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Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.
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Heterogeneidade Genética , Neoplasias/genética , Variações do Número de Cópias de DNA , DNA de Neoplasias/química , DNA de Neoplasias/metabolismo , Bases de Dados Genéticas , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Neoplasias/patologia , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do GenomaRESUMO
The properties of polycrystalline materials are often dominated by defects; two-dimensional (2D) crystals can even be divided and disrupted by a line defect1-3. However, 2D crystals are often required to be processed into films, which are inevitably polycrystalline and contain numerous grain boundaries, and therefore are brittle and fragile, hindering application in flexible electronics, optoelectronics and separation1-4. Moreover, similar to glass, wood and plastics, they suffer from trade-off effects between mechanical strength and toughness5,6. Here we report a method to produce highly strong, tough and elastic films of an emerging class of 2D crystals: 2D covalent organic frameworks (COFs) composed of single-crystal domains connected by an interwoven grain boundary on water surface using an aliphatic bi-amine as a sacrificial go-between. Films of two 2D COFs have been demonstrated, which show Young's moduli and breaking strengths of 56.7 ± 7.4 GPa and 73.4 ± 11.6 GPa, and 82.2 ± 9.1 N m-1 and 29.5 ± 7.2 N m-1, respectively. We predict that the sacrificial go-between guided synthesis method and the interwoven grain boundary will inspire grain boundary engineering of various polycrystalline materials, endowing them with new properties, enhancing their current applications and paving the way for new applications.
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All normal somatic cells are thought to acquire mutations, but understanding of the rates, patterns, causes and consequences of somatic mutations in normal cells is limited. The uterine endometrium adopts multiple physiological states over a lifetime and is lined by a gland-forming epithelium1,2. Here, using whole-genome sequencing, we show that normal human endometrial glands are clonal cell populations with total mutation burdens that increase at about 29 base substitutions per year and that are many-fold lower than those of endometrial cancers. Normal endometrial glands frequently carry 'driver' mutations in cancer genes, the burden of which increases with age and decreases with parity. Cell clones with drivers often originate during the first decades of life and subsequently progressively colonize the epithelial lining of the endometrium. Our results show that mutational landscapes differ markedly between normal tissues-perhaps shaped by differences in their structure and physiology-and indicate that the procession of neoplastic change that leads to endometrial cancer is initiated early in life.
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Análise Mutacional de DNA , Endométrio/citologia , Endométrio/metabolismo , Epitélio/metabolismo , Saúde , Mutação , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Carcinogênese/genética , Células Clonais/citologia , Neoplasias do Endométrio/genética , Endométrio/patologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Epitélio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Paridade/genética , Fatores de Tempo , Adulto JovemRESUMO
Cancer develops through a process of somatic evolution1,2. Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes3. Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA)4, we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.
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Evolução Molecular , Genoma Humano/genética , Neoplasias/genética , Reparo do DNA/genética , Dosagem de Genes , Genes Supressores de Tumor , Variação Genética , Humanos , Mutagênese Insercional/genéticaRESUMO
Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes1,2. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution1,3,4. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9, MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2+ breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.
