Activation of microglia and astrocytes secondary to inflammatory processes contributes to the development and perpetuation of pain with a neuropathic phenotype. This pain state presents as a chronic debilitating condition and affects a large population of patients with conditions like rheumatoid arthritis and diabetes, or after surgery, trauma, or chemotherapy. Here, we review the regulation of lipid rafts in glial cells and the role they play as a key component of neuroinflammatory sensitization of central pain signaling pathways. In this context, we introduce the concept of an inflammaraft (i-raft), enlarged lipid rafts harboring activated receptors and adaptor molecules and serving as an organizing platform to initiate inflammatory signaling and the cellular response. Characteristics of the inflammaraft include increased relative abundance of lipid rafts in inflammatory cells, increased content of cholesterol per raft, and increased levels of inflammatory receptors, such as toll-like receptor (TLR)4, adaptor molecules, ion channels, and enzymes in lipid rafts. This inflammaraft motif serves an important role in the membrane assembly of protein complexes, for example, TLR4 dimerization. Operating within this framework, we demonstrate the involvement of inflammatory receptors, redox molecules, and ion channels in the inflammaraft formation and the regulation of cholesterol and sphingolipid metabolism in the inflammaraft maintenance and disruption. Strategies for targeting inflammarafts, without affecting the integrity of lipid rafts in noninflammatory cells, may lead to developing novel therapies for neuropathic pain states and other neuroinflammatory conditions.

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The ribosome biogenesis factor Las1 is an essential endoribonuclease that is well-conserved across eukaryotes and a newly established member of the higher eukaryotes and prokaryotes nucleotide-binding (HEPN) domain-containing nuclease family. HEPN nucleases participate in diverse RNA cleavage pathways and share a short HEPN nuclease motif (RφXXXH) important for RNA cleavage. Most HEPN nucleases participate in stress-activated RNA cleavage pathways; Las1 plays a fundamental role in processing pre-rRNA. Underscoring the significance of Las1 function in the cell, mutations in the human LAS1L (LAS1-like) gene have been associated with neurological dysfunction. Two juxtaposed HEPN nuclease motifs create Las1's composite nuclease active site, but the roles of the individual HEPN motif residues are poorly defined. Here using a combination of in vivo experiments in Saccharomyces cerevisiae and in vitro assays, we show that both HEPN nuclease motifs are required for Las1 nuclease activity and fidelity. Through in-depth sequence analysis and systematic mutagenesis, we determined the consensus HEPN motif in the Las1 subfamily and uncovered its canonical and specialized elements. Using reconstituted Las1 HEPN-HEPN' chimeras, we defined the molecular requirements for RNA cleavage. Intriguingly, both copies of the Las1 HEPN motif were important for nuclease function, revealing that both HEPN motifs participate in coordinating the RNA within the Las1 active site. We also established that conformational flexibility of the two HEPN domains is important for proper nuclease function. The results of our work reveal critical information about how dual HEPN domains come together to drive Las1-mediated RNA cleavage.

Kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are two major, closely related receptor subtypes in the glutamate ion channel family. Excessive activities of these receptors have been implicated in a number of central nervous system diseases. Designing potent and selective antagonists of these receptors, especially of kainate receptors, is useful for developing potential treatment strategies for these neurological diseases. Here, we report on two RNA aptamers designed to individually inhibit kainate and AMPA receptors. To improve the biostability of these aptamers, we also chemically modified these aptamers by substituting their 2'-OH group with 2'-fluorine. These 2'-fluoro aptamers, FB9s-b and FB9s-r, were markedly resistant to RNase-catalyzed degradation, with a half-life of ∼5 days in rat cerebrospinal fluid or serum-containing medium. Furthermore, FB9s-r blocked AMPA receptor activity. Aptamer FB9s-b selectively inhibited GluK1 and GluK2 kainate receptor subunits, and also GluK1/GluK5 and GluK2/GluK5 heteromeric kainate receptors with equal potency. This inhibitory profile makes FB9s-b a powerful template for developing tool molecules and drug candidates for treatment of neurological diseases involving excessive activities of the GluK1 and GluK2 subunits.

