ABSTRACT We investigate the ultraharmonics response of a protoplanetary disk to an orbiting planet. We find that the multi-armed spiral structure can be excited by the higher-order forcing due to ...nonlinear mode-coupling. In particular, the preferential excitation of the gas response with a small azimuthal wavenumber is a direct consequence of mode-coupling among linear waves. The presence of multiple Fourier components in a planet's potential is a distinct feature compared to the previous studies in the context of spiral galaxies, which turns out to be crucial for the generation of ultraharmonics waves. This analysis may shed light on the understanding of some results regarding the spiral structures excited by a massive planet.
The tumor microenvironment (TME) of nasopharyngeal carcinoma (NPC) harbors a heterogeneous and dynamic stromal population. A comprehensive understanding of this tumor-specific ecosystem is necessary ...to enhance cancer diagnosis, therapeutics, and prognosis. However, recent advances based on bulk RNA sequencing remain insufficient to construct an in-depth landscape of infiltrating stromal cells in NPC. Here we apply single-cell RNA sequencing to 66,627 cells from 14 patients, integrated with clonotype identification on T and B cells. We identify and characterize five major stromal clusters and 36 distinct subpopulations based on genetic profiling. By comparing with the infiltrating cells in the non-malignant microenvironment, we report highly representative features in the TME, including phenotypic abundance, genetic alternations, immune dynamics, clonal expansion, developmental trajectory, and molecular interactions that profoundly influence patient prognosis and therapeutic outcome. The key findings are further independently validated in two single-cell RNA sequencing cohorts and two bulk RNA-sequencing cohorts. In the present study, we reveal the correlation between NPC-specific characteristics and progression-free survival. Together, these data facilitate the understanding of the stromal landscape and immune dynamics in NPC patients and provides deeper insights into the development of prognostic biomarkers and therapeutic targets in the TME.
Ever increasing environmental presence of cadmium as a consequence of industrial activities is considered a health hazard and is closely linked to deteriorating global health status. General animal ...and human cadmium exposure ranges from ingestion of foodstuffs sourced from heavily polluted hotspots and cigarette smoke to widespread contamination of air and water, including cadmium-containing microplastics found in household water. Cadmium is promiscuous in its effects and exerts numerous cellular perturbations based on direct interactions with macromolecules and its capacity to mimic or displace essential physiological ions, such as iron and zinc. Cell organelles use lipid membranes to form complex tightly-regulated, compartmentalized networks with specialized functions, which are fundamental to life. Interorganellar communication is crucial for orchestrating correct cell behavior, such as adaptive stress responses, and can be mediated by the release of signaling molecules, exchange of organelle contents, mechanical force generated through organelle shape changes or direct membrane contact sites. In this review, cadmium effects on organellar structure and function will be critically discussed with particular consideration to disruption of organelle physiology in vertebrates.
The genome is organized in three-dimensional units called topologically associating domains (TADs), through a process dependent on the cooperative action of cohesin and the DNA-binding factor CTCF. ...Genomic rearrangements of TADs have been shown to cause gene misexpression and disease, but genome-wide depletion of CTCF has no drastic effects on transcription. Here, we investigate TAD function in vivo in mouse limb buds at the Sox9-Kcnj2 locus. We show that the removal of all major CTCF sites at the boundary and within the TAD resulted in a fusion of neighboring TADs, without major effects on gene expression. Gene misexpression and disease phenotypes, however, were achieved by redirecting regulatory activity through inversions and/or the repositioning of boundaries. Thus, TAD structures provide robustness and precision but are not essential for developmental gene regulation. Aberrant disease-related gene activation is not induced by a mere loss of insulation but requires CTCF-dependent redirection of enhancer-promoter contacts.
