Single copy/knock-in models of ALS SOD1 in C. elegans suggest loss and gain of function have different contributions to cholinergic and glutamatergic neurodegeneration

Mutations in Cu/Zn superoxide dismutase 1 (SOD1) lead to Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease that disproportionately affects glutamatergic and cholinergic motor neurons. Previous work with SOD1 overexpression models supports a role for SOD1 toxic gain of function in ALS pathogenesis. However, the impact of SOD1 loss of function in ALS cannot be directly examined in overexpression models. In addition, overexpression may obscure the contribution of SOD1 loss of function in the degeneration of different neuronal populations. Here, we report the first single-copy, ALS knock-in models in C. elegans generated by transposon- or CRISPR/Cas9- mediated genome editing of the endogenous sod-1 gene. Introduction of ALS patient amino acid changes A4V, H71Y, L84V, G85R or G93A into the C. elegans sod-1 gene yielded single-copy/knock-in ALS SOD1 models. These differ from previously reported overexpression models in multiple assays. In single-copy/knock-in models, we observed differential impact of sod-1 ALS alleles on glutamatergic and cholinergic neurodegeneration. A4V, H71Y, G85R, and G93A animals showed increased SOD1 protein accumulation and oxidative stress induced degeneration, consistent with a toxic gain of function in cholinergic motor neurons. By contrast, H71Y, L84V, and G85R lead to glutamatergic neuron degeneration due to sod-1 loss of function after oxidative stress. However, dopaminergic and serotonergic neuronal populations were spared in single-copy ALS models, suggesting a neuronal-subtype specificity previously not reported in invertebrate ALS SOD1 models. Combined, these results suggest that knock-in models may reproduce the neurotransmitter-type specificity of ALS and that both SOD1 loss and gain of toxic function differentially contribute to ALS pathogenesis in different neuronal populations.Peer reviewe

Nesting by Canada Geese on Baffin Island, Nunavut

Outside of northern Quebec, there is little evidence to confirm reports of nesting by Canada Geese in Arctic habitats of North America, but they nest regularly in the Arctic tundra of West Greenland, from about 62˚ N to as far north as 76.96˚ N, 71.11˚ W. In 2013, we documented successful nesting by a pair of Canada Geese on northern Baffin Island (71.36˚ N, 79.59˚ W), approximately 1200 km north of the nearest known site of regular nesting by this species in northern Quebec. Photographs, egg measurements, and mitochondrial DNA evidence confirmed that these were Canada Geese. Egg laying began around 17 June, the nest of five eggs hatched on 18 July, and we determined that fledging should have occurred around 20 September. Daily mean temperatures on northern Baffin Island fell below freezing after 5 September 2013, and we suspect that the probability of recruitment for this brood was very low. Climate warming in the Arctic is likely to favor northward range expansion by Canada Geese.En dehors du nord du Québec, il existe peu de preuves permettant de confirmer des rapports selon lesquels la bernache du Canada nidifierait dans les habitats arctiques de l’Amérique du Nord. Cela dit, la bernache du Canada nidifie régulièrement dans la toundra arctique de l’ouest du Groenland, à partir d’environ 62˚ N et aussi loin qu’à 76,96˚ N, 71,11˚ O. En 2013, nous avons documenté la nidification réussie d’une paire de bernaches du Canada dans le nord de l’île de Baffin (71,36˚ N, 79,59˚ O), à environ 1 200 km au nord du site le plus près de nidification habituel connu de cette espèce dans le nord du Québec. Des photographies, la mesure des oeufs et des échantillons d’ADN mitochondrial ont permis de confirmer qu’il s’agissait effectivement de bernaches du Canada. La ponte a commencé vers le 17 juin, puis la couvée de cinq oeufs a éclos le 18 juillet. Nous avons ensuite déterminé que la prise des ailes aurait eu lieu vers le 20 septembre. Dans le nord de l’île de Baffin, les températures moyennes quotidiennes sont tombées sous le point de congélation après le 5 septembre 2013, si bien que nous estimons que pour cette nichée, la probabilité de recrutement était très faible. Le réchauffement climatique dans l’Arctique favorisera vraisemblablement l’expansion du parcours naturel de la bernache du Canada vers le nord.

