John A. Young

Bio: John A. Young is an academic researcher from University of Wisconsin-Madison. The author has contributed to research in topics: Receptor & Patch clamp. The author has an hindex of 40, co-authored 123 publications receiving 6289 citations. Previous affiliations of John A. Young include Salk Institute for Biological Studies & University of Sydney.

Identification of the cellular receptor for anthrax toxin.

Abstract: The tripartite toxin secreted by Bacillus anthracis, the causative agent of anthrax, helps the bacterium evade the immune system and can kill the host during a systemic infection. Two components of the toxin enzymatically modify substrates within the cytosol of mammalian cells: oedema factor (OF) is an adenylate cyclase that impairs host defences through a variety of mechanisms including inhibiting phagocytosis; lethal factor (LF) is a zinc-dependent protease that cleaves mitogen-activated protein kinase kinase and causes lysis of macrophages. Protective antigen (PA), the third component, binds to a cellular receptor and mediates delivery of the enzymatic components to the cytosol. Here we describe the cloning of the human PA receptor using a genetic complementation approach. The receptor, termed ATR (anthrax toxin receptor), is a type I membrane protein with an extracellular von Willebrand factor A domain that binds directly to PA. In addition, a soluble version of this domain can protect cells from the action of the toxin.

Human capillary morphogenesis protein 2 functions as an anthrax toxin receptor

Abstract: Bacillus anthracis secretes two bipartite toxins thought to be involved in anthrax pathogenesis and resulting death of the host. The current model for intoxication is that protective antigen (PA) toxin subunits bind a single group of cell-surface anthrax toxin receptors (ATRs), encoded by the tumor endothelial marker 8 (TEM8) gene. The ATR/TEM8-PA interaction is mediated by the receptor's extracellular domain related to von Willebrand factor type A or integrin inserted domains (VWA/I domains). A metal ion-dependent adhesion site (MIDAS) located within this domain of the ATR/TEM8 protein chelates a divalent cation critical for PA binding. In this report, we identify a second PA receptor encoded by capillary morphogenesis gene 2 (CMG2), which has 60% amino acid identity to ATR/TEM8 within the VWA/I domain, as well as a conserved MIDAS motif. A recombinant CMG2 protein bound PA and mediated toxin internalization when expressed on receptor-deficient cells. Binding between the CMG2 VWA/I domain and PA was shown to be direct and metal-dependent, although the cation specificity of this interaction is different than that observed with ATR/TEM8. Northern blot analysis revealed that CMG2 is widely expressed in human tissues, indicating that this receptor is likely to be relevant for disease pathogenesis. Finally, a soluble version of the CMG2 VWA/I domain inhibited intoxication of cells expressing endogenous toxin receptors when it was added to PA at a 3:1 ratio. These studies distinguish CMG2 as a second anthrax toxin receptor and identify a potent antitoxin that may prove useful for the treatment of anthrax.

Dose-dependent stimulation and inhibition of proximal tubular sodium reabsorption by angiotensin II in the rat kidney

Abstract: The effect of val5-angiotensin II on steady-state sodium concentration gradients (deltacNa) was studied in rat proximal tubules by stationary micro-perfusion combined with perfusion of the peritubular capillaries. Angiotensin added to the peritubular perfusion fluid had a biphasic action with stimulation of sodium reabsorption at low doses (10(-12)-10(-10)M) and inhibition at high doses (3 X 10(-7) - 3 X 10(-6)M). Stimulation of transport was also observed with intraluminal angiotensin but only at a dose of 10(-9)M. Transepithelial potential difference was calculated from the steady-state chloride distribution; no significant change was observed at low (10(-11)M) or high (10(-6)M) concentrations and a direct action on sodium transport is postulated. This biphasic effect is discussed in relation to the responses of the intact kidney to intra-renal infusion of angiotensin, and to the control of tubulo-glomerular feed-back.

Probable maximum precipitation and climate change

Abstract: [1] Probable maximum precipitation (PMP) is the greatest accumulation of precipitation for a given duration meteorologically possible for an area Climate change effects on PMP are analyzed, in particular, maximization of moisture and persistent upward motion, using both climate model simulations and conceptual models of relevant meteorological systems Climate model simulations indicate a substantial future increase in mean and maximum water vapor concentrations For the RCP85 scenario, the changes in maximum values for the continental United States are approximately 20%–30% by 2071–2100 The magnitudes of the maximum water vapor changes follow temperature changes with an approximate Clausius-Clapeyron relationship Model-simulated changes in maximum vertical and horizontal winds are too small to offset water vapor changes Thus, our conclusion is that the most scientifically sound projection is that PMP values will increase in the future due to higher levels of atmospheric moisture content and consequent higher levels of moisture transport into storms

The composition of fluid collected by micropuncture and catheterization from the seminiferous tubules and rete testis of rats

Abstract: Fluid and electrolyte secretion in the rat testis has been studied by micropuncture and catheterization. Three fluids have been collected and analyzed: 1. Rete-testis fluid, obtained by catheterization of the rete testis. 2. Free-flow fluid, obtained by micropuncture of seminiferous tubules. 3. Primary fluid, also obtained by micropuncture but after first filling a tubule segment with oil and allowing new secretion to form and break up the oil column into droplets.

