Therapeutic application of human type 2 innate lymphoid cells via induction of granzyme B-mediated tumor cell death.

The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. Although not observed in mouse ILC2s, we found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing pyroptosis and/or apoptosis, which is governed by a DNAM-1-CD112/CD155 interaction that inactivates the negative regulator FOXO1. Over time, the high surface density expression of CD155 in acute myeloid leukemia cells impairs the expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profiles were validated by single-cell RNA sequencing. In both leukemia and solid tumor models, exogenously administered expanded human ILC2s show significant antitumor effects in vivo. Collectively, we demonstrate previously unreported properties of human ILC2s and identify this innate immune cell subset as a member of the cytolytic immune effector cell family.

ILC1s control leukemia stem cell fate and limit development of AML.

Type I innate lymphoid cells (ILC1s) are critical regulators of inflammation and immunity in mammalian tissues. However, their function in cancer is mostly undefined. Here, we show that a high density of ILC1s induces leukemia stem cell (LSC) apoptosis in mice. At a lower density, ILC1s prevent LSCs from differentiating into leukemia progenitors and promote their differentiation into non-leukemic cells, thus blocking the production of terminal myeloid blasts. All of these effects, which require ILC1s to produce interferon-γ after cell-cell contact with LSCs, converge to suppress leukemogenesis in vivo. Conversely, the antileukemia potential of ILC1s wanes when JAK-STAT or PI3K-AKT signaling is inhibited. The relevant antileukemic properties of ILC1s are also functional in healthy individuals and impaired in individuals with acute myeloid leukemia (AML). Collectively, these findings identify ILC1s as anticancer immune cells that might be suitable for AML immunotherapy and provide a potential strategy to treat AML and prevent relapse of the disease.

Sunlight-powered sustained flight of an ultralight micro aerial vehicle.

Limited flight duration is a considerable obstacle to the widespread application of micro aerial vehicles (MAVs)1-3, especially for ultralightweight MAVs weighing less than 10 g, which, in general, have a flight endurance of no more than 10 min (refs. 1,4). Sunlight power5-7 is a potential alternative to improve the endurance of ultralight MAVs, but owing to the restricted payload capacity of the vehicle and low lift-to-power efficiency of traditional propulsion systems, previous studies have not achieved untethered sustained flight of MAVs fully powered by natural sunlight8,9. Here, to address these challenges, we introduce the CoulombFly, an electrostatic flyer consisting of an electrostatic-driven propulsion system with a high lift-to-power efficiency of 30.7 g W-1 and an ultralight kilovolt power system with a low power consumption of 0.568 W, to realize solar-powered sustained flight of an MAV under natural sunlight conditions (920 W m-2). The vehicle's total mass is only 4.21 g, within 1/600 of the existing lightest sunlight-powered aerial vehicle6.

Structure-guided design of VAR2CSA-based immunogens and a cocktail strategy for a placental malaria vaccine.

Placental accumulation of Plasmodium falciparum infected erythrocytes results in maternal anemia, low birth weight, and pregnancy loss. The parasite protein VAR2CSA facilitates the accumulation of infected erythrocytes in the placenta through interaction with the host receptor chondroitin sulfate A (CSA). Antibodies that prevent the VAR2CSA-CSA interaction correlate with protection from placental malaria, and VAR2CSA is a high-priority placental malaria vaccine antigen. Here, structure-guided design leveraging the full-length structures of VAR2CSA produced a stable immunogen that retains the critical conserved functional elements of VAR2CSA. The design expressed with a six-fold greater yield than the full-length protein and elicited antibodies that prevent adhesion of infected erythrocytes to CSA. The reduced size and adaptability of the designed immunogen enable efficient production of multiple variants of VAR2CSA for use in a cocktail vaccination strategy to increase the breadth of protection. These designs form strong foundations for the development of potent broadly protective placental malaria vaccines.

Notopterol Inhibits the NF-κB Pathway and Activates the PI3K/Akt/Nrf2 Pathway in Periodontal Tissue.

Notopterol, an active component isolated from the traditional Chinese medicine Notopterygium incisum Ting ex H.T. Chang, exerts anti-inflammatory activity in rheumatoid arthritis. However, its roles in suppression of inflammatory insults and halting progression of tissue destruction in periodontitis remain elusive. In this study, we reveal that notopterol can inhibit osteoclastogenesis, thereby limiting alveolar bone loss in vivo. In vitro results demonstrated that notopterol administration inhibited synthesis of inflammatory mediators such as IL-1ß, IL-32, and IL-8 in LPS-stimulated human gingival fibroblasts. Mechanistically, notopterol inhibits activation of the NF-κB signaling pathway, which is considered a prototypical proinflammatory signaling pathway. RNA sequencing data revealed that notopterol activates the PI3K/protein kinase B (Akt)/NF-E2-related factor 2 (Nrf2) signaling pathway in LPS-stimulated human gingival fibroblasts, a phenomenon validated via Western blot assay. Additionally, notopterol treatment suppressed reactive oxygen species levels by upregulating the expression of antioxidant genes, including heme oxygenase 1 (HO-1), NAD(P)H quinone oxidoreductase 1 (NQO1), catalase (CAT), and glutathione reductase (GSR), indicating that notopterol confers protection against oxidative stress. Notably, inhibition of Akt activity by the potent inhibitor, MK-2206, partially attenuated both anti-inflammatory and antioxidant effects of notopterol. Collectively, these results raise the possibility that notopterol relieves periodontal inflammation by suppressing and activating the NF-κB and PI3K/AKT/Nrf2 signaling pathways in periodontal tissue, respectively, suggesting its potential as an efficacious treatment therapy for periodontitis.

The Yun/Prohibitin complex regulates adult Drosophila intestinal stem cell proliferation through the transcription factor E2F1.

Stem cells constantly divide and differentiate to maintain adult tissue homeostasis, and uncontrolled stem cell proliferation leads to severe diseases such as cancer. How stem cell proliferation is precisely controlled remains poorly understood. Here, from an RNA interference (RNAi) screen in adult Drosophila intestinal stem cells (ISCs), we identify a factor, Yun, required for proliferation of normal and transformed ISCs. Yun is mainly expressed in progenitors; our genetic and biochemical evidence suggest that it acts as a scaffold to stabilize the Prohibitin (PHB) complex previously implicated in various cellular and developmental processes and diseases. We demonstrate that the Yun/PHB complex is regulated by and acts downstream of EGFR/MAPK signaling. Importantly, the Yun/PHB complex interacts with and positively affects the levels of the transcription factor E2F1 to regulate ISC proliferation. In addition, we find that the role of the PHB complex in cell proliferation is evolutionarily conserved. Thus, our study uncovers a Yun/PHB-E2F1 regulatory axis in stem cell proliferation.

Surface-Patterned DNA Origami Rulers Reveal Nanoscale Distance Dependency of the Epidermal Growth Factor Receptor Activation.

The nanoscale arrangement of ligands can have a major effect on the activation of membrane receptor proteins and thus cellular communication mechanisms. Here we report on the technological development and use of tailored DNA origami-based molecular rulers to fabricate "Multiscale Origami Structures As Interface for Cells" (MOSAIC), to enable the systematic investigation of the effect of the nanoscale spacing of epidermal growth factor (EGF) ligands on the activation of the EGF receptor (EGFR). MOSAIC-based analyses revealed that EGF distances of about 30-40 nm led to the highest response in EGFR activation of adherent MCF7 and Hela cells. Our study emphasizes the significance of DNA-based platforms for the detailed investigation of the molecular mechanisms of cellular signaling cascades.

Calycosin alleviates titanium particle-induced osteolysis by modulating macrophage polarization and subsequent osteogenic differentiation.

Periprosthetic osteolysis (PPO) caused by wear particles is one of the leading causes of implant failure after arthroplasty. Macrophage polarization imbalance and subsequent osteogenic inhibition play a crucial role in PPO. Calycosin (CA) is a compound with anti-inflammatory and osteoprotective properties. This study aimed to evaluate the effects of CA on titanium (Ti) particle-induced osteolysis, Ti particle-induced macrophage polarization and subsequent osteogenic deficits, and explore the associated signalling pathways in a Ti particle-stimulated calvarial osteolysis mouse model using micro-CT, ELISA, qRT-PCR, immunofluorescence and western blot techniques. The results showed that CA alleviated inflammation, osteogenic inhibition and osteolysis in the Ti particle-induced calvarial osteolysis mouse model in vivo. In vitro experiments showed that CA suppressed Ti-induced M1 macrophage polarization, promoted M2 macrophage polarization and ultimately enhanced osteogenic differentiation of MC3T3-E1 cells. In addition, CA alleviated osteogenic deficits by regulating macrophage polarization homeostasis via the NF-κB signalling pathway both in vivo and in vitro. All these findings suggest that CA may prove to be an effective therapeutic agent for wear particle-induced osteolysis.

Genome-wide identification and expression analysis of the SPL transcription factor family and its response to abiotic stress in Pisum sativum L.

