Genomic and epigenomic EBF1 alterations modulate TERT expression in gastric cancer

Transcriptional reactivation of telomerase catalytic subunit (TERT) is a frequent hallmark of cancer, occurring in 90% of human malignancies. However, specific mechanisms driving TERT reactivation remain obscure for many tumor types and in particular gastric cancer (GC), a leading cause of global cancer mortality. Here, through comprehensive genomic and epigenomic analysis of primary GCs and GC cell lines, we identified the transcription factor early B cell factor 1 (EBF1) as a TERT transcriptional repressor and inactivation of EBF1 function as a major cause of TERT upregulation. Abolishment of EBF1 function occurs through 3 distinct (epi)genomic mechanisms. First, EBF1 is epigenetically silenced via DNA methyltransferase, polycomb-repressive complex 2 (PRC2), and histone deacetylase activity in GCs. Second, recurrent, somatic, and heterozygous EBF1 DNA–binding domain mutations result in the production of dominant-negative EBF1 isoforms. Third, more rarely, genomic deletions and rearrangements proximal to the TERT promoter remobilize or abolish EBF1-binding sites, derepressing TERT and leading to high TERT expression. EBF1 is also functionally required for various malignant phenotypes in vitro and in vivo, highlighting its importance for GC development. These results indicate that multimodal genomic and epigenomic alterations underpin TERT reactivation in GC, converging on transcriptional repressors such as EBF1

Biomechanical analysis of the lumbar spine on facet joint force and intradiscal pressure - a finite element study

<p>Abstract</p> <p>Background</p> <p>Finite element analysis results will show significant differences if the model used is performed under various material properties, geometries, loading modes or other conditions. This study adopted an FE model, taking into account the possible asymmetry inherently existing in the spine with respect to the sagittal plane, with a more geometrically realistic outline to analyze and compare the biomechanical behaviour of the lumbar spine with regard to the facet force and intradiscal pressure, which are associated with low back pain symptoms and other spinal disorders. Dealing carefully with the contact surfaces of the facet joints at various levels of the lumbar spine can potentially help us further ascertain physiological behaviour concerning the frictional effects of facet joints under separate loadings or the responses to the compressive loads in the discs.</p> <p>Methods</p> <p>A lumbar spine model was constructed from processes including smoothing the bony outline of each scan image, stacking the boundary lines into a smooth surface model, and subsequent further processing in order to conform with the purpose of effective finite element analysis performance. For simplicity, most spinal components were modelled as isotropic and linear materials with the exception of spinal ligaments (bilinear). The contact behaviour of the facet joints and changes of the intradiscal pressure with different postures were analyzed.</p> <p>Results</p> <p>The results revealed that asymmetric responses of the facet joint forces exist in various postures and that such effect is amplified with larger loadings. In axial rotation, the facet joint forces were relatively larger in the contralateral facet joints than in the ipsilateral ones at the same level. Although the effect of the preloads on facet joint forces was not apparent, intradiscal pressure did increase with preload, and its magnitude increased more markedly in flexion than in extension and axial rotation.</p> <p>Conclusions</p> <p>Disc pressures showed a significant increase with preload and changed more noticeably in flexion than in extension or in axial rotation. Compared with the applied preloads, the postures played a more important role, especially in axial rotation; the facet joint forces were increased in the contralateral facet joints as compared to the ipsilateral ones at the same level of the lumbar spine.</p

Pantropical modelling of canopy functional traits using Sentinel-2 remote sensing data

Tropical forest ecosystems are undergoing rapid transformation as a result of changing environmental conditions and direct human impacts. However, we cannot adequately understand, monitor or simulate tropical ecosystem responses to environmental changes without capturing the high diversity of plant functional characteristics in the species-rich tropics. Failure to do so can oversimplify our understanding of ecosystems responses to environmental disturbances. Innovative methods and data products are needed to track changes in functional trait composition in tropical forest ecosystems through time and space. This study aimed to track key functional traits by coupling Sentinel-2 derived variables with a unique data set of precisely located in-situ measurements of canopy functional traits collected from 2434 individual trees across the tropics using a standardised methodology. The functional traits and vegetation censuses were collected from 47 field plots in the countries of Australia, Brazil, Peru, Gabon, Ghana, and Malaysia, which span the four tropical continents. The spatial positions of individual trees above 10 cm diameter at breast height (DBH) were mapped and their canopy size and shape recorded. Using geo-located tree canopy size and shape data, community-level trait values were estimated at the same spatial resolution as Sentinel-2 imagery (i.e. 10 m pixels). We then used the Geographic Random Forest (GRF) to model and predict functional traits across our plots. We demonstrate that key plant functional traits can be accurately predicted across the tropicsusing the high spatial and spectral resolution of Sentinel-2 imagery in conjunction with climatic and soil information. Image textural parameters were found to be key components of remote sensing information for predicting functional traits across tropical forests and woody savannas. Leaf thickness (R2 = 0.52) obtained the highest prediction accuracy among the morphological and structural traits and leaf carbon content (R2 = 0.70) and maximum rates of photosynthesis (R2 = 0.67) obtained the highest prediction accuracy for leaf chemistry and photosynthesis related traits, respectively. Overall, the highest prediction accuracy was obtained for leaf chemistry and photosynthetic traits in comparison to morphological and structural traits. Our approach offers new opportunities for mapping, monitoring and understanding biodiversity and ecosystem change in the most species-rich ecosystems on Earth

Genome-wide association study identifies multiple risk loci for renal cell carcinoma

Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10−10), 3p22.1 (rs67311347, P=2.5 × 10−8), 3q26.2 (rs10936602, P=8.8 × 10−9), 8p21.3 (rs2241261, P=5.8 × 10−9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10−8), 11q22.3 (rs74911261, P=2.1 × 10−10) and 14q24.2 (rs4903064, P=2.2 × 10−24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 &times; 10-11 to 5.0 &times; 10-21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 &times; 10-6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation

Track D Social Science, Human Rights and Political Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138414/1/jia218442.pd

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic

A Survey of Bayesian Statistical Approaches for Big Data

The modern era is characterised as an era of information or Big Data. This has motivated a huge literature on new methods for extracting information and insights from these data. A natural question is how these approaches differ from those that were available prior to the advent of Big Data. We present a review of published studies that present Bayesian statistical approaches specifically for Big Data and discuss the reported and perceived benefits of these approaches. We conclude by addressing the question of whether focusing only on improving computational algorithms and infrastructure will be enough to face the challenges of Big Data