The generation of high-affinity antibodies depends on the ability of cells to extract antigens from the surfaces of antigen-presenting cells. cells that express high-affinity cell receptors (BCRs) ...acquire more antigen and obtain better T cell help. However, the mechanisms by which cells extract antigen remain unclear. Using fluid and flexible membrane substrates to mimic antigen-presenting cells, we showed that cells acquire antigen by dynamic myosin lla-mediated contractions that pull out and invaginate the presenting membranes. The forces generated by myosin lla contractions ruptured most individual BCR-antigen bonds and promoted internalization of only high-affinity, multivalent BCR microclusters. Thus, cell contractility contributes to affinity discrimination by mechanically testing the strength of antigen binding.
We investigate how planets interact with viscous accretion disks, in the limit that the disk is sufficiently low mass that the planet migrates more slowly than the disk material. In that case, the ...disk's surface density profile is determined by the disk being in viscous steady state (VSS) while overflowing the planet's orbit. We compute the VSS profiles with 2D hydrodynamical simulations, and show that disk material piles up behind the planet, with the planet effectively acting as a leaky dam. Previous 2D hydrodynamical simulations missed the pileup effect because of incorrect boundary conditions, while previous 1D models greatly overpredicted the pileup due to the neglect of nonlocal deposition. Our simulations quantify the magnitude of the pileup for a variety of planet masses and disk viscosities. We also calculate theoretically the magnitude of the pileup for moderately deep gaps, showing good agreement with simulations. For very deep gaps, current theory is inadequate, and we show why and what must be understood better. The pileup is important for two reasons. First, it is observable in directly imaged protoplanetary disks, and hence can be used to diagnose the mass of a planet that causes it or the viscosity within the disk. Second, it determines the planet's migration rate. Our simulations determine a new Type-II migration rate (valid for low-mass disks), and show how it connects continuously with the well-verified Type-I rate.
Cadmium (Cd
2+
) is a toxic and non-essential divalent metal ion in eukaryotic cells. Cells can only be targeted by Cd
2+
if it hijacks physiological high-affinity entry pathways, which transport ...essential divalent metal ions in a process termed “ionic and molecular mimicry”. Hence, “free” Cd
2+
ions and Cd
2+
complexed with small organic molecules are transported across cellular membranes via ion channels, carriers and ATP hydrolyzing pumps, whereas receptor-mediated endocytosis (RME) internalizes Cd
2+
-protein complexes. Only Cd
2+
transport pathways validated by stringent methodology, namely electrophysiology,
109
Cd
2+
tracer studies, inductively coupled plasma mass spectrometry, atomic absorption spectroscopy, Cd
2+
-sensitive fluorescent dyes, or specific ligand binding and internalization assays for RME are reviewed whereas indirect correlative studies are excluded. At toxicologically relevant concentrations in the submicromolar range, Cd
2+
permeates voltage-dependent Ca
2+
channels (“T-type” Ca
V
3.1, CatSper), transient receptor potential (TRP) channels (TRPA1, TRPV5/6, TRPML1), solute carriers (SLCs) (DMT1/SLC11A2, ZIP8/SLC39A8, ZIP14/SLC39A14), amino acid/cystine transporters (SLC7A9/SLC3A1, SLC7A9/SLC7A13), and Cd
2+
-protein complexes are endocytosed by the lipocalin-2/NGAL receptor SLC22A17. Cd
2+
transport via the mitochondrial Ca
2+
uniporter, ATPases ABCC1/2/5 and transferrin receptor 1 is likely but requires further evidence. Cd
2+
flux occurs through the influx carrier OCT2/SLC22A2, efflux MATE proteins SLC47A1/A2, the efflux ATPase ABCB1, and RME of Cd
2+
-metallothionein by the receptor megalin (low density lipoprotein receptor-related protein 2, LRP2):cubilin albeit at high concentrations thus questioning their relevance in Cd
2+
loading. Which Cd
2+
-protein complexes are internalized by megalin:cubilin in vivo still needs to be determined. A stringent conservative and reductionist approach is mandatory to verify relevance of transport pathways for Cd
2+
toxicity and to overcome dissemination of unsubstantiated conjectures.