Squamous promoter binding protein-like (SPL) genes encode plant-specific transcription factors (TFs) that play essential roles in modulating plant growth, development, and stress response. Pea (Pisum sativum L.) is a coarse grain crop of great importance in food production, biodiversity conservation and molecular genetic research, providing genetic information and nutritional resources for improving agricultural production and promoting human health. However, only limited researches on the structure and functions of SPL genes exist in pea (PsSPLs). In this study, we identified 22 PsSPLs and conducted a genome-wide analysis of their physical characteristics, chromosome distribution, gene structure, phylogenetic evolution and gene expression patterns. As a result, the PsSPLs were unevenly distributed on the seven chromosomes of pea and harbored the SBP domain, which is composed of approximately 76 amino acid residues. The phylogenetic analysis revealed that the PsSPLs clustered into eight subfamilies and showed high homology with SPL genes in soybean. Further analysis showed the presence of segmental duplications in the PsSPLs. The expression patterns of 22 PsSPLs at different tissues, developmental stages and under various stimulus conditions were evaluated by qRT-PCR method. It was found that the expression patterns of PsSPLs from the same subfamily were similar in different tissues, the transcripts of most PsSPLs reached the maximum peak value at 14 days after anthesis in the pod. Abiotic stresses can cause significantly up-regulated PsSPL19 expression with spatiotemporal specificity, in addition, four plant hormones can cause the up-regulated expression of most PsSPLs including PsSPL19 in a time-dependent manner. Therefore, PsSPL19 could be a key candidate gene for signal transduction during pea growth and development, pod formation, abiotic stress and plant hormone response. Our findings should provide insights for the elucidating of development regulation mechanism and breeding for resistance to abiotic stress pea.

Characterization of CYP82 genes involved in the biosynthesis of structurally diverse benzylisoquinoline alkaloids in Corydalis yanhusuo.

Benzylisoquinoline alkaloids (BIAs) represent a significant class of secondary metabolites with crucial roles in plant physiology and substantial potential for clinical applications. CYP82 genes are involved in the formation and modification of various BIA skeletons, contributing to the structural diversity of compounds. In this study, Corydalis yanhusuo, a traditional Chinese medicine rich in BIAs, was investigated to identify the catalytic function of CYP82s during BIA formation. Specifically, 20 CyCYP82-encoding genes were cloned, and their functions were identified in vitro. Ten of these CyCYP82s were observed to catalyze hydroxylation, leading to the formation of protopine and benzophenanthridine scaffolds. Furthermore, the correlation between BIA accumulation and the expression of CyCYP82s in different tissues of C. yanhusuo was assessed their. The identification and characterization of CyCYP82s provide novel genetic elements that can advance the synthetic biology of BIA compounds such as protopine and benzophenanthridine, and offer insights into the biosynthesis of BIAs with diverse structures in C. yanhusuo.

Role of miRNAs in glucose metabolism of mouse cumulus cells†.

It is known that the oocyte has a limited capacity to acquire and metabolize glucose, and it must rely on cumulus cells (CCs) to take up glucose and produce pyruvate for use to produce ATP through oxidative phosphorylation. We therefore propose that miRNAs might regulate glucose metabolism (GM) in CCs and might be used as markers for oocyte quality assessment. Here, mouse CC models with impaired glycolysis or pentose phosphate pathway (PPP) were established, and miRNAs targeting the key enzymes in glycolysis/PPP were predicted using the miRNA target prediction databases. Expression of the predicted miRNAs was compared between CCs with normal and impaired glycolysis/PPP to identify candidate miRNAs. Function of the candidate miRNAs was validated by transfecting CCs or cumulus-oocyte-complexes (COCs) with miRNA inhibitors and observing effects on glucose metabolites of CCs and on competence of oocytes. The results validated that miR-23b-3p, let-7b-5p, 34b-5p and 145a-5p inhibited glycolysis, and miR-24-3p, 3078-3p,183-5p and 7001-5p inhibited PPP of CCs. Our observation using a more physiologically relevant model (intact cultured COCs) further validated the four glycolysis-targeting miRNAs we identified. Furthermore, miR-let-7b-5p, 34b-5p and 145a-5p may also inhibit PPP, as they decreased the production of glucose-6-phosphate. In conclusion, miRNAs play critical roles in GM of CCs and may be used as markers for oocyte quality assessment. Summary sentence:  We identified and validated eight new miRNAs that inhibit glycolysis and/or pentose phosphate pathways in cumulus cells (CCs) suggesting that miRNAs play critical roles in glucose metabolism of CCs and may be used for oocyte quality markers.

Establishment of an in vitro model of monocyte-like THP-1 cells for trained immunity induced by bacillus Calmette-Guérin.

