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After a cosmic cube rewrites Captain America's history, he becomes the ultimate sleeper agent and is poised to embrace his destiny as Hydra's supreme leader. As his plans unfold, will there be anyone left to stand against him?

Genome sequencing has uncovered a new mutational phenomenon in cancer and congenital disorders called chromothripsis. Chromothripsis is characterized by extensive genomic rearrangements and an oscillating pattern of DNA copy number levels, all curiously restricted to one or a few chromosomes. The mechanism for chromothripsis is unknown, but we previously proposed that it could occur through the physical isolation of chromosomes in aberrant nuclear structures called micronuclei. Here, using a combination of live cell imaging and single-cell genome sequencing, we demonstrate that micronucleus formation can indeed generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis. These events are restricted to the mis-segregated chromosome and occur within one cell division. We demonstrate that the mechanism for chromothripsis can involve the fragmentation and subsequent reassembly of a single chromatid from a micronucleus. Collectively, these experiments establish a new mutational process of which chromothripsis is one extreme outcome. The mechanism for chromothripsis, “shattered” chromosomes that can be observed in cancer cells, is unknown; here, using live-cell imaging and single-cell sequencing, chromothripsis is shown to occur after a chromosome is isolated into a micronucleus, an abnormal nuclear structure. Chromothripsis recreated Chromothripsis, a dramatic chromosomal event involving massive chromosome breakage and rearrangement, typically restricted to one or a few of a cell's chromosomes, has been observed in various cancers and congenital diseases. A new study uses a combination of live-cell imaging and single-cell genome sequencing to recreate chromothripsis-like rearrangements. The results show that after single chromosomes are missegregated into so-called micronuclei, they can shatter. After cell division, these fragments can be incorporated back into the genome, generating rearrangements that in some cases bear all the hallmark features of chromothripsis. Chromosome shattering in micronuclei can also lead to the formation of small circular chromosome fragments, the initial step in forming 'double minute chromosomes', which carry amplified oncogenes in cancer. This study thus provides the first experimental demonstration of a molecular mechanism underlying chromothripsis.

\"The events of Dark Nights: Metal have transformed the universe in ways both wonderful and terrifying...and unleashed four ancient entities with the power to destroy it all. Mystery. Wonder. Wisdom. Entropy. These four forces govern all of existence, and now the godlike beings who embody them have awakened. All life is in jeopardy, and the only chance the superheroes of Earth have to stop the unthinkable lies in new alliances...the likes of which have never been seen before! Superman, Starfire and Martian Manhunter search for the secrets of the cosmos in Team Mystery! Batman, Beast Boy and Deathstroke battle chaos itself as Team Entropy! Wonder Woman, Zatanna and Etrigan the Demon unlock bizarre alien technologies with Team Wonder! And the Flash, Cyborg and Harley Quinn learn the astonishing truths of Team Wisdom! Can these amazing new Justice Leagues stick together to stop universal annihilation? Some heroes will not live long enough to find out.\"-- Provided by publisher.

Matthew Meyerson and colleagues identify focal amplifications of regions harboring super-enhancers near KLF5 , USP12 , PARD6B and MYC in epithelial cancers. CRISPR/Cas9-mediated repression or deletion of a MYC enhancer in a lung adenocarcinoma cell line with the enhancer amplification results in downregulation of MYC and its target genes and impaired anchorage-independent and clonogenic growth. Whole-genome analysis approaches are identifying recurrent cancer-associated somatic alterations in noncoding DNA regions. We combined somatic copy number analysis of 12 tumor types with tissue-specific epigenetic profiling to identify significant regions of focal amplification harboring super-enhancers. Copy number gains of noncoding regions harboring super-enhancers near KLF5 , USP12 , PARD6B and MYC are associated with overexpression of these cancer-related genes. We show that two distinct focal amplifications of super-enhancers 3′ to MYC in lung adenocarcinoma ( MYC -LASE) and endometrial carcinoma ( MYC -ECSE) are physically associated with the MYC promoter and correlate with MYC overexpression. CRISPR/Cas9-mediated repression or deletion of a constituent enhancer within the MYC -LASE region led to significant reductions in the expression of MYC and its target genes and to the impairment of anchorage-independent and clonogenic growth, consistent with an oncogenic function. Our results suggest that genomic amplification of super-enhancers represents a common mechanism to activate cancer driver genes in multiple cancer types.

