Non-targeted metabolomics reveals the characteristics of the unique bitterness substances in quinoa.

Bitterness is a key factor that affects the consumption of quinoa products, even if they are nutritious. In this study, a non-targeted metabolomics approach based on UHPLC-Orbitrap-MS was applied to comprehensively profile the characteristic metabolites of twenty-two quinoas. A total of twenty key metabolites were identified correlated with bitterness, among which, fifteen were triterpenoid saponins. In addition, these metabolites bind to the active site of the human bitter taste receptor and are the main compounds that produce the bitter taste of quinoa. Our results contribute to a deeper understanding of the origin of quinoa bitterness and provide directions for optimizing its flavor to improve market acceptance.

The p-MYH9/USP22/HIF-1α axis promotes lenvatinib resistance and cancer stemness in hepatocellular carcinoma.

Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma (HCC). A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed. In this study, we aimed to dissect the underlying mechanism of lenvatinib resistance (LR) and provide effective treatment strategies. We established an HCC model of acquired LR. Cell counting, migration, self-renewal ability, chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells. Molecular and biochemical strategies such as RNA-sequencing, immunoprecipitation, mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms. Patient-derived HCC models and HCC samples from patients were used to demonstrate clinical significance. We identified that increased cancer stemness driven by the hypoxia-inducible factor-1α (HIF-1α) pathway activation is responsible for acquired LR in HCC. Phosphorylated non-muscle myosin heavy chain 9 (MYH9) at Ser1943, p-MYH9 (Ser1943), could recruit ubiquitin-specific protease 22 (USP22) to deubiquitinate and stabilize HIF-1α in lenvatinib-resistant HCC. Clinically, p-MYH9 (Ser1943) expression was upregulated in HCC samples, which predicted poor prognosis and LR. A casein kinase-2 (CK2) inhibitor and a USP22 inhibitor effectively reversed LR in vivo and in vitro. Therefore, the p-MYH9 (Ser1943)/USP22/HIF-1α axis is critical for LR and cancer stemness. For the diagnosis and treatment of LR in HCC, p-MYH9 (Ser1943), USP22, and HIF-1α might be valuable as novel biomarkers and targets.

PLXNA1 confers enzalutamide resistance in prostate cancer via AKT signaling pathway.

Although targeting the androgen signaling pathway by androgen receptor (AR) inhibitors, including enzalutamide, has shown therapeutic effectiveness, inevitable emergence of acquired resistance remains a critical challenge in the treatment of advanced prostate cancer (PCa). Recognizing targetable genomic aberrations that trigger endocrine treatment failure holds great promise for advancing therapeutic interventions. Here, we characterized PLXNA1, amplified in a subset of PCa patients, as a contributor to enzalutamide resistance (ENZR). Elevated PLXNA1 expression facilitated PCa proliferation under enzalutamide treatment due to AKT signaling activation. Mechanistically, PLXNA1 recruited NRP1 forming a PLXNA1-NRP1 complex, which in turn potentiated the phosphorylation of the AKT. Either inhibiting PLXNA1-NRP1 complex with an NRP1 inhibitor, EG01377, or targeting PLXNA1-mediated ENZR with AKT inhibitors, abolished the pro-resistance phenotype of PLXNA1. Taken together, combination of AKT inhibitor and AR inhibitors presents a promising therapeutic strategy for PCa, especially in advanced PCa patients exhibiting PLXNA1 overexpression.

Discovery of Novel PROTAC SIRT6 Degraders with Potent Efficacy against Hepatocellular Carcinoma.

Sirtuin 6 (SIRT6), a member of the SIRT family, plays essential roles in the regulation of metabolism, inflammation, aging, DNA repair, and cancer development, making it a promising anticancer drug target. Herein, we present our use of proteolysis-targeting chimera (PROTAC) technology to formulate a series of highly potent and selective SIRT6 degraders. One of the degraders, SZU-B6, induced the near-complete degradation of SIRT6 in both SK-HEP-1 and Huh-7 cell lines and more potently inhibited hepatocellular carcinoma (HCC) cell proliferation than the parental inhibitors. In preliminary mechanistic studies, SZU-B6 hampered DNA damage repair, promoting the cellular radiosensitization of cancer cells. Our SIRT6 degrader SZU-B6 displayed promising antitumor activity, particularly when combined with the well-known kinase inhibitor sorafenib or irradiation in an SK-HEP-1 xenograft mouse model. Our results suggest that these PROTACs might constitute a potent therapeutic strategy for HCC.

