Communal reconciliation : corporate responsibility and opposition to systemic sin

Recent events have given rise to considerations of systemic sin and how the church should respond to it. This article looks at passages in the Hebrew Bible which demonstrate the communal character of sin and atonement. God holds the whole nation responsible despite righteous individuals, often for the sins of individuals. Paul develops this relation between individuals and groups in his ecclesiology. I argue from this development that responsibility for sins, individual or systemic, is placed on the whole community. Thus, there is for the church a corporate responsibility for reconciliation, demanding group agency in rectifying systemic sins like racism.Publisher PDFPeer reviewe

AAV-Mediated Cone Rescue in a Naturally Occurring Mouse Model of CNGA3-Achromatopsia

Achromatopsia is a rare autosomal recessive disorder which shows color blindness, severely impaired visual acuity, and extreme sensitivity to bright light. Mutations in the alpha subunits of the cone cyclic nucleotide-gated channels (CNGA3) are responsible for about 1/4 of achromatopsia in the U.S. and Europe. Here, we test whether gene replacement therapy using an AAV5 vector could restore cone-mediated function and arrest cone degeneration in the cpfl5 mouse, a naturally occurring mouse model of achromatopsia with a CNGA3 mutation. We show that gene therapy leads to significant rescue of cone-mediated ERGs, normal visual acuities and contrast sensitivities. Normal expression and outer segment localization of both M- and S-opsins were maintained in treated retinas. The therapeutic effect of treatment lasted for at least 5 months post-injection. This study is the first demonstration of substantial, relatively long-term restoration of cone-mediated light responsiveness and visual behavior in a naturally occurring mouse model of CNGA3 achromatopsia. The results provide the foundation for development of an AAV5-based gene therapy trial for human CNGA3 achromatopsia

The interaction of alpha-conotoxins PnIA and MII with alpha3beta2 neuronal nicotinic acetylcholine receptors

alpha3beta2 neuronal nicotinic receptors are at least 1000-fold more sensitive to blockade by alpha-conotoxin-PnIA than are alpha2beta2 receptors. A series of chimeric subunits, formed from portions of alpha2 and alpha3, were coexpressed with beta2 in Xenopus oocytes and tested for toxin sensitivity. Determinants of toxin sensitivity were widely distributed in the extracellular domain of alpha3. Analysis of mutant receptors allowed identification of three determinants of alpha-conotoxin-PnIA sensitivity: proline 182, isoleucine 188 and glutamine 198. A homology model of the alpha3beta2 receptor extracellular domain was then generated and each residue was shown to be located on the C-loop of the alpha3 subunit, with isoleucine 188 nearest the acetylcholine-binding pocket.alpha-Conotoxin-MII was examined to find residues on the toxin that are important for conferring specificity for alpha3beta2 receptors. Each of the twelve non-cysteine residues from MII were mutated to alanine and tested for their ability to block alpha3beta2 receptors. Dose inhibition data for each mutant was acquired and IC50s were determined. Circular dichroism and protein modeling were used to confirm the structural integrity of the mutant toxins.Three residues were identified as major determinants of MII potency. Replacement of N5, P6, or H12 with alanine resulted in \u3e2700-fold, 700-fold and ∼2700-fold losses in potency, respectively. The side chains of these residues are exposed on the surface of the toxin, suggesting that they could interact with the alpha3beta2 receptor. A decrease in pH improved MII potency, while an increase in pH decreased MII potency, suggesting that in the active form of MII, H12 is charged.Finally, a computational docking approach was used to examine the interaction between alpha-conotoxin-MII and alpha3beta2. Docking simulations place the MII toxin in the large cavity located below the C loop of the alpha3 subunit. A series of point mutations on the alpha3 and beta2 subunits were tested to confirm docking results. When aspartate 199 on the alpha3 subunit was mutated to an alanine, a tenfold loss in toxin sensitivity was observed. Aspartate 199 is the closest negatively charged residue on the receptor to the major determinant of alpha3beta2 selectivity on the toxin, the positively charged histidine 12

<i>Communio Dei</i> : particularity in the universal humanity of Jesus Christ

This thesis explores the role of particularity, especially racial and gendered particularity, in human nature through an exploration of Christological anthropology. If all humanity is revealed and redeemed in Christ’s particular humanity, what does it mean that Christ became human in particular ways, such as his maleness and Palestinian-Jewishness? Specifically, what does Christ’s assumption of a particular humanity mean for our own particularity as human beings made in his Image. Many feminist Christologies argue that this makes Christ unqualified to save women, while theologies of race often emphasize the solidarity of Christ with black and brown bodies. Particularity appears to play a significant role in our being human, but it also appears to make salvific union with Christ impossible for some. Instead, this thesis argues that human nature ought to be conceived of in onto-relational terms, so that human beings are constituted by their relations to other persons within the created order. Human nature is not defined by a set of properties held in common by all, but by a shared telos for communion with God, fellow-humanity, and the created order. In such a communion, called the communio Dei, human persons share second-personally that which is particular to themselves with others in a human reflection of divine perichoresis. Human nature is thus created to be an essentially diverse community united not by a common set of features or faculties, but by a shared telos to be a community comprised of every tribe, tongue, and nation united in worship of YHWH. Christ embodies this in how he transforms the relationship between particularities, such as race and gender, so that alienated peoples may have loving, self-giving communion with one another in the Spirit-wrought community, the body of Christ

