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The present study investigated the prevalence of mutations in the -550 (H/L) and -221 (X/Y) mannose-binding lectin (MBL) gene promoter regions and their impact on infection by human immunodeficiency virus 1 (HIV-

The present study investigated the frequency of the mutations at positions -550 and -221

Background: AGTC is developing a recombinant adenoassociated virus (rAAV) vector expressing the human CNGB3 gene, for treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity and absence of color discrimination. Here we report results of a toxicology and biodistribution study of this vector administered by subretinal injection in CNGB3-deficient mice. Methods: Three groups of CNGB3-deficient mice (n= 35 per sex per group) received a subretinal injection in one eye of 1 µL of vehicle (balanced salt solution with 0.014% Tween 20) or rAAV2tYF-PR1.7-hCNGB3 vector at a concentration of 1 × 10 12 vg/mL (1 × 10 9 vg/eye) or 4 × 10 12 vg/mL (4 × 10 9 vg/eye). The other eye was untreated. Ten animals/sex/group were used for toxicology evaluation with ophthalmic examinations and pathological evaluations, 10 animals/ sex/group were used for biodistribution evaluation, and 15 animals/ sex/group were used for efficacy evaluation. Half the animals in the biodistribution and toxicology groups were euthanized 4 weeks after vector administration and the remaining animals were euthanized 12 weeks after vector administration. For animals in the biodistribution groups, blood for qPCR analysis was obtained on Study Days 3, 8 and at euthanasia. At necropsy, samples of eyes, brain, heart, liver, gall bladder, kidneys, spleen, thymus, lungs, adrenals, ovaries, epididymides and testes were obtained for histopathology (for animals in the toxicology groups) or DNA PCR (for animals in the biodistribution groups). For animals scheduled for efficacy evaluations, electroretinography (ERG) testing included scotopic and photopic tests performed at Week 4, 8, and 12 on each eye and serum was collected at euthanasia for measurement of antibodies to AAV and hCNGB3. Results: There were no test article-related changes in clinical observations, body weights, food consumption, ocular examinations, clinical pathology parameters, organ weights, or macroscopic observations at necropsy. Cone-mediated ERG responses were detected after vector administration in the treated eyes in 90% of animals in the higher dose group, 31% of animals in the lower dose group, and none of the untreated or vehicle-treated eyes. Microscopic pathology results demonstrated minimal mononuclear cell infiltrates in the retina and vitreous of some animals at the interim euthanasia, and in the vitreous of some animals at the terminal euthanasia. Serum anti-AAV antibodies developed in most vector-injected animals. No animals developed antibodies to hCNGB3. Biodistribution studies demonstrated high levels of vector DNA in vector-injected eyes but little or no vector DNA in non-ocular tissue. Conclusions: Subretinal injection of rAAV2tYF-PR1.7-hCNGB3 in CNGB3-deficient mice was associated with no clinically important toxicology findings, rescue of cone-mediated ERG responses in vector-treated eyes, and vector DNA detection limited primarily to vector-injected eyes. These results support the use of rAAV2tYF-PR1.7-...

<p>This study presents new high-resolution reconstructions of sea surface temperatures (SSTs) obtained from alkenones off the coast of North West Africa between 19 °N and xx 27°N latitude. Sediment grain-size distributions were also generated to provide new information on the Moroccan and Mauritanian upwelling zone over the Industrial Era. Our data shows that over the past two centuries, SSTs gradually increased in the southernmost cores, while in the northernmost sites they show cooling. Changes in sea level pressure and temperature gradients between land and sea would have caused major changes in atmospheric circulation by disrupting and intensifying the system of North-East winds (Trade winds) and southwest Monsoon winds. With global warming, increase in the monsoon might be expected, causing the weakening easterly winds favorable to the formation of upwellings. Enhanced stratification of the water column would prevent upwelling to develop accounting for surface water warming with consequences on the ecosystems and fisheries.</p>