Search

Abstract Objective Accumulation of misfolded superoxide dismutase‐1 (SOD1) is a pathological hallmark of SOD1‐related amyotrophic lateral sclerosis (ALS) and is observed in sporadic ALS where its role in pathogenesis is controversial. Understanding in vivo protein kinetics may clarify how SOD1 influences neurodegeneration and inform optimal dosing for therapies that lower SOD1 transcripts. Methods We employed stable isotope labeling paired with mass spectrometry to evaluate in vivo protein kinetics and concentration of soluble SOD1 in cerebrospinal fluid (CSF) of SOD1 mutation carriers, sporadic ALS participants and controls. A deaminated SOD1 peptide, SDGPVKV, that correlates with protein stability was also measured. Results In participants with heterozygous SOD1A5V mutations, known to cause rapidly progressive ALS, mutant SOD1 protein exhibited ~twofold faster turnover and ~ 16‐fold lower concentration compared to wild‐type SOD1 protein. SDGPVKV levels were increased in SOD1A5V carriers relative to controls. Thus, SOD1 mutations impact protein kinetics and stability. We applied this approach to sporadic ALS participants and found that SOD1 turnover, concentration, and SDGPVKV levels are not significantly different compared to controls. Interpretation These results highlight the ability of stable isotope labeling approaches and peptide deamidation to discern the influence of disease mutations on protein kinetics and stability and support implementation of this method to optimize clinical trial design of gene and molecular therapies for neurological disorders. Trial Registration Clinicaltrials.gov: NCT03449212.

OBJECTIVE: Adiposity has been hypothesized to interfere with the activity of bevacizumab (BEV), an anti-angiogenic agent. Measurements of adiposity, BMI, surface fat area (SFA), and visceral fat area (VFA) were investigated as prognostic of oncologic outcomes among patients treated with chemotherapy, with or without BEV, on GOG 218, a prospective phase III trial. METHOD: Pretreatment computed tomography (CT) for 1538 GOG 218 participants were analyzed. Proportional hazards models assessed association between adiposity and overall survival (OS) adjusted for other prognostic factors. The predictive value of adiposity as a function of BEV treatment was assessed in 1019 patients randomized to either chemotherapy (CT) + placebo (P) → P or CT + BEV → BEV. RESULTS: After adjusting for prognostic factors, SFA was not associated with the overall hazard of death (p = 0.981). There was a non-significant 0.1% (p = 0.062) increase in hazard of death associated with a unit increase in VFA. When comparing the treatment HRs for patients who did and did not receive BEV, there was no association with SFA (p = 0.890) or VFA (p = 0.106). A non-significant 0.8% increase in the hazard of death with unit increase in BMI (p = 0.086) was observed. BMI values were not predictive of a longer survival for patients with BEV vs placebo (p = 0.606). CONCLUSION: Measures of adiposity strongly correlated to one another but were not predictive of efficacy for BEV. VFA is a weak prognostic factor.

Quantifying the effect of public health actions on population health is essential when justifying sustained public health investment. Using modeling, we conservatively estimated that rapid response to a multistate foodborne outbreak of Salmonella Typhimurium in the United States in 2018 potentially averted 106 cases and $715,458 in medical costs and productivity losses.

The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development.sup.1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure.sup.2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation. MC3R deficiency is associated with a delay in the onset of puberty, and a reduction in growth and lean mass., Author(s): B. Y. H. Lam [sup.1] [sup.2] , A. Williamson [sup.1] [sup.2] [sup.3] , S. Finer [sup.4] , F. R. Day [sup.3] , J. A. Tadross [sup.1] [sup.2] [sup.5] , [...]

The US Centers for Disease Control and Prevention estimates that 48 million illnesses, 128,000 hospitalizations, and 3,000 deaths are caused by foodborne illnesses each year in the United States (1). [...]

