Ocular A-to-I RNA editing signatures associated with SARS-CoV-2 infection.

Ophthalmic manifestations have recently been observed in acute and post-acute complications of COVID-19 caused by SARS-CoV-2 infection. Our precious study has shown that host RNA editing is linked to RNA viral infection, yet ocular adenosine to inosine (A-to-I) RNA editing during SARS-CoV-2 infection remains uninvestigated in COVID-19. Herein we used an epitranscriptomic pipeline to analyze 37 samples and investigate A-to-I editing associated with SARS-CoV-2 infection, in five ocular tissue types including the conjunctiva, limbus, cornea, sclera, and retinal organoids. Our results revealed dramatically altered A-to-I RNA editing across the five ocular tissues. Notably, the transcriptome-wide average level of RNA editing was increased in the cornea but generally decreased in the other four ocular tissues. Functional enrichment analysis showed that differential RNA editing (DRE) was mainly in genes related to ubiquitin-dependent protein catabolic process, transcriptional regulation, and RNA splicing. In addition to tissue-specific RNA editing found in each tissue, common RNA editing was observed across different tissues, especially in the innate antiviral immune gene MAVS and the E3 ubiquitin-protein ligase MDM2. Analysis in retinal organoids further revealed highly dynamic RNA editing alterations over time during SARS-CoV-2 infection. Our study thus suggested the potential role played by RNA editing in ophthalmic manifestations of COVID-19, and highlighted its potential transcriptome impact, especially on innate immunity.

Enantio- and Diastereoselective Total Synthesis of Belzutifan Enabled by Rh-Catalyzed Hydrogenation.

Herein, we report a nine-step synthesis of belzutifan enabled by a novel Rh-catalyzed asymmetric hydrogenation to install the contiguous fluorinated stereocenters with high enantioselectivity. Moreover, the final ketone reduction in the synthesis proceeds with high diastereoselectivity, leading to the expedient assembly of the stereotriad. In contrast to the original 16-step synthesis, this route avoids a lengthy bromination-oxidation sequence and introduces the sulfone functionality via nucleophilic aromatic substitution, obviating the need for transition metal catalysis.

Facile Synthesis of a Multifunctional Porous Organic Polymer Nanosonosensitizer (mHM@HMME) for Enhanced Cancer Sonodynamic Therapy.

Sonodynamic therapy (SDT), which involves the activation of sonosensitizers to generate cytotoxic reactive oxygen species under ultrasound irradiation, is a promising noninvasive modality for cancer treatment. However, the clinical translational application of SDT is impeded by the lack of efficient sonosensitizers, the inefficient accumulation of sonosensitizers at tumor sites, and the complicated immunosuppressive tumor microenvironment. Herein, we developed a facilely synthesized multifunctional porous organic polymer nanosonosensitizer (mHM@HMME) for enhanced SDT. Specifically, mHM@HMME nanosonosensitizers were prepared by incorporating chemotherapeutic mitoxantrone into the one-step synthesis process of disulfide bond containing porous organic polymers, followed by loading with organic sonosensitizer (HMME) and camouflaging with a cancer cell membrane. Due to the cancer cell membrane camouflage, this multifunctional mHM@HMME nanosonosensitizer showed prolonged blood circulation and tumor targeting aggregation. Under ultrasound irradiation, the mHM@HMME nanosonosensitizer exhibited a satisfactory SDT performance both in vitro and in vivo. Moreover, the potent SDT combined with glutathione-responsive drug release in tumor cells induced robust immunogenic cell death to enhance the antitumor effect of SDT in turn. Overall, this facilely synthesized multifunctional mHM@HMME nanosonosensitizer shows great potential application in enhanced SDT.

Secure cross-chain interaction solution in multi-blockchain environment.

