Magma genesis in the northern Lau Basin, S.W. Pacific

The northern Lau Basin contains the northeastern-most part of the Tonga arc-basin system. Volcanic rocks associated with the recent-arc have been sampled from Tafahi and Niuatoputapu, and young basalts «1.5Ma) have been dredged from Northern Lau Spreading Centre (NLSC), the northeastern limb of the King's Triple Junction. The 1982 'Kallisto' cruise dredged two ophiolite sections, one containing boninitic, and the other tholeiitic, lavas, from the inner wall of the northern Tonga trench. The magma genesis of these lava suites is related to the structural and geochemical controls imposed during the tectonic evolution of the region. The geochemical controls result from processes related to the mantle dynamics in the northern Lau Basin, and to along-trench variations and the degree of influence of the subduction component. The lavas associated with the Central Lau Spreading Centre are derived from the Lau Basin mantle reservoir, which has Indian MORB mantle (!MM) isotopic characteristics. This reservoir has been present under the region since early-arc magmatism, as indicated by the trace elements and !MM isotopic signatures of the tholeiitic lavas from the eastern ophiolite section, and Eocene lavas from 'Eua. A reservoir with the geochemical characteristics of residual Samoan plume mantle underlies the northern Lau Basin. This mantle has been influxing through the rip in the Pacific plate, at the northern termination of the Tonga trench, since the Lau Basin began to open « 6Ma), as a result of processes relating to subduction roll-back. The north Tongan boninites, the lavas from Tafahi and Niuatoputapu have residual plume mantle sources. However, prior to the opening of the Lau Basin, the proto-Tonga trench formed a barrier to this influx, and therefore, the influence of the plume cannot be detected in lavas associated with the early-arc, such as the tholeiites from one of the ophiolite sections and the Eocene lavas from 'Bua. The variations in the trace element and Pb isotopic compositions of the lavas from the Northern Lau Spreading Centre indicate that mixing has occurred between Lau Basin and residual plume mantle end-members in the central northern Lau Basin. The residual plume mantle sources of the north Tongan boninites and the lavas from Tafahi, Niuatoputapu and the Tofua arc have been enriched by a subduction component, the characteristics of which are enrichment in Lll..E, Ph ± LREE. In the south, the subduction component is made up of fluids derived from subducted Pacific altered oceanic crust and pelagic sediments. However, in the north, it is comprised predominantly of fluids derived from Pacific volcanogenic sediments, with a contribution from altered oceanic crust and possibly subducted plume crust

Identification of Genetic Variation and Haplotype Structure of the Canine \u3cem\u3eABCA4\u3c/em\u3e Gene for Retinal Disease Association Studies

Over 200 mutations in the retina specific member of the ATP-binding cassette transporter superfamily (ABCA4) have been associated with a diverse group of human retinal diseases. The disease mechanisms, and genotype–phenotype associations, nonetheless, remain elusive in many cases. As orthologous genes are commonly mutated in canine models of human blinding disorders, canine ABCA4 appears to be an ideal candidate gene to identify and study sequence changes in dogs affected by various forms of inherited retinal degeneration. However, the size of the gene and lack of haplotype assignment significantly limit targeted association and/or linkage approaches. This study assessed the naturally observed sequence diversity of ABCA4 in the dog, identifying 80% of novel variations. While none of the observed polymorphisms have been associated with blinding disorders to date, breed and potentially disease specific haplotypes have been identified. Moreover, a tag SNP map of 17 (15) markers has been established that accurately predicts common ABCA4 haplotypes (frequency \u3e 5%) explaining \u3e85% (\u3e80%) of the observed genetic diversity and will considerably advance future studies. Our sequence analysis of the complete canine ABCA4 coding region will clearly provide a baseline and tools for future association studies and comparative genomics to further delineate the role of ABCA4 in canine blinding disorders

Bestrophin Gene Mutations Cause Canine Multifocal Retinopathy: A Novel Animal Model for Best Disease

PURPOSE. Canine multifocal retinopathy (cmr) is an autosomal recessive disorder of multiple dog breeds. The disease shares a number of clinical and pathologic similarities with Best macular dystrophy (BMD), and cmr is proposed as a new large animal model for Best disease. METHODS. cmr was characterized by ophthalmoscopy and histopathology and compared with BMD-affected patients. BEST1 (alias VMD2), the bestrophin gene causally associated with BMD, was evaluated in the dog. Canine ortholog cDNA sequence was cloned and verified using RPE/choroid 5′- and 3′-RACE. Expression of the canine gene transcripts and protein was analyzed by Northern and Western blotting and immunocytochemistry. All exons and the flanking splice junctions were screened by direct sequencing. RESULTS. The clinical phenotype and pathology of cmr closely resemble lesions of BMD. Canine VMD2 spans 13.7 kb of genomic DNA on CFA18 and shows a high level of conservation among eukaryotes. The transcript is predominantly expressed in RPE/choroid and encodes bestrophin, a 580-amino acid protein of 66 kDa. Immunocytochemistry of normal canine retina demonstrated specific localization of protein to the RPE basolateral plasma membranes. Two disease-specific sequence alterations were identified in the canine VMD2 gene: a C73T stop mutation in cmr1 and a G482A missense mutation in cmr2. CONCLUSIONS. The authors propose these two spontaneous mutations in the canine VMD2 gene, which cause cmr, as the first naturally occurring animal model of BMD. Further development of the cmr models will permit elucidation of the complex molecular mechanism of these retinopathies and the development of potential therapies

