Remnant lipoproteins inhibit malaria sporozoite invasion of hepatocytes

Remnants of lipoproteins, intestinal chylomicrons, and very low density lipoprotein (VLDL), are rapidly cleared from plasma and enter hepatocytes. It has been suggested that remnant lipoproteins are initially captured in the space of Disse by heparan sulfate proteoglycans (HSPGs), and that their subsequent internalization into hepatocytes is mediated by members of the LDL-receptor gene family. Similarly to lipoprotein remnants, malaria sporozoites are removed from the blood circulation by the liver within minutes after injection by Anopheles mosquitoes. The sporozoite's surface is covered by the circumsporozoite protein (CS), and its region II-plus has been implicated in the binding of the parasites to glycosaminoglycan chains of hepatocyte HSPGs. Lactoferrin, a protein with antibacterial properties found in breast milk and neutrophil granules, is also rapidly cleared from the circulation by hepatocytes, and can inhibit the hepatic uptake of lipoprotein remnants. Here we provide evidence that sporozoites, lactoferrin, and remnant lipoproteins are cleared from the blood by similar mechanisms. CS, lactoferrin, and remnant lipoproteins compete in vitro and in vivo for binding sites on liver cells. The relevance of this binding event for sporozoite infectivity is highlighted by our demonstration that apoliprotein E-enriched beta-VLDI and lactoferrin inhibit sporozoite invasion of HepG2 cells. In addition, malaria sporozoites are less infective in LDL-receptor knockout (LDLR -/-) mice maintained on a high fat diet, as compared with littermates maintained on a normal diet. We conclude that the clearance of lipoprotein remnants and sporozoites from the blood is mediated by the same set of highly sulfated HSPGs on the hepatocyte plasma membrane

Plasmodium sporozoites trickle out of the injection site

Plasmodium sporozoites make a remarkable journey from the skin, where they are deposited by an infected Anopheline mosquito, to the liver, where they invade hepatocytes and develop into exoerythrocytic stages. Although much work has been done to elucidate the molecular mechanisms by which sporozoites invade hepatocytes, little is known about the interactions between host and parasite before the sporozoite enters the blood circulation. It has always been assumed that sporozoites rapidly exit the injection site, making their interactions with the host at this site, brief and difficult to study. Using quantitative PCR, we determined the kinetics with which sporozoites leave the injection site and arrive in the liver and found that the majority of infective sporozoites remain in the skin for hours. We then performed sub-inoculation experiments which confirmed these findings and showed that the pattern of sporozoite exit from the injection site resembles a slow trickle. Last, we found that drainage of approximately 20% of the sporozoite inoculum to the lymphatics is associated with a significant enlargement of the draining lymph node, a response not observed after intravenous inoculation. These findings indicate that there is ample time for host and parasite to interact at the inoculation site and are of relevance to the pre-erythrocytic stage malaria vaccine effort

Silicon-based resonant-cavity-enchanced photodiode with a buried SiO2 reflector

We report on a silicon-based resonant cavity photodiode with a buried silicon dioxide layer as the bottom reflector. The buried oxide is created by using a separation by implantation of oxygen technique. The device shows large Fabry-Perot oscillations. Resonant peaks and antiresonant troughs are observed as a function of the wavelength, with a peak responsivity of about 50 mA/W at 650 and 709 nm. The leakage current density is 85 pA/mm(2) at -5 V, and the average zero-bias capacitance is 12 pF/mm(2). We also demonstrate that the buried oxide prevents carriers generated deep within the substrate from reaching the top contacts, thus removing any slow carrier diffusion tail from the impulse response. (C) 1999 American Institute of Physics. (DOI: 10.1063/1.123499)

Planning the Future of U.S. Particle Physics (Snowmass 2013): Chapter 4: Cosmic Frontier

These reports present the results of the 2013 Community Summer Study of the APS Division of Particles and Fields ("Snowmass 2013") on the future program of particle physics in the U.S. Chapter 4, on the Cosmic Frontier, discusses the program of research relevant to cosmology and the early universe. This area includes the study of dark matter and the search for its particle nature, the study of dark energy and inflation, and cosmic probes of fundamental symmetries.Comment: 61 page

TeV Gamma-Ray Sources from a Survey of the Galactic Plane with Milagro

A survey of Galactic gamma-ray sources at a median energy of ~20 TeV has been performed using the Milagro Gamma Ray Observatory. Eight candidate sources of TeV emission are detected with pre-trials significance $>4.5\sigma$ in the region of Galactic longitude $l\in[30^\circ,220^\circ]$ and latitude $b\in[-10^\circ,10^\circ]$. Four of these sources, including the Crab nebula and the recently published MGRO J2019+37, are observed with significances $>4\sigma$ after accounting for the trials involved in searching the 3800 square degree region. All four of these sources are also coincident with EGRET sources. Two of the lower significance sources are coincident with EGRET sources and one of these sources is Geminga. The other two candidates are in the Cygnus region of the Galaxy. Several of the sources appear to be spatially extended. The fluxes of the sources at 20 TeV range from ~25% of the Crab flux to nearly as bright as the Crab.Comment: Submitted to Ap

Discovery of Localized Regions of Excess 10-TeV Cosmic Rays

An analysis of 7 years of Milagro data performed on a 10-degree angular scale has found two localized regions of excess of unknown origin with greater than 12 sigma significance. Both regions are inconsistent with gamma-ray emission with high confidence. One of the regions has a different energy spectrum than the isotropic cosmic-ray flux at a level of 4.6 sigma, and it is consistent with hard spectrum protons with an exponential cutoff, with the most significant excess at ~10 TeV. Potential causes of these excesses are explored, but no compelling explanations are found.Comment: Submitted to PhysRevLet