Partial rescue of retinal function in chronically hypoglycemic mice

Purpose. Mice rendered hypoglycemic by a null mutation in the glucagon receptor gene Gcgr display late-onset retinal degeneration and loss of retinal sensitivity. Acute hyperglycemia induced by dextrose ingestion does not restore their retinal function, which is consistent with irreversible loss of vision. The goal of this study was to establish whether long-term administration of high dietary glucose rescues retinal function and circuit connectivity in aged Gcgr−/− mice. Methods. Gcgr−/− mice were administered a carbohydrate-rich diet starting at 12 months of age. After 1 month of treatment, retinal function and structure were evaluated using electroretinographic (ERG) recordings and immunohistochemistry. Results. Treatment with a carbohydrate-rich diet raised blood glucose levels and improved retinal function in Gcgr−/− mice. Blood glucose increased from moderate hypoglycemia to euglycemic levels, whereas ERG b-wave sensitivity improved approximately 10-fold. Because the b-wave reflects the electrical activity of second-order cells, we examined for changes in rod-to-bipolar cell synapses. Gcgr−/− retinas have 20% fewer synaptic pairings than Gcgr+/− retinas. Remarkably, most of the lost synapses were located farthest from the bipolar cell body, near the distal boundary of the outer plexiform layer (OPL), suggesting that apical synapses are most vulnerable to chronic hypoglycemia. Although treatment with the carbohydrate-rich diet restored retinal function, it did not restore these synaptic contacts. Conclusions. Prolonged exposure to diet-induced euglycemia improves retinal function but does not reestablish synaptic contacts lost by chronic hypoglycemia. These results suggest that retinal neurons have a homeostatic mechanism that integrates energetic status over prolonged periods of time and allows them to recover functionality despite synaptic loss.Supported by National Institutes of Health Grants EY00067 and F32NRSAEY017246, Spanish Ministry of Science and Innovation Grants BFU2009-07793/BFI and RETICS RD07/0062/0012, an unrestricted grant from Research to Prevent Blindness, Fight for Sight, and the Lions of Central New York

Identification of residues that confer alpha-conotoxin-PnIA sensitivity on the alpha 3 subunit of neuronal nicotinic acetylcholine receptors

Neuronal nicotinic receptors composed of the alpha3 and beta2 subunits are at least 1000-fold more sensitive to blockade by alpha-conotoxin-PnIA than are alpha2beta2 receptors. A series of chimeric subunits, formed from portions of alpha2 and alpha3, were coexpressed with beta2 in Xenopus oocytes and tested for toxin sensitivity. We found determinants of toxin sensitivity to be widely distributed in the extracellular domain of alpha3. Analysis of receptors formed by a series of mutant alpha3 subunits, in which residues that differ between alpha3 and alpha2 were changed from what occurs in alpha3 to what occurs in alpha2, allowed identification of three determinants of alpha-conotoxin-PnIA sensitivity: proline 182, isoleucine 188, and glutamine 198. Comparison with determinants of alpha-conotoxin-MII and kappa-bungarotoxin sensitivity on the alpha3 subunit revealed overlapping, but distinct, arrays of determinants for each of these three toxins. When tested against an EC50 concentration of acetylcholine, the IC50 for alpha-conotoxin-PnIA blockade was 25 +/- 4 nM for alpha3beta2, 84 +/- 7 nM for alpha3P182Tbeta2, 700 +/- 92 nM for alpha3I188Kbeta2, and 870 +/- 61 nM for alpha3Q198Pbeta2. To examine the location of these residues within the receptor structure, we generated a homology model of the alpha3beta2 receptor extracellular domain using the structure of the acetylcholine binding protein as a template. All three residues are located on the C-loop of the alpha3 subunit, with isoleucine 188 nearest the acetylcholine-binding pocket

Determinants of potency on alpha-conotoxin MII, a peptide antagonist of neuronal nicotinic receptors

Alpha-conotoxin MII, a peptide toxin isolated from Conus magus, antagonizes a subset of neuronal nicotinic receptors. Rat alpha3beta2 receptors, expressed in Xenopus oocytes, are blocked with an IC(50) of 3.7 +/- 0.3 nM. To identify structural features that determine toxin potency, a series of alanine-substituted toxins were synthesized and tested for the ability to block the function of alpha3beta2 receptors. Circular dichroism and protein modeling were used to assess the structural integrity of the mutant toxins. Three residues were identified as major determinants of toxin potency. Replacement of asparagine 5, proline 6, or histidine 12 with alanine resulted in >2700-fold, 700-fold, and approximately 2700-fold losses in toxin potency, respectively. A decrease in pH improved toxin potency, while an increase in pH eliminated toxin blockade, suggesting that, in the active form of the toxin, histidine 12 is charged. The imidazole ring of histidine 12 protrudes from one side, while asparagine 5 and proline 6 are located at the opposite end of the toxin structure. The side chains of these three residues are exposed on the surface of the toxin, suggesting that they directly interact with the alpha3beta2 receptor