Climate Benefits Tenure Costs: The Economic Case for Securing Indigenous Land Rights in the Amazon

A new report offers evidence that the modest investments needed to secure land rights for indigenous communities will generate billions in returns—economically, socially and environmentally—for local communities and the world's changing climate. The report, Climate Benefits, Tenure Costs: The Economic Case for Securing Indigenous Land Rights, quantifies for the first time the economic value of securing land rights for the communities who live in and protect forests, with a focus on Colombia, Brazil, and Bolivia

Effect of a Low Carbohydrate-Moderate Protein Supplement on Endurance Performance in Female Athletes

Previous research has shown that consuming a carbohydrate supplement during prolonged endurance exercise improves performance compared to water or placebo. The addition of protein to traditional carbohydrate supplement has been shown to further improve perfomance beyond that of carbohydrate alone. However, few investigations have explored the effect of adding protein to a supplement containing a low carbohydrate concentration. PURPOSE: To investigate if a low carbohydrate and moderate protein supplement, provided during prolonged variable intensity exercise, would improve time to exhaustion in comparison to a traditional carbohydrate supplement. METHODS: Fourteen (n = 14) trained females cyclists and triathletes (30.4 ±1.6 yrs, 2.90 ± 0.15 L⋅min¬-1) cycled on two different occasions for three hours at intensities varying between 45% - 70% VO2max. After three hours, the intensity was increased (average 72.5 % VO2max) and held until exhaustion. Exhaustion was defined as the point at which subjects could no longer hold cadence above 60RPM. Supplements (275ml) were provided every 20 min during exercise and were composed of a 3% carbohydrate/1.2% protein mix (CHO+PRO) or a 6% carbohydrate-only (CHO). The CHO+PRO treatment contained a mixture of glucose (dextrose), maltodextrin and fructose, and whey protein isolate. The CHO treatment was composed of dextrose. CHO+PRO contained half the carbohydrate content and 30% less calories in comparison to CHO. RESULTS: Time to exhaustion (TTE) was significantly greater with CHO+PRO in comparison to CHO (49.94 ± 7.01 vs 42.36 ± 6.21 min, respectively, p = 0.039). CONCLUSIONS: The above result suggests that addition of a moderate protein to a low carbohydrate supplement enhances performance in endurance trained females above that of carbohydrate alone. Improvement in performance occurred despite a lower carbohydrate and caloric content. It is unknown whether the greater performance seen with CHO+PRO was a result of the added protein, the use of a mixture of carbohydrate sources (glucose, maltodextrin and fructose), or their combination

Ref-1/APE1 as Transcriptional Regulator and Novel Therapeutic Target in Pediatric T-cell Leukemia

The increasing characterization of childhood acute lymphoblastic leukemia (ALL) has led to the identification of multiple molecular targets, but have yet to translate into more effective targeted therapies, particularly for high-risk, relapsed T-cell ALL. Searching for master regulators controlling multiple signaling pathways in T-ALL, we investigated the multi-functional protein redox factor-1 (Ref-1/APE1), which acts as a signaling "node" by exerting redox regulatory control of transcription factors important in leukemia. Leukemia patients' transcriptome databases showed increased expression in T-ALL of Ref-1 and other genes of the Ref-1/SET interactome. Validation studies demonstrated that Ref-1 is expressed in high-risk leukemia T-cells, including in patient biopsies. Ref-1 redox function is active in leukemia T-cells, regulating the Ref-1 target NF-kB, and inhibited by the redox-selective Ref-1 inhibitor E3330. Ref-1 expression is not regulated by Notch signaling, but is upregulated by glucocorticoid treatment. E3330 disrupted Ref-1 redox activity in functional studies and resulted in marked inhibition of leukemia cell viability, including T-ALL lines representing different genotypes and risk groups. Potent leukemia cell inhibition was seen in primary cells from ALL patients, relapsed and glucocorticoid-resistant T-ALL cells, and cells from a murine model of Notch-induced leukemia. Ref-1 redox inhibition triggered leukemia cell apoptosis and down-regulation of survival genes regulated by Ref-1 targets. For the first time, this work identifies Ref-1 as a novel molecular effector in T-ALL and demonstrates that Ref-1 redox inhibition results in potent inhibition of leukemia T-cells, including relapsed T-ALL. These data also support E3330 as a specific Ref-1 small molecule inhibitor for leukemia

