Chemical characteristics and sources apportionment of volatile organic compounds in the primary urban area of Shijiazhuang, North China Plain.

VOCs (Volatile organic compounds) exert a vital role in ozone and secondary organic aerosol production, necessitating investigations into their concentration, chemical characteristics, and source apportionment for the effective implementation of measures aimed at preventing and controlling atmospheric pollution. From July to October 2020, online monitoring was conducted in the main urban area of Shijiazhuang to collect data on VOCs and analyze their concentrations and reactivity. Additionally, the PMF (positive matrix factorization) method was utilized to identify the VOCs sources. Results indicated that the TVOCs (total VOCs) concentration was (96.7 ± 63.4 µg/m3), with alkanes exhibiting the highest concentration of (36.1 ± 26.4 µg/m3), followed by OVOCs (16.4 ± 14.4 µg/m3). The key active components were alkenes and aromatics, among which xylene, propylene, toluene, propionaldehyde, acetaldehyde, ethylene, and styrene played crucial roles as reactive species. The sources derived from PMF analysis encompassed vehicle emissions, solvent and coating sources, combustion sources, industrial emissions sources, as well as plant sources, the contribution of which were 37.80%, 27.93%, 16.57%, 15.24%, and 2.46%, respectively. Hence, reducing vehicular exhaust emissions and encouraging neighboring industries to adopt low-volatile organic solvents and coatings should be prioritized to mitigate VOCs levels.

[Guidelines for construction of traditional Chinese medicine pharmacovigilance system in medical institutions].

The group standard Guidelines for construction of traditional Chinese medicine(TCM) pharmacovigilance system in medical institutions, managed by Chinese Association of Chinese Medicine and led by the Institute of Basic Research in Clinical Medicine,China Academy of Chinese Medical Sciences and Dongfang Hospital of Beijing University of Chinese Medicine, was announced on National Group Standard Information Platform on January 16, 2024, with the standard number T/CACM 1563. 2-2024. According to EU pharmacovigilance regulations and the second-level guidance principles of International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use(ICH), the unique characteristics of TCM were fully considered, and the relevant systems and procedures for constructing TCM pharmacovigilance systems in medical institutions were clearly defined. This included establishing TCM pharmacovigilance information platforms, arranging staff, formulating various regulations, and monitoring adverse reactions of TCM(including TCM decoction pieces, granules, Chinese patent medicines, in-hospital preparations, and pre-marketed Chinese patent medicines). It aimed to develop a TCM pharmacovigilance system in medical institutions that was tailored to the characteristics of TCM. The system could be appropriately adjusted according to the scope of practice and actual circumstances of medical institutions at different levels. This will enhance the implementation of TCM pharmacovigilance work and safeguard medication safety. The group standard underwent multiple rounds of consultations with internal and external experts and has ultimately evolved into a guiding document applicable to medical institutions and related entities engaged in pharmacovigilance activities.

[Pharmacovigilance guidelines for clinical application of oral Chinese patent medicines].

Oral Chinese patent medicine is the essence of effective prescriptions created and summarized by Chinese medical scientists through thousands of years of medical practice. It is portable and convenient, with an obvious curative effect and other characteristics. However, at present, oral Chinese patent medicine is rich in dosage forms, various in types, complex in mechanism of action, and broad in clinical positioning. In clinical application, there are often cases of drug use without reference to instructions,repeated drug use, and prolonged drug use, which highlights safety problems such as adverse reactions and hepatorenal toxicity. Oral Chinese patent medicine pharmacovigilance is facing challenges. World Health Organization(WHO) has issued the WHO guidelines on safety monitoring of herbal medicines in pharmacovigilance systems, and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use(ICH) has issued the ICH E2 pharmacovigilance guidelines. The United States has issued the Pharmacovigilance management standards and pharmacoepidemiological assessment guidelines, and the European Union has issued the Guidelines on good pharmacovigilance practices. Japan, South Korea, and other countries in the Asia Pacific region have established their own pharmacovigilance systems, but currently, there are no pharmacovigilance guidelines related to oral Chinese patent medicine in China. Therefore, experts from many disciplines and fields in China were invited to jointly develop the Pharmacovigilance guidelines for clinical application of oral Chinese patent medicines, which aims to develop pharmacovigilance guidelines for clinical application that are consistent with China's national conditions and highlight the characteristics of oral Chinese patent medicine, and provide guidance for clinically safe and rational drug application in medical institutions.

