PMP22 exon 4 deletion causes ER retention of PMP22 and a gain-of-function allele in CMT1E

OBJECTIVE: To determine whether predicted fork stalling and template switching (FoSTeS) during mitosis deletes exon 4 in peripheral myelin protein 22 KD (PMP22) and causes gain‐of‐function mutation associated with peripheral neuropathy in a family with Charcot–Marie–Tooth disease type 1E. METHODS: Two siblings previously reported to have genomic rearrangements predicted to involve exon 4 of PMP22 were evaluated clinically and by electrophysiology. Skin biopsies from the proband were studied by RT‐PCR to determine the effects of the exon 4 rearrangements on exon 4 mRNA expression in myelinating Schwann cells. Transient transfection studies with wild‐type and mutant PMP22 were performed in Cos7 and RT4 cells to determine the fate of the resultant mutant protein. RESULTS: Both affected siblings had a sensorimotor dysmyelinating neuropathy with severely slow nerve conduction velocities (<10 m/sec). RT‐PCR studies of Schwann cell RNA from one of the siblings demonstrated a complete in‐frame deletion of PMP22 exon 4 (PMP22Δ4). Transfection studies demonstrated that PMP22Δ4 protein is retained within the endoplasmic reticulum and not transported to the plasma membrane. CONCLUSIONS: Our results confirm that that FoSTeS‐mediated genomic rearrangement produced a deletion of exon 4 of PMP22, resulting in expression of both PMP22 mRNA and protein lacking this sequence. In addition, we provide experimental evidence for endoplasmic reticulum retention of the mutant protein suggesting a gain‐of‐function mutational mechanism consistent with the observed CMT1E in this family. PMP22Δ4 is another example of a mutated myelin protein that is misfolded and contributes to the pathogenesis of the neuropathy

Hot Gaseous Coronae around Spiral Galaxies: Probing the Illustris Simulation

The presence of hot gaseous coronae around present-day massive spiral galaxies is a fundamental prediction of galaxy formation models. However, our observational knowledge remains scarce, since to date only four gaseous coronae were detected around spirals with massive stellar bodies ($\gtrsim2\times10^{11} \ \rm{M_{\odot}}$). To explore the hot coronae around lower mass spiral galaxies, we utilized Chandra X-ray observations of a sample of eight normal spiral galaxies with stellar masses of $(0.7-2.0)\times10^{11} \ \rm{M_{\odot}}$. Although statistically significant diffuse X-ray emission is not detected beyond the optical radii ($\sim20$ kpc) of the galaxies, we derive $3\sigma$ limits on the characteristics of the coronae. These limits, complemented with previous detections of NGC 1961 and NGC 6753, are used to probe the Illustris Simulation. The observed $3\sigma$ upper limits on the X-ray luminosities and gas masses exceed or are at the upper end of the model predictions. For NGC 1961 and NGC 6753 the observed gas temperatures, metal abundances, and electron density profiles broadly agree with those predicted by Illustris. These results hint that the physics modules of Illustris are broadly consistent with the observed properties of hot coronae around spiral galaxies. However, a shortcoming of Illustris is that massive black holes, mostly residing in giant ellipticals, give rise to powerful radio-mode AGN feedback, which results in under luminous coronae for ellipticals.Comment: 12 pages, 6 figures, accepted for publication in Ap

Can Deflagration-Detonation-Transitions occur in Type Ia Supernovae?

The mechanism for deflagration-detonation-transition (DDT) by turbulent preconditioning, suggested to explain the possible occurrence of delayed detonations in Type Ia supernova explosions, is argued to be conceptually inconsistent. It relies crucially on diffusive heat losses of the burned material on macroscopic scales. Regardless of the amplitude of turbulent velocity fluctuations, the typical gradient scale for temperature fluctuations is shown to be the laminar flame width or smaller, rather than the factor of thousand more required for a DDT. Furthermore, thermonuclear flames cannot be fully quenched in regions much larger than the laminar flame width as a consequence of their simple ``chemistry''. Possible alternative explosion scenarios are briefly discussed.Comment: 8 pages, uses aastex; added references. Accepted by ApJ Letter

Active Response Gravity Offload and Method

A variable gravity field simulator can be utilized to provide three dimensional simulations for simulated gravity fields selectively ranging from Moon, Mars, and micro-gravity environments and/or other selectable gravity fields. The gravity field simulator utilizes a horizontally moveable carriage with a cable extending from a hoist. The cable can be attached to a load which experiences the effects of the simulated gravity environment. The load can be a human being or robot that makes movements that induce swinging of the cable whereby a horizontal control system reduces swinging energy. A vertical control system uses a non-linear feedback filter to remove noise from a load sensor that is in the same frequency range as signals from the load sensor

