Explore the vast range of titles available.

Infection and tissue damage induces assembly of supramolecular organizing centres (SMOCs)), such as the Toll-like receptor (TLR) MyDDosome, to co-ordinate inflammatory signaling. SMOC assembly is thought to drive digital all-or-none responses, yet TLR activation by diverse microbes induces anything from mild to severe inflammation. Using single-molecule imaging of TLR4-MyDDosome signaling in living macrophages, we find that MyDDosomes assemble within minutes of TLR4 stimulation. TLR4/MD2 activation leads only to formation of TLR4/MD2 heterotetramers, but not oligomers, suggesting a stoichiometric mismatch between activated receptors and MyDDosomes. The strength of TLR4 signalling depends not only on the number and size of MyDDosomes formed but also how quickly these structures assemble. Activated TLR4, therefore, acts transiently nucleating assembly of MyDDosomes, a process that is uncoupled from receptor activation. These data explain how the oncogenic mutation of MyD88 (L265P) assembles MyDDosomes in the absence of receptor activation to cause constitutive activation of pro-survival NF-κB signalling. Cells in the immune system have proteins at their surface that detect molecules produced by invading microbes. One of these proteins is Toll-like receptor 4, TLR4 for short. Once TLR4 is activated, the immune cells form MyDDosomes – intricate complexes made of many different proteins. These structures form a signal that mobilizes the cell to fight the infection. In particular, the complexes set up a chain of events that leads to a gene-regulating protein getting access to the cell’s DNA. There, the protein switches on genes which produce other proteins important for inflammation, one of the body’s most important tools to fight an infection. The activation of TLR4 is thought to be an all-or-nothing mechanism: the receptors are either ‘on’ or ‘off’. However, different microbial molecules recognized by TLR4 trigger different levels of inflammation, ranging from mild to severe. It remained unclear how an all-or-none response from the frontline receptors could lead to a gradual response from the cell. Here, Latty et al. compare what happens to TLR4, MyDDosomes and the gene-regulating proteins when living immune cells are stimulated by different doses of two microbial molecules. These agents are both recognized by TLR4, but they lead to different levels of inflammation. The type of microbial molecule, or their concentration, does not change how TLR4 is activated. Two TLR4 proteins can loosely associate with each together to form a dimer. When they bind a microbial molecule, the dimer becomes more stable. This changes the shape of the TLR4 proteins, which in turn triggers the formation of a scaffold of MyDDosomes. More stable TLR4 dimers are formed when the cells is in contact with a microbial molecule that triggers a strong immune reaction, and possibly when its concentration is higher. Crucially, the different microbial agents and their concentration levels modify how MyDDosomes assemble. By ‘tagging’ each protein in the complex with a fluorescent chemical, Latty et al. can follow its formation as it actually happens. When the cells are stimulated with microbial molecules that provoke a strong inflammation, the MyDDosomes may be bigger, in greater numbers, and form more quickly. In turn, under strong microbial activation, the gene-regulating protein that switches on the immune response genes goes to the DNA faster and in higher numbers. This suggests that the pace of assembly, the size and the number of MyDDosomes control the strength of the immune response. TLR4 is involved in diseases such as cancer or Alzheimer’s disease, where the body has an incorrect inflammation response. Knowing in greater detail the cellular processes activated by TLR4 could help efforts to find new drug targets for these conditions.

A partir de la década de los cuarentas la sociedad mexicana vive una profunda transformación ante la acelerada industrialización observada en el país.Esta innegable transformación económica, política y social sólo se concreta por la conjunción histórica de una serie de factores internos y externos cuyos orígenes deben encontrarse tanto en un pasado remoto —en el caso de los factores internos serían: la experiencia de la colonia, la reforma, el porfiriato, la revolución, etcétera—, hasta en uno más cercano o inmediato al periodo en que la industrialización mexicana se cristaliza, como son: la gran crisis económica mundial de los veinte, el cardenismo, la Segunda Guerra Mundial, etcétera.

Glucose metabolism is essential for the brain: it not only provides the required energy for cellular function and communication but also participates in balancing the levels of oxidative stress in neurons. Defects in glucose metabolism have been described in neurodegenerative disease; however, it remains unclear how this fundamental process contributes to neuronal cell death in these disorders. Here, we investigated the molecular mechanisms driving the selective neurodegeneration in an ataxic mouse model lacking oxidation resistance 1 (Oxr1) and discovered an unexpected function for this protein as a regulator of the glycolytic enzyme, glucose-6-phosphate isomerase (GPI/Gpi1). Initially, we present a dysregulation of metabolites of glucose metabolism at the pre-symptomatic stage in the Oxr1 knockout cerebellum. We then demonstrate that Oxr1 and Gpi1 physically and functionally interact and that the level of Gpi1 oligomerisation is disrupted when Oxr1 is deleted in vivo. Furthermore, we show that Oxr1 modulates the additional and less well-understood roles of Gpi1 as a cytokine and neuroprotective factor. Overall, our data identify a new molecular function for Oxr1, establishing this protein as important player in neuronal survival, regulating both oxidative stress and glucose metabolism in the brain.

Bacterial outer membrane lipopolysaccharide (LPS) potently stimulates the mammalian innate immune system and can lead to sepsis, the primary cause of death from infections. LPS is sensed by Toll-like receptor 4 (TLR4) in complex with its lipid-binding coreceptor MD-2, but subtle structural variations in LPS can profoundly modulate the response. To better understand the mechanism of LPS-induced stimulation and bacterial evasion, we have calculated the binding affinity to MD-2 of agonistic and antagonistic LPS variants including lipid A, lipid IVa and synthetic antagonist Eritoran and provide evidence that the coreceptor is a molecular switch that undergoes ligand-induced conformational changes to appropriately activate or inhibit the receptor complex. The plasticity of the coreceptor binding cavity is shown to be essential for distinguishing between ligands, whilst similar calculations for a model bacterial LPS bilayer reveal the “membrane-like” nature of the protein cavity. The ability to predict the activity of LPS variants should facilitate the rational design of TLR4 therapeutics.

Infection and tissue damage induces assembly of supramolecular organizing centres (SMOCs)), such as the Toll-like receptor (TLR) MyDDosome, to co-ordinate inflammatory signaling. SMOC assembly is thought to drive digital all-or-none responses, yet TLR activation by diverse microbes induces anything from mild to severe inflammation. Using single-molecule imaging of TLR4-MyDDosome signaling in living macrophages, we find that MyDDosomes assemble within minutes of TLR4 stimulation. TLR4/MD2 activation leads only to formation of TLR4/MD2 heterotetramers, but not oligomers, suggesting a stoichiometric mismatch between activated receptors and MyDDosomes. The strength of TLR4 signalling depends not only on the number and size of MyDDosomes formed but also how quickly these structures assemble. Activated TLR4, therefore, acts transiently nucleating assembly of MyDDosomes, a process that is uncoupled from receptor activation. These data explain how the oncogenic mutation of MyD88 (L265P) assembles MyDDosomes in the absence of receptor activation to cause constitutive activation of pro-survival NF-κB signalling.

Television is an important part of popular culture all over the world. For almost fifty years, telenovelas—similar to soap operas—have become an important economic cultural industry and a significant element of popular culture in numerous countries around the world. Scholars have speculated on telenovelas' social impact, and there is an abundance of studies concerned with textual analysis, but little is known about the relationship established between this genre and its audiences. For almost 37 years, U.S. Hispanic television networks have aired telenovelas; however, nobody has studied how telenovelas relate to these audiences, what their sociocultural consequences are, and how U.S. Hispanic audiences relate to this genre. This dissertation is concerned with the study of the U.S. Hispanic audience's relationship to telenovelas. Special focus is placed on: (1) Sociopsychological dimensions of the Hispanic reading process; (2) Hispanics' social identity relation to this genre; (3) Hispanics' daily life relation to this genre; (4) How Hispanics deal with the telenovela's social values and stereotypes.

