Targeting TrkB with a Brain-Derived Neurotrophic Factor Mimetic Promotes Myelin Repair in the Brain.

Methods to promote myelin regeneration in response to central myelin loss are essential to prevent the progression of clinical disability in demyelinating diseases. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to promote myelination during development via oligodendrocyte expressed TrkB receptors. Here, we use a structural mimetic of BDNF to promote myelin regeneration in a preclinical mouse model of central demyelination. In female mice, we show that selective targeting of TrkB with the BDNF-mimetic enhances remyelination, increasing oligodendrocyte differentiation, the frequency of myelinated axons, and myelin sheath thickness after a demyelinating insult. Treatment with exogenous BDNF exerted an attenuated effect, increasing myelin sheath thickness only. Further, following conditional deletion of TrkB from premyelinating oligodendrocytes, we show the effects of the BDNF-mimetic on oligodendrocyte differentiation and remyelination are lost, indicating these are dependent on oligodendrocyte expression of TrkB. Overall, these studies demonstrate that targeting oligodendrocyte TrkB promotes in vivo remyelination in the brain.SIGNIFICANCE STATEMENT Novel strategies to promote myelin regeneration are required to prevent progressive neurodegeneration and clinical disability in patients with central demyelinating disease. Here, we test whether selectively targeting the TrkB receptor on the myelin-producing oligodendrocytes, can promote remyelination in the brain. Using a structural mimetic of its native ligand, BDNF, we show that stimulation of TrkB enhances remyelination, increasing oligodendrocyte differentiation, the frequency of myelinated axons and thickness of the myelin sheath following a demyelinating insult. Further, we show that these effects are dependent on the phosphorylation of oligodendrocyte expressed TrkB receptors in vivo Overall, we demonstrate that selective targeting of TrkB has therapeutic potential to promote remyelination in the brain.

Physician Burnout and the Calling to Care for the Dying: A National Survey.

BACKGROUND: Physician burnout raises concerns over what sustains physicians' career motivations. We assess whether physicians in end-of-life specialties had higher rates of burnout and/or calling to care for the dying. We also examined whether the patient centeredness of the clinical environment was associated with burnout. METHODS: In 2010 to 2011, we conducted a national survey of US physicians from multiple specialties. Primary outcomes were a validated single-item measure of burnout or sense of calling to end-of-life care. Primary predictors of burnout (or calling) included clinical specialty, frequency of encounters with dying patients, and patient centeredness of the clinical environments ("My clinical environment prioritizes the need of the patient over maximizing revenue"). RESULTS: Adjusted response rate among eligible respondents was 62% (1156 of 1878). Nearly a quarter of physicians (23%) experienced burnout, and rates were similar across all specialties. Half of the responding physicians (52%) agreed that they felt called to take care of patients who are dying. Burned-out physicians were more likely to report working in profit-centered clinical environments (multivariate odds ratio [OR] of 1.9; confidence interval [CI]: 1.3-2.8) or experiencing emotional exhaustion when caring for the dying (multivariate OR of 2.1; CI: 1.4-3.0). Physicians who identified their work as a calling were more likely to work in end-of-life specialties, to feel emotionally energized when caring for the dying, and to be religious. CONCLUSION: Physicians from end-of-life specialties not only did not have increased rates of burnout but they were also more likely to report a sense of calling in caring for the dying.

Methodology of metal criticality determination.

A comprehensive methodology has been created to quantify the degree of criticality of the metals of the periodic table. In this paper, we present and discuss the methodology, which is comprised of three dimensions: supply risk, environmental implications, and vulnerability to supply restriction. Supply risk differs with the time scale (medium or long), and at its more complex involves several components, themselves composed of a number of distinct indicators drawn from readily available peer-reviewed indexes and public information. Vulnerability to supply restriction differs with the organizational level (i.e., global, national, and corporate). The criticality methodology, an enhancement of a United States National Research Council template, is designed to help corporate, national, and global stakeholders conduct risk evaluation and to inform resource utilization and strategic decision-making. Although we believe our methodological choices lead to the most robust results, the framework has been constructed to permit flexibility by the user. Specific indicators can be deleted or added as desired and weighted as the user deems appropriate. The value of each indicator will evolve over time, and our future research will focus on this evolution. The methodology has proven to be sufficiently robust as to make it applicable across the entire spectrum of metals and organizational levels and provides a structural approach that reflects the multifaceted factors influencing the availability of metals in the 21st century.

Criticality of the geological copper family.

Because modern technology depends on reliable supplies of a wide variety of materials, and because of increasing concern about those supplies, a comprehensive methodology has been created to quantify the degree of criticality of the metals of the periodic table. In this paper, we apply this methodology to the elements of the geological copper family: Cu, As, Se, Ag, Te, and Au. These elements are technologically important, but show a substantial variation in different factors relating to their supply risk, vulnerability to supply restriction, and environmental implications. Assessments are made on corporate, national, and global levels for year 2008. Evaluations of each of the multiple indicators are presented and the results plotted in "criticality space", together with Monte Carlo simulation-derived "uncertainty cloud" estimates for each of the aggregated evaluations. For supply risk over both the medium term and long term, As is the highest risk of the six metals, with Se and Ag nearly as high. Gold has the most severe environmental implications ranking. Vulnerability to supply restriction (VSR) at the corporate level for an invented solar cell manufacturing firm shows Se, Te, and Cu as approximately equal, Cu has the highest VSR at the national level, and Cu and Au have the highest VSRs at the global level. Criticality vector magnitudes are greatest at the global level for As (and then Au and Ag) and at the national level for As and Au; at the corporate level, Se is highest with Te and Cu lower. An extension of this work, now in progress, will provide criticality estimates for several different development scenarios for the period 2010-2050.

Developmental characteristics of dendritic spines in the dentate gyrus of Fmr1 knockout mice.

Fragile X Syndrome (FXS) is the most common form of inherited mental retardation. The neuroanatomical phenotype of adult FXS patients, as well as adult Fmr1 knockout (KO) mice, includes elevated dendritic spine density and a spine morphology profile in neocortex that resembles younger individuals. Developmental studies in mouse neocortex have revealed a dynamic phenotype that varies with age, especially during the period of synaptic pruning. Here we investigated the hippocampal dentate gyrus to determine if the FXS spine phenotype is similarly tied to periods of maturation and pruning in this brain region. We used high-voltage electron microscopy to characterize Golgi-stained spines along granule cell dendrites in Fmr1 KO and wildtype (WT) mouse dentate gyrus at postnatal days 15, 21, 30, and 60. In contrast to neocortex, dendritic spine density was higher in Fmr1 KO mice across development. Interestingly, neither genotype showed specific phases of synaptogenesis or pruning, potentially explaining the phenotypic differences from neocortex. Similarly, although the KO mice showed a more immature morphological phenotype overall than WT (higher proportion of thin headed spines, lower proportion of mushroom and stubby spines), both genotypes showed gradual development, rather than impairments during specific phases of maturation. Finally, spine length showed a complex developmental pattern that differs from other brain regions examined, suggesting dynamic regulation by FMRP and other brain region-specific proteins. These findings shed new light on FMRP's role in development and highlight the need for new techniques to further understand the mechanisms by which FMRP affects synaptic maturation.