WRFv3.2-SPAv2: development and validation of a coupled ecosystem-atmosphere model, scaling from surface fluxes of CO2 and energy to atmospheric profiles

The Weather Research and Forecasting meteorological (WRF) model has been coupled to the Soil–Plant–Atmosphere (SPA) terrestrial ecosystem model, to produce WRF-SPA. SPA generates realistic land–atmosphere exchanges through fully coupled hydrological, carbon and energy cycles. The addition of a~land surface model (SPA) capable of modelling biospheric CO₂ exchange allows WRF-SPA to be used for investigating the feedbacks between biosphere carbon balance, meteorology, and land use and land cover change. We have extensively validated WRF-SPA using multi-annual observations of air temperature, turbulent fluxes, net radiation and net ecosystem exchange of CO₂ at three sites, representing the dominant vegetation types in Scotland (forest, managed grassland and arable agriculture). For example air temperature is well simulated across all sites (forest <i>R</i>² = 0.92, RMSE = 1.7 °C, bias = 0.88 °C; managed grassland <i>R</i>² = 0.73, RMSE = 2.7 °C, bias = −0.30 °C; arable agriculture <i>R</i>² = 0.82, RMSE = 2.2 °C, bias = 0.46 °C; RMSE, root mean square error). WRF-SPA generates more realistic seasonal behaviour at the site level compared to an unmodified version of WRF, such as improved simulation of seasonal transitions in latent heat flux in arable systems. WRF-SPA also generates realistic seasonal CO₂ exchanges across all sites. WRF-SPA is also able to realistically model atmospheric profiles of CO₂ over Scotland, spanning a 3 yr period (2004–2006), capturing both profile structure, indicating realistic transport, and magnitude (model–data residual <±4 ppm) indicating appropriate source sink distribution and CO₂ exchange. WRF-SPA makes use of CO₂ tracer pools and can therefore identify and quantify land surface contributions to the modelled atmospheric CO₂ signal at a specified location

The social underpinnings of mental distress in the time of COVID-19 – time for urgent action

We argue that predictions of a ‘tsunami’ of mental health problems as a consequence of the pandemic of coronavirus disease 2019 (COVID-19) and the lockdown are overstated; feelings of anxiety and sadness are entirely normal reactions to difficult circumstances, not symptoms of poor mental health. Some people will need specialised mental health support, especially those already leading tough lives; we need immediate reversal of years of underfunding of community mental health services. However, the disproportionate effects of COVID-19 on the most disadvantaged, especially BAME people placed at risk by their social and economic conditions, were entirely predictable. Mental health is best ensured by urgently rebuilding the social and economic supports stripped away over the last decade. Governments must pump funds into local authorities to rebuild community services, peer support, mutual aid and local community and voluntary sector organisations. Health care organisations must tackle racism and discrimination to ensure genuine equal access to universal health care. Government must replace highly conditional benefit systems by something like a universal basic income. All economic and social policies must be subjected to a legally binding mental health audit. This may sound unfeasibly expensive, but the social and economic costs, not to mention the costs in personal and community suffering, though often invisible, are far greater

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy

Measurements of CO2 exchange over a woodland savanna (Cerrado Sensu stricto) in southeast Brasil

The technique of eddy correlation was used to measure the net ecosystem exchange over a woodland savanna (Cerrado Sensu stricto) site (Gleba Pé de Gigante) in southeast Brazil. The data set included measurements of climatological variables and soil respiration using static soil chambers. Data were collected during the period from 10 October 2000 to 30 March 2002. Measured soil respiration showed average values of 4.8 molCO2 m-2s-1 year round. Its seasonal differences varied from 2 to 8 molCO2 m-2s-1 (Q10 = 4.9) during the dry (April to August) and wet season, respectively, and was concurrent with soil temperature and moisture variability. The net ecosystem CO2 flux (NEE) variability is controlled by solar radiation, temperature and air humidity on diel course. Seasonally, soil moisture plays a strong role by inducing litterfall, reducing canopy photosynthetic activity and soil respiration. The net sign of NEE is negative (sink) in the wet season and early dry season, with rates around -25 kgC ha-1day-1, and values as low as 40 kgC ha-1day-1. NEE was positive (source) during most of the dry season, and changed into negative at the onset of rainy season. At critical times of soil moisture stress during the late dry season, the ecosystem experienced photosynthesis during daytime, although the net sign is positive (emission). Concurrent with dry season, the values appeared progressively positive from 5 to as much as 50 kgC ha-1day-1. The annual NEE sum appeared to be nearly in balance, or more exactly a small sink, equal to 0.1 0.3 tC ha-1yr-1, which we regard possibly as a realistic one, giving the constraining conditions imposed to the turbulent flux calculation, and favourable hypothesis of succession stages, climatic variability and CO2 fertilization

Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types

Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN. We present a computational study determining the frequency and extent of alterations of the MYC network across the 33 human cancers of TCGA. These data, together with MYC, positively correlated pathways as well as mutually exclusive cancer genes, will be a resource for understanding MYC-driven cancers and designing of therapeutics

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

Long noncoding RNAs (lncRNAs) are commonly dysregulated in tumors, but only a handful are known to play pathophysiological roles in cancer. We inferred lncRNAs that dysregulate cancer pathways, oncogenes, and tumor suppressors (cancer genes) by modeling their effects on the activity of transcription factors, RNA-binding proteins, and microRNAs in 5,185 TCGA tumors and 1,019 ENCODE assays. Our predictions included hundreds of candidate onco- and tumor-suppressor lncRNAs (cancer lncRNAs) whose somatic alterations account for the dysregulation of dozens of cancer genes and pathways in each of 14 tumor contexts. To demonstrate proof of concept, we showed that perturbations targeting OIP5-AS1 (an inferred tumor suppressor) and TUG1 and WT1-AS (inferred onco-lncRNAs) dysregulated cancer genes and altered proliferation of breast and gynecologic cancer cells. Our analysis indicates that, although most lncRNAs are dysregulated in a tumor-specific manner, some, including OIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergistically dysregulate cancer pathways in multiple tumor contexts. Chiu et al. present a pan-cancer analysis of lncRNA regulatory interactions. They suggest that the dysregulation of hundreds of lncRNAs target and alter the expression of cancer genes and pathways in each tumor context. This implies that hundreds of lncRNAs can alter tumor phenotypes in each tumor context

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

Renal cell carcinoma(RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival

lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer

We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1 (epigenetically-induced lncRNA1). Overexpression of EPIC1 is associated with poor prognosis in luminal B breast cancer patients and enhances tumor growth in vitro and in vivo. Mechanistically, EPIC1 promotes cell-cycle progression by interacting with MYC through EPIC1's 129\u2013283 nt region. EPIC1 knockdown reduces the occupancy of MYC to its target genes (e.g., CDKN1A, CCNA2, CDC20, and CDC45). MYC depletion abolishes EPIC1's regulation of MYC target and luminal breast cancer tumorigenesis in vitro and in vivo. Wang et al. characterize the epigenetic landscape of lncRNAs genes across a large number of human tumors and cancer cell lines and observe recurrent hypomethylation of lncRNA genes, including EPIC1. EPIC1 RNA promotes cell-cycle progression by interacting with MYC and enhancing its binding to target genes