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We studied 1859 subjects with confirmed COVID-19 from seven centers in Wuhan 1651 of whom recovered and 208 died. We interrogated diverse covariates for correlations with risk of death from COVID-19. In multi-variable Cox regression analyses increased hazards of in-hospital death were associated with several admission covariates: (1) older age (HR = 1.04; 95% Confidence Interval [CI], 1.03, 1.06 per year increase; P < 0.001); (2) smoking (HR = 1.84 [1.17, 2.92]; P = 0.009); (3) admission temperature per °C increase (HR = 1.32 [1.07, 1.64]; P = 0.009); (4) Log10 neutrophil-to-lymphocyte ratio (NLR; HR = 3.30 [2.10, 5.19]; P < 0.001); (5) platelets per 10 E + 9/L decrease (HR = 0.996 [0.994, 0.998]; P = 0.001); (6) activated partial thromboplastin (aPTT) per second increase (HR = 1.04 [1.02, 1.05]; P < 0.001); (7) Log10 D-dimer per mg/l increase (HR = 3.00 [2.17, 4.16]; P < 0.001); and (8) Log10 serum creatinine per μmol/L increase (HR = 4.55 [2.72, 7.62]; P < 0.001). In piecewise linear regression analyses Log10NLR the interval from ≥0.4 to ≤1.0 was significantly associated with an increased risk of death. Our data identify covariates associated with risk of in hospital death in persons with COVID-19.

We studied admission and dynamic demographic, hematological and biochemical co-variates in 1449 hospitalized subjects with coronavirus infectious disease-2019 (COVID-19) in five hospitals in Wuhan, Hubei province, China. We identified two admission co-variates: age (Odds Ratio [OR] = 1.18, 95% Confidence Interval [CI] [1.02, 1.36]; P = 0.026) and baseline D-dimer (OR = 3.18 [1.48, 6.82]; P = 0.003) correlated with an increased risk of death in persons with COVID-19. We also found dynamic changes in four co-variates, Δ fibrinogen (OR = 6.45 [1.31, 31.69]; P = 0.022), Δ platelets (OR = 0.95 [0.90–0.99]; P = 0.029), Δ C-reactive protein (CRP) (OR = 1.09 [1.01, 1.18]; P = 0.037), and Δ lactate dehydrogenase (LDH) (OR = 1.03 [1.01, 1.06]; P = 0.007) correlated with an increased risk of death. The potential risk factors of old age, high baseline D-dimer, and dynamic co-variates of fibrinogen, platelets, CRP, and LDH could help clinicians to identify and treat subjects with poor prognosis.

Tumor‐associated macrophages (TAMs) are one of the most abundant cell types in colorectal cancer (CRC) tumor microenvironment (TME). Recent studies observed complicated “cross‐talks” between cancer cells and macrophages in TME. However, the underlying mechanisms are still poorly elucidated. Here, PD‐L1 levels are very low in CRC cells but highly abundant in TAMs, and a specific PD‐L1+CD206+ macrophage subpopulation are identified, which is induced by tumor cells and associated with a poor prognosis. Mechanistic investigations reveal that CRC cells can secrete small extracellular vesicles (sEVs) taken up by macrophages that induce M2 like polarization and PD‐L1 expression, resulting in increased PD‐L1+CD206+ macrophage abundance and decreased T cell activity in CRC TME. sEV‐derived miR‐21‐5p and miR‐200a are identified as key signaling molecules mediating the regulatory effects of CRC on macrophages. Further studies reveal that CRC‐derived miR‐21‐5p and miR‐200a synergistically induces macrophage M2 like polarization and PD‐L1 expression by regulating the PTEN/AKT and SCOS1/STAT1 pathways, resulting in decreased CD8+ T cell activity and increased tumor growth. This study suggests that inhibiting the secretion of specific sEV‐miRNAs from CRC and targeting PD‐L1 in TAMs may serve as novel methods for CRC treatment as well as a sensitization method for anti‐PD‐L1 therapy in CRC. A specific PD‐L1+CD206+ macrophage risk subgroup is identified in colorectal cancer, which is induced by tumor‐derived sEV‐miRNAs. This subgroup promotes tumor growth by inducing an immunosuppressive tumor microenvironment. Hence, targeting specific tumor sEV‐miRNAs that regulate PD‐L1 in tumor‐associated macrophages may serve as a novel treatment strategy and a sensitization method for anti‐PD‐L1 therapy in colorectal cancer.

Although hard carbon (HC) demonstrates superior initial Coulombic efficiency, cycling durability, and rate capability in ether‐based electrolytes compared to ester‐based electrolytes for sodium‐ion batteries (SIBs), the underlying mechanisms responsible for these disparities remain largely unexplored. Herein, ex situ electron paramagnetic resonance (EPR) spectra and in situ Raman spectroscopy are combined to investigate the Na storage mechanism of HC under different electrolytes. Through deconvolving the EPR signals of Na in HC, quasi‐metallic‐Na is successfully differentiated from adsorbed‐Na. By monitoring the evolution of different Na species during the charging/discharging process, it is found that the initial adsorbed‐Na in HC with ether‐based electrolytes can be effectively transformed into intercalated‐Na in the plateau region. However, this transformation is obstructed in ester‐based electrolytes, leading to the predominant storage of Na in HC as adsorbed‐Na and pore‐filled‐Na. Furthermore, the intercalated‐Na in HC within the ether‐based electrolytes contributes to the formation of a uniform, dense, and stable solid–electrolyte interphase (SEI) film and eventually enhances the electrochemical performance of HC. This work successfully deciphers the electrolyte‐dominated Na+ storage mechanisms in HC and provides fundamental insights into the industrialization of HC in SIBs. Hard carbon (HC) is a promising anode for SIBs. But the understanding storage mechanism in HC under different electrolytes remain largely unexplored. To address this gap, ex situ EPR spectra and in situ Raman spectroscopy are combined to investigate the Na storage mechanism of HC under different electrolytes.

Background Colorectal cancer (CRC) is a major cause of cancer-related deaths worldwide, and chemoresistance is a major obstacle in its treatment. Despite advances in therapy, the molecular mechanism underlying chemoresistance in CRC is not fully understood. Recent studies have implicated the key roles of long noncoding RNAs (lncRNAs) in the regulation of CRC chemoresistance. Methods In this study, we investigated the role of the lncRNA LINC01852 in CRC chemoresistance. LINC01852 expression was evaluated in multiple CRC cohorts using quantitative reverse transcription PCR. We conducted in vitro and in vivo functional experiments using cell culture and mouse models. RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, and dual luciferase assays were used to investigate the molecular mechanism of LINC01852 in CRC. Results Our findings revealed that a lncRNA with tumor-inhibiting properties, LINC01852, was downregulated in CRC and inhibited cell proliferation and chemoresistance both in vitro and in vivo. Further mechanistic investigations revealed that LINC01852 increases TRIM72-mediated ubiquitination and degradation of SRSF5, inhibiting SRSF5-mediated alternative splicing of PKM and thereby decreasing the production of PKM2. Overexpression of LINC01852 induces a metabolic switch from aerobic glycolysis to oxidative phosphorylation, which attenuates the chemoresistance of CRC cells by inhibiting PKM2-mediated glycolysis. Conclusions Our results demonstrate that LINC01852 plays an important role in repressing CRC malignancy and chemoresistance by regulating SRSF5-mediated alternative splicing of PKM, and that targeting the LINC01852/TRIM72/SRSF5/PKM2 signaling axis may represent a potential therapeutic strategy for CRC.

