Nutrient availability has profound influence on development. In the nematode C. elegans, nutrient availability governs post-embryonic development. L1-stage larvae remain in a state of developmental ...arrest after hatching until they feed. This "L1 arrest" (or "L1 diapause") is associated with increased stress resistance, supporting starvation survival. Loss of the transcription factor daf-16/FOXO, an effector of insulin/IGF signaling, results in arrest-defective and starvation-sensitive phenotypes. We show that daf-16/FOXO regulates L1 arrest cell-nonautonomously, suggesting that insulin/IGF signaling regulates at least one additional signaling pathway. We used mRNA-seq to identify candidate signaling molecules affected by daf-16/FOXO during L1 arrest. dbl-1/TGF-β, a ligand for the Sma/Mab pathway, daf-12/ NHR and daf-36/oxygenase, an upstream component of the daf-12 steroid hormone signaling pathway, were up-regulated during L1 arrest in a daf-16/FOXO mutant. Using genetic epistasis analysis, we show that dbl-1/TGF-β and daf-12/NHR steroid hormone signaling pathways are required for the daf-16/FOXO arrest-defective phenotype, suggesting that daf-16/FOXO represses dbl-1/TGF-β, daf-12/NHR and daf-36/oxygenase. The dbl-1/TGF-β and daf-12/NHR pathways have not previously been shown to affect L1 development, but we found that disruption of these pathways delayed L1 development in fed larvae, consistent with these pathways promoting development in starved daf-16/FOXO mutants. Though the dbl-1/TGF-β and daf-12/NHR pathways are epistatic to daf-16/FOXO for the arrestdefective phenotype, disruption of these pathways does not suppress starvation sensitivity of daf-16/FOXO mutants. This observation uncouples starvation survival from developmental arrest, indicating that DAF-16/FOXO targets distinct effectors for each phenotype and revealing that inappropriate development during starvation does not cause the early demise of daf-16/FOXO mutants. Overall, this study shows that daf-16/FOXO promotes developmental arrest cell-nonautonomously by repressing pathways that promote larval development.
Nutrient availability has profound influence on development. In the nematode C. elegans, nutrient availability governs post-embryonic development. L1-stage larvae remain in a state of developmental ...arrest after hatching until they feed. This "L1 arrest" (or "L1 diapause") is associated with increased stress resistance, supporting starvation survival. Loss of the transcription factor daf-16/FOXO, an effector of insulin/IGF signaling, results in arrest-defective and starvation-sensitive phenotypes. We show that daf-16/FOXO regulates L1 arrest cell-nonautonomously, suggesting that insulin/IGF signaling regulates at least one additional signaling pathway. We used mRNA-seq to identify candidate signaling molecules affected by daf-16/FOXO during L1 arrest. dbl-1/TGF-beta, a ligand for the Sma/Mab pathway, daf-12/ NHR and daf-36/oxygenase, an upstream component of the daf-12 steroid hormone signaling pathway, were up-regulated during L1 arrest in a daf-16/FOXO mutant. Using genetic epistasis analysis, we show that dbl-1/TGF-beta and daf-12/NHR steroid hormone signaling pathways are required for the daf-16/FOXO arrest-defective phenotype, suggesting that daf-16/FOXO represses dbl-1/TGF-beta, daf-12/NHR and daf-36/oxygenase. The dbl-1/TGF-beta and daf-12/NHR pathways have not previously been shown to affect L1 development, but we found that disruption of these pathways delayed L1 development in fed larvae, consistent with these pathways promoting development in starved daf-16/FOXO mutants. Though the dbl-1/TGF-beta and daf-12/NHR pathways are epistatic to daf-16/FOXO for the arrestdefective phenotype, disruption of these pathways does not suppress starvation sensitivity of daf-16/FOXO mutants. This observation uncouples starvation survival from developmental arrest, indicating that DAF-16/FOXO targets distinct effectors for each phenotype and revealing that inappropriate development during starvation does not cause the early demise of daf-16/FOXO mutants. Overall, this study shows that daf-16/FOXO promotes developmental arrest cell-nonautonomously by repressing pathways that promote larval development.
Nutrient availability has profound influence on development. In the nematode C. elegans, nutrient availability governs post-embryonic development. L1-stage larvae remain in a state of developmental ...arrest after hatching until they feed. This "L1 arrest" (or "L1 diapause") is associated with increased stress resistance, supporting starvation survival. Loss of the transcription factor daf-16/FOXO, an effector of insulin/IGF signaling, results in arrest-defective and starvation-sensitive phenotypes. We show that daf-16/FOXO regulates L1 arrest cell-nonautonomously, suggesting that insulin/IGF signaling regulates at least one additional signaling pathway. We used mRNA-seq to identify candidate signaling molecules affected by daf-16/FOXO during L1 arrest. dbl-1/TGF-Beta, a ligand for the Sma/Mab pathway, daf-12/NHR and daf-36/oxygenase, an upstream component of the daf-12 steroid hormone signaling pathway, were up-regulated during L1 arrest in a daf-16/FOXO mutant. Using genetic epistasis analysis, we show that dbl-1/TGF-Beta and daf-12/NHR steroid hormone signaling pathways are required for the daf-16/FOXO arrest-defective phenotype, suggesting that daf-16/FOXO represses dbl-1/TGF-Beta, daf-12/NHR and daf-36/oxygenase. The dbl-1/TGF-Beta and daf-12/NHR pathways have not previously been shown to affect L1 development, but we found that disruption of these pathways delayed L1 development in fed larvae, consistent with these pathways promoting development in starved daf-16/FOXO mutants. Though the dbl-1/TGF-Beta and daf-12/NHR pathways are epistatic to daf-16/FOXO for the arrest-defective phenotype, disruption of these pathways does not suppress starvation sensitivity of daf-16/FOXO mutants. This observation uncouples starvation survival from developmental arrest, indicating that DAF-16/FOXO targets distinct effectors for each phenotype and revealing that inappropriate development during starvation does not cause the early demise of daf-16/FOXO mutants. Overall, this study shows that daf-16/FOXO promotes developmental arrest cell-nonautonomously by repressing pathways that promote larval development.
Abstract Based on our previously published risk stratification model, 295 (19%) of a consecutive series of 1594 TJA patients were triaged to the ICU. However, only 67 patients (22%) required ...intensive care interventions. We identified 5 independent multivariate predictors ( P < 0.001) including COPD, CAD, CHF (1 point each), EBL > 1000 mL, and intraoperative vasopressors (2 points each) to form the Penn Arthroplasty Risk Score (PARS). Patients with a score of 0 through 7 had a probability of requiring critical care of 7.0%, 13.2%, 23.5%, 38.1%, 55.4%, 71.4%, 83.4%, and 91.1% respectively. Based on these results, our previous risk stratification protocol is overly sensitive and non-specific. Any risk stratification algorithm for ICU admission should include intraoperative risk factors in order to be fully predictive.
Summary Background Country comparisons that consider the effect of fatal and non-fatal disease outcomes are needed for health-care planning. We calculated disability-adjusted life-years (DALYs) to ...estimate the global burden of cancer in 2008. Methods We used population-based data, mostly from cancer registries, for incidence, mortality, life expectancy, disease duration, and age at onset and death, alongside proportions of patients who were treated and living with sequelae or regarded as cured, to calculate years of life lost (YLLs) and years lived with disability (YLDs). We used YLLs and YLDs to derive DALYs for 27 sites of cancers in 184 countries in 12 world regions. Estimates were grouped into four categories based on a country's human development index (HDI). We applied zero discounting and uniform age weighting, and age-standardised rates to enable cross-country and regional comparisons. Findings Worldwide, an estimated 169·3 million years of healthy life were lost because of cancer in 2008. Colorectal, lung, breast, and prostate cancers were the main contributors to total DALYs in most world regions and caused 18–50% of the total cancer burden. We estimated an additional burden of 25% from infection-related cancers (liver, stomach, and cervical) in sub-Saharan Africa, and 27% in eastern Asia. We noted substantial global differences in the cancer profile of DALYs by country and region; however, YLLs were the most important component of DALYs in all countries and for all cancers, and contributed to more than 90% of the total burden. Nonetheless, low-resource settings had consistently higher YLLs (as a proportion of total DALYs) than did high-resource settings. Interpretation Age-adjusted DALYs lost from cancer are substantial, irrespective of world region. The consistently larger proportions of YLLs in low HDI than in high HDI countries indicate substantial inequalities in prognosis after diagnosis, related to degree of human development. Therefore, radical improvement in cancer care is needed in low-resource countries. Funding Dutch Scientific Society, Erasmus University Rotterdam, and International Agency for research on Cancer.
Along the Florida reef tract, stony-coral-tissue-loss disease (SCTLD) has caused extensive mortality of more than 20 scleractinian coral species. The pathogen is unknown, but its epizoology indicates ...that the disease, facilitated by water currents, has progressed linearly along the tract, affecting reefs at the scale of hundreds of kilometers. To inform ongoing disease mitigation efforts, we examined the small-scale spatial and temporal epidemiology of SCTLD. We established a series of sites in the middle Florida Keys at offshore and inshore locations that had not yet shown signs of SCTLD. We then conducted high-frequency monitoring from February 2018 through September 2019 and documented the onset of SCTLD and its progression through the sites. SCTLD was first observed at one site during early February 2018 and by early March 2018 all sites showed signs of the disease. A dynamic multistate model suggested that disease transmission was independent of coral density and found little evidence of a positive association between a colony showing signs of SCTLD and the condition or distance to its neighboring colonies. The model did, however, indicate that the probability of a colony showing signs of SCTLD increased with increasing colony surface area. These results are consistent with the water-borne transmission of a pathogen that progressed rapidly through the survey area. However, by the end of our survey the progression of SCTLD had slowed, particularly at inshore sites. Many affected colonies no longer exhibited progressive tissue mortality typical of the disease, suggesting the existence of differentially resilient colonies or coral communities, meriting their use for future coral rescue and propagation and disease research. These results are useful for refining ongoing SCTLD mitigation strategies, particularly by determining when disease rates are sufficiently low for direct intervention efforts designed to arrest disease progression on individual coral colonies will be most effective.
Estimates of the worldwide incidence and mortality from 27 cancers in 2008 have been prepared for 182 countries as part of the GLOBOCAN series published by the International Agency for Research on ...Cancer. In this article, we present the results for 20 world regions, summarizing the global patterns for the eight most common cancers. Overall, an estimated 12.7 million new cancer cases and 7.6 million cancer deaths occur in 2008, with 56% of new cancer cases and 63% of the cancer deaths occurring in the less developed regions of the world. The most commonly diagnosed cancers worldwide are lung (1.61 million, 12.7% of the total), breast (1.38 million, 10.9%) and colorectal cancers (1.23 million, 9.7%). The most common causes of cancer death are lung cancer (1.38 million, 18.2% of the total), stomach cancer (738,000 deaths, 9.7%) and liver cancer (696,000 deaths, 9.2%). Cancer is neither rare anywhere in the world, nor mainly confined to high‐resource countries. Striking differences in the patterns of cancer from region to region are observed.
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