Mutations Involving RBP4 and SOX3 Underlie Two Novel Forms of Congenital Eye Malformations.

The spectrum of congenital eye malformations including microphthalmia (small eyes), anophthalmia (absent eyes) and coloboma (ventral eye defects), or MAC, causes blindness in approximately 1 in 10,000 children. We have discovered novel RBP4 coding and SOX3 regulatory mutations in patients with MAC disease. RBP4 encodes plasma retinol binding protein, a lipocalin that transports vitamin A, an essential nutrient for eye development, in the bloodstream. We show RBP4 missense mutations p.A73T and p.A75T alter the ligand-binding pocket, causing autosomal dominant MAC with reduced penetrance and a maternal parent-of-origin effect. Both mutant alleles encode dominant-negative RBPs that bind poorly to vitamin A but strongly to the STRA6 receptor on recipient cell membranes. Consequently, a vitamin A “bottleneck” is created at the maternal-fetal interface, which is likely to reduce vitamin A delivery to the fetus, particularly when the mutation is inherited from the mother. This is the first report of such a defective interfering allele for a blood cargo protein in human disease. In a separate case, we describe a novel SOX3 regulatory mutation in a 46,XX child with bilateral anophthalmia and SRY-negative female-to-male sex reversal. In this patient, a paternal de novo 9q21 Xq27 insertional translocation has juxtaposed TRPM3 exons 1 and 2 downstream from SOX3, at the midpoint of a 180-bp pallindrome. This implicates a dominant, gain-of-function mechanism whereby ectopic SOX3 transcription disrupts early eye and gonadal development. Transgenic mouse models test this hypothesis and reveal sensitivity of the developing eye to alterations in SoxB1 (Sox2) spatiotemporal activity. This thesis highlights genetic and environmental factors that influence eye development, and it has broad implications for other congenital disorders.PHDHuman GeneticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/107085/1/chouster_1.pd

Decreases in Antimicrobial Use Associated With Multihospital Implementation of Electronic Antimicrobial Stewardship Tools.

BackgroundAntimicrobial stewards may benefit from comparative data to inform interventions that promote optimal inpatient antimicrobial use.MethodsAntimicrobial stewards from 8 geographically dispersed Veterans Affairs (VA) inpatient facilities participated in the development of antimicrobial use visualization tools that allowed for comparison to facilities of similar complexity. The visualization tools consisted of an interactive web-based antimicrobial dashboard and, later, a standardized antimicrobial usage report updated at user-selected intervals. Stewards participated in monthly learning collaboratives. The percent change in average monthly antimicrobial use (all antimicrobial agents, anti-methicillin-resistant Staphylococcus aureus [anti-MRSA] agents, and antipseudomonal agents) was analyzed using a pre-post (January 2014-January 2016 vs July 2016-January 2018) design with segmented regression and external comparison with uninvolved control facilities (n = 118).ResultsIntervention sites demonstrated a 2.1% decrease (95% confidence interval [CI], -5.7% to 1.6%) in total antimicrobial use pre-post intervention vs a 2.5% increase (95% CI, 0.8% to 4.1%) in nonintervention sites (absolute difference, 4.6%; P = .025). Anti-MRSA antimicrobial use decreased 11.3% (95% CI, -16.0% to -6.3%) at intervention sites vs a 6.6% decrease (95% CI, -9.1% to -3.9%) at nonintervention sites (absolute difference, 4.7%; P = .092). Antipseudomonal antimicrobial use decreased 3.4% (95% CI, -8.2% to 1.7%) at intervention sites vs a 3.6% increase (95% CI, 0.8% to 6.5%) at nonintervention sites (absolute difference, 7.0%; P = .018).ConclusionsComparative data visualization tool use by stewards at 8 VA facilities was associated with significant reductions in overall antimicrobial and antipseudomonal use relative to uninvolved facilities

Rare Complications of Cervical Spine Surgery: Pseudomeningocoele.

