SNORA28 Promotes Proliferation and Radioresistance in Colorectal Cancer Cells through the STAT3 Pathway by Increasing H3K9 Acetylation in the LIFR Promoter.

Radiotherapy is essential for treating colorectal cancer (CRC), especially in advanced rectal cancer. However, the low radiosensitivity of CRC cells greatly limits radiotherapy efficacy. Small nucleolar RNAs (snoRNAs) are a class of noncoding RNA that primarily direct post-transcriptional modifications of ribosomal RNAs (rRNAs), small nuclear RNAs (snRNAs), and other cellular RNAs. While snoRNAs are involved in tumor progression and chemoresistance, their association with radiosensitivity remains largely unknown. Herein, SNORA28 is shown highly expressed in CRC and is positively associated with poor prognosis. Furthermore, SNORA28 overexpression enhances the growth and radioresistance of CRC cells in vitro and in vivo. Mechanistically, SNORA28 acts as a molecular decoy that recruits bromodomain-containing protein 4 (BRD4), which increases the level of H3K9 acetylation at the LIFR promoter region. This stimulates LIFR transcription, which in turn triggers the JAK1/STAT3 pathway, enhancing the proliferation and radioresistance of CRC cells. Overall, these results highlight the ability of snoRNAs to regulate radiosensitivity in tumor cells and affect histone acetylation modification in the promoter region of target genes, thus broadening the current knowledge of snoRNA biological functions and the mechanism underlying target gene regulation.

Disrupted mitochondrial transcription factor A expression promotes mitochondrial dysfunction and enhances ocular surface inflammation by activating the absent in melanoma 2 inflammasome.

PURPOSE: Severe dry eye disease causes ocular surface damage, which is highly associated with mitochondrial dysfunction. Mitochondrial transcription factor A (TFAM) is essential for packaging mitochondrial DNA (mtDNA) and is crucial for maintaining mitochondrial function. Herein, we aimed to explore the effect of a decreased TFAM expression on ocular surface damage. METHODS: Female C57BL/6 mice were induced ocular surface injury by topical administrating benzalkonium chloride (BAC). Immortalized human corneal epithelial cells (HCECs) were stimulated by tert-butyl hydroperoxide (t-BHP) to create oxidative stress damage. HCECs with TFAM knockdown were established. RNA sequencing was employed to analyze the whole-genome expression. Mitochondrial changes were measured by transmission electron microscopy, Seahorse metabolic flux analysis, mitochondrial membrane potential, and mtDNA copy number. TFAM expression and inflammatory cytokines were determined using RT-qPCR, immunohistochemistry, immunofluorescence, and immunoblotting. RESULTS: In both the corneas of BAC-treated mice and t-BHP-induced HCECs, we observed impaired TFAM expression, accompanied by mitochondrial structure and function defects. TFAM downregulation in HCECs suppressed mitochondrial respiratory capacity, reduced mtDNA content, induced mtDNA leakage into the cytoplasm, and led to inflammation. RNA sequencing revealed the absent in melanoma 2 (AIM2) inflammasome was activated in the corneas of BAC-treated mice. The AIM2 inflammasome activation was confirmed in TFAM knockdown HCECs. TFAM knockdown in t-BHP-stimulated HCECs aggravated mitochondrial dysfunction and the AIM2 inflammasome activation, thereby further triggering the secretion of inflammatory factors such as interleukin (IL) -1ß and IL-18. CONCLUSIONS: TFAM reduction impaired mitochondrial function, activated AIM2 inflammasome and promoted ocular surface inflammation, revealing an underlying molecular mechanism for ocular surface disorders.

Modeling alcohol-associated liver disease in humans using adipose stromal or stem cell-derived organoids.