The sungazer (Smaug giganteus) is a strict grassland specialist lizard endemic to South Africa's highveld grasslands. It is currently listed as Vulnerable (IUCN) and is primarily threatened by anthropogenic activities. Because sungazers are habitat specialists, climate change may be detrimental to the species, considering their life‐history traits, and the area of available suitable habitat. We assessed how climate change may impact the sungazers' geographic range by first producing an ecological niche model (ENM) for the species within a buffered region of its extent of occurrence (buffered EOO). The ENM was then projected to 2040, 2060, 2080 and 2100 under two climate change scenarios using Shared Socioeconomic Pathways (SSP); SSP245 (moderate‐case) and SSP585 (worst‐case). A mean ensemble of three global circulation models for each time period and scenario was used to create habitat suitability maps which were refined using a natural grassland variable overlay. Resulting maps were clipped to the sungazers' EOO and interpreted distribution. Within the interpreted distribution, models predicted an area of 10 198 km2 of current suitable habitat. At this scale, future habitat suitability is predicted to remain relatively stable (area: 9910 km2; 3% decline) under SSP245 by 2100. However, a 24% decline (area: 7705 km2) in habitat suitability was predicted under SSP585. Within the buffered EOO, habitat suitability increased in south‐western regions, which was more prominent under SSP585. Although this finding suggests that sungazers could track favourable conditions, their life history and low dispersal ability makes climate tracking unlikely. Because sungazers only occur in primary grasslands, regions dominated by agricultural activities, further land use developments are likely to affect the species survival. Thus, careful conservation management is essential, and we recommend the establishment of protected areas with cognizance of our predictions for current and future suitable habitat within the sungazers' interpreted distribution. [ABSTRACT FROM AUTHOR]

The text of the federal-provincial division of powers in sections 91 to 95 of the Constitution Act, 1867 (1) seems to place a premium on exclusive jurisdiction. (2) It explicitly [...]

Elucidating factors that drive microhabitat selection in a species is important for informing the conservation management of the species. For species that use microhabitats as long-term refuge sites, selection pressures are likely to be strong because the microhabitat must fulfil their eco-physiological and life history requirements. Smaug giganteus (Sungazer) is a threatened (Vulnerable) cordylid lizard species in the highveld grasslands of South Africa – a key agricultural area in the country. Individuals dig burrows as refuges, which increases their sensitivity to habitat transformation. In addition, previous attempts to translocate populations have failed due to a lack of knowledge about their specific microhabitat requirements. We assessed microhabitat characteristics that may influence burrow site selection by measuring vegetation characteristics surrounding Sungazer burrows and comparing these to vegetation at randomly selected sites. We also recorded orientation, aspect, soil composition, and the presence of other animal dung. Sungazers selected sites with sparse vegetation cover, and where grass height was short, but had no preference for soil composition. There was no relationship between the presence of ungulate dung and the placement of Sungazer burrows. Most Sungazer burrows were orientated in a northerly direction on north-facing slopes, suggesting that burrow placement has thermoregulatory advantages. We recommend that to identify suitable sites for Sungazer translocations, landscapes are thoroughly surveyed with cognisance to the findings in this study, and that a soft-release translocation protocol follows to maximise translocation success. [ABSTRACT FROM AUTHOR]

Objective: Accumulation of misfolded superoxide dismutase‐1 (SOD1) is a pathological hallmark of SOD1‐related amyotrophic lateral sclerosis (ALS) and is observed in sporadic ALS where its role in pathogenesis is controversial. Understanding in vivo protein kinetics may clarify how SOD1 influences neurodegeneration and inform optimal dosing for therapies that lower SOD1 transcripts. Methods: We employed stable isotope labeling paired with mass spectrometry to evaluate in vivo protein kinetics and concentration of soluble SOD1 in cerebrospinal fluid (CSF) of SOD1 mutation carriers, sporadic ALS participants and controls. A deaminated SOD1 peptide, SDGPVKV, that correlates with protein stability was also measured. Results: In participants with heterozygous SOD1A5V mutations, known to cause rapidly progressive ALS, mutant SOD1 protein exhibited ~twofold faster turnover and ~ 16‐fold lower concentration compared to wild‐type SOD1 protein. SDGPVKV levels were increased in SOD1A5V carriers relative to controls. Thus, SOD1 mutations impact protein kinetics and stability. We applied this approach to sporadic ALS participants and found that SOD1 turnover, concentration, and SDGPVKV levels are not significantly different compared to controls. Interpretation: These results highlight the ability of stable isotope labeling approaches and peptide deamidation to discern the influence of disease mutations on protein kinetics and stability and support implementation of this method to optimize clinical trial design of gene and molecular therapies for neurological disorders. Trial Registration: Clinicaltrials.gov: NCT03449212. [ABSTRACT FROM AUTHOR]

