Summary
The RNA‐directed DNA methylation (RdDM) pathway is of central importance to the initiation and maintenance of transcriptional gene silencing in plants. DNA methylation is directed to target ...sequences by a mechanism that involves production of small RNAs by RNA polymerase IV and long non‐coding RNAs by RNA polymerase V. DNA methylation then leads to recruitment of histone‐modifying enzymes, followed by establishment of a silenced chromatin state. Recently MORC6, a member of the microrchidia (MORC) family of adenosine triphosphatases (ATPases), has been shown to be involved in transcriptional gene silencing. However, reports differ regarding whether MORC6 is involved in RdDM itself or acts downstream of DNA methylation to enable formation of higher‐order chromatin structure. Here we demonstrate that MORC6 is required for efficient RdDM at some target loci, and, using a GFP reporter system, we found that morc6 mutants show a stochastic silencing phenotype. By using cell sorting to separate silenced and unsilenced cells, we show that release of silencing at this locus is associated with a loss of DNA methylation. Thus our data support a view that MORC6 influences RdDM and that it is not acting downstream of DNA methylation. For some loci, efficient initiation or maintenance of DNA methylation may depend on the ability to form higher‐order chromatin structure.
The NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC) employed a pair of reference xenograft proteomes for initial platform validation and ongoing quality control of its data collection for ...The Cancer Genome Atlas (TCGA) tumors. These two xenografts, representing basal and luminal-B human breast cancer, were fractionated and analyzed on six mass spectrometers in a total of 46 replicates divided between iTRAQ and label-free technologies, spanning a total of 1095 LC–MS/MS experiments. These data represent a unique opportunity to evaluate the stability of proteomic differentiation by mass spectrometry over many months of time for individual instruments or across instruments running dissimilar workflows. We evaluated iTRAQ reporter ions, label-free spectral counts, and label-free extracted ion chromatograms as strategies for data interpretation (source code is available from http://homepages.uc.edu/~wang2x7/Research.htm). From these assessments, we found that differential genes from a single replicate were confirmed by other replicates on the same instrument from 61 to 93% of the time. When comparing across different instruments and quantitative technologies, using multiple replicates, differential genes were reproduced by other data sets from 67 to 99% of the time. Projecting gene differences to biological pathways and networks increased the degree of similarity. These overlaps send an encouraging message about the maturity of technologies for proteomic differentiation.
We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and ...includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The triglyceride glucose (TyG) index is an easily accessible surrogate marker of insulin resistance, an important pathway in the development of type 2 diabetes and cardiovascular diseases. However, ...the association of the TyG index with cardiovascular diseases and mortality has mainly been investigated in Asia, with few data available from other regions of the world. We assessed the association of insulin resistance (as determined by the TyG index) with mortality and cardiovascular diseases in individuals from five continents at different levels of economic development, living in urban or rural areas. We also examined whether the associations differed according to the country's economical development.
We used the TyG index as a surrogate measure for insulin resistance. Fasting triglycerides and fasting plasma glucose were measured at the baseline visit in 141 243 individuals aged 35–70 years from 22 countries in the Prospective Urban Rural Epidemiology (PURE) study. The TyG index was calculated as Ln (fasting triglycerides mg/dL x fasting plasma glucose mg/dL/2). We calculated hazard ratios (HRs) using a multivariable Cox frailty model with random effects to test the associations between the TyG index and risk of cardiovascular diseases and mortality. The primary outcome of this analysis was the composite of mortality or major cardiovascular events (defined as death from cardiovascular causes, and non-fatal myocardial infarction, or stroke). Secondary outcomes were non-cardiovascular mortality, cardiovascular mortality, all myocardial infarctions, stroke, and incident diabetes. We also did subgroup analyses to examine the magnitude of associations between insulin resistance (ie, the TyG index) and outcome events according to the income level of the countries.
During a median follow-up of 13·2 years (IQR 11·9–14·6), we recorded 6345 composite cardiovascular diseases events, 2030 cardiovascular deaths, 3038 cases of myocardial infarction, 3291 cases of stroke, and 5191 incident cases of type 2 diabetes. After adjusting for all other variables, the risk of developing cardiovascular diseases increased across tertiles of the baseline TyG index. Compared with the lowest tertile of the TyG index, the highest tertile (tertile 3) was associated with a greater incidence of the composite outcome (HR 1·21; 95% CI 1·13–1·30), myocardial infarction (1·24; 1·12–1·38), stroke (1·16; 1·05–1·28), and incident type 2 diabetes (1·99; 1·82–2·16). No significant association of the TyG index was seen with non-cardiovascular mortality. In low-income countries (LICs) and middle-income countries (MICs), the highest tertile of the TyG index was associated with increased hazards for the composite outcome (LICs: HR 1·31; 95% CI 1·12–1·54; MICs: 1·20; 1·11–1·31; pinteraction=0·01), cardiovascular mortality (LICs: 1·44; 1·15–1·80; pinteraction=0·01), myocardial infarction (LICs: 1·29; 1·06–1·56; MICs: 1·26; 1·10–1·45; pinteraction=0·08), stroke (LICs: 1·35; 1·02–1·78; MICs: 1·17; 1·05–1·30; pinteraction=0·19), and incident diabetes (LICs: 1·64; 1·38–1·94; MICs: 2·68; 2·40–2·99; pinteraction <0·0001). In contrast, in high-income countries, higher TyG index tertiles were only associated with an increased hazard of incident diabetes (2·95; 2·25–3·87; pinteraction <0·0001), but not of cardiovascular diseases or mortality.
