Electroporation-mediated novel albumin-fused Flt3L DNA delivery promotes cDC1-associated anticancer immunity
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Trained immunity in type 2 immune responses
Immunological memory of innate immune cells, also termed “trained immunity”, allows for cross-protection against distinct pathogens, but may also drive chronic inflammation. Recent studies have shown that memory responses associated with type 2 immunity do not solely rely on adaptive immune cells, such as T- and B cells, but also involve the innate immune system and epithelial cells. Memory responses have been described for monocytes, macrophages and airway epithelial cells of asthmatic patients as well as for macrophages and group 2 innate lymphoid cells (ILC2) from allergen-sensitized or helminth-infected mice. The metabolic and epigenetic mechanisms that mediate allergen- or helminth-induced reprogramming of innate immune cells are only beginning to be uncovered. Trained immunity has been implicated in helminth-driven immune regulation and allergen-specific immunotherapy, suggesting its exploitation in future therapies. Here, we discuss recent advances and key remaining questions regarding the mechanisms and functions of trained type 2 immunity in infection and inflammation.
Determinants of consumer intention to use autonomous delivery vehicles: based on the planned behavior theory and normative activation model
Autonomous delivery vehicles (ADVs) that provide contactless services have attracted much academic and practical attention in China in recent years. Despite this, there is a lack of in-depth research on what motivates customers to embrace ADVs. The study integrates the theory of planned behavior (TPB) and normative activation model (NAM) and explores how environmental factors, situational factors, and individual factors affect original TPB constructs and ultimately consumers’ intention to use ADVs. Structural equation modeling was performed on survey data of 561 Chinese consumers through an online sampling platform. The results show that among the factors affecting consumer intention, word-of-mouth recommendations have the greatest impact, followed by perceived enjoyment, COVID-19 risk, ascription of responsibility, subjective norm, attitude, and perceived behavioral control. The results not only make important theoretical contributions to the technology acceptance fields but also provide helpful references to logistics enterprises, ADVs technology providers, and policymakers.
Apaf-1 is an evolutionarily conserved DNA sensor that switches the cell fate between apoptosis and inflammation
Apoptotic protease activating factor 1 (Apaf-1) was traditionally defined as a scaffold protein in mammalian cells for assembling a caspase activation platform known as the ‘apoptosome’ after its binding to cytochrome c. Although Apaf-1 structurally resembles animal NOD-like receptor (NLR) and plant resistance (R) proteins, whether it is directly involved in innate immunity is still largely unknown. Here, we found that Apaf-1-like molecules from lancelets, fruit flies, mice, and humans have conserved DNA sensing functionality. Mechanistically, mammalian Apaf-1 recruits receptor-interacting protein 2 (RIP2, also known as RIPK2) via its WD40 repeat domain and promotes RIP2 oligomerization to initiate NF-κB-driven inflammation upon cytoplasmic DNA recognition. Furthermore, DNA binding of Apaf-1 determines cell fate by switching the cellular processes between intrinsic stimuli-activated apoptosis and inflammation. These findings suggest that Apaf-1 is an evolutionarily conserved DNA sensor and may serve as a cell fate checkpoint, which determines whether cells initiate inflammation or undergo apoptosis by distinct ligand binding.
KorB switching from DNA-sliding clamp to repressor mediates long-range gene silencing in a multi-drug resistance plasmid
Examples of long-range gene regulation in bacteria are rare and generally thought to involve DNA looping. Here, using a combination of biophysical approaches including X-ray crystallography and single-molecule analysis for the KorB–KorA system in Escherichia coli, we show that long-range gene silencing on the plasmid RK2, a source of multi-drug resistance across diverse Gram-negative bacteria, is achieved cooperatively by a DNA-sliding clamp, KorB, and a clamp-locking protein, KorA. We show that KorB is a CTPase clamp that can entrap and slide along DNA to reach distal target promoters up to 1.5 kb away. We resolved the tripartite crystal structure of a KorB–KorA–DNA co-complex, revealing that KorA latches KorB into a closed clamp state. DNA-bound KorA thus stimulates repression by stalling KorB sliding at target promoters to occlude RNA polymerase holoenzymes. Together, our findings explain the mechanistic basis for KorB role switching from a DNA-sliding clamp to a co-repressor and provide an alternative mechanism for long-range regulation of gene expression in bacteria.
Targeting LMO2-induced autocrine FLT3 signaling to overcome chemoresistance in early T-cell precursor acute lymphoblastic leukemia
Early T-cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL) is an immature subtype of T-cell acute lymphoblastic leukemia (T-ALL) commonly show deregulation of the LMO2-LYL1 stem cell transcription factors, activating mutations of cytokine receptor signaling, and poor early response to intensive chemotherapy. Previously, studies of the Lmo2 transgenic mouse model of ETP-ALL identified a population of stem-like T-cell progenitors with long-term self-renewal capacity and intrinsic chemotherapy resistance linked to cellular quiescence. Here, analyses of Lmo2 transgenic mice, patient-derived xenografts, and single-cell RNA-sequencing data from primary ETP-ALL identified a rare subpopulation of leukemic stem cells expressing high levels of the cytokine receptor FLT3. Despite a highly proliferative state, these FLT3-overexpressing cells had long-term self-renewal capacity and almost complete resistance to chemotherapy. Chromatin immunoprecipitation and assay for transposase-accessible chromatin sequencing demonstrated FLT3 and its ligand may be direct targets of the LMO2 stem-cell complex. Media conditioned by Lmo2 transgenic thymocytes revealed an autocrine FLT3-dependent signaling loop that could be targeted by the FLT3 inhibitor gilteritinib. Consequently, gilteritinib impaired in vivo growth of ETP-ALL and improved the sensitivity to chemotherapy. Furthermore, gilteritinib enhanced response to the BCL2 inhibitor venetoclax, which may enable “chemo-free” treatment of ETP-ALL. Together, these data provide a cellular and molecular explanation for enhanced cytokine signaling in LMO2-driven ETP-ALL beyond activating mutations and a rationale for clinical trials of FLT3 inhibitors in ETP-ALL.
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