with the third intracellular loop and the C-terminal tail of CXCR4. Disruption of FLNA binding to the ICL3 attenuates signaling and restores CXCL12-mediated endocytosis of WHIM-like CXCR4 receptor mutants. Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare congenital immunodeficiency often caused by mutations in the last 10 to 19 C-terminal amino acids of CXCR4. These mutations impair CXCR4 internalization and increase responsiveness to CXCL12. The CXCR4 C-terminal domain (C-tail) also has a binding site for the actin-binding protein filamin A (FLNA); it is not known whether FLNA binds to WHIM CXCR4 mutants or whether this interaction is implicated in the hyperfunction of these receptors. Here we show that, in addition to interacting with the CXCR4 C-tail, FLNA interacted with a region in the receptor third intracellular loop (ICL3) spanningaminoacids238 to246.This interaction involvedspecificFLNArepeatsandwas sensitive to Rho kinase inhibition. Deletion of the 238-246 motif accelerated CXCL12-induced wild-type (WT) receptor endocytosis but enabled CXCL12-mediated endocy-tosis and normalized signaling by the WHIM-associated receptor CXCR4R334X. CXCL12 stimulation triggered CXCR4R334X internalization in FLNA-deficient M2 cells but not in the FLNA-expressing M2 subclone A7; this suggests a role for FLNA in stabilization of WHIM-like CXCR4 at the cell surface. FLNA increasedb-arrestin2binding toCXCR4R334X in vivo,whichprovides amolecular basis for FLNA-mediatedhyperactivationofWHIM receptor signaling. We propose that FLNA interaction with ICL3 is central for endocytosis and signaling of WT and WHIM-like CXCR4 receptors. (Blood. 2015;125(7):1116-1125)

Biology is in the post-genomic era. We can sequence the whole genome or DNA library of organisms. The challenge now is to understand how DNA works on a detailed level. This paper attempts to model the mechanics of gene expression. The model is ambitious as it incorporates data from a multiple of experimental sources.

This research briefing reports on some key findings from a study of doctors and patients relationships in general and family practice medicine. The study examined how patients, all parents with young children, and general practitioners (GPs) defined what personal care means to them, what importance

on leukocytes is essential for chemokine-induced signaling, adhesion, cytoskeletal rearrangement, and migration. • Leukocyte-expressed ADAM10 promotes leukocyte recruitment and edema formation in a murine model of acute pulmonary inflammation. Inflammation is a key process in various diseases

. Tropomodulin-3 (Tmod3), the only Tmod isoform detected in platelets and megakaryocytes (MKs), caps actin filament (F-actin) pointed ends and binds tropomyosins (TMs), regulating actin polymerization and stability. To determine the function of Tmod3 in platelet biogenesis, we studied Tmod32/2 embryos, which

the practice of healthcare professionals and to relate these specifically to the administration of drugs via enteral feeding tubes. It is appropriate at this point to state that providing the healthcare professional is acting in the patient’s best interest, following locally agreed protocols and effecting

crfr centre for research on families and relationships Childrenʼs concerns about the health and well-being of their parents and significant others This briefing reports on the key findings from an ESRC funded study conducted in collaboration with ChildLine Scotland which utilised ChildLine’s unique

• Ikaros inhibits megakaryocyte specification and terminal differentiation by suppressing key megakaryocyte genes. • The GATA switch inhibits Ikaros expression during megakaryocyte development. The transcription factor Ikaros regulates the development of hematopoietic cells. Ikaros

soluble and cell-associated tumor antigens by human DC subsets is enhanced by addi-tion of adjuvant TLR agonists. Ability to cross-present exog-enous antigen with high IFN secretion puts human pDCs as activators of CD8 T cells in antitumor responses. In human peripheral blood, 4 populations of dendritic cells (DCs) can be distinguished, plasmacytoid dendritic cells (pDCs) and CD16, CD1c, and BDCA-3 myeloid DCs (mDCs), each with distinct functional characteristics. DCs have the unique capacity to cross-present exogenously encountered antigens (Ags) to CD8 T cells. Here we studied the ability of all 4 blood DC subsets to take up, process, and present tumor Ags to T cells. Although pDCs take up less Ags than CD1c and BDCA3mDCs, pDCs induce potent Ag-specific CD4 and CD8 T-cell responses. We show that pDCs can preserve Ags for prolonged periods of time and on stimulation show strong induction of both MHC class I and II, which explains their efficient activation of both CD4 and CD8 T cells. Furthermore, pDCs cross-present soluble and cell-associated tumor Ags to cytotoxic T lymphocytes equally well as BDCA3 mDCs. These findings, and the fact that pDCs outnumber BDCA3 mDCs, both in peripheral blood and lymph nodes, together with their potent IFN-I production, known to activate both components of the innate and adaptive immune system, put human pDCs forward as potent activators of CD8 T cells in antitumor responses. Our findings may therefore have important consequences for the development of antitumor immunotherapy. (Blood. 2013;121(3):459-467)

tant mutations and/or hepatitis B immune globu-lin–resistant mutations are the main cause of hepa-titis B virus reinfections post–liver transplant. 2. Early diagnosis of antiviral drug resistance and prompt initiation of rescue therapy are important in preventing hepatitis flares and hepatic decompensa-tion. 3. Virologic breakthrough is the first indication of an-tiviral drug resistance. 4. Genotypic resistance testing should be performed when possible to avoid unnecessary modification of treatment in patients who do not have confirmed antiviral drug resistance and to permit appropriate selection of rescue therapy in those who have con-firmed antiviral drug resistance.