The TyG index is significantly associated with future cardiovascular mortality, myocardial infarction, stroke, and type 2 diabetes, suggesting that insulin resistance plays a promoting role in the pathogenesis of cardiovascular and metabolic diseases. Potentially, the association between the TyG index and the higher risk of cardiovascular diseases and type 2 diabetes in LICs and MICs might be explained by an increased vulnerability of these populations to the presence of insulin resistance.
Full funding sources are listed at the end of the paper (see Acknowledgments).
Purpose
There is limited information on how the COVID-19 pandemic has changed health behaviors among cancer patients. We examined changes in exercise behaviors since the pandemic and identified ...characteristics associated with these changes among cancer patients.
Methods
Cancer patients (
n
= 1,210) completed a survey from August to September 2020 to assess COVID-19 pandemic-related changes in health behaviors and psychosocial factors. Patients were categorized into three groups: exercising less, exercising did not change, and exercising more. Patient characteristics were compared by exercise groups.
Results
One-third of the patients reported a decreased amount of regular exercise, while 10% reported exercising more during the pandemic. Patients who exercised less were more likely to be unemployed/retired and have poor health status and psychosocial stressors such as disruptions in daily life while less likely to be former smokers (all
p
< 0.05). In contrast, patients who exercised more were younger, had stage IV diagnosis, and also reported disruptions in daily life (all
p
< 0.05). Patients who were living in rural areas were also more likely not to experience changes in exercise habits (all
p
< 0.05), although rural–urban status was not identified as a strong predictor.
Conclusion
A significant proportion of cancer patients experienced changes in exercise habits, especially exercising less, during the first 6 months of the COVID-19 pandemic. Age, employment status, tumor stage, health status, smoking status, and psychosocial factors were associated with changes in exercise behaviors. Our results highlight the importance of promoting physical activity guidelines for cancer survivorship during the COVID-19 pandemic and may help improve the identification of cancer patients susceptible to exercising less.
In our continuing effort to expand the SAR of the quinoline domain of dihydropyrrolopyrazole series, we have discovered compound 15d, which demonstrated the antitumor efficacy with oral ...bioavailability. This effort also demonstrated that the PK/PD in vivo target inhibition paradigm is an effective approach to assess potential for antitumor efficacy. The dihydropyrrolopyrazole inhibitor 15d (LY2109761) is representative of a novel series of antitumor agents.
Arctic climate in the Late Cretaceous has long been recognized to have been warm and wet relative to the present, but quantitative assessments of paleoclimate have been challenging due, in part, to ...disagreements between proxies in marine and terrestrial environments. This study provides a first multiproxy evaluation of Late Cretaceous (~93–90 Ma to 73–72 Ma) paleoclimate and paleohydrology from Devon Island in the Canadian High Arctic (modern location: 76°17′N, 91°12′W; Late Cretaceous location: ~71°30′N, ~24°30′W). Surface temperatures are reconstructed at ~12.6 to 20.6 °C for the ocean and 11.7 to 16.9 °C over land, using glycerol dialkyl glycerol tetraether (GDGT) based proxies measured from marine (TEX86) and terrestrial samples (MBT′5ME). These proxies are likely skewed toward warm month temperatures, based on novel analysis and interpretation of biomarkers in sediment and co-occurring marine vertebrate coprolites. The hydrogen isotopic composition (δ2H) of precipitation is constrained to have varied from −123‰ to −82‰ (VSMOW) using evidence from n-alkanes likely derived from higher plants. δ18O of shelfal marine surface water is constrained to have been between −10.5‰ to −3.4‰, using phosphate oxygen isotopes of marine vertebrate teeth and coprolites. From these, marine salinity is modeled to have varied from 10 PSU and 30 PSU, indicative of periodic freshwater influx. These estimates indicate that large marine vertebrates lived and fed, at least intermittently, in near-shore brackish waters. Finally, the Arctic was similarly warm in both the Late Cretaceous and Paleocene/Eocene, but the Late Cretaceous isotopic composition of precipitation at Devon Island was enriched in the heavy isotope of hydrogen by up to +60 to +70‰ relative to Arctic Eocene sites. The combination of techniques used here reduces uncertainties related to the application of proxies to an environment without a modern analogue, providing novel paleoclimatic constraints on the Late Cretaceous Arctic region.
