Age Validation and Population Structure of Warsaw Grouper and Snowy Grouper, and Age and Growth Relationships of Warsaw Grouper in the Gulf of Mexico

Warsaw grouper (Hyporthodus nigritus) and snowy grouper (H. niveatus) are deepwater grouper (F. Epinephelidae) found in the western Atlantic Ocean from the northern eastern seaboard of the United States of America to the central coast of Brazil, including in the Gulf of Mexico and Caribbean Sea. Considered periodic life history strategists, both species are long-lived, with slow growth and late maturation and therefore, are exceptionally vulnerable to overexploitation. Furthermore, both species are likely protogynous hermaphrodites (individuals first mature as females and after an environmentally dictated size or age transition to male) whose populations are sustained through episodic recruitment and infrequent year-class success when environmental conditions promote survival and settlement. However, little is known of their general life history due to the difficulties of common fisheries research methods for deepwater species due to barotrauma caused mortality associated preventing the use of techniques designed to directly estimate population demographics (e.g. abundance, density, age and growth, mortality, etc.), such as in-situ visual surveys or mark and recapture. Here, I attempt to clarify some population demographics using indirect estimation methods to assist in the development of effective fisheries policy. In order two accomplish these ends, the population structure of both species was assessed by analyzing and comparing the geochemical makeup of fish otoliths (“ear stones”) collected from different geographical regions of the Gulf of Mexico (GOM). For both Warsaw grouper and snowy grouper, the chemical composition in otoliths resulted in region-specific signatures leading to the conclusion that individual movement between regions is minimal and therefore mixing limited, thereby suggesting the population is composed of distinct regional components and potential subpopulations. Before evaluating potential differences in population demographics from potentially distinct regions, a bomb radiocarbon age validation was conducted on both species. Typical of deepwater species, bomb radiocarbon age validation revealed an inherent underage bias for older fish in age determination methods, likely due to inability to distinguish annual growth increments in later ages as a result of depressed growth rates. These revelations led to a substantial increase in longevity estimates for both species, with both validated to have a minimum estimate of age-56. Using a newly validated age determination method and insights into population structure, age-length relationships were developed for Warsaw Grouper from multiple regions of the GoM. Growth relationships consistently resulted in a slower growth and lower natural mortality than current estimates, with subtle differences between the eastern GoM and western GoM. These results help to clarify population structure and demographics for two data-limited species subjected to commercial and recreational fishery exploitation that can be directly applied to fishery management and the development of effect conservation policy

Trial protocol OPPTIMUM : does progesterone prophylaxis for the prevention of preterm labour improve outcome?

Background Preterm birth is a global problem, with a prevalence of 8 to 12% depending on location. Several large trials and systematic reviews have shown progestogens to be effective in preventing or delaying preterm birth in selected high risk women with a singleton pregnancy (including those with a short cervix or previous preterm birth). Although an improvement in short term neonatal outcomes has been shown in some trials these have not consistently been confirmed in meta-analyses. Additionally data on longer term outcomes is limited to a single trial where no difference in outcomes was demonstrated at four years of age of the child, despite those in the “progesterone” group having a lower incidence of preterm birth. Methods/Design The OPPTIMUM study is a double blind randomized placebo controlled trial to determine whether progesterone prophylaxis to prevent preterm birth has long term neonatal or infant benefit. Specifically it will study whether, in women with singleton pregnancy and at high risk of preterm labour, prophylactic vaginal natural progesterone, 200 mg daily from 22 – 34 weeks gestation, compared to placebo, improves obstetric outcome by lengthening pregnancy thus reducing the incidence of preterm delivery (before 34 weeks), improves neonatal outcome by reducing a composite of death and major morbidity, and leads to improved childhood cognitive and neurosensory outcomes at two years of age. Recruitment began in 2009 and is scheduled to close in Spring 2013. As of May 2012, over 800 women had been randomized in 60 sites. Discussion OPPTIMUM will provide further evidence on the effectiveness of vaginal progesterone for prevention of preterm birth and improvement of neonatal outcomes in selected groups of women with singleton pregnancy at high risk of preterm birth. Additionally it will determine whether any reduction in the incidence of preterm birth is accompanied by improved childhood outcome

A Cautionary Tale: MARVELS Brown Dwarf Candidate Reveals Itself To Be A Very Long Period, Highly Eccentric Spectroscopic Stellar Binary

We report the discovery of a highly eccentric, double-lined spectroscopic binary star system (TYC 3010-1494-1), comprising two solar-type stars that we had initially identified as a single star with a brown dwarf companion. At the moderate resolving power of the MARVELS spectrograph and the spectrographs used for subsequent radial-velocity (RV) measurements (R ~ <30,000), this particular stellar binary mimics a single-lined binary with an RV signal that would be induced by a brown dwarf companion (Msin(i)~50 M_Jup) to a solar-type primary. At least three properties of this system allow it to masquerade as a single star with a very low-mass companion: its large eccentricity (e~0.8), its relatively long period (P~238 days), and the approximately perpendicular orientation of the semi-major axis with respect to the line of sight (omega~189 degrees). As a result of these properties, for ~95% of the orbit the two sets of stellar spectral lines are completely blended, and the RV measurements based on centroiding on the apparently single-lined spectrum is very well fit by an orbit solution indicative of a brown dwarf companion on a more circular orbit (e~0.3). Only during the ~5% of the orbit near periastron passage does the true, double-lined nature and large RV amplitude of ~15 km/s reveal itself. The discovery of this binary system is an important lesson for RV surveys searching for substellar companions; at a given resolution and observing cadence, a survey will be susceptible to these kinds of astrophysical false positives for a range of orbital parameters. Finally, for surveys like MARVELS that lack the resolution for a useful line bisector analysis, it is imperative to monitor the peak of the cross-correlation function for suspicious changes in width or shape, so that such false positives can be flagged during the candidate vetting process.Comment: 16 pages, 11 figures, 6 table

Banff 2022 liver group meeting report: monitoring long term allograft health.

The Banff Working Group on Liver Allograft Pathology met in September 2022. Participantsincluded hepatologists, surgeons, pathologists, immunologists and histocompatibility specialists.Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimisation and long-term structural changes.Potential revision of the rejection classification scheme to better accommodate and communicate lateT cell-mediated rejection patterns and related structural changes, such as nodular regenerativehyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression tomatch the heterogeneity of patient settings will be central to improving long-term patient survival.Such personalised therapeutics are in turn contingent on better understanding and monitoring ofallograft status within a rational decision-making approach, likely to be facilitated in implementationwith emerging decision support tools. Proposed revisions to rejection classification emerging fromthe meeting include incorporation of interface hepatitis and fibrosis staging. These will be opened toonline testing, modified accordingly and subject to consensus discussion leading up to the next Banffconference

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

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

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

Models of <i>KPTN</i>-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.</p

Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas

Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: (1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy-number changes, with low mutational loads and only a few genes (, , ) highly recurrently mutated across sarcoma types; (2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome; and (3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma-type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types