Amino-terminal sequence of phenobarbital-inducible cytochrome P-450 from rabbit liver microsomes: Similarity to hydrophobic amino-terminal segments of preproteins

SummaryThe amino-terminal sequence of two electrophoretically homogeneous forms of rabbit liver microsomal cytochrome P-450, P-450LM2 and P-45LM4, has been examined by automated Edman degradation. Methionine is the amino terminus of P-450LM2, and 17 of the first 20 residues are hydrophobic, including two clusters of five consecutive leucines. The composition and sequence of this region are similar to those of the short-lived hydrophobic amino-terminal precursor segments of certain other proteins, especially myeloma immunoglobulin light chains and pancreatic zymogens. Multiple amino-terminal residues, including methionine, were detected for P-450LM4 suggesting the presence of several highly similar forms of P-450 or that partial proteolysis had occurred.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22857/1/0000419.pd

Prognosis of Differentiated Thyroid Cancer in Relation to Serum Thyrotropin and Thyroglobulin Antibody Status at Time of Diagnosis

BACKGROUND: Serum thyrotropin (TSH) concentration and thyroid autoimmunity may be of prognostic importance in differentiated thyroid cancer (DTC). Preoperative serum TSH level has been associated with higher DTC stage in cross-sectional studies; data are contradictory on the significance of thyroid autoimmunity at the time of diagnosis. OBJECTIVE: We sought to assess whether preoperative serum TSH and perioperative antithyroglobulin antibodies (TgAb) were associated with thyroid cancer stage and outcome in DTC patients followed by the National Thyroid Cancer Treatment Cooperative Study, a large multicenter thyroid cancer registry. METHODS: Patients registered after 1996 with available preoperative serum TSH (n=617; the TSH cohort) or perioperative TgAb status (n=1770; the TgAb cohort) were analyzed for tumor stage, persistent disease, recurrence, and overall survival (OS; median follow-up, 5.5 years). Parametric tests assessed log-transformed TSH, and categorical variables were tested with chi square. Disease-free survival (DFS) and OS was assessed with Cox models. RESULTS: Geometric mean serum TSH levels were higher in patients with higher-stage disease (Stage III/IV=1.48 vs. 1.02 mU/L for Stages I/II; p=0.006). The relationship persisted in those aged ≥45 years after adjusting for sex (p=0.01). Gross extrathyroidal extension (p=0.03) and presence of cervical lymph node metastases (p=0.003) were also significantly associated with higher serum TSH. Disease recurrence and all-cause mortality occurred in 37 and 38 TSH cohort patients respectively, which limited the power for survival analysis. Positive TgAb was associated with lower stage on univariate analysis (positive TgAb in 23.4% vs. 17.8% of Stage I/II vs. III/IV patients, respectively; p=0.01), although the relationship lost significance when adjusting for age and sex (p=0.34). Perioperative TgAb was not an independent predictor of DFS (hazard ratio=1.12 [95% confidence interval=0.74-1.69]) or OS (hazard ratio=0.98 [95% confidence interval=0.56-1.72]). CONCLUSIONS: Preoperative serum TSH level is associated with higher DTC stage, gross extrathyroidal extension, and neck node metastases. Perioperative TgAb is not an independent predictor of DTC prognosis. A larger cohort is required to assess whether preoperative serum TSH level predicts recurrence or mortality

Global Education Handbook: Modules for Teaching Pre-School to Secondary School

This handbook was developed to assist K-12 teachers who wish to introduce a global perspective into their curriculum. The modules were developed by classroom teachers and include such topics as: Anti-bias Curriculum: A Multicultural Perspective,” “The African Influence in Puerto Rican Music,” and “Multicultural Education: An Approach through Beauty, Fashion and Art.” Organized according to grade levels, each module is divided into a series of lessons complete with objectives and a detailed description of materials and activities. It is the purpose of the Global Education Handbook to contribute to networking within the community of educators, locally and globally. The Handbook provides examples of lesson plans and units with a global perspective for use at the pre-school, elementary, middle, and secondary grade levels. It identifies a global network of resources which is available to educators who want to bring the world into their classrooms. Included is an account of an early childhood educator in a rural elementary school in Western Massachusetts who is attempting to instill a global perspective in her curriculum. Her experiences bring to light many of the challenges which confront new and veteran educators who wish to globalize their classrooms and their schools. The Handbook is organized into chapters according to grade level: pre-school, elementary, middle, and secondary. The material within each of these chapters was developed by teachers who implemented these global education units in their classrooms. Each unit is comprised of several lessons that have either a geographic, cultural, or issue-based focus. These resources can be used directly from the Handbook and it is hoped that they will inspire the development of other lessons and units particular to the unique needs of each educator

Cross-Sectional Exploration of Plasma Biomarkers of Alzheimer\u27s Disease in Down Syndrome: Early Data from the Longitudinal Investigation for Enhancing Down Syndrome Research (LIFE-DSR) Study