Effects of Chocolate Milk Supplementation on Recovery from Cycling Exercise and Subsequent Time Trial Performance

PURPOSE: Supplementing with carbohydrate plus protein following strenuous endurance exercise has been found to improve both recovery and subsequent aerobic endurance performance beyond that of a carbohydrate supplement alone. The purpose of the present study was to compare the effects of chocolate milk (CM), an isocaloric carbohydrate only supplement (CHO), and placebo (PLA) on markers of endurance exercise recovery and subsequent time trial performance in trained cyclists. METHODS: Ten trained male and female cyclists (5 males, 5 females) performed 3 trials in which they first cycled for 1.5 h at 70% of VO2max, followed by 10 min of intervals that alternated 45% and 90% VO2max. They then recovered in the laboratory for 4 h, and performed a 40 km time trial (TT). The supplements were provided immediately after the first bout and 2 h into the recovery period. Treatments were administered using a double-blind randomized design. RESULTS: TT time was significantly shorter in CM than CHO and PLA (79.43±2.11 vs. 85.74±3.44 and 86.92±3.28 min, respectively, p=\u3c.05). Significant treatment differences were found for plasma insulin, glucose, free fatty acids (FFA) and glycerol. Plasma insulin levels were significantly lower in CM than CHO at recovery time points R45 (47.30±10.54 vs. 58.71±6.01 &#;U/ml, p\u3c.05), R120 (14.32±1.34 vs. 22.53±3.37 &#;U/ml, p\u3c.05) and REnd (15.57±1.53 vs. 34.35±4.55 &#;U/ml, p\u3c.05). Plasma glucose was significantly lower in CM than CHO at recovery time points R45 (76.61±3.08 vs. 101.65±3.47 mg/dL, p\u3c.05) and R120 (74.72±2.22 vs. 81.46±4.87 mg/dL, p\u3c.05). While FFA and glycerol were both higher in PLA than in CM and CHO overall (p\u3c.05 for both), FFA and glycerol were higher in CM than in CHO (p\u3c.05 for both) during recovery and at TTEnd. Blood lactate was significantly higher at R45 and TTEnd in both CM and CHO than in PLA, but no differences were found between CM and CHO. No significant treatment differences were found for myoglobin, CPK, cortisol, and 5 pro- and anti-inflammatory cytokines (TNF-&#;, IL-6, IL-10, IL-8, and IL-1Ra). CONCLUSIONS: Chocolate milk provided during recovery can improve subsequent time trial performance in trained cyclists more effectively than an isocaloric CHO supplement. This may be due to a faster rate of muscle glycogen resynthesis

GenomeVIP: A cloud platform for genomic variant discovery and interpretation

Identifying genomic variants is a fundamental first step toward the understanding of the role of inherited and acquired variation in disease. The accelerating growth in the corpus of sequencing data that underpins such analysis is making the data-download bottleneck more evident, placing substantial burdens on the research community to keep pace. As a result, the search for alternative approaches to the traditional “download and analyze” paradigm on local computing resources has led to a rapidly growing demand for cloud-computing solutions for genomics analysis. Here, we introduce the Genome Variant Investigation Platform (GenomeVIP), an open-source framework for performing genomics variant discovery and annotation using cloud- or local high-performance computing infrastructure. GenomeVIP orchestrates the analysis of whole-genome and exome sequence data using a set of robust and popular task-specific tools, including VarScan, GATK, Pindel, BreakDancer, Strelka, and Genome STRiP, through a web interface. GenomeVIP has been used for genomic analysis in large-data projects such as the TCGA PanCanAtlas and in other projects, such as the ICGC Pilots, CPTAC, ICGC-TCGA DREAM Challenges, and the 1000 Genomes SV Project. Here, we demonstrate GenomeVIP's ability to provide high-confidence annotated somatic, germline, and de novo variants of potential biological significance using publicly available data sets.</jats:p

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment