Talking Through My Heart

Photo of Jack Benny holding sheet music behind microphone; Pictures of various artistshttps://scholarsjunction.msstate.edu/cht-sheet-music/11522/thumbnail.jp

Closing the Gap: Mechanisms of Epithelial Fusion During Optic Fissure Closure

A key embryonic process that occurs early in ocular development is optic fissure closure (OFC). This fusion process closes the ventral optic fissure and completes the circumferential continuity of the 3-dimensional eye. It is defined by the coming together and fusion of opposing neuroepithelia along the entire proximal-distal axis of the ventral optic cup, involving future neural retina, retinal pigment epithelium (RPE), optic nerve, ciliary body, and iris. Once these have occurred, cells within the fused seam differentiate into components of the functioning visual system. Correct development and progression of OFC, and the continued integrity of the fused margin along this axis, are important for the overall structure of the eye. Failure of OFC results in ocular coloboma—a significant cause of childhood visual impairment that can be associated with several complex ocular phenotypes including microphthalmia and anterior segment dysgenesis. Despite a large number of genes identified, the exact pathways that definitively mediate fusion have not yet been found, reflecting both the biological complexity and genetic heterogeneity of the process. This review will highlight how recent developmental studies have become focused specifically on the epithelial fusion aspects of OFC, applying a range of model organisms (spanning fish, avian, and mammalian species) and utilizing emerging high-resolution live-imaging technologies, transgenic fluorescent models, and unbiased transcriptomic analyses of segmentally-dissected fissure tissue. Key aspects of the fusion process are discussed, including basement membrane dynamics, unique cell behaviors, and the identities and fates of the cells that mediate fusion. These will be set in the context of what is now known, and how these point the way to new avenues of research

Study of ophthalmo acromelic syndromes in human and mouse

The combination of severe ocular and distal limb malformations is rare. Ophthalmo-acromelic syndrome (OAS; MIM 206920) is characterised by anophthalmia with lower limb oligodactyly. To date <40 cases of this autosomal recessive disorder have been reported. Genome-wide analysis of ~10,000 SNPs typed on two apparently unrelated families - comprising a total of three affected individuals, four unaffected siblings and their consanguineous parents - identified a large region of overlapping autozygosity on chromosome 14q. Adding data from a third consanguineous family gave a combined LOD score of >5 with no evidence of locus heterogeneity. Collaborative data from a further 6 individuals refined the critical interval to a 3.4 Mb region on chromosome14:69,652,605-73,059,612 Mb. To sequence all 19 known protein-coding genes in the region, the 238 exons were ranked by evolutionary sequence conservation and divided equally between the Edinburgh and Nijmegen groups. Complete sequence coverage has been obtained for 61% of the “Edinburgh” exons but no potentially causative mutations have been identified. Further mutation analysis of the OAS locus is on-going. Mice homozygous for the X-ray induced Mp mutation were reportedly anophthalmic with hind limb oligodactyly and thus represented a potential model for human OAS. This line was rederived in Edinburgh and phenotypic analysis of Mp/Mp homozygotes showed runting, malformed pinnae with microphthalmia but not anophthalmia. The apparent hind-limb oligodactyly was due to osseous syndactyly. Mp heterozygotes had milder microphthalmia and pinnae deformities, but lacked the syndactyly. In both heterozygotes and homozygotes the eye malformations were fully penetrant, pan-ocular and characterised by failure of both the ciliary apparatus and vitreous body to form and abnormal retinal lamination. Genome-wide microsatellite marker analysis showed linkage of the Mp phenotype to chromosome 18. Fbn2 mapped within the linkage interval and was a good candidate for Mp based on the finding of hind limb osseous syndactyly in Fbn2-null mice. However, Fbn2-null mice have no eye phenotype. 3’-RACE identified that Mp was as a 660 kb inversion affecting the 3’-regions of Fbn2 and the adjacent gene Isoc1. This created two aberrant reciprocal fusion transcripts: Fbn2 exons 1-63 are fused to Isoc1 exon 5; and Isoc1 exons 1-4 are fused to Fbn2 exons 64-65. This predicts nonsense-mediated decay of the Isoc1 Mp transcript and production of a truncated Fbn2 Mp protein. Ocular development was analysed in homozygote and wild type embryos to define the basis of the “worse than null phenotype” seen in Mp mice. RNA in situ hybridisations (ISH) failed to detect expression of Isoc1 in the embryonic eye. In contrast, normal expression of Fbn2 in the ciliary body and retina was consistent with the Mp phenotype. A combination of EM and immunocytochemistry showed that truncated Fbn2 (Fbn2Mp) was retained within the ER. Fbn2Mp co-localised with markers of ER stress: Grp78 expression and UPR-specific Xbp1 splicing. Signalling by Wnt2b is thought to be critical for ciliary development and Lef1, a Wnt-responsive transcription factor, showed increased and ectopic ocular expression in the region affected by ER stress. Sox2 is a direct transcriptional target of Lef1 and we observed apparent ectopic expression of Sox2 in the ciliary body. Throughout the developing retina in mutant embryos we also observed individual cells that were ectopically expressing the transcription factor Chx10 and other cells expressing the apoptotic marker Activated- Caspase-3. The apoptotic marker did not specifically co-localise with Fbn2Mp. Taken together, these findings suggest that the ocular malformations in Mp are a direct result of the ER stress induced by Fbn2Mp in a specific group of cells in the early ciliary body. The ER stress presumably halts post-translational modification of a developmentally critical signaling molecule, possibly Wnt2b, which happens to be expressed in the same cells. We have termed the resulting pathological mechanism a synodiporic effect (synodiporia = the ones walking the street together or fellow travellers). Such effects may have significant implications for human genetic disease analysis, and may provide an explanation for other “worse than null” mutations