BACKGROUND: Mycobacteria bloodstream infections are common in immunocompromised people and usually have disastrous consequences. As the primary phagocytes in the bloodstream, monocytes and neutrophils play critical roles in the fight against bloodstream mycobacteria infections. In contrast to macrophages, the responses of monocytes infected with the mycobacteria have been less investigated. RESULTS: In this study, we first established a protocol for infection of non-adherent monocyte-like THP-1 cells (i.e. without the differentiation induced by phorbol 12-myristate 13-acetate (PMA) by bacillus Calmette-Guérin (BCG). Via the protocol, we were then capable of exploring the global transcriptomic profiles of non-adherent THP-1 cells infected with BCG, and found that NF-κB, MAPK and PI3K-Akt signaling pathways were enhanced, as well as some inflammatory chemokine/cytokine genes (e.g. CCL4, CXCL10, TNF and IL-1ß) were up-regulated. Surprisingly, the Akt-HIF-mTOR signaling pathway was also activated, which induces trained immunity. In this in vitro infection model, increased cytokine responses to lipopolysaccharides (LPS) restimulation, higher cell viability, and decreased Candida albicans loads were observed. CONCLUSIONS: We have first characterized the transcriptomic profiles of BCG-infected non-adherent THP-1 cells, and first developed a trained immunity in vitro model of the cells.

Expression profiling and function analysis identified new genes regulating cumulus expansion and apoptosis.

Studies on the mechanisms behind cumulus expansion and cumulus cell (CC) apoptosis are essential for understanding the mechanisms for oocyte maturation. Genes expressed in CCs might be used as markers for competent oocytes and/or embryos. In this study, both in vitro (IVT) and in vivo (IVO) mouse oocyte models with significant difference in cumulus expansion and CC apoptosis were used to identify and validate new genes regulating cumulus expansion and CC apoptosis of mouse oocytes. We first performed mRNA sequencing and bioinformatic analysis using the IVT oocyte model to identify candidate genes. We then analyzed functions of the candidate genes by RNAi or gene overexpression to select the candidate cumulus expansion and CC apoptosis-regulating genes. Finally, we validated the cumulus expansion and CC apoptosis-regulating genes using the IVO oocyte model. The results showed that while Spp1, Sdc1, Ldlr, Ezr and Mmp2 promoted, Bmp2, Angpt2, Edn1, Itgb8, Cxcl10 and Agt inhibited cumulus expansion. Furthermore, Spp1, Sdc1 and Ldlr inhibited CC apoptosis. In conclusion, by using both IVT and IVO oocyte models, we have identified and validated a new group of cumulus expansion and/or apoptosis-regulating genes, which may be used for selection of quality oocytes/embryos and for elucidating the molecular mechanisms behind oocyte maturation.

Octave soliton microcombs in lithium niobate microresonators.

Soliton microcombs are regarded as an ideal platform for applications such as optical communications, optical sensing, low-noise microwave sources, optical atomic clocks, and frequency synthesizers. Many of these applications require a broad comb spectrum that covers an octave, essential for implementing the f - 2f self-referencing techniques. In this work, we have successfully generated an octave-spanning soliton microcomb based on a z-cut thin-film lithium niobate (TFLN) microresonator. This achievement is realized under on-chip optical pumping at 340 mW and through extensive research into the broadening of dual dispersive waves (DWs). Furthermore, the repetition rate of the octave soliton microcomb is accurately measured using an electro-optic comb generated by an x-cut TFLN racetrack microresonator. Our results represent a crucial step toward the realization of practical, integrated, and fully stabilized soliton microcomb systems based on TFLN.

YTHDF1's grip on CRC vasculature: insights into LINC01106 and miR-449b-5p-VEGFA axis.

BACKGROUND: Investigating the unexplored territory of lncRNA m6A modification in colorectal cancer (CRC) vasculature, this study focuses on LINC01106 and YTHDF1. METHODS: Clinical assessments reveal upregulated LINC01106 promoting vascular generation via the miR-449b-5p-VEGFA pathway. RESULTS: YTHDF1, elevated in CRC tissues, emerges as an adverse prognostic factor. Functional experiments showcase YTHDF1's inhibitory effects on CRC cell dynamics. Mechanistically, Me-CLIP identifies m6A-modified LINC01106, validated as a YTHDF1 target through Me-RIP. CONCLUSIONS: This study sheds light on the YTHDF1-mediated m6A modification of LINC01106, presenting it as a key player in suppressing CRC vascular generation.

Insulin Resistance Impairs Biological Agents Response in Moderate-to-Severe Plaque Psoriasis: Insights from a Prospective Cohort Study in China.

