Further supporting evidence for REEP1 phenotypic and allelic heterogeneity.

Heterozygous mutations in REEP1 (MIM #609139) encoding the receptor expression-enhancing protein 1 (REEP1) are a well-recognized and relatively frequent cause of autosomal dominant hereditary spastic paraplegia (HSP), SPG31.1 REEP1 localizes in the mitochondria and endoplasmic reticulum (ER) and facilitates ER-mitochondria interactions.2 In addition to the HSP phenotype, REEP1 has been associated with an autosomal dominant spinal type of Charcot-Marie-Tooth disease in 2 families.3 More recently, a patient with homozygous REEP1 mutation with a much more severe phenotype akin to spinal muscular atrophy with respiratory distress type 1 (SMARD1) was reported.4 In this report, we present a patient with a homozygous mutation in REEP1 manifesting a severe congenital distal spinal muscular atrophy (SMA) with diaphragmatic paralysis, expanding the phenotype from mild autosomal dominant HSP through to severe recessive distal SMA pattern

Neuroadaptations in the Cellular and Postsynaptic Group 1 Metabotropic Glutamate Receptor mGluR5 and Homer Proteins Following Extinction of Cocaine Self-administration

This study examined the role of group1 metabotropic glutamate receptor mGluR5 and associated postsynaptic scaffolding protein Homer1b/c in behavioral plasticity after three withdrawal treatments from cocaine self-administration. Rats self-administered cocaine or saline for 14 days followed by a withdrawal period during which rats underwent extinction training, remained in their home cages, orwere placed in the self-administration chambers in the absence of extinction. Subsequently, the tissue level and distribution of proteins in the synaptosomal fraction associated with the postsynaptic densitywere examined. Cocaine self-administration followed by home cage exposure reduced the mGluR5 protein in nucleus accumbens (NA) shell and dorsolateral striatum. While extinction training reduced mGluR5 protein in NAshell, NAcore and dorsolateral striatum did not display any change. The scaffolding protein PSD95 increased in NAcore of the extinguished animals. Extinction of drug seeking was associated with a significant decrease in the synaptosomal mGluR5 protein in NAshell and an increase in dorsolateral striatum, while that of NAcore was not modified. Interestingly, both Homer1b/c and PSD95 scaffolding proteins were decreased in the synaptosomal fraction after extinction training in NAshell but not NAcore. Extinguished drug-seeking behavior was also associated with an increase in the synaptosomal actin proteins in dorsolateral striatum. Therefore, extinction of cocaine seeking is associated with neuroadaptations in mGluR5 expression and distribution that are region-specific and consist of extinction-induced reversal of cocaine-induced adaptations aswell as emergent extinction-induced alterations. Concurrent plasticity in the scaffolding proteins further suggests that mGluR5 receptor neuroadaptations may have implications for synaptic function

Glutamatergic Plasticity in Medial Prefrontal Cortex and Ventral Tegmental Area Following Extended-Access Cocaine Self-Administration

Glutamate signaling in prefrontal cortex and ventral tegmental area plays an important role in the molecular and behavioral plasticity associated with addiction to drugs of abuse. The current study investigated the expression and postsynaptic density redistribution of glutamate receptors and synaptic scaffolding proteins in dorsomedial and ventromedial prefrontal cortex and ventral tegmental area after cocaine self-administration. After 14 days of extended-access (6 h/day) cocaine self-administration, rats were exposed to one of three withdrawal regimen for 10 days. Animals either stayed in home cages (Home), returned to self-administration boxes with the levers withdrawn (Box), or underwent extinction training (Extinction). Extinction training was associated with significant glutamatergic plasticity. In dorsomedial prefrontal cortex of the Extinction group, there was an increase in postsynaptic density GluR1, PSD95, and actin proteins; while postsynaptic density mGluR5 protein decreased and there was no change in NMDAR1, Homer1b/c, or PICK1 proteins. These changes were not observed in ventromedial prefrontal cortex or ventral tegmental area. In ventral tegmental area, Extinction training reversed the decreased postsynaptic density NMDAR1 protein in the Home and Box withdrawal groups. These data suggest that extinction of drug seeking is associated with selective glutamatergic plasticity in prefrontal cortex and ventral tegmental area that include modulation of receptor trafficking to postsynaptic density

Corticosteroid Administration to Prevent Complications of Anterior Cervical Spine Fusion: A Systematic Review.

Study Design: Systematic review. Objectives: Anterior cervical approach is associated with complications such as dysphagia and airway compromise. In this study, we aimed to systematically review the literature on the efficacy and safety of corticosteroid administration as a preventive measure of such complications in anterior cervical spine surgery with fusion. Methods: Following a systematic literature search of MEDLINE, Embase, and Cochrane databases in July 2016, all comparative human studies that evaluated the effect of steroids for prevention of complications in anterior cervical spine surgery with fusion were included, irrespective of number of levels and language. Risk of bias was assessed using MINORS (Methodological Index for Non-Randomized Studies) checklist and Cochrane Back and Neck group recommendations, for nonrandomized and randomized studies, respectively. Results: Our search yielded 556 articles, of which 9 studies (7 randomized controlled trials and 2 non-randomized controlled trials) were included in the final review. Dysphagia was the most commonly evaluated complication, and in most studies, its severity or incidence was significantly lower in the steroid group. Although prevertebral soft tissue swelling was less commonly assessed, the results were generally in favor of steroid use. The evidence for airway compromise and length of hospitalization was inconclusive. Steroid-related complications were rare, and in both studies that evaluated the fusion rate, it was comparable between steroid and control groups in long-term follow-up. Conclusions: Current literature supports the use of steroids for prevention of complications in anterior cervical spine surgery with fusion. However, evidence is limited by substantial risk of bias and small number of studies reporting key outcomes

On particles in the Arctic stratosphere

Soon after the discovery of the Antarctic ozone hole it became clear that particles in the polar stratosphere had an infl uence on the destruction of the ozone layer. Two major types of particles, sulphate aerosols and Polar Stratospheric Clouds (PSCs), provide the surfaces where fast heterogeneous chemical reactions convert inactive halogen reservoir species into potentially ozone-destroying radicals. Lidar measurements have been used to classify the PSCs. Following the Mt. Pinatubo eruption in June 1991 it was found that the Arctic stratosphere was loaded with aerosols, and that aerosols observed with lidar and ozone observed with ozone sondes displayed a layered structure, and that the aerosol and ozone contents in the layers frequently appeared to be negatively correlated. The layered structure was probably due to modulation induced by the dynamics at the edge of the polar vortex. Lidar observations of the Mt. Pinatubo aerosols were in several cases accompanied by balloon-borne backscatter soundings, whereby backscatter measurements in three different wavelengths made it possible to obtain information about the particle sizes. An investigation of the infl uence of synoptic temperature histories on the physical properties of PSC particles has shown that most of the liquid type 1b particles were observed in the process of an ongoing, relatively fast, and continuous cooling from temperatures clearly above the nitric acid trihydrate condensation temperature (TNAT). On the other hand, it appeared that a relatively long period, with a duration of at least 1-2 days, at temperatures below TNAT provide the conditions which may lead to the production of solid type 1a PSCs

Seismogenic faulting of the sedimentary sequence and laterally variable material properties in the Zagros Mountains (Iran) revealed by the August 2014 Murmuri (E. Dehloran) earthquake sequence

We present source models for the August 2014 Murmuri (Dehloran) earthquake sequence in the Zagros Mountains of Iran. An Mw6.2 mainshock was followed by an aftershock sequence containing five events of Mw ≥ 5.4. Models of P and SH waveforms show that all events had dominantly thrust-faulting mechanisms, and had centroid depths that place them within the thick sedimentary sequence, above the crystalline basement. The combination of our estimated focal mechanisms, relative relocations of the event hypocentres and the surface displacement patterns observed using InSAR imply that the mainshock and largest aftershock ruptured different fault planes and both contributed to the surface deformation. The fault planes both slipped in horizontally elongated patches, possibly due to rheological layering limiting the updip and downdip extent of rupture. The slip vector of the Murmuri mainshock implies that the decollement beneath the Lorestan Arc is weaker than any such feature beneath the Dezful Embayment, providing an explanation for the plan-view sinuosity of the range-front of the Zagros Mountains

