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Rush Hour of LATs towards Their Transport Cycle.

ABSTRACT: The mammalian SLC7 family comprises the L-amino acid transporters (LATs) and the cationic amino acid transporters (CATs). The relevance of these transporters is highlighted by their involvement in several human pathologies, including inherited rare diseases and acquired diseases, such as cancer. In the last four years, several crystal or cryo-EM structures of LATs and CATs have been solved. These structures have started to fill our knowledge gap that previously was based on the structural biology of remote homologs of the amino acid-polyamine-organocation (APC) transporters. This review recovers this structural and functional information to start generating the molecular bases of the transport cycle of LATs. Special attention is given to the known transporter conformations within the transport cycle and the molecular bases for substrate interaction and translocation, including the asymmetric interaction of substrates at both sides of the plasma membrane.

SUBMITTER: Nicolas-Arago A

PROVIDER: S-EPMC8399266 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Rush Hour of LATs towards Their Transport Cycle.

Nicolàs-Aragó Adrià A Fort Joana J Palacín Manuel M Errasti-Murugarren Ekaitz E

Membranes 20210808 8

The mammalian SLC7 family comprises the L-amino acid transporters (LATs) and the cationic amino acid transporters (CATs). The relevance of these transporters is highlighted by their involvement in several human pathologies, including inherited rare diseases and acquired diseases, such as cancer. In the last four years, several crystal or cryo-EM structures of LATs and CATs have been solved. These structures have started to fill our knowledge gap that previously was based on the structural biolog ...[more]

PMID: 34436365

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Project description:Despite advances in monitoring and modelling of intra-urban variation in multiple pollutants, few studies have attempted to separate spatial patterns by time of day, or incorporated organic tracers into spatial monitoring studies. Due to varying emissions sources from diesel and gasoline vehicular traffic, as well as within-day temporal variation in source mix and intensity (e.g., rush-hours vs. full-day measures), accurately assessing diesel-related air pollution within an urban core can be challenging. We allocated 24 sampling sites across downtown Pittsburgh, Pennsylvania (2.8 km²) to capture fine-scale variation in diesel-related pollutants, and to compare these patterns by sampling interval (i.e., "rush-hours" vs. "work-week" concentrations), and by season. Using geographic information system (GIS)-based methods, we allocated sampling sites to capture spatial variation in key traffic-related pollution sources (i.e., truck, bus, overall traffic densities). Programmable monitors were used to collect integrated work-week and rush-hour samples of fine particulate matter (PM2.5), black carbon (BC), trace elements, and diesel-related organics (polycyclic aromatic hydrocarbons (PAHs), hopanes, steranes), in summer and winter 2014. Land use regression (LUR) models were created for PM2.5, BC, total elemental carbon (EC), total organic carbon (OC), elemental (Al, Ca, Fe), and organic constituents (total PAHs, total hopanes), and compared by sampling interval and season. We hypothesized higher pollution concentrations and greater spatial contrast in rush-hour, compared to full work-week samples, with variation by season and pollutant. Rush-hour sampling produced slightly higher total PM2.5 and BC concentrations in both seasons, compared to work-week sampling, but no evident difference in spatial patterns. We also found substantial spatial variability in most trace elements and organic compounds, with comparable spatial patterns using both sampling paradigms. Overall, we found higher concentrations of traffic-related trace elements and organic compounds in rush-hour samples, and higher concentrations of coal-related elements (e.g., As, Se) in work-week samples. Mean bus density was the strongest LUR predictor in most models, in both seasons, under each sampling paradigm. Within each season and constituent, the bus-related terms explained similar proportions of variance in the rush-hour and work-week samples. Rush-hour and work-week LUR models explained similar proportions of spatial variation in pollutants, suggesting that the majority of emissions may be produced during rush-hour traffic across downtown. Results suggest that rush-hour emissions may predominantly shape overall spatial variance in diesel-related pollutants.

Project description:BackgroundTo examine whether whole genome expression profiling could reveal changes in mRNA expression of peripheral blood mononuclear cells (PBMC) from allergic patients undergoing rush immunotherapy (RIT) that might be manifest within the first few months of treatment.MethodsFor this study, PBMC from three allergic patients undergoing RIT were assessed at four timepoints: prior to RIT, at 1 week and 7 week post-RIT, during build-up and at 4 months, after establishment of a maintenance dose. PBMC mRNA gene expression changes over time were determined by oligonucleotide microarrays using the Illumina Human-6 BeadChip Platform, which simultaneously interrogates expression profiles of > 47,000 transcripts. Differentially expressed genes were identified using well-established statistical analysis for microarrays. In addition, we analyzed peripheral blood basophil high-affinity IgE receptor (Fc epsilon RI) expression and T-regulatory cell frequency as detected by expression of CD3+CD4+CD25bright cells at each timepoint using flow cytometry.ResultsIn comparing the initial 2 timepoints with the final 2 timepoints and analyzing for genes with ≥1.5-fold expression change (p less than or equal to 0.05, BH-FDR), we identified 507 transcripts. At a 2-fold change (p less than or equal to 0.05, BH-FDR), we found 44 transcripts. Of these, 28 were up-regulated and 16 were down-regulated genes. From these datasets, we have identified changes in immunologically relevant genes from both the innate and adaptive response with upregulation of expressed genes for molecules including IL-1β, IL-8, CD40L, BTK and BCL6. At the 4 month timepoint, we noted a downward trend in Fc epsilon RI expression in each of the three patients and increased allergen-specific IgG4 levels. No change was seen in the frequency of peripheral T-regulatory cells expressed over the four timepoints.ConclusionsWe observed significant changes in gene expression early in peripheral blood samples from allergic patients undergoing RIT. Moreover, serum levels for allergen specific IgG4 also increased over the course of treatment. These studies suggest that RIT induces rapid and dynamic alterations in both innate and adaptive immunity which can be observed in the periphery of allergic patients. These alterations could be directly related to the therapeutic shift in the allergen-specific class of immunoglobulin.

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Rush Hour of LATs towards Their Transport Cycle.

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Rush Hour of LATs towards Their Transport Cycle.

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