Abstract: The Guiyang Biota fossil assemblage reveals the rapid rise of a modern-type marine ecosystem after the Permian-Triassic mass extinction.

Abstract: Understanding humoral responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for improving diagnostics, therapeutics, and vaccines. Deep serological profiling of 232 coronavirus disease 2019 (COVID-19) patients and 190 pre–COVID-19 era controls using VirScan revealed more than 800 epitopes in the SARS-CoV-2 proteome, including 10 epitopes likely recognized by neutralizing antibodies. Preexisting antibodies in controls recognized SARS-CoV-2 ORF1, whereas only COVID-19 patient antibodies primarily recognized spike protein and nucleoprotein. A machine learning model trained on VirScan data predicted SARS-CoV-2 exposure history with 99% sensitivity and 98% specificity; a rapid Luminex-based diagnostic was developed from the most discriminatory SARS-CoV-2 peptides. Individuals with more severe COVID-19 exhibited stronger and broader SARS-CoV-2 responses, weaker antibody responses to prior infections, and higher incidence of cytomegalovirus and herpes simplex virus 1, possibly influenced by demographic covariates. Among hospitalized patients, males produce stronger SARS-CoV-2 antibody responses than females.

Abstract: Substantial improvements in cycle life, rate performance, accessible voltage, and reversible capacity are required to realize the promise of Li-ion batteries in full measure. Here, we have examined insertion electrodes of the same composition (V 2 O 5 ) prepared according to the same electrode specifications and comprising particles with similar dimensions and geometries that differ only in terms of their atomic connectivity and crystal structure, specifically two-dimensional (2D) layered α-V 2 O 5 that crystallizes in an orthorhombic space group and one-dimensional (1D) tunnel-structured ζ-V 2 O 5 crystallized in a monoclinic space group. By using particles of similar dimensions, we have disentangled the role of specific structural motifs and atomistic diffusion pathways in affecting electrochemical performance by mapping the dynamical evolution of lithiation-induced structural modifications using ex situ scanning transmission X-ray microscopy, operando synchrotron X-ray diffraction measurements, and phase-field modeling. We find the operation of sharply divergent mechanisms to accommodate increasing concentrations of Li-ions: a series of distortive phase transformations that result in puckering and expansion of interlayer spacing in layered α-V 2 O 5 , as compared with cation reordering along interstitial sites in tunnel-structured ζ-V 2 O 5 . By alleviating distortive phase transformations, the ζ-V 2 O 5 cathode shows reduced voltage hysteresis, increased Li-ion diffusivity, alleviation of stress gradients, and improved capacity retention. The findings demonstrate that alternative lithiation mechanisms can be accessed in metastable compounds by dint of their reconfigured atomic connectivity and can unlock substantially improved electrochemical performance not accessible in the thermodynamically stable phase.

Abstract: The observed intercellular heterogeneity within a clonal cell population can be mapped as dynamical states clustered around an attractor point in gene expression space, owing to a balance between homeostatic forces and stochastic fluctuations. These dynamics have led to the cancer cell attractor conceptual model, with implications for both carcinogenesis and new therapeutic concepts. Immortalized and malignant EBV-carrying B-cell lines were used to explore this model and characterize the detailed structure of cell attractors. Any subpopulation selected from a population of cells repopulated the whole original basin of attraction within days to weeks. Cells at the basin edges were unstable and prone to apoptosis. Cells continuously changed states within their own attractor, thus driving the repopulation, as shown by fluorescent dye tracing. Perturbations of key regulatory genes induced a jump to a nearby attractor. Using the Fokker–Planck equation, this cell population behavior could be described as two virtual, opposing influences on the cells: one attracting toward the center and the other promoting diffusion in state space (noise). Transcriptome analysis suggests that these forces result from high-dimensional dynamics of the gene regulatory network. We propose that they can be generalized to all cancer cell populations and represent intrinsic behaviors of tumors, offering a previously unidentified characteristic for studying cancer.