Background and aimsPopulation ageing is a typical phenomenon of developed countries with a great influence in their economy and society, with an increment on age-related expenditures. Disruptive solutions are needed to deploy new cost-effective and sustainable solutions for aging well and independent living of our seniors. In this sense, new technological paradigms as IoT technologies and smart cities have the potential to become main drivers for innovation uptake. The purpose of this study is to describe a longitudinal cohort study in smart cities for assessing early frailty symptoms deploying an unobtrusive IoT-based system in the Madrid city.MethodsA system was deployed in the Madrid city with the participation of 45 elderly users for an average of 71 weeks. Metrics were assessed by the available sensors in combination with the open data infrastructure of Madrid. Metrics include activity of the user, weekly visits pattern and transport daily usage pattern. System engagement was also monitored. Participants are assessed bimonthly with health and functional questionnaires.Results45 older adults with a mean age of 79.1 years. Participants activity patterns monitor detected changes during potentially risky situations that usually were not reported by traditional assessment tools. Analysis of data collected enabled to identify absence of frailty (robust or post-robust status)Discussion and conclusionsThe results demonstrate the feasibility of engaging older adults with an IoT-based system and the successful collection of their activity metrics. Variation in the activity patterns may be a first sign of functional decline and enables to identify potential areas of early intervention.

Prolonged activation of glutamate receptors leads to excitotoxicity. Several processes such as reactive oxygen species (ROS) production and activation of the calcium-dependent protease, calpain, contribute to glutamate-induced damage. It has been suggested that the ROS-producing enzyme, NADPH oxidase (NOX), plays a role in excitotoxicity. Studies have reported NOX activation after NMDA receptor stimulation during excitotoxic damage, but the role of non-NMDA and metabotropic receptors is unknown. We evaluated the roles of different glutamate receptor subtypes on NOX activation and neuronal death induced by the intrastriatal administration of glutamate in mice. In wild-type mice, NOX2 immunoreactivity in neurons and microglia was stimulated by glutamate administration, and it progressively increased as microglia became activated; calpain activity was also induced. By contrast, mice lacking NOX2 were less vulnerable to excitotoxicity, and there was reduced ROS production and protein nitrosylation, microglial reactivity, and calpain activation. These results suggest that NOX2 is stimulated by glutamate in neurons and reactive microglia through the activation of ionotropic and metabotropic receptors. Neuronal damage involves ROS production by NOX2, which, in turn, contributes to calpain activation.

We evaluated the association between anti-cyclic citrullinated peptide antibodies (anti-CCP) and anti-mutated citrullinated vimentin antibodies (anti-MCV) with the presence of extra-articular (ExRA) manifestations in 225 patients with rheumatoid arthritis (RA). Ninety-five patients had ExRA and 130 had no ExRA. There was no association of anti-CCP and anti-MCV levels with the presence of ExRA as total group ( P = 0.40 and P = 0.91 , resp.). Making an analysis of individual manifestations, rheumatoid nodules were associated with positivity for rheumatoid factor (RF); ( P = 0.01 ), anti-CCP ( P = 0.048 ), and anti-MCV ( P = 0.02 ). Instead, RF, anti-CCP, or anti-MCV were not associated with SS, chronic anemia, or peripheral neuropathy. Levels of anti-CCP correlated with the score of the Health Assessment Questionnaire-Disability Index (HAQ-Di) ( r = 0.154 , P = 0.03 ), erythrocyte sedimentation rate (ESR); ( r = 0.155 , P = 0.03 ), and RF ( P = 0.254 , P < 0.001 ), whereas anti-MCV titres only correlated with RF ( r = 0.169 , P = 0.02 ). On adjusted analysis, ExRA was associated with longer age ( P = 0.015 ), longer disease duration ( P = 0.007 ), higher DAS-28 score ( P = 0.002 ), and higher HAQ-DI score ( P = 0.007 ), but serum levels of anti-CCP and anti-MCV were not associated. These findings show the need to strengthen the evaluation of the pathogenic mechanisms implied in each specific ExRA manifestation.