STUDY DESIGN: This study was a retrospective, multicenter cohort study. OBJECTIVES: Rare complications of cervical spine surgery are inherently difficult to investigate. Pseudomeningocoele (PMC), an abnormal collection of cerebrospinal fluid that communicates with the subarachnoid space, is one such complication. In order to evaluate and better understand the incidence, presentation, treatment, and outcome of PMC following cervical spine surgery, we conducted a multicenter study to pool our collective experience. METHODS: This study was a retrospective, multicenter cohort study of patients who underwent cervical spine surgery at any level(s) from C2 to C7, inclusive; were over 18 years of age; and experienced a postoperative PMC. RESULTS: Thirteen patients (0.08%) developed a postoperative PMC, 6 (46.2%) of whom were female. They had an average age of 48.2 years and stayed in hospital a mean of 11.2 days. Three patients were current smokers, 3 previous smokers, 5 had never smoked, and 2 had unknown smoking status. The majority, 10 (76.9%), were associated with posterior surgery, whereas 3 (23.1%) occurred after an anterior procedure. Myelopathy was the most common indication for operations that were complicated by PMC (46%). Seven patients (53%) required a surgical procedure to address the PMC, whereas the remaining 6 were treated conservatively. All PMCs ultimately resolved or were successfully treated with no residual effects. CONCLUSIONS: PMC is a rare complication of cervical surgery with an incidence of less than 0.1%. They prolong hospital stay. PMCs occurred more frequently in association with posterior approaches. Approximately half of PMCs required surgery and all ultimately resolved without residual neurologic or other long-term effects

Two-dimensional optomechanical crystal resonator in gallium arsenide

In the field of quantum computation and communication there is a compelling need for quantum-coherent frequency conversion between microwave electronics and infra-red optics. A promising platform for this is an optomechanical crystal resonator that uses simultaneous photonic and phononic crystals to create a co-localized cavity coupling an electromagnetic mode to an acoustic mode, which then via electromechanical interactions can undergo direct transduction to electronics. The majority of work in this area has been on one-dimensional nanobeam resonators which provide strong optomechanical couplings but, due to their geometry, suffer from an inability to dissipate heat produced by the laser pumping required for operation. Recently, a quasi-two-dimensional optomechanical crystal cavity was developed in silicon exhibiting similarly strong coupling with better thermalization, but at a mechanical frequency above optimal qubit operating frequencies. Here we adapt this design to gallium arsenide, a natural thin-film single-crystal piezoelectric that can incorporate electromechanical interactions, obtaining a mechanical resonant mode at f_m ~ 4.5 GHz ideal for superconducting qubits, and demonstrating optomechanical coupling g_om/(2pi) ~ 650 kHz

Penultimate predecessors of the 2004 Indian Ocean tsunami in Aceh, Sumatra: stratigraphic, archeological, and historical evidence

We present stratigraphic, archeological and historical evidence for two closely timed predecessors of the giant 2004 tsunami on the northern coast of Aceh, northern Sumatra. This is the first direct evidence that a tsunami played a role in a fifteenth century cultural hiatus along the northern Sumatran portion of the maritime silk route. One seacliff exposure on the eastern side of the Lambaro headlands reveals two beds of tsunamigenic coral rubble within a small alluvial fan. Radiocarbon and Uranium-Thorium disequilibrium dates indicate emplacement of the coral rubble after 1344 ± 3 C.E. Another seacliff exposure, on the western side of the peninsula, contains evidence of nearly continuous settlement from ~1240 C.E. to soon after 1366 ± 3 C.E., terminated by tsunami destruction. At both sites, the tsunamis are likely coincident with sudden uplift of coral reefs above the Sunda megathrust 1394 ± 2 C.E., evidence for which has been published previously. The tsunami (or tsunami pair) appears to have destroyed a vibrant port community and led to the temporary recentering of marine trade dominance to more protected locations farther east. The reestablishment of vibrant communities along the devastated coast by about 1500 CE set the stage for the 2004 disaster