In the context of the increasingly diversified blockchain technology, interoperability among heterogeneous blockchains has become key to further advancing this field. Existing cross-chain technologies, while facilitating data and asset exchange between different blockchains to some extent, have exposed issues such as insufficient security, low efficiency, and inconsistent standards. Consequently, these issues give rise to significant obstacles in terms of both scalability and seamless communication among blockchains within a multi-chain framework. To address this, this paper proposes an efficient method for cross-chain interaction in a multi-chain environment. Building upon the traditional sidechain model, this method employs smart contracts and hash time-locked contracts (HTLCs) to design a cross-chain interaction scheme. This approach decentralizes the execution of locking, verifying, and unlocking stages in cross-chain transactions, effectively avoiding centralization risks associated with third-party entities in the process. It also greatly enhances the efficiency of fund transfers between the main chain and sidechains, while ensuring the security of cross-chain transactions to some extent. Additionally, this paper innovatively proposes a cross-chain data interaction strategy. Through smart contracts on the main chain, data from sidechains can be uploaded, verified, and stored on the main chain, achieving convenient and efficient cross-chain data sharing. The contribution of this paper is the development of a decentralized protocol that coordinates the execution of cross-chain interactions without the need to trust external parties, thereby reducing the risk of centralization and enhancing security. Experimental results validate the effectiveness of our solution in increasing transaction security and efficiency, with significant improvements over existing models. Our experiments emphasize the system's ability to handle a variety of transaction scenarios with improved throughput and reduced latency, highlighting the practical applicability and scalability of our approach.

Structural insights into human organic cation transporter 1 transport and inhibition.

The human organic cation transporter 1 (hOCT1), also known as SLC22A1, is integral to hepatic uptake of structurally diversified endogenous and exogenous organic cations, influencing both metabolism and drug pharmacokinetics. hOCT1 has been implicated in the therapeutic dynamics of many drugs, making interactions with hOCT1 a key consideration in novel drug development and drug-drug interactions. Notably, metformin, the frontline medication for type 2 diabetes, is a prominent hOCT1 substrate. Conversely, hOCT1 can be inhibited by agents such as spironolactone, a steroid analog inhibitor of the aldosterone receptor, necessitating a deep understanding of hOCT1-drug interactions in the development of new pharmacological treatments. Despite extensive study, specifics of hOCT1 transport and inhibition mechanisms remain elusive at the molecular level. Here, we present cryo-electron microscopy structures of the hOCT1-metformin complex in three distinct conformational states - outward open, outward occluded, and inward occluded as well as substrate-free hOCT1 in both partially and fully open states. We also present hOCT1 in complex with spironolactone in both outward and inward facing conformations. These structures provide atomic-level insights into the dynamic metformin transfer process via hOCT1 and the mechanism by which spironolactone inhibits it. Additionally, we identify a 'YER' motif critical for the conformational flexibility of hOCT1 and likely other SLC22 family transporters. Our findings significantly advance the understanding of hOCT1 molecular function and offer a foundational framework for the design of new therapeutic agents targeting this transporter.

MCT1-governed pyruvate metabolism is essential for antibody class-switch recombination through H3K27 acetylation.

Monocarboxylate transporter 1 (MCT1) exhibits essential roles in cellular metabolism and energy supply. Although MCT1 is highly expressed in activated B cells, it is not clear how MCT1-governed monocarboxylates transportation is functionally coupled to antibody production during the glucose metabolism. Here, we report that B cell-lineage deficiency of MCT1 significantly influences the class-switch recombination (CSR), rendering impaired IgG antibody responses in Mct1f/fMb1Cre mice after immunization. Metabolic flux reveals that glucose metabolism is significantly reprogrammed from glycolysis to oxidative phosphorylation in Mct1-deficient B cells upon activation. Consistently, activation-induced cytidine deaminase (AID), is severely suppressed in Mct1-deficient B cells due to the decreased level of pyruvate metabolite. Mechanistically, MCT1 is required to maintain the optimal concentration of pyruvate to secure the sufficient acetylation of H3K27 for the elevated transcription of AID in activated B cells. Clinically, we found that MCT1 expression levels are significantly upregulated in systemic lupus erythematosus patients, and Mct1 deficiency can alleviate the symptoms of bm12-induced murine lupus model. Collectively, these results demonstrate that MCT1-mediated pyruvate metabolism is required for IgG antibody CSR through an epigenetic dependent AID transcription, revealing MCT1 as a potential target for vaccine development and SLE disease treatment.