Alcohol-associated liver disease (ALD) is a prevalent liver disease, yet research is hampered by the lack of suitable and reliable human ALD models. Herein, we generated human adipose stromal/stem cell (hASC)-derived hepatocellular organoids (hAHOs) and hASC-derived liver organoids (hALOs) in a three-dimensional system using hASC-derived hepatocyte-like cells and endodermal progenitor cells, respectively. The hAHOs were composed of major hepatocytes and cholangiocytes. The hALOs contained hepatocytes and nonparenchymal cells and possessed a more mature liver function than hAHOs. Upon ethanol treatment, both steatosis and inflammation were present in hAHOs and hALOs. The incubation of hALOs with ethanol resulted in increases in the levels of oxidative stress, the endoplasmic reticulum protein thioredoxin domain-containing protein 5 (TXNDC5), the alcohol-metabolizing enzymes ADH1B and ALDH1B1, and extracellular matrix accumulation, similar to those of liver tissues from patients with ALD. These results present a useful approach for understanding the pathogenesis of ALD in humans, thus facilitating the discovery of effective treatments.

Correction: Cell Therapy: A Safe and Efficacious Therapeutic Treatment for Alzheimer's Disease in APP+PS1 Mice.

[This corrects the article DOI: 10.1371/journal.pone.0049468.].

Serum sSelectin-L is an early specific indicator of radiation injury.

Objective: It's crucial to identify an easily detectable biomarker that is specific to radiation injury in order to effectively classify injured individuals in the early stage in large-scale nuclear accidents. Methods: C57BL/6J mice were subjected to whole-body and partial-body γ irradiation, as well as whole-body X-ray irradiation to explore the response of serum sSelectin-L to radiation injury. Then, it was compared with its response to lipopolysaccharide-induced acute infection and doxorubicin-induced DNA damage to study the specificity of sSelectin-L response to radiation. Furthermore, it was further evaluated in serum samples from nasopharyngeal carcinoma patients before and after radiotherapy. Simulated rescue experiments using Amifostine or bone marrow transplantation were conducted in mice with acute radiation syndrome to determine the potential for establishing sSelectin-L as a prognostic marker. The levels of sSelectin-L were dynamically measured using the ELISA method. Results: Selectin-L is mainly expressed in hematopoietic tissues and lymphatic tissues. Mouse sSelectin-L showed a dose-dependent decrease from 1 day after irradiation and exhibited a positive correlation with lymphocyte counts. Furthermore, the level of sSelectin-L reflected the degree of radiation injury in partial-body irradiation mice and in nasopharyngeal carcinoma patients. sSelectin-L was closely related to the total dose of γ or X ray. There was no significant change in the sSelectin-L levels in mice intraperitoneal injected with lipopolysaccharide or doxorubicin. The sSelectin-L was decreased slower and recovered faster than lymphocyte count in acute radiation syndrome mice treated with Amifostine or bone marrow transplantation. Conclusions: Our study shows that sSelectin-L has the potential to be an early biomarker to classify injured individuals after radiation accidents, and to be a prognostic indicator of successful rescue of radiation victims.

Kikuchi disease: A case report about Sintilimab-induced Kikuchi histiocytic necrotizing lymphadenitis and literature review.

Immune checkpoint inhibitors have become one of the effective means of solid tumor treatment, among which anti-programmed death-1 (PD-1) antibodies are more maturely applied and can effectively inhibit tumor immune escape, thus enhancing the anti-tumor effect, but it can also lead to a series of immune-related adverse events (irAEs) in the process of clinical use. Here, we report a Patient with pancreatic solid pseudopapilloma treated with Sintilimab for the fifteenth cycles who developed chills, fever, and lymph node enlargement. Considering that the patient did not have infection, without history of autoimmune disease, we diagnosed the patient with Sintilimab-induced histiocytic necrotizing lymphadenitis (Kikuchi disease). The symptoms are alleviated after rapid use of glucocorticoids. Histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis) with anti-programmed death-1 (PD-1) antibody is a rare immune-related adverse events (irAEs).

Astragaloside-IV promotes autophagy via the Akt/mTOR pathway to improve cellular lipid deposition.

