Marmaray Project - a railway under the sea

Opisuje se Projekt Marmaray kojim se rješava prijelaz željeznice tunelom ispod Instanbulskog tjesnaca. Tim sustavom će se u cijelosti renovirati postojeći sustav prigradske željeznice u Istanbulu i povezati europsko i azijsko kopno. Ispod razine tla bit će 13,4 km pruge. Prikazuju se ciljevi Projekta, a posebno složeni tehnički zahvati koji su predstavljali izazove sa kojima su se suočili graditelji ovog pothvata. Istaknuti su napori za spašavanje i zaštitu povijesnog nasljeđa.The Marmaray Project, in the scope of which the railway tunnel below the Istanbul Strait will be built, is described. Upon completion of this system, the Istanbul\u27s existing suburban railway system will be fully upgraded, and a proper link will be established between Europe and Asia. 13.4 km of railway will be built below the ground level. Project objectives are presented, and highly complex technical problems, presenting a veritable challenge to the builders, are described. A special emphasis is placed on efforts that are being invested in preserving and protecting historic heritage

CD81 interacts with the T cell receptor to suppress signaling

CD81 (TAPA-1) is a ubiquitously expressed tetraspanin protein identified as a component of the B lymphocyte receptor (BCR) and as a receptor for the Hepatitis C Virus. In an effort to identify trans-membrane proteins that interact with the T-cell antigen receptor (TCR), we performed a membrane yeast two hybrid screen and identified CD81 as an interactor of the CD3delta subunit of the TCR. We found that in the absence of CD81, in thymocytes from knockout mice, TCR engagement resulted in stronger signals. These results were recapitulated in T cell lines that express low levels of CD81 through shRNA mediated silencing. Increased signaling did not result from alterations in the levels of TCR on the surface of T lymphocytes. Although CD81 is not essential for normal T lymphocyte development, it plays an important role in regulating TCR and possibly pre-TCR signal transduction by controlling the strength of signaling. CD81 dependent alterations in thymocyte signaling are evident in increased CD5 expression on CD81 deficient double positive (DP) thymocytes. We conclude that CD81 interacts with the T cell receptor to suppress signaling

Cd81 Interacts with the T Cell Receptor to Suppress Signaling

CD81 (TAPA-1) is a ubiquitously expressed tetraspanin protein identified as a component of the B lymphocyte receptor (BCR) and as a receptor for the Hepatitis C Virus. In an effort to identify trans-membrane proteins that interact with the T-cell antigen receptor (TCR), we performed a membrane yeast two hybrid screen and identified CD81 as an interactor of the CD3delta subunit of the TCR. We found that in the absence of CD81, in thymocytes from knockout mice, TCR engagement resulted in stronger signals. These results were recapitulated in T cell lines that express low levels of CD81 through shRNA mediated silencing. Increased signaling did not result from alterations in the levels of TCR on the surface of T lymphocytes. Although CD81 is not essential for normal T lymphocyte development, it plays an important role in regulating TCR and possibly pre-TCR signal transduction by controlling the strength of signaling. CD81 dependent alterations in thymocyte signaling are evident in increased CD5 expression on CD81 deficient double positive (DP) thymocytes. We conclude that CD81 interacts with the T cell receptor to suppress signaling. © 2012 Cevik et al

Homozygous NLRP1 gain-of-function mutation in siblings with a syndromic form of recurrent respiratory papillomatosis