[Pharmacovigilance guidelines of Chinese patent medicines].

Drug administration law of the People's Republic of China(2019 revised edition), which came into effect on December 1, 2019, proposed that " the state shall establish a pharmacovigilance system". Pharmacovigilance work of Chinese patent medicines is more difficult, and it is necessary to carry out Pharmacovigilance activities that are in line with the characteristics of Chinese patent medicines. Pharmacovigilance guidelines of Chinese patent medicines(T/CACM 1563. 1-2024), based on the principles of Drug Administration Law of the People's Republic of China(2019 revised edition) and Pharmacovigilance quality management standards(No. 65 of 2021) of the National Medical Products Administration, draws on the EU Pharmacovigilance regulation and the secondary guidelines of International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use(ICH), and it is drafted in accordance with the provisions of Guidelines for standardization work part 1: structure and drafting rules of standardization documents(GB/T1. 1-2020) based on the characteristics of Chinese patent medicines. It serves as a general document for a series of pharmacovigilance guidelines of Chinese patent medicines, such as Guidelines for construction of traditional Chinese medicine pharmacovigilance system in medical institutions(T/CACM 1563. 2-2024), Pharmacovigilance guidelines for clinical application of oral Chinese patent medicines(T/CACM 1563. 3-2024), Pharmacovigilance guidelines for clinical application of traditional Chinese medicine injections(T/CACM 1563. 4-2024), Pharmacovigilance guidelines for clinical application of Chinese patent medicines for external use(T/CACM 1563. 5-2024), and Pharmacovigilance guidelines for clinical application of Chinese patent medicines for mucosal administration(T/CACM 1563. 6-2024), including four major elements of pharmacovigilance monitoring and reporting of Chinese patent medicines, signal identification, risk evaluation, and risk control, as well as pharmacovigilance activities for Chinese patent medicines, ensuring the safety of public drug use.

[Pharmacovigilance guidelines for clinical application of Chinese patent medicines for mucosal administration].

The group standard Pharmacovigilance guidelines for clinical application of Chinese patent medicines for mucosal administration was released on January 16, 2024, on the national group standards information platform by the Institute of Basic Research in Clinical Medicine of China Academy of Chinese Medical Sciences and School and Hospital of Stomatology of Peking University, under the centralized management by the China Association of Chinese Medicine. The standard number is T/CACM 1563.6-2024. It aims to propose key elements and specify technical methods for safety monitoring and reporting, signal identification, risk assessment, and risk control based on the Drug administration law of the People's Republic of China(revised in 2019), which establishes normative pharmacovigilance guideline of Chinese patent medicine for mucosal administration that is in line with the characteristics of traditional Chinese Medicine(TCM) based on the pharmacovigilance content for clinical application of Chinese patent medicine for mucosal administration. The group standard has been discussed by internal and external experts through multiple rounds of consultation. It serves as a guiding document for stakeholders involved in pharmacovigilance activities, including pharmaceutical license holders, drug manufacturers, medical institutions, research institutes, and pharmaceutical trading enterprises.

SGLT2 inhibitors ameliorate NAFLD in mice via downregulating PFKFB3, suppressing glycolysis and modulating macrophage polarization.

