AbstractThe instability of structural members under axial compression most likely causes spatial structural collapse. Therefore, the configuration of double-layer members (DLMs) is proposed in this ...study to improve the stability of compression members. Experiments on four specimens (two single-layer members and two DLMs) were conducted, where the failure mechanism was revealed based on analysis of a validated finite-element (FE) model. Parametric studies were also performed to investigate the effects of different parameters on the compressive mechanical behaviors of the DLMs. Results showed that the desired failure mode of the DLMs was high-order buckling with torsion of the inner tube and no global buckling failure prior to contact between the outer tube and end plate (HTCG). Under the failure mode of HTCG, the ultimate load and ductility were greatly improved due to the constraint of the outer tube. Finally, predictions of the crucial loads derived from the equilibrium differential equation and empirical formula were in good agreement with the test and FE results.
As core units of organ tissues, cells of various types play their harmonious rhythms to maintain the homeostasis of the human body. It is essential to identify the characteristics of cells in human ...organs and their regulatory networks for understanding the biological mechanisms related to health and disease. However, a systematic and comprehensive single-cell transcriptional profile across multiple organs of a normal human adult is missing.
We perform single-cell transcriptomes of 84,363 cells derived from 15 tissue organs of one adult donor and generate an adult human cell atlas. The adult human cell atlas depicts 252 subtypes of cells, including major cell types such as T, B, myeloid, epithelial, and stromal cells, as well as novel COCH
fibroblasts and FibSmo cells, each of which is distinguished by multiple marker genes and transcriptional profiles. These collectively contribute to the heterogeneity of major human organs. Moreover, T cell and B cell receptor repertoire comparisons and trajectory analyses reveal direct clonal sharing of T and B cells with various developmental states among different tissues. Furthermore, novel cell markers, transcription factors, and ligand-receptor pairs are identified with potential functional regulations in maintaining the homeostasis of human cells among tissues.
The adult human cell atlas reveals the inter- and intra-organ heterogeneity of cell characteristics and provides a useful resource in uncovering key events during the development of human diseases in the context of the heterogeneity of cells and organs.
TP53
is the most frequently mutated tumor suppressor gene in human cancer. The majority of mutations of p53 are missense mutations, leading to the expression of the full length p53 mutant proteins. ...Mutant p53 (Mutp53) proteins not only lose wild-type p53-dependent tumor suppressive functions, but also frequently acquire oncogenic gain-of-functions (GOF) that promote tumorigenesis. In this review, we summarize the recent advances in our understanding of the oncogenic GOF of mutp53 and the potential therapies targeting mutp53 in human cancers. In particular, we discuss the promising drugs that are currently under clinical trials as well as the emerging therapeutic strategies, including CRISPR/Cas9 based genome edition of mutant
TP53
allele, small peptide mediated restoration of wild-type p53 function, and immunotherapies that directly eliminate mutp53 expressing tumor cells.
MYCN amplification is tightly associated with the poor prognosis of pediatric neuroblastoma (NB). The regulation of NB cell death by MYCN represents an important aspect, as it directly contributes to ...tumor progression and therapeutic resistance. However, the relationship between MYCN and cell death remains elusive. Ferroptosis is a newly identified cell death mode featured by lipid peroxide accumulation that can be attenuated by GPX4, yet whether and how MYCN regulates ferroptosis are not fully understood. Here, we report that MYCN-amplified NB cells are sensitive to GPX4-targeting ferroptosis inducers. Mechanically, MYCN expression reprograms the cellular iron metabolism by upregulating the expression of TFRC, which encodes transferrin receptor 1 as a key iron transporter on the cell membrane. Further, the increased iron uptake promotes the accumulation of labile iron pool, leading to enhanced lipid peroxide production. Consistently, TFRC overexpression in NB cells also induces selective sensitivity to GPX4 inhibition and ferroptosis. Moreover, we found that MYCN fails to alter the general lipid metabolism and the amount of cystine imported by System X
(-) for glutathione synthesis, both of which contribute to ferroptosis in alternative contexts. In conclusion, NB cells harboring MYCN amplification are prone to undergo ferroptosis conferred by TFRC upregulation, suggesting that GPX4-targeting ferroptosis inducers or TFRC agonists can be potential strategies in treating MYCN-amplified NB.
Tumor-infiltrating myeloid cells (TIMs) are key regulators in tumor progression, but the similarity and distinction of their fundamental properties across different tumors remain elusive. Here, by ...performing a pan-cancer analysis of single myeloid cells from 210 patients across 15 human cancer types, we identified distinct features of TIMs across cancer types. Mast cells in nasopharyngeal cancer were found to be associated with better prognosis and exhibited an anti-tumor phenotype with a high ratio of TNF+/VEGFA+ cells. Systematic comparison between cDC1- and cDC2-derived LAMP3+ cDCs revealed their differences in transcription factors and external stimulus. Additionally, pro-angiogenic tumor-associated macrophages (TAMs) were characterized with diverse markers across different cancer types, and the composition of TIMs appeared to be associated with certain features of somatic mutations and gene expressions. Our results provide a systematic view of the highly heterogeneous TIMs and suggest future avenues for rational, targeted immunotherapies.