A single sentence summarizing your paper (websum), which will appear online on the table of contents and in e-alerts, has been provided below. Please check this sentence for accuracy and appropriate emphasis. Cancer stem cells in oligodendrogliomas Itay Tirosh et al . use single-cell RNA-seq to show that human oligodendrogliomas contain cancer cells specialized into two types of glia, as well as a rare subpopulation of cells that are undifferentiated and display a gene expression program that is characteristic of neural stem cells. By coupling this analysis with functional assessment of oligodendroglioma cell lines, the authors provide support for a cancer stem cell model of tumour development in this particular context. Although human tumours are shaped by the genetic evolution of cancer cells, evidence also suggests that they display hierarchies related to developmental pathways and epigenetic programs in which cancer stem cells (CSCs) can drive tumour growth and give rise to differentiated progeny 1 . Yet, unbiased evidence for CSCs in solid human malignancies remains elusive. Here we profile 4,347 single cells from six IDH1 or IDH2 mutant human oligodendrogliomas by RNA sequencing (RNA-seq) and reconstruct their developmental programs from genome-wide expression signatures. We infer that most cancer cells are differentiated along two specialized glial programs, whereas a rare subpopulation of cells is undifferentiated and associated with a neural stem cell expression program. Cells with expression signatures for proliferation are highly enriched in this rare subpopulation, consistent with a model in which CSCs are primarily responsible for fuelling the growth of oligodendroglioma in humans. Analysis of copy number variation (CNV) shows that distinct CNV sub-clones within tumours display similar cellular hierarchies, suggesting that the architecture of oligodendroglioma is primarily dictated by developmental programs. Subclonal point mutation analysis supports a similar model, although a full phylogenetic tree would be required to definitively determine the effect of genetic evolution on the inferred hierarchies. Our single-cell analyses provide insight into the cellular architecture of oligodendrogliomas at single-cell resolution and support the cancer stem cell model, with substantial implications for disease management.

Whole-exome sequencing of circulating tumor cells enables accurate and powered calling of somatic point mutations. Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming the challenges of isolating rare cells and sequencing low-input material. Here we report an integrated process to isolate, qualify and sequence whole exomes of CTCs with high fidelity using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs. We validated our process in two patients with prostate cancer, including one for whom we sequenced CTCs, a lymph node metastasis and nine cores of the primary tumor. Fifty-one of 73 CTC mutations (70%) were present in matched tissue. Moreover, we identified 10 early trunk and 56 metastatic trunk mutations in the non-CTC tumor samples and found 90% and 73% of these mutations, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.

Chordoma is a primary bone cancer with no approved therapy 1 . The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors 2 , 3 . Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT ) is the top selectively essential gene in chordoma, and that transcriptional cyclin-dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation. In other cancer types, transcriptional CDK inhibitors have been observed to downregulate highly expressed, enhancer-associated oncogenic transcription factors 4 , 5 . In chordoma, we find that T is associated with a 1.5-Mb region containing ‘super-enhancers’ and is the most highly expressed super-enhancer-associated transcription factor. Notably, transcriptional CDK inhibition leads to preferential and concentration-dependent downregulation of cellular brachyury protein levels in all models tested. In vivo, CDK7/12/13-inhibitor treatment substantially reduces tumor growth. Together, these data demonstrate small-molecule targeting of brachyury transcription factor addiction in chordoma, identify a mechanism of T gene regulation that underlies this therapeutic strategy, and provide a blueprint for applying systematic genetic and chemical screening approaches to discover vulnerabilities in genomically quiet cancers. A combination of genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling enables the discovery of therapeutically targetable tumor dependencies in rare tumors.

