Topological organization and dynamic regulation of human tRNA genes during macrophage differentiation

BACKGROUND: The human genome is hierarchically organized into local and long-range structures that help shape cell-type-specific transcription patterns. Transfer RNA (tRNA) genes (tDNAs), which are transcribed by RNA polymerase III (RNAPIII) and encode RNA molecules responsible for translation, are dispersed throughout the genome and, in many cases, linearly organized into genomic clusters with other tDNAs. Whether the location and three-dimensional organization of tDNAs contribute to the activity of these genes has remained difficult to address, due in part to unique challenges related to tRNA sequencing. We therefore devised integrated tDNA expression profiling, a method that combines RNAPIII mapping with biotin-capture of nascent tRNAs. We apply this method to the study of dynamic tRNA gene regulation during macrophage development and further integrate these data with high-resolution maps of 3D chromatin structure. RESULTS: Integrated tDNA expression profiling reveals domain-level and loop-based organization of tRNA gene transcription during cellular differentiation. tRNA genes connected by DNA loops, which are proximal to CTCF binding sites and expressed at elevated levels compared to non-loop tDNAs, change coordinately with tDNAs and protein-coding genes at distal ends of interactions mapped by in situ Hi-C. We find that downregulated tRNA genes are specifically marked by enhanced promoter-proximal binding of MAF1, a transcriptional repressor of RNAPIII activity, altogether revealing multiple levels of tDNA regulation during cellular differentiation. CONCLUSIONS: We present evidence of both local and coordinated long-range regulation of human tDNA expression, suggesting the location and organization of tRNA genes contribute to dynamic tDNA activity during macrophage development

Disruption of mesoderm formation during cardiac differentiation due to developmental exposure to 13-cis-retinoic acid.

13-cis-retinoic acid (isotretinoin, INN) is an oral pharmaceutical drug used for the treatment of skin acne, and is also a known teratogen. In this study, the molecular mechanisms underlying INN-induced developmental toxicity during early cardiac differentiation were investigated using both human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs). Pre-exposure of hiPSCs and hESCs to a sublethal concentration of INN did not influence cell proliferation and pluripotency. However, mesodermal differentiation was disrupted when INN was included in the medium during differentiation. Transcriptomic profiling by RNA-seq revealed that INN exposure leads to aberrant expression of genes involved in several signaling pathways that control early mesoderm differentiation, such as TGF-beta signaling. In addition, genome-wide chromatin accessibility profiling by ATAC-seq suggested that INN-exposure leads to enhanced DNA-binding of specific transcription factors (TFs), including HNF1B, SOX10 and NFIC, often in close spatial proximity to genes that are dysregulated in response to INN treatment. Altogether, these results identify potential molecular mechanisms underlying INN-induced perturbation during mesodermal differentiation in the context of cardiac development. This study further highlights the utility of human stem cells as an alternative system for investigating congenital diseases of newborns that arise as a result of maternal drug exposure during pregnancy

Static and Dynamic DNA Loops form AP-1-Bound Activation Hubs during Macrophage Development

The three-dimensional arrangement of the human genome comprises a complex network of structural and regulatory chromatin loops important for coordinating changes in transcription during human development. To better understand the mechanisms underlying context-specific 3D chromatin structure and transcription during cellular differentiation, we generated comprehensive in situ Hi-C maps of DNA loops during human monocyte-to-macrophage differentiation. We demonstrate that dynamic looping events are regulatory rather than structural in nature and uncover widespread coordination of dynamic enhancer activity at preformed and acquired DNA loops. Enhancer-bound loop formation and enhancer-activation of preformed loops represent two distinct modes of regulation that together form multi-loop activation hubs at key macrophage genes. Activation hubs connect 3.4 enhancers per promoter and exhibit a strong enrichment for Activator Protein 1 (AP-1) binding events, suggesting multi-loop activation hubs driven by cell-type specific transcription factors may represent an important class of regulatory chromatin structures for the spatiotemporal control of transcription

Appetite and gut hormone responses to moderate-intensity continuous exercise versus high-intensity interval exercise, in normoxic and hypoxic conditions.

This study investigated the effects of continuous moderate-intensity exercise (MIE) and high-intensity interval exercise (HIIE) in combination with short exposure to hypoxia on appetite and plasma concentrations of acylated ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). Twelve healthy males completed four, 2.6 h trials in a random order: 1) MIE-normoxia, 2) MIE-hypoxia, 3) HIIE-normoxia, and 4) HIIE-hypoxia. Exercise took place in an environmental chamber. During MIE, participants ran for 50 min at 70% of altitude-specific maximal oxygen uptake ( 2max) and during HIIE performed 6 x 3 min running at 90% 2max interspersed with 6 x 3 min active recovery at 50% 2max with a 7 min warm-up and cool-down at 70% 2max (50 min total). In hypoxic trials, exercise was performed at a simulated altitude of 2,980 m (14.5% O2). Exercise was completed after a standardised breakfast. A second meal standardised to 30% of participants’ daily energy requirements was provided 45 min after exercise. Appetite was suppressed more in hypoxia than normoxia during exercise, post-exercise, and for the full 2.6 h trial period (linear mixed modelling, p 0.05). These findings demonstrate that short exposure to hypoxia causes suppressions in appetite and plasma acylated ghrelin concentrations. Furthermore, appetite responses to exercise do not appear to be influenced by exercise modality

The melanoma-specific graded prognostic assessment does not adequately discriminate prognosis in a modern population with brain metastases from malignant melanoma

The melanoma-specific graded prognostic assessment (msGPA) assigns patients with brain metastases from malignant melanoma to 1 of 4 prognostic groups. It was largely derived using clinical data from patients treated in the era that preceded the development of newer therapies such as BRAF, MEK and immune checkpoint inhibitors. Therefore, its current relevance to patients diagnosed with brain metastases from malignant melanoma is unclear. This study is an external validation of the msGPA in two temporally distinct British populations.Performance of the msGPA was assessed in Cohort I (1997-2008, n=231) and Cohort II (2008-2013, n=162) using Kaplan-Meier methods and Harrell's c-index of concordance. Cox regression was used to explore additional factors that may have prognostic relevance.The msGPA does not perform well as a prognostic score outside of the derivation cohort, with suboptimal statistical calibration and discrimination, particularly in those patients with an intermediate prognosis. Extra-cerebral metastases, leptomeningeal disease, age and potential use of novel targeted agents after brain metastases are diagnosed, should be incorporated into future prognostic models.An improved prognostic score is required to underpin high-quality randomised controlled trials in an area with a wide disparity in clinical care

Agricultural intensification heightens food safety risks posed by wild birds

Agricultural intensification and simplification are key drivers of recent declines in wild bird populations, heightening the need to better balance conservation with food production. This is hindered, however, by perceptions that birds threaten food safety. While birds are known reservoirs of foodborne pathogens, there remains uncertainty about the links between landscape context, farming practices, and actual crop contamination by birds. Here, we examine relationships between landscape context, farming practices, and pathogen contamination by birds using a barrier-to-spillover approach. First, we censused bird communities using point count surveys. Second, we collected 2,024 faecal samples from captured birds alongside 1,215 faecal samples from brassica fields and food processing areas across 50 farms spanning the USA West Coast. We then estimated the prevalence of three foodborne pathogens across landscape and livestock intensification gradients. Finally, we quantified the number of plants with faeces. Campylobacterspp. were detected in 10.2% of faeces from captured birds and 13.1% of faeces from production areas. Non-native birds were 4.1 times more likely to haveCampylobacterspp. than native birds.Salmonellaspp. were detected in 0.2% of faeces from production areas and were never detected in captured birds. We detected evidence of Shiga toxigenicE. coliin one sample across the >3,200 tested. Campylobacterspp. prevalence in faeces from production areas increased with increasing mammalian livestock densities in the landscape but decreased with increasing amounts of natural habitat. We encountered bird faeces on 3.3% of plants examined. Despite the impact on pathogen prevalence, amount of natural habitat in the landscape did not increase the number of plants with bird faeces, although on-farm mammalian livestock density slightly did. Synthesis and applications. Food safety and wildlife conservation are often thought to be in conflict. However, our findings suggest that natural habitat around farms may reduce crop contamination rates by birds. This is perhaps because natural habitat can promote native birds that are less likely to harbour foodborne pathogens or because it decreases contact with livestock waste. Our results suggest that preservation of natural habitats around farms could benefit both conservation and food safety, contrary to current standards for 'best practices'