Abstract: Our study revealed that MED23 senses and relays the hyperactive Ras signaling to the downstream target genes through interacting with the phosphorylated ELK1, thus controlling the cancer cell proliferation and tumorigenicity. The selective requirement for MED23 in lung cancer may depend on the strength of the Ras/MAPK signaling as indicated by ERK- and ELK1-phosphorylation levels. Moreover, these findings suggest that the malignant phenotype of cancer cells harboring K-Ras mutations is dependent not only on the oncogenic K-Ras but also on the entire Ras/MAPK pathway, including the downstream cofactor MED23. Thus, the model of “oncogenic pathway addiction” may better describe the up-regulation of the entire Ras/MAPK pathway by the oncogenic Ras mutation, including ELK1/MED23 as key modulators and effectors within the nucleus ( Fig. P1 ). In other words, Ras signaling is dependent on ELK1 and MED23 for its addiction. Because multiple often-mutated oncogenes in the Ras/MAPK pathway, such as EGFR, Ras, and Raf, share a common signal transduction cascade, patients with mutations in any of these oncogenes might benefit from targeting MED23. Indeed, we have observed that the depletion of Med23 can inhibit the growth of cancer cells with EGFR or B-raf mutations also. Knockdown of Med23 or Elk1 attenuates the transduction of the oncogenic signaling to the nucleus; therefore, targeting MED23, ELK1, or their interaction interface by specific inhibitors may represent multiple opportunities to treat lung cancer or other types of cancer harboring hyperactive Ras signaling for which there is no effective therapy. To understand further the function of MED23 in Ras-driven tumorigenesis, we determined the expression of MED23 in a series of lung cancer cell lines and in a large panel of clinical lung cancer samples. Consistent with findings for cell lines transformed by Ras, MED23 was found to be overexpressed in lung cancer cell lines and in lung cancer samples, and this increased level of expression corresponded to the active Ras activities indicated by ERK- and ELK1-phosphorylation. Therefore, the elevation in MED23 expression was not only required for but also resulted from Ras hyperactivity during lung carcinogenesis, suggesting their mutual dependence. Remarkably, we found that the expression level of Med23 correlated specifically with clinical outcomes of patients with a positive Ras signature (i.e., a gene-expression profile associated with mutated Ras ). Specifically, lower Med23 expression levels predict better survival in lung cancer patients with a positive Ras signature. This observation was recapitulated further in a xenograft mice model with an inducible Med23 knockdown strategy. Taken together, our results suggest that MED23 may serve as a diagnostic marker and a therapeutic target for individualized therapy for lung cancers harboring activated Ras. Genetic and biochemical interaction studies demonstrated that MED23 is targeted specifically by the ternary complex factor ELK1 for channeling the Ras/MAPK signaling to the nucleus ( 5 ). We asked whether Mediator MED23 controls Ras-driven oncogenesis and downstream gene expression through its binding partner, ELK1, and found that ELK1 was also selectively required for the cancer cell proliferation and fibroblast transformation in a Ras-dependent manner. Thus, Elk1 seems to reiterate the phenotype specified by Med23 in regulating tumorigenesis. Further, to gain an understanding of how MED23 and ELK1 control gene expression in lung cancer cells harboring activated Ras, gene-profiling experiments were performed and revealed that MED23 and ELK1 exerted similar effects on global gene regulation and coregulated a set of genes involved the cell cycle. These findings suggest that interaction between MED23 and ELK1 is important for transduction of the oncogenic Ras signaling and may account for the Ras-driven oncogenesis. To establish further the direct relationship between MED23 and Ras during oncogenesis, we used oncogenic transformation assays to model the MED23 dependence in fibroblast transformation by different oncogenes. We found that Med23 deficiency in fibroblasts selectively inhibited oncogenic transformation by Ras but not by c-Myc. Moreover, the expression level of MED23 was highly up-regulated during the transformation by Ras but less so by other oncogenes, including c-Myc and T-antigen, further confirming the specific codependency of active Ras and MED23 in Ras-driven oncogenesis. Mediator is an evolutionarily conserved cofactor complex of the RNA polymerase II machinery that functions as an integrative hub to coordinate signaling pathways and gene activities that direct diverse biological processes ( 3 ). The Mediator MED23 subunit was considered a downstream nuclear factor for the Ras–MAPK signaling pathway ( 4 ). In this study, we examined the role of MED23 in lung cancer. Using viral-mediated shRNA to inhibit Med23 expression in a large panel of human lung cancer cell lines with or without a Ras mutation, we found that depletion of Med23 selectively inhibited the proliferation and tumorigenicity of cancer cells with mutated Ras but not with wild-type Ras . Introducing the mutated Ras into the cell lines with wild-type Ras renders them dependent on MED23 for growth. Thus, our finding indicates that MED23 controls the proliferation of lung cancer cells in a Ras-dependent manner. Lung cancer is the leading cause of cancer-related mortality worldwide and arises from the accumulation of multiple oncogenic lesions. A point mutation in the Ras gene family member, the K-Ras gene, and constitutive activation of the Ras–MAPK signaling pathway are involved in certain lung cancers ( 1 ). Efforts to develop Ras-directed therapies are challenged by the difficulty in selectively targeting the activated Ras GTPase ( 2 ). Here, we screened a panel of lung cancer cells with and without Ras mutations and demonstrated that MED23, a component of the Mediator complex, and its interacting transcription factor, ELK1, are critical for Ras-driven oncogenesis and may provide potential targets for “undruggable” Ras-driven lung cancer.