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Instabilidade Cromossômica/genética , Evolução Molecular , Cariótipo , Metástase Neoplásica/genética , Neoplasias/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 8/genética , Células Clonais/metabolismo , Células Clonais/patologia , Ciclina E/genética , Variações do Número de Cópias de DNA/genética , Feminino , Humanos , Perda de Heterozigosidade/genética , Masculino , Mutagênese , Metástase Neoplásica/patologia , Neoplasias/patologia , Proteínas Oncogênicas/genéticaRESUMO
The personality trait neuroticism is tightly linked to mental health, and neurotic people experience stronger negative emotions in everyday life. But, do their negative emotions also show greater fluctuation? This commonsensical notion was recently questioned by [Kalokerinos et al. Proc Natl Acad Sci USA 112, 15838-15843 (2020)], who suggested that the associations found in previous studies were spurious. Less neurotic people often report very low levels of negative emotion, which is usually measured with bounded rating scales. Therefore, they often pick the lowest possible response option, which severely constrains the amount of emotional variability that can be observed in principle. Applying a multistep statistical procedure that is supposed to correct for this dependency, [Kalokerinos et al. Proc Natl Acad Sci USA 112, 15838-15843 (2020)] no longer found an association between neuroticism and emotional variability. However, like other common approaches for controlling for undesirable effects due to bounded scales, this method is opaque with respect to the assumed mechanism of data generation and might not result in a successful correction. We thus suggest an alternative approach that a) takes into account that emotional states outside of the scale bounds can occur and b) models associations between neuroticism and both the mean and variability of emotion in a single step with the help of Bayesian censored location-scale models. Simulations supported this model over alternative approaches. We analyzed 13 longitudinal datasets (2,518 individuals and 11,170 measurements in total) and found clear evidence that more neurotic people experience greater variability in negative emotion.
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Emoções , Saúde Mental , Humanos , Neuroticismo/fisiologia , Teorema de Bayes , Emoções/fisiologiaRESUMO
The ability to label proteins by fusion with genetically encoded fluorescent proteins is a powerful tool for understanding dynamic biological processes. However, current approaches for expressing fluorescent protein fusions possess drawbacks, especially at the whole organism level. Expression by transgenesis risks potential overexpression artifacts while fluorescent protein insertion at endogenous loci is technically difficult and, more importantly, does not allow for tissue-specific study of broadly expressed proteins. To overcome these limitations, we have adopted the split fluorescent protein system mNeonGreen21-10/11 (split-mNG2) to achieve tissue-specific and endogenous protein labeling in zebrafish. In our approach, mNG21-10 is expressed under a tissue-specific promoter using standard transgenesis while mNG211 is inserted into protein-coding genes of interest using CRISPR/Cas-directed gene editing. Each mNG2 fragment on its own is not fluorescent, but when co-expressed the fragments self-assemble into a fluorescent complex. Here, we report successful use of split-mNG2 to achieve differential labeling of the cytoskeleton genes tubb4b and krt8 in various tissues. We also demonstrate that by anchoring the mNG21-10 component to specific cellular compartments, the split-mNG2 system can be used to manipulate protein localization. Our approach should be broadly useful for a wide range of applications.
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Proteínas de Peixe-Zebra , Peixe-Zebra , Peixe-Zebra/genética , Peixe-Zebra/embriologia , Animais , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Sistemas CRISPR-Cas , Animais Geneticamente Modificados , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Especificidade de Órgãos/genética , Proteínas de Fluorescência Verde/metabolismo , Proteínas de Fluorescência Verde/genética , Edição de Genes/métodos , Regiões Promotoras Genéticas/genética , Tubulina (Proteína)/metabolismo , Tubulina (Proteína)/genéticaRESUMO
MOTIVATION: Few methods exist for timing individual amplification events in regions of focal amplification. Current methods are also limited in the copy number states that they are able to time. Here we introduce AmplificationTimeR, a method for timing higher level copy number gains and inferring the most parsimonious order of events for regions that have undergone both single gains and whole genome duplication. Our method is an extension of established approaches for timing genomic gains. RESULTS: We can time more copy number states, and in states covered by other methods our results are comparable to previously published methods. AVAILABILITY AND IMPLEMENTATION: AmplificationTimer is freely available as an R package hosted at https://github.com/Wedge-lab/AmplificationTimeR.