Effect of travelling fire on structural response of a generic steel fire protected moment resisting frame

To simulate a fire inside large compartments, there is a pioneering method called ‘traveling fire’. As steel structures are vulnerable to high temperatures, they are normally fireproofed by insulation materials appropriate for a specific duration of time. An investigation is performed here to examine the robustness of a generic fourstory moment-resisting steel structure, fireproofed to comply with the one-hour standard curve, when it is subjected to traveling fire. The results show that while no collapse occurs during the 12.5%, 50% and 100%, the structure collapses under the 25% fire size at 75 min. This seems to be in contradiction with traditional belief, where it is assumed that taking into consideration a larger-scale fire in a compartment would increase the safety margin. The investigation performed also underlines that the fireproofing of structures does not necessarily provide adequate resistance under traveling fires

Uncertainty Analysis in Population-Based Disease Microsimulation Models

Objective. Uncertainty analysis (UA) is an important part of simulation model validation. However, literature is imprecise as to how UA should be performed in the context of population-based microsimulation (PMS) models. In this expository paper, we discuss a practical approach to UA for such models. Methods. By adapting common concepts from published UA guidelines, we developed a comprehensive, step-by-step approach to UA in PMS models, including sample size calculation to reduce the computational time. As an illustration, we performed UA for POHEM-OA, a microsimulation model of osteoarthritis (OA) in Canada. Results. The resulting sample size of the simulated population was 500,000 and the number of Monte Carlo (MC) runs was 785 for 12-hour computational time. The estimated 95% uncertainty intervals for the prevalence of OA in Canada in 2021 were 0.09 to 0.18 for men and 0.15 to 0.23 for women. The uncertainty surrounding the sex-specific prevalence of OA increased over time. Conclusion. The proposed approach to UA considers the challenges specific to PMS models, such as selection of parameters and calculation of MC runs and population size to reduce computational burden. Our example of UA shows that the proposed approach is feasible. Estimation of uncertainty intervals should become a standard practice in the reporting of results from PMS models

Large scale structure around a z=2.1 cluster

The most prodigious starburst galaxies are absent in massive galaxy clusters today, but their connection with large scale environments is less clear at $z\gtrsim2$. We present a search of large scale structure around a galaxy cluster core at $z=2.095$ using a set of spectroscopically confirmed galaxies. We find that both color-selected star-forming galaxies (SFGs) and dusty star-forming galaxies (DSFGs) show significant overdensities around the $z=2.095$ cluster. A total of 8 DSFGs (including 3 X-ray luminous active galactic nuclei, AGNs) and 34 SFGs are found within a 10 arcmin radius (corresponds to $\sim$15 cMpc at $z\sim2.1$) from the cluster center and within a redshift range of $\Delta z=0.02$, which leads to galaxy overdensities of $\delta_{\rm DSFG}\sim12.3$ and $\delta_{\rm SFG}\sim2.8$. The cluster core and the extended DSFG- and SFG-rich structure together demonstrate an active cluster formation phase, in which the cluster is accreting a significant amount of material from large scale structure while the more mature core may begin to virialize. Our finding of this DSFG-rich structure, along with a number of other protoclusters with excess DSFGs and AGNs found to date, suggest that the overdensities of these rare sources indeed trace significant mass overdensities. However, it remains puzzling how these intense star formers are triggered concurrently. Although an increased probability of galaxy interactions and/or enhanced gas supply can trigger the excess of DSFGs, our stacking analysis based on 850 $\mu$m images and morphological analysis based on rest-frame optical imaging do not show such enhancements of merger fraction and gas content in this structure.Comment: 11 pages, 4 figures, ApJ accepte