Crucial role of SLP-76 and ADAP for neutrophil recruitment in mouse kidney ischemia-reperfusion injury.

Neutrophils trigger inflammation-induced acute kidney injury (AKI), a frequent and potentially lethal occurrence in humans. Molecular mechanisms underlying neutrophil recruitment to sites of inflammation have proved elusive. In this study, we demonstrate that SLP-76 (SH2 domain-containing leukocyte phosphoprotein of 76 kD) and ADAP (adhesion and degranulation promoting adaptor protein) are involved in E-selectin-mediated integrin activation and slow leukocyte rolling, which promotes ischemia-reperfusion-induced AKI in mice. By using genetically engineered mice and transduced Slp76(-/-) primary leukocytes, we demonstrate that ADAP as well as two N-terminal-located tyrosines and the SH2 domain of SLP-76 are required for downstream signaling and slow leukocyte rolling. The Tec family kinase Bruton tyrosine kinase is downstream of SLP-76 and, together with ADAP, regulates PI3Kγ (phosphoinositide 3-kinase-γ)- and PLCγ2 (phospholipase Cγ2)-dependent pathways. Blocking both pathways completely abolishes integrin affinity and avidity regulation. Thus, SLP-76 and ADAP are involved in E-selectin-mediated integrin activation and neutrophil recruitment to inflamed kidneys, which may underlie the development of life-threatening ischemia-reperfusion-induced AKI in humans

Use of country of birth as an indicator of refugee background in health datasets

BACKGROUND: Routine public health databases contain a wealth of data useful for research among vulnerable or isolated groups, who may be under-represented in traditional medical research. Identifying specific vulnerable populations, such as resettled refugees, can be particularly challenging; often country of birth is the sole indicator of whether an individual has a refugee background. The objective of this article was to review strengths and weaknesses of different methodological approaches to identifying resettled refugees and comparison groups from routine health datasets and to propose the application of additional methodological rigour in future research. DISCUSSION: Methodological approaches to selecting refugee and comparison groups from existing routine health datasets vary widely and are often explained in insufficient detail. Linked data systems or datasets from specialized refugee health services can accurately select resettled refugee and asylum seeker groups but have limited availability and can be selective. In contrast, country of birth is commonly collected in routine health datasets but a robust method for selecting humanitarian source countries based solely on this information is required. The authors recommend use of national immigration data to objectively identify countries of birth with high proportions of humanitarian entrants, matched by time period to the study dataset. When available, additional migration indicators may help to better understand migration as a health determinant. Methodologically, if multiple countries of birth are combined, the proportion of the sample represented by each country of birth should be included, with sub-analysis of individual countries of birth potentially providing further insights, if population size allows. United Nations-defined world regions provide an objective framework for combining countries of birth when necessary. A comparison group of economic migrants from the same world region may be appropriate if the resettlement country is particularly diverse ethnically or the refugee group differs in many ways to those born in the resettlement country. SUMMARY: Routine health datasets are valuable resources for public health research; however rigorous methods for using country of birth to identify resettled refugees would optimize usefulness of these resources

Skap2 is required for β2 integrin-mediated neutrophil recruitment and functions.

Integrin activation is required for neutrophil functions. Impaired integrin activation on neutrophils is the hallmark of leukocyte adhesion deficiency (LAD) syndrome in humans, characterized by impaired leukocyte recruitment and recurrent infections. The Src kinase-associated phosphoprotein 2 (Skap2) is involved in integrin functions in different leukocyte subtypes. However, the role of Skap2 in β2 integrin activation and neutrophil recruitment is unknown. In this study, we demonstrate the crucial role of Skap2 in regulating actin polymerization and binding of talin-1 and kindlin-3 to the β2 integrin cytoplasmic domain, thereby being indispensable for β2 integrin activation and neutrophil recruitment. The direct interaction of Skap2 with the Wiskott-Aldrich syndrome protein via its SH3 domain is critical for integrin activation and neutrophil recruitment in vivo. Furthermore, Skap2 regulates integrin-mediated outside-in signaling events and neutrophil functions. Thus, Skap2 is essential to activate the β2 integrins, and loss of Skap2 function is sufficient to cause a LAD-like phenotype in mice

Ruminal bacterial communities differ in early-lactation dairy cows with differing risk of ruminal acidosis

IntroductionEarly-lactation Holstein cows (n= 261) from 32 herds in three regions (Australia, California, and Canada) were previously categorized using a discriminant analysis model as being at a high (26.1% of cows), medium (26.8% of cows), or low risk (47.1% of cows) of ruminal acidosis. We aimed to investigate if (1) risk of acidosis would be associated with ruminal bacterial taxa and dietary nutrient components, (2) there would be individual or combinations of bacterial taxa associated with acidosis-risk groups, and (3) the abundance of bacterial taxa would be associated with the intake of dietary nutrient components.MethodsDiets ranged from pasture supplemented with concentrates to total mixed rations. Bacteria 16S ribosomal DNA sequences from rumen samples collected < 3 hours after feeding via stomach tube were analyzed to determine bacterial presence. The relative abundance of each bacterial phylum and family was center log transformed and the transformed family data were subjected to two redundancy analysis biplots, one for acidosis risk group and one for region, to identify the 20 best-fit bacterial families from each respective redundancy analysis. A total of 29 unique families were identified when the lists of 20 families were combined from each redundancy analysis, and these 29 families were termed "influential" families." The association of acidosis-risk groups with the abundance of individual influential families was assessed by mixed models. Backward stepwise elimination mixed models were used to determine the bacterial taxa associated with each acidosis-risk group and the dietary nutrients associated with the abundance of the bacterial taxa.Results and discussionHigh-risk acidosis cows were associated with increased abundances of Anaerocella_f and Veillonellaceae and decreased abundances of several bacterial families with different characteristics. Five phyla: Firmicutes [odds ratio (OR) = 7.47 ± 7.43], Spirochaetes (OR = 1.28 ± 0.14), Lentisphaerae (OR = 0.70 ± 0.07), Planctomycetes (OR = 0.70 ± 0.09), and Tenericutes (OR = 0.44 ± 0.15), and nine families were associated with a higher risk of acidosis. Of the nine phyla identified to be of interest based on abundance and strength of association with acidosis-risk groups, all had one or more dietary nutrient that predicted their abundance. Sugar was the most frequently associated nutrient with the nine phyla, and was present in 78% (seven out of nine phyla) of the models; crude protein was present in 56% of models and crude fat was present in 44% of the models. Sugar and crude protein were most associated with the influential families and all but three families had one or more nutrient predictive of their abundance. Ruminal bacterial taxa are associated with ruminal acidosis; dietary sugar and crude protein are vital predictors of these and, thus, of ruminal acidosis risk

