Deficiency of intramuscular ICC increases fundic muscle excitability but does not impede nitrergic innervation

The motility of the gastrointestinal tract is generated by smooth muscle cells and is controlled to a large extent by an intrinsic neural network. A gap of approximately 200 nm usually separates nerve varicosities from smooth muscle cells, which suggests that direct innervation of the smooth muscle by synapses does not occur. Enteric nerves do make synapse-like contact with proposed regulatory cells, the interstitial cells of Cajal (ICC), which in turn may be in gap junction contact with smooth muscle cells. The role played by ICC in enteric innervation is controversial. Experimental evidence has been presented in vitro for the hypothesis that nitrergic inhibitory innervation is strongly reduced in the absence of ICC. However, in vivo data appear to dispute that. The present report provides evidence that explains the discrepancy between in vivo and in vitro data and provides evidence that inhibitory neurotransmitters can reach smooth muscle cells without hindrance when ICC are absent. The fundic musculature shows increased responses to substance P-mediated innervation and shows marked spontaneous activity, which is consistent with increased muscle excitability.     

Transmitted HIV-1 is more virulent in heterosexual individuals than men-who-have-sex-with-men

Transmission bottlenecks introduce selection pressures on HIV-1 that vary with the mode of transmission. Recent studies on small cohorts have suggested that stronger selection pressures lead to fitter transmitted/founder (T/F) strains. Manifestations of this selection bias at the population level have remained elusive. Here, we analysed early CD4 cell count measurements reported from ∼340,000 infected heterosexual individuals (HET) and men-who-have-sex-with-men (MSM), across geographies, ethnicities and calendar years. The reduction in CD4 counts early in infection is reflective of the virulence of T/F strains. MSM and HET use predominant modes of transmission, namely, anal and penile-vaginal, with among the largest differences in the selection pressures at transmission across modes. Further, in most geographies, the groups show little inter-mixing, allowing for the differential selection bias to be sustained and amplified. We found that the early reduction in CD4 counts was consistently greater in HET than MSM (P<0.05). To account for inherent variations in baseline CD4 counts, we constructed a metric to quantify the extent of progression to AIDS as the ratio of the reduction in measured CD4 counts from baseline and the reduction associated with AIDS. We found that this progression corresponding to the early CD4 measurements was ∼68% for MSM and ∼87% for HET on average (P<10⁻⁴; Cohen’s d, d_s = 0.36), reflecting the more severe disease caused by T/F strains in HET than MSM at the population level. Interestingly, the set-point viral load was not different between the groups (d_s<0.12), suggesting that MSM were more tolerant and not more resistant to their T/F strains than HET. This difference remained when we controlled for confounding factors using multivariable regression. We concluded that the different selection pressures at transmission have resulted in more virulent T/F strains in HET than MSM. These findings have implications for our understanding of HIV-1 pathogenesis, evolution, and epidemiology.     

Neither the HIV Protease Inhibitor Lopinavir-Ritonavir nor the Antimicrobial Trimethoprim-Sulfamethoxazole Prevent Malaria Relapse in Plasmodium cynomolgi-Infected Non-Human Primates

Plasmodium vivax malaria causes significant morbidity and mortality worldwide, and only one drug is in clinical use that can kill the hypnozoites that cause P. vivax relapses. HIV and P. vivax malaria geographically overlap in many areas of the world, including South America and Asia. Despite the increasing body of knowledge regarding HIV protease inhibitors (HIV PIs) on P. falciparum malaria, there are no data regarding the effects of these treatments on P. vivax''s hypnozoite form and clinical relapses of malaria. We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV) and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX) inhibit Plasmodium actively dividing liver stages in rodent malarias and in vitro in P. falciparum, but effect against Plasmodium dormant hypnozoite forms remains untested. Separately, although other antifolates have been tested against hypnozoites, the antibiotic trimethoprim sulfamethoxazole, commonly used in HIV infection and exposure management, has not been evaluated for hypnozoite-killing activity. Since Plasmodium cynomolgi is an established animal model for the study of liver stages of malaria as a surrogate for P. vivax infection, we investigated the antimalarial activity of these drugs on Plasmodium cynomolgi relapsing malaria in rhesus macaques. Herein, we demonstrate that neither TMP-SMX nor LPV-RTV kills hypnozoite parasite liver stage forms at the doses tested. Because HIV and malaria geographically overlap, and more patients are being managed for HIV infection and exposure, understanding HIV drug impact on malaria infection is important.     