Sodium-glucose co-transporter 2 (SGLT2) inhibitor (SGLT2i) is a novel class of anti-diabetic drug, which has displayed a promising benefit for non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the protective effects of SGLT2i against NAFLD and the underlying mechanisms. The db/db mice and western diet-induced NAFLD mice were treated with dapagliflozin (1 mg·kg-1·d-1, i.g.) or canagliflozin (10 mg·kg-1·d-1, i.g.) for 8 weeks. We showed that the SGLT2i significantly improved NAFLD-associated metabolic indexes, and attenuated hepatic steatosis and fibrosis. Notably, SGLT2i reduced the levels of pro-inflammatory cytokines and chemokines, downregulated M1 macrophage marker expression and upregulated M2 macrophage marker expression in liver tissues. In cultured mouse bone marrow-derived macrophages and human peripheral blood mononuclear cell-derived macrophages, the SGLT2i (10, 20 and 40 µmol/L) significantly promoted macrophage polarization from M1 to M2 phenotype. RNA sequencing, Seahorse analysis and liquid chromatography-tandem mass spectrometry analysis revealed that the SGLT2i suppressed glycolysis and triggered metabolic reprogramming in macrophages. By using genetic manipulation and pharmacological inhibition, we identified that the SGLT2i targeted PFKFB3, a key enzyme of glycolysis, to modulate the macrophage polarization of M1 to M2 phenotype. Using a co-culture of macrophages with hepatocytes, we demonstrated that the SGLT2i inhibited lipogenesis in hepatocytes via crosstalk with macrophages. In conclusion, this study highlights a potential therapeutic application for repurposing SGLT2i and identifying a potential target PFKFB3 for NAFLD treatment.

Diverse BCR usage and T cell activation induced by different COVID-19 sequential vaccinations.

Limited knowledge is available on the differences in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specific antibody breadth and T cell differentiation among different COVID-19 sequential vaccination strategies. In this study, we compared the immunogenicity of the third different dose of COVID-19 vaccines, such as mRNA (I-I-M), adenoviral vector (I-I-A), and recombinant protein (I-I-R) vaccines, in terms of the magnitude and breadth of antibody response and differentiation of SARS-CoV-2-specific T and B cells. These studies were performed in the same clinical trial, and the samples were assessed in the same laboratory. IGHV1-69, IGHV3-9, and IGHV4-34 were the dominant B cell receptor (BCR) usages of the I-I-M, I-I-A, and I-I-R groups, respectively; the RBD+ B cell activation capacities were comparable. Additionally, the I-I-R group was characterized by higher numbers of regulatory T cells, circulating T follicular helper cells (cTFH) - cTFH1 (CXRC3+CCR6-), cTFH1-17 (CXRC3+CCR6+), cTFH17 (CXRC3-CCR6+), and cTFH-CM (CD45RA-CCR7+), and lower SMNE+ T cell proliferative capacity than the other two groups, whereas I-I-A showed a higher proportion and number of virus-specific CD4+ T cells than I-I-R, as determined in ex vivo experiments. Our data confirmed different SARS-CoV-2-specific antibody profiles among the three different vaccination strategies and also provided insights regarding BCR usage and T/B cell activation and differentiation, which will guide a better selection of vaccination strategies in the future. IMPORTANCE: Using the same laboratory test to avoid unnecessary interference due to cohort ethnicity, and experimental and statistical errors, we have compared the T/B cell immune response in the same cohort sequential vaccinated by different types of COVID-19 vaccine. We found that different sequential vaccinations can induce different dominant BCR usage with no significant neutralizing titers and RBD+ B-cell phenotype. Recombinant protein vaccine can induce higher numbers of regulatory T cells, circulating TFH (CTFH)1, CTFH17, and CTFH-CM, and lower SMNE+ T-cell proliferative capacity than the other two groups, whereas I-I-A showed higher proportion and number of virus-specific CD4+ T cells than I-I-R. Overall, our study provides a deep insight about the source of differences in immune protection of different types of COVID-19 vaccines, which further improves our understanding of the mechanisms underlying the immune response to SARS-CoV-2.

CpG Island Definition and Methylation Mapping of the T2T-YAO Genome.

Precisely defining and mapping all cytosine (C) positions and their clusters, known as CpG islands (CGIs), as well as their methylation status, are pivotal for genome-wide epigenetic studies, especially when population-centric reference genomes are ready for timely application. Here, we first align the two high-quality reference genomes, T2T-YAO and T2T-CHM13, from different ethnic backgrounds in a base-by-base fashion and compute their genome-wide density-defined and position-defined CGIs. Second, by mapping some representative genome-wide methylation data from selected organs onto the two genomes, we find that there are about 4.7%-5.8% sequence divergency of variable categories depending on quality cutoffs. Genes among the divergent sequences are mostly associated with neurological functions. Moreover, CGIs associated with the divergent sequences are significantly different with respect to CpG density and observed CpG/expected CpG (O/E) ratio between the two genomes. Finally, we find that the T2T-YAO genome not only has a greater CpG coverage than that of the T2T-CHM13 genome when whole-genome bisulfite sequencing (WGBS) data from the European and American populations are mapped to each reference, but also shows more hyper-methylated CpG sites as compared to the T2T-CHM13 genome. Our study suggests that future genome-wide epigenetic studies of the Chinese populations rely on both acquisition of high-quality methylation data and subsequent precision CGI mapping based on the Chinese T2T reference.