•Arctic TEX86 sea surface temperatures of ~13–21 °C in Late Cretaceous•MBT′5ME terrestrial temperature estimates of ~12–17 °C•Warm month bias of TEX86 suggested by biomarker analysis of marine coprolites•Neritic salinity highly variable (10–30 PSU)•Isotopic composition of precipitation highly enriched relative to modern
gene rearrangement with transcriptional superenhancers leads to
overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with
-rearranged neuroblastoma.
...Anticancer agents exerting the best synergistic anticancer effects with BET bromodomain inhibitors were identified by screening an FDA-approved oncology drug library. The synergistic effects of the BET bromodomain inhibitor OTX015 and the proteasome inhibitor carfilzomib were examined by immunoblot and flow cytometry analysis. The anticancer efficacy of OTX015 and carfilzomib combination therapy was investigated in mice xenografted with
-rearranged neuroblastoma cell lines or patient-derived xenograft (PDX) tumor cells, and the role of TERT reduction in the anticancer efficacy was examined through rescue experiments in mice.
The BET bromodomain protein BRD4 promoted
-rearranged neuroblastoma cell proliferation through upregulating TERT expression. Screening of an approved oncology drug library identified the proteasome inhibitor carfilzomib as the agent exerting the best synergistic anticancer effects with BET bromodomain inhibitors including OTX015. OTX015 and carfilzomib synergistically reduced TERT protein expression, induced endoplasmic reticulum stress, and induced
-rearranged neuroblastoma cell apoptosis which was blocked by TERT overexpression and endoplasmic reticulum stress antagonists. In mice xenografted with
-rearranged neuroblastoma cell lines or PDX tumor cells, OTX015 and carfilzomib synergistically blocked TERT expression, induced tumor cell apoptosis, suppressed tumor progression, and improved mouse survival, which was largely reversed by forced TERT overexpression.
OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with
-rearranged neuroblastoma.
Partnership for Health (PFH) was found to increase smoking cessation among smokers in the Childhood Cancer Survivors Study (CCSS) at the 8- and 12-month postbaseline follow-up. This report provides ...outcomes at 2 to 6 years postbaseline; the primary outcome is a four-category smoking status variable (quit at all follow-ups, quit at final follow-up only, smoker at all follow-ups, and smoker at final follow-up only); quit attempts among those who reported smoking at the final follow-up is a secondary outcome.
PFH was a randomized control trial with two conditions, peer phone counseling (PC) and self-help (SH), that involved smokers (n = 796) enrolled in the CCSS cohort.
Long-term quit rates were higher in PC versus SH participants. Long-term smoking cessation outcomes were lower among those who were nicotine dependent, of lower educational levels, and among men, and were higher among those who used nicotine replacement therapy and who had higher levels of situational self-efficacy. There were no significant differences in relapse rates between conditions or in quit attempts among continued smokers.
Cessation rates continue to be significantly higher among participants in the PC condition versus SH, although the differences were not large. This article highlights differences in long-term engagement with smoking cessation among those who received the intervention.
The world's oceans contain a complex mixture of micro-organisms that are for the most part, uncharacterized both genetically and biochemically. We report here a metagenomic study of the marine ...planktonic microbiota in which surface (mostly marine) water samples were analyzed as part of the Sorcerer II Global Ocean Sampling expedition. These samples, collected across a several-thousand km transect from the North Atlantic through the Panama Canal and ending in the South Pacific yielded an extensive dataset consisting of 7.7 million sequencing reads (6.3 billion bp). Though a few major microbial clades dominate the planktonic marine niche, the dataset contains great diversity with 85% of the assembled sequence and 57% of the unassembled data being unique at a 98% sequence identity cutoff. Using the metadata associated with each sample and sequencing library, we developed new comparative genomic and assembly methods. One comparative genomic method, termed "fragment recruitment," addressed questions of genome structure, evolution, and taxonomic or phylogenetic diversity, as well as the biochemical diversity of genes and gene families. A second method, termed "extreme assembly," made possible the assembly and reconstruction of large segments of abundant but clearly nonclonal organisms. Within all abundant populations analyzed, we found extensive intra-ribotype diversity in several forms: (1) extensive sequence variation within orthologous regions throughout a given genome; despite coverage of individual ribotypes approaching 500-fold, most individual sequencing reads are unique; (2) numerous changes in gene content some with direct adaptive implications; and (3) hypervariable genomic islands that are too variable to assemble. The intra-ribotype diversity is organized into genetically isolated populations that have overlapping but independent distributions, implying distinct environmental preference. We present novel methods for measuring the genomic similarity between metagenomic samples and show how they may be grouped into several community types. Specific functional adaptations can be identified both within individual ribotypes and across the entire community, including proteorhodopsin spectral tuning and the presence or absence of the phosphate-binding gene PstS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