Multiple Resonance Quasi-fluorescence from BN-Doped Aromatic Compounds Modified with "Naphthalene" Units Approaches the BT.2020 Green Light Standard.

Developing fluorophores that conform to the Broadcast Service Television 2020 (BT.2020) standard presents a formidable challenge. Here, we propose an innovative approach that integrates two and three-boron/nitrogen (BN2)-embedded [4]helicene subunits with naphthalene, resulting in the synthesis of two novel narrowband bright green quasi-fluorescent emitters, NT-2B and NT-3B for ultra-high-definition displays. These emitters exhibit minimal reorganization energy and Huang-Rhys factor, emitting at 510 and 511 nm in dilute toluene solution with exceptionally narrow full width at half maximum values of 15 and 14 nm, respectively. Notably, NT-2B demonstrates an impressive photoluminescence quantum yield of 92.5 %, rapid radiative decay rate, and slow non-radiative decay rate. Owing to their narrowband emission characteristics and outstanding optoelectronic properties, corresponding OLEDs based on NT-2B demonstrate a high external quantum efficiency of 30.6 %, with an FWHM value of 21.5 nm and a CIEy of 0.74, positioning it as one of the leading narrow-band green emitters.

Tumor microenvironment biomarkers predicting pathological response to neoadjuvant chemoimmunotherapy in locally advanced esophageal squamous cell carcinoma: post-hoc analysis of a single center, phase 2 study.

BACKGROUND: Neoadjuvant chemoimmunotherapy has a promising effect on locally advanced esophageal squamous cell carcinoma (ESCC). However, reliable biomarkers robustly predicting therapeutic response are still lacking. METHODS: Formalin-fixed and paraffin-embedded pre-neoadjuvant chemoimmunotherapy biopsy samples from locally advanced ESCC patients were collected. Cohort 1 composed of 66 locally advanced ESCC patients from a prospective clinical trial (NCT04506138) received two cycles of camrelizumab in combination with nab-paclitaxel and carboplatin every 3 weeks. Cohort 2 included 48 patients receiving various types of immune checkpoint inhibitors with (nab-)paclitaxel and platinum-based chemotherapy as neoadjuvant therapy. Cohort 3 consisted of 27 ESCC patients receiving neoadjuvant treatment of toripalimab with chemotherapy and was used as the external validation dataset. Targeted RNA sequencing, immunohistochemistry for programmed death ligand 1 (PD-L1), and multiplex immunofluorescence (mIF) imaging were performed. RESULTS: Integration of targeted RNA sequencing, PD-L1 immunohistochemistry, and mIF revealed a significant immune-suppressive microenvironment with higher neutrophil infiltration, enriched TGF-ß, and cell cycle pathways in non-pathological complete response (non-pCR) patients. NK, activated CD4+ T cell infiltration, interferon-gamma, antigen processing and presentation, and other immune response signatures were significantly associated with pCR. Based on discovered tumor microenvironmental characteristics and their closely related genes were screened. Consequently, a seven-gene neoadjuvant chemoimmunotherapy risk prediction signature (NCIRPs) model, was constructed. In addition to cohort 1, this model alone or with PD-L1-combined positive score (CPS) demonstrated a higher prediction accuracy of pathological response than PD-L1 CPS or other routinely used immune signatures, such as IFN-γ, in cohorts 2 and 3. Neither prognostic association nor correlation with response to chemoradiotherapy was observed in The Cancer Genome Atlas Program ESCC dataset or in ESCC patients in the neoadjuvant chemoradiotherapy cohort (cohort 4). CONCLUSION: The NCIRPs model that was developed and validated using treatment-naïve endoscopic samples from the largest ESCC neoadjuvant chemoimmunotherapy dataset represents a robust and clinically meaningful approach to select a putative responder for neoadjuvant chemoimmunotherapy in locally advanced ESCC patients.

