Klotho controls the brain-immune system interface in the choroid plexus.

Located within the brain's ventricles, the choroid plexus produces cerebrospinal fluid and forms an important barrier between the central nervous system and the blood. For unknown reasons, the choroid plexus produces high levels of the protein klotho. Here, we show that these levels naturally decline with aging. Depleting klotho selectively from the choroid plexus via targeted viral vector-induced knockout in Klotho flox/flox mice increased the expression of multiple proinflammatory factors and triggered macrophage infiltration of this structure in young mice, simulating changes in unmanipulated old mice. Wild-type mice infected with the same Cre recombinase-expressing virus did not show such alterations. Experimental depletion of klotho from the choroid plexus enhanced microglial activation in the hippocampus after peripheral injection of mice with lipopolysaccharide. In primary cultures, klotho suppressed thioredoxin-interacting protein-dependent activation of the NLRP3 inflammasome in macrophages by enhancing fibroblast growth factor 23 signaling. We conclude that klotho functions as a gatekeeper at the interface between the brain and immune system in the choroid plexus. Klotho depletion in aging or disease may weaken this barrier and promote immune-mediated neuropathogenesis

Hysterosalpingography Versus Sonohysterography for Intrauterine Abnormalities

Sonohysterography was found to be more sensitive, specific, and accurate in the evaluation of specific intrauterine defects than hysterosalpingography

Multi-attributes tradespace exploration for survivability: Application to satellite radar

Multi-Attribute Tradespace Exploration (MATE) for Survivability is introduced as a general methodology for survivability analysis and demonstrated through an application to a satellite radar system. MATE for Survivability applies decision theory to the parametric modeling of thousands of design alternatives across representative distributions of disturbance environments. Survivability considerations are incorporated into the existing MATE process (i.e., a solution-generating and decision-making framework that applies decision theory to model-based design) by applying empirically-validated survivability design principles and value-based survivability metrics to concept generation and concept evaluation activities, respectively. MATE for Survivability consists of eight iterative phases: (1) define system value proposition, (2) generate concepts, (3) specify disturbances, (4) apply survivability principles, (5) model baseline system performance, (6) model impact of disturbances on dynamic system performance, (7) apply survivability metrics, and (8) select designs for further analysis. The application of MATE for Survivability to satellite radar demonstrates the importance of incorporating survivability considerations into conceptual design for identifying inherently survivable architectures that efficiently balance competing performance metrics of lifecycle cost, mission utility, and operational survivability

Transcriptional Auto-Regulation of RUNX1 P1 Promoter

RUNX1 a member of the family of runt related transcription factors (RUNX), is essential for hematopoiesis. The expression of RUNX1 gene is controlled by two promoters; the distal P1 promoter and the proximal P2 promoter. Several isoforms of RUNX1 mRNA are generated through the use of both promoters and alternative splicing. These isoforms not only differs in their temporal expression pattern but also exhibit differences in tissue specificity. The RUNX1 isoforms derived from P2 are expressed in a variety of tissues, but expression of P1-derived isoform is restricted to cells of hematopoietic lineage. However, the control of hematopoietic-cell specific expression is poorly understood. Here we report regulation of P1-derived RUNX1 mRNA by RUNX1 protein. In silico analysis of P1 promoter revealed presence of two evolutionary conserved RUNX motifs, 0.6kb upstream of the transcription start site, and three RUNX motifs within 170bp of the 5\u27UTR. Transcriptional contribution of these RUNX motifs was studied in myeloid and T-cells. RUNX1 genomic fragment containing all sites show very low basal activity in both cell types. Mutation or deletion of RUNX motifs in the UTR enhances basal activity of the RUNX1 promoter. Chromatin immunoprecipitation revealed that RUNX1 protein is recruited to these sites. Overexpression of RUNX1 in non-hematopoietic cells results in a dose dependent activation of the RUNX1 P1 promoter. We also demonstrate that RUNX1 protein regulates transcription of endogenous RUNX1 mRNA in T-cell. Finally we show that SCL transcription factor is recruited to regions containing RUNX motifs in the promoter and the UTR and regulates activity of the RUNX1 P1 promoter in vitro. Thus, multiple lines of evidence show that RUNX1 protein regulates its own gene transcription

