (CWD) is a fatal prion disease of North American deer and elk and poses an unclear risk for transmission to humans. Human exposure to CWD occurs through hunting activities and consumption of venison from prion-infected animals. Although the amino acid residues of the prion protein (PrP) that prevent or permit human CWD infection are unknown, NMR-based structural studies suggest that the β2-α2 loop (residues 165-175) may impact species barriers. Here we sought to define PrP sequence determinants that affect CWD transmission to humans. We engineered transgenic mice that express human PrP with four amino acid substitutions that result in expression of PrP with a β2-α2 loop (residues 165-175) that exactly matches that of elk PrP. Compared with transgenic mice expressing unaltered human PrP, mice expressing the human-elk chimeric PrP were highly susceptible to elk and deer CWD prions but were concurrently less susceptible to human Creutzfeldt-Jakob disease prions. A systematic in vitro survey of amino acid differences between humans and cervids identified two additional residues that impacted CWD conversion of human PrP. This work identifies amino acids that constitute a substantial structural barrier for CWD transmission to humans and helps illuminate the molecular requirements for cross-species prion transmission.

Nutrition Education in an Era of Global Obesity and Diabetes: Thinking Outside the Box.

Abstract: In an era when rates of obesity, diabetes, and other lifestyle-related diseases challenge medical educators and governments worldwide, it is necessary to consider novel educational strategies, both didactic and experiential, whereby current and future health professionals can be better prepared to proactively advise and teach patients enhanced self-care skills (e.g., diet, movement, stress management, and enhanced behavioral change).In this Perspective, the authors summarize current circumstances involving rising rates of obesity and diabetes worldwide, the lack of nutrition- and lifestyle-related curricular requirements for professional medical certification, societal trends regarding modern food culture and food availability in health care settings, and the misalignment of financial incentives to promote health.The authors assess what elements of self-care should or should not be required within future curricula and certification exams. They consider how best to educate trainees about diet and how to "translate" nutrition, exercise, and behavioral science knowledge into practical advice. They explore several ideas for reforming nutrition education, including "teaching kitchens" as required laboratory classes for nutrition and lifestyle instruction, wearable technologies for tracking behaviors and physiological data relating to lifestyle choices, and the prospect of hospitals and other medical venues serving as exemplars of healthy, delicious food options. Finally, the authors argue that "salutogenesis"-the study of the creation and maintenance of health and well-being-should assume its rightful position alongside the study of "pathogenesis"-disease diagnosis and treatment-in medical education and practice.

Inhibition by small-molecule ligands of formation of amyloid fibrils of an immunoglobulin light chain variable domain

Abstract: Overproduction of immunoglobulin light chains leads to systemic amyloidosis, a lethal disease characterized by the formation of amyloid fibrils in patients' tissues. Excess light chains are in equilibrium between dimers and less stable monomers which can undergo irreversible aggregation to the amyloid state. The dimers therefore must disassociate into monomers prior to forming amyloid fibrils. Here we identify ligands that inhibit amyloid formation by stabilizing the Mcg light chain variable domain dimer and shifting the equilibrium away from the amyloid-prone monomer.

How effective is health coaching in reducing health services expenditures

Abstract: Background:Health coaching interventions aim to identify high-risk enrollees and encourage them to play a more proactive role in improving their health, improve their ability to navigate the health care system, and reduce costs.Objectives:Evaluate the effect of health coaching on inpatient, emergenc

Indexing amyloid peptide diffraction from serial femtosecond crystallography: new algorithms for sparse patterns

Abstract: Still diffraction patterns from peptide nanocrystals with small unit cells are challenging to index using conventional methods owing to the limited number of spots and the lack of crystal orientation information for individual images. New indexing algorithms have been developed as part of the Computational Crystallography Toolbox (cctbx) to overcome these challenges. Accurate unit-cell information derived from an aggregate data set from thousands of diffraction patterns can be used to determine a crystal orientation matrix for individual images with as few as five reflections. These algorithms are potentially applicable not only to amyloid peptides but also to any set of diffraction patterns with sparse properties, such as low-resolution virus structures or high-throughput screening of still images captured by raster-scanning at synchrotron sources. As a proof of concept for this technique, successful integration of X-ray free-electron laser (XFEL) data to 2.5 A resolution for the amyloid segment GNNQQNY from the Sup35 yeast prion is presented.