Label-free fluorescence turn-on detection of alkaline phosphatase activity using the calcein-Ce3+ complex.

This study introduces an innovative approach for the real-time and efficient detection of alkaline phosphatase (ALP) activity, using a calcein fluorescence probe and leveraging the static quenching properties of calcein fluorescence by Ce3+ metal ions. In this method, calcein serves as the signal element, with its fluorescence effectively preserved through energy transfer or charge transfer when coordinated with Ce3+. Conversely, ALP catalyzes the phosphopeptide substrate to generate a substantial amount of Pi, preventing calcein fluorescence quenching due to the higher affinity between Pi and Ce3+ compared with that between calcein and Ce3+. The fluorescence intensity ratio (F-F0/F0) exhibited excellent linearity, facilitating sensitive ALP detection. The proposed ALP detection method covers a range from 0 to 1.4 mU/mL (R2 = 0.9942), with the limit of detection at 0.069 mU/mL (S/N = 3). Additionally, this method was successfully applied for detecting ALP in serum samples and studying its inhibitors. This research introduces a novel clinical diagnosis approach for ALP sensing while broadening the potential applications of calcein.

Ubiquitination of NS1 Confers Differential Adaptation of Zika Virus in Mammalian Hosts and Mosquito Vectors.

Arboviruses, transmitted by medical arthropods, pose a serious health threat worldwide. During viral infection, Post Translational Modifications (PTMs) are present on both host and viral proteins, regulating multiple processes of the viral lifecycle. In this study, a mammalian E3 ubiquitin ligase WWP2 (WW domain containing E3 ubiquitin ligase 2) is identified, which interacts with the NS1 protein of Zika virus (ZIKV) and mediates K63 and K48 ubiquitination of Lys 265 and Lys 284, respectively. WWP2-mediated NS1 ubiquitination leads to NS1 degradation via the ubiquitin-proteasome pathway, thereby inhibiting ZIKV infection in mammalian hosts. Simultaneously, it is found Su(dx), a protein highly homologous to host WWP2 in mosquitoes, is capable of ubiquitinating NS1 in mosquito cells. Unexpectedly, ubiquitination of NS1 in mosquitoes does not lead to NS1 degradation; instead, it promotes viral infection in mosquitoes. Correspondingly, the NS1 K265R mutant virus is less infectious to mosquitoes than the wild-type (WT) virus. The above results suggest that the ubiquitination of the NS1 protein confers different adaptations of ZIKV to hosts and vectors, and more importantly, this explains why NS1 K265-type strains have become predominantly endemic in nature. This study highlights the potential application in antiviral drug and vaccine development by targeting viral proteins' PTMs.

Formation mechanism of off-flavor and the inhibition regulatory strategies in the algal oil-loaded emulsions-a review.

Algal oil rich in docosahexaenoic acid is easily oxidized and degraded to produce volatile short-chain compounds, leading to the deterioration of product flavor. Currently, the emulsion delivery of algal oil provides a promising approach to minimize oxidative deterioration and conceal its off-flavor. However, algal oil emulsions would also experience unanticipated oxidation as a result of the large specific surface area between the aqueous phase and the oil phase. The current paper offers a mechanism overview behind off-flavor formation in algal oil emulsions and explores corresponding strategies for the inhibition regulation. Additionally, the paper delves into the factors influencing lipid oxidation and the perception of off-flavors in such emulsions. To mitigate the development of off-flavors in algal oil emulsions resulting from oxidation, it is crucial to decline the likelihood of lipid oxidation and proactively prevent the creation of off-flavors whenever possible. Minimizing the release of volatile off-flavor compounds that are inevitably generated is also considered effective for weakening off-flavor. Moreover, co-encapsulation with particular desirable aroma substances could improve the overall flavor characteristics of emulsions.

Differences in hypersensitivity reactions and gadolinium deposition disease/symptoms associated with gadolinium exposure to gadolinium-based contrast agents: new insights based on global databases VigiBase, FAERS, and IQVIA-MIDAS.