Mergers and Mass Accretion Rates in Galaxy Assembly: The Millennium Simulation Compared to Observations of z~2 Galaxies

Recent observations of UV-/optically selected, massive star forming galaxies at z~2 indicate that the baryonic mass assembly and star formation history is dominated by continuous rapid accretion of gas and internal secular evolution, rather than by major mergers. We use the Millennium Simulation to build new halo merger trees, and extract halo merger fractions and mass accretion rates. We find that even for halos not undergoing major mergers the mass accretion rates are plausibly sufficient to account for the high star formation rates observed in z~2 disks. On the other hand, the fraction of major mergers in the Millennium Simulation is sufficient to account for the number counts of submillimeter galaxies (SMGs), in support of observational evidence that these are major mergers. When following the fate of these two populations in the Millennium Simulation to z=0, we find that subsequent mergers are not frequent enough to convert all z~2 turbulent disks into elliptical galaxies at z=0. Similarly, mergers cannot transform the compact SMGs/red sequence galaxies at z~2 into observed massive cluster ellipticals at z=0. We argue therefore, that secular and internal evolution must play an important role in the evolution of a significant fraction of z~2 UV-/optically and submillimeter selected galaxy populations.Comment: 5 pages, 4 figures, Accepted for publication in Ap

Reversal of compromised bonding in bleached enamel

Oxygen inhibits polymerization of resin-based materials. We hypothesized that compromised bonding to bleached enamel can be reversed with sodium ascorbate, an anti-oxidant. Sandblasted human enamel specimens were treated with distilled water (control) and 10% carbamide peroxide gel with or without further treatment with 10% sodium ascorbate. They were bonded with Single Bond (3M-ESPE) or Prime&Bond NT (Dentsply DeTrey) and restored with a composite. Specimens were prepared for microtensile bond testing and transmission electron microscopy after immersion in ammoniacal silver nitrate for nanoleakage evaluation. Bond strengths of both adhesives were reduced after bleaching but were reversed following sodium ascorbate treatment (P < 0.001). Resin-enamel interfaces in bleached enamel exhibited more extensive nanoleakage in the form of isolated silver grains and bubble-like silver deposits. Reduction of resin-enamel bond strength in bleached etched enamel is likely to be caused by a delayed release of oxygen that affects the polymerization of resin components.published_or_final_versio

Conventional spark versus nanosecond repetitively pulsed discharge for a turbulence facilitated ignition phenomenon

This work applies both conventional-single-spark-discharge (CSSD) at 500-µs pulse duration time and nanosecond-repetitively-pulsed-discharge (NRPD) at various pulsed-repetitive-frequency PRF = 5–70 kHz to explore a turbulence facilitated ignition (TFI) phenomenon using a pair of pin-to-pin electrodes at an inter-electrode gap of 0.8 mm in randomly-stirred lean n-butane/air mixture with Lewis number ≫ 1. For CSSD, measured laminar and turbulent minimum ignition energies (MIE$_{L}$ and MIE$_{T}$) at 50% ignitability show that MIE$_{L}$≈ 23 mJ > the smallest MIE$_{T}$≈ 19.7 mJ at u′ = 0.9 m/s (TFI) and then MIE$_{T}$≈ 28.6/30.8/36.8 mJ at u′ = 1.4/2.1/2.8 m/s (no TFI), where u′ is the r.m.s turbulent fluctuating velocity. For comparison, all NRPD experiments apply the same total ignition energy E$_{tot}$≈ 23 mJ via a fixed train of 11 pulses, each pulse with 2.2 mJ except for the first pulse with 1 mJ. NRPD results show a cumulatively synergistic effect depending on the coherence between PRF and an inward reactant flow recirculation frequency (f$_{RC}$) inside the torus-like kernel induced by the discharge that could enhance ignition. When PRF is approximately synchronizing with f$_{RC}$, the synergistic effect is most profound at PRF = 20-kHz/40-kHz with very high ignition probability P$_{ig}$ = 90%/85% > 50% in quiescence, whereas lower values of P$_{ig}$ = 42%/34% are found at PRF = 10-kHz/60-kHz. Further, P$_{ig}$ = 0 at PRF = 5-kHz even when 5000 pulses (E$_{tot}$≈ 10 J) are applied. We discover that P$_{ig}$ decreases significantly with increasing u′ for most PRFs (no TFI) except at higher PRF ≥ 60 kHz showing possible TFI. These results are attributed to the interactions between turbulent dissipation, differential diffusion, and synergistic influence, which are substantiated by Schlieren images of initial kernel development and the ignition time determined at one half of the flame critical radius that leads to a self-sustained spherical flame propagation