Tumor targeting peptide TMTP1 modified Antigen capture Nano-vaccine combined with chemotherapy and PD-L1 blockade effectively inhibits growth of ovarian cancer.

The mortality of ovarian cancer (OC) has long been the highest among gynecological malignancies. Although OC is considered to be an immunogenic tumor, the effect of immunotherapy is not satisfactory. The immunosuppressive microenvironment is one reason for this, and the absence of recognized effective antigens for vaccines is another. Chemotherapy, as one of the most commonly used treatment for OC, can produce chemotherapy-associated antigens (CAAs) during treatment and show the effect of in situ vaccine. Herein, we designed an antigen capture nano-vaccine NP-TP1@M-M with tumor targeting peptide TMTP1 and dendritic cell (DC) receptor mannose assembled on the surface and adjuvant monophosphoryl lipid A (MPLA) encapsulated in the core of poly (D, L-lactide-co-glycolide) (PLGA) nanoparticles. PLGA itself possessed the ability of antigen capture. TMTP1 was a tumor-homing peptide screened by our research team, which held extensive and excellent tumor targeting ability. After these modifications, NP-TP1@M-M could capture and enrich more tumor-specific antigens after chemotherapy, stimulate DC maturation, activate the adaptive immunity and combined with immune checkpoint blockade to maximize the release of the body's immune potential, providing an eutherapeutic strategy for the treatment of OC.

A Nanoconfined FeCo2O4-Embedded Ceramic Membrane Regulates Electron Transfer in Peroxymonosulfate Activation to Selectively Generate Singlet Oxygen for Water Decontamination.

Peroxymonosulfate (PMS)-based advanced oxidation processes (AOPs), as a promising technology for water decontamination, are constrained by low reaction kinetics due to limited reaction selectivity and mass transfer. Herein, we designed a nanoconfined FeCo2O4-embedded ceramic membrane (FeCo2O4-CM) under flow-through pattern for PMS activation. Confining PMS and FeCo2O4 within nanochannels (3.0-4.7 nm) enhanced adsorption interactions (-7.84 eV vs -2.20 eV), thus boosting mass transfer. Nanoconfinement effect regulated electron transfer pathways from PMS to FeCo2O4-CM by modulating the active site transformation to ≡Co(III) in nanoconfined FeCo2O4-CM, enabling selectively generating 1O2. The primary role of 1O2 in the nanoconfined system was confirmed by kinetic solvent isotope experiments and indicative anthracene endoperoxide (DPAO2). The system enabled 100% removal of atrazine (ATZ) within a hydraulic retention time of 2.124 ms, demonstrating a rate constant over 5 orders of magnitude higher than the nonconfined system (3.50 × 103 s-1 vs 0.42 min-1). It also exhibited strong resilience to pH variations (3.3-9.0) and coexisting substances, demonstrating excellent stability indicated by consistent 100% ATZ removal for 14 days. This study sheds light on regulating electron transfer pathways to selectively generate 1O2 through the nanoconfinement effect, boosting the practical application of PMS-based AOPs in environmental remediation and potentially applying them to various other AOPs.

(Phosphino)(stannyl)carbene.

The synthesis of a (phosphino)(stannyl)carbene is documented. The combination of phosphino and stannyl substituents imparts a highly ambiphilic nature to this carbene, enabling reactions with cyanide, isocyanide, and carbon monoxide. This leads to rare stannylketenimines and a stannylketene.

Human-induced pluripotent stem cell-derived hepatocyte platform in modeling of SARS-CoV-2 infection.

