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The full neutrophil heterogeneity and differentiation landscape remains incompletely characterized. Here, we profiled >25,000 differentiating and mature mouse neutrophils using single-cell RNA sequencing to provide a comprehensive transcriptional landscape of neutrophil maturation, function and fate decision in their steady state and during bacterial infection. Eight neutrophil populations were defined by distinct molecular signatures. The three mature peripheral blood neutrophil subsets arise from distinct maturing bone marrow neutrophil subsets. Driven by both known and uncharacterized transcription factors, neutrophils gradually acquire microbicidal capability as they traverse the transcriptional landscape, representing an evolved mechanism for fine-tuned regulation of an effective but balanced neutrophil response. Bacterial infection reprograms the genetic architecture of neutrophil populations, alters dynamic transitions between subpopulations and primes neutrophils for augmented functionality without affecting overall heterogeneity. In summary, these data establish a reference model and general framework for studying neutrophil-related disease mechanisms, biomarkers and therapeutic targets at single-cell resolution. Luo and colleagues use single-cell RNA sequencing to provide a comprehensive transcriptional landscape of neutrophil maturation, function and fate decision in their steady state and during bacterial infection.

Candida albicans is the most common cause of fungal sepsis. Inhibition of inflammasome activity confers resistance to polymicrobial and LPS-induced sepsis; however, inflammasome signaling appears to protect against C. albicans infection, so inflammasome inhibitors are not clinically useful for candidiasis. Here we show disruption of GSDMD, a known inflammasome target and key pyroptotic cell death mediator, paradoxically alleviates candidiasis, improving outcomes and survival of Candida -infected mice. Mechanistically, C. albicans hijacked the canonical inflammasome-GSDMD axis-mediated pyroptosis to promote their escape from macrophages, deploying hyphae and candidalysin, a pore-forming toxin expressed by hyphae. GSDMD inhibition alleviated candidiasis by preventing C. albicans escape from macrophages while maintaining inflammasome-dependent but GSDMD-independent IL-1β production for anti-fungal host defenses. This study demonstrates key functions for GSDMD in Candida ’s escape from host immunity in vitro and in vivo and suggests that GSDMD may be a potential therapeutic target in C. albicans -induced sepsis. Inflammasome signalling has been shown to protect Candida albicans during infection and as such limits inflammasome inhibitors in this context. Here the authors implicate Gasdermin D in C.ablicans immune evasion and suggests its targeting therapeutically.

Previous research has found that female entrepreneurs are disadvantaged in traditional funding markets. Yet, whether the same conclusion can be drawn in the equity crowdfunding market has not yet been determined. Leveraging both stereotype content theory and warm-glow theory, and based on a data set drawn from 259 projects from three equity crowdfunding platforms in China between October 2014 and April 2019, this study empirically examines the underlying relationship between female entrepreneurs and equity crowdfunding. Using Poisson regression analysis, we find that female entrepreneurs are more likely to be funded through equity crowdfunding than their male counterparts. Moreover, we use the presence or absence of lead investors and venture stage (i.e., early versus late) as potential moderators. Our results reveal that while lead investors augment the financing advantage of female entrepreneurs in the equity crowdfunding market, this advantage is weakened in later-development-stage ventures. The findings of this research contribute to the equity crowdfunding and the female entrepreneurship literature by showing that an entrepreneur’s gender influences equity crowdfunding performance. Our findings also extend previous research by demonstrating that both lead investors and venture stage moderate the impact of gender in the equity crowdfunding market.

Since residual learning was proposed, identity mapping has been widely utilized in various neural networks. The method enables information transfer without any attenuation, which plays a significant role in training deeper networks. However, interference with unhindered transmission also affects the network’s performance. Accordingly, we propose a generalized residual learning architecture called reverse attention (RA), which applies high-level semantic features to supervise low-level information in the identity mapping branch. It means that higher semantic features selectively transmit low-level information to deeper layers. In addition, we propose a Modified Global Response Normalization(M-GRN) to implement reverse attention. RA-Net is derived by embedding M-GRN in the residual learning framework. The experiments show that the RA-Net brings significant improvements over residual networks on typical computer vision tasks. For classification on ImageNet-1K, compared with resnet101, RA-Net improves the Top-1 accuracy by 1.7% with comparable parameters and computational cost. For COCO detection, on Faster R-CNN, reverse attention improves box AP by 1.9%. Meanwhile, reverse attention improves UpperNet’s mIoU by 0.7% on ADE20K segmentation.

Both lytic and apoptotic cell death remove senescent and damaged cells in living organisms. However, they elicit contrasting pro- and anti-inflammatory responses, respectively. The precise cellular mechanism that governs the choice between these two modes of death remains incompletely understood. Here we identify Gasdermin E (GSDME) as a master switch for neutrophil lytic pyroptotic death. The tightly regulated GSDME cleavage and activation in aging neutrophils are mediated by proteinase-3 and caspase-3, leading to pyroptosis. GSDME deficiency does not alter neutrophil overall survival rate; instead, it specifically precludes pyroptosis and skews neutrophil death towards apoptosis, thereby attenuating inflammatory responses due to augmented efferocytosis of apoptotic neutrophils by macrophages. In a clinically relevant acid-aspiration-induced lung injury model, neutrophil-specific deletion of GSDME reduces pulmonary inflammation, facilitates inflammation resolution, and alleviates lung injury. Thus, by controlling the mode of neutrophil death, GSDME dictates host inflammatory outcomes, providing a potential therapeutic target for infectious and inflammatory diseases. Apoptotic and lytic cell death pathways are both utilised in the removal of damaged cells; however, the downstream inflammatory outcomes widely vary according to the chosen pathway. Here authors show that in mice with genetic deletion of Gasdermin E specifically in neutrophils, these cells undergo apoptosis rather than pyroptotic cell death upon senescence, with consequential attenuation of reactive inflammatory responses.

