Posts Tagged ‘switching’

CCNA Routing and Switching Complete Deluxe Study Guide: Exam 100-105, Exam 200-105, Exam 200-125, 2nd Edition

  The bestselling CCNA prep guide with the field’s leading Cisco authorityCCNA Routing and Switching Complete Deluxe Study Guide, 2nd Edition is a leading resource for those taking the Cisco Certified Network Associate exams. Whether you’r…

Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system

Germinal centers (GCs) promote humoral immunity and vaccine efficacy. In GCs, antigen (Ag)-activated B lymphocytes proliferate, are selected for high affinity antibody (Ab), promote Ab class switching, and yield B cell memory1,2. Whereas the cytokine milieu has long been known to regulate effector functions that include the choice of immunoglobulin class 3,4, both cell-autonomous5 and extrinsic6,7 metabolic programming have emerged as modulators of T cell-mediated immunity8. We now show that GC light zones are hypoxic and low oxygen (pO2) alters B cell physiology and function. In addition to reduced proliferation and increased B cell death, low pO2 impaired Ab class switching to the pro-inflammatory IgG2c Ab isotype by limiting expression of the cytosine deaminase AID. Hypoxia induces HIF transcription factors by restricting activity of prolyl hydroxyl dioxygenases (PHD), enzymes that hydroxylate HIF-1a and HIF-2a to destabilize HIF through binding of Von Hippel–Landau protein (pVHL)7. B cell-specific pVHL depletion led to constitutive HIF stabilization, decreased Ag-specific GC B cells and undermined the generation of high-affinity IgG, switching to IgG2c, early memory B cells, and recall Ab responses. HIF induction can reprogram metabolic and growth factor gene expression. Sustained hypoxia or HIF induction via pVHL deficiency inhibited mTOR complex 1 (mTORC1) activity in B lymphoblasts, and mTORC1 haploinsufficient B cells had reduced clonal expansion, AID expression, and capacities to yield IgG2c and high-affinity Ab. Thus, the normal physiology of GCs involves regional variegation of hypoxia, and HIF-dependent oxygen sensing regulates vital functions of B cells. We propose that restriction of oxygen in lymphoid organs, which can be altered in pathophysiological states, modulates humoral immunity.

Operation of a homeostatic sleep switch

Sleep disconnects animals from the external world, at considerable risks and costs that must be offset by a vital benefit. Insight into this mysterious benefit will come from understanding sleep homeostasis: to monitor sleep need, an internal bookkeeper must track physiological changes that are linked to the core function of sleep. In Drosophila, a crucial component of the machinery for sleep homeostasis is a cluster of neurons innervating the dorsal fan-shaped body (dFB) of the central complex. Artificial activation of these cells induces sleep, whereas reductions in excitability cause insomnia. dFB neurons in sleep-deprived flies tend to be electrically active, with high input resistances and long membrane time constants, while neurons in rested flies tend to be electrically silent. Correlative evidence thus supports the simple view that homeostatic sleep control works by switching sleep-promoting neurons between active and quiescent states. Here we demonstrate state switching by dFB neurons, identify dopamine as a neuromodulator that operates the switch, and delineate the switching mechanism. Arousing dopamine caused transient hyperpolarization of dFB neurons within tens of milliseconds and lasting excitability suppression within minutes. Both effects were transduced by Dop1R2 receptors and mediated by potassium conductances. The switch to electrical silence involved the downregulation of voltage-gated A-type currents carried by Shaker and Shab, and the upregulation of voltage-independent leak currents through a two-pore-domain potassium channel that we term Sandman. Sandman is encoded by the CG8713 gene and translocates to the plasma membrane in response to dopamine. dFB-restricted interference with the expression of Shaker or Sandman decreased or increased sleep, respectively, by slowing the repetitive discharge of dFB neurons in the ON state or blocking their entry into the OFF state. Biophysical changes in a small population of neurons are thus linked to the control of sleep–wake state.

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