Background Human umbilical cord mesenchymal stem cells (hUC-MSCs) are widely used in cell therapy due to their robust immunomodulatory and tissue regenerative capabilities. Currently, the predominant method for obtaining hUC-MSCs for clinical use is through planar culture expansion, which presents several limitations. Specifically, continuous cell passaging can lead to cellular aging, susceptibility to contamination, and an absence of process monitoring and control, among other limitations. To overcome these challenges, the technology of microcarrier–bioreactor culture was developed with the aim of ensuring the therapeutic efficacy of cells while enabling large-scale expansion to meet clinical requirements. However, there is still a knowledge gap regarding the comparison of biological differences in cells obtained through different culture methods. Methods We developed a culture process for hUC-MSCs using self-made microcarrier and stirred bioreactor. This study systematically compares the biological properties of hUC-MSCs amplified through planar culture and microcarrier–bioreactor systems. Additionally, RNA-seq was employed to compare the differences in gene expression profiles between the two cultures, facilitating the identification of pathways and genes associated with cell aging. Results The findings revealed that hUC-MSCs expanded on microcarriers exhibited a lower degree of cellular aging compared to those expanded through planar culture. Additionally, these microcarrier-expanded hUC-MSCs showed an enhanced proliferation capacity and a reduced number of cells in the cell cycle retardation period. Moreover, bioreactor-cultured cells differ significantly from planar cultures in the expression of genes associated with the cytoskeleton and extracellular matrix. Conclusions The results of this study demonstrate that our microcarrier–bioreactor culture method enhances the proliferation efficiency of hUC-MSCs. Moreover, this culture method exhibits the potential to delay the process of cell aging while preserving the essential stem cell properties of hUC-MSCs.

Colorectal cancer (CRC) is characterized by a heterogeneous tumor microenvironment (TME) that regulates cancer progression and therapeutic response. Overexpression of FOXP3 and CTLA4 is associated with immunosuppressive TME and poor prognosis in many cancer types. However, opposite results were reported in CRC. Thus, we performed comprehensive analyses to evaluate the exact prognostic value of FOXP3 and CTLA4 in CRC. Here, the expression levels of FOXP3 and CTLA4 were used to construct a subtyping system based on >1200 CRC patients from multiple independent public datasets. We revealed that, in CRC patients with relatively high expression of FOXP3, there exist two different subpopulations with opposite survival patterns according to CLTA4 expression. We further established a method for evaluating all cohorts and identified a novel FOXP3 High CTLA4 High* CRC risk subpopulation that accounts for 5–10% of CRC patients. Moreover, different methods of functional enrichment and immune evaluation were used to analyze the TME characteristics of different FOXP3/CTLA4 subtypes. The FOXP3 High CTLA4 High* CRC risk subpopulation was characterized by an immune overdrive TME phenotype, including high immune cell infiltration, low tumor purity, high immune checkpoint levels, and TGF-β activation. Finally, the constructed FOXP3/CTLA4 subtyping system was further validated by quantitative RT-PCR, immunochemistry staining, and multicolor immunofluorescence in an independent CRC cohort we collected. This high-risk subpopulation was also observed in kidney cancers and low-grade glioma patients by a Pan-cancer analysis. Together, our study revealed that the established FOXP3/CTLA4 molecular subtyping system could be used to select treatment and management strategies for CRC and other cancers.

Disuse osteoporosis is characterized by decreased bone mass caused by abnormal mechanical stimulation of bone. Piezo1 is a major mechanosensitive ion channel in bone homeostasis. However, whether intervening in the action of Piezo1 can rescue disuse osteoporosis remains unresolved. In this study, a commonly‐used hindlimb‐unloading model is employed to simulate microgravity. By single‐cell RNA sequencing, bone marrow‐derived mesenchymal stem cells (BMSCs) are the most downregulated cell cluster, and coincidentally, Piezo1 expression is mostly enriched in those cells, and is substantially downregulated by unloading. Importantly, activation of Piezo1 by systemically‐introducing yoda1 mimics the effects of mechanical stimulation and thus ameliorates bone loss under simulated microgravity. Mechanistically, Piezo1 activation promotes the proliferation and osteogenic differentiation of Gli1 + BMSCs by activating the β‐catenin and its target gene activating transcription factor 4 (ATF4). Inhibiting β‐catenin expression substantially attenuates the effect of yoda1 on bone loss, possibly due to inhibited proliferation and osteogenic differentiation capability of Gli1 + BMSCs mediated by ATF4. Lastly, Piezo1 activation also slightly alleviates the osteoporosis of OVX and aged mice. In conclusion, impaired function of Piezo1 in BMSCs leads to insufficient bone formation especially caused by abnormal mechanical stimuli, and is thus a potential therapeutic target for osteoporosis.