Experience with 2 years' intervention to progressively reduce salt supply to kitchens in elderly care facilities-challenges and further research: post hoc analysis of the DECIDE-Salt randomized clinical trial.

BACKGROUND: Progressive reduction of sodium intake is an attractive approach for addressing excessive salt intake, but evidence for this strategy in real practice is limited. We aimed to determine the feasibility, effectiveness, and safety of a progressive sodium intake reduction intervention in real-world setting. METHODS: We randomized 48 residential elderly care facilities in China, with 1612 participants aged 55 years and older, to either progressive reduction (PR, 24 facilities) or no reduction (NR, 24 facilities) of the supply of study salt to the kitchens of these facilities for 2 years. The primary efficacy outcome was systolic blood pressure (SBP) at any scheduled follow-up visit. Secondary efficacy outcomes included diastolic blood pressure (DBP) at any scheduled follow-up visit, and major adverse cardiovascular events (comprising non-fatal stroke, non-fatal myocardial infarction, hospitalized non-fatal heart failure, or vascular death) and total mortality. The perception of food saltiness, the addition of out-of-study salt in meals, and 24-h urinary sodium excretion were used as process indicators. RESULTS: Pre-specified analysis per randomization found no effect of the intervention on the 2-year overall mean systolic and diastolic blood pressure (SBP, DBP) and any other outcomes. However, post hoc analysis showed that the intervention effect on blood pressure varied over multiple follow-up visits (p for interaction < 0.046) and presented favorable differences at the 24-month visit (SBP = - 3.0 mmHg, 95%CI = - 5.6, - 0.5; p = 0.020; DBP = - 2.0 mmHg, 95%CI - 3.4, - 0.63; p = 0.004). The effect on 24-h sodium was non-significant (- 8.4 mmol, 95%CI = - 21.8 to 4.9, p = 0.216), though fewer participants with NR than with PR reported food tasting bland (odds ratio 0.46; 95%CI 0.29 to 0.73; p = 0.001). Reporting of bland food taste and other process measures indicated that intervention delivery and adherence were not fully achieved as designed. CONCLUSIONS: The experience of this real-world study demonstrated that achieving acceptability and sustainability of the progressive sodium intake reduction strategy among older adults was challenging, but it has shown potential for effectiveness in these and potentially other residential settings if the lessons of DECIDE-Salt are applied in further studies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03290716).

Chonggu Granules Improve Cartilage Matrix Metabolism in Knee Osteoarthritis via the miR-148a-3p/Wnt/ß-Catenin Pathway.