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Software , Genômica/métodos , Algoritmos , Humanos , Variações do Número de Cópias de DNARESUMO
Chordoma is a rare malignant tumor demonstrating notochordal differentiation. It is dependent on brachyury (TBXT), a hallmark notochordal gene and transcription factor, and shares histologic features and the same anatomic location as the notochord. This study involved a molecular comparison of chordoma and notochord to identify dysregulated cellular pathways. The lack of a molecular reference from appropriate control tissue limits our understanding of chordoma and its relationship to notochord. Therefore, an unbiased comparison of chordoma, human notochord, and an atlas of normal and cancerous tissue was conducted using gene expression profiling to clarify the chordoma/notochord relationship and potentially identify novel drug targets. The study found striking consistency in gene expression profiles between chordoma and notochord, supporting the hypothesis that chordoma develops from notochordal remnants. A 12-gene diagnostic chordoma signature was identified and the TBXT/transforming growth factor beta (TGF-ß)/SOX6/SOX9 pathway was hyperactivated in the tumor, suggesting that pathways associated with chondrogenesis were a central driver of chordoma development. Experimental validation in chordoma cells confirmed these findings and emphasized the dependence of chordoma proliferation and survival on TGF-ß. The computational and experimental evidence provided the first molecular connection between notochord and chordoma and identified core members of a chordoma regulatory pathway involving TBXT. This pathway provides new therapeutic targets for this unique malignant neoplasm and highlights TGF-ß as a prime druggable candidate.
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Cordoma , Humanos , Cordoma/genética , Cordoma/patologia , Notocorda/metabolismo , Notocorda/patologia , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Deleterious effects caused by Joule heating in electrically-pumped continuous-wave InP-based topological insulator lasers based on two-dimensional microring resonator arrays are estimated in this theoretical study. Steady-state temperature distributions within such an array are developed using a full numerical solution. Thermal interactions between active gain regions and ring resonators pose significant operational and integration challenges, as these devices are extremely sensitive to temperature-induced changes in a material's index of refraction. Designing such an array benefits from clear understanding on the effects of systematic non-uniform heating profiles due to temperature variations among the rings. This paper first presents the thermal modeling of a single isolated ring under electrical pumping and then discusses its impact on an operational array composed of 10 × 10 such rings. The simulation results reported here were benchmarked against experimental measurements of the mircoring lasers, wherever possible. Calculations based on a tight-binding model for the array suggest that the laser exhibits single-mode optical output with the preservation of topological properties up to 4 times the threshold current. The useful operating range of the array is mainly limited by the thermal shifts of wavelengths in addition to the wavelength disorders due to fabrication imperfections.
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Forestation efforts are accelerating across the globe in the fight against global climate change, in order to restore biodiversity, and to improve local livelihoods. Yet, so far the non-local effects of forestation on rainfall have largely remained a blind spot. Here we build upon emerging work to propose that targeted rainfall enhancement may also be considered in the prioritization of forestation. We show that the tools to achieve this are rapidly becoming available, but we also identify drawbacks and discuss which further developments are still needed to realize robust assessments of the rainfall effects of forestation in the face of climate change. Forestation programs may then mitigate not only global climate change itself but also its adverse effects in the form of drying.
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Biodiversidade , Mudança Climática , EcossistemaRESUMO
Northern peatlands store large amounts of carbon. Observations indicate that forests and peatlands in northern biomes can be alternative stable states for a range of landscape settings. Climatic and hydrological changes may reduce the resilience of peatlands and forests, induce persistent shifts between these states, and release the carbon stored in peatlands. Here, we present a dynamic simulation model constrained and validated by a wide set of observations to quantify how feedbacks in water and carbon cycling control resilience of both peatlands and forests in northern landscapes. Our results show that 34% of Europe (area) has a climate that can currently sustain existing rainwater-fed peatlands (raised bogs). However, raised bog initiation and restoration by water conservation measures after the original peat soil has disappeared is only possible in 10% of Europe where the climate allows raised bogs to initiate and outcompete forests. Moreover, in another 10% of Europe, existing raised bogs (concerning â¼20% of the European raised bogs) are already affected by ongoing climate change. Here, forests may overgrow peatlands, which could potentially release in the order of 4% (â¼24 Pg carbon) of the European soil organic carbon pool. Our study demonstrates quantitatively that preserving and restoring peatlands requires looking beyond peatland-specific processes and taking into account wider landscape-scale feedbacks with forest ecosystems.