The current study aimed to investigate the potential role of astragaloside IV (AS-IV) in improving cellular lipid deposition and its underlying mechanism. A fatty liver cell model was established by treating hepatoma cells with palmitic acid. AS-IV and SC79 were used for treatment. Oil Red O staining was applied to detect intracellular lipid deposition, and transmission electron microscopy was utilized to assess autophagosome formation. Immunofluorescence double staining was applied to determine microtubule-associated proteins 1A/1B light chain 3 (LC3) expression. Western blot analysis was performed to detect the expression of LC3, prostacyclin, Beclin-1, V-akt murine thymoma viral oncogene homolog (Akt), phosphorylated Akt, mTOR, and phosphorylated mTOR. Oil Red O staining revealed that AS-IV reduced intracellular lipid accumulation. Further, it increased autophagosome synthesis and the expression of autophagy proteins LC3 and Beclin-1 in the cells. It also reduced the phosphorylation levels of Akt and mTOR and the levels of prostacyclin. However, the effects of AS-IV decreased with SC79 treatment. In addition, LC3B + BODIPY493/503 fluorescence double staining showed that AS-IV reduced intracellular lipid deposition levels by enhancing autophagy. AS-IV can reduce lipid aggregation in fatty liver cells, which can be related to enhanced hepatocyte autophagy by inhibiting the Akt/mTOR signaling pathway.

The α subunit of AMP-activated protein kinase is critical for the metabolic success and tachyzoite proliferation of Toxoplasma gondii.

Toxoplasma gondii is a zoonotic parasite infecting humans and nearly all warm-blooded animals. Successful parasitism in diverse hosts at various developmental stages requires the parasites to fine tune their metabolism according to environmental cues and the parasite's needs. By manipulating the ß and γ subunits, we have previously shown that AMP-activated protein kinase (AMPK) has critical roles in regulating the metabolic and developmental programmes. However, the biological functions of the α catalytic subunit have not been established. T. gondii encodes a canonical AMPKα, as well as a KIN kinase whose kinase domain has high sequence similarities to those of classic AMPKα proteins. Here, we found that TgKIN is dispensable for tachyzoite growth, whereas TgAMPKα is essential. Depletion of TgAMPKα expression resulted in decreased ATP levels and reduced metabolic flux in glycolysis and the tricarboxylic acid cycle, confirming that TgAMPK is involved in metabolic regulation and energy homeostasis in the parasite. Sequential truncations at the C-terminus found an α-helix that is key for the function of TgAMPKα. The amino acid sequences of this α-helix are not conserved among various AMPKα proteins, likely because it is involved in interactions with TgAMPKß, which only have limited sequence similarities to AMPKß in other eukaryotes. The essential role of the less conserved C-terminus of TgAMPKα provides opportunities for parasite specific drug designs targeting TgAMPKα.

The complete plastome genome sequence of Cynanchum otophyllum (Asclepiadaceae), a unique medicinal species in China.

Cynanchum otophyllum Schneid is an important medicinal plant in China. In this paper, the chloroplast genome of C. otophyllum was sequenced based on high-throughput technology, and the chloroplast genome structure characteristics and phylogenetic relationship of C. otophyllum were analyzed. The results showed the complete plastome genome size of C. otophyllumis 160,874bp, including one small single copy (SSC, 19,851bp) and one large single copy (LSC, 92,009bp) regions isolated by a pair of inverted repeat regions (IRs, 24,507bp). The whole plastome genome including 84 protein encoding genes, 8 rRNA and 37 tRNA. Based on the phylogenetic topologies, C. otophyllum shows close association with additional Gomphocarpus and Asclepias genus. This study contributes to an enhanced understanding of the genetic information of C. otophyllum and provides a theoretical basis for the development of molecular markers and phylogeographic of the species, as well as for constructing the phylogenetic tree of Asclepiadaceae.

Integrated full-length transcriptome and metabolome analysis reveals the defence response of melon to gummy stem blight.