K. A. Mirzoev and T. A. Safonova
Trans. Moscow Math. Soc. 80 (2020), 133-151.
Abstract, references and article information

S. A. Nazarov
Trans. Moscow Math. Soc. 80 (2020), 1-51.
Abstract, references and article information

Prótese auditiva ancorada em osso não emite um som como o aparelho convencional. Seu diferencial é vibrar o osso da cabeça.

The post SUS vai oferecer aparelho de última geração para tipo de perda auditiva até então sem tratamento appeared first on Saúde Próspera.

Todo mundo quer ter um sorriso bonito. Justamente por isso, a ideia de perder um ou mais dentes deixa qualquer pessoa desesperada.

The post Saiba como ter um sorriso perfeito appeared first on Saúde Próspera.

Aos primeiros sinais de visão embaçada, as hipóteses mais frequentes sempre são miopia, astigmatismo, hipermetropia. Mas esses sintomas podem indicar outra doença ocular chamada ceratocone - uma deformidade progressiva da córnea, que assume o formato...

The post Visão embaçada e distorcida nem sempre é miopia: fique atento aos sinais do ceratocone appeared first on Saúde Próspera.

The leak exposed millions of records with full names, emails, user conversations, payment logs, and IP addresses dating back to March.

Researchers have poked another small hole in air gapped security by showing how the electronics inside computer power supply units (PSUs) can be turned into covert data transmission devices.

Corporate Members Event

Event participants

Dr Yu Jie, Senior Research Fellow on China, Asia-Pacific Programme, Chatham House
David Lubin, Associate Fellow, Global Economy and Finance Programme, Chatham House; Managing Director and Head of Emerging Markets Economics, Citi
Jinny Yan, Managing Director and Chief China Economist, ICBC Standard
Chair: Creon Butler, Director, Global Economy and Finance Programme, Chatham House

It.s often a challenge to get from Point A to Point B in normal circumstances, but after a disaster it can be almost impossible to transport food, water, and clothing from the usual supply points to the people in desperate need. A new mathematical model employs probability and nonlinear programming to design supply chains that have the best chance of functioning after a disaster. For each region or country, the model generates a robust chain of supply and delivery points that can respond to the combination of disruptions in the network and increased needs of the population. Math also helps medical agencies operate more efficiently during emergencies, such as an infectious outbreak. Fluid dynamics and combinatorial optimization are applied to facility layout and epidemiological models to allocate resources and improve operations while minimizing total infection within dispensing facilities. This helps ensure fast, effective administering of vaccines and other medicines. Furthermore, solution times are fast enough that officials can input up-to-the-minute data specific to their situation and make any necessary redistribution of supplies or staff in real time. For More Information: Supply Chain Network Economics: Dynamics of Prices, Flows, and Profits, Anna Nagurney, 2006.

Van Wedeen talks about the geometry of the brain's communication pathways.

Researcher: John A. Adam, Old Dominion University. John A. Adam explains the math and physics behind rainbows.

Researcher: Daniel Rothman, MIT. Dan Rothman talks about how math helped understand a mass extinction.

Dear Shareholders, As Chairwoman of the Supervisory Board, I am contacting you personally today in advance of the Annual General Meeting to ask for your continued trust and support.

THERE'S nothing like the sweet taste of victory, especially when it's long in coming.

In-form American sprinter, Michael Rodgers, ran a world-leading 9.94 seconds and there were no Caribbean

In these unprecedented times, we are all spending much more time at home and in our gardens. And, now that spring has well and truly arrived, it's the perfect time to get reacquainted with one of our country's busiest workers - the bee.

Sovereign nations typically measure economic success in terms of GDP (income) but this approach is risky as it fails to track and measure the impact of this on nature. Inclusive wealth, on the other hand captures financial and produced capital, but also the skills in our workforce (human capital), the cohesion in our society (social capital) and the value of our environment (natural capital).

Tropical rainforests are the world's richest land habitats for biodiversity, harbouring stunning numbers of plant and animal species. The Amazon and the Congo basins, together with Asian rainforests, represent only 6 per cent of earth's land surface, and yet more than 50 per cent of global biodiversity can be found under their shade.

Outcomes of the Meeting of the Friends of the Co-Chairs on liability and redress, Bonn, 7-10 May 2008