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Carbono/química , Ciclo do Carbono , Mudança Climática , Ecossistema , Europa (Continente) , Florestas , Solo/química , Água/química , Áreas AlagadasRESUMO
BACKGROUND: Many clinicians overestimate mortality and disability rates in infants born extremely preterm. We developed a digital tool ('NIC-PREDICT') that predicts infant mortality and survival with and without major disability in infants born 23-27 weeks' gestation. AIMS: To determine if clinicians could use NIC-PREDICT accurately, and if their perceptions of infant outcomes improved after its release in 2021. MATERIALS AND METHODS: Midwives, nurses, obstetricians, neonatologists and paediatricians working in tertiary and non-tertiary hospitals in Victoria were asked to use NIC-PREDICT to estimate three mutually exclusive outcomes: (i) mortality; (ii) survival free of major disability; and (iii) survival with major disability for six different scenarios where a liveborn infant was offered survival-focused care after birth. The proportions who completed the survey (responded to all six scenarios) and the proportions able to provide 100% accurate results for all scenarios were determined. Estimates of the three outcomes were compared with true rates. RESULTS: A total of 85 clinicians responded: 70 (82%) completed the survey, with an overall accuracy of 76%. Overall, predictions of mortality were accurate (mean difference from true value 0.7% (95% confidence interval (CI) -0.7, 2.1) P = 0.33), as were predictions of survival without major disability (mean difference - 0.7 (95% CI -3.0, 1.7) P = 0.58). However, survival with major disability was overestimated by 4.9% ((95% CI 1.7, 8.0) P = 0.003). CONCLUSIONS: Most perinatal clinicians who responded used NIC-PREDICT correctly to estimate expected outcomes in infants born extremely preterm who are offered intensive care. Undue pessimism about survival with major disability remains an ongoing concern.
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Mortalidade Infantil , Lactente Extremamente Prematuro , Humanos , Recém-Nascido , Vitória , Feminino , Lactente , Inquéritos e Questionários , Gravidez , Idade Gestacional , Atitude do Pessoal de SaúdeRESUMO
Molecular scaffolds that enable the combinatorial synthesis of new supramolecular building blocks are promising targets for the construction of functional molecular systems. Here, we report a supramolecular scaffold based on boroxine that enables the formation of chiral and ordered 1D supramolecular polymers, which can be easily functionalized for circularly polarized luminescence. The boroxine monomers are quantitatively synthesized in situ, both in bulk and in solution, from boronic acid precursors and cooperatively polymerize into 1D helical aggregates stabilized by threefold hydrogen-bonding and π-π stacking. We then demonstrate amplification of asymmetry in the co-assembly of chiral/achiral monomers and the co-condensation of chiral/achiral precursors in classical and in situ sergeant-and-soldiers experiments, respectively, showing fast boronic acid exchange reactions occurring in the system. Remarkably, co-condensation of pyrene boronic acid with a hydrogen-bonding chiral boronic acid results in chiral pyrene aggregation with circularly polarized excimer emission and g-values in the order of 10-3. Yet, the electron deficiency of boron in boroxine makes them chemically addressable by nucleophiles, but also sensitive to hydrolysis. With this sensitivity in mind, we provide first insights into the prospects offered by boroxine-based supramolecular polymers to make chemically addressable, functional, and adaptive systems.
