Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy

Acknowledgments Blood biochemistry analysis and serum analysis were performed by the Easter Bush Pathology Department, University of Edinburgh. Animal husbandry was performed by Centre for Integrative Physiology bio-research restructure technical staff, University of Edinburgh. Assistance with intravenous injections was provided by Ian Coldicott (University of Sheffield) and Hannah Shorrock (University of Edinburgh). Human blood cDNA was a gift to GH from Kathy Evans, University of Edinburgh. Imaging was performed at the IMPACT imaging facility, University of Edinburgh, with technical assistance from Anisha Kubasik-Thayil. The authors would also like to thank Lyndsay Murray for technical discussions relating to qRT-PCR analysis. This work was supported by funding from the SMA Trust and the Anatomical Society (via grants to THG); the Euan MacDonald Centre for Motor Neurone Disease Research (via grants to THG and SHP); the Wellcome Trust (via grants to EJNG and THG); Muscular Dystrophy UK (via grants to THG and CGB); a Elphinstone Scholarship from the University of Aberdeen (to SHP); and The French Muscular Dystrophy Association (via grants to CM and JC).Peer reviewedPublisher PD

Solid-state laser system for laser cooling of Sodium

We demonstrate a frequency-stabilized, all-solid laser source at 589 nm with up to 800 mW output power. The laser relies on sum-frequency generation from two laser sources at 1064 nm and 1319 nm through a PPKTP crystal in a doubly-resonant cavity. We obtain conversion efficiency as high as 2 W/W^2 after optimization of the cavity parameters. The output wavelength is tunable over 60 GHz, which is sufficient to lock on the Sodium D2 line. The robustness, beam quality, spectral narrowness and tunability of our source make it an alternative to dye lasers for atomic physics experiments with Sodium atoms

The linear ubiquitin chain assembly complex regulates TRAIL-induced gene activation and cell death.

The linear ubiquitin chain assembly complex (LUBAC) is the only known E3 ubiquitin ligase which catalyses the generation of linear ubiquitin linkages de novo LUBAC is a crucial component of various immune receptor signalling pathways. Here, we show that LUBAC forms part of the TRAIL-R-associated complex I as well as of the cytoplasmic TRAIL-induced complex II In both of these complexes, HOIP limits caspase-8 activity and, consequently, apoptosis whilst being itself cleaved in a caspase-8-dependent manner. Yet, by limiting the formation of a RIPK1/RIPK3/MLKL-containing complex, LUBAC also restricts TRAIL-induced necroptosis. We identify RIPK1 and caspase-8 as linearly ubiquitinated targets of LUBAC following TRAIL stimulation. Contrary to its role in preventing TRAIL-induced RIPK1-independent apoptosis, HOIP presence, but not its activity, is required for preventing necroptosis. By promoting recruitment of the IKK complex to complex I, LUBAC also promotes TRAIL-induced activation of NF-κB and, consequently, the production of cytokines, downstream of FADD, caspase-8 and cIAP1/2. Hence, LUBAC controls the TRAIL signalling outcome from complex I and II, two platforms which both trigger cell death and gene activation

An all-solid-state laser source at 671 nm for cold atom experiments with lithium

We present an all solid-state narrow line-width laser source emitting $670\,\mathrm{mW}$ output power at $671\,\mathrm{nm}$ delivered in a diffraction-limited beam. The \linebreak source is based on a fre-quency-doubled diode-end-linebreak pumped ring laser operating on the ${^4F}_{3/2} \rightarrow {^4I}_{13/2}$ transition in Nd:YVO$_4$. By using periodically-poled po-tassium titanyl phosphate (ppKTP) in an external build-up cavity, doubling efficiencies of up to 86% are obtained. Tunability of the source over $100\,\rm GHz$ is accomplished. We demonstrate the suitability of this robust frequency-stabilized light source for laser cooling of lithium atoms. Finally a simplified design based on intra-cavity doubling is described and first results are presented

High-power laser therapy improves healing of the equine suspensory branch in a standardized lesion model

High-power laser therapy is often used as a treatment for human sport injuries but controlled standardized studies on its efficacy are lacking. The technique has also been introduced in the equine field and recently promising results were reported in a retrospective study focusing on 150 sporthorses suffering from tendinopathy and desmopathy of the SDFT, DDFT, suspensory ligament, and suspensory branches. The goal of the present study was to evaluate the effect of high-power laser in a standardized lesion model in horses. Lesions were created in all lateral suspensory branches of 12 warmblood horses. In each horse, 2 of the 4 lesioned branches were treated daily with a multi-frequency high-power laser for 4 weeks. Color Doppler ultrasonography was performed during and after the treatment period. Six horses were euthanized 4 weeks post-surgery (short-term) and 6 were further rehabilitated until 6 months and then euthanized (long-term). High-field MRI evaluation was performed on all cadaver limbs. On ultrasound, transverse size of the lesion was significantly smaller after 2- and 3 months (p= 0.026 andp= 0.015) in the treated branches. The expected post-surgery enlargement of the lesion circumference and cross-sectional area (CSA) over time, was significantly lower in the short-term laser treated group (p= 0.016 andp= 0.010). Treated lesions showed a significantly increased Doppler signal during treatment (p< 0.001) compared with control. On MRI, in the short and long-term group, the CSA of the lesions was significantly smaller (p= 0.002), and the mean signal significantly lower in the treatment groups (p= 0.006). This standardized controlled study shows that multi-frequency high-power laser therapy significantly improves healing of a suspensory branch ligament lesion