Exposure of fibrinogen and thrombin to nitric oxide donor ProliNONOate affects fibrin clot properties

Fibrin fibers form the structural backbone of blood clots. The structural properties of fibrin clots are highly dependent on formation kinetics. Environmental factors such as protein concentration, pH, salt, and protein modification, to name a few, can affect fiber kinetics through altered fibrinopeptide release, monomer association, and/or lateral aggregation. The objective of our study was to determine the effect of thrombin and fibrinogen exposed to nitric oxide on fibrin clot properties. ProliNONOate (5 [mu]mol/l) was added to fibrinogen and thrombin before clot initiation and immediately following the addition of thrombin to the fibrinogen solution. Resulting fibrin fibers were probed with an atomic force microscope to determine their diameter and extensibility and fibrin clots were analyzed for clot density using confocal microscopy. Fiber diameters were also determined by confocal microscopy and the rate of clot formation was recorded using UV-vis spectrophotometry. Protein oxidation and S-nitrosation was determined by UV-vis, ELISA, and chemiluminescence. The addition of ProliNONOate to fibrinogen or thrombin resulted in a change in clot structure. ProliNONOate exposure produced clots with lower fiber density, thicker fibers, and increased time to maximum turbidity. The effect of the exposure of nitric oxide to thrombin and fibrinogen were measured independently and indicated that each plays a role in altering clot properties. We detected thrombin S-nitrosation and protein carbonyl formation after nitric oxide exposure. Our study reveals a regulation of fibrin clot properties by nitric oxide exposure and suggests a role of peroxynitrite in oxidative modifications of the proteins. These results relate nitric oxide bioavailability and oxidative stress to altered clot properties

Health-related quality of life in KEYNOTE-010 : a phase II/III study of pembrolizumab versus docetaxel in patients with previously treated advanced, programmed death ligand 1-expressing NSCLC

Introduction: In the phase II/III KEYNOTE-010 study (ClinicalTrials.gov, NCT01905657), pembrolizumab significantly prolonged overall survival over docetaxel in patients with previously treated, programmed death ligand 1-expressing (tumor proportion score >= 1%), advanced NSCLC. Health-related quality of life (HRQoL) results are reported here. Methods: Patients were randomized 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks or docetaxel 75 mg/m(2) every 3 weeks. HRQoL was assessed using European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLC) Core 30 (C30), EORTC QLQ-Lung Cancer 13 (LC13), and EuroQoL-5D. Key analyses included mean baseline-to-week-12 change in global health status (GHS)/quality of life (QoL) score, functioning and symptom domains, and time to deterioration in a QLQ-LC13 composite endpoint of cough, dyspnea, and chest pain. Results: Patient reported outcomes compliance was high across all three instruments. Pembrolizumab was associated with better QLQ-C30 GHS/QoL scores from baseline to 12 weeks than docetaxel, regardless of pembrolizumab dose or tumor proportion score status (not significant). Compared with docetaxel, fewer pembrolizumab-treated patients had "deteriorated" status and more had "improved" status in GHS/QoL. Nominally significant improvement was reported in many EORTC symptom domains with pembrolizumab, and nominally significant worsening was reported with docetaxel. Significant prolongation in true time to deterioration for the QLQ-LC13 composite endpoint emerged for pembrolizumab 10 mg/kg compared to docetaxel (nominal two-sided p = 0.03), but not for the 2-mg/kg dose. Conclusions: These findings suggest that HRQoL and symptoms are maintained or improved to a greater degree with pembrolizumab than with docetaxel in this NSCLC patient population. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Thoracoscopic Repair of Congenital Diaphragmatic Hernia in Neonates: Lessons Learned

