Abstract
The ultra-faint dwarf galaxy Reticulum II was enriched by a rare and prolific
r
-process event, such as a neutron star merger (NSM). To investigate the nature of this event, we present ...high-resolution
Magellan
/MIKE spectroscopy of the brightest star in this galaxy. The high signal-to-noise allows us to determine the abundances of 41 elements, including the radioactive actinide element Th and first ever detections of third
r
-process peak elements (Os and Ir) in a star outside the Milky Way. The observed neutron-capture element abundances closely match the solar
r
-process component, except for the first
r
-process peak, which is significantly lower than solar but matches other
r
-process enhanced stars. The ratio of the first peak to heavier
r
-process elements implies that the
r
-process site produces roughly equal masses of high and low electron fraction ejecta, within a factor of 2. We compare the detailed abundance pattern to predictions from nucleosynthesis calculations of NSMs and magnetorotationally driven jet supernovae, finding that nuclear physics uncertainties dominate over astrophysical uncertainties. We measure
, somewhat lower than all previous Th/Eu observations. The youngest age we derive from this ratio is 21.7 ± 2.8 (stat) ± 10.3 (sys) Gyr, indicating that current initial production ratios do not describe the
r
-process event in Reticulum II. The abundances of light elements up to Zn are consistent with extremely metal-poor Milky Way halo stars. They may eventually provide a way to distinguish between NSMs and magnetorotationally driven jet supernovae, but this would require more detailed knowledge of the chemical evolution of Reticulum II.
ABSTRACT
We present chemical abundances derived from high-resolution
Magellan
/Magellan Inamori Kyocera Echelle spectra of the nine brightest known red giant members of the ultra-faint dwarf galaxy ...Reticulum II (Ret II). These stars span the full metallicity range of Ret II (−3.5 < Fe/H < −2). Seven of the nine stars have extremely high levels of
r
-process material (Eu/Fe ∼ 1.7), in contrast to the extremely low neutron-capture element abundances found in every other ultra-faint dwarf galaxy studied to date. The other two stars are the most metal-poor stars in the system (Fe/H < −3), and they have neutron-capture element abundance limits similar to those in other ultra-faint dwarf galaxies. We confirm that the relative abundances of Sr, Y, and Zr in these stars are similar to those found in
r
-process halo stars, but they are ∼0.5 dex lower than the solar
r
-process pattern. If the universal
r
-process pattern extends to those elements, the stars in Ret II display the least contaminated known
r
-process pattern. The abundances of lighter elements up to the iron peak are otherwise similar to abundances of stars in the halo and in other ultra-faint dwarf galaxies. However, the scatter in abundance ratios is large enough to suggest that inhomogeneous metal mixing is required to explain the chemical evolution of this galaxy. The presence of low amounts of neutron-capture elements in other ultra-faint dwarf galaxies may imply the existence of additional
r
-process sites besides the source of
r
-process elements in Ret II. Galaxies like Ret II may be the original birth sites of
r
-process enhanced stars now found in the halo.
Single-cell RNA sequencing has enabled the characterization of highly specific cell types in many tissues, as well as both primary and stem cell-derived cell lines. An important facet of these ...studies is the ability to identify the transcriptional signatures that define a cell type or state. In theory, this information can be used to classify an individual cell based on its transcriptional profile. Here, we present scPred, a new generalizable method that is able to provide highly accurate classification of single cells, using a combination of unbiased feature selection from a reduced-dimension space, and machine-learning probability-based prediction method. We apply scPred to scRNA-seq data from pancreatic tissue, mononuclear cells, colorectal tumor biopsies, and circulating dendritic cells and show that scPred is able to classify individual cells with high accuracy. The generalized method is available at https://github.com/powellgenomicslab/scPred/.
Cancer genomic instability contributes to the phenomenon of intratumoral genetic heterogeneity, provides the genetic diversity required for natural selection, and enables the extensive phenotypic ...diversity that is frequently observed among patients. Genomic instability has previously been associated with poor prognosis. However, we have evidence that for solid tumors of epithelial origin, extreme levels of genomic instability, where more than 75% of the genome is subject to somatic copy number alterations, are associated with a potentially better prognosis compared with intermediate levels under this threshold. This has been observed in clonal subpopulations of larger size, especially when genomic instability is shared among a limited number of clones. We hypothesize that cancers with extreme levels of genomic instability may be teetering on the brink of a threshold where so much of their genome is adversely altered that cells rarely replicate successfully. Another possibility is that tumors with high levels of genomic instability are more immunogenic than other cancers with a less extensive burden of genetic aberrations. Regardless of the exact mechanism, but hinging on our ability to quantify how a tumor's burden of genetic aberrations is distributed among coexisting clones, genomic instability has important therapeutic implications. Herein, we explore the possibility that a high genomic instability could be the basis for a tumor's sensitivity to DNA-damaging therapies. We primarily focus on studies of epithelial-derived solid tumors.