© 2019 National Academy of Sciences. All rights reserved. Juvenile-onset recurrent respiratory papillomatosis (JRRP) is a rare and debilitating childhood disease that presents with recurrent growth of papillomas in the upper airway. Two common human papillomaviruses (HPVs), HPV-6 and -11, are implicated in most cases, but it is still not understood why only a small proportion of children develop JRRP following exposure to these common viruses. We report 2 siblings with a syndromic form of JRRP associated with mild dermatologic abnormalities. Whole-exome sequencing of the patients revealed a private homozygous mutation in NLRP1, encoding Nucleotide-Binding Domain Leucine-Rich Repeat Family Pyrin Domain-Containing 1. We find the NLRP1 mutant allele to be gain of function (GOF) for inflammasome activation, as demonstrated by the induction of inflammasome complex oligomerization and IL-1β secretion in an overexpression system. Moreover, patient-derived keratinocytes secrete elevated levels of IL-1β at baseline. Finally, both patients displayed elevated levels of inflammasome-induced cytokines in the serum. Six NLRP1 GOF mutations have previously been described to underlie 3 allelic Mendelian diseases with differing phenotypes and modes of inheritance. Our results demonstrate that an autosomal recessive, syndromic form of JRRP can be associated with an NLRP1 GOF mutation

Dynamic Modulation of Thymic MicroRNAs in Response to Stress

thymocyte subsets. Several of the differentially regulated murine thymic miRs are also stress responsive in the heart, kidney, liver, brain, and/or spleen. The most dramatic thymic microRNA down modulated is miR-181d, exhibiting a 15-fold reduction following stress. This miR has both similar and distinct gene targets as miR-181a, another member of miR-181 family. Many of the differentially regulated microRNAs have known functions in thymopoiesis, indicating that their dysregulation will alter T cell repertoire selection and the formation of naïve T cells. This data has implications for clinical treatments involving anti-inflammatory steroids, ablation therapies, and provides mechanistic insights into the consequences of infections

Life-threatening influenza pneumonitis in a child with inherited IRF9 deficiency

Life-threatening pulmonary influenza can be caused by inborn errors of type I and III IFN immunity. We report a 5-yr-old child with severe pulmonary influenza at 2 yr. She is homozygous for a loss-of-function IRF9 allele. Her cells activate gamma-activated factor (GAF) STAT1 homodimers but not IFN-stimulated gene factor 3 (ISGF3) trimers (STAT1/STAT2/IRF9) in response to IFN-α2b. The transcriptome induced by IFN-α2b in the patient's cells is much narrower than that of control cells; however, induction of a subset of IFN-stimulated gene transcripts remains detectable. In vitro, the patient's cells do not control three respiratory viruses, influenza A virus (IAV), parainfluenza virus (PIV), and respiratory syncytial virus (RSV). These phenotypes are rescued by wild-type IRF9, whereas silencing IRF9 expression in control cells increases viral replication. However, the child has controlled various common viruses in vivo, including respiratory viruses other than IAV. Our findings show that human IRF9- and ISGF3-dependent type I and III IFN responsive pathways are essential for controlling IAV

Identification of the interacting protein partners of the ThPOK transcription factor

T lymphocytes are an essential part of the adaptive immune system. In the course of T lymphocyte development, one crucial step is the decision to commit to one of two lineages: CD4 and CD8 single positive (SP) T cells. The cellular and molecular mechanisms underlying T cell lineage commitment has long been the subject of intense debate. ThPOK, T-helper-inducing POZ/Krüppel like factor, is a zinc finger transcription factor containing both a Krüppel-like zinc finger domain and a BTP/POZ domain, which has been linked to homodimerization and recruitment of other proteins. During the development of thymocytes, the ThPOK protein mediates the differentiation of MHC-II restricted thymocytes into the CD4 SP lineage, using its N-terminal BTB/POZ domain. We screened a human thymic cDNA library against the BTB/POZ domain of the ThPOK protein to identify its interacting protein partners by using a conventional yeast two hybrid system. We identified putative interacting proteins by performing DNA sequencing and bioinformatics analysis on relevant prey protein encoding plasmids. We re-confirmed these interactions in yeast cells by secondary yeast two hybrid screens. We confirmed the biological relevance of the identified interactions by performing co-immunoprecipitation experiments in transfected mammalian tissue culture cells. We demonstrated that seven proteins, named POMP, MEF2B, TCF7, ZNF384, DPP7, HINT2 and PARP12 can interact with the BTB/POZ domain of the ThPOK protein