New strategies for cancer immunotherapy are needed since most solid tumors do not respond to current approaches. Here we used epithelial cell adhesion molecule EpCAM (a tumor-associated antigen highly expressed on common epithelial cancers and their tumor-initiating cells) aptamer-linked small-interfering RNA chimeras (AsiCs) to knock down genes selectively in EpCAM⁺ tumors with the goal of making cancers more visible to the immune system. Knockdown of genes that function in multiple steps of cancer immunity was evaluated in aggressive triple-negative and HER2⁺ orthotopic, metastatic, and genetically engineered mouse breast cancer models. Gene targets were chosen whose knockdown was predicted to promote tumor neoantigen expression (Upf2, Parp1, Apex1), phagocytosis, and antigen presentation (Cd47), reduce checkpoint inhibition (Cd274), or cause tumor cell death (Mcl1). Four of the six AsiC (Upf2, Parp1, Cd47, and Mcl1) potently inhibited tumor growth and boosted tumor-infiltrating immune cell functions. AsiC mixtures were more effective than individual AsiC and could synergize with anti–PD-1 checkpoint inhibition.

The social networks of entrepreneurs are an important factor affecting new venture performance. Based on the survey data of 316 new ventures in China, this paper explores the relationship between the social networks of female tech-entrepreneurs and new venture performance, and examines the moderating effects of entrepreneurial alertness and gender discrimination on this relationship. Our findings reveal that: (a) the social networks of female tech-entrepreneurs have a positive effect on new venture performance; (b) the entrepreneurial alertness of female tech-entrepreneurs has a positive effect on new venture performance; and (c) gender discrimination against women has a negative effect on new venture performance. Moreover, we found that gender discrimination negatively moderates the relationship between the social networks of female tech-entrepreneurs and new venture performance. We also found that entrepreneurial alertness positively moderates the relationship between the social networks of female tech-entrepreneurs and new venture performance. Our findings provide theoretical and practical implications for female technical individuals in the entrepreneurial practice, and shed light on the study of entrepreneurship theory in other emerging economies.

C-JUN N-terminal kinases (JNKs), which belong to the mitogen-activated protein kinase (MAPK) family, are evolutionarily conserved kinases that mediate cell responses to various types of extracellular stress insults. They regulate physiological processes such as embryonic development and tissue regeneration, playing roles in cell proliferation and programmed cell death. JNK signaling is also involved in tumorigenesis and progression of several types of malignancies. Recent studies have shown that JNK signaling has crucial roles in regulating the traits of cancer stem cells (CSCs). Here we describe the functions of the JNK signaling pathway in self-renewal and differentiation, which are essential features of various types of stem cells, such as embryonic, induced pluripotent, and adult tissue-specific stem cells. We also review current knowledge of JNK signaling in CSCs and discuss its role in maintaining the CSC phenotype. A better understanding of JNK signaling as an essential regulator of stemness may provide a basis for the development of regenerative medicine and new therapeutic strategies against malignant tumors.

China’s East–West Computing Resources Transmission Project (EWCRT Project) is a unique and innovative path toward developing China’s green digital economy. The EWCRT Project consists of building transregional digital infrastructure, including eight data center hubs and 10 data center clusters across China. Our estimations indicate that the EWCRT Project could result in a reduction of 2125 metric tons (Mt) of CO 2 between 2020 and 2050. Combined with other improvement measures, such as an increase in power usage effectiveness (PUE) and a boost in the use of green electricity in these data centers, the project could result in a reduction of 9500 Mt of carbon emissions over the next three decades. Recognizing the heterogeneous makeup of data centers in general, it is crucial to identify diverse strategies that can transform each into “green engines” for the digital economy. Therefore, in this study, we use fuzzy-set qualitative comparative analysis (fsQCA) to characterize the complex conditions of different data center configurations. By doing so, we highlight differentiated strategies for data centers to support the greening of the digital economy.

Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer characterized by metastasis, drug resistance and high rates of recurrence. With a lack or targeted therapies, TNBC is challenging to treat and carries a poor prognosis. Patients with TNBC tumors expressing high levels of ERK2 have a poorer prognosis than those with low ERK2-expressing tumors. The MAPK pathway is often found to be highly activated in TNBC, however the precise functions of the ERK isoforms (ERK1 and ERK2) in cancer progression have not been well defined. We hypothesized that ERK2, but not ERK1, promotes the cancer stem cell (CSC) phenotype and metastasis in TNBC. Stable knockdown clones of the ERK1 and ERK2 isoforms were generated in SUM149 and BT549 TNBC cells using shRNA lentiviral vectors. ERK2 knockdown significantly inhibited anchorage-independent colony formation and mammosphere formation, indicating compromised self-renewal capacity. This effect correlated with a reduction in migration and invasion. SCID-beige mice injected via the tail vein with ERK clones were employed to determine metastatic potential. SUM149 shERK2 cells had a significantly lower lung metastatic burden than control mice or mice injected with SUM149 shERK1 cells. The Affymetrix HGU133plus2 microarray platform was employed to identify gene expression changes in ERK isoform knockdown clones. Comparison of gene expression levels between SUM149 cells with ERK2 or ERK1 knockdown revealed differential and in some cases opposite effects on mRNA expression levels. Those changes associated with ERK2 knockdown predominantly altered regulation of CSCs and metastasis. Our findings indicate that ERK2 promotes metastasis and the CSC phenotype in TNBC.