Why Dream

Photograph of Henry Wadsworth; Illustration of jazz ensemble with various objectshttps://scholarsjunction.msstate.edu/cht-sheet-music/6788/thumbnail.jp

Direct Digital Engagement of Patients and Democratizing Health Care

Direct Digital Engagement of Patients and Democratizing Health Car

Here\u27s Love in Your Eye

Photographs of the cast of The Big Broadcast of 1937 line the left and right edges of the page and a photograph of Jack Benny in front of a microphone is in the center.https://scholarsjunction.msstate.edu/cht-sheet-music/3018/thumbnail.jp

Studies of low-mass interacting binary stars

Spectroscopic and photometric observations of eight contact/near-contact binaries are presented and analysed. Spectroscopic observations were obtained at 4200 Å (radial velocity spectra) and 6563 Å (hydrogen-alpha line profiles). New photometric observations were obtained at visual and infrared wavelengths, and other previously published light curves are also re-analysed. Absolute dimensions have been obtained for five systems; TY Boo, VW Boo, BX And, SS Ari and AG Vir, and their evolutionary positions discussed. Four of the systems are found to be in marginal but poor thermal contact, exhibiting regions of apparent "excess luminosity" in their light curves. A qualitative analysis of these "hot spot" regions has been attempted for the first time using spot models now incorporated into a light curve synthesis programme. Substantial time for this project was awarded on telescopes funded by the United Kingdom Science and Engineering Research Council (SERC), comprising 14 nights at the Issac Newton Telescope (INT) on La Palma, and 4 nights at the United Kingdom Infrared Telescope (UKIRT) on Mauna Kea. Additional observations were made during an 8 night commissioning run on the Jacobus Kapteyn Telescope (JKT) on La Palma, and extensive observations were made with the Twin Photometric Telescope (TPT) at St Andrews University Observatory between 1985 and 1989. These resulted in over 100 spectra at 4200 Å and over 50 spectra at 6563 Å (INT and JKT observations), over 300 infrared photometric observations (UKIRT), and over 3500 visual photometric observations (TPT). Of the five systems analysed in detail in this work, TY Boo appears to be a normal shallow-contact W-type system. Both VW Boo and BX And exhibit regions of "excess luminosity" around the ingress and egress of secondary minimum which are well modelled by a warm spot on the cooler component sitting symmetrically around the neck joining the pair. Such a phenomenon may be expected to arise naturally in systems which have come into contact but are not yet/currently in thermal contact, exhibiting a temperature difference between the components. BXAnd like other B-type systems seems to be reaching this contact state for the first time, but the position of VW Boo is uncertain, and whilst evidence that it could be in the "broken contact" state predicted by the TRO Theory is far from conclusive, its lower orbital angular momentum clearly marks the system as worthy of further study. SS Ari and AG Vir exhibit light curves with unequal quadrature heights. Attempts to treat the higher quadrature as a region of "excess luminosity" due to an energy transfer "warm spot" does not however provide a good model of this phenomenon. Since invoking a dark starspot model also does not provide a good explanation for such systems, it may be that this form of light curve distortion is due to an entirely different form of distorting surface phenomenon. Like BX And, AG Vir appears to be just reaching contact for the first time, but like VW Boo, the slightly lower angular momentum of SS Ari warrants further study