Exploring Halo Substructure with Giant Stars: The Velocity Dispersion Profiles of the Ursa Minor and Draco Dwarf Spheroidals At Large Angular Separations

We analyze velocity dispersion profiles for the Draco and Ursa Minor (UMi) dwarf spheroidal (dSph) galaxies based on published and new Keck HIRES spectra for stars in the outer UMi field. Washington+DDO51 filter photometric catalogs provide additional leverage on membership of individual stars, and beyond 0.5 King limiting radii (R_lim) identify bona fide dSph members up to 4.5 times more efficiently than simple color-magnitude diagram selections. Previously reported ``cold populations'' R_lim are not obvious in the data and appear only with particular binning; more or less constant and platykurtic dispersion profiles are characteristic of these dSphs to large radii. We report discovery of UMi stars to at least 2.7 R_lim (i.e.,210 arcmin or 4 kpc). Even with conservative assumptions, a UMi mass of M > 4.9 x 10^8 M_(sun) is required to bind these stars, implying an unlikely global mass-to-light ratio of M/L > 900 (M/L)_(sun). We conclude that we have found stars tidally stripped from UMi.Comment: 9 pages, 4 figures. Published in the Astrophysical Journal Letter

“Zipped Synthesis” by Cross-Metathesis Provides a Cystathionine β‑Synthase Inhibitor that Attenuates Cellular H\u3csub\u3e2\u3c/sub\u3eS Levels and Reduces Neuronal Infarction in a Rat Ischemic Stroke Model

The gaseous neuromodulator H2S is associated with neuronal cell death pursuant to cerebral ischemia. As cystathionine β-synthase (CBS) is the primary mediator of H2S biogenesis in the brain, it has emerged as a potential target for the treatment of stroke. Herein, a “zipped” approach by alkene cross-metathesis into CBS inhibitor candidate synthesis is demonstrated. The inhibitors are modeled after the pseudo-C2-symmetric CBS product (L,L)-cystathionine. The “zipped” concept means only half of the inhibitor needs be constructed; the two halves are then fused by olefin cross-metathesis. Inhibitor design is also mechanism-based, exploiting the favorable kinetics associated with hydrazine-imine interchange as opposed to the usual imine−imine interchange. It is demonstrated that the most potent “zipped” inhibitor 6S reduces H2S production in SHSY5Y cells overexpressing CBS, thereby reducing cell death. Most importantly, CBS inhibitor 6S dramatically reduces infarct volume (1 h post-stroke treatment; ∼70% reduction) in a rat transient middle cerebral artery occlusion model for ischemia. Supplementary information (112 pp.) is attached (below)

“Zipped Synthesis” by Cross-Metathesis Provides a Cystathionine β‑Synthase Inhibitor that Attenuates Cellular H\u3csub\u3e2\u3c/sub\u3eS Levels and Reduces Neuronal Infarction in a Rat Ischemic Stroke Model

The gaseous neuromodulator H2S is associated with neuronal cell death pursuant to cerebral ischemia. As cystathionine β-synthase (CBS) is the primary mediator of H2S biogenesis in the brain, it has emerged as a potential target for the treatment of stroke. Herein, a “zipped” approach by alkene cross-metathesis into CBS inhibitor candidate synthesis is demonstrated. The inhibitors are modeled after the pseudo-C2-symmetric CBS product (L,L)-cystathionine. The “zipped” concept means only half of the inhibitor needs be constructed; the two halves are then fused by olefin cross-metathesis. Inhibitor design is also mechanism-based, exploiting the favorable kinetics associated with hydrazine-imine interchange as opposed to the usual imine−imine interchange. It is demonstrated that the most potent “zipped” inhibitor 6S reduces H2S production in SHSY5Y cells overexpressing CBS, thereby reducing cell death. Most importantly, CBS inhibitor 6S dramatically reduces infarct volume (1 h post-stroke treatment; ∼70% reduction) in a rat transient middle cerebral artery occlusion model for ischemia. Supplementary information (112 pp.) is attached (below)