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•Pan-cancer analysis reveals heterogeneity in tumor-infiltrating myeloid cell composition•The ratio of TNF+ versus VEGFA+ mast cells underlines their cancer-type-specific functions•LAMP3+ cDCs are widely present, with diverse developmental origins and functions•Pro-angiogenic TAMs exhibit distinct expression profiles across different cancer types
A systemic analysis of tumor-infiltrating myeloid cells across 15 human cancer types features the molecular basis of pro- versus anti-tumor effect of mast cells, the connection between developmental origins and functions in LAMP3+ cDCs, and the diversity in pro-angiogenic tumor-associated macrophages across different cancers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The heterogeneous nature of tumour microenvironment (TME) underlying diverse treatment responses remains unclear in nasopharyngeal carcinoma (NPC). Here, we profile 176,447 cells from 10 NPC ...tumour-blood pairs, using single-cell transcriptome coupled with T cell receptor sequencing. Our analyses reveal 53 cell subtypes, including tumour-infiltrating CD8
T, regulatory T (Treg), and dendritic cells (DCs), as well as malignant cells with different Epstein-Barr virus infection status. Trajectory analyses reveal exhausted CD8
T and immune-suppressive TNFRSF4
Treg cells in tumours might derive from peripheral CX3CR1
CD8
T and naïve Treg cells, respectively. Moreover, we identify immune-regulatory and tolerogenic LAMP3
DCs. Noteworthily, we observe intensive inter-cell interactions among LAMP3
DCs, Treg, exhausted CD8
T, and malignant cells, suggesting potential cross-talks to foster an immune-suppressive niche for the TME. Collectively, our study uncovers the heterogeneity and interacting molecules of the TME in NPC at single-cell resolution, which provide insights into the mechanisms underlying NPC progression and the development of precise therapies for NPC.
To evaluate the efficacy of laparoscopic pyeloplasty relative to retrograde balloon dilatation for the treatment of ureteropelvic junction obstruction (UPJO).
This retrospective study enrolled UPJO ...patients with stricture length < 2 cm who had been treated with laparoscopic pyeloplasty (LP; 44 cases) or balloon dilatation (BD; 38 cases) from Jan 2010 to Jan 2012, according to patients' preference after consultation. Demographics and clinical parameters were collected. Patients were followed-up at 3, 6, 12, and 24 months. Ultrasonography, intravenous urography, and diuretic renography were applied to evaluate the remission of hydronephrosis.
Both groups were comparable with respect to age, UPJO location, gender, and other baseline parameters. Compared to the LP group, patients receiving BD experienced significantly shorter operative time, analgesia time, hospital stay, and urethral catheter indwelling time, and less cost (P<0.001). Three and 6 months after their respective procedures, the success rates of the LP (97.7%, both) and BD (94.7% and 86.8%) groups were similar, and at 12 and 24 months the long-term success rate of LP (95.5%, both) was better than that of BD (78.9% and 71.0%).
LP showed better long-term success rate than did BD in the management of UPJO with length of stricture < 2 cm. Considering that BD is more minimally invasive, simpler and easier to perform, and costs less, we recommend it for some selective UPJO patients as the first-line therapy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A dysfunctional immune response in coronavirus disease 2019 (COVID-19) patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent immune cells is not ...complete. We applied single-cell RNA sequencing to 284 samples from 196 COVID-19 patients and controls and created a comprehensive immune landscape with 1.46 million cells. The large dataset enabled us to identify that different peripheral immune subtype changes are associated with distinct clinical features, including age, sex, severity, and disease stages of COVID-19. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in diverse epithelial and immune cell types, accompanied by dramatic transcriptomic changes within virus-positive cells. Systemic upregulation of S100A8/A9, mainly by megakaryocytes and monocytes in the peripheral blood, may contribute to the cytokine storms frequently observed in severe patients. Our data provide a rich resource for understanding the pathogenesis of and developing effective therapeutic strategies for COVID-19.
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•Detailed COVID-19 immune landscape depicted by integrated 1.46 million single cells•Peripheral immune subtypes differentially associated with distinct clinical features•SARS-CoV-2 RNA is present in diverse epithelial and immune cells•Megakaryocytes and monocyte subsets may contribute to cytokine storms
Analysis of the immune landscape in the lung and peripheral blood of COVID patients across different regions in China at the single-cell level documents the presence of viral RNAs in diverse cell types and highlights the potential contribution of megakaryocytes and monocyte subsets to cytokine storms.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Uncovering the immune response to an inactivated SARS‐CoV‐2 vaccine (In‐Vac) and natural infection is crucial for comprehending COVID‐19 immunology. Here we conducted an integrated analysis of ...single‐cell RNA sequencing (scRNA‐seq) data from serial peripheral blood mononuclear cell (PBMC) samples derived from 12 individuals receiving In‐Vac compared with those from COVID‐19 patients. Our study reveals that In‐Vac induces subtle immunological changes in PBMC, including cell proportions and transcriptomes, compared with profound changes for natural infection. In‐Vac modestly upregulates IFN‐α but downregulates NF‐κB pathways, while natural infection triggers hyperactive IFN‐α and NF‐κB pathways. Both In‐Vac and natural infection alter T/B cell receptor repertoires, but COVID‐19 has more significant change in preferential VJ gene, indicating a vigorous immune response. Our study reveals distinct patterns of cellular communications, including a selective activation of IL‐15RA/IL‐15 receptor pathway after In‐Vac boost, suggesting its potential role in enhancing In‐Vac‐induced immunity. Collectively, our study illuminates multifaceted immune responses to In‐Vac and natural infection, providing insights for optimizing SARS‐CoV‐2 vaccine efficacy.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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