Abstract Purpose: We sought to characterize our recent experience with thoracoscopic congenital diaphragmatic hernia (CDH) repair and identify patient selection factors. Methods: We reviewed the medical records of full-term neonatal (<1 month of age) patients who underwent thoracoscopic CDH repair between 2004 and 2008 (n=15). We obtained data on prenatal diagnosis, characteristics of the CDH and repair, complications, and outcome. Results: All patients were stabilized preoperatively and underwent repair at an average of 5.7+/-1.3 days. Six patients were prenatally diagnosed, including the 5 inborn. Thirteen defects were left-sided. All were intubated shortly after birth and 2 required extracorporeal membrane oxygenation (ECMO). Twelve of 15 (80%) patients underwent successful thoracoscopic primary repair, including 1 of the patients who required ECMO prior to repair. Conversion to open repair occurred in 3 of 15 (20%) patients because of the need for patch closure or intraoperative instability. Among those converted to open, all had left-sided CDH defects and 3 had stomach herniation (of 5 such patients). Patients spent an average of 6.9+/-1.0 days on the ventilator following repair. The average time until full-enteral feeding was 16.7+/-2.25 days, and average length of hospital stay was 23.8+/-2.73 days. All patients survived to discharge, and average length of follow-up was 15.3+/-3.6 months. Conclusions: Thoracoscopic repair of CDH is a safe, effective strategy in patients who have undergone prior stabilization. Stomach herniation is associated with, but does not categorically predict, conversion to open repair. ECMO use prior to repair should not be an absolute contraindication to thoracoscopic repair.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78119/1/lap.2009.0129.pd

Complete genome sequence of Syntrophobacter fumaroxidans strain (MPOB(T)).

Syntrophobacter fumaroxidans strain MPOB(T) is the best-studied species of the genus Syntrophobacter. The species is of interest because of its anaerobic syntrophic lifestyle, its involvement in the conversion of propionate to acetate, H2 and CO2 during the overall degradation of organic matter, and its release of products that serve as substrates for other microorganisms. The strain is able to ferment fumarate in pure culture to CO2 and succinate, and is also able to grow as a sulfate reducer with propionate as an electron donor. This is the first complete genome sequence of a member of the genus Syntrophobacter and a member genus in the family Syntrophobacteraceae. Here we describe the features of this organism, together with the complete genome sequence and annotation. The 4,990,251 bp long genome with its 4,098 protein-coding and 81 RNA genes is a part of the Microbial Genome Program (MGP) and the Genomes to Life (GTL) Program project

Development and evaluation of a clinical model for lung cancer patients using stereotactic body radiotherapy (SBRT) within a knowledge-based algorithm for treatment planning

The purpose of this study was to describe the development of a clinical model for lung cancer patients treated with stereotactic body radiotherapy (SBRT) within a knowledge-based algorithm for treatment planning, and to evaluate the model performance and applicability to different planning techniques, tumor locations, and beam arrangements. 105 SBRT plans for lung cancer patients previously treated at our institution were included in the development of the knowledge-based model (KBM). The KBM was trained with a combination of IMRT, VMAT, and 3D CRT techniques. Model performance was validated with 25 cases, for both IMRT and VMAT. The full KBM encompassed lesions located centrally vs. peripherally (43:62), upper vs. lower (62:43), and anterior vs. posterior (60:45). Four separate sub-KBMs were created based on tumor location. Results were compared with the full KBM to evaluate its robustness. Beam templates were used in conjunction with the optimizer to evaluate the model\u27s ability to handle suboptimal beam placements. Dose differences to organs-at-risk (OAR) were evaluated between the plans gener-ated by each KBM. Knowledge-based plans (KBPs) were comparable to clinical plans with respect to target conformity and OAR doses. The KBPs resulted in a lower maximum spinal cord dose by 1.0 ± 1.6 Gy compared to clinical plans, p = 0.007. Sub-KBMs split according to tumor location did not produce significantly better DVH estimates compared to the full KBM. For central lesions, compared to the full KBM, the peripheral sub-KBM resulted in lower dose to 0.035 cc and 5 cc of the esophagus, both by 0.4Gy ± 0.8Gy, p = 0.025. For all lesions, compared to the full KBM, the posterior sub-KBM resulted in higher dose to 0.035 cc, 0.35 cc, and 1.2 cc of the spinal cord by 0.2 ± 0.4Gy, p = 0.01. Plans using template beam arrangements met target and OAR criteria, with an increase noted in maximum heart dose (1.2 ± 2.2Gy, p = 0.01) and GI (0.2 ± 0.4, p = 0.01) for the nine-field plans relative to KBPs planned with custom beam angles. A knowledge-based model for lung SBRT consisting of multiple treatment modalities and lesion loca-tions produced comparable plan quality to clinical plans. With proper training and validation, a robust KBM can be created that encompasses both IMRT and VMAT techniques, as well as different lesion locations

