Syntaxin 11 is required for NK and CD8+ T‐cell cytotoxicity and neutrophil degranulation

Syntaxin 11 (STX11) controls vesicular trafficking and is a key player in exocytosis. Since Stx11 mutations are causally associated with a familial hemophagocytic lymphohistio‐cytosis, we wanted to clarify whether STX11 is functionally important for key immune cell populations. This was studied in primary cells obtained from newly generated Stx11^?/? mice. Our data revealed that STX11 is not only widely expressed in different immune cells, but also induced upon LPS or IFN‐γ treatment. However, Stx11 deficiency does not affect macrophage phagocytic function and cytokine secretion, mast cell activation, or antigen presentation by DCs. Instead, STX11 selectively controls lymphocyte cytotoxicity in NK and activated CD8⁺ T cells and degranulation in neutrophils. Stx11^?/? NK cells and CTLs show impaired degranulation, despite a comparable activation, maturation and expression of the complex‐forming partners MUNC18–2 and VTI1B. In addition, Stx11^?/? CTLs and NK cells produce abnormal levels of IFN‐γ. Since functional reconstitution rescues the defective phenotype of Stx11^?/? CTLs, we suggest a direct, specific and key role of STX11 in controlling lymphocyte cytotoxicity, cytokine production and secretion. Finally, we show that these mice are a very useful tool for dissecting the role of STX11 in vesicular trafficking and secretion.     

Ephrin-B2 controls PDGFRβ internalization and signaling

B-class ephrins, ligands for EphB receptor tyrosine kinases, are critical regulators of growth and patterning processes in many organs and species. In the endothelium of the developing vasculature, ephrin-B2 controls endothelial sprouting and proliferation, which has been linked to vascular endothelial growth factor (VEGF) receptor endocytosis and signaling. Ephrin-B2 also has essential roles in supporting mural cells (namely, pericytes and vascular smooth muscle cells [VSMCs]), but the underlying mechanism is not understood. Here, we show that ephrin-B2 controls platelet-derived growth factor receptor β (PDGFRβ) distribution in the VSMC plasma membrane, endocytosis, and signaling in a fashion that is highly distinct from its role in the endothelium. Absence of ephrin-B2 in cultured VSMCs led to the redistribution of PDGFRβ from caveolin-positive to clathrin-associated membrane fractions, enhanced PDGF-B-induced PDGFRβ internalization, and augmented downstream mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK) activation but impaired Tiam1–Rac1 signaling and proliferation. Accordingly, mutant mice lacking ephrin-B2 expression in vascular smooth muscle developed vessel wall defects and aortic aneurysms, which were associated with impaired Tiam1 expression and excessive activation of MAP kinase and JNK. Our results establish that ephrin-B2 is an important regulator of PDGFRβ endocytosis and thereby acts as a molecular switch controlling the downstream signaling activity of this receptor in mural cells.     

Virus species polemics: 14 senior virologists oppose a proposed change to the ICTV definition of virus species

The Executive Committee of the International Committee on Taxonomy of Viruses (ICTV) has recently decided to modify the current definition of virus species (Code of Virus Classification and Nomenclature Rule 3.21) and will soon ask the full ICTV membership (189 voting members) to ratify the proposed controversial change. In this discussion paper, 14 senior virologists, including six Life members of the ICTV, compare the present and proposed new definition and recommend that the existing definition of virus species should be retained. Since the pros and cons of the proposal posted on the ICTV website are not widely consulted, the arguments are summarized here in order to reach a wider audience.     

Objectively characterizing Huntington’s disease using a novel upper limb dexterity test

Journal of Neurology - The Clinch Token Transfer Test (C3t) is a bi-manual coin transfer task that incorporates cognitive tasks to add complexity. This study explored the concurrent and convergent...     

An Analysis of the Impact of Brain-Computer Interfaces on Autonomy

Research conducted on Brain-Computer Interfaces (BCIs) has grown considerably during the last decades. With the help of BCIs, users can (re)gain a wide range of functions. Our aim in this paper is to analyze the impact of BCIs on autonomy. To this end, we introduce three abilities that most accounts of autonomy take to be essential: (1) the ability to use information and knowledge to produce reasons; (2) the ability to ensure that intended actions are effectively realized (control); and (3) the ability to enact intentions within concrete relationships and contexts. We then consider the impact of BCI technology on each of these abilities. Although on first glance, BCIs solely enhance self-determination because they restore or improve abilities, we will show that there are other positive, but also negative impacts on user autonomy, which require further philosophical and ethical discussions.

     

Tumor–microenvironment interactions studied by zonal transcriptional profiling of squamous cell lung carcinoma

Invasion is a critical step in lung tumor progression. The interaction between tumor cells and their surroundings may play an important role in tumor invasion and metastasis. To better understand the mechanisms of tumor invasion and tumor–microenvironment interactions in lung tumors, total RNA was isolated from the inner tumor, tumor invasion front, adjacent lung, and distant normal lung tissue from 17 patients with primary squamous cell lung carcinoma using punch‐aided laser capture microdissection. Messenger RNA expression profiles were obtained by microarray analysis, and microRNA profiles were generated from eight of these samples using TaqMan Low Density Arrays. Statistical analysis of the expression data showed extensive changes in gene expression in the inner tumor and tumor front compared with the normal lung and adjacent lung tissue. Only a few genes were differentially expressed between tumor front and the inner tumor. Several genes were validated by immunohistochemistry. Evaluation of the microRNA data revealed zonal expression differences in nearly a fourth of the microRNAs analyzed. Validation of selected microRNAs by in situ hybridization demonstrated strong expression of hsa‐miR‐196a in the inner tumor; moderate expression of hsa‐miR‐224 in the inner tumor and tumor front, and strong expression of hsa‐miR‐650 in the adjacent lung tissue. Pathway analysis placed the majority of genes differentially expressed between tumor and nontumor cells in intrinsic processes associated with inflammation and extrinsic processes related to lymphocyte physiology. Genes differentially expressed between the inner tumor and the adjacent lung/normal lung tissue affected pathways of arachidonic acid metabolism and eicosanoid signaling. © 2012 Wiley Periodicals, Inc.     

Balance and gait performance after maximal and submaximal endurance exercise in seniors: is there a higher fall-risk?

Impaired balance and gait performance increase fall-risk in seniors. Acute effects of different exercise bouts on gait and balance were not yet addressed. Therefore, 19 healthy seniors (10 women, 9 men, age: 64.6 ± 3.2 years) were examined on 3 days. After exhaustive treadmill testing, participants randomly completed a 2-km treadmill walking test (76 ± 8 % VO_2max) and a resting control condition. Standing balance performance (SBALP) was assessed by single limb-eyes opened (SLEO) and double limb-eyes closed (DLEC) stance. Gait parameters were collected at comfortable walking velocity. A condition × time interaction of center of pressure path length (COP_path) was observed for both balance tasks (p < 0.001). Small (Cohen’s d = 0.42, p = 0.05) and large (d = 1.04, p < 0.001) COP_path increases were found after 2-km and maximal exercise during DLEC. Regarding SLEO, slightly increased COP_path occurred after 2-km walking (d = 0.29, p = 0.65) and large increases after exhaustive exercise (d = 1.24, p < 0.001). No significant differences were found for gait parameters. Alterations of SBALP after exhaustive exercise might lead to higher fall-risk in seniors. Balance changes upon 2-km testing might be of minor relevance. Gait is not affected during single task walking at given velocities.