Gummy stem blight (GSB), a widespread disease causing great loss to cucurbit production, has become a major threat to melon cultivation. However, the melon-GSB interaction remains largely unknown. Here, full-length transcriptome and widely targeted metabolome were used to investigate the defence responses of resistant (PI511089) and susceptible (Payzawat) melon accessions to GSB pathogen infection at 24 h. The biosynthesis of secondary metabolites and MAPK signalling pathway were specifically enriched for differentially expressed genes in PI511890, while carbohydrate metabolism and amino acid metabolism were specifically enriched in Payzawat. More than 1000 novel genes were identified and MAPK signalling pathway was specifically enriched for them in PI511890. There were 11 793 alternative splicing events involving in the defence response to GSB. Totally, 910 metabolites were identified in Payzawat and PI511890, and flavonoids were the dominant metabolites. Integrated full-length transcriptome and metabolome analysis showed eriodictyol and oxalic acid were the potential marker metabolites for GSB resistance in melon. Moreover, posttranscription regulation was widely involved in the defence response of melon to GSB pathogen infection. These results not only improve our understanding on the interaction between melon and GSB, but also facilitate the genetic improvement of melon with GSB resistance.

Oncogene SCARNA12 as a potential diagnostic biomarker for colorectal cancer.

Colorectal cancer (CRC) is one of the most common malignant tumors of the digestive system, and represents a severe threat to the life and health of individuals. Increasing evidence supports the role of small nucleolar RNAs (snoRNAs) as critical regulatory gene in cancer development. Small Cajal body-specific RNAs (scaRNAs), a subtype of snoRNAs, are named for their subcellular localization within Cajal bodies. SCARNA12, which located at the intronic region of PHB2 in chromosome 12p13.31 with 270 nucleotides (nt) in length. It has been reported function as a diagnostic marker for cervical cancer. However, its biological functions and molecular mechanisms in CRC have yet to be elucidated. In this study, bioinformatics analysis revealed that SCARNA12 was highly expressed in CRC and positively correlated with poor prognosis in CRC patients. Additionally, SCARNA12 showed upregulated expression in CRC cell lines and clinical CRC tissue samples. Moreover, SCARNA12 overexpression in SW620 cells accelerated cell proliferation, suppressed the apoptosis rate, and enhanced tumorigenesis in vivo. The knockdown of SCARNA12 expression in HCT116 and HT29 cells resulted in contrasting effects. The functioning of SCARNA12 is mechanically independent of its host gene PHB2. Notably, the overexpression of SCARNA12 activated PI3K/AKT pathway in SW620 cells, and the malignancy degree of CRC cells was attenuated after treatment with MK2206 (a specific AKT inhibitor). Our findings demonstrated that SCARNA12 plays an oncogenic role in CRC progression and can be used as a potential diagnostic biomarker for CRC.

The Green Synthesis of Reduced Graphene Oxide Using Ellagic Acid: Improving the Contrast-Enhancing Effect of Microbubbles in Ultrasound.

There is an urgent need to realize precise clinical ultrasound with ultrasound contrast agents that provide high echo intensity and mechanical index tolerance. Graphene derivatives possess exceptional characteristics, exhibiting great potential in fabricating ideal ultrasound contrast agents. Herein, we reported a facile and green approach to synthesizing reduced graphene oxide with ellagic acid (rGO-EA). To investigate the application of a graphene derivative in ultrasound contrast agents, rGO-EA was dispersed in saline solution and mixed with SonoVue (SV) to fabricate SV@rGO-EA microbubbles. To determine the properties of the product, analyses were performed, including ultraviolet-visible spectroscopy (UV-vis), Fourier-transform infrared spectroscopy (FTIR), Raman spectroscopy, transmission electron microscopy (TEM), thermal gravimetric analysis (TGA), X-ray photoelectron spectrum (XPS), X-ray diffraction analysis (XRD) and zeta potential analysis. Additionally, cell viability measurements and a hemolysis assay were conducted for a biosafety evaluation. SV@rGO-EA microbubbles were scanned at various mechanical index values to obtain the B-mode and contrast-enhanced ultrasound (CEUS) mode images in vitro. SV@rGO-EA microbubbles were administered to SD rats, and their livers and kidneys were imaged in CEUS and B-mode. The absorption of rGO-EA resulted in an enhanced echo intensity and mechanical index tolerance of SV@rGO-EA, surpassing the performance of SV microbubbles both in vitro and in vivo. This work exhibited the application potential of graphene derivatives in the field of ultrasound precision medicine.

Blockade of TGF-ß signalling alleviates human adipose stem cell senescence induced by native ECM in obesity visceral white adipose tissue.

BACKGROUND: Abdominal obesity is appreciated as a major player in insulin resistance and metabolically dysfunctional adipose tissue. Inappropriate extracellular matrix (ECM) remodelling and functional alterations in human adipose stromal/stem cells (hASCs) have been linked with visceral white adipose tissue (vWAT) dysfunction in obesity. Understanding the interactions between hASCs and the native ECM environment in obese vWAT is required for the development of future therapeutic approaches for obesity-associated metabolic complications. METHODS: The phenotypes and transcriptome properties of hASCs from the vWAT of obese patients and lean donors were assessed. The hASC-derived matrix from vWAT of obese or lean patients was generated in vitro using a decellularized method. The topography and the major components of the hASC-derived matrix were determined. The effects of the obese hASC-derived matrix on cell senescence and mitochondrial function were further determined. RESULTS: We showed that hASCs derived from the vWAT of obese patients exhibited senescence and were accompanied by the increased production of ECM. The matrix secreted by obese hASCs formed a fibrillar suprastructure with an abundance of fibronectin, type I collagen, and transforming growth factor beta 1 (TGF-ß1), which resembles the native matrix microenvironment of hASCs in vWAT derived from obese patients. Furthermore, the obese hASC-derived matrix promoted lean hASC ageing and induced mitochondrial dysfunction compared to the lean hASC-derived matrix. Blockade of TGF-ß1 signalling using an anti-TGF-ß1 neutralizing antibody alleviated the lean hASC senescence and mitochondrial dysfunction induced by the obese hASC-derived matrix. CONCLUSIONS: Native ECM in obesity vWAT initiates hASC senescence through TGF-ß1-mediated mitochondrial dysfunction. These data provide a key mechanism for understanding the importance of cell-ECM interactions in hASCs senescence in obesity.

Enhancing the Photocatalytic Activity of Zirconium-Based Metal-Organic Frameworks Through the Formation of Mixed-Valence Centers.

Despite the desirability of metal-organic frameworks (MOFs) as heterogeneous photocatalysts, current strategies available to enhance the performance of MOF photocatalysts are complicated and expensive. Herein, a simple strategy is presented for improving the activity of MOF photocatalysts by regulating the atomic interface structure of the metal active sites on the MOF. In this study, MOF (PCN-222) is hybridized with cellulose acetate (CA@PCN-222) through an optimized atomic interface strategy, which lowers the average valence state of Zr ions. The electronic metal-support interaction mechanism of CA@PCN-222 is revealed by evaluating the photocatalytic CO2 reduction reaction (CO2 RR). The experimental results suggested that the electron migration efficiency at the atomic interface of the MOFs strongly coupled with cellulose is significantly improved. In particular, the CO2 RR to formate activity of CA@PCN-222 photocatalyst greatly increased from 778.2 to 2816.0 µmol g-1 compared with pristine PCN-222 without cellulose acetate. The findings suggest that the strongly coupled metal-ligand moiety at the atomic interface of MOFs may play a synergistic role in heterogeneous catalysts.

Modeling and analysis of the magnetic force and stiffness of a low-frequency vibration isolator with axial magnetized magnetic rings.

The vibration isolator is a key part of many ultra-precision machines and measuring apparatus. Magnetic suspension vibration isolators (MSVIs) will have excellent application prospects in these instruments to restrain external oscillations. So this paper firstly proposes a new basic configuration of MSVI. Then, in order to study the mechanical characteristics of the MSVI, an analytical expression of the magnetic force is established. The effectiveness of which is demonstrated by the experiment and finite element analysis (FEA). The stiffness of the MSVI is obtained by the derivative of the established analytical magnetic force. Both the axial magnetic force and stiffness appear strong nonlinearity when the inner ring moves at both ends of the fixed outer ring. While the inner ring travels in the middle of the fixed outer one, the axial magnetic force and stiffness indicate approximate linearity with enough bearing capacity. Furthermore, parametric analysis, based on the created magnetic force and stiffness, is performed. The analytical results show that the axial magnetic stiffness may achieve a zero or even negative stiffness value in this range at some size dimensions. The MSVI appears to have a negative stiffness characteristic. More importantly, if a linear and nonlinear positive stiffness spring is combined with the MSVI, it can increase the load capacity of the MSVI. As an example study, the vibration isolation performance of the MSVI is analyzed. The vibration isolation calculation and experiment with the zero stiffness MSVI will be the further focus of the paper.

Study on Contrast-Enhanced Ultrasound Imaging and Anti-Tumor Effects of Drug-Loaded Nanodroplets with Tumor Targeting and Ultrasound Sensitivity.

BACKGROUND: Ultrasound-responsive nanodroplets (NDs) targeting tumors have shown great potential in ultrasound imaging and tumor therapy, but most of these studies are based NDs with lipid shells that cannot overcome the uptake by cells of the reticulo-endothelial system (RES). NDs with shells comprised of polyethylene glycol (PEG)-based polymers could effectively suppressed the uptake of RES, but the phase transition, contrast-enhanced imaging and drug release about these NDs have not been well illuminated. METHODS: Folate receptor targeted NDs with shells of polymers and loaded with DOX (FA-NDs/DOX) were prepared. The particle size distribution and morphology of NDs was characterized with dynamic light scattering (DLS) and microscope. Phase transition and contrast-enhanced ultrasound imaging under different mechanical indices (MIs) was studied, and the intensity of contrast enhancement were quantitatively analyzed. The targeting property of FA-NDs/DOX to MDA-MB-231 cells and cellular uptake were observed using a fluorescence microscope. The anti-tumor effects of FA-NDs/DOX combined with low-intensity focused ultrasound (LIFU) was studied through cytotoxicity tests. Flow cytometry assays were used to detect cell apoptosis. RESULTS: The average particle size of the FA-NDs/DOX was 448.0 ± 8.9 nm, and the zeta potential was 30.4 ± 0.3 mV. When exposed to ultrasound at 37 °C, ultrasound contrast enhancement of FA-NDs/DOX was observed when MI ≥0.19. A stronger acoustic signal was observed under higher MIs and concentrations. The results of quantitative analysis showed that the contrast enhancement intensity of FA-NDs/DOX (1.5 mg/mL) at MI of 0.19, 0.29 and 0.48 was 26.6 ± 0.9 dB, 97.0 ± 3.8 dB and 153.1 ± 5.7 dB, respectively. The contrast enhancement of the FA-NDs/DOX lasted for more than 30 minutes at an MI of 0.48. In targeting experiments, FA-NDs could be recognized by MDA-MB-231 cells, and significant cellular uptake was observed. The blank FA-NDs showed good biocompatibility, while the FA-NDs/DOX induced apoptosis of MDA-MB-231 and MCF-7 cells. By combining LIFU irradiation and FA-NDs/DOX treatment, the best cell-killing effect was achieved. CONCLUSIONS: The FA-NDs/DOX prepared in this study has excellent performance in contrast-enhanced ultrasound imaging, tumor targeting and enhanced chemotherapy. This FA-NDs/DOX with polymer shells provides a novel platform for ultrasound molecular imaging and tumor therapy.

Modulating the Conduction Band of MOFs by Introducing Tiny TiO2 Nanoparticles for Enhanced Photocatalytic Performance: Importance of the Loading Position.