Purpose: This study aims to explore the effect and underlying mechanism of Chonggu Granules (CGG) in knee osteoarthritis (KOA) in rats. Methods: A papain-induced KOA model was established in rats. The pathological alterations of extracellular matrix in rat cartilage tissues were observed through hematoxylin and eosin (H&E) staining, followed by Mankin score for quantitative scoring. The ultrastructure of cartilage extracellular matrix was examined under a transmission electron microscopy (TEM). ELISA was used to measure the levels of IL-6, TNF-α, and IL-1ß in rat serum. Immunofluorescence was performed for assessing the levels of MMP-3, MMP-13, and Col2al in rat cartilage. Western blot was used to identify the protein expressions of wnt1, GSK-3ß, ß-catenin, and Aggrecan in rat cartilage. The mRNA relative expressions of miR-148a-3p, wnt1, ß-catenin, and GSK-3ß in rat cartilage were detected by RT-PCR. Luciferase reporter gene was used to detect the target genes of miR-148a-3p. Results: CGG significantly improved articular cartilage tissue and extracellular matrix metabolism compared to the model group as indicated by H&E, Mankin score, and TEM data. Moreover, low, medium, and high doses of CGG reduced the levels of IL-6, TNF-α, IL-1ß, MMP-3, and MMP-13 in serum to varying degrees but increased the levels of Col2al and Aggrecan. Mechanistically, CGG targeted wnt1 by increasing the expression of miR-148a-3p in a dose-dependent manner, thereby downregulating the mRNA and protein expressions of ß-catenin in cartilage tissue and upregulating the mRNA and protein expressions of GSK-3ß. Conclusion: CGG may control the miR-148a-3p/wnt/ß-catenin signaling pathway to decrease the levels of its downstream target genes MMP-13 and MMP-3, increase the expressions of Col2al and Aggrecan, and downregulate the contents of inflammatory cytokines IL-6, TNF-α, and IL-1ß, thereby improving the metabolism of cartilage extracellular matrix and alleviating the degeneration of articular cartilage in KOA.

Case Report: Molecular and microenvironment change upon midostaurin treatment in mast cell leukemia at single-cell level.

Mast cell leukemia is a rare and aggressive disease, predominantly with KIT D816V mutation. With poor response to conventional poly-chemotherapy, mast cell leukemia responded to the midostaurin treatment with a 50% overall response rate (ORR), but complete remission rate is approximately 0%. Therefore, the potential mechanisms of midostaurin resistance and the exact impacts of midostaurin on both gene expression profile and mast cell leukemia microenvironment in vivo are essential for design tailored combination therapy targeting both the tumor cells and the tumor microenvironment. Here we report a 59-year-old male mast cell leukemia patient with KIT F522C mutation treated with midostaurin. Single-cell sequencing of peripheral blood and whole exome sequencing (WES) of bone marrow were performed before and 10 months after midostaurin treatment. In accordance with the clinical response, compared to the pretreatment aberration, the decline of mast cells and increase of T-, NK, B-cells in peripheral blood, and the decrease of the KIT F522C mutation burden in bone marrow were observed. Meanwhile, the emergence of RUNX1 mutation, upregulations of genes expression (RPS27A, RPS6, UBA52, RACK1) on tumor cells, and increased frequencies of T and NK cells with TIGIT, CTLA4, and LAG3 expression were observed after midostaurin treatment, predicting the disease progression of this patient. As far as we know, this is the first case reporting the clinical, immunological, and molecular changes in mast cell leukemia patients before and after midostaurin treatment, illustrating the in vivo mechanisms of midostaurin resistance in mast cell leukemia, providing important clues to develop a sequential option to circumvent tumor progression after targeting oncogene addiction and prolong patients' survival.

Multifunctional hybrid exosomes enhanced cancer chemo-immunotherapy by activating the STING pathway.

Due to the immunosuppressive tumor microenvironment (ITM) resulting from tumor-associated macrophages (TAMs) and regulatory T cells, immune checkpoint blockade and vaccine therapies often lead to an inadequate immune response. Recently, cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon gene (cGAS/STING)-mediated innate immunity has emerged as a promising cancer therapeutic, as STING pathway activation could promote dendritic cells (DCs) maturation and tumor-specific cytotoxic T lymphocyte (CTL) and natural killer (NK) cell infiltration. Herein, multifunctional hybrid exosomes for cGAS/STING activation are designed by fusing genetically engineered exosomes carrying CD47 derived from tumor cells with exosomes from M1 macrophages, which are further encapsulated with DNA-targeting agent (SN38) and STING-agonist (MnO2). The hybrid exosomes demonstrate great tumor-targeting capacity and prolong blood circulation time due to the surface decoration of CD47. At the tumor site, the hybrid exosomes induce TAMs polarization to the M1 phenotype and release SN38 to induce DNA damage and Mn2+ to stimulate cGAS/STING activation. Furthermore, the resulting multifunctional hybrid exosomes (SN/Mn@gHE) promote DCs maturation and facilitate CTL infiltration and NK cell recruitment to the tumor region, leading to significant anti-tumor and antimetastatic efficacy. Our study suggests a novel strategy to enhance cancer immunotherapy by activating the STING pathway and ameliorating ITM.