Background and Aim: Currently, SARS-CoV-2 is still spreading rapidly and globally. A large proportion of patients with COVID-19 developed liver injuries. The human-induced pluripotent stem cell (iPSC)-derived hepatocytes recapitulate primary human hepatocytes and have been widely used in studies of liver diseases. Methods: To explore the susceptibility of hepatocytes to SARS-CoV-2, we differentiated iPSCs to functional hepatocytes and tried infecting them with different MOI (1, 0.1, 0.01) of SARS-CoV-2. Results: The iPSC-derived hepatocytes are highly susceptible to virus infection, even at 0.01 MOI. Other than the ancestral strain, iHeps also support the replication of SARS-CoV-2 variants including alpha, beta, theta, and delta. More interestingly, the ACE2 expression significantly upregulated after infection, suggesting a vicious cycle between virus infection and liver injury. Conclusions: The iPSC-derived hepatocytes can support the replication of SARS-CoV-2, and this platform could be used to investigate the SARS-CoV-2 hepatotropism and hepatic pathogenic mechanisms.

Pioglitazone alleviates lacrimal gland impairments induced by high-fat diet by suppressing M1 polarization.

A high-fat diet (HFD) contributes to the pathogenesis of various inflammatory and metabolic diseases. Previous research confirms that under HFD conditions, the extraorbital lacrimal glands (ELGs) can be impaired, with significant infiltration of pro-inflammatory macrophages (Mps). However, the relationship between HFD and Mps polarization in the ELGs remains unexplored. We first identified and validated the differential expression of PPAR-γ in murine ELGs fed ND and HFD through RNA sequencing. Tear secretion was measured using the Schirmer test. Lipid droplet deposition within the ELGs was observed through Oil Red O staining and transmission electron microscopy. Mps phenotypes were determined through quantitative RT-PCR, immunofluorescence, and flow cytometric analysis. An in vitro high-fat culture system for Mps was established using palmitic acid (PA), with supernatants collected for co-culture with lacrimal gland acinar cells. Gene expression was determined through ELISA, immunofluorescence, immunohistochemistry, quantitative RT-PCR, and Western blot analysis. Pioglitazone reduced M1-predominant infiltration induced by HFD by increasing PPAR-γ levels in ELGs, thereby alleviating lipid deposition and enhancing tear secretion. In vitro tests indicated that PPAR-γ agonist shifted Mps from M1-predominant to M2-predominant phenotype in PA-induced Mps, reducing lipid synthesis in LGACs and promoting lipid catabolism, thus alleviating lipid metabolic disorders within ELGs. Conversely, the PPAR-γ antagonist induced opposite effects. In summary, the lacrimal gland is highly sensitive to high-fat and lipid metabolic disorders. Downregulation of PPAR-γ expression in ELGs induces Mps polarization toward predominantly M1 phenotype, leading to lipid metabolic disorder and inflammatory responses via the NF-κb/ERK/JNK/P38 pathway.

A crystalline stannyne.

The synthesis of heteronuclear alkyne analogues incorporating heavier group 14 elements (R1-C≡E-R2, E = Si, Ge, Sn, Pb) has posed a long-standing challenge. Neutral silynes (R1-C≡Si(L)-R2) and germynes (R1-C≡Ge(L)-R2) stabilized by a Lewis base have achieved sufficient stability for structural characterization at low temperatures. Here we show the isolation of a base-free stannyne (R1-C≡Sn-R2) at room temperature, achieved through the strategic use of a bulky cyclic phosphino ligand in combination with a bulky terphenyl substituent. Despite an allenic structure with strong delocalization of π-electrons, this compound exhibits adjacent ambiphilic carbon and tin centres, forming a carbon-tin multiple bond with ionic character. The stannyne demonstrates reactivity similar to carbenes or stannylenes, reacting with 1-adamantyl isocyanide and 2,3-dimethyl-1,3-butadiene. Additionally, its carbon-tin bond can be saturated by Et3N·HCl or cleaved by isopropyl isocyanate.

Ocular biometric characteristics of Han ethnicity in Tianjin and Uyghur ethnicity in Xinjiang undergoing cataract surgery.