The tensile strength behavior and recyclability of the paper prepared with the addition of polyamideamine-epichlorohydrin (PAE) were investigated. The dry and wet tensile strengths obtained with different PAE dosage were measured. The highest wet-to-dry strength ratio of 35% was obtained at 10 mg/g; above this addition level wet strength dropped slightly and then remained constant. The repulpability of strengthened paper was correlated directly with wet strength. The effect of electrolyte on tensile strength was also quantified by varying sodium chloride and calcium chloride concentration in the furnish stock. Without PAE, high salt concentrations (100 mM) reduced the tensile strength by 15-20%. At constant PAE addition level of 10 mg/g, low levels of salt addition (of either 10 mM NaCl or 10 mM CaCl2) slightly improved the strength; paper strength decreased at high salts concentrations. The cation valency and concentration in the process water were important variables which affected the efficiency of PAE. These results present the significance of developing sustainable wet strength agents that can be applied in demanding salty conditions while maintaining the product recyclability.

OBJECTIVES/SPECIFIC AIMS: We aimed to develop an assay to measure new protein synthesis after Antisense Oligonucleotide treatment, which we hypothesized to be the earliest biochemical identification of RNA-targeting therapy efficacy. METHODS/STUDY POPULATION: We treated 2 transgenic animal models expressing proteins implicated in neurodegenerative disease: human tau protein (hTau) and human superoxide dismutase 1 (hSOD1), with ASO against these mRNA transcripts. Animals received isotope-labeled 13C6-Leucine via drinking water to label newly synthesized proteins. We assayed target protein synthesis and concentration after ASO treatment to determine the earliest identification of ASO target engagement. RESULTS/ANTICIPATED RESULTS: hTau ASO treatment in transgenic mice lowered hTau protein concentration 23 days post-treatment in cortex (95% CI: 0.05%–64.0% reduction). In the same tissue, we observed lowering of hTau protein synthesis as early as 13 days (95% CI: 29.4%–123%). In hSOD1 transgenic rats, we observed lowering of 13C6-leucine-labeled hSOD1 in the cerebrospinal fluid 30 days after ASO treatment compared with inactive ASO control (95% CI: 12.0%–48.4%). DISCUSSION/SIGNIFICANCE OF IMPACT: In progressive neurodegenerative diseases, it is crucial to develop measurements that identify treatment efficacy early to improve patient outcomes. These data support the use of stable isotope labeling of amino acids to measure new protein synthesis as an early pharmacodynamics measurement for therapies that target RNA and inhibit the translation of proteins.

Research demonstrates the synthesis and characterization of new class of porphyrazines containing 'polyetherol' groups, which bind metal ions and aid in pophyrazines solubility. Absorbance and fluorescence spectral data on the modified porphyrazines are provided and their usage in chemical sensors is discussed.

A study on the effect of endurance-oriented exercise training on myosin heavy chain (MHC) isoform regulation in human skeletal muscle is presented. By determining the effect of exercise on the predominant isoforms of MHC, the study aims to understand the responses of these genes. Results of the study suggest that MHC IIx mRNA is downregulated during the early stage of endurance-oriented exercise training but only following iterative contractile activity. The degree of this response may be altered by pretraining MHC IIx mRNA content.