Conformational plasticity of NaK2K and TREK2 potassium channel selectivity filters

The

The Dynamics of Functional Brain Networks:Integrated Network States during Cognitive Task Performance

Higher brain function relies upon the ability to flexibly integrate information across specialized communities of brain regions, however it is unclear how this mechanism manifests over time. In this study, we use time-resolved network analysis of functional magnetic resonance imaging data to demonstrate that the human brain traverses between two functional states that maximize either segregation into tight-knit communities or integration across otherwise disparate neural regions. The integrated state enables faster and more accurate performance on a cognitive task, and is associated with dilations in pupil diameter, suggesting that ascending neuromodulatory systems may govern the transition between these alternative modes of brain function. Our data confirm a direct link between cognitive performance and the dynamic reorganization of the network structure of the brain.Comment: 38 pages, 4 figure

Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: a combined analysis of 12 mathematical models.

BACKGROUND: New WHO guidelines recommend ART initiation for HIV-positive persons with CD4 cell counts ≤500 cells/µL, a higher threshold than was previously recommended. Country decision makers must consider whether to further expand ART eligibility accordingly. METHODS: We used multiple independent mathematical models in four settings-South Africa, Zambia, India, and Vietnam-to evaluate the potential health impact, costs, and cost-effectiveness of different adult ART eligibility criteria under scenarios of current and expanded treatment coverage, with results projected over 20 years. Analyses considered extending eligibility to include individuals with CD4 ≤500 cells/µL or all HIV-positive adults, compared to the previous recommendation of initiation with CD4 ≤350 cells/µL. We assessed costs from a health system perspective, and calculated the incremental cost per DALY averted ($/DALY) to compare competing strategies. Strategies were considered 'very cost-effective' if the$/DALY was less than the country's per capita gross domestic product (GDP; South Africa: $8040, Zambia:$1425, India: $1489, Vietnam:$1407) and 'cost-effective' if $/DALY was less than three times per capita GDP. FINDINGS: In South Africa, the cost per DALY averted of extending ART eligibility to CD4 ≤500 cells/µL ranged from$237 to $1691/DALY compared to 2010 guidelines; in Zambia, expanded eligibility ranged from improving health outcomes while reducing costs (i.e. dominating current guidelines) to$749/DALY. Results were similar in scenarios with substantially expanded treatment access and for expanding eligibility to all HIV-positive adults. Expanding treatment coverage in the general population was therefore found to be cost-effective. In India, eligibility for all HIV-positive persons ranged from $131 to$241/DALY and in Vietnam eligibility for CD4 ≤500 cells/µL cost $290/DALY. In concentrated epidemics, expanded access among key populations was also cost-effective. INTERPRETATION: Earlier ART eligibility is estimated to be very cost-effective in low- and middle-income settings, although these questions should be revisited as further information becomes available. Scaling-up ART should be considered among other high-priority health interventions competing for health budgets. FUNDING: The Bill and Melinda Gates Foundation and World Health Organization

Functional Heterogeneity of Embryonic Stem Cells Revealed through Translational Amplification of an Early Endodermal Transcript

Detection of low-level, lineage-specific transcription aids in the identification of lineage-primed populations of ES cells provides a new framework for pluripotency

\u27Struggling with Language\u27 : Indigenous movements for Linguistic Security and the Politics of Local Community

In this article, I explore the relationship between linguistic diversity and political power. Specifically, I outline some of the ways that linguistic diversity has served as a barrier to the centralization of power, thus constraining, for example, the political practice of empire-formation. A brief historical example of this dynamic is presented in the case of Spanish colonialism of the 16th-century. The article proceeds then to demonstrate how linguistic diversity remains tied to struggles against forms of domination. I argue that in contemporary indigenous movements for linguistic security, the languages themselves are not merely conceived of as the object of the political struggle, but also as the means to preserve a space for local action and deliberation – a ‘politics of local community’. I show that linguistic diversity and the devolution of political power to the local level are in a mutually reinforcing relationship. Finally, I consider the implications of this thesis for liberal theorizing on language rights, arguing that such theory cannot fully come to terms with this political-strategic dimension of language struggles

The neural correlates of dreaming.

Consciousness never fades during waking. However, when awakened from sleep, we sometimes recall dreams and sometimes recall no experiences. Traditionally, dreaming has been identified with rapid eye-movement (REM) sleep, characterized by wake-like, globally 'activated', high-frequency electroencephalographic activity. However, dreaming also occurs in non-REM (NREM) sleep, characterized by prominent low-frequency activity. This challenges our understanding of the neural correlates of conscious experiences in sleep. Using high-density electroencephalography, we contrasted the presence and absence of dreaming in NREM and REM sleep. In both NREM and REM sleep, reports of dream experience were associated with local decreases in low-frequency activity in posterior cortical regions. High-frequency activity in these regions correlated with specific dream contents. Monitoring this posterior 'hot zone' in real time predicted whether an individual reported dreaming or the absence of dream experiences during NREM sleep, suggesting that it may constitute a core correlate of conscious experiences in sleep

A Glycemia Risk Index (GRI) of Hypoglycemia and Hyperglycemia for Continuous Glucose Monitoring Validated by Clinician Ratings

BackgroundA composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data.MethodsWe assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low-glucose and low-glucose hypoglycemia; very high-glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation.ResultsThe analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals.ConclusionThe GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth