Hexanucleotide G
C
repeat expansions in the
gene are the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Dipeptide repeat proteins (DPRs) generated by ...translation of repeat-containing RNAs show toxic effects in vivo as well as in vitro and are key targets for therapeutic intervention. We generated human antibodies that bind DPRs with high affinity and specificity. Anti-GA antibodies engaged extra- and intra-cellular poly-GA and reduced aggregate formation in a poly-GA overexpressing human cell line. However, antibody treatment in human neuronal cultures synthesizing exogenous poly-GA resulted in the formation of large extracellular immune complexes and did not affect accumulation of intracellular poly-GA aggregates. Treatment with antibodies was also shown to directly alter the morphological and biochemical properties of poly-GA and to shift poly-GA/antibody complexes to more rapidly sedimenting ones. These alterations were not observed with poly-GP and have important implications for accurate measurement of poly-GA levels including the need to evaluate all centrifugation fractions and disrupt the interaction between treatment antibodies and poly-GA by denaturation. Targeting poly-GA and poly-GP in two mouse models expressing G
C
repeats by systemic antibody delivery for up to 16 mo was well-tolerated and led to measurable brain penetration of antibodies. Long-term treatment with anti-GA antibodies produced improvement in an open-field movement test in aged
mice. However, chronic administration of anti-GA antibodies in AAV-(G
C
)
mice was associated with increased levels of poly-GA detected by immunoassay and did not significantly reduce poly-GA aggregates or alleviate disease progression in this model.
We examined the proportion of American adults without type 2 diabetes that engages in lifestyle behaviors known to reduce type 2 diabetes risk.
We conducted a cross-sectional analysis of 3,679 ...nonpregnant, nonlactating individuals aged ≥20 years without diabetes (self-reported diagnosis or glycated hemoglobin ≥6.5% 8 mmol/mol or fasting plasma glucose ≥126 mg/dL) and who provided 2 days of reliable dietary data in the 2007-2012 National Health and Nutrition Examination Surveys (NHANES). We used the average of 2 days of dietary recall and self-reported leisure-time physical activity to assess whether participants met type 2 diabetes risk reduction goals (meeting four or more MyPlate recommendations adequate consumption of fruits, vegetables, dairy, grains, meat, beans, and eggs; not exceeding three maximum allowances for alcoholic beverages, added sugars, fat, and cholesterol; and meeting physical activity recommendations ≥150 min/week).
Approximately 21%, 29%, and 13% of individuals met fruit, vegetable, and dairy goals, respectively. Half (51.6%) met the goal for total grains, compared with 18% for whole grains, and 54.2% met the meat/beans goal and 40.6% met the oils goal. About one-third (37.8%) met the physical activity goal, and 58.6% met the weight loss/maintenance goal. Overall, 3.1% (95% CI 2.4-4.0) of individuals met the majority of type 2 diabetes risk reduction goals. Younger age and lower educational attainment were associated with lower probability of meeting goals.
A small proportion of U.S. adults engages in risk reduction behaviors. Research and interventions targeted at young and less-educated segments of the population may help close gaps in risk reduction behaviors.
Since 2013, the sorghum aphid (SA), Melanaphis sorghi (Theobald), has been a serious pest that hampers all types of sorghum production in the U.S. Known sorghum aphid resistance in sorghum is limited ...to a few genetic regions on SBI-06. In this study, a subset of the Sorghum Association Panel (SAP) was used along with some additional lines to identify genomic regions that confer sorghum aphid resistance. SAP lines were grown in the field and visually evaluated for SA resistance during the growing seasons of 2019 and 2020 in Tifton, GA. In 2020, the SAP accessions were also evaluated for SA resistance in the field using drone-based high throughput phenotyping (HTP). Flowering time was recorded in the field to confirm that our methods were sufficient for identifying known quantitative trait loci (QTL). This study combined phenotypic data from field-based visual ratings and reflectance data to identify genome-wide associated (GWAS) marker-trait associations (MTA) using genotyping-by-sequencing (GBS) data. Several MTAs were identified for SA-related traits across the genome, with a few common markers that were consistently identified on SBI-08 and SBI-10 for aphid count and plant damage, as well as loci for reflectance-based traits on SBI-02, SBI-03, and SBI-05. Candidate genes encoding leucine-rich repeats (LRR), Avr proteins, lipoxygenases (LOXs), calmodulins (CAM) dependent protein kinase, WRKY transcription factors, flavonoid biosynthesis genes, and 12-oxo-phytodienoic acid reductase were identified near SNPs that had significant associations with different SA traits. In this study, flowering time-related genes were also identified as a positive control for the methods. The total phenotypic variation explained by significant SNPs across SA-scored traits, reflectance data, and flowering time ranged from 6 to 61%, while the heritability value ranged from 4 to 69%. This study identified three new sources of resistant lines to sorghum aphid. These results supported the existing literature, and also revealed several new loci. Markers identified in this study will support marker-assisted breeding for sorghum aphid resistance.
Background: The aim of this study was to compare the use of pedicled local (PFs) versus random pattern flaps (RpFs) in foot and ankle reconstruction in patients with chronic, nonhealing wounds. ...Methods: A single-center, retrospective review of 204 patients with 118 PFs and 86 RpFs was performed. The primary outcome included rates of limb salvage. Results: PFs were used more often in the hindfoot (44.1% versus 30.2%, P = 0.045), lateral and medial surface (39.8% versus 18.6%, P = 0.001), and wounds containing exposed bone and hardware (78.8% versus 62.8%, P = 0.018). RpFs were used more for forefoot (19.8% versus 10.2%, P = 0.053) and plantar defects (58.1% versus 30.3%, P = 0.000). RpFs had a higher rate of immediate success (100% versus 95.8%, P = 0.053), with no significant differences in rate of long-term limb salvage (77.1% versus 69.8%, P = 0.237). PFs had higher rates of ischemia requiring intervention (11.0% versus 3.5%, P = 0.048). RpFs had a higher rate of minor amputations (15.12% versus 6.8%, P = 0.053) but similar rates of major amputation (15.1% versus 16.1%, P = 0.848). There were no significant differences in rates of mortality or ambulatory status. Conclusions: Both RpFs and PFs remain reliable options to reconstruct defects of the foot and ankle. Optimizing the use of each flap type should consider wound characteristics. RpFs are preferred for dorsal and plantar defects, whereas PFs are protective for minor infections and preferred for deeper wounds despite a higher rate of partial necrosis.
► We define the energy consumption of domestic investment as the investment-driven energy consumption (IDEC). ► We build an energy input–output model to identify quantitatively the amounts of China’s ...IDEC from 1992 to 2007. ► We improve the understanding of the effects of China’s domestic investment on its energy consumption expansion. ► We provide some quantitative information for further determining the energy-saving potentials of China’s economy.
In this study, we first define the energy consumption of domestic investment as the investment-driven energy consumption (IDEC). Then, we build an energy input–output model to identify quantitatively the amounts of China’s IDEC from 1992 to 2007. We also use the model to analyze the sector distributions of the IDEC for the same time period. The key findings derived from this study improve the understanding of the effects of China’s domestic investment on its energy consumption expansion and reflect the fact that China’s rapid urbanization and industrialization processes are among the main reasons for the large amount of energy consumption in China. We provide some quantitative information for further determining the energy-saving potentials of China’s economy during these processes.
Non-governmental organizations (NGOs) sometimes disagree with their funders’ accountability requirements; however, their dependence on the funders’ resources makes it difficult to express their ...disagreement. This dilemma for NGOs may keep funders from substantively holding NGOs to account and cause mission drift for the NGOs. This paper analyzes an in-depth case study of an understudied scenario: how a newly founded NGO engages with multiple funders with varying competence in accountability practices. By analyzing a Chinese NGO’s accountability relationships with its funders, we found that the NGO’s responses varied according to its organizational interests and how it perceived the funders’ competence. Better trust meant better compliance. Therefore, to secure compliance, it is important to enhance NGOs’ trust in funders’ competence. Based on the findings, we suggest that funders be more aware of NGOs’ agency, be ready to engage in ongoing collaborative learning with NGOs and align NGOs’ interests with the accountability requirements.
To estimate the maximum tolerated dose (MTD) of single-agent PF-04449913, and to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity in patients with ...advanced tumors.
A 3+3 design was used in this open-label, multicenter, phase I study and dose escalation/de-escalation applied until identification of the MTD. PF-04449913 was orally administered once daily in continuous 28-day treatment cycles. The starting dose was 80 mg.
A total of 23 patients were enrolled; 19 were evaluable for first-cycle dose-limiting toxicity (DLT). The first-cycle DLT rate at the 640 mg dose level was 33.3%, and the MTD was estimated to be 320 mg once daily. The recommended phase II dose was not determined. PF-04449913 was generally well tolerated at doses of 80 to 320 mg once daily. The most common treatment-related adverse events (AE) were grade 1-2 dysgeusia, fatigue, decreased appetite, nausea, dizziness, dehydration, and diarrhea. Treatment-related grade 3 AEs only occurred in patients receiving PF-04449913 640 mg once daily. No treatment-related grade 4-5 AEs were reported. Pharmacokinetic analysis indicated a generally dose-proportional kinetics with biphasic elimination, supporting once-daily dosing. PF-04449913 modulated hedgehog signaling at the dose levels tested, as demonstrated by >80% downregulation of GLI1 expression in the skin of treated patients. Eight patients (34.8%) achieved stable disease; none had complete or partial response. Three patients with disease progression at enrollment had prolonged disease stabilization (≥6 months).
The results obtained in this study support further evaluation of PF-04449913 in patients with advanced solid tumors.
Abstract
Background
Acute lymphoblastic leukemia (ALL) is the most common cancer in children and can arise in B or T lymphoid lineages. Although risk loci have been identified for B-ALL, the ...inherited basis of T-ALL is mostly unknown, with a particular paucity of genome-wide investigation of susceptibility variants in large patient cohorts.
Methods
We performed a genome-wide association study (GWAS) in 1191 children with T-ALL and 12 178 controls, with independent replication using 117 cases and 5518 controls. The associations were tested using an additive logistic regression model. Top risk variants were tested for effects on enhancer activity using luciferase assay. All statistical tests were two sided.
Results
A novel risk locus in the USP7 gene (rs74010351, odds ratio OR = 1.44, 95% confidence interval CI = 1.27 to 1.65, P = 4.51 × 10–8) reached genome-wide significance in the discovery cohort, with independent validation (OR = 1.51, 95% CI = 1.03 to 2.22, P = .04). The USP7 risk allele was overrepresented in individuals of African descent, thus contributing to the higher incidence of T-ALL in this race/ethnic group. Genetic changes in USP7 (germline variants or somatic mutations) were observed in 56.4% of T-ALL with TAL1 overexpression, statistically significantly higher than in any other subtypes. Functional analyses suggested this T-ALL risk allele is located in a putative cis-regulatory DNA element with negative effects on USP7 transcription. Finally, comprehensive comparison of 14 susceptibility loci in T- vs B-ALL pointed to distinctive etiology of these leukemias.
Conclusions
These findings indicate strong associations between inherited genetic variation and T-ALL susceptibility in children and shed new light on the molecular etiology of ALL, particularly commonalities and differences in the biology of the two major subtypes (B- vs T-ALL).
Beta blockers, a class of medications that inhibit endogenous catecholamines interaction with beta adrenergic receptors, are often administered to patients hospitalized after traumatic brain injury ...(TBI). We tested the hypothesis that beta blocker use after TBI is associated with lower mortality, and secondarily compared propranolol to other beta blockers.
The American Association for the Surgery of Trauma Clinical Trial Group conducted a multi-institutional, prospective, observational trial in which adult TBI patients who required intensive care unit admission were compared based on beta blocker administration.
From January 2015 to January 2017, 2,252 patients were analyzed from 15 trauma centers in the United States and Canada with 49.7% receiving beta blockers. Most patients (56.3%) received the first beta blocker dose by hospital day 1. Those patients who received beta blockers were older (56.7 years vs. 48.6 years, p < 0.001) and had higher head Abbreviated Injury Scale scores (3.6 vs. 3.4, p < 0.001). Similarities were noted when comparing sex, admission hypotension, mean Injury Severity Score, and mean Glasgow Coma Scale. Unadjusted mortality was lower for patients receiving beta blockers (13.8% vs. 17.7%, p = 0.013). Multivariable regression determined that beta blockers were associated with lower mortality (adjusted odds ratio, 0.35; p < 0.001), and propranolol was superior to other beta blockers (adjusted odds ratio, 0.51, p = 0.010). A Cox-regression model using a time-dependent variable demonstrated a survival benefit for patients receiving beta blockers (adjusted hazard ratio, 0.42, p < 0.001) and propranolol was superior to other beta blockers (adjusted hazard ratio, 0.50, p = 0.003).
Administration of beta blockers after TBI was associated with improved survival, before and after adjusting for the more severe injuries observed in the treatment cohort. This study provides a robust evaluation of the effects of beta blockers on TBI outcomes that supports the initiation of a multi-institutional randomized control trial.
Therapeutic/care management, level III.
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