Increased isolation of two Biosphere Reserves and surrounding protected areas (WAP ecological complex, West Africa)

Protected areas such as nature reserves have been found to be effective in preventing habitat destruction and protecting ecosystems within their borders. Recent studies however found extensive loss of tropical forest habitat around protected areas, vastly contributing to increase the levels of ecological isolation. Using high-resolution satellite data we investigated the isolation trend occurring in the W-Arly-Pendjari (WAP) ecological complex in West Africa. A land-cover change analysis was performed for the period 1984–2002: savanna vegetation extension and loss were derived within the complex and in a 30 km peripheral buffer. Sample regions in the buffer were also analysed using selected spatial indicators to quantify temporal trends in habitat fragmentation. Implications for change in relative capacity to conserve biodiversity were discussed through the calculation of the species richness capacity (SRC). More than 14.5% of savanna habitat was lost in the WAP peripheral areas, while 0.3% was converted inside the complex. The degree of fragmentation of remnant savanna habitat has also drastically increased. Despite the effectiveness of the park conservation programme, we found through the SRC approach that the WAP complex is decreasing its potential capacity to conserve species richness. This process is mainly due to the rapid and extended agricultural expansion taking place around the complex. A better understanding of the ecological dynamics occurring in the peripheral regions of reserves and the consideration of development needs are key variables to achieve conservation goals in protected areas.     

Identification of new antigenic peptide presented by HLA-Cw7 and encoded by several MAGE genes using dendritic cells transduced with lentiviruses

Antigens encoded by MAGE genes are of particular interest for cancer immunotherapy because they are tumor specific and shared by tumors of different histological types. Several clinical trials are in progress with MAGE peptides, proteins, recombinant poxviruses, and dendritic cells (DC) pulsed with peptides or proteins. The use of gene-modified DC would offer the major advantage of a long-lasting expression of the transgene and a large array of antigenic peptides that fit into the different HLA molecules of the patient. In this study, we tested the ability of gene-modified DC to prime rare Ag-specific T cells, and we identified a new antigenic peptide of clinical interest. CD8(+) T lymphocytes from an individual without cancer were stimulated with monocyte-derived DC, which were infected with a second-generation lentiviral vector encoding MAGE-3. A CTL clone was isolated that recognized peptide EGDCAPEEK presented by HLA-Cw7 molecules, which are expressed by >40% of Caucasians. Interestingly, this new tumor-specific antigenic peptide corresponds to position 212-220 of MAGE-2, -3, -6, and -12. HLA-Cw7 tumor cell lines expressing one of these MAGE genes were lysed by the CTL, indicating that the peptide is efficiently processed in tumor cells and can therefore be used as target for antitumoral vaccination. The risk of tumor escape due to appearance of Ag-loss variants should be reduced by the fact that the peptide is encoded by several MAGE genes.     

Host Determinants of Helicobacter pylori Infection and Its Clinical Outcome

Greater than one-half of the world's population harbors Helicobacter pylori. The majority of infected individuals, however, remain asymptomatic, with only 10% to 20% developing diseases, including peptic ulcer disease, gastric cancer, and gastric mucosa–associated lymphoid tissue lymphoma. This article reviews host factors that may predispose an individual to both the acquisition of H. pylori infection and subsequent clinical outcome. Individuals with specific blood group antigens and human leukocyte antigen genotypes may be more susceptible to H. pylori infection. Additional factors, such as the age of acquisition, the host immune response, the site of infection, acid secretion, and interactions with nonhost factors (including bacterial virulence factors and environmental influences) may play a role in determining clinical outcome. Further investigation is required to clarify the mechanisms by which these interactions occur and, more critically, to determine their relative importance. This knowledge will enable the identification of individuals at risk of developing clinical disease with H. pylori infection.     

TatB functions as an oligomeric binding site for folded Tat precursor proteins

Twin-arginine-containing signal sequences mediate the transmembrane transport of folded proteins. The cognate twin-arginine translocation (Tat) machinery of Escherichia coli consists of the membrane proteins TatA, TatB, and TatC. Whereas Tat signal peptides are recognized by TatB and TatC, little is known about molecular contacts of the mature, folded part of Tat precursor proteins. We have placed a photo-cross-linker into Tat substrates at sites predicted to be either surface-exposed or hidden in the core of the folded proteins. On targeting of these variants to the Tat machinery of membrane vesicles, all surface-exposed sites were found in close proximity to TatB. Correspondingly, incorporation of the cross-linker into TatB revealed multiple precursor-binding sites in the predicted transmembrane and amphipathic helices of TatB. Large adducts indicative of TatB oligomers contacting one precursor molecule were also obtained. Cross-linking of Tat substrates to TatB required an intact twin-arginine signal peptide and disappeared upon transmembrane translocation. Our collective data are consistent with TatB forming an oligomeric binding site that transiently accommodates folded Tat precursors.     