BACKGROUND: Psoriasis and insulin resistance (IR) are closely related, but it remains unclear whether IR affects the treatment of patients with psoriasis. OBJECTIVE: The objective of this study was to investigate whether IR impairs the treatment response to biologic agents in patients with moderate-to-severe plaque psoriasis. METHODS: This project was based on a prospective cohort study design. Data for this study were collected from the Shanghai Psoriasis Effectiveness Evaluation CoHort (SPEECH), which is a prospective cohort exploring treatment strategies for psoriasis in China. IR was assessed using the triglyceride glucose-body mass index (TyG-BMI). Psoriasis severity was assessed using the Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA). Multiple logistic regression was used to explore the differences between patients with high and low levels of IR. Subgroup and sensitivity analyses were performed to examine the robustness of the study results. RESULTS: A total of 290 patients were included in the analysis. Based on the median TyG-BMI, the patients were divided into two groups: High and Low. The High group exhibited a higher prevalence of diabetes, higher BMI, fasting blood glucose, and triglyceride compared with the Low group. Further analysis of the treatment efficacy revealed that the High group had lower response rates for PASI 75, PASI 90, and PGA 0/1 after 12 weeks of treatment. In the Low group, 81.94% of patients achieved PASI 75, 58.33% achieved PASI 90, and 75.69% achieved PGA 0/1. However, the proportion of responses at each endpoint was significantly lower in the High group. The impairment in response to PGA 0/1 was more significant in the High group, indicated by lower odd ratios. Subsequent subgroup analysis and sensitivity analysis produced consistent results. CONCLUSION: IR is associated with lower effectiveness of biologics in patients with psoriasis. CLINICAL TRIAL REGISTRATION: [www.chictr.org.cn], identifier [ChiCTR2000036186].

Constructing the Interconnected and Hierarchical Nanoarchitectonics in Coal-Derived Carbon for High-Performance Supercapacitor.

Because of the deep and zigzag microporous structure, porous carbon materials exhibit inferior capacitive performance and sluggish electrochemical kinetics for supercapacitor electrode materials. Herein, a single-step carbonation and activation approach was utilized to synthesize coal-based porous carbon with an adjustable pore structure, using CaO as a hard template, KOH as an activator, and oxidized coal as precursors to carbon. The obtained sample possesses an interconnected and hierarchical porous structure, higher SSA (1060 m2 g-1), suitable mesopore volume (0.25 cm3 g-1), and abundant surface heteroatomic functional groups. Consequently, the synthesized carbon exhibits an exceptionally high specific capacitance of 323 F g-1 at 1 A g-1, along with 80.3% capacitance retention at 50 A g-1. The assembled two-electrode configuration demonstrates a remarkable capacitance retention of up to 95% and achieves Coulombic efficiency of nearly 100% with 10,000 cycles in a 6 M KOH electrolyte. Furthermore, the Zn-ion hybrid capacitor also exhibits a specific capacity of up to 139.1 mA h g-1 under conditions of 0.2 A g-1. This work offers a simple method in preparation of coal-based porous carbon with controllable pore structure.

Inferring biophysical properties of membranes during endocytosis using machine learning.

Endocytosis is a fundamental cellular process in eukaryotic cells that facilitates the transport of molecules into the cell. With the help of fluorescence microscopy and electron tomography, researchers have accumulated extensive geometric data of membrane shapes during endocytosis. These data contain rich information about the mechanical properties of membranes, which are hard to access via experiments due to the small dimensions of the endocytic patch. In this study, we propose an approach that combines machine learning with the Helfrich theory of membranes to infer the mechanical properties of membranes during endocytosis from a dataset of membrane shapes extracted from electron tomography. Our results demonstrate that machine learning can output solutions that both match the experimental profile and satisfy the membrane shape equations derived from Helfrich theory. The learning results show that during the early stage of endocytosis, the inferred membrane tension is negative, indicating the presence of strong compressive forces at the boundary of the endocytic invagination. Our method presents a generic framework for extracting membrane information from super-resolution imaging.

Spontaneous stable rotation of flocking flexible active matter.

In this paper we present an n-node flexible active matter model to study the collective motion due to the flocking of individual achiral agents on a two-dimensional surface. By introducing a measure of the direction detectability of the agents to tune their body direction towards the food source, we find that a spontaneous stable cluster rotation emerges with increasing direction detectability. The spontaneous rotation is synchronized with the chirality produced by the alignment of their bodies under the impetus of the active force. A linear relationship between the normalized angular velocity and chirality is observed and the numerical simulation agrees well with the analytical derivation. The conclusions explain well the spontaneous stable rotation of clusters that exists in many flexible active matter systems, like worms or dogs, when they flock to the same single source.