Mycobacteria-responsive sonic hedgehog signaling mediates programmed death-ligand 1-and prostaglandin E-2-induced regulatory T cell expansion

CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) are exploited by mycobacteria to subvert the protective host immune responses. The Treg expansion in the periphery requires signaling by professional antigen presenting cells and in particularly dendritic cells (DC). However, precise molecular mechanisms by which mycobacteria instruct Treg expansion via DCs are not established. Here we demonstrate that mycobacteria-responsive sonic hedgehog (SHH) signaling in human DCs leads to programmed death ligand-1 (PD-L1) expression and cyclooxygenase (COX)-2-catalyzed prostaglandin E-2 (PGE(2)) that orchestrate mycobacterial infection-induced expansion of Tregs. While SHH-responsive transcription factor GLI1 directly arbitrated COX-2 transcription, specific microRNAs, miR-324-5p and miR-338-5p, which target PD-L1 were downregulated by SHH signaling. Further, counter-regulatory roles of SHH and NOTCH1 signaling during mycobacterial-infection of human DCs was also evident. Together, our results establish that Mycobacterium directs a fine-balance of host signaling pathways and molecular regulators in human DCs to expand Tregs that favour immune evasion of the pathogen.

Rigorous finite-time guarantees for optimization on continuous domains by simulated annealing

Simulated annealing is a popular method for approaching the solution of a global optimization problem. Existing results on its performance apply to discrete combinatorial optimization where the optimization variables can assume only a finite set of possible values. We introduce a new general formulation of simulated annealing which allows one to guarantee finite-time performance in the optimization of functions of continuous variables. The results hold universally for any optimization problem on a bounded domain and establish a connection between simulated annealing and up-to-date theory of convergence of Markov chain Monte Carlo methods on continuous domains. This work is inspired by the concept of finite-time learning with known accuracy and confidence developed in statistical learning theory.

Regulatory quality and the regulatory system in the UK

Busca identificar como o sistema regulatório britânico se desenvolveu nos últimos anos contribuindo para a melhoria da regulação no país. Aborda o tema da qualidade legislativa no Reino Unido.

Panel Discussion - Management of Eurasian watermilfoil in the United States using native insects: State regulatory and management issues

While researchers have evaluated the potential of native insect herbivores to manage nonindigenous aquatic plant species such as Eurasian watermilfoil ( Myriophyllum spicatum L.), the practical matters of regulatory compliance and implementation have been neglected. A panel of aquatic nuisance species program managers from three state natural resource management agencies (Minnesota, Vermont and Washington) discussed their regulatory and policy concerns. In addition, one ecological consultant attempting to market one of the native insects to manage Eurasian watermilfoil added his perspective on the special challenges of distributing a native biological control agent for management of Eurasian watermilfoil.

USP1 deubiquitinase: cellular functions, regulatory mechanisms and emerging potential as target in cancer therapy

12 p.

Civil framework of the Internet : Law n°. 12.965, of April 23, 2014, which establishes the principles, guarantees, rights and duties for use of the Internet in Brazil

Traz atualizado o texto do Marco Civil Brasileiro da Internet, a Lei nº 12.965, de 23 de abril de 2014.

Climate adaptation and the fifth amendment of the United States Constitution: How do adaptation strategies impact regulatory takings claims?

As the impacts and potential of climate change are realized at the governance level, states are moving towards adaptation strategies that include greater regulatory restrictions on development within coastal zones. The purpose of this paper is to outline the impacts of existing and planned regulatory mechanisms on the Fifth Amendment to the United States Constitution, which prevents the government taking of private property for public use without just compensation. A short history of regulatory takings is explained, and the potential legal issues surrounding mitigation and adaptation measures for coastal communities are discussed. The goal is to gain an understanding of the legal issues that must be resolved by governments to effectively deal with regulatory takings claims as coastal mitigation and adaptation plans are implemented. (PDF contains 3 pages)