Pre-exposure prophylaxis uptake for high-risk men who have sex with men in China: a multi-city cross-sectional survey.

BACKGROUND: Pre-exposure prophylaxis (PrEP) is a proven biomedical strategy to prevent HIV transmission among men who have sex with men (MSM). Despite oral PrEP is safe and effective in MSM, the use of PrEP has been discouraging, especially in high-risk MSM. And there are no relevant studies showing the use of PrEP in high-risk MSM. The purpose of this study was to get the rate of PrEP use and the factors influencing PrEP use among high-risk MSM. METHODS: A cross-sectional study was conducted through an electronic questionnaire on the "i guardian Platform", and "snowballing" method was used to recruit MSM in six cities in China, including Beijing, Shenzhen, Chengdu, Changsha, Jinan and Nanjing in China, from January to April 2021. Univariate and multivariate logistic regression analysis were used to analyze the factors associated with the use of PrEP among high-risk MSM who had heard about PrEP. RESULTS: Among the 1865 high-risk MSM who had heard of PrEP, the rates of those who were willing to use PrEP, had knowledge awareness of PrEP, and had used PrEP were 96.7%, 24.7%, and 22.4%, respectively. Multivariate logistic regression analysis of PrEP use in high-risk MSM showed that more PrEP was used by those who were 26 years or older (OR = 1.86, 95%CI 1.17 ~ 2.99), had master degree or above (OR = 2.37, 95% CI 1.21 ~ 4.72), had unstable work (OR = 1.86, 95% CI 1.16 ~ 2.96), had tested five or more HIV times in the past year (OR = 3.09, 95% CI 1.65 ~ 6.04), had consulted PrEP (OR = 22.05, 95% CI 14.87 ~ 33.91) and had PrEP knowledge awareness (OR = 1.90, 95% CI 1.41 ~ 2.55) (P < 0.05). CONCLUSIONS: The rate of PrEP use in high-risk MSM was relatively low. PrEP was used more by high-risk MSM with unstable jobs, higher education, frequent HIV testing, and PrEP counseling. Public education on PrEP for MSM should continue to be enhanced to help them use PrEP in a timely and accurate manner.

Salt substitution and salt-supply restriction for lowering blood pressure in elderly care facilities: a cluster-randomized trial.

There is a paucity of high-quality evidence on the effectiveness and safety of salt reduction strategies, particularly for older people, who have the most to benefit but are at higher risk of adverse effects. Here, we conducted a clinical trial in which 48 residential elderly care facilities in China (1,612 participants including 1,230 men and 382 women, 55 years or older) were cluster-randomized using a 2 × 2 factorial design to provision of salt substitute (62.5% NaCl and 25% KCl) versus usual salt and to a progressively restricted versus usual supply of salt or salt substitute for 2 years. Salt substitute compared with usual salt lowered systolic blood pressure (-7.1 mmHg, 95% confidence interval (CI) -10.5 to -3.8), meeting the primary outcome of the trial, whereas restricted supply compared with usual supply of salt or salt substitute had no effect on systolic blood pressure. Salt substitute also lowered diastolic blood pressure (-1.9 mmHg, 95% CI -3.6 to -0.2) and resulted in fewer cardiovascular events (hazard ratio (HR) 0.60, 95% CI 0.38-0.96), but had no effect on total mortality (HR 0.84, 95% CI 0.63-1.13). From a safety standpoint, salt substitute increased mean serum potassium and led to more frequent biochemical hyperkalemia, but was not associated with adverse clinical outcomes. In contrast, salt restriction had no effect on any study outcome. The results of this trial indicate that use of salt substitute, but not efforts to restrict salt supply, may achieve blood pressure lowering and deliver health benefits to residents of elderly care facilities in China. Clinicaltrials.gov registration: NCT03290716.