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Genome instability is a hallmark of cancer cells. Chromosome instability (CIN), which is often mutually exclusive from hypermutation genotypes, represents a distinct subtype of genome instability. ...Hypermutations in cancer cells are due to defects in DNA repair genes, but the cause of CIN is still elusive. However, because of the extensive chromosomal abnormalities associated with CIN, its cause is likely a defect in a network of genes that regulate mitotic checkpoints and chromosomal organization and segregation. Emerging evidence has shown that the chromosomal decatenation checkpoint, which is critical for chromatin untangling and packing during genetic material duplication, is defective in cancer cells with CIN. The decatenation checkpoint is known to be regulated by a family of enzymes called topoisomerases. Among them, the gene encoding topoisomerase IIα (TOP2A) is commonly altered at both gene copy number and gene expression level in cancer cells. Thus, abnormal alterations of TOP2A, its interacting proteins, and its modifications may have a critical role in CIN in human cancers. Clinically, a large arsenal of topoisomerase inhibitors has been used to suppress DNA replication in cancer. However, they often lead to the secondary development of leukemia because of their effect on the chromosomal decatenation checkpoint. Therefore, topoisomerase drugs must be used judiciously and administered on an individual basis. In this review, we highlight the biological function of TOP2A in chromosome segregation and the mechanisms that regulate this enzyme's expression and activity. We also review the roles of TOP2A and related proteins in human cancers, and raise a perspective for how to target TOP2A in personalized cancer therapy.
To investigate the antibacterial mechanism of carvacrol and thymol against Escherichia coli. The time-kill curve results showed that carvacrol and thymol at 200 mg l⁻¹ could inhibit the growth of E. ...coli. Flow cytometry and fluorescent dyes were used to explore the effect of two components on membrane permeability and membrane potential. In membrane permeability experiment, the mean fluorescence intensity of cells treated with 200 mg l⁻¹ carvacrol or thymol were lower than nonexposed cells. The ratio of red to green fluorescence intensity of DiOC₂(3) reflected the change of membrane potential. Carvacrol and thymol at 200 mg l⁻¹ caused the ratio of red/green decreasing from 0·42 of control to 0·08 and 0·07, respectively. Carvacrol and thymol had desired antimicrobial effect on E. coli. The antibacterial effects were attributed to their ability to permeabilize and depolarize the cytoplasmic membrane. This study showed the potential use of flow cytometry as a suitable method to investigate the mode of antibacterial action of essential oil components.
We model early star-forming regions and their chemical enrichment by Population III (Pop III) supernovae with nucleosynthetic yields featuring high C/Fe ratios and pair-instability supernova (PISN) ...signatures. We aim to test how well these chemical abundance signatures are preserved in the gas prior to forming the first long-lived low-mass stars (or second-generation stars). Our results show that second-generation stars can retain the nucleosynthetic signature of their Pop III progenitors, even in the presence of nucleosynthetically normal Pop III core-collapse supernovae. We find that carbon-enhanced metal-poor stars are likely second-generation stars that form in minihaloes. Furthermore, it is likely that the majority of Pop III supernovae produce high C/Fe yields. In contrast, metals ejected by a PISN are not concentrated in the first star-forming haloes, which may explain the absence of observed PISN signatures in metal-poor stars. We also find that unique Pop III abundance signatures in the gas are quickly wiped out by the emergence of Pop II supernovae. We caution that the observed fractions of stars with Pop III signatures cannot be directly interpreted as the fraction of Pop III stars producing that signature. Such interpretations require modelling the metal enrichment process prior to the second-generation stars’ formation, including results from simulations of metal mixing. The full potential of stellar archaeology can likely be reached in ultrafaint dwarf galaxies, where the simple formation history may allow for straightforward identification of second-generation stars.