Shape-Induced Asymmetric Diffusion in Dendritic Spines Allows Efficient Synaptic AMPA Receptor Trapping

Dendritic spines are the primary postsynaptic sites of excitatory neurotransmission in the brain. They exhibit a remarkable morphological variety, ranging from thin protrusions, to stubby shapes, to bulbous mushroom shapes. The remodeling of spines is thought to regulate the strength of the synaptic connection, which depends vitally on the number and the spatial distribution of AMPA-type glutamate receptors (AMPARs). We present numerical and analytical analyses demonstrating that this shape strongly affects AMPAR diffusion. We report a pronounced suppression of the receptor exit rate out of spines with decreasing neck radius. Thus, mushroomlike spines become highly effective at retaining receptors in the spine head. Moreover, we show that the postsynaptic density further enhances receptor trapping, particularly in mushroomlike spines local exocytosis in the spine head, in contrast to release at the base, provides rapid and specific regulatory control of AMPAR concentration at synapses.     

Immunological challenges associated with artificial skin grafts: available solutions and stem cells in future design of synthetic skin

The repair or replacement of damaged skins is still an important, challenging public health problem. Immune acceptance and long-term survival of skin grafts represent the major problem to overcome in grafting given that in most situations autografts cannot be used. The emergence of artificial skin substitutes provides alternative treatment with the capacity to reduce the dependency on the increasing demand of cadaver skin grafts. Over the years, considerable research efforts have focused on strategies for skin repair or permanent skin graft transplantations. Available skin substitutes include pre- or post-transplantation treatments of donor cells, stem cell-based therapies, and skin equivalents composed of bio-engineered acellular or cellular skin substitutes. However, skin substitutes are still prone to immunological rejection, and as such, there is currently no skin substitute available to overcome this phenomenon. This review focuses on the mechanisms of skin rejection and tolerance induction and outlines in detail current available strategies and alternatives that may allow achieving full-thickness skin replacement and repair.     

Multiplicity of human immunodeficiency virus infections in lymphoid tissue

Human immunodeficiency virus type 1 (HIV-1)-infected splenocytes in humans were recently shown to harbor three to four proviruses per cell on average (A. Jung et al., Nature 418:144, 2002). However, the mechanisms that lead to such extensive multiple infections are not understood. Here, we find by using mathematical analysis that two mechanisms quantitatively capture the distribution of proviral genomes in HIV-1-infected splenocytes, one where multiple genomes are acquired one at a time in a series of sequential infectious contacts of a target cell with free virions and infected cells, and the other where cell-to-cell transmission of multiple virions or genomes results from a single infectious contact of a target cell with an infected cell. The two mechanisms imply different genetic diversities of proviruses within an infected cell and therefore different rates of emergence of drug resistance via recombination.     

Boo, a novel negative regulator of cell death, interacts with Apaf-1.

In this report, we describe the cloning and characterization of Boo, a novel anti-apoptotic member of the Bcl-2 family. The expression of Boo was highly restricted to the ovary and epididymis implicating it in the control of ovarian atresia and sperm maturation. Boo contains the conserved BH1 and BH2 domains, but lacks the BH3 motif. Like Bcl-2, Boo possesses a hydrophobic C-terminus and localizes to intracellular membranes. Boo also has an N-terminal region with strong homology to the BH4 domain found to be important for the function of some anti-apoptotic Bcl-2 homologues. Chromosomal localization analysis assigned Boo to murine chromosome 9 at band d9. Boo inhibits apoptosis, homodimerizes or heterodimerizes with some death-promoting and -suppressing Bcl-2 family members. More importantly, Boo interacts with Apaf-1 and forms a multimeric protein complex with Apaf-1 and caspase-9. Bak and Bik, two pro-apoptotic homologues disrupt the association of Boo and Apaf-1. Furthermore, Boo binds to three distinct regions of Apaf-1. These results demonstrate the evolutionarily conserved nature of the mechanisms of apoptosis. Like Ced-9, the mammalian homologues Boo and Bcl-xL interact with the human counterpart of Ced-4, Apaf-1, and thereby regulate apoptosis.     

Correlation of surface sediment diatoms with the present lake water pH in 28 Algoma lakes,Ontario, Canada

The surface sediment diatom analysis of 28 Algoma lakes (pH 4.40–8.13) indicates that even though each lake has a widely different aquatic environment and characteristic diatom assemblage, a definite relationship exists between the lake water pH and their diatom assemblages. In the acidic lakes acidobiontic and acidophilous diatom species predominate whereas in circumneutral and alkaline lakes circumneutral and alkaliphilous diatoms were most common. Cluster analysis of the pH indicator diatom assemblages grouped the study lakes into three distinct cluster groups. These groups also closely corresponded to lake water pH. On the basis of published ecological information as well as their presence in our study lakes, the pH indicator status of a number of diatom taxa have been discussed. A detailed listing of the diatom taxa identified and their pH indicator status is provided in order to facilitate their use in future diatom-inferred pH studies.