Background Small nucleolar RNA host gene (SNHG) long noncoding RNAs (lncRNAs) are frequently dysregulated in human cancers and involved in tumorigenesis and progression. SNHG17 has been reported as a candidate oncogene in several cancer types, however, its regulatory role in colorectal cancer (CRC) is unclear. Methods SNHG17 expression in multiple CRC cohorts was assessed by RT-qPCR or bioinformatic analyses. Cell viability was evaluated using Cell Counting Kit-8 (CCK-8) and colony formation assays. Cell mobility and invasiveness were assessed by Transwell assays. Tumor xenograft and metastasis models were applied to confirm the effects of SNHG17 on CRC tumorigenesis and metastasis in vivo. Immunohistochemistry staining was used to measure protein expression in cancer tissues. RNA pull-down, RNA immunoprecipitation, chromatin immunoprecipitation, and dual luciferase assays were used to investigate the molecular mechanism of SNHG17 in CRC. Results Using multiple cohorts, we confirmed that SNHG17 is aberrantly upregulated in CRC and correlated with poor survival. In vitro and in vivo functional assays indicated that SNHG17 facilitates CRC proliferation and metastasis. SNHG17 impedes PES1 degradation by inhibiting Trim23-mediated ubiquitination of PES1. SNHG17 upregulates FOSL2 by sponging miR-339-5p, and FOSL2 transcription activates SNHG17 expression, uncovering a SNHG17-miR-339-5p-FOSL2-SNHG17 positive feedback loop. Conclusions We identified SNHG17 as an oncogenic lncRNA in CRC and identified abnormal upregulation of SNHG17 as a prognostic risk factor for CRC. Our mechanistic investigations demonstrated, for the first time, that SNHG17 promotes tumor growth and metastasis through two different regulatory mechanisms, SNHG17-Trim23-PES1 axis and SNHG17-miR-339-5p-FOSL2-SNHG17 positive feedback loop, which may be exploited for CRC therapy.

Radiotherapy (RT) represents one of the major treatment methods for cancers. However, many studies have observed that in descendant surviving tumor cells, sublethal irradiation can promote metastatic ability, which is closely related to the tumor microenvironment. We therefore investigated the functions and mechanisms of sublethal irradiated liver nonparenchymal cells (NPCs) in hepatocellular carcinoma (HCC). In this study, primary rat NPCs and McA‐RH7777 hepatoma cells were irradiated with 6 Gy X‐ray. Conditioned media (CM) from nonirradiated (SnonR), irradiated (SR), or irradiated plus radiosensitizer celecoxib‐treated (S[R + D]) NPCs were collected and added to sublethal irradiated McA‐RH7777 cells. We showed that CM from sublethal irradiated NPCs significantly promoted the migration and invasion ability of sublethal irradiated McA‐RH7777 cells, which was reversed by celecoxib. The differentially expressed genes in differently treated McA‐RH7777 cells were enriched mostly in the AMP‐activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway. SR increased the migration and invasion ability of HCC cells by inhibiting AMPK/mTOR signaling, which was enhanced by the AMPK inhibitor compound C and blocked by the AMPK activator GSK‐621. Analyses of HCC tissues after neoadjuvant radiotherapy confirmed the effects of radiation on the AMPK/mTOR pathway. Cytokine antibody arrays and further functional investigations showed that matrix metalloproteinase‐8 (MMP‐8) partly mediates the promotion effects of SR on the migration and invasion ability of HCC cells by regulating AMPK/mTOR signaling. In summary, our data indicate that MMP‐8 secreted by irradiated NPCs enhanced the migration and invasion of HCC by regulating AMPK/mTOR signaling, revealing a novel mechanism mediating sublethal irradiation–induced HCC metastasis at the level of the tumor microenvironment. In this work, we observed that conditioned media from sublethally irradiated liver nonparenchymal cells (NPCs) promoted the migration and invasion ability of sublethally irradiated McA‐RH7777 hepatoma cells. Further mechanistic studies revealed that matrix metalloproteinase‐8 (MMP‐8) secreted by NPCs enhanced the migration and invasion of hepatocellular carcinoma (HCC) by regulating the AMPK/mTOR signaling pathway. These findings might offer a new strategy for improving the therapeutic effect of radiotherapy.