BACKGROUND: Hypersensitivity reactions (HSRs) can occur unexpectedly and be life-threatening when gadolinium-based contrast agents (GBCAs) are used. Gadolinium deposition disease (GDD) and symptoms associated with gadolinium exposure (SAGE) have been controversial for a long time. However, similar studies are currently incomplete or outdated. Therefore, comparing the safety of different GBCAs in terms of HSRs and GDD/SAGE using the latest post-marketing safety data should yield further insights into safely using GBCAs. METHODS: The safety differences between all GBCAs to GDD and the spectrum of GBCA-related HSRs were all compared and analyzed by using the World Health Organization database VigiBase and the FDA Adverse Event Reporting System (FAERS) database in this study. A further analysis of SAGE was also conducted using FAERS data. The lower limit of the reporting odds ratio (ROR) 95% confidence interval was used for signal detection. Moreover, the frequency of HSRs was calculated by dividing the number of reports in VigiBase by the total sales volume (measured in millions) from 2008 to 2022 in the IQVIA Multinational Integrated Data Analysis System. All adverse events were standardized using the Medical Dictionary for Drug Regulatory Activities (MedDRA) 26.0. RESULTS: This study shows that all GBCAs have the potential to induce HSRs, with nonionic linear GBCAs exhibiting a comparatively lower signal. According to standardized MedDRA query stratification analysis, gadobutrol had a greater ROR025 for angioedema. The ROR025 of gadobenate dimeglumine and gadoteridol is larger for anaphylactic/anaphylactoid shock conditions. Regarding severe cutaneous adverse reactions, only gadoversetamide and gadodiamide showed signals in FAERS and VigiBase. There were also differences in the frequency of HSRs between regions. Regarding GDD, gadoterate meglumine, and gadoteridol had a lower ROR025. An analysis of the 29 preferred terms linked to SAGE indicated that special consideration should be given to the risk of skin induration associated with gadoversetamide, gadopentetate dimeglumine, gadobenate dimeglumine, gadodiamide, and gadoteridol. Additionally, gadodiamide and gadoteridol pose a greater risk of skin tightness compared to other GBCAs. CONCLUSIONS: The risk differences among GBCAs using data from several sources were compared in this study. However, as a hypothesis-generating method, a clear causal relationship would require further research and validation.

Antirheumatic drug leflunomide attenuates atherosclerosis by regulating lipid metabolism and endothelial dysfunction via DHODH/AMPK signaling pathway.

The probability of cardiovascular events has been reported lower in rheumatoid arthritis (RA) patients treated with leflunomide. However, the anti-atherosclerotic and cardiovascular protective effects and metabolism of leflunomide are not explored. In this study, we assessed the potential benefits of leflunomide on atherosclerosis and revealed the underlying mechanism. ApoE-/- mice were fed a western diet (WD) alone or supplemented with leflunomide (20 mg/kg, oral gavage, once per day) for 12 weeks. Samples of the aorta, heart, liver, serum, and macrophages were collected. We found that leflunomide significantly reduced lesion size in both en-face aortas and aortic root in WD-fed ApoE-/- mice. Leflunomide also obviously improved dyslipidemia, reduced hepatic lipid content, and improved disorders of glucose and lipid metabolism in vivo. RNA-Seq results showed that leflunomide effectively regulated the genes' expression involved in the lipid metabolism pathway. Importantly, leflunomide significantly increased the phosphorylation levels of AMPKα and acetyl-CoA carboxylase (ACC) in vivo. Furthermore, leflunomide and its active metabolite teriflunomide suppressed lipid accumulation in free fatty acid (FFA)-induced AML12 cells and improved endothelial dysfunction in palmitic acid (PA)-induced HUVECs through activating AMPK signaling and inhibiting dihydroorotate dehydrogenase (DHODH) signaling pathway. We present evidence that leflunomide and teriflunomide ameliorate atherosclerosis by regulating lipid metabolism and endothelial dysfunction. Our findings suggest a promising use of antirheumatic small-molecule drugs leflunomide and teriflunomide for the treatment of atherosclerosis and related cardiovascular diseases (CVDs).