Within-team Patterns of Communication and Referral in Multimodal Treatment of Chronic Low Back Pain Patients by an Integrative Care Team

Abstract: Background: Nonspecific chronic low back pain (CLBP) is a highly prevalent and costly public health problem with few treatment options that provide consistent and greater than modest benefits. Treatment of CLBP is shifting from unimodal to multimodal and multidisciplinary approaches, including biopsychosocially-based complementary and integrative care. Multidisciplinary approaches require unique levels of communication and coordination amongst clinicians; however, to date few studies have evaluated patterns of communication and decision making amongst clinicians collaborating in the care of challenging patients with CLBP. Methods: As part of an observational study evaluating the effectiveness and cost-effectiveness of an integrative, team-based care model for the treatment of CLBP, we used multiple qualitative research methods to characterize within-team cross-referral and communication amongst jointly-trained practitioners representing diverse biomedical and complementary disciplines. Patterns of communi...

Shared Medical Appointments: A Portal for Nutrition and Culinary Education in Primary Care—A Pilot Feasibility Project

Abstract: Introduction: Diseases linked to obesity such as cardiovascular disease, diabetes, degenerative joint disease, gastroesophageal reflux, and sleep apnea constitute a large portion of primary care visits. Patients with these conditions often lack knowledge, skills, and support needed to maintain health. Shared medical appointments (SMAs) that include culinary skills and nutrition education offer a novel, cost-effective way to address these diseases in primary care. Methods: Adult patients in a primary care practice at a large academic hospital in Boston, Massachusetts, who had at least 1 cardiovascular risk factor were invited to participate in SMAs that included cooking demonstrations and teaching about nutrition in addition to medical management of their conditions. Sessions were conducted by a physician and an assistant in a conference room of a traditional primary care practice as part of a pilot feasibility project. Results: Seventy patients, contributing a total of 156 patient visits, attended 17 nutr...

Imaging the Anisotropic Reactivity of a Tungsten Diselenide Photocathode

Abstract: The reported activity of a photoelectrode reflects all kinds of reactive sites, good or bad. To understand localized behavior, such as catalytic sites or recombination centers, methods for mapping the anisotropic surface photoreactivity are constantly sought. The layered crystal structure of tungsten diselenide, a small bandgap semiconductor of great importance to solar fuels research, makes it especially prone to step-edge defects. Such steps are detrimental to photoelectrochemical performance. The first direct mapping of the photoreactivity of pdoped WSe2 single crystals in solution by using scanning electrochemical microscopy under illumination (photo-SECM) is presented herein. This nondestructive method reveals the anisotropic reactivity of step edges of p-WSe2 photocathodes, which serve as sites for both dark oxidation and lowered photoreduction in the dark and under illumination.

Nutrition Education in 2040-An Imagined Retrospective.

Abstract: “If all primary care physicians are expected to address obesity, nutrition, and physical activity with their adult patients, training programs need to change.”1 This statement, from an article by Smith et al1 in this issue of the Journal of Graduate Medical Education, is based on a survey of 219 senior medical residents in Ohio, all of whom were about to begin a career in family medicine, internal medicine, or obstetrics and gynecology. The article provides a snapshot of how prepared the current US primary care workforce is to address the current epidemics of obesity, diabetes, and other lifestyle-related chronic diseases. Smith et al1 conclude that newly minted primary care practitioners score poorly with regard to knowledge about obesity risks and how to effectively counsel patients regarding nutrition, weight management, and physical activity. Senior primary care residents' scores attesting to perceived professional competencies in these key areas are just shy of abysmal, and the group perceives that its members are not prepared to counsel their future patients about these topics.

Cylindrins as etiologic agents of amyloid diseases

Abstract: This invention relates, e.g., to a cylindrin, which is a non-covalent assembly of substantially identical chains of an amyloid or amyloid-related protein, which is a non-covalent assembly of substantially identical chains of an amyloid or amyloid-related protein, wherein each chain has a length of about 10-100 amino acid residues and comprises a single copy of a cylindrin-forming segment, or tandem adjacent copies of a cylindrin-forming segment, optionally separated by spacers, or adjacent copies of a first cylindrin-forming segment and a second complementary segment of the first cylindrin-forming segment, optionally separated by spacers, wherein at least about ⅔ of the amino acid residues in the chain are cylindrin-forming segments, wherein the cylindrin is a curved beta sheet formed from anti-parallel out-of-register extended protein strands, which is substantially filled with packed side chains. Also disclosed are methods for designing and making cylindrins, and methods for using them to identify inhibitors cylindrin-mediated cell toxicity.