With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer’s disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid β peptides (Aβ1-40, Aβ1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology

Mitochondria, Energetics, Epigenetics, and Cellular Responses to Stress

Background: Cells respond to environmental stressors through several key pathways, including response to reactive oxygen species (ROS), nutrient and ATP sensing, DNA damage response (DDR), and epigenetic alterations. Mitochondria play a central role in these pathways not only through energetics and ATP production but also through metabolites generated in the tricarboxylic acid cycle, as well as mitochondria–nuclear signaling related to mitochondria morphology, biogenesis, fission/fusion, mitophagy, apoptosis, and epigenetic regulation. Objectives: We investigated the concept of bidirectional interactions between mitochondria and cellular pathways in response to environmental stress with a focus on epigenetic regulation, and we examined DNA repair and DDR pathways as examples of biological processes that respond to exogenous insults through changes in homeostasis and altered mitochondrial function. Methods: The National Institute of Environmental Health Sciences sponsored the Workshop on Mitochondria, Energetics, Epigenetics, Environment, and DNA Damage Response on 25–26 March 2013. Here, we summarize key points and ideas emerging from this meeting. Discussion: A more comprehensive understanding of signaling mechanisms (cross-talk) between the mitochondria and nucleus is central to elucidating the integration of mitochondrial functions with other cellular response pathways in modulating the effects of environmental agents. Recent studies have highlighted the importance of mitochondrial functions in epigenetic regulation and DDR with environmental stress. Development and application of novel technologies, enhanced experimental models, and a systems-type research approach will help to discern how environmentally induced mitochondrial dysfunction affects key mechanistic pathways. Conclusions: Understanding mitochondria–cell signaling will provide insight into individual responses to environmental hazards, improving prediction of hazard and susceptibility to environmental stressors. Citation: Shaughnessy DT, McAllister K, Worth L, Haugen AC, Meyer JN, Domann FE, Van Houten B, Mostoslavsky R, Bultman SJ, Baccarelli AA, Begley TJ, Sobol RW, Hirschey MD, Ideker T, Santos JH, Copeland WC, Tice RR, Balshaw DM, Tyson FL. 2014. Mitochondria, energetics, epigenetics, and cellular responses to stress. Environ Health Perspect 122:1271–1278; http://dx.doi.org/10.1289/ehp.140841

The Future of Health / Fitness / Sports Performance

Exercise relative to health/fitness and sports performance has displayed an evolutionary role over time. Large scale, overriding, factors are present which are likely to help us understand the likely future evolutionary path of health/fitness and sports performance. These factors include: 1) the history of exercise, 2) exercise in its' relationship to health, 3) the need for fitness in the military and first responders, 4) the conflicted relationship between top sport (representing the apex of the human genomic capacity for exercise) versus the overly competitive and compensated nature of top sport. Dominantly, the need for exercise as preventive medicine in a progressively more sedentary society, the need to provide social integration and inclusion in a highly mobile society, the risk of undesirable social outcomes related to top sport and the likelihood of human-cyber interactions are likely to drive the evolution of exercise in the future

Description and evaluation of an EBM curriculum using a block rotation

BACKGROUND: While previous authors have emphasized the importance of integrating and reinforcing evidence-based medicine (EBM) skills in residency, there are few published examples of such curricula. We designed an EBM curriculum to train family practice interns in essential EBM skills for information mastery using clinical questions generated by the family practice inpatient service. We sought to evaluate the impact of this curriculum on interns, residents, and faculty. METHODS: Interns (n = 13) were asked to self-assess their level of confidence in basic EBM skills before and after their 2-week EBM rotation. Residents (n = 21) and faculty (n = 12) were asked to assess how often the answers provided by the EBM intern to the inpatient service changed medical care. In addition, residents were asked to report how often they used their EBM skills and how often EBM concepts and tools were used in teaching by senior residents and faculty. Faculty were asked if the EBM curriculum had increased their use of EBM in practice and in teaching. RESULTS: Interns significantly increased their confidence over the course of the rotation. Residents and faculty felt that the answers provided by the EBM intern provided useful information and led to changes in patient care. Faculty reported incorporating EBM into their teaching (92%) and practice (75%). Residents reported applying the EBM skills they learned to patient care (86%) and that these skills were reinforced in the teaching they received outside of the rotation (81%). All residents and 11 of 12 faculty felt that the EBM curriculum had improved patient care. CONCLUSIONS: To our knowledge, this is the first published EBM curriculum using an individual block rotation format. As such, it may provide an alternative model for teaching and incorporating EBM into a residency program

Comparison of Francisella tularensis genomes reveals evolutionary events associated with the emergence of human pathogenic strains

.Sequencing of the non-pathogenic Francisella tularensis sub-species novicida U112, and comparison with two pathogenic sub-species, provides insights into the evolution of pathogenicity in these species