Regional Functionalization Molecular Design Strategy: A Key to Enhancing the Efficiency of Multi-Resonance OLEDs.

Herein, we propose a regional functionalization molecular design strategy that enables independent control of distinct pivotal parameters through different molecule segments. Three novel multiple resonances thermally activated delayed fluorescence (MR-TADF) emitters A-BN, DA-BN, and A-DBN, have been successfully synthesized by integrating highly rigid and three-dimensional adamantane-containing spirofluorene units into the MR framework. These molecules form two distinctive functional parts: part 1 comprises a boron-nitrogen (BN)-MR framework with adjacent benzene and fluorene units forming a central luminescent core characterized by an exceptionally rigid planar geometry, allowing for narrow FWHM values; part 2 includes peripheral mesitylene, benzene, and adamantyl groups, creating a unique three-dimensional "umbrella-like" conformation to mitigate intermolecular interactions and suppress exciton annihilation. The resulting A-BN, DA-BN, and A-DBN exhibit remarkably narrow FWHM values ranging from 18 to 14 nm and near-unity photoluminescence quantum yields. Particularly, OLEDs based on DA-BN and A-DBN demonstrate outstanding efficiencies of 35.0 % and 34.3 %, with FWHM values as low as 22 nm and 25 nm, respectively, effectively accomplishing the integration of high color purity and high device performance.

Lactylated Apolipoprotein C-II Induces Immunotherapy Resistance by Promoting Extracellular Lipolysis.

Mortality rates due to lung cancer are high worldwide. Although PD-1 and PD-L1 immune checkpoint inhibitors boost the survival of patients with non-small-cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build-up and potential lysine-lactylation (Kla), links immune dysfunction to tumor metabolism. The role of non-histone Kla in tumor immune microenvironment and immunotherapy remains to be clarified. Here, global lactylome profiling and metabolomic analyses of samples from patients with NSCLC is conducted. By combining multi-omics analysis with in vitro and in vivo validation, that intracellular lactate promotes extracellular lipolysis through lactyl-APOC2 is revealed. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis. Moreover, the anti-APOC2K70-lac antibody that sensitized anti-PD-1 therapy in vivo is developed. This findings highlight the potential of anti lactyl-APOC2-K70 approach as a new combination therapy for sensitizing immunotherapeutic responses.

Mechanism and therapeutic targets of the involvement of a novel lysosomal proton channel TMEM175 in Parkinson's disease.

Parkinson's disease (PD), recognized as the second most prevalent neurodegenerative disease in the aging population, presents a significant challenge due to the current lack of effective treatment methods to mitigate its progression. Many pathogenesis of PD are related to lysosomal dysfunction. Moreover, extensive genetic studies have shown a significant correlation between the lysosomal membrane protein TMEM175 and the risk of developing PD. Building on this discovery, TMEM175 has been identified as a novel potassium ion channel. Intriguingly, further investigations have found that potassium ion channels gradually close and transform into hydrion "excretion" channels in the microenvironment of lysosomes. This finding was further substantiated by studies on TMEM175 knockout mice, which exhibited pronounced motor dysfunction in pole climbing and suspension tests, alongside a notable reduction in dopamine neurons within the substantia nigra compacta. Despite these advancements, the current research landscape is not without its controversies. In light of this, the present review endeavors to methodically examine and consolidate a vast array of recent literature on TMEM175. This comprehensive analysis spans from the foundational research on the structure and function of TMEM175 to expansive population genetics studies and mechanism research utilizing cellular and animal models.A thorough understanding of the structure and function of TMEM175, coupled with insights into the intricate mechanisms underpinning lysosomal dysfunction in PD dopaminergic neurons, is imperative. Such knowledge is crucial for pinpointing precise intervention targets, thereby paving the way for novel therapeutic strategies that could potentially alter the neurodegenerative trajectory of PD.

A New Phenothiazine-Based Fluorescent Probe for Rapid and Specific Detection of Fluoride.

