Prickle1 is required for EMT and migration of zebrafish cranial neural crest

The neural crest—a key innovation of the vertebrates—gives rise to diverse cell types including melanocytes, neurons and glia of the peripheral nervous system, and chondrocytes of the jaw and skull. Proper development of the cephalic region is dependent on the tightly-regulated specification and migration of cranial neural crest cells (NCCs). The core PCP proteins Frizzled and Disheveled have previously been implicated in NCC migration. Here we investigate the functions of the core PCP proteins Prickle1a and Prickle1b in zebrafish cranial NCC development. Using analysis of pk1a and pk1b mutant embryos, we uncover similar roles for both genes in facilitating cranial NCC migration. Disruption of either gene causes pre-migratory NCCs to cluster together at the dorsal aspect of the neural tube, where they adopt aberrant polarity and movement. Critically, in investigating Pk1-deficient cells that fail to migrate ventrolaterally, we have also uncovered roles for pk1a and pk1b in the epithelial-to-mesenchymal transition (EMT) of pre-migratory NCCs that precedes their collective migration to the periphery. Normally, during EMT, pre-migratory NCCs transition from a neuroepithelial to a bleb-based and subsequently, mesenchymal morphology capable of directed migration. When either Pk1a or Pk1b is disrupted, NCCs continue to perform blebbing behaviors characteristic of pre-migratory cells over extended time periods, indicating a block in a key transition during EMT. Although some Pk1-deficient NCCs transition successfully to mesenchymal, migratory morphologies, they fail to separate from neighboring NCCs. Additionally, Pk1b-deficient NCCs show elevated levels of E-Cadherin and reduced levels of N-Cadherin, suggesting that Prickle1 molecules regulate Cadherin levels to ensure the completion of EMT and the commencement of cranial NCC migration. We conclude that Pk1 plays crucial roles in cranial NCCs both during EMT and migration. These roles are dependent on the regulation of E-Cad and N-Cad

Multi-Agent Deep Reinforcement Learning for Request Dispatching in Distributed-Controller Software-Defined Networking

Recently, distributed controller architectures have been quickly gaining popularity in Software-Defined Networking (SDN). However, the use of distributed controllers introduces a new and important Request Dispatching (RD) problem with the goal for every SDN switch to properly dispatch their requests among all controllers so as to optimize network performance. This goal can be fulfilled by designing an RD policy to guide distribution of requests at each switch. In this paper, we propose a Multi-Agent Deep Reinforcement Learning (MA-DRL) approach to automatically design RD policies with high adaptability and performance. This is achieved through a new problem formulation in the form of a Multi-Agent Markov Decision Process (MA-MDP), a new adaptive RD policy design and a new MA-DRL algorithm called MA-PPO. Extensive simulation studies show that our MA-DRL technique can effectively train RD policies to significantly outperform man-made policies, model-based policies, as well as RD policies learned via single-agent DRL algorithms

Decentralization in Argentina

Human development, reflected in the status of people's levels of health and education, affects future growth and, in turn, is affected by decentralization. Unlike earlier exclusive emphasis on budgetary issues, this study focuses on the impact of fiscal decentralization on the level of human development. It traces the origin and recent development of revenue-sharing arrangements across Argentina's provinces over time (1970-94). The study regresses two indicators of health and educational status on two decentralization measures. It highlights the link between decentralization and human development outcomes and suggests that devolutionary decentralization has a positive influence on the effectiveness of public policy directed towards an improvement in the level of human development. Decentralization is shown to reduce intra- regional disparities and increase levels of human development. While the paper also recognizes problems associated with decentralization, including addressing inter-regional disparities, the positive impact of decentralization schemes on human development is seen to be of relevance in evaluating the Argentine co-participation regime which is currently under negotiation.Fiscal Decentralization, Human Development, Argentina

Rocky Mountain High Titer: An Unusual Delay In Surgical Clearance

Rocky Mountain Spotted Fever, carried by a variety of ticks, is classically caused by Ricksettsia rickettsii, but may be clinically indistinguishable from other bacteria in the same family. A 47 year old female presented in December for presurgical clearance due to fever, petechial rash on the thighs and trunk, and ecchymoses on the forearms, gluteal region, and toes; additional symptoms included arthralgia in bilateral lower limbs. Bacterial infection was suspected and empirical doxycycline was initiated pending specific PCR testing. Patient adherence was unclear at the followup visit, so IV ceftriaxone was initiated and repeated immunoglobulin testing was ordered to follow her course. Her symptoms waxed and waned over the next several weeks, but ultimately improved and resolved over the next two months, at which point she was successfully cleared for surgery. This case was unusual as she presented in December but disease prevalence typically wanes by August. She was evaluated by rheumatology and dermatology for arthralgia and rash prior to presentation to infectious disease service, but prior treatment was unsuccessful; a missed opportunity to prevent delay in surgery and potential sequelae of long-term infectious vasculitis. As changes in climate increase host range for the variety of vectors, geographic range and temporal duration is also expected to increase, and so it should be considered in the differential more frequently

Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development

Parasitic infections remain one of the most pressing global health concerns of our day, affecting billions of people and producing unsustainable economic burdens. The rise of drug-resistant parasites has created an urgent need to study their biology in hopes of uncovering new potential drug targets. It has been established that disrupting gene expression by interfering with lysine acetylation is detrimental to survival of apicomplexan (Toxoplasma gondii and Plasmodium spp.) and kinetoplastid (Leishmania spp. and Trypanosoma spp.) parasites. As "readers" of lysine acetylation, bromodomain proteins have emerged as key gene expression regulators and a promising new class of drug target. Here we review recent studies that demonstrate the essential roles played by bromodomain-containing proteins in parasite viability, invasion, and stage switching and present work showing the efficacy of bromodomain inhibitors as novel antiparasitic agents. In addition, we performed a phylogenetic analysis of bromodomain proteins in representative pathogens, some of which possess unique features that may be specific to parasite processes and useful in future drug development

Lights, Camera, Empathy: A Request to Slow the Emergency Medicine Standardized Video Interview Project Study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141594/1/aet210062_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141594/2/aet210062.pd

Simultaneous inversion for fast azimuth and dispersion of borehole flexural waves using cross-dipole data

This paper presents an inversion algorithm for obtaining azimuthal angle and borehole flexural wave dispersion in an anisotropic formation. The technique constructs an objective function that can be minimized using standard non-linear inversion methods, which is sensitive to both dispersion and rotation. The method is tested on both synthetic and real borehole data and gives good agreement with traditional processing.Massachusetts Institute of Technology. Borehole Acoustics and Logging Consortiu