Genome-wide characterization of aldehyde dehydrogenase gene family members in groundnut (Arachis hypogaea) and the analysis under saline-alkali stress.

Groundnut or peanut (Arachis hypogaea) is a legume crop. Its seeds are rich in protein and oil. Aldehyde dehydrogenase (ALDH, EC: 1.2.1.3) is an important enzyme involved in detoxification of aldehyde and cellular reactive oxygen species, as well as in attenuation of lipid peroxidation-meditated cellular toxicity under stress conditions. However, few studies have been identified and analyzed about ALDH members in Arachis hypogaea. In the present study, 71 members of the ALDH superfamily (AhALDH) were identified using the reference genome obtained from the Phytozome database. A systematic analysis of the evolutionary relationship, motif, gene structure, cis-acting elements, collinearity, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and expression patterns was conducted to understand the structure and function of AhALDHs. AhALDHs exhibited tissue-specific expression, and quantitative real-time PCR identified significant differences in the expression levels of AhALDH members under saline-alkali stress. The results revealed that some AhALDHs members could be involved in response to abiotic stress. Our findings on AhALDHs provide insights for further study.

Nickel-Catalyzed Sulfonylation of Aryl Bromides Enabled by Potassium Metabisulfite as a Uniquely Effective SO2 Surrogate.

The development and mechanistic investigation of a nickel-catalyzed sulfonylation of aryl bromides is disclosed. The reaction proceeds in good yields for a variety of substrates and utilizes an inexpensive, stench-free, inorganic sulfur salt (K2 S2 O5 ) as a uniquely effective SO2 surrogate. The active oxidative addition complex was synthesized, isolated, and fully characterized by a combination of NMR spectroscopy and X-ray crystallography analysis. The use of the isolated oxidative addition complex in both stoichiometric and catalytic reactions revealed that SO2 insertion occurs via dissolved SO2 , likely released upon thermal decomposition of K2 S2 O5 . Key to the success of the reaction is the role of K2 S2 O5 as a reservoir of SO2 that is slowly released, thus preventing catalyst poisoning.

Hepatic mitochondrial NAD + transporter SLC25A47 activates AMPKα mediating lipid metabolism and tumorigenesis.

BACKGROUND AIMS: SLC25A47 was initially identified as a mitochondrial HCC-downregulated carrier protein, but its physiological functions and transport substrates are unknown. We aimed to investigate the physiological role of SLC25A47 in hepatic metabolism. APPROACH RESULTS: In the treatment of hepatocytes with metformin, we found that metformin can transcriptionally activate the expression of Slc25a47 , which is required for AMP-activated protein kinase α (AMPKα) phosphorylation. Slc25a47 -deficient mice had increased hepatic lipid content, triglycerides, and cholesterol levels, and we found that Slc25a47 deficiency suppressed AMPKα phosphorylation and led to an increased accumulation of nuclear SREBPs, with elevated fatty acid and cholesterol biosynthetic activities. Conversely, when Slc25a47 was overexpressed in mouse liver, AMPKα was activated and resulted in the inhibition of lipogenesis. Moreover, using a diethylnitrosamine-induced mouse HCC model, we found that the deletion of Slc25a47 promoted HCC tumorigenesis and development through the activated mammalian target of rapamycin cascade. Employing homology modeling of SLC25A47 and virtual screening of the human metabolome database, we demonstrated that NAD + was an endogenous substrate for SLC25A47, and the activity of NAD + -dependent sirtuin 3 declined in Slc25a47 -deficient mice, followed by inactivation of AMPKα. CONCLUSIONS: Our findings reveal that SLC25A47, a hepatocyte-specific mitochondrial NAD + transporter, is one of the pharmacological targets of metformin and regulates lipid homeostasis through AMPKα, and may serve as a potential drug target for treating NAFLD and HCC.