Predicting potentially pathogenic effects of hRPE65 missense mutations: a computational strategy based on molecular dynamics simulations

The human retinal pigment epithelium-specific 65-kDa protein (hRPE65) plays a crucial role within the retinoid visual cycle and several mutations affecting either its expression level or its enzymatic function are associated with inherited retinal diseases such as Retinitis Pigmentosa. The gene therapy product voretigene neparvovec (Luxturna) has been recently approved for treating hereditary retinal dystrophies; however, the treatment is currently accessible only to patients presenting confirmed biallelic mutations that severely impair hRPE65 function, and many reported hRPE65 missense mutations lack sufficient evidences for proving their pathogenicity. In this context, we developed a computational approach aimed at evaluating the potential pathogenic effect of hRPE65 missense variants located on the dimerisation domain of the protein. The protocol evaluates how mutations may affect folding and conformation stability of this protein region, potentially helping clinicians to evaluate the eligibility for gene therapy of patients diagnosed with this type of hRPE65 variant of uncertain significance.     

Dynamic partitioning into lipid rafts controls the endo-exocytic cycle of the alphaL/beta2 integrin, LFA-1, during leukocyte chemotaxis

Cell migration entails the dynamic redistribution of adhesion receptors from the cell rear toward the cell front, where they form new protrusions and adhesions. This process may involve regulated endo-exocytosis of integrins. Here we show that in primary neutrophils unengaged alphaL/beta2 integrin (LFA-1) is internalized and rapidly recycled upon chemoattractant stimulation via a clathrin-independent, cholesterol-sensitive pathway involving dynamic partitioning into detergent-resistant membranes (DRM). Persistent DRM association is required for recycling of the internalized receptor because 1) >90% of endocytosed LFA-1 is associated with DRM, and a large fraction of the internalized receptor colocalizes intracellularly with markers of DRM and the recycling endocytic compartment; 2) a recycling-defective mutant (alphaL/beta2Y735A) dissociates rapidly from DRM upon being endocytosed and is subsequently diverted into a late endosomal pathway; and 3) a dominant negative Rab11 mutant (Rab11S25N) induces intracellular accumulation of endocytosed alphaL/beta2 and prevents its enrichment in chemoattractant-induced lamellipodia. Notably, chemokine-induced migration of neutrophils over immobilized ICAM-1 is abrogated by cholesterol-sequestering agents. We propose that DRM-associated endocytosis allows efficient retrieval of integrins, as they detach from their ligands, followed by polarized recycling to areas of the plasma membrane, such as lamellipodia, where they establish new adhesive interactions and promote outside-in signaling events.     

A simple mathematical model of the interaction between intracranial pressure and cerebral hemodynamics

Ursino, Mauro, and Carlo Alberto Lodi. A simplemathematical model of the interaction between intracranial pressure andcerebral hemodynamics. J. Appl.Physiol. 82(4): 1256-1269, 1997.A simplemathematical model of intracranial pressure (ICP) dynamics oriented toclinical practice is presented. It includes the hemodynamics of thearterial-arteriolar cerebrovascular bed, cerebrospinal fluid (CSF)production and reabsorption processes, the nonlinear pressure-volumerelationship of the craniospinal compartment, and a Starling resistormechanism for the cerebral veins. Moreover, arterioles are controlledby cerebral autoregulation mechanisms, which are simulated by means ofa time constant and a sigmoidal static characteristic. The model isused to simulate interactions between ICP, cerebral blood volume, andautoregulation. Three different related phenomena are analyzed: thegeneration of plateau waves, the effect of acute arterial hypotensionon ICP, and the role of cerebral hemodynamics during pressure-volume index (PVI) tests. Simulation results suggest the following:1) ICP dynamics may become unstablein patients with elevated CSF outflow resistance and decreasedintracranial compliance, provided cerebral autoregulation is efficient.Instability manifests itself with the occurrence of self-sustainedplateau waves. 2) Moderate acutearterial hypotension may have completely different effects on ICP,depending on the value of model parameters. If physiological compensatory mechanisms (CSF circulation and intracranial storage capacity) are efficient, acute hypotension has only negligible effectson ICP and cerebral blood flow (CBF). If these compensatory mechanismsare poor, even modest hypotension may induce a large transient increasein ICP and a significant transient reduction in CBF, with risks ofsecondary brain damage. 3) The ICPresponse to a bolus injection (PVI test) is sharply affected, viacerebral blood volume changes, by cerebral hemodynamics andautoregulation. We suggest that PVI tests may be used to extractinformation not only on intracranial compliance and CSF circulation,but also on the status of mechanisms controlling CBF.