Identical Mutation in a Novel Retinal Gene Causes Progressive Rod-Cone Degeneration in Dogs and Retinitis Pigmentosa in Humans

Progressive rod–cone degeneration (prcd) is a late-onset, autosomal recessive photoreceptor degeneration of dogs and a homolog for some forms of human retinitis pigmentosa (RP). Previously, the disease-relevant interval was reduced to a 106-kb region on CFA9, and a common phenotype-specific haplotype was identified in all affected dogs from several different breeds and breed varieties. Screening of a canine retinal EST library identified partial cDNAs for novel candidate genes in the disease-relevant interval. The complete cDNA of one of these, PRCD, was cloned in dog, human, and mouse. The gene codes for a 54-amino-acid (aa) protein in dog and human and a 53-aa protein in the mouse; the first 24 aa, coded for by exon 1, are highly conserved in 14 vertebrate species. A homozygous mutation (TGC → TAC) in the second codon shows complete concordance with the disorder in 18 different dog breeds/breed varieties tested. The same homozygous mutation was identified in a human patient from Bangladesh with autosomal recessive RP. Expression studies support the predominant expression of this gene in the retina, with equal expression in the retinal pigment epithelium, photoreceptor, and ganglion cell layers. This study provides strong evidence that a mutation in the novel gene PRCD is the cause of autosomal recessive retinal degeneration in both dogs and humans

An Equity-focused Assessment of the City of Richmond’s RVAgreen 2050 Planning Process

Local climate action and sustainability initiatives are often critiqued for their inattention to issues of equity and justice. In response, an increasing number of cities are now attempting to respond to this critique by making equity a more explicit goal of their climate action plans: Richmond Virginia is among those cities. The City of Richmond\u27s Office of Sustainability committed to prioritizing equity in the RVAGreen 2050 plan by recognizing how Richmond’s history of racism and structural inequalities have exacerbated climate concerns for largely Black and Latinx communities and centering historically marginalized communities of color in the engagement process. Students in URSP 637 Sustainable Community Development were asked to provide an external evaluation of the RVAGreen 2050 planning process. This report summarizes the findings of this evaluation and highlights recommendations for how to improve equity-centered engagement processed moving forward

Poly(β-Amino Ester)-Nanoparticle Mediated Transfection of Retinal Pigment Epithelial Cells In Vitro and In Vivo

A variety of genetic diseases in the retina, including retinitis pigmentosa and leber congenital amaurosis, might be excellent targets for gene delivery as treatment. A major challenge in non-viral gene delivery remains finding a safe and effective delivery system. Poly(beta-amino ester)s (PBAEs) have shown great potential as gene delivery reagents because they are easily synthesized and they transfect a wide variety of cell types with high efficacy in vitro. We synthesized a combinatorial library of PBAEs and evaluated them for transfection efficacy and toxicity in retinal pigment epithelial (ARPE-19) cells to identify lead polymer structures and transfection formulations. Our optimal polymer (B5-S5-E7 at 60 w/w polymer∶DNA ratio) transfected ARPE-19 cells with 44±5% transfection efficacy, significantly higher than with optimized formulations of leading commercially available reagents Lipofectamine 2000 (26±7%) and X-tremeGENE HP DNA (22±6%); (p<0.001 for both). Ten formulations exceeded 30% transfection efficacy. This high non-viral efficacy was achieved with comparable cytotoxicity (23±6%) to controls; optimized formulations of Lipofectamine 2000 and X-tremeGENE HP DNA showed 15±3% and 32±9% toxicity respectively (p>0.05 for both). Our optimal polymer was also significantly better than a gold standard polymeric transfection reagent, branched 25 kDa polyethyleneimine (PEI), which achieved only 8±1% transfection efficacy with 25±6% cytotoxicity. Subretinal injections using lyophilized GFP-PBAE nanoparticles resulted in 1.1±1×103-fold and 1.5±0.7×103-fold increased GFP expression in the retinal pigment epithelium (RPE)/choroid and neural retina respectively, compared to injection of DNA alone (p = 0.003 for RPE/choroid, p<0.001 for neural retina). The successful transfection of the RPE in vivo suggests that these nanoparticles could be used to study a number of genetic diseases in the laboratory with the potential to treat debilitating eye diseases

Monitoring the Systemic Human Memory B Cell Compartment of Melanoma Patients for Anti-Tumor IgG Antibodies

Melanoma, a potentially lethal skin cancer, is widely thought to be immunogenic in nature. While there has been much focus on T cell-mediated immune responses, limited knowledge exists on the role of mature B cells. We describe an approach, including a cell-based ELISA, to evaluate mature IgG antibody responses to melanoma from human peripheral blood B cells. We observed a significant increase in antibody responses from melanoma patients (n = 10) to primary and metastatic melanoma cells compared to healthy volunteers (n = 10) (P<0.0001). Interestingly, we detected a significant reduction in antibody responses to melanoma with advancing disease stage in our patient cohort (n = 21) (P<0.0001). Overall, 28% of melanoma patient-derived B cell cultures (n = 1,800) compared to 2% of cultures from healthy controls (n = 600) produced antibodies that recognized melanoma cells. Lastly, a patient-derived melanoma-specific monoclonal antibody was selected for further study. This antibody effectively killed melanoma cells in vitro via antibody-mediated cellular cytotoxicity. These data demonstrate the presence of a mature systemic B cell response in melanoma patients, which is reduced with disease progression, adding to previous reports of tumor-reactive antibodies in patient sera, and suggesting the merit of future work to elucidate the clinical relevance of activating humoral immune responses to cancer