Inbreeding Avoidance Influences the Viability of Reintroduced Populations of African Wild Dogs (Lycaon pictus)

The conservation of many fragmented and small populations of endangered African wild dogs (Lycaon pictus) relies on understanding the natural processes affecting genetic diversity, demographics, and future viability. We used extensive behavioural, life-history, and genetic data from reintroduced African wild dogs in South Africa to (1) test for inbreeding avoidance via mate selection and (2) model the potential consequences of avoidance on population persistence. Results suggested that wild dogs avoided mating with kin. Inbreeding was rare in natal packs, after reproductive vacancies, and between sibling cohorts (observed on 0.8%, 12.5%, and 3.8% of occasions, respectively). Only one of the six (16.7%) breeding pairs confirmed as third-order (or closer) kin consisted of animals that were familiar with each other, while no other paired individuals had any prior association. Computer-simulated populations allowed to experience inbreeding had only a 1.6% probability of extinction within 100 years, whereas all populations avoiding incestuous matings became extinct due to the absence of unrelated mates. Populations that avoided mating with first-order relatives became extinct after 63 years compared with persistence of 37 and 19 years for those also prevented from second-order and third-order matings, respectively. Although stronger inbreeding avoidance maintains significantly more genetic variation, our results demonstrate the potentially severe demographic impacts of reduced numbers of suitable mates on the future viability of small, isolated wild dog populations. The rapid rate of population decline suggests that extinction may occur before inbreeding depression is observed

Early-type stars in the young open cluster NGC 2244 and in the Mon OB2 association I. The multiplicity of O-type stars

Aims. We present the results obtained from a long-term spectroscopic campaign devoted to the multiplicity of O-type stars in the young open cluster NGC2244 and in the Mon OB2 association. Methods. Our spectroscopic monitoring was performed over several years, allowing us to probe different time-scales. For each star, several spectral diagnostic tools are applied, in order to search for line shifts and profile variations. We also measure the projected rotational velocity and revisit the spectral classification. Results. In our sample, several stars were previously considered as spectroscopic binaries, though only a few scattered observations were available. Our results now reveal a more complex situation. Our study identifies two new spectroscopic binaries (HD46149 in NGC2244 and HD46573 in MonOB2). The first object is a long-period double-lined spectroscopic binary, though the exact value of its period remains uncertain and the second object is classified as an SB1 system with a period of about 10.67 days but the time series of our observations do not enable us to derive a unique orbital solution for this system. We also classify another star as variable in radial velocity (HD46150) and we detect line profile variations in two rapid rotators (HD46056 and HD46485). Conclusions. This spectroscopic investigation places a firm lower limit (17%) on the binary fraction of O-stars in NGC2244 and reveals the lack of short-period O+OB systems in this cluster. In addition, a comparison of these new results with two other well-studied clusters (NGC6231 and IC1805) puts forward possible hints of a relation between stellar density and binarity, which could provide constraints on the theories about the formation and early evolution of hot stars.Comment: 14 pages, 10 figures, 9 table

Optical spectroscopy of X-Mega targets in the Carina nebula - VII On the multiplicity of Tr 16-112, HD 93343 and HD 93250

We present the results of a spectroscopic monitoring campaign devoted to three O-type stars in the Carina nebula. We derive the full SB2 orbital solution of the binary system Tr 16-112, an exceptional dissymmetrical system consisting of an O5.5-6V((f$^+$?p)) primary and a B2V-III secondary. We also report on low-amplitude brightness variations in Tr 16-112 that are likely due to the ellipsoidal shape of the O5.5-6 primary revolving in an eccentric orbit around the system's centre of mass. We detect for the first time a clear SB2 binary signature in the spectrum of HD 93343 (O8 + O8), although our data are not sufficient to establish an orbital solution. This system also displays low amplitude photometric modulations. On the other hand, no indication of multiplicity is found in the optical spectra of HD 93250. Finally, we discuss the general properties of multiple massive stars in the Carina OB1 association.Comment: Accepted for publication in MNRA

Spectroscopic and photometric variability of the O9.5Vp star HD93521

The line profile variability and photometric variability of the O9.5 Vp star HD93521 are examined in order to establish the properties of the non-radial pulsations in this star. Fourier techniques are used to characterize the modulations of the He I 5876, 6678 and H-alpha lines in several spectroscopic time series and to search for variations in a photometric time series. Our spectroscopic data confirm the existence of two periods of 1.75 and 2.89 hr. The line profiles, especially those affected by emission wings, exhibit also modulations on longer time scales, but these are epoch-dependent and change from line to line. Unlike previous claims, we find no unambiguous signature of the rotational period in our data, nor of a third pulsation period (corresponding to a frequency of 2.66 day$^{-1}$). HD 93521 very likely exhibits non-radial pulsations with periods of 1.75 and 2.89 hr with $l \simeq 8 \pm 1$ and $l \simeq 4 \pm 1$ respectively. No significant signal is found in the first harmonics of these two periods. The 2.89 hr mode is seen at all epochs and in all lines investigated, while the visibility of the 1.75 hr mode is clearly epoch dependent. Whilst light variations are detected, their connection to these periodicities is not straightforward.Comment: 13 pages, 11 figures, accepted for publication in Astronomy & Astrophysic

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

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

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

Detailed Analysis of ITPR1 Missense Variants Guides Diagnostics and Therapeutic Design

BACKGROUND: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3 ) receptor type 1 (IP3 R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. OBJECTIVES: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. METHODS: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. RESULTS: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3 -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. CONCLUSIONS: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society