Mechanism of recruitment of WASP to the immunological synapse and of its activation following TCR ligation

Producción CientíficaF-actin polymerization following engagement of the T cell receptor (TCR) is dependent on WASP and is critical for T cell activation. The link between TCR and WASP is not fully understood. In resting cells, WASP exists in a complex with WIP, which inhibits its activation by Cdc42. We show that the adaptor protein CrkL binds directly to WIP. Further, TCR ligation results in the formation of a ZAP-70-CrkL-WIP-WASP complex, which is recruited to lipid rafts and the immunological synapse. TCR engagement also causes PKCtheta-dependent phosphorylation of WIP, causing the disengagement of WASP from the WIP-WASP complex, thereby releasing it from WIP inhibition. These results suggest that the ZAP-70-CrkL-WIP pathway and PKCtheta link TCR to WASP activation

"Acute pseudo-pericardial tamponade": the compression of the thoracal inferior vena cava – a case report

We describe a case of 68-year-old woman which was admitted to our hospital for mitral valve replacement (MVR), in whom acute compresion of the vena cava inferior developed after repair of lacerated atrio-caval junction with hemostatic tissue sealant, biologic glue (BioGlue, Cryolife, ınc, Kennesaw, Ga). Removal of the BioGlue relieved the unexpected problem

Liquid racism and the Danish Prophet Muhammad cartoons

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2010 The Author.This article examines reactions to the October 2005 publication of the Prophet Muhammad cartoons in the Danish newspaper Jyllands-Posten. It does so by using the concept of ‘liquid racism’. While the controversy arose because it is considered blasphemous by many Muslims to create images of the Prophet Muhammad, the article argues that the meaning of the cartoons is multidimensional, that their analysis is significantly more complex than most commentators acknowledge, and that this complexity can best be addressed via the concept of liquid racism. The article examines the liquidity of the cartoons in relation to four readings. These see the cartoons as: (1) a criticism of Islamic fundamentalism; (2) blasphemous images; (3) Islamophobic and racist; and (4) satire and a defence of freedom of speech. Finally, the relationship between postmodernity and the rise of fundamentalism is discussed because the cartoons, reactions to them, and Islamic fundamentalism, all contain an important postmodern dimension.ESR

Transcellular diapedesis is initiated by invasive podosomes

Producción CientíficaDiapedesis is critical for immune system function and inflammatory responses. This occurs by migration of blood leukocytes either directly through individual microvascular endothelial cells (the “transcellular” route) or between them (the “paracellular” route). Mechanisms for transcellular pore formation in endothelium remain unknown. Here we demonstrate that lymphocytes used podosomes and extended “invasive podosomes” to palpate the surface of, and ultimately form transcellular pores through, the endothelium. In lymphocytes, these structures were dependent on Src kinase and the actin regulatory protein WASP; inhibition of podosome formation selectively blocked the transcellular route of diapedesis. In endothelium, membrane fusion events dependent on the SNARE-containing membrane fusion complex and intracellular calcium were required for efficient transcellular pore formation in response to podosomes. These findings provide insights into basic mechanisms for leukocyte trafficking and the functions of podosomes

The influence of chlorine in indoor swimming pools on the composition of breathing phase of professional swimmers

Objectives: Swimming is one of the most popular forms of physical activity. Pool water is cleaned with chlorine, which - in combination with compounds contained in water - could form chloramines and trichloromethane in the swimmer’s lungs. The aim of the present study was to examine the effect of swimming training in an indoor pool on the composition of swimmers’ respiratory phase metabolomics, and develop a system to provide basic information about its impact on the swimmer’s airway mucosa metabolism, which could help to assess the risk of secondary respiratory tract diseases i.e. sport results, condition, and health including lung acute and chronic diseases). Design: A group of competitive swimmers participated in the study and samples of their respiratory phase before training, immediately after training, and 2 h after training were assessed. Methods: Sixteen male national and international-level competitive swimmers participated in this study. Respiratory phase analysis of the indoor swimming pool swimmers was performed. Gas chromatography combined with mass spectrometry (GCMS) was used in the measurements. All collected data were transferred to numerical analysis for trends of tracking and mapping. The breathing phase was collected on special porous material and analyzed using GCMS headspace. Results: The obtained samples of exhaled air were composed of significantly different metabolomics when compared before, during and after exercise training. This suggests that exposition to indoor chlorine causes changes in the airway mucosa Conclusion: This phenomenon may be explained by occurrence of a chlorine-initiated bio-reaction in the swimmers’ lungs. The obtained results indicate that chromatographic exhaled gas analysis is a sensitive method of pulmonary metabolomic changes assessment. Presented analysis of swimmers exhaled air indicates, that indoor swimming may be responsible for airway irritation caused by volatile chlorine compounds and their influence on lung metabolism

Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice

Ion channel-controlled cell volume regulation is of fundamental significance to the physiological function of sperm. In addition to volume regulation, LRRC8A-dependent volume-regulated anion channel (VRAC) activity is involved in cell cycle progression, insulin signaling, and cisplatin resistance. Nevertheless, the contribution of LRRC8A and its dependent VRAC activity in the germ cell lineage remain unknown. By utilizing a spontaneous Lrrc8a mouse mutation (c.1325delTG, p.F443*) and genetically engineered mouse models, we demonstrate that LRRC8A-dependent VRAC activity is essential for male germ cell development and fertility. Lrrc8a-null male germ cells undergo progressive degeneration independent of the apoptotic pathway during postnatal testicular development. Lrrc8a-deficient mouse sperm exhibit multiple morphological abnormalities of the flagella (MMAF), a feature commonly observed in the sperm of infertile human patients. Importantly, we identified a human patient with a rare LRRC8A hypomorphic mutation (c.1634G>A, p.Arg545His) possibly linked to Sertoli cell-only syndrome (SCOS), a male sterility disorder characterized by the loss of germ cells. Thus, LRRC8A is a critical factor required for germ cell development and volume regulation in the mouse, and it might serve as a novel diagnostic and therapeutic target for SCOS patients

TRIM16 Acts as an E3 Ubiquitin Ligase and Can Heterodimerize with Other TRIM Family Members

The TRIM family of proteins is distinguished by its tripartite motif (TRIM). Typically, TRIM proteins contain a RING finger domain, one or two B-box domains, a coiled-coil domain and the more variable C-terminal domains. TRIM16 does not have a RING domain but does harbour two B-box domains. Here we showed that TRIM16 homodimerized through its coiled-coil domain and heterodimerized with other TRIM family members; TRIM24, Promyelocytic leukaemia (PML) protein and Midline-1 (MID1). Although, TRIM16 has no classic RING domain, three-dimensional modelling of TRIM16 suggested that its B-box domains adopts RING-like folds leading to the hypothesis that TRIM16 acts as an ubiquitin ligase. Consistent with this hypothesis, we demonstrated that TRIM16, devoid of a classical RING domain had auto-polyubiquitination activity and acted as an E3 ubiquitin ligase in vivo and in vitro assays. Thus via its unique structure, TRIM16 possesses both heterodimerization function with other TRIM proteins and also has E3 ubiquitin ligase activity

Comprehensive Genetic Results for Primary Immunodeficiency Disorders in a Highly Consanguineous Population

Objective: To present the genetic causes of patients with primary immune deficiencies (PIDs) in Kuwait between 2004 and 2017.Methods: The data was obtained from the Kuwait National Primary Immunodeficiency Disorders Registry. Genomic DNA from patients with clinical and immunological features of PID was sequenced using Sanger sequencing (SS), next generation sequencing (NGS) of targeted genes, whole exome sequencing (WES), and/or whole genome sequencing (WGS). Functional assays were utilized to assess the biologic effect of identified variants. Fluorescence in situ hybridization (FISH) for 22q11.2 deletion and genomic hybridizations arrays were performed when thymic defects were suspected.Results: A total of 264 patients were registered during the study period with predominance of patients with immunodeficiencies affecting cellular and humoral immunity (35.2%), followed by combined immunodeficiencies with associated syndromic features (24%). Parental consanguinity and family history suggestive of PID were reported in 213 (81%) and 145 patients (55%), respectively. Genetic testing of 206 patients resulted in a diagnostic yield of 70%. Mutations were identified in 46 different genes and more than 90% of the reported genetic defects were transmitted by in an autosomal recessive pattern. The majority of the mutations were missense mutations (57%) followed by deletions and frame shift mutations. Five novel disease-causing genes were discovered.Conclusions: Genetic testing should be an integral part in the management of primary immunodeficiency patients. This will help the delivery of precision medicine and facilitate proper genetic counseling. Studying inbred populations using sophisticated diagnostic methods can allow better understanding of the genetics of primary immunodeficiency disorders