Chromosome conformation capture methods have identified subchromosomal structures of higher-order chromatin interactions called topologically associated domains (TADs) that are separated from each ...other by boundary regions. By subdividing the genome into discrete regulatory units, TADs restrict the contacts that enhancers establish with their target genes. However, the mechanisms that underlie partitioning of the genome into TADs remain poorly understood. Here we show by chromosome conformation capture (capture Hi-C and 4C-seq methods) that genomic duplications in patient cells and genetically modified mice can result in the formation of new chromatin domains (neo-TADs) and that this process determines their molecular pathology. Duplications of non-coding DNA within the mouse Sox9 TAD (intra-TAD) that cause female to male sex reversal in humans, showed increased contact of the duplicated regions within the TAD, but no change in the overall TAD structure. In contrast, overlapping duplications that extended over the next boundary into the neighbouring TAD (inter-TAD), resulted in the formation of a new chromatin domain (neo-TAD) that was isolated from the rest of the genome. As a consequence of this insulation, inter-TAD duplications had no phenotypic effect. However, incorporation of the next flanking gene, Kcnj2, in the neo-TAD resulted in ectopic contacts of Kcnj2 with the duplicated part of the Sox9 regulatory region, consecutive misexpression of Kcnj2, and a limb malformation phenotype. Our findings provide evidence that TADs are genomic regulatory units with a high degree of internal stability that can be sculptured by structural genomic variations. This process is important for the interpretation of copy number variations, as these variations are routinely detected in diagnostic tests for genetic disease and cancer. This finding also has relevance in an evolutionary setting because copy-number differences are thought to have a crucial role in the evolution of genome complexity.
The eighth edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage classification (TNM) for nasopharyngeal carcinoma (NPC) was launched. It ...remains unknown if incorporation of nonanatomic factors into the stage classification would better predict survival. We prospectively recruited 518 patients with nonmetastatic NPC treated with radical intensity‐modulated radiation therapy ± chemotherapy based on the eighth edition TNM. Recursive partitioning analysis (RPA) incorporating pretreatment plasma Epstein–Barr virus (EBV) DNA derived new stage groups. Multivariable analyses to calculate adjusted hazard ratios (AHRs) derived another set of stage groups. Five‐year progression‐free survival (PFS), overall survival (OS) and cancer‐specific survival (CSS) were: Stage I (PFS 100%, OS 90%, CSS 100%), II (PFS 88%, OS 84%, CSS 95%), III (PFS 84%, OS 84%, CSS 90%) and IVA (PFS 71%, OS 75%, CSS 80%) (p < 0.001, p = 0.066 and p = 0.002, respectively). RPA derived four new stages: RPA‐I (T1–T4 N0–N2 & EBV DNA <500 copies per mL; PFS 94%, OS 89%, CSS 96%), RPA‐II (T1–T4 N0–N2 & EBV DNA ≥500 copies per mL; PFS 80%, OS 83%, CSS 89%), RPA‐III (T1–T2 N3; PFS 64%, OS 83%, CSS 83%) and RPA‐IVA (T3–T4 N3; PFS 63%, OS 60% and CSS 68%) (all with p < 0.001). AHR using covariate adjustment also yielded a valid classification (I: T1–T2 N0–N2; II: T3–T4 N0–N2 or T1–T2 N3 and III: T3–T4 N3) (all with p < 0.001). However, RPA stages better predicted survival for PS and CSS after bootstrapping replications. Our RPA‐based stage groups revealed better survival prediction compared to the eighth edition TNM and the AHR stage groups.
What's new?
The AJCC/UICC TNM stage classification is the most widely accepted common language to describe the magnitude and spread of cancer. However, a new pretreatment staging system comprising both anatomic and non‐anatomic factors is warranted to improve survival prediction. Here, the authors propose new stage groups incorporating pretreatment plasma Epstein–Barr virus (EBV) DNA for non‐metastatic nasopharyngeal carcinoma (NPC). Their prospective study measuring pretreatment plasma EBV DNA in 518 completely staged non‐metastatic NPC patients who were later treated with intensity‐modulated radiation therapy with/without adjunct chemotherapy demonstrates significantly better survival prediction with the newly proposed stages as compared to the current edition TNM.
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