Coordinatively Saturated Tris(oxazolinyl)borato Zinc Hydride-Catalyzed Cross Dehydrocoupling of Silanes and Alcohols

The four-coordinate zinc compound ToMZnH (1, ToM = tris(4,4-dimethyl-2-oxazolinyl)phenylborate) catalyzes selective alcoholysis of substituted hydrosilanes. The catalytic reaction of PhMeSiH2 and aliphatic alcohols favors the monodehydrocoupled product PhMeHSi–OR. With the aryl alcohol 3,5-C6H3Me2OH, the selectivity for mono(aryloxy)hydrosilane PhMeHSiOC6H3Me2 and bis(aryloxy)silane PhMeSi(OC6H3Me2)2 is controlled by relative reagent concentrations. Reactions of secondary organosilanes and diols provide cyclic bis(oxo)silacycloalkanes in high yield. The empirical rate law for the ToMZnH-catalyzed reaction of 3,5-dimethylphenol and PhMeSiH2 is −d[PhMeSiH2]/dt = k′obs[ToMZnH]1[3,5-C6H3Me2OH]0[PhMeSiH2]1 (determined at 96 °C) which indicates that Si–O bond formation is turnover-limiting in the presence of excess phenol

PTEN Depletion Decreases Disease Severity and Modestly Prolongs Survival in a Mouse Model of Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is the second most common genetic cause of death in childhood. However, no effective treatment is available to halt disease progression. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene. We previously reported that PTEN depletion leads to an increase in survival of SMN-deficient motor neurons. Here, we aimed to establish the impact of PTEN modulation in an SMA mouse model in vivo. Initial experiments using intramuscular delivery of adeno-associated vector serotype 6 (AAV6) expressing shRNA against PTEN in an established mouse model of severe SMA (SMNΔ7) demonstrated the ability to ameliorate the severity of neuromuscular junction pathology. Subsequently, we developed self-complementary AAV9 expressing siPTEN (scAAV9-siPTEN) to allow evaluation of the effect of systemic suppression of PTEN on the disease course of SMA in vivo. Treatment with a single injection of scAAV9-siPTEN at postnatal day 1 resulted in a modest threefold extension of the lifespan of SMNΔ7 mice, increasing mean survival to 30 days, compared to 10 days in untreated mice. Our data revealed that systemic PTEN depletion is an important disease modifier in SMNΔ7 mice, and therapies aimed at lowering PTEN expression may therefore offer a potential therapeutic strategy for SMA

Accumulation and transport of microbial-size particles in a pressure protected model burn unit: CFD simulations and experimental evidence

<p>Abstract</p> <p>Background</p> <p>Controlling airborne contamination is of major importance in burn units because of the high susceptibility of burned patients to infections and the unique environmental conditions that can accentuate the infection risk. In particular the required elevated temperatures in the patient room can create thermal convection flows which can transport airborne contaminates throughout the unit. In order to estimate this risk and optimize the design of an intensive care room intended to host severely burned patients, we have relied on a computational fluid dynamic methodology (CFD).</p> <p>Methods</p> <p>The study was carried out in 4 steps: i) patient room design, ii) CFD simulations of patient room design to model air flows throughout the patient room, adjacent anterooms and the corridor, iii) construction of a prototype room and subsequent experimental studies to characterize its performance iv) qualitative comparison of the tendencies between CFD prediction and experimental results. The Electricité De France (EDF) open-source software <it>Code_Saturne</it>^®(<url>http://www.code-saturne.org</url>) was used and CFD simulations were conducted with an hexahedral mesh containing about 300 000 computational cells. The computational domain included the treatment room and two anterooms including equipment, staff and patient. Experiments with inert aerosol particles followed by time-resolved particle counting were conducted in the prototype room for comparison with the CFD observations.</p> <p>Results</p> <p>We found that thermal convection can create contaminated zones near the ceiling of the room, which can subsequently lead to contaminate transfer in adjacent rooms. Experimental confirmation of these phenomena agreed well with CFD predictions and showed that particles greater than one micron (i.e. bacterial or fungal spore sizes) can be influenced by these thermally induced flows. When the temperature difference between rooms was 7°C, a significant contamination transfer was observed to enter into the positive pressure room when the access door was opened, while 2°C had little effect. Based on these findings the constructed burn unit was outfitted with supplemental air exhaust ducts over the doors to compensate for the thermal convective flows.</p> <p>Conclusions</p> <p>CFD simulations proved to be a particularly useful tool for the design and optimization of a burn unit treatment room. Our results, which have been confirmed qualitatively by experimental investigation, stressed that airborne transfer of microbial size particles via thermal convection flows are able to bypass the protective overpressure in the patient room, which can represent a potential risk of cross contamination between rooms in protected environments.</p

Constraining Martian Regolith and Vortex Parameters From Combined Seismic and Meteorological Measurements

The InSight mission landed on Mars in November 2018 and has since observed multiple convective vortices with both the high performance barometer and the low-noise seismometer SEIS that has unprecedented sensitivity. Here, we present a new method that uses the simultaneous pressure and seismic measurements of convective vortices to place constraints on the elastic properties of the Martian subsurface and the Martian vortex properties, while also allowing a reconstruction of the convective vortex trajectories. From data filtered in the (0.02–0.3 Hz) frequency band, we estimate that the mean value of η (η = E/[1 − ν2], where E is the Young's modulus and ν is the Poisson's ratio) of the Martian ground in the region around SEIS is 239 ± 140 MPa. In addition, we suggest that the previously reported paucity of vortex seismic observations to the west of InSight may be due to the fact that the ground is harder to the west than to the east, consistent with geomorphological surface interpretations