The Beta-Bernoulli process and algebraic effects

In this paper we use the framework of algebraic effects from programming language theory to analyze the Beta-Bernoulli process, a standard building block in Bayesian models. Our analysis reveals the importance of abstract data types, and two types of program equations, called commutativity and discardability. We develop an equational theory of terms that use the Beta-Bernoulli process, and show that the theory is complete with respect to the measure-theoretic semantics, and also in the syntactic sense of Post. Our analysis has a potential for being generalized to other stochastic processes relevant to Bayesian modelling, yielding new understanding of these processes from the perspective of programming

Bcl3 prevents acute inflammatory lung injury in mice by restraining emergency granulopoiesis

Granulocytes are pivotal regulators of tissue injury. However, the transcriptional mechanisms that regulate granulopoiesis under inflammatory conditions are poorly understood. Here we show that the transcriptional coregulator B cell leukemia/lymphoma 3 (Bcl3) limits granulopoiesis under emergency (i.e., inflammatory) conditions, but not homeostatic conditions. Treatment of mouse myeloid progenitors with G-CSF — serum concentrations of which rise under inflammatory conditions — rapidly increased Bcl3 transcript accumulation in a STAT3-dependent manner. Bcl3-deficient myeloid progenitors demonstrated an enhanced capacity to proliferate and differentiate into granulocytes following G-CSF stimulation, whereas the accumulation of Bcl3 protein attenuated granulopoiesis in an NF-κB p50–dependent manner. In a clinically relevant model of transplant-mediated lung ischemia reperfusion injury, expression of Bcl3 in recipients inhibited emergency granulopoiesis and limited acute graft damage. These data demonstrate a critical role for Bcl3 in regulating emergency granulopoiesis and suggest that targeting the differentiation of myeloid progenitors may be a therapeutic strategy for preventing inflammatory lung injury

Electrophysiological Signatures of Spatial Boundaries in the Human Subiculum.

Environmental boundaries play a crucial role in spatial navigation and memory across a wide range of distantly related species. In rodents, boundary representations have been identified at the single-cell level in the subiculum and entorhinal cortex of the hippocampal formation. Although studies of hippocampal function and spatial behavior suggest that similar representations might exist in humans, boundary-related neural activity has not been identified electrophysiologically in humans until now. To address this gap in the literature, we analyzed intracranial recordings from the hippocampal formation of surgical epilepsy patients (of both sexes) while they performed a virtual spatial navigation task and compared the power in three frequency bands (1-4, 4-10, and 30-90 Hz) for target locations near and far from the environmental boundaries. Our results suggest that encoding locations near boundaries elicited stronger theta oscillations than for target locations near the center of the environment and that this difference cannot be explained by variables such as trial length, speed, movement, or performance. These findings provide direct evidence of boundary-dependent neural activity localized in humans to the subiculum, the homolog of the hippocampal subregion in which most boundary cells are found in rodents, and indicate that this system can represent attended locations that rather than the position of one\u27s own body

Incentive-based approaches to sustainable fisheries

The failures of traditional target-species management have led many to propose an ecosystem approach to fisheries to promote sustainability. The ecosystem approach is necessary, especially to account for fishery-ecosystem interactions, but by itself is not sufficient to address two important factors contributing to unsustainable fisheries — inappropriate incentives bearing on fishers, and the ineffective governance that frequently exists in commercial, developed fisheries managed primarily by total harvest limits and input-controls. We contend that much greater emphasis must be placed on fisher motivation when managing fisheries. Using evidence from more than a dozen ‘natural experiments’ in commercial fisheries, we argue that incentive-based approaches that better specify community, individual harvest, or territorial rights and also price ecosystem services — coupled with public research, monitoring and effective oversight — promote sustainable fisheries.incentives, sustainability, rights, fisheries management

Incentive-based approaches to sustainable fisheries (now replaced by EEN0508)

Using examples from more than a dozen fisheries, we highlight the failures of ‘command control’ management and show that approaches that empower fishers with the incentives and the mandate to be co-custodians of the marine environment can promote sustainability. Evidence is provided that where harvesters share well-defined management responsibilities over fish, and experience both the pain of overexploitation and the gains from conservation, they are much more likely to protect fish stocks and habitat. The key insight is that to maintain marine ecosystems for present and future generations, fishing incentives must be compatible with long-term goals of sustainability.incentives, sustainability, rights, fisheries management