Underwater Videogrammetry with Adaptive Feature Detection at "See am Mondsee", Austria

We present a complete, video-based 3d documentation process for the submerged remains of Neolithic pile dwellings at the UNESCO World Heritage Site "See am Mondsee" in Austria. We discuss good practice routines and solutions, such as cable management, supporting the Unmanned Underwater Vehicle (UUV) when strong currents are prevalent, and documentation/record keeping. The recorded site is a Neolithic lake village dating to the 4th millenium BC. Based on initial reconstruction results, we improved the image matching process of our Structure from Motion (SfM) pipeline (built around the free end-user application VisualSFM), by replacing its default feature detector (SiftGPU) with our own implementation of adaptive feature detection. The campaign was accompanied by a German television film crew. Their documentary was shown on the German public television (ARD) broadcast "W wie Wissen"

Dissociation of VE-PTP from VE-cadherin is required for leukocyte extravasation and for VEGF-induced vascular permeability in vivo

Artificially stabilizing contacts between VE-cadherin and VE-PTP reduce vascular permeability and leukocyte extravasation in vivo

Whole Grain Products, Fish and Bilberries Alter Glucose and Lipid Metabolism in a Randomized, Controlled Trial: The Sysdimet Study

Due to the growing prevalence of type 2 diabetes, new dietary solutions are needed to help improve glucose and lipid metabolism in persons at high risk of developing the disease. Herein we investigated the effects of low-insulin-response grain products, fatty fish, and berries on glucose metabolism and plasma lipidomic profiles in persons with impaired glucose metabolism.Altogether 106 men and women with impaired glucose metabolism and with at least two other features of the metabolic syndrome were included in a 12-week parallel dietary intervention. The participants were randomized into three diet intervention groups: (1) whole grain and low postprandial insulin response grain products, fatty fish three times a week, and bilberries three portions per day (HealthyDiet group), (2) Whole grain enriched diet (WGED) group, which includes principally the same grain products as group (1), but with no change in fish or berry consumption, and (3) refined wheat breads (Control). Oral glucose tolerance, plasma fatty acids and lipidomic profiles were measured before and after the intervention. Self-reported compliance with the diets was good and the body weight remained constant. Within the HealthyDiet group two hour glucose concentration and area-under-the-curve for glucose decreased and plasma proportion of (n-3) long-chain PUFAs increased (False Discovery Rate p-values <0.05). Increases in eicosapentaenoic acid and docosahexaenoic acid associated curvilinearly with the improved insulin secretion and glucose disposal. Among the 364 characterized lipids, 25 changed significantly in the HealthyDiet group, including multiple triglycerides incorporating the long chain (n-3) PUFA.The results suggest that the diet rich in whole grain and low insulin response grain products, bilberries, and fatty fish improve glucose metabolism and alter the lipidomic profile. Therefore, such a diet may have a beneficial effect in the efforts to prevent type 2 diabetes in high risk persons.ClinicalTrials.gov NCT00573781

Mutual regulation of CD4+ T cells and intravascular fibrin in infections

Innate myeloid cells especially neutrophils and their extracellular traps are known to promote intravascular coagulation and thrombosis formation in infections and various other conditions. Innate myeloid cell dependent fibrin formation can support systemic immunity while its dysregulation enhances the severity of infectious diseases. Less is known about the immune mechanisms preventing dysregulation of fibrin homeostasis in infection. During experimental systemic infections local fibrin deposits in the liver microcirculation cause rapid arrest of CD4+ T cells. Arrested T helper cells mostly represent Th17 cells that partially originate from the small intestine. Intravascular fibrin deposits activate mouse and human CD4+ T cells which can be mediated by direct fibrin - CD4+ T cell interactions. Activated CD4+ T cells suppress fibrin deposition and microvascular thrombosis by directly counteracting coagulation activation by neutrophils and classical monocytes. T cell activation, which is initially triggered by IL- 12p40- and MHC-II dependent mechanisms, enhances intravascular fibrinolysis via LFA-1. Moreover, CD4+ T cells disfavor the association of the fibrinolysis inhibitor TAFI with fibrin whereby fibrin deposition is increased by TAFI in the absence but not presence of T cells. In human infections thrombosis development is inversely related to microvascular levels of CD4+ T cells. Thus, fibrin promotes LFA-1 dependent T helper cell activation in infections which drives a negative feedback cycle that rapidly restricts intravascular fibrin and thrombosis development