AIM: To analyze and compare the differences among ocular biometric parameters in Han and Uyghur populations undergoing cataract surgery. METHODS: In this hospital-based prospective study, 410 patients undergoing cataract surgery (226 Han patients in Tianjin and 184 Uyghur patients in Xinjiang) were enrolled. The differences in axial length (AL), anterior chamber depth (ACD), keratometry [steep K (Ks) and flat K (Kf)], and corneal astigmatism (CA) measured using IOL Master 700 were compared between Han and Uyghur patients. RESULTS: The average age of Han patients was higher than that of Uyghur patients (70.22±8.54 vs 63.04±9.56y, P<0.001). After adjusting for age factors, Han patients had longer AL (23.51±1.05 vs 22.86±0.92 mm, P<0.001), deeper ACD (3.06±0.44 vs 2.97±0.37 mm, P=0.001), greater Kf (43.95±1.40 vs 43.42±1.69 D, P=0.001), steeper Ks (45.00±1.47 vs 44.26±1.71 D, P=0.001), and higher CA (1.04±0.68 vs 0.79±0.65, P=0.025) than Uyghur patients. Intra-ethnic male patients had longer AL, deeper ACD, and lower keratometry than female patients; however, CA between the sexes was almost similar. In the correlation analysis, we observed a positive correlation between AL and ACD in patients of both ethnicities (rHan =0.48, rUyghur =0.44, P<0.001), while AL was negatively correlated with Kf (rHan =-0.42, rUyghur =-0.64, P<0.001) and Ks (rHan =-0.38, rUyghur =-0.66, P<0.001). Additionally, Kf was positively correlated with Ks (rHan =0.89, rUyghur =0.93, P<0.001). CONCLUSION: There are differences in ocular biometric parameters between individuals of Han ethnicity in Tianjin and those of Uyghur ethnicity in Xinjiang undergoing cataract surgery. These ethnic variances can enhance our understanding of ocular diseases related to these parameters and provide guidance for surgical procedures.

Crocin's role in modulating MMP2/TIMP1 and mitigating hypoxia-induced pulmonary hypertension in mice.

To explore the molecular pathogenesis of pulmonary arterial hypertension (PAH) and identify potential therapeutic targets, we performed transcriptome sequencing of lung tissue from mice with hypoxia-induced pulmonary hypertension. Our Gene Ontology analysis revealed that "extracellular matrix organization" ranked high in the biological process category, and matrix metallopeptidases (MMPs) and other proteases also played important roles in it. Moreover, compared with those in the normoxia group, we confirmed that MMPs expression was upregulated in the hypoxia group, while the hub gene Timp1 was downregulated. Crocin, a natural MMP inhibitor, was found to reduce inflammation, decrease MMPs levels, increase Timp1 expression levels, and attenuate hypoxia-induced pulmonary hypertension in mice. In addition, analysis of the cell distribution of MMPs and Timp1 in the human lung cell atlas using single-cell RNAseq datasets revealed that MMPs and Timp1 are mainly expressed in a population of fibroblasts. Moreover, in vitro experiments revealed that crocin significantly inhibited myofibroblast proliferation, migration, and extracellular matrix deposition. Furthermore, we demonstrated that crocin inhibited TGF-ß1-induced fibroblast activation and regulated the pulmonary arterial fibroblast MMP2/TIMP1 balance by inhibiting the TGF-ß1/Smad3 signaling pathway. In summary, our results indicate that crocin attenuates hypoxia-induced pulmonary hypertension in mice by inhibiting TGF-ß1-induced myofibroblast activation.

Multifunctional elastomeric composites based on 3D graphene porous materials.

3D graphene porous materials (3GPM), which have low density, large porosity, excellent compressibility, high conductivity, hold huge promise for a wide range of applications. Nevertheless, most 3GPM have brittle and weak network structures, which limits their widespread use. Therefore, the preparation of a robust and elastic graphene porous network is critical for the functionalization of 3GPM. Herein, the recent research of 3GPM with excellent mechanical properties are summarized and the focus is on the effect factors that affect the mechanical properties of 3GPM. Moreover, the applications of elastic 3GPM in various fields, such as adsorption, energy storage, solar steam generation, sensors, flexible electronics, and electromagnetic wave shielding are comprehensively reviewed. At last, the new challenges and perspective for fabrication and functionalization of robust and elastic 3GPM are outlined. It is expected that the perspective will inspire more new ideas in preparation and functionalization of 3GPM.

Positive feedback regulation between glycolysis and histone lactylation drives oncogenesis in pancreatic ductal adenocarcinoma.

