Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies.

PURPOSE: To investigate the effect of PLXNA1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and to functionally characterize the zebrafish homologs plxna1a and plxna1b during development. METHODS: We assembled ten patients from seven families with biallelic or de novo PLXNA1 variants. We describe genotype-phenotype correlations, investigated the variants by structural modeling, and used Morpholino knockdown experiments in zebrafish to characterize the embryonic role of plxna1a and plxna1b. RESULTS: Shared phenotypic features among patients include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Notably, seizures were predominantly reported in patients with monoallelic variants. Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Our zebrafish studies enforce an embryonic role of plxna1a and plxna1b in the development of the central nervous system and the eye. CONCLUSION: We propose that different biallelic and monoallelic variants in PLXNA1 result in a novel neurodevelopmental syndrome mainly comprising developmental delay, brain, and eye anomalies. We hypothesize that biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect

Social Networks and Social Support: Implications for Natural Helper and Community Level Interventions

The convincing evidence of the relationship between social support, social networks, and health status has influenced the development of program strategies which are relevant to health education. This article focuses on the linkage between social support and social networks and health education programs which involve interventions at the network and community level. Two broad strategies are addressed: programs enhancing entire networks through natural helpers; and programs strengthening overlapping networks/communities through key opinion and infor mal leaders who are engaged in the process of community wide problem-solving. Following a brief overview of definitions, this article highlights several network characteristics which are often found to be related to physical and mental health status. Suggestions are made for how these network characteristics can be applied to the two program strategies. Principles of practice for the health educator, and some of the limitations of a social network approach are delineated. The article concludes with a recommendation for engaging in action research—a perspective highly consistent with both the strategies discussed and the concepts of social networks and social support. This approach not only recognizes, but also acts to strengthen indigenous skills and resources.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67587/2/10.1177_109019818501200106.pd

Equilibration of Tyrosyl Radicals (Y[• over 356], Y[• over 731], Y[• over 730]) in the Radical Propagation Pathway of the Escherichia coli Class Ia Ribonucleotide Reductase

Escherichia coli ribonucleotide reductase is an α2β2 complex that catalyzes the conversion of nucleotides to deoxynucleotides using a diferric tyrosyl radical (Y[• over 122]) cofactor in β2 to initiate catalysis in α2. Each turnover requires reversible long-range proton-coupled electron transfer (PCET) over 35 Å between the two subunits by a specific pathway (Y• over 122] [arrows facing left and right] [W[subscript 48]?] [arrows facing left and right] Y[subscript 356] within β to Y[subscript 731] [arrows facing left and right] Y[subscript 730] [arrows facing left and right] C[subscript 439] within α). Previously, we reported that a β2 mutant with 3-nitrotyrosyl radical (NO[subscript 2]Y[superscript •]; 1.2 radicals/β2) in place of Y[• over 122] in the presence of α2, CDP, and ATP catalyzes formation of 0.6 equiv of dCDP and accumulates 0.6 equiv of a new Y[superscript •] proposed to be located on Y[subscript 356] in β2. We now report three independent methods that establish that Y[subscript 356] is the predominant location (85–90%) of the radical, with the remaining 10–15% delocalized onto Y[subscript 731] and Y[subscript 730] in α2. Pulsed electron–electron double-resonance spectroscopy on samples prepared by rapid freeze quench (RFQ) methods identified three distances: 30 ± 0.4 Å (88% ± 3%) and 33 ± 0.4 and 38 ± 0.5 Å (12% ± 3%) indicative of NO[subscript 2]Y[• over 122]–Y[• over 356], NO[subscript 2]Y[• over 122]–NO[subscript 2]Y[• over 122], and NO[subscript 2]Y[• over 122–Y[• over 731(730)], respectively. Radical distribution in α2 was supported by RFQ electron paramagnetic resonance (EPR) studies using Y[subscript 731](3,5-F[subscript 2]Y) or Y[subscript 730](3,5-F[subscript 2]Y)-α2, which revealed F[subscript 2]Y[superscript •], studies using globally incorporated [β-[superscript 2]H[subscript 2]]Y-α2, and analysis using parameters obtained from 140 GHz EPR spectroscopy. The amount of Y[superscript •] delocalized in α2 from these two studies varied from 6% to 15%. The studies together give the first insight into the relative redox potentials of the three transient Y[superscript •] radicals in the PCET pathway and their conformations.National Institutes of Health (U.S.) (Grant GM29595)National Institutes of Health (U.S.) (Grant EB002804)National Institutes of Health (U.S.) (Grant EB002026