The T cell receptor displays lateral signal propagation involving non-engaged receptors

T cells are highly sensitive to low levels of antigen, but how this sensitivity is achieved is currently unknown. Here, we imaged proximal TCR-CD3 signal propagation with single molecule localization microscopy (SMLM) in T cells activated with nanoscale clusters of TCR stimuli. We observed the formation of large TCR-CD3 clusters that exceeded the area of the ligand clusters, and required multivalent interactions facilitated by TCR-CD3 phosphorylation for assembly. Within these clustered TCR-CD3 domains, TCR-CD3 signaling spread laterally for ∼500 nm, far beyond the activating site, via non-engaged receptors. Local receptor density determined the functional cooperativity between engaged and non-engaged receptors, but lateral signal propagation was not influenced by the genetic deletion of ZAP70. Taken together, our data demonstrates that clustered ligands induced the clustering of non-ligated TCR-CD3 into domains that cooperatively facilitate lateral signal propagation

Lectin-mediated bacterial modulation by the intestinal nematode Ascaris suum

Ascariasis is a global health problem for humans and animals. Adult Ascaris nematodes are long-lived in the host intestine where they interact with host cells as well as members of the microbiota resulting in chronic infections. Nematode interactions with host cells and the microbial environment are prominently mediated by parasite-secreted proteins and peptides possessing immunomodulatory and antimicrobial activities. Previously, we discovered the C-type lectin protein AsCTL-42 in the secreted products of adult Ascaris worms. Here we tested recombinant AsCTL-42 for its ability to interact with bacterial and host cells. We found that AsCTL-42 lacks bactericidal activity but neutralized bacterial cells without killing them. Treatment of bacterial cells with AsCTL-42 reduced invasion of intestinal epithelial cells by Salmonella. Furthermore, AsCTL-42 interacted with host myeloid C-type lectin receptors. Thus, AsCTL-42 is a parasite protein involved in the triad relationship between Ascaris, host cells, and the microbiota

Investigating spatial heterogeneity of nanoparticles movement in live cells with pair-correlation microscopy and phasor analysis

How nanoparticles distribute in living cells and overcome cellular barriers are important criteria in the design of drug carriers. Pair-correlation microscopy is a correlation analysis of fluctuation in the fluorescence intensity obtained by a confocal line scan that can quantify the dynamic properties of nanoparticle diffusion including the number of mobile nanoparticles, diffusion coefficient, and transit time across a spatial distance. Due to the potential heterogeneities in nanoparticle properties and the complexity within the cellular environment, quantification of averaged auto- and pair-correlation profiles may obscure important insights into the ability of nanoparticles to deliver drugs. To overcome this issue, we used phasor analysis to develop a data standardizing method, which can segment the scanned line into several subregions according to diffusion and address the spatial heterogeneity of nanoparticles moving inside cells. The phasor analysis is a fit-free method that represents autocorrelation profiles for each pixel relative to free diffusion on the so-called phasor plots. Phasor plots can then be used to select subpopulations for which the auto- and pair-correlation analysis can be performed separately. We demonstrate the phasor analysis for pair-correlation microscopy for investigating 16 nm, Cy5-labeled silica nanoparticles diffusing across the plasma membrane and green fluorescent proteins (GFP) diffusing across nuclear envelope in MCF-7 cells

Drivers of phytoplankton responses to summer wind events in a stratified lake: A modeling study

Extreme wind events affect lake phytoplankton by deepening the mixed layer and increasing internal nutrient loading. Both increases and decreases in phytoplankton concentration after strong wind events have been observed, but the precise mechanisms driving these responses remain poorly understood or quantified. We coupled a one-dimensional physical model to a biogeochemical model to investigate the factors regulating short-term phytoplankton responses to summer wind events, now and under expected warmer future conditions. We simulated physical, chemical, and biological dynamics in Lake Erken, Sweden, and found that strong wind could increase or decrease the phytoplankton concentration in the euphotic zone 1 week after the event, depending on antecedent lake physical and chemical conditions. Wind had little effect on phytoplankton concentration if the mixed layer was deep prior to wind exposure. Higher incoming shortwave radiation and hypolimnetic nutrient concentration boosted phytoplankton concentration, whereas higher surface water temperatures decreased concentrations after wind events. Medium-intensity wind events resulted in more phytoplankton than high-intensity wind. Simulations under a future climate scenario did not show marked differences in the way wind events affect phytoplankton concentration. These findings help to better understand how wind impacts vary as a function of local environmental conditions and how climate warming and changing extreme weather dynamics will affect lake ecosystems

Drivers of phytoplankton responses to summer wind events in a stratified lake: A modeling study

Extreme wind events affect lake phytoplankton by deepening the mixed layer and increasing internal nutrient loading. Both increases and decreases in phytoplankton concentration after strong wind events have been observed, but the precise mechanisms driving these responses remain poorly understood or quantified. We coupled a one-dimensional physical model to a biogeochemical model to investigate the factors regulating short-term phytoplankton responses to summer wind events, now and under expected warmer future conditions. We simulated physical, chemical, and biological dynamics in Lake Erken, Sweden, and found that strong wind could increase or decrease the phytoplankton concentration in the euphotic zone 1 week after the event, depending on antecedent lake physical and chemical conditions. Wind had little effect on phytoplankton concentration if the mixed layer was deep prior to wind exposure. Higher incoming shortwave radiation and hypolimnetic nutrient concentration boosted phytoplankton concentration, whereas higher surface water temperatures decreased concentrations after wind events. Medium-intensity wind events resulted in more phytoplankton than high-intensity wind. Simulations under a future climate scenario did not show marked differences in the way wind events affect phytoplankton concentration. These findings help to better understand how wind impacts vary as a function of local environmental conditions and how climate warming and changing extreme weather dynamics will affect lake ecosystems

Ulcerative colitis-risk loci on chromosomes 1p36 and 12q15 found by genome-wide association study.

Ulcerative colitis is a chronic inflammatory disease of the colon that presents as diarrhea and gastrointestinal bleeding. We performed a genome-wide association study using DNA samples from 1,052 individuals with ulcerative colitis and preexisting data from 2,571 controls, all of European ancestry. In an analysis that controlled for gender and population structure, ulcerative colitis loci attaining genome-wide significance and subsequent replication in two independent populations were identified on chromosomes 1p36 (rs6426833, combined P = 5.1 x 10(-13), combined odds ratio OR = 0.73) and 12q15 (rs1558744, combined P = 2.5 x 10(-12), combined OR = 1.35). In addition, combined genome-wide significant evidence for association was found in a region spanning BTNL2 to HLA-DQB1 on chromosome 6p21 (rs2395185, combined P = 1.0 x 10(-16), combined OR = 0.66) and at the IL23R locus on chromosome 1p31 (rs11209026, combined P = 1.3 x 10(-8), combined OR = 0.56; rs10889677, combined P = 1.3 x 10(-8), combined OR = 1.29)

Prediction of Candidate Primary Immunodeficiency Disease Genes Using a Support Vector Machine Learning Approach

Screening and early identification of primary immunodeficiency disease (PID) genes is a major challenge for physicians. Many resources have catalogued molecular alterations in known PID genes along with their associated clinical and immunological phenotypes. However, these resources do not assist in identifying candidate PID genes. We have recently developed a platform designated Resource of Asian PDIs, which hosts information pertaining to molecular alterations, protein–protein interaction networks, mouse studies and microarray gene expression profiling of all known PID genes. Using this resource as a discovery tool, we describe the development of an algorithm for prediction of candidate PID genes. Using a support vector machine learning approach, we have predicted 1442 candidate PID genes using 69 binary features of 148 known PID genes and 3162 non-PID genes as a training data set. The power of this approach is illustrated by the fact that six of the predicted genes have recently been experimentally confirmed to be PID genes. The remaining genes in this predicted data set represent attractive candidates for testing in patients where the etiology cannot be ascribed to any of the known PID genes

Sighting acute myocardial infarction through platelet gene expression

© 2019, The Author(s). Acute myocardial infarction is primarily due to coronary atherosclerotic plaque rupture and subsequent thrombus formation. Platelets play a key role in the genesis and progression of both atherosclerosis and thrombosis. Since platelets are anuclear cells that inherit their mRNA from megakaryocyte precursors and maintain it unchanged during their life span, gene expression profiling at the time of an acute myocardial infarction provides information concerning the platelet gene expression preceding the coronary event. In ST-segment elevation myocardial infarction (STEMI), a gene-by-gene analysis of the platelet gene expression identified five differentially expressed genes: FKBP5, S100P, SAMSN1, CLEC4E and S100A12. The logistic regression model used to combine the gene expression in a STEMI vs healthy donors score showed an AUC of 0.95. The same five differentially expressed genes were externally validated using platelet gene expression data from patients with coronary atherosclerosis but without thrombosis. Platelet gene expression profile highlights five genes able to identify STEMI patients and to discriminate them in the background of atherosclerosis. Consequently, early signals of an imminent acute myocardial infarction are likely to be found by platelet gene expression profiling before the infarction occurs

The prognostic significance of genetic polymorphisms (Methylenetetrahydrofolate Reductase C677T, Methionine Synthase A2756G, Thymidilate Synthase tandem repeat polymorphism) in multimodally treated oesophageal squamous cell carcinoma

The present study retrospectively examined the correlation between the outcome of patients with locally advanced oesophageal squamous cell carcinoma (cT3-4 cN0-1 cM0) after multimodal treatment (radiochemotherapy±surgical resection), and the presence of genetic polymorphisms in genes involved in folate metabolism. In total, 68 patients who took part in a prospective multicentric trial received 5-fluorouracil (FU)-based radiochemotherapy, optionally followed by surgery. DNA was extracted from pretherapeutic tumour biopsies and was subsequently genotyped for common genetic polymorphisms of three genes (MTHFR C677T, MTR A2756G, TS tandem repeat polymorphism) involved in folate metabolism and potentially in sensitivity to 5-FU-based chemotherapy. The genotypes were correlated with tumour response to polychemotherapy, radiochemotherapy and with overall survival. Tumours with the MTR wild-type genotype (2756AA) showed a median survival time of 16 months, whereas tumours with an MTR variant genotype (2756AG/2756GG) showed a median survival time of 42 months (P=0.0463). No prognostic impact could be verified for the genotypes of the MTHFR genes and the TS gene. Among tumours treated with radiochemotherapy and subsequent resection, MTR variant genotype showed higher histopathological response rate than tumours with MTR wild-type genotype (P=0.0442). In contrast, no significant relationship between clinically determined tumour regression after polychemotherapy and polymorphisms of the three genes under analysis was observed. In conclusion, pretherapeutic determination of the MTR A2756G polymorphism may predict survival of multimodally treated oesophageal squamous cell carcinomas. Determination of MTHFR C677T and TS tandem repeat polymorphism has no predictive value