Geologic Controls on Nitrogen Isotopes in Marine Black Shale: a Case Study of the Woodford Shale, Anadarko Basin, Oklahoma

Determining depositional environments of organic-rich black shale can enhance the identification of hydrocarbon producing intervals. Several methods have been utilized to identify depositional environments; however, for this study an isotopic approach was used. Bulk sedimentary δ15N signals have been used to identify water column redox states of sediments, but affects of thermal maturity on δ15N are unknown. Understanding the thermal maturity alterations on bulk sedimentary δ15N is relevant to identifying target intervals for ultimate hydrocarbon recovery. In attempt to understand the depositional, diagenetic, and thermal maturation affects on the bulk sedimentary δ15N signals, we sampled the Devonian-age Woodford Shale at different depths from the depocenter of the Anadarko Basin to an outcrop east of the Anadarko Shelf in the Ozark Plateau to test different thermal maturity levels. The Ro maturity levels of the Woodford Shale at the sample locations ranged from 0.56 % to 1.43 %, which cover oil generation to gas generation. The results indicate that the δ15N values of the Woodford Shale produce two different populations. One population has an average δ15N value that is 3.4 ‰ heavier than the average δ15N value of the other population. On an individual location and basin wide scale, deeper sediments are isotopically lighter than shallower sediments in terms of nitrogen, and these deeper sediments are more thermally mature. Data suggests high concentrations of redox sensitive trace metals, uranium (U) and molybdenum (Mo), are associated with the population of low bulk sedimentary δ15N values, while low concentrations of U and Mo and the presence of burrows are associated with the population of high bulk sedimentary δ15N values. The observed relationship between bulk sedimentary δ15N and Ro is opposite than that expected to be seen by nitrogen isotopes affected by thermal maturity. On the other hand, the observed relationship between bulk sedimentary δ15N and trace metal concentrations indicates that bulk sedimentary δ15N values are strongly influenced by the redox state of the water column during deposition. This relationship was observed on both an individual scale and basin wide scale, which suggests redox water column conditions changed during Woodford deposition and were locally dependent.Geolog

A crisis planning and monitoring intervention to reduce compulsory hospital readmissions (FINCH study): protocol for a randomised controlled feasibility study

BACKGROUND: Rates of compulsory (also known as involuntary) detention under mental health legislation have been rising over several decades in countries including England. Avoiding such detentions should be a high priority given their potentially traumatic nature and departure from usual ethical principles of consent and collaboration. Those who have been detained previously are at high risk of being detained again, and thus a priority group for preventive interventions. In a very sparse literature, interventions based on crisis planning emerge as having more supporting evidence than other approaches to preventing compulsory detention. METHOD: We have adapted and manualised an intervention previously trialled in Zürich Switzerland, aimed at reducing future compulsory detentions among people being discharged following a psychiatric admission that has included a period of compulsory detention. A co-production group including people with relevant lived and clinical experience has co-designed the adaptations to the intervention, drawing on evidence on crisis planning and self-management and on qualitative interviews with service users and clinicians. We will conduct a randomised controlled feasibility trial of the intervention, randomising 80 participants to either the intervention in addition to usual care, or usual care only. Feasibility and acceptability of the intervention and trial procedures will be assessed through process evaluation (including rates of randomisation, recruitment, and retention) and qualitative interviews. We will also assess and report on planned trial outcomes. The planned primary outcome for a full trial is repeat compulsory detention within one year of randomisation, and secondary outcomes include compulsory detention within 2 years, and symptoms, service satisfaction, self-rated recovery, self-management confidence, and service engagement. A health economic evaluation is also included. DISCUSSION: This feasibility study, and any subsequent full trial, will add to a currently limited literature on interventions to prevent involuntary detention, a goal valued highly by service users, carers, clinicians, and policymakers. There are significant potential impediments to recruiting and retaining this group, whose experiences of mental health care have often been negative and traumatising, and who are at high risk of disengagement. TRIAL REGISTRATION: ISRCTN, ISRCTN11627644. Registered 25th May 2022, https://www.isrctn.com/ISRCTN11627644

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

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

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

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Reconstructing the Deep Population History of Central and South America

We report genome-wide ancient DNA from 49 individuals forming four parallel time transects in Belize, Brazil, the Central Andes, and the Southern Cone, each dating to at least 9,000 years ago. The common ancestral population radiated rapidly from just one of the two early branches that contributed to Native Americans today. We document two previously unappreciated streams of gene flow between North and South America. One affected the Central Andes by 4,200 years ago, while the other explains an affinity between the oldest North American genome associated with the Clovis culture and the oldest Central and South Americans from Chile, Brazil, and Belize. However, this was not the primary source for later South Americans, as the other ancient individuals derive from lineages without specific affinity to the Clovis-associated genome, suggesting a population replacement that began at least 9,000 years ago and was followed by substantial population continuity in multiple regions

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Protein ubiquitination is a dynamic and reversibleprocess of adding single ubiquitin molecules orvarious ubiquitin chains to target proteins. Here,using multidimensional omic data of 9,125 tumorsamples across 33 cancer types from The CancerGenome Atlas, we perform comprehensive molecu-lar characterization of 929 ubiquitin-related genesand 95 deubiquitinase genes. Among them, we sys-tematically identify top somatic driver candidates,including mutatedFBXW7with cancer-type-specificpatterns and amplifiedMDM2showing a mutuallyexclusive pattern withBRAFmutations. Ubiquitinpathway genes tend to be upregulated in cancermediated by diverse mechanisms. By integratingpan-cancer multiomic data, we identify a group oftumor samples that exhibit worse prognosis. Thesesamples are consistently associated with the upre-gulation of cell-cycle and DNA repair pathways, char-acterized by mutatedTP53,MYC/TERTamplifica-tion, andAPC/PTENdeletion. Our analysishighlights the importance of the ubiquitin pathwayin cancer development and lays a foundation fordeveloping relevant therapeutic strategies