Force Analysis Using Self-Expandable Valve Fluoroscopic Imaging: a way Through Artificial Intelligence.

This study aimed to develop a force analysis model correlating fluoroscopic images of self-expandable valves with stress distribution. For this purpose, a nonmetallic measuring device designed to apply diverse forces at specific positions on a valve stent while simultaneously measuring force magnitude was manufactured, obtaining 465 sets of fluorescent films under different force conditions, resulting in 5580 images and their corresponding force tables. Using the XrayGLM, a mechanical analysis model based on valve fluorescence images was trained. The accuracy of the image force analysis using this model was approximately 70% (50-88.3%), with a relative accuracy of 93.3% (75-100%). This confirms that fluoroscopic images of transcatheter aortic valve replacement (TAVR) valve stents contain a wealth of mechanical information, and machine learning can be used to train models to recognize the relationship between stent images and force distribution, enhancing the understanding of TAVR complications.

CRISPR/Cas13a-based genome editing for establishing the detection method of H9N2 subtype avian influenza virus.

Avian influenza virus (AIV) subtype H9N2 has significantly threatened the poultry business in recent years by having become the predominant subtype in flocks of chickens, ducks, and pigeons. In addition, the public health aspects of H9N2 AIV pose a significant threat to humans. Early and rapid diagnosis of H9N2 AIV is therefore of great importance. In this study, a new method for the detection of H9N2 AIV based on fluorescence intensity was successfully established using CRISPR/Cas13a technology. The Cas13a protein was first expressed in a prokaryotic system and purified using nickel ion affinity chromatography, resulting in a high-purity Cas13a protein. The best RPA (recombinase polymerase amplification) primer pairs and crRNA were designed and screened, successfully constructing the detection of H9N2 AIV based on CRISPR/Cas13a technology. Optimal concentration of Cas13a and crRNA was determined to optimize the constructed assay. The sensitivity of the optimized detection system is excellent, with a minimum detection limit of 10° copies/µL and didn't react with other avian susceptible viruses, with excellent specificity. The detection method provides the basis for the field detection of the H9N2 AIV.

A single-cell analysis of the NK-cell landscape reveals that dietary restriction boosts NK cell antitumor immunity via Eomesdermin.

Abnormal metabolism in tumor cells represents a potential target for tumor therapy. In this regard, dietary restriction (DR) or its combination with anticancer drugs is of interest as it can impede the growth of tumor cells. In addition to its effects on tumor cell, DR also plays an extrinsic role in restricting tumor growth by regulating immune cells. Natural killer (NK) cells are innate immune cells involved in tumor immunosurveillance. However, it remains uncertain whether DR can assist NK cells in controlling tumor growth. Herein, we demonstrate that DR effectively inhibits metastasis of melanoma cells to the lung. Consistent with this, the regression of tumors induced by DR was minimal in mice lacking NK cells. Single-cell RNA sequencing analysis revealed that DR enriched a rejuvenated subset of CD27+CD11b+ NK cells. Mechanistically, DR activated a regulatory network involving the transcription factor Eomesodermin (Eomes), which is essential for NK-cell development. Firstly, DR promoted the expression of Eomes by optimizing mTORC1 signaling. The upregulation of Eomes revived the subset of functional CD27+CD11b+ NK cells by counteracting the expression of T-bet and downstream Zeb2. Moreover, DR enhanced the function and chemotaxis of NK cells by increasing the accessibility of Eomes to chromatin, leading to elevated expression of adhesion molecules and chemokines. Consequently, we conclude that DR therapy enhances tumor immunity through non-tumor autonomous mechanisms, including promoting NK-cell tumor immunosurveillance and activation.

Intestinal Nogo-B reduces GLP1 levels by binding to proglucagon on the endoplasmic reticulum to inhibit PCSK1 cleavage.