BACKGROUND: Metabolic reprogramming and epigenetic alterations contribute to the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). Lactate-dependent histone modification is a new type of histone mark, which links glycolysis metabolite to the epigenetic process of lactylation. However, the role of histone lactylation in PDAC remains unclear. METHODS: The level of histone lactylation in PDAC was identified by western blot and immunohistochemistry, and its relationship with the overall survival was evaluated using a Kaplan-Meier survival plot. The participation of histone lactylation in the growth and progression of PDAC was confirmed through inhibition of histone lactylation by glycolysis inhibitors or lactate dehydrogenase A (LDHA) knockdown both in vitro and in vivo. The potential writers and erasers of histone lactylation in PDAC were identified by western blot and functional experiments. The potential target genes of H3K18 lactylation (H3K18la) were screened by CUT&Tag and RNA-seq analyses. The candidate target genes TTK protein kinase (TTK) and BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) were validated through ChIP-qPCR, RT-qPCR and western blot analyses. Next, the effects of these two genes in PDAC were confirmed by knockdown or overexpression. The interaction between TTK and LDHA was identified by Co-IP assay. RESULTS: Histone lactylation, especially H3K18la level was elevated in PDAC, and the high level of H3K18la was associated with poor prognosis. The suppression of glycolytic activity by different kinds of inhibitors or LDHA knockdown contributed to the anti-tumor effects of PDAC in vitro and in vivo. E1A binding protein p300 (P300) and histone deacetylase 2 were the potential writer and eraser of histone lactylation in PDAC cells, respectively. H3K18la was enriched at the promoters and activated the transcription of mitotic checkpoint regulators TTK and BUB1B. Interestingly, TTK and BUB1B could elevate the expression of P300 which in turn increased glycolysis. Moreover, TTK phosphorylated LDHA at tyrosine 239 (Y239) and activated LDHA, and subsequently upregulated lactate and H3K18la levels. CONCLUSIONS: The glycolysis-H3K18la-TTK/BUB1B positive feedback loop exacerbates dysfunction in PDAC. These findings delivered a new exploration and significant inter-relationship between lactate metabolic reprogramming and epigenetic regulation, which might pave the way toward novel lactylation treatment strategies in PDAC therapy.

Self-reporting electroswitchable colorimetric platform for smart ammonium recovery from wastewater.

Recovery of ammonium from wastewater represents a sustainable strategy within the context of global resource depletion, environmental pollution and carbon neutralization. The present study developed an advanced self-reporting electroswitchable colorimetric platform (SECP) to realize smart ammonium recovery based on the electrically stimulated transformation of Prussian blue/Prussian white (PB/PW) redox couple. The key to SECP was the selectivity of ammonium adsorption, sensitivity of desorption to electric signals and visualability of color change during switchable adsorption/desorption transformation. The results demonstrated the electrochemical intercalation-induced selective adsorption of NH4+ (selectivity coefficient of 3-19 versus other cations) and deintercalation-induced desorption on the PB-film electrode. At applied voltage of 1.2 V for 20 min, the negatively charged PB-film electrode achieved the maximum adsorption capacity of 3.2 mmol g-1. Reversing voltage to -0.2 V for 20 min resulted in desorption efficiency as high as 99%, indicating high adsorption/desorption reversibility and cyclic stability. The Fe(III)/Fe(II) redox dynamics were responsible for PB/PW transformation during reversible intercalation/deintercalation of NH4+. Based on the blue/transparence color change of PB/PW, the quantitative relationship was established between amounts of NH4+ adsorbed and extracted RGB values by multiple linear regression (R2 = 0.986, RMSE = 0.095). Then, the SECP was created upon the unique capability of real-time monitoring and feedback of color change of electrode to realize the automatic control of NH4+ adsorption/desorption. During five cycles of tests, the adsorption process consistently peaked at an average value of 3.15±0.04 mmol g-1, while desorption reliably approached the near-zero average of 0.06±0.04 mmol g-1. The average time of duration was 19.6±1.67 min for adsorption and 18.8±1.10 min for desorption, respectively. With electroswitchability, selectivity and self-reporting functionalities, the SECP represents a paradigm shift in smart ammonium recovery from wastewater, making wastewater treatment and resource recovery more efficient, more intelligent and more sustainable.