Abstract: Stem cells serve as the source of new cells for plant development. A group of stem cells form a stem cell niche (SCN) at the root tip and in the center of the SCN are slowly dividing cells called the quiescent center (QC). QC is thought to function as a signaling hub that inhibits differentiation of surrounding stem cells. Although it has been generally assumed that cell-to-cell communication provides positional information for QC and SCN maintenance, the tools for testing this hypothesis have long been lacking. Here we exploit a system that effectively blocks plasmodesmata (PD)-mediated signaling to explore how cell-to-cell communication functions in the SCN. We showed that the symplastic signaling between the QC and adjacent cells directs the formation of local auxin maxima and establishment of AP2-domain transcription factors, PLETHORA gradients. Interestingly we found symplastic signaling is essential for local auxin biosynthesis, which acts together with auxin polar transport to provide the guidance for local auxin enrichment. Therefore, we demonstrate the crucial role of cell-to-cell communication in the SCN maintenance and further uncover a mechanism by which symplastic signaling initiates and reinforces the positional information during stem cell maintenance via auxin regulation.

Abstract: The purinergic signaling molecule adenosine (Ado) modulates many physiological and pathological functions in the brain. However, the exact source of extracellular Ado remains controversial. Here, utilizing a newly optimized genetically encoded GPCR-Activation-Based Ado fluorescent sensor (GRAB Ado ), we discovered that the neuronal activity–induced extracellular Ado elevation is due to direct Ado release from somatodendritic compartments of neurons, rather than from the axonal terminals, in the hippocampus. Pharmacological and genetic manipulations reveal that the Ado release depends on equilibrative nucleoside transporters but not the conventional vesicular release mechanisms. Compared with the fast-vesicular glutamate release, the Ado release is slow (~40 s) and requires calcium influx through L-type calcium channels. Thus, this study reveals an activity-dependent second-to-minute local Ado release from the somatodendritic compartments of neurons, potentially serving modulatory functions as a retrograde signal.

Abstract: GPR34 is a functional G-protein-coupled receptor of Lysophosphatidylserine (LysoPS), and has pathogenic roles in numerous diseases, yet remains poorly targeted. We herein report a cryo-electron microscopy (cryo-EM) structure of GPR34 bound with LysoPS (18:1) and G i protein, revealing a unique ligand recognition mode with the negatively charged head group of LysoPS occupying a polar cavity formed by TM3, 6 and 7, and the hydrophobic tail of LysoPS residing in a lateral open hydrophobic groove formed by TM3-5. Virtual screening and subsequent structural optimization led to the identification of a highly potent and selective antagonist (YL-365). Design of fusion proteins allowed successful determination of the challenging cryo-EM structure of the inactive GPR34 complexed with YL-365, which revealed the competitive binding of YL-365 in a portion of the orthosteric binding pocket of GPR34 and the antagonist-binding-induced allostery in the receptor, implicating the inhibition mechanism of YL-365. Moreover, YL-365 displayed excellent activity in a neuropathic pain model without obvious toxicity. Collectively, this study offers mechanistic insights into the endogenous agonist recognition and antagonist inhibition of GPR34, and provides proof of concept that targeting GPR34 represents a promising strategy for disease treatment.