A Dipole Mode in the Tropical Indian Ocean

Abstract: For the tropical Pacific and Atlantic oceans, internal modes of variability that lead to climatic oscillations have been recognized1,2, but in the Indian Ocean region a similar ocean–atmosphere interaction causing interannual climate variability has not yet been found3. Here we report an analysis of observational data over the past 40 years, showing a dipole mode in the Indian Ocean: a pattern of internal variability with anomalously low sea surface temperatures off Sumatra and high sea surface temperatures in the western Indian Ocean, with accompanying wind and precipitation anomalies. The spatio-temporal links between sea surface temperatures and winds reveal a strong coupling through the precipitation field and ocean dynamics. This air–sea interaction process is unique and inherent in the Indian Ocean, and is shown to be independent of the El Nino/Southern Oscillation. The discovery of this dipole mode that accounts for about 12% of the sea surface temperature variability in the Indian Ocean—and, in its active years, also causes severe rainfall in eastern Africa and droughts in Indonesia—brightens the prospects for a long-term forecast of rainfall anomalies in the affected countries.

Mechanisms of Endocytosis

Abstract: Endocytic mechanisms control the lipid and protein composition of the plasma membrane, thereby regulating how cells interact with their environments. Here, we review what is known about mammalian endocytic mechanisms, with focus on the cellular proteins that control these events. We discuss the well-studied clathrin-mediated endocytic mechanisms and dissect endocytic pathways that proceed independently of clathrin. These clathrin-independent pathways include the CLIC/GEEC endocytic pathway, arf6-dependent endocytosis, flotillin-dependent endocytosis, macropinocytosis, circular doral ruffles, phagocytosis, and trans-endocytosis. We also critically review the role of caveolae and caveolin1 in endocytosis. We highlight the roles of lipids, membrane curvature-modulating proteins, small G proteins, actin, and dynamin in endocytic pathways. We discuss the functional relevance of distinct endocytic pathways and emphasize the importance of studying these pathways to understand human disease processes.

Progress and problems with the use of viral vectors for gene therapy

Abstract: Gene therapy has a history of controversy. Encouraging results are starting to emerge from the clinic, but questions are still being asked about the safety of this new molecular medicine. With the development of a leukaemia-like syndrome in two of the small number of patients that have been cured of a disease by gene therapy, it is timely to contemplate how far this technology has come, and how far it still has to go.

Signals for Sorting of Transmembrane Proteins to Endosomes and Lysosomes

Abstract: Sorting of transmembrane proteins to endosomes and lysosomes is mediated by signals present within the cytosolic domains of the proteins. Most signals consist of short, linear sequences of amino acid residues. Some signals are referred to as tyrosine-based sorting signals and conform to the NPXY or YXXO consensus motifs. Other signals known as dileucine-based signals fit [DE]XXXL[LI] or DXXLL consensus motifs. All of these signals are recognized by components of protein coats peripherally associated with the cytosolic face of membranes. YXXO and [DE]XXXL[LI] signals are recognized with characteristic fine specificity by the adaptor protein (AP) complexes AP-1, AP-2, AP-3, and AP-4, whereas DXXLL signals are recognized by another family of adaptors known as GGAs. Several proteins, including clathrin, AP-2, and Dab2, have been proposed to function as recognition proteins for NPXY signals. YXXO and DXXLL signals bind in an extended conformation to the mu2 subunit of AP-2 and the VHS domain of the GGAs, respectively. Phosphorylation events regulate signal recognition. In addition to peptide motifs, ubiquitination of cytosolic lysine residues also serves as a signal for sorting at various stages of the endosomal-lysosomal system. Conjugated ubiquitin is recognized by UIM, UBA, or UBC domains present within many components of the internalization and lysosomal targeting machinery. This complex array of signals and recognition proteins ensures the dynamic but accurate distribution of transmembrane proteins to different compartments of the endosomal-lysosomal system.

Determination of Bulk Properties of Tropical Cloud Clusters from Large-Scale Heat and Moisture Budgets

Abstract: The bulk properties of tropical cloud clusters, such as the vertical mass flux, the excess temperature, and moisture and the liquid water content of the clouds, are determined from a combination of 1) the observed large-scale heat and moisture budgets over an area covering the cloud cluster, and 2) a model of a cumulus ensemble which exchanges mass, heat, water vapor and liquid water with the environment through entrainment and detrainment The method also provides an understanding of how the environmental air is heated and moistened by the cumulus convection An estimate of the average cloud cluster properties and the heat and moisture balance of the environment, obtained from 1956 Marshall Islands data, is presented