Glucagon-like peptide 1 (GLP1), which is mainly processed and cleaved from proglucagon in enteroendocrine cells (EECs) of the intestinal tract, acts on the GLP1 receptor in pancreatic cells to stimulate insulin secretion and to inhibit glucagon secretion. However, GLP1 processing is not fully understood. Here, we show that reticulon 4B (Nogo-B), an endoplasmic reticulum (ER)-resident protein, interacts with the major proglucagon fragment of proglucagon to retain proglucagon on the ER, thereby inhibiting PCSK1-mediated cleavage of proglucagon in the Golgi. Intestinal Nogo-B knockout in male type 2 diabetes mellitus (T2DM) mice increases GLP1 and insulin levels and decreases glucagon levels, thereby alleviating pancreatic injury and insulin resistance. Finally, we identify aberrantly elevated Nogo-B expression and inhibited proglucagon cleavage in EECs from diabetic patients. Our study reveals the subcellular regulatory processes involving Nogo-B during GLP1 production and suggests intestinal Nogo-B as a potential therapeutic target for T2DM.

Microglial cGAS-STING signaling underlies glaucoma pathogenesis.

Characterized by progressive degeneration of retinal ganglion cells (RGCs) and vision loss, glaucoma is the primary cause of irreversible blindness, incurable and affecting over 78 million patients. However, pathogenic mechanisms leading to glaucoma-induced RGC loss are incompletely understood. Unexpectedly, we found that cGAS-STING (2'3'-cyclic GMP-AMP-stimulator of interferon genes) signaling, which surveils displaced double-stranded DNA (dsDNA) in the cytosol and initiates innate immune responses, was robustly activated during glaucoma in retinal microglia in distinct murine models. Global or microglial deletion of STING markedly relieved glaucoma symptoms and protected RGC degeneration and vision loss, while mice bearing genetic cGAS-STING supersensitivity aggravated retinal neuroinflammation and RGC loss. Mechanistically, dsDNA from tissue injury activated microglial cGAS-STING signaling, causing deleterious macroglia reactivity in retinas by cytokine-mediated microglia-macroglia interactions, progressively driving apoptotic death of RGCs. Remarkably, preclinical investigations of targeting cGAS-STING signaling by intraocular injection of TBK1i or anti-IFNAR1 antibody prevented glaucoma-induced losses of RGCs and vision. Therefore, we unravel an essential role of cGAS-STING signaling underlying glaucoma pathogenesis and suggest promising therapeutic strategies for treating this devastating disease.

Co-exposure of bisphenol A and selenium deficiency induces pyroptosis via ROS/NLRP3 pathway in chicken spleen.

Bisphenol A (BPA) is widely applied in plastic products, which will produce immunotoxicity to organisms after spilling in the environment, and become a kind of endocrine disruptor. Selenium (Se) is an essential trace element and plays an important role in maintaining redox homeostasis and immune function. BPA exposure and Se deficiency often occur together in livestock and poultry farming, however, studies on the effects of joint exposure on chicken immunotoxins have not been reported. Therefore, this study established a chicken spleen and MDCC-MSB1 cell model under the combined effects of BPA exposure or/and Se deficiency. Transcriptomic analysis showed that BPA exposure and/or Se deficiency induced differential enrichment of positive regulatory pathways such as NLRP3 inflammatory complex assembly, inflammatory response and cellular oxidative stress response. In the -Se+BPA group, pathological damage was significantly increased, Se content decreased, BPA accumulation, oxidative stress and pyroptosis. Meanwhile, the roles and mechanisms of oxidative stress and pyroptosis in BPA exposure or/and Se deficiency-induced splenic tissue injury were investigated by using IF and qRT-PCR methods. The results showed that joint BPA exposure with Se deficiency resulted in more significant changes in the above outcomes than 1 of them. The oxidative stress inhibitor NAC effectually reduced Se deficiency and BPA-induced oxidative stress and pyroptosis, further suggests that oxidative stress mediated Se deficiency or/and BPA-induced pyroptosis. This study revealed that BPA exposure and Se deficiency induced spleen pyroptosis in chickens via the ROS/NLRP3 pathway. These results provide the theoretical basis for the toxicity of BPA in poultry and enrich the toxicological mechanism of combined exposure of Se deficiency and environmental toxins.

Geniposide alleviates heart failure with preserved ejection fraction in mice by regulating cardiac oxidative stress via MMP2/SIRT1/GSK3ß pathway.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome with cardiac dysfunction, fluid retention and reduced exercise tolerance as the main manifestations. Current treatment of HFpEF is using combined medications of related comorbidities, there is an urgent need for a modest drug to treat HFpEF. Geniposide (GE), an iridoid glycoside extracted from Gardenia Jasminoides, has shown significant efficacy in the treatment of cardiovascular, digestive and central nervous system disorders. In this study we investigated the therapeutic effects of GE on HFpEF experimental models in vivo and in vitro. HFpEF was induced in mice by feeding with HFD and L-NAME (0.5 g/L) in drinking water for 8 weeks, meanwhile the mice were treated with GE (25, 50 mg/kg) every other day. Cardiac echocardiography and exhaustive exercise were performed, blood pressure was measured at the end of treatment, and heart tissue specimens were collected after the mice were euthanized. We showed that GE administration significantly ameliorated cardiac oxidative stress, inflammation, apoptosis, fibrosis and metabolic disturbances in the hearts of HFpEF mice. We demonstrated that GE promoted the transcriptional activation of Nrf2 by targeting MMP2 to affect upstream SIRT1 and downstream GSK3ß, which in turn alleviated the oxidative stress in the hearts of HFpEF mice. In H9c2 cells and HL-1 cells, we showed that treatment with GE (1 µM) significantly alleviated H2O2-induced oxidative stress through the MMP2/SIRT1/GSK3ß pathway. In summary, GE regulates cardiac oxidative stress via MMP2/SIRT1/GSK3ß pathway and reduces cardiac inflammation, apoptosis, fibrosis and metabolic disorders as well as cardiac dysfunction in HFpEF. GE exerts anti-oxidative stress properties by binding to MMP2, inhibiting ROS generation in HFpEF through the SIRT1/Nrf2 signaling pathway. In addition, GE can also affect the inhibition of the downstream MMP2 target GSK3ß, thereby suppressing the inflammatory and apoptotic responses in HFpEF. Taken together, GE alleviates oxidative stress/apoptosis/fibrosis and metabolic disorders as well as HFpEF through the MMP2/SIRT1/GSK3ß signaling pathway.

Alpha-ketoglutarate is required for chronic hypoxia-induced cardiac remodeling.

Chronic hypoxia (CH) is commonly associated with various cardiovascular diseases, with cardiac hypertrophy being the most frequently observed alteration. Metabolic remodeling is another consequence seen in the hypoxic heart. However, the mechanistic linkage between metabolic remodeling and cardiac hypertrophy in the hypoxic heart remains clear. In this study, wild-type C57BL/6J mice were subjected to CH for four weeks. Echocardiography and morphological analysis were used to assess the cardiac effects. We found that four weeks of CH led to significant cardiac hypertrophy in the mice, while cardiac function remained unchanged compared to normoxic mice. Additionally, CH induced an elevation in cardiac alpha-ketoglutarate (α-KG) content. Promoting α-KG degradation in the CH hearts prevented CH-induced cardiac hypertrophy but led to noticeable cardiac dysfunction. Mechanistically, α-KG promoted the transcription of hypertrophy-related genes by regulating histone methylation. Silencing lysine-specific demethylase 5 (KDM5), a histone demethylation enzyme, blunted α-KG-induced transcription of hypertrophy-related genes. These data suggest that α-KG is required for CH-induced cardiac remodeling, thus establishing a connection between metabolic changes and cardiac remodeling in hypoxic hearts.

Gambogic Acid Improves Cisplatin Resistance of Bladder Cancer Cells through the Epithelial-Mesenchymal Transition Pathway Mediated by the miR-205-5p/ZEB1 Axis.

OBJECTIVE: Bladder cancer (BC) is primarily treated with cisplatin-based chemotherapy, but the development of cisplatin resistance often leads to BC recurrence. This study is focused on assessing the potential of gambogic acid (GA) in mitigating BC cells' cisplatin resistance, along with an analysis of the underlying mechanism involved. METHODS: Cisplatin was administered to human bladder transitional cell carcinoma cells (T24) at various concentration gradients to induce cisplatin-resistant (T24-DDP) cells. Several experimental groups were set: T24 group, T24-DDP group, T24-DDP+DDP group, T24-DDP+GA group, T24-DDP+DDP+GA group, T24-DDP+DDP+GA+miR-NC group, and T24-DDP+DDP+GA+miR-205-5p inhibitor group. The cell counting kit-8 (CCK-8) assay, Transwell migration assay, and scratch assay were respectively carried out for assessment of cell proliferation, invasion, and migration. Western blot analysis was conducted for detection of the protein expression of E-cadherin, ZEB1, Vimentin, N-cadherin, LRP, MRP, and P-gp in the cells, while the relative expression level of miR-205-5p was determined by qRT-PCR. RESULTS: In comparison with the T24-DDP group, cells in the T24-DDP+GA group showed enhanced sensitivity to cisplatin. Furthermore, as indicated by CCK-8 assay, GA improved T24-DDP cells' sensitivity to cisplatin, potentiated the effects of cisplatin, and exerted an inhibitory effect on the invasion, proliferation, as well as migration of T24-DDP cells. Through Western blot analysis, GA was revealed to significantly inhibit the expression of N-cadherin, E-cadherin, and Vimentin, as well as that of cisplatin-resistant proteins MRP, P-gp, and LRP in BC cells. In addition, shown by further experiments, GA promoted miR-205-5p expression and simultaneously inhibited ZEB1 expression within the cells. CONCLUSION: GA alleviates BC cells' cisplatin resistance through the epithelial-mesenchymal transition pathway mediated by the miR-205-5p/ZEB1 axis.

Entropy drives the ligand recognition in G-protein-coupled receptor subtypes.

Achieving ligand subtype selectivity within highly homologous subtypes of G-protein-coupled receptor (GPCR) is critical yet challenging for GPCR drug discovery, primarily due to the unclear mechanism underlying ligand subtype selectivity, which hampers the rational design of subtype-selective ligands. Herein, we disclose an unusual molecular mechanism of entropy-driven ligand recognition in cannabinoid (CB) receptor subtypes, revealed through atomic-level molecular dynamics simulations, cryoelectron microscopy structure, and mutagenesis experiments. This mechanism is attributed to the distinct conformational dynamics of the receptor's orthosteric pocket, leading to variations in ligand binding entropy and consequently, differential binding affinities, which culminate in specific ligand recognition. We experimentally validated this mechanism and leveraged it to design ligands with enhanced or ablated subtype selectivity. One such ligand demonstrated favorable pharmacokinetic properties and significant efficacy in rodent inflammatory analgesic models. More importantly, it is precisely due to the high subtype selectivity obtained based on this mechanism that this ligand does not show addictive properties in animal models. Our findings elucidate the unconventional role of entropy in CB receptor subtype selectivity and suggest a strategy for rational design of ligands to achieve entropy-driven subtype selectivity for many pharmaceutically important GPCRs.

Adaptive median filter salt and pepper noise suppression approach for common path coherent dispersion spectrometer.

The Common-path Coherent-dispersion Spectrometer (CODES), an exoplanet detection instrument, executes high-precision Radial Velocity (RV) inversions by recording the phase shifts of interference fringes. Salt-and-pepper noise caused by factors such as improper operation of the CCD probe/analog-to-digital converter and strong dark currents may interfere with the phase information of the fringe. This lowers the quality of the interfering fringe image and significantly interferes with the RV's inversion. In this study, an adaptive median filtering algorithm (CODESmF) based on submaximum and subminimum values is designed to eliminate the interference fringe image's salt-and-pepper noise as well as to reduce RV error. This allows the interference fringe image's phase information to be retained more completely. The algorithm consists of two major modules. Pixel Sub-extreme-based Filtered Noise Monitoring Module: discriminates signal pixels and noise pixels based on the submaximum and subminimum values of the pixels in the filtering window. Adaptive Median Filter Noise Suppression Module: the signal pixel is kept at the original value output, the noise pixel serves as the filtering window's center pixel, and the adaptive median filtering procedure is repeated numerous times with various filtering window sizes. According to the experimental findings, the CODESmF outperforms comparable algorithms and works better at recovering interference fringes. More than 90% of the phase/RV error caused by salt-and-pepper noise is typically eliminated by the CODESmF algorithm, and in certain circumstances, it can even remove roughly 98% of the phase error.

Remedy of a deep downward shift of a valve using double snares and "sandwich" technique.

A 76-year-old man diagnosed with severe pure native aortic regurgitation (PNAR) underwent transcatheter aortic valve replacement (TAVR) due to high surgical risk. The computed tomography angiography showed no calcification and no stenosis of the aortic valve, with an annulus perimeter of 81.1 mm and sinus diameters of 35 to 38 mm.

Association of in situ thrombus within the patent foramen ovale and patients with migraine: A prospective cohort study.

Background: Patent foramen ovale (PFO) is associated with migraine; however, the mechanism of PFO-associated migraine is not well known; additionally, percutaneous closure is controversial. This study aimed to investigate in situ thrombi within the PFO and explore the possible predictors of the effectiveness of PFO closure in migraineurs. Methods: This prospective cohort study included 48 asymptomatic patients and 92 migraineurs with PFO. Optical coherence tomography (OCT) was used to evaluate the PFO microstructure. Only migraineurs underwent percutaneous closure. Migraineurs were divided into two cohorts based on the presence of a thrombus within the PFO. The symptoms were assessed at the 12-month follow-up visit. Predictors were evaluated employing multivariate logistic regression and receiver operating characteristic curve analyses. Results: In situ thrombi within PFO were identified in 69 migraineurs and in two asymptomatic patients (76.7 % vs. 4.3 %; P < 0.001). Additionally, endocardial irregularity, discontinuity, low signal, and spasm were found in 59 (65.6 %), 15 (16.7 %), 13 (14.4 %), and six (6.7 %) patients, respectively, in the migraine group. In situ thrombus was associated with migraine risk (OR 49.03; 95%CI 8.52-282.18; P < 0.001). At the 12-month follow-up of the migraineur cohort, the primary endpoint, a 50 % reduction in migraine frequency after closure (with or without thrombus in PFO) was met (85.3 % vs. 25.0 %; P < 0.001). In situ thrombus was associated with migraine relief (OR 6.75; 95%CI 1.28-35.56; P = 0.024). Conclusions: In situ thrombus and abnormal endocardium within PFOs were common in migraineurs, and in situ thrombus was a risk factor for migraine. Percutaneous closure was more effective in migraineurs with thrombi within the PFO. OCT imaging improved the understanding of pathogenic PFOs and may be helpful in selecting suitable migraineurs for PFO closure.

SLAM-family receptors promote resolution of ILC2-mediated inflammation.

Type 2 innate lymphoid cells (ILC2) initiate early allergic inflammation in the lung, but the factors that promote subsequent resolution of type 2 inflammation and prevent prolonged ILC2 activation are not fully known. Here we show that SLAM-family receptors (SFR) play essential roles in this process. We demonstrate dynamic expression of several SFRs on ILC2s during papain-induced type 2 immunity in mice. SFR deficiency exacerbates ILC2-driven eosinophil infiltration in the lung, and results in a significant increase in IL-13 production by ILC2s exclusively in mediastinal lymph nodes (MLN), leading to increased dendritic cell (DC) and TH2 cell numbers. In MLNs, we observe more frequent interaction between ILC2s and bystander T cells, with T cell-expressed SFRs (especially SLAMF3 and SLAMF5) acting as self-ligands to suppress IL-13 production by ILC2s. Mechanistically, homotypic engagement of SFRs at the interface between ILC2s and T cells delivers inhibitory signaling primarily mediated by SHIP-1. This prevents activation of NF-κB, driven by IL-7 and IL-33, two major drivers of ILC2-mediated type 2 immunity. Thus, our study shows that an ILC2-DC-TH2 regulatory axis may promote the resolution of pulmonary type 2 immune responses, and highlights SLAMF3/SLAMF5 as potential therapeutic targets for ameliorating type 2 immunity.

Long-term outcomes in patients with bicuspid valve stenosis and aortic dilation undergoing transcatheter valve implantation.

BACKGROUND: To date, whether ascending aorta dilation (AAD) should be considered a contraindication for transcatheter aortic valve replacement (TAVR) remains a topic of debate.. OBJECTIVE: The study investigated the clinical outcome of TAVR in patients with bicuspid aortic valve stenosis (BAV-AS) complicated by AAD. METHODS: We included patients with BAV-AS who underwent TAVR between 2012 and 2019. We collected patient perioperative clinical data., tracked clinical outcomes for over four years post-TAVR, and obtained echocardiography images one year postoperatively. The Kaplan-Meier method was employed for analyzing both unadjusted and adjusted survival data, which was compared using the log-rank test. COX regression and nomograms were used to assess the impact of AAD on post-TAVR clinical outcomes in patients with aortic stenosis (AS), with all-cause mortality as the primary clinical endpoint. RESULTS: A total of 111 BAV patients were included in this study. Long-term follow-up showed an increased mortality risk in patients with BAV-AAD (adjusted Kaplan-Meier analysis: P = .02/0.001). Cox correlation analysis indicated that age (OR = 1.137; P = .034), AAD (OR = 3.51; P = .038), and postoperative left ventricular pressure (LVSP) (OR: 0.959; P = .044) were predictive factors for mortality more than four years after TAVR in patients with BAV. The area under the curve of the Nomogram predicting long-term survival for the training set of patients based on the above metrics was 0.845 (95% CI: 0.696-0.994). Short-term cardiac ultrasound follow-up showed a more rapid rate of AA expansion (0.29 [0-0.34] vs. -1 [-3.3-1] mm/month, P = .001) and a smaller proportion of AA diameter reduction (7.1% vs. 53.7%, P = .001) in patients who died. CONCLUSIONS: Patients with BAV-AAD-AS treated with TAVR have an increased risk of long-term mortality, and clinical prediction models, including AAD age and postoperative LVSP, may predict long-term patient survival. CONDENSED ABSTRACT: The study investigated the clinical outcome of transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valve stenosis (BAV-AS) complicated by ascending aorta dilation (AAD). Patients with BAV-AAD-AS treated with TAVR have an increased risk of long-term mortality. AAD, age and postoperative LVSP, may predict long-term patient survival. Short-term cardiac ultrasound follow-up showed a more rapid rate of AA expansion and a smaller proportion of AA diameter reduction in patients who died. A high postoperative AAD expansion rate may indicate an adverse clinical outcome. Surgery regimens for tolerable BAV-AADs and can be considered as a treatment option.

Comparisons of noncoronary sinus pivot implantation (NCPI) and conventional method for transcatheter aortic valve replacement with self-expanding valve in pure aortic regurgitation (PAR).

BACKGROUND: As compared to treatment of aortic stenosis (AS), transcatheter aortic valve replacement (TAVR) using the commercially available valves to treat pure aortic regurgitation (PAR) has a lower device success rate and higher complication rates. AIMS: The study compared the acute results between TAVR using a novel noncoronary sinus pivot implantation (NCPI) method and that using the conventional method, aiming to explore a more optimized and effective operation method for TAVR in PAR. METHODS: PAR patients who underwent TAVR with self-expanding valves in our center from September 2021 to September 2023 were enrolled were divided into the NCPI (group A, N = 16) and conventional method (group B, N = 39) groups. We analyzed the pre-operative evaluation parameters and procedural and postoperative data of the two subgroups. RESULTS: The total patients' mean age was 71.2 ± 8.7 years and most were male (61.8%), with a mean Society of Thoracic Surgeons score of 3.4 ± 1.9%. The device success rate of groups A and B was 100% and 71.8%, respectively. In group B, 48.7% had major adverse cardiac events (MACE); 46.2% patients had permanent pacemaker implantation or valve in valve implantation. None had MACE in group A. The noncoronary sinus implantation depth in NCPI was -1.1 + 1.0 and 4.2 + 3.7 mm in groups A and B (p < 0.001), respectively. CONCLUSIONS: TAVR with a self-expanding valve using the NCPI method had a higher procedure success rate and dramatically low complications than that using the conventional method in PAR patients.

Dual Activity of Type III PI3K Kinase Vps34 is Critical for NK Cell Development and Senescence.

Vps34 is the unique member of the class III phosphoinositide 3-kinase family that performs both vesicular transport and autophagy. Its role in natural killer (NK) cells remains uncertain. In this study, a model without Vps34 (Vps34fl/fl/CD122Cre/+) is generated, deleting Vps34 during and after NK-cell commitment. These mice exhibit a nearly 90% decrease in NK cell count and impaired differentiation. A mechanistic study reveals that the absence of Vps34 disrupts the transport of IL-15 receptor subunit alpha CD122 to the cell membrane, resulting in reduced responsiveness of NK cells to IL-15. In mice lacking Vps34 at the terminal stage of NK-cell development (Vps34fl/fl/Ncr1Cre/+), NK cells gradually diminish during aging. This phenotype is associated with autophagy deficiency and the stress induced by reactive oxygen species (ROS). Therefore, terminally differentiated NK cells lacking Vps34 display an accelerated senescence phenotype, while the application of antioxidants effectively reverses the senescence caused by Vps34 deletion by neutralizing ROS. In summary, this study unveils the dual and unique activity of Vps34 in NK cells. Vps34-mediated vesicular transport is crucial for CD122 membrane trafficking during NK cell commitment, whereas Vps34-mediated autophagy can delay NK cell senescence.

Bioorthogonal labeling and profiling of N6-isopentenyladenosine (i6A) modified RNA.

Chemical modifications in RNAs play crucial roles in diversifying their structures and regulating numerous biochemical processes. Since the 1990s, several hydrophobic prenyl-modifications have been discovered in various RNAs. Prenyl groups serve as precursors for terpenes and many other biological molecules. The processes of prenylation in different macromolecules have been extensively studied. We introduce here a novel chemical biology toolkit that not only labels i6A, a prenyl-modified RNA residue, by leveraging the unique reactivity of the prenyl group, but also provides a general strategy to incorporate fluorescence functionalities into RNAs for molecular tracking purposes. Our findings revealed that iodine-mediated cyclization reactions of the prenyl group occur rapidly, transforming i6A from a hydrogen-bond acceptor to a donor. Based on this reactivity, we developed an Iodine-Mediated Cyclization and Reverse Transcription (IMCRT) tRNA-seq method, which can profile all nine endogenous tRNAs containing i6A residues in Saccharomyces cerevisiae with single-base resolution. Furthermore, under stress conditions, we observed a decline in i6A levels in budding yeast, accompanied by significant decrease of mutation rate at A37 position. Thus, the IMCRT tRNA-seq method not only permits semi-quantification of i6A levels in tRNAs but also holds potential for transcriptome-wide detection and analysis of various RNA species containing i6A modifications.

Unleashing a safe and potent pro-senescence anti-tumor strategy.

Inducing senescence in tumor cells can stimulate anti-tumor immune responses. In this issue of Cancer Cell, Colucci et al. demonstrate that the combination of the RAR agonist Adapalene with the chemotherapy drug Docetaxel enhances tumor-suppressing senescence and activates an anti-tumor immune response through natural killer cells.