Anesthetic Management of Patients With Kartagener Syndrome: A Systematic Review of 99 Cases.

KARTAGENER SYNDROME (KS) is characterized by the triad of chronic sinusitis, bronchiectasis, and situs inversus. The mirrored anatomy and respiratory infections in patients with KS patients pose great challenges for anesthetic management. The aim of this review is to summarize published cases with the hope of helping anesthesiologists perform anesthesia in patients with KS more safely. A comprehensive literature search for all cases of anesthetic management of KS patients was performed in Pubmed, EMBASE, CNKI, and Wanfang Database. The extracted data included age, sex, type of surgery, preoperative treatment, type of anesthesia, anesthetic agents, airway management, central venous catheterization, transesophageal echocardiogram, reversal of neuromuscular blockade, adverse events during the surgery, and postoperative complications. The study authors included 82 single-case reports, 3 case series, and 1 case cohort, with a total number of 99 patients. The most common surgical procedures were thoracic surgery (51.5%), which was followed by ear, nose, and throat surgery (16.5%), and general surgery (14.5%). The preoperative treatment of the patients was reported in only 20 patients, and included antibiotics, bronchodilators, steroids, chest physiotherapy, and postural drainage. General anesthesia was performed for 85.4% of the surgeries, and regional anesthesia was performed in 14.6% of the cases. For nonthoracic surgery, an endotracheal tube was the most commonly used airway device. For thoracic surgery, a double-lumen tube was the most commonly used airway device. The intraoperative process was uneventful in most patients, and most patients recovered smoothly in the postoperative course.

Surface programmed bacteria as photo-controlled NO generator for tumor immunological and gas therapy.

The use of bacteria as living vehicles has attracted increasing attentions in tumor therapy field. The combination of functional materials with bacteria dramatically facilitates the antitumor effect. Here, we presented a rationally designed living system formed by programmed Escherichia Coli MG1655 cells (Ec) and black phosphorus (BP) nanoparticles (NPs). The bacteria were genetically engineered to express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), via an outer membrane YiaT protein (Ec-T). The Ec-T cells were associated with BP NPs on their surface to acquire BP@Ec-T. The designed living system could transfer the photoelectrons produced by BP NPs after laser irradiation and triggered the reductive metabolism of nitrate to nitric oxide for the in situ release at tumor sites, facilitating the therapeutic efficacy and the polarization of tumor associated macrophages to M1 phenotype. Meanwhile, the generation of reactive oxygen species induced the immunogenic cell death to further improve the antitumor efficacy. Additionally, the living system enhanced the immunological effect by promoting the apoptosis of tumor cells, activating the effect of T lymphocytes and releasing the pro-inflammatory cytokines. The integration of BP NPs, MG1655 cells and TRAIL led to an effective tumor therapy. Our work established an approach for the multifunctional antitumor living therapy.

Auxin and CmAP1 regulate the reproductive development of axillary buds in Chinese chestnut (Castanea mollissima).