Unbiased metabolome screen leads to personalized medicine strategy for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disease that affects 1/350 individuals in the United Kingdom. The cause of amyotrophic lateral sclerosis is unknown in the majority of cases. Two-sample Mendelian randomization enables causal inference between an exposure, such as the serum concentration of a specific metabolite, and disease risk. We obtained genome-wide association study summary statistics for serum concentrations of 566 metabolites which were population matched with a genome-wide association study of amyotrophic lateral sclerosis. For each metabolite, we performed Mendelian randomization using an inverse variance weighted estimate for significance testing. After stringent Bonferroni multiple testing correction, our unbiased screen revealed three metabolites that were significantly linked to the risk of amyotrophic lateral sclerosis: Estrone-3-sulphate and bradykinin were protective, which is consistent with literature describing a male preponderance of amyotrophic lateral sclerosis and a preventive effect of angiotensin-converting enzyme inhibitors which inhibit the breakdown of bradykinin. Serum isoleucine was positively associated with amyotrophic lateral sclerosis risk. All three metabolites were supported by robust Mendelian randomization measures and sensitivity analyses; estrone-3-sulphate and isoleucine were confirmed in a validation amyotrophic lateral sclerosis genome-wide association study. Estrone-3-sulphate is metabolized to the more active estradiol by the enzyme 17β-hydroxysteroid dehydrogenase 1; further, Mendelian randomization demonstrated a protective effect of estradiol and rare variant analysis showed that missense variants within HSD17B1, the gene encoding 17β-hydroxysteroid dehydrogenase 1, modify risk for amyotrophic lateral sclerosis. Finally, in a zebrafish model of C9ORF72-amyotrophic lateral sclerosis, we present evidence that estradiol is neuroprotective. Isoleucine is metabolized via methylmalonyl-CoA mutase encoded by the gene MMUT in a reaction that consumes vitamin B12. Multivariable Mendelian randomization revealed that the toxic effect of isoleucine is dependent on the depletion of vitamin B12; consistent with this, rare variants which reduce the function of MMUT are protective against amyotrophic lateral sclerosis. We propose that amyotrophic lateral sclerosis patients and family members with high serum isoleucine levels should be offered supplementation with vitamin B12

The Grizzly, November 17, 1989

Inspired Voices Speak Out Nationally • Appealing for Unborn Lives • Boorstin Speaks at U.C. • Letters: Pledging Under Siege; Grizzly Growls; Did Berman Ask You?; Doctors do it Right; Only Doug; Wipe Mud From Shoudt\u27s Face; Wrong!; GDI Promotes Disunity • Changing Dining Atmosphere • Save a Forest: Recycle! • Career Day • Running Bears Finish Strong • Grizzlies Downed by Devils • Ladies Finish Winning Season • Praise Hockey Team • Swimming Prospectives • Greek News • Stroke on A\u27Bears • Don\u27t Talk Dirty to Me • Top Ten Things Loved at U.C.https://digitalcommons.ursinus.edu/grizzlynews/1247/thumbnail.jp

A population of luminous accreting black holes with hidden mergers

Major galaxy mergers are thought to play an important part in fuelling the growth of supermassive black holes. However, observational support for this hypothesis is mixed, with some studies showing a correlation between merging galaxies and luminous quasars and others showing no such association. Recent observations have shown that a black hole is likely to become heavily obscured behind merger-driven gas and dust, even in the early stages of the merger, when the galaxies are well separated (5 to 40 kiloparsecs). Merger simulations further suggest that such obscuration and black-hole accretion peaks in the final merger stage, when the two galactic nuclei are closely separated (less than 3 kiloparsecs). Resolving this final stage requires a combination of high-spatial-resolution infrared imaging and high-sensitivity hard-X-ray observations to detect highly obscured sources. However, large numbers of obscured luminous accreting supermassive black holes have been recently detected nearby (distances below 250 megaparsecs) in X-ray observations. Here we report high-resolution infrared observations of hard-X-ray-selected black holes and the discovery of obscured nuclear mergers, the parent populations of supermassive-black-hole mergers. We find that obscured luminous black holes (bolometric luminosity higher than 2x10^44 ergs per second) show a significant (P<0.001) excess of late-stage nuclear mergers (17.6 per cent) compared to a sample of inactive galaxies with matching stellar masses and star formation rates (1.1 per cent), in agreement with theoretical predictions. Using hydrodynamic simulations, we confirm that the excess of nuclear mergers is indeed strongest for gas-rich major-merger hosts of obscured luminous black holes in this final stage.Comment: To appear in the 8 November 2018 issue of Nature. This is the authors' version of the wor