The appearance of Alain Resnais' 1955 French documentaryNight and Fogheralded the beginning of a new form of cinema, one that used the narrative techniques of modernism to provoke a new historical consciousness.Afterimagepresents a theory of posttraumatic film based on the encounter between cinema and the Holocaust. Locating its origin in the vivid shock of wartime footage,Afterimagefocuses on a group of crucial documentary and fiction films that were pivotal to the spread of this cinematic form across different nations and genres.Joshua Hirsch explores the changes in documentary brought about by cinema verite, culminating in Shoah. He then turns to teh appearance of a fictional posttraumatic cinema, tracing its development through the vivid flashbacks in Resnais'Hiroshima, mon amourto the portrayal of pain and memory inPawnbroker. He excavates a posttraumatic autobiography in three early films by the Hungarian Istvan Szabo. Finally, Hirsch examines the effects of postmodernism on posttraumatic cinema, looking atSchindler's Listand a work about a different form of historical trauma,History and Memory, a videotape dealing with the internment of Japanese Americans during the Second World War.Sweeping in its scope,Afterimagepresents a new way of thinking about film and history, trauma and its representation.

Few studies are available to inform duration of intravenous antibiotics for children and when it is safe and appropriate to switch to oral antibiotics. We have systematically reviewed antibiotic duration and timing of intravenous to oral switch for 36 paediatric infectious diseases and developed evidence-graded recommendations on the basis of the review, guidelines, and expert consensus. We searched databases and obtained information from references identified and relevant guidelines. All eligible studies were assessed for quality. 4090 articles were identified and 170 studies were included. Evidence relating antibiotic duration to outcomes in children for some infections was supported by meta-analyses or randomised controlled trials; in other infections data were from retrospective series only. Criteria for intravenous to oral switch commonly included defervescence and clinical improvement with or without improvement in laboratory markers. Evidence suggests that intravenous to oral switch can occur earlier than previously recommended for some infections. We have synthesised recommendations for antibiotic duration and intravenous to oral switch to support clinical decision making and prospective research.

Following reduction of public health and social measures concurrent with SARS-CoV-2 Omicron emergence in late 2021 in Australia, COVID-19 case notification rates rose rapidly. As rates of direct viral testing and reporting dropped, true infection rates were most likely to be underestimated. To better understand infection rates and immunity in this population, we aimed to estimate SARS-CoV-2 seroprevalence in Australians aged 0-19 years. We conducted a national cross sectional serosurvey from June 1, 2022, to August 31, 2022, in children aged 0-19 years undergoing an anesthetic procedure at eight tertiary pediatric hospitals. Participant questionnaires were administered, and blood samples tested using the Roche Elecsys Anti-SARS-CoV-2 total spike and nucleocapsid antibody assays. Spike and nucleocapsid seroprevalence adjusted for geographic and socioeconomic imbalances in the participant sample compared to the Australian population was estimated using multilevel regression and poststratification within a Bayesian framework. Blood was collected from 2,046 participants (median age: 6.6 years). The overall adjusted seroprevalence of spike-antibody was 92.1% (95% credible interval (CrI) 91.0-93.3%) and nucleocapsid-antibody was 67.0% (95% CrI 64.6-69.3). In unvaccinated children spike and nucleocapsid antibody seroprevalences were 84.2% (95% CrI 81.9-86.5) and 67.1% (95%CrI 64.0-69.8), respectively. Seroprevalence was similar across geographic remoteness index and socioeconomic quintiles. Nucleocapsid antibody seroprevalence increased with age while the point seroprevalence of the spike antibody seroprevalence decreased in the first year of life and then increased to 97.8 (95% Crl 96.1-99.2) by 12-15 years of age. Most Australian children and adolescents aged 0-19 years, across all jurisdictions were infected with SARS-CoV-2 by August 2022, suggesting rapid and uniform spread across the population in a very short time period. High seropositivity in unvaccinated children informed COVID-19 vaccine recommendations in Australia.