The preparation of TiO2 and metal-organic framework (MOF) into composite photocatalysts has been proven to be a mature and effective strategy to achieve stronger catalytic activity. In this work, we focus on exploring the significant effects and mechanisms of the relative positions of decorated titanium oxide nanoparticles and MOFs on the final catalytic activity. We first used a simple in situ method to encapsulate tiny TiO2 nanoparticles into a Zr-MOF (PCN-222), where Zr-Ti bonds were created at the interface of the two components. Thanks to the strong interfacial interaction forces, band bending occurred in TiO2@PCN-222 and a more negative conduction band (Δ = 0.26 V) with better electron transport properties was obtained. The results of photocatalytic CO2 reduction experiments under visible light showed a 78% increase (142 µmol g-1 h-1) in the production rate of HCOO-. Surprisingly, the loading of TiO2 nanoparticles on the MOF surface (TiO2@PCN-222) resulted in a significant decrease of 56% in the catalyst yield activity due to poor adsorption and electron transfer properties. This work demonstrates the possibility of tuning the band structure and catalytic activity of MOFs with the help of changing the position of the dopant and shows the importance of the rational design of MOF-based composites.

In Situ STING-Activating Nanovaccination with TIGIT Blockade for Enhanced Immunotherapy of Anti-PD-1-Resistant Tumors.

Immunotherapies comprising programmed cell death protein 1/PD ligand 1 (PD-1/PD-L1) immune checkpoint inhibitors are effective cancer treatments. However, the low response rate and immunoresistance resulting from alternative immune checkpoint upregulation and inefficient immune stimulation by T cells are problematic. The present report describes a biomimetic nanoplatform that simultaneously blocks the alternative T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) checkpoint and activates the stimulator of interferon genes (STING) signaling pathway in situ for enhanced antitumor immunity. The nanoplatform is engineered by fusing a red blood cell membrane with glutathione-responsive liposome-encapsulated cascade-activating chemoagents (ß-lapachone and tirapazamine), and anchoring them with a detachable TIGIT block peptide (named as RTLT). In the tumor environment, the peptide is spatiotemporally released to reverse T-cell exhaustion and restore antitumor immunity. The cascade activation of chemotherapeutic agents causes DNA damage and inhibits the repair of double-stranded DNA, which induces robust in situ STING activation for an efficient immune response. The RTLT inhibits anti-PD-1-resistant tumor growth, and prevents tumor metastasis and recurrence in vivo by inducing antigen-specific immune memory. This biomimetic nanoplatform thus provides a promising strategy for in situ cancer vaccination.

Can a heavy trinitromethyl group always result in a higher density?

Density is an important property of energetic materials and is believed to increase with the addition of heavy trinitromethyl groups, as shown in previous literature. However, this study determined that the introduction of these groups produced a decrease in density, as evidenced by the lower density of 1-trinitromethyl-4-amino-3,5-dinitropyrazole ((TN-116), 1.899 g cm-3) compared to that of its precursor (4-amino-3,5-dinitropyrazole (LLM-116), 1.900 g cm-3). Mechanistic studies indicated that the reduced density was due to the significantly weaker H-bonding and π-π interactions of TN-116, which produced looser stacking compared to that of LLM-116.

Rapid metabolic reprogramming mediated by the AMP-activated protein kinase during the lytic cycle of Toxoplasma gondii.

The ubiquitous pathogen Toxoplasma gondii has a complex lifestyle with different metabolic activities at different stages that are intimately linked to the parasitic environments. Here we identified the eukaryotic regulator of cellular homeostasis AMP-activated protein kinase (AMPK) in Toxoplasma and discovered its role in metabolic programming during parasite's lytic cycle. The catalytic subunit AMPKα is quickly phosphorylated after the release of intracellular parasites to extracellular environments, driving energy-producing catabolism to power parasite motility and invasion into host cells. Once inside host cells, AMPKα phosphorylation is reduced to basal level to promote a balance between energy production and biomass synthesis, allowing robust parasite replication. AMPKγ depletion abolishes AMPKα phosphorylation and suppresses parasite growth, which can be partially rescued by overexpressing wildtype AMPKα but not the phosphorylation mutants. Thus, through the cyclic reprogramming by AMPK, the parasites' metabolic needs at each stage are satisfied and the lytic cycle progresses robustly.