Complementary Patents and Market Structure

Many high technology goods are based on standards that require several essential patents owned by different IP holders. This gives rise to a complements and a double mark-up problem. We compare the welfare effects of two different business strategies dealing with these problems. Vertical integration of an IP holder and a downstream producer solves the double mark-up problem between these firms. Nevertheless, it may raise royalty rates and reduce output as compared to non-integration. Horizontal integration of IP holders solves the complements problem but not the double mark-up problem. Vertical integration discourages entry and reduces innovation incentives, while horizontal integration always benefits from entry and innovatio

The Interactive Effect of Major Depression and Nonsuicidal Self-Injury On Current Suicide Risk and Lifetime Suicide Attempts

Objectives: This study examined the main and interactive effects of MDD and lifetime nonsuicidal self-injury (NSSI) on current suicide risk and past suicide attempts. We predicted that individuals with a history of NSSI and current MDD would be at greater suicide risk than those with either risk factor alone. An interaction between lifetime MDD and NSSI was hypothesized for past suicide attempts. Methods: 204 substance dependent inpatients completed self-report measures and a diagnostic interview. Results: Patients with both a history of NSSI and current MDD, relative to all other groups, had the greatest suicide risk. No support was found for the lifetime MDD by NSSI interaction. Conclusion: Findings suggest the relevance of both NSSI and MDD in suicide risk

Why do models overestimate surface ozone in the Southeast United States

Ozone pollution in the Southeast US involves complex chemistry driven by emissions of anthropogenic nitrogen oxide radicals (NOx  ≡  NO + NO2) and biogenic isoprene. Model estimates of surface ozone concentrations tend to be biased high in the region and this is of concern for designing effective emission control strategies to meet air quality standards. We use detailed chemical observations from the SEAC4RS aircraft campaign in August and September 2013, interpreted with the GEOS-Chem chemical transport model at 0.25°  ×  0.3125° horizontal resolution, to better understand the factors controlling surface ozone in the Southeast US. We find that the National Emission Inventory (NEI) for NOx from the US Environmental Protection Agency (EPA) is too high. This finding is based on SEAC4RS observations of NOx and its oxidation products, surface network observations of nitrate wet deposition fluxes, and OMI satellite observations of tropospheric NO2 columns. Our results indicate that NEI NOx emissions from mobile and industrial sources must be reduced by 30–60 %, dependent on the assumption of the contribution by soil NOx emissions. Upper-tropospheric NO2 from lightning makes a large contribution to satellite observations of tropospheric NO2 that must be accounted for when using these data to estimate surface NOx emissions. We find that only half of isoprene oxidation proceeds by the high-NOx pathway to produce ozone; this fraction is only moderately sensitive to changes in NOx emissions because isoprene and NOx emissions are spatially segregated. GEOS-Chem with reduced NOx emissions provides an unbiased simulation of ozone observations from the aircraft and reproduces the observed ozone production efficiency in the boundary layer as derived from a regression of ozone and NOx oxidation products. However, the model is still biased high by 6 ± 14 ppb relative to observed surface ozone in the Southeast US. Ozonesondes launched during midday hours show a 7 ppb ozone decrease from 1.5 km to the surface that GEOS-Chem does not capture. This bias may reflect a combination of excessive vertical mixing and net ozone production in the model boundary layer