The tumor microenvironment (TME) consists of a heterogenous cellular milieu that can influence cancer cell behavior. Its characteristics have an impact on treatments such as immunotherapy. These ...features can be revealed with single-cell RNA sequencing (scRNA-seq). We hypothesized that scRNA-seq analysis of gastric cancer together with paired normal tissue and peripheral blood mononuclear cells (PBMC) would identify critical elements of cellular deregulation not apparent with other approaches.
scRNA-seq was conducted on seven patients with gastric cancer and one patient with intestinal metaplasia. We sequenced 56,167 cells comprising gastric cancer (32,407 cells), paired normal tissue (18,657 cells), and PBMCs (5,103 cells). Protein expression was validated by multiplex immunofluorescence.
Tumor epithelium had copy number alterations, a distinct gene expression program from normal, with intratumor heterogeneity. Gastric cancer TME was significantly enriched for stromal cells, macrophages, dendritic cells (DC), and Tregs. TME-exclusive stromal cells expressed distinct extracellular matrix components than normal. Macrophages were transcriptionally heterogenous and did not conform to a binary M1/M2 paradigm. Tumor DCs had a unique gene expression program compared to PBMC DCs. TME-specific cytotoxic T cells were exhausted with two heterogenous subsets. Helper, cytotoxic T, Treg, and NK cells expressed multiple immune checkpoint or co-stimulatory molecules. Receptor-ligand analysis revealed TME-exclusive intercellular communication.
Single-cell gene expression studies revealed widespread reprogramming across multiple cellular elements in the gastric cancer TME. Cellular remodeling was delineated by changes in cell numbers, transcriptional states, and intercellular interactions. This characterization facilitates understanding of tumor biology and enables identification of novel targets including for immunotherapy.
Intratumor heterogeneity (ITH) drives neoplastic progression and therapeutic resistance. We used the bioinformatics tools 'expanding ploidy and allele frequency on nested subpopulations' (EXPANDS) ...and PyClone to detect clones that are present at a ≥10% frequency in 1,165 exome sequences from tumors in The Cancer Genome Atlas. 86% of tumors across 12 cancer types had at least two clones. ITH in the morphology of nuclei was associated with genetic ITH (Spearman's correlation coefficient, ρ = 0.24-0.41; P < 0.001). Mutation of a driver gene that typically appears in smaller clones was a survival risk factor (hazard ratio (HR) = 2.15, 95% confidence interval (CI): 1.71-2.69). The risk of mortality also increased when >2 clones coexisted in the same tumor sample (HR = 1.49, 95% CI: 1.20-1.87). In two independent data sets, copy-number alterations affecting either <25% or >75% of a tumor's genome predicted reduced risk (HR = 0.15, 95% CI: 0.08-0.29). Mortality risk also declined when >4 clones coexisted in the sample, suggesting a trade-off between the costs and benefits of genomic instability. ITH and genomic instability thus have the potential to be useful measures that can universally be applied to all cancers.
Multimessenger observations of the neutron star merger GW170817 and its kilonova proved that neutron star mergers can synthesize large quantities of r-process elements. If neutron star mergers in ...fact dominate all r-process element production, then the distribution of kilonova ejecta compositions should match the distribution of r-process abundance patterns observed in stars. The lanthanide fraction (XLa) is a measurable quantity in both kilonovae and metal-poor stars, but it has not previously been explicitly calculated for stars. Here we compute the lanthanide fraction distribution of metal-poor stars (Fe/H < − 2.5) to enable comparison to current and future kilonovae. The full distribution peaks at log XLa ∼ −1.8, but r-process-enhanced stars (Eu/Fe > 0.7) have distinctly higher lanthanide fractions: . We review observations of GW170817 and find general consensus that the total , somewhat lower than the typical metal-poor star and inconsistent with the most highly r-enhanced stars. For neutron star mergers to remain viable as the dominant r-process site, future kilonova observations should be preferentially lanthanide-rich (including a population of ∼10% with ). These high-XLa kilonovae may be fainter and more rapidly evolving than GW170817, posing a challenge for discovery and follow-up observations. Both optical and (mid-)infrared observations will be required to robustly constrain kilonova lanthanide fractions. If such high-XLa kilonovae are not found in the next few years, that likely implies that the stars with the highest r-process enhancements have a different origin for their r-process elements.
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