Fluorescent probes with specific and rapid response to fluoride ions are important mediators for detecting fluoride ions in biological systems. In this study, a phenothiazine-based fluorescent probe, PTC, was designed and synthesized, which undergoes cleavage activation and cyclization induced by fluoride ions targeting Si-O bonds. The probe exhibits strong anti-interference properties and reaches peak fluorescence within 5 min, allowing for quantitative detection of fluoride ions content in the concentration range of 0 to 12.5µM, suitable for live cell fluorescence imaging. The research findings suggest its potential application value in biological systems.

Early ß-blocker use and in-hospital outcomes in patients with chronic obstructive pulmonary disease hospitalized with acute coronary syndrome: findings from the CCC-ACS project.

Background: Patients with chronic obstructive pulmonary disease (COPD) after acute coronary artery syndrome (ACS) are at an increased risk of heart failure and death. However, ß-blockers have been underused in this population group due to concerns of adverse reactions. Objective: This study aims to investigate the ß-blocker prescription at admission and its impact on the in-hospital outcomes in patients with COPD after ACS in a Chinese national cohort. Methods: Among 113,650 patients with ACS enrolled in the national registry of the Improving Care for Cardiovascular Disease in China between November 2014 and July 2019, a total of 1,084 ACS patients with COPD were included in this study. The primary endpoint was in-hospital mortality, and the secondary endpoint was the composite of in-hospital all-cause death and heart failure. Results: Early oral ß-blocker therapy was administered to 49.8% of patients. The Kaplan-Meier analysis showed that the early ß-blocker treatment group had lower all-cause mortality (0.9% vs. 2.9%; P < 0.05) and lower combined endpoint event rate (8.2% vs. 12.0%; P < 0.05) compared to the those of the non-early ß-blocker treatment group. The analysis of inverse probability of treatment weighting showed that the early ß-blocker treatment group was associated with a significantly reduced incidence of all-cause death (risk ratio, 0.332, 0.119-0.923, P = 0.035), heart failure (risk ratio, 0.625, 95% CI 0.414-0.943, P = 0.025), and combined endpoint events (risk ratio: 0.616, 95% CI: 0.418-0.908, P = 0.014). In the subgroup of patients over 70 years of age, the corresponding hazard ratio was 0.268 (95% CI 0.077-0.938) for all-cause mortality and 0.504 (95% CI 0.316-0.805) for combined endpoint events. Conclusion: ß-blockers have been underused in patients with COPD and ACS in China. Early ß-blocker therapy is associated with an improvement in in-hospital outcomes in patients with COPD after ACS. Clinical Trial Registration: ClinicalTrials.gov, identifier (NCT02306616).

The transcriptome of MHV-infected RAW264.7 cells offers an alternative model for macrophage innate immunity research.

BACKGROUND: Macrophages are the primary innate immune cells encountered by the invading coronaviruses, and their abilities to initiate inflammatory reactions, to maintain the immunity homeostasis by differential polarization, to train the innate immune system by epigenic modification have been reported in laboratory animal research. METHODS: In the current in vitro research, murine macrophage RAW 264.7 cell were infected by mouse hepatitis virus, a coronavirus existed in mouse. At 3-, 6-, 12-, 24-, and 48-h post infection (hpi.), the attached cells were washed with PBS and harvested in Trizol reagent. Then The harvest is subjected to transcriptome sequencing. RESULTS: The transcriptome analysis showed the immediate (3 hpi.) up regulation of DEGs related to inflammation, like Il1b and Il6. DEGs related to M2 differential polarization, like Irf4 showed up regulation at 24 hpi., the late term after viral infection. In addition, DEGs related to metabolism and histone modification, like Ezh2 were detected, which might correlate with the trained immunity of macrophages. CONCLUSIONS: The current in vitro viral infection study showed the key innated immunity character of macrophages, which suggested the replacement value of viral infection cells model, to reduce the animal usage in preclinical research.

Effectiveness and safety of a novel modified homemade snare in retrograde percutaneous coronary intervention for chronic total occlusion lesions: a retrospective cohort study.