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Vinylene-linked two-dimensional polymers (V-2DPs) and their layer-stacked covalent organic frameworks (V-2D COFs) featuring high in-plane π-conjugation and robust frameworks have emerged as promising candidates for energy-related applications. However, current synthetic approaches are restricted to producing V-2D COF powders that lack processability, impeding their integration into devices, particularly within membrane technologies reliant upon thin films. Herein, we report the novel on-water surface synthesis of vinylene-linked cationic 2DPs films (V-C2DP-1 and V-C2DP-2) via Knoevenagel polycondensation, which serve as the anion-selective electrode coating for highly-reversible and durable zinc-based dual-ion batteries (ZDIBs). Model reactions and theoretical modeling revealed the enhanced reactivity and reversibility of the Knoevenagel reaction on the water surface. On this basis, we demonstrated the on-water surface 2D polycondensation towards V-C2DPs films that show large lateral size, tunable thickness, and high chemical stability. Representatively, V-C2DP-1 presents as a fully crystalline and face-on oriented film with in-plane lattice parameters of a=b≈43.3â Å. Profiting from its well-defined cationic sites, oriented 1D channels, and stable frameworks, V-C2DP-1 film possesses superior bis(trifluoromethanesulfonyl)imide anion (TFSI-)-transport selectivity (transference, t_=0.85) for graphite cathode in high-voltage ZDIBs, thus triggering additional TFSI--intercalation stage and promoting its specific capacity (from ~83 to 124â mAh g-1) and cycling life (>1000â cycles, 95 % capacity retention).
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Deep learning for computer vision has shown promising results in the field of entomology, however, there still remains untapped potential. Deep learning performance is enabled primarily by large quantities of annotated data which, outside of rare circumstances, are limited in ecological studies. Currently, to utilize deep learning systems, ecologists undergo extensive data collection efforts, or limit their problem to niche tasks. These solutions do not scale to region agnostic models. However, there are solutions that employ data augmentation, simulators, generative models, and self-supervised learning that can supplement limited labelled data. Here, we highlight the success of deep learning for computer vision within entomology, discuss data collection efforts, provide methodologies for optimizing learning from limited annotations, and conclude with practical guidelines for how to achieve a foundation model for entomology capable of accessible automated ecological monitoring on a global scale.
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Artrópodes , Animais , ComputadoresRESUMO
Non-fullerene acceptor molecules developed for organic solar cells feature a very intense absorption band in the near-infrared. In the solid phase, the strong interaction between light and the transition dipole moment for molecular excitation should induce formation of polaritons. The reflection spectra for polycrystalline films of a non-fullerene acceptor with a thienothienopyrrolo-thienothienoindole core of the so-called Y6 type indeed show a signature of polaritons. A local minimum in the middle of the reflection band is associated with the allowed molecular transition. The minimum in reflection allows efficient entry of light into the solid, resulting in a local maximum in external quantum efficiency of a photovoltaic cell made of the pure acceptor.
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sp2 carbon-conjugated covalent organic frameworks (sp2c-COFs) with superb in-plane π-conjugations, high chemical stability, and robust framework structure are expected to be ideal films/membranes for a wide range of applications including energy-related devices and optoelectronics. However, so far, sp2c-COFs have been mainly limited to microcrystalline powders, and this consequently hampered their performances in devices. Herein, we report a simple and robust methodology to fabricate large-area, free-standing, and crystalline sp2c-COF films (TFPT-TMT and TB-TMT) on various solid substrates (e.g., fluorine-doped tin oxide, aluminum sheet, polyacrylonitrile membrane) by self-assembly monolayer-assisted surface-initiated Schiff-base-mediated aldol polycondensation (namely, SI-SBMAP). The resultant sp2c-COF films show lateral sizes up to 120 cm2 and tunable thickness from tens of nanometers to a few micrometers. Owing to the robust framework and highly ordered quasi-1D channels, the sp2c-COF membrane-based osmotic power generator presents an output power density of 14.1 W m-2 under harsh conditions, outperforming most reported COF membranes as well as commercialized benchmark devices (5 W m-2). This work demonstrates a simple and robust interfacial methodology for the fabrication of sp2c-COF films/membranes for green energy applications and potential optoelectronics.