KEY MESSAGE: Auxin accumulation upregulates the expression of APETALA1 (CmAP1) and subsequently activates inflorescence primordium development in axillary buds of chestnut. The architecture of fruiting branches is a key determinant of chestnut yield. Normally, axillary buds at the top of mother fruiting branches develop into flowering shoots and bear fruits, and the lower axillary buds develop into vegetative shoots. Decapitation of the upper axillary buds induces the lower buds to develop into flowering shoots. How decapitation modulates the tradeoff between vegetative and reproductive development is unclear. We detected inflorescence primordia within both upper and lower axillary buds on mother fruiting branches. The level of the phytohormones 3-indoleacetic acid (IAA) and trans-zeatin (tZ) increased in the lower axillary buds in response to decapitation. Exogenous application of the synthetic analogues 1-naphthylacetic acid (NAA) or 6-benzyladenine (6-BA) blocked or promoted, respectively, the development of the inflorescence primordia in axillary buds. The transcript levels of the floral identity gene CmAP1 increased in axillary buds following decapitation. An auxin response element TGA-box is present in the CmAP1 promoter and influenced the CmAP1 promoter-driven expression of ß-glucuronidase (GUS) in floral organs in Arabidopsis, suggesting that CmAP1 is induced by auxin. We propose that decapitation releases axillary bud outgrowth from inhibition caused by apical dominance. During this process, decapitation-induced accumulation of auxin induces CmAP1 expression, subsequently promoting the reproductive development of axillary buds.

Tracing Sulfate Source and Transformation in the Groundwater of the Linhuan Coal Mining Area, Huaibei Coalfield, China.

Mining activities cause surface sulfate enrichment, which has negative impacts on human health and ecosystems. These high concentrations of sulfate may enter groundwater through the unsaturated zone (UZ), threatening groundwater quality. Therefore, we combined hydrochemical and dual isotopic analyses of sulfate in surface water, soil water and groundwater with evaluations of the UZ to identify the groundwater sulfate source and transformation in the coal mining area. Soil profile samples were collected near gangue heaps (UZ-1, UZ-2) and the mean sulfate concentrations of the UZ-1 profile and UZ-2 profile were 35.4 mg/L and 69.63 mg/L, respectively. The shallow groundwater sulfate was mainly from dissolution of evaporite, sulfide oxidation and sewage. Different sulfate contaminated areas showed different characteristics of sulfate sources. The sulfate source to groundwater near the coal gangue heaps was sulfide oxidation. The groundwater sulfate near the gangue heaps and industrial park compound contamination area was mainly derived from industrial and domestic sewage and sulfide oxidation. In addition, the role of bacterial sulfate reduction (BSR) in the groundwater was not obvious. This research result is of great significance for promoting the safe mining of coal resources and sustainable utilization of groundwater in the Huaibei coal mining area and other coal mining areas in China.

A hydrochemical and multi-isotopic study of groundwater sulfate origin and contribution in the coal mining area.

Coal mining cities are universally confronted with the degradation of groundwater quality, and the sulfate pollution of groundwater has become a widely studied environmental problem. In this study, we combined multi-isotope (δ34S, δ18O-SO42- and 87Sr/86Sr) approach with hydrochemical technique and a Bayesian mixed model to clarify sources and transformations and to quantitatively assess the contribution of sulfate from potential sources. The concentrations of SO42- in groundwater ranged from 7.7 mg/L to 172.9 mg/L, and the high-value areas were located in coal mining area and residential area. The total values of δ34S and δ18O-SO42- varied from 10.6‰ to 26.9‰ and 6.9‰ to 14.1‰, respectively, in the groundwater. Analyses of SO42- and Sr isotopes and water chemistry indicated that SO42- in groundwater originated from various sources, such as atmospheric precipitation, sulfide mineral oxidation, evaporite dissolution, sewage and mine drainage. The oxidation of pyrite and bacterial sulfate reduction (BSR) had no significant impact on the stable isotopes of groundwater. At the same time, the calculation results of the Bayesian mixed model showed that the sources of SO42- in groundwater mainly include evaporite dissolution in aquifer and mine drainage in the mixture of shallow and deep groundwater, with high contribution proportions of 39.8 ± 10.9% and 31.9 ± 5.7%, respectively, while the contributions of sewage (13.9 ± 8.5%), atmospheric precipitation (9.6 ± 8.6%) and the oxidation of sulfide (4.7 ± 3.3%) to SO42- were lower. The research results revealed the source of SO42- pollution in shallow groundwater in the coal mine area and provided an important scientific basis for the effective management and protection of groundwater resources.