Background: The use of a commercial snare for retrograde chronic total occlusion (CTO) percutaneous coronary intervention (PCI) is time-consuming and expensive. This study aimed to evaluate the benefits and complications of a novel modified homemade snare (MHS) for retrograde CTO-PCI. Methods: This retrospective cohort study included patients with CTO who underwent retrograde PCI with guidewire snaring between January 2017 and June 2022 at Beijing Anzhen Hospital. The patients were divided into the MHS and gooseneck snare (GS) groups according to the devices used for externalization. Clinical, procedural, and angiographic data were collected. Results: Ninety patients (46 with MHS and 44 with GS) were included. There was no significant difference in the location of the CTO vessel between the MHS and GS groups, and the target CTO vessel was mainly located in the right coronary artery (RCA) in both groups (73.9% and 68.2% respectively). There were no significant differences in the J-CTO (Multicenter CTO Registry in Japan) and PROGRESS-CTO (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention) scores between the two groups. More patients in the MHS group had lesions with ambiguous proximal caps compared with the GS group (54.3% vs. 31.8%, P=0.04). Retrograde wire crossing technique was used more in the GS group (54.5% vs. 41.3%, P=0.04), while reverse-controlled antegrade and retrograde subintimal tracking (CART) technique was used more in the MHS group (58.7% vs. 45.5%, P=0.037). The mean guidewire capture time was shorter in the MHS group than in the GS group (2.7±0.6 vs. 3.4±0.7 min, P<0.001). One case of delayed pericardial tamponade was observed in the MHS group. No other complications occurred. Conclusions: MHS appears to facilitate externalization in retrograde PCI for complex CTO lesions.

Reshaping the root endophytic microbiota in plants to combat mercury-induced stress.

Emerging evidence suggests that plants experiencing abiotic stress actively seek help from soil microbes. However, the empirical evidence supporting this strategy is limited, especially in response to heavy metal stress. We used integrated microbial community profiling and culture-based methods to investigate the interaction between mercury (Hg) stress, the entophytic root microbiome, and maize seedlings. The results of the pot experiment showed that soil Hg (20 mg/kg) strongly inhibited maize growth, indicating its strong phytotoxicity. Furthermore, Hg stress significantly altered the structure of the bacterial and fungal communities and enriched the potentially pathogenic Fusarium sp., suggesting that soil Hg stress may enhance the bio-stress induced by Fusarium species in maize. Additionally, soil Hg also led to the enrichment of beneficial bacterial members of Streptomyces, Lysobacter, and Sphingomonas (defined as differential species), which were also identified as keystone species in the Hg treatment by the analysis of co-occurrence networks. Therefore, it can be postulated that the members of Streptomyces, Lysobacter, and Sphingomonas function as stress-alleviating microbes. We successfully isolated the representatives of these stress-alleviating microbes. As expected, these strains mitigated the detrimental effects of Hg stess for the maize seedlings, suggesting that plants recruit the stress-alleviated microbiota to combat Hg stress. This study provides insights into the potential of manipulating the root microbiome to enhance plant growth in polluted environments.

A Hydrogen-Bonded Organic Framework-Based Mitochondrion-Targeting Bioorthogonal Platform for the Modulation of Mitochondrial Epigenetics.

Bioorthogonal chemistry represents a powerful tool in chemical biology, which shows great potential in epigenetic modulation. As a proof of concept, the epigenetic modulation model of mitochondrial DNA (mtDNA) is selected because mtDNA establishes a relative hypermethylation stage under oxidative stress, which impairs the mitochondrion-based therapeutic effect during cancer therapy. Herein, we design a new biocompatible hydrogen-bonded organic framework (HOF) for a HOF-based mitochondrion-targeting bioorthogonal platform TPP@P@PHOF-2. PHOF-2 can activate a prodrug (pro-procainamide) in situ, which can specifically inhibit DNA methyltransferase 1 (DNMT1) activity and remodel the epigenetic modification of mtDNA, making it more susceptible to ROS damage. In addition, PHOF-2 can also catalyze artemisinin to produce large amounts of ROS, effectively damaging mtDNA and achieving better chemodynamic therapy demonstrated by both in vitro and in vivo studies. This work provides new insights into developing advanced bioorthogonal therapy and expands the applications of HOF and bioorthogonal catalysis.