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N6-Methyladenosine (m6A) is the most prevalent internal modification of mammalian mRNAs. Recent studies have shown that m6A methyltransferases METTL3 and METTL14 play important roles in urothelial bladder carcinoma (BLCA). To provide a more comprehensive understanding of the m6A regulatory landscape in bladder cancer, we investigated the role of YTHDF2, a crucial m6A reader, in BLCA. YTHDF2 was frequently upregulated at both the RNA and protein level in BLCA. Functionally, YTHDF2 promoted the proliferation and tumor growth of BLCA cells in vitro and in vivo, respectively. Integrative RNA sequencing and m6A sequencing analyses identified RIG-I as a downstream target of YTHDF2. Mechanistically, YTHDF2 bound to the coding sequence of DDX58 mRNA, which encodes RIG-I, and mediated its degradation in an m6A-dependent manner. Knockdown of RIG-I inhibited apoptosis and promoted the proliferation of BLCA cells. Depleting RIG-I was also able to reverse the effects of YTHDF2 deficiency. YTHDF2-deficient BLCA cells implanted orthotopically in recipient mice activated an innate immune response and promoted recruitment of CD8+ T lymphocytes into the tumor bed and the urothelium. Moreover, YTHDF2 deficiency enhanced the efficacy of Bacillus Calmette-Guérin immunotherapy treatment. This study reveals that YTHDF2 acts as an oncogene in BLCA. YTHDF2 inhibits RIG-I to facilitate immune evasion, supporting testing YTHDF2 inhibition in combination with immunotherapy. Significance: YTHDF2 regulates RIG-I–mediated innate immune signaling to support bladder cancer progression, highlighting the functional importance of m6A modifications in bladder cancer and uncovering therapeutic opportunities to improve patient outcomes.

Traffic is becoming more and more developed today, and at the same time the problem of intersection congestion is becoming more and more serious. As a key traffic scene in urban network, signalized intersection is much more important and complex than other parts. Vehicles in the connected vehicles environment can carry out data interaction with multiple platforms such as background control center, which can effectively solve the problems of traffic congestion at intersections. Therefore, for signalized intersections in the connected vehicles environment, this paper summarizes the research results of its control methods. The paper first introduces the speed guidance method and optimized signal timing method respectively, then discusses the speed and timing collaborative optimization method combining the two above, and finally introduces a new idea of future intersection zoning control. This paper summarizes the update researches and the future research direction of intersection control in the connected vehicles environment.

Yujin Mei,1 Xue Yang,1 Yuqing Li,1 Xiaoyun Zhang,1 Jiaofeng Gui,1 Ying Wang,1 Wenyue Chen,1 Mingjia Chen,1 Changjun Liu,2 Lin Zhang3 1School of Nursing, Wannan Medical College, Wuhu City, Anhui Province, People’s Republic of China; 2School of Marxism, Jinzhou Medical University, Jinzhou City, Liaoning Province, People’s Republic of China; 3Department of Internal Medicine Nursing, Wannan Medical College, Wuhu City, Anhui Province, People’s Republic of ChinaCorrespondence: Lin Zhang, Email yaoran2008@163.comBackground: In China, diabetes has become a serious healthcare problem that plagues individuals and the government because of its high mortality rate and social burden, with type 2 diabetes mellitus (T2DM) accounting for the vast majority (about 90%) of cases. T2DM patients face a huge medication burden and it is imperative to find appropriate tools to assess the medication burden for patients. This study aimed to translate the original Diabetes Treatment Burden Questionnaire (DTBQ) into Chinese and assessed the reliability and validity of the DTBQ concerning the burden of medication treatment in patients with type 2 diabetes.Methods: A total of 329 T2DM patients were recruited to participate in the survey. The original version scale was first translated into Chinese using the backward and forward translation procedures. The internal consistency reliability of the scale was measured by the Cronbach alpha coefficient, the test-retest reliability, and the item-total correlation. The validity of the scale was assessed by the content validity index, exploratory factor analysis and confirmatory factor analysis.Results: The content validity index of the scale was 0.920. Cronbach alpha coefficient for the scale was 0.831. Exploratory factor analysis (EFA) supported a 15-item and 3-factor structure of the translated questionnaire. Confirmatory factor analysis (CFA) showed in the model fitness index, the chi-square degree of freedom was 3.575, the incremental fit index (IFI) was 0.917, the comparative fit index(CFI) was 0.916, the Tucker Lewis Index(TLI) was 0.900, all within acceptable limits. The retest reliability was 0.892, and the corrected item-total correlations for the items ranged from 0.293 to 0.729.Conclusion: Verification results showed that the Chinese version of the 15-item DTBQ had reliable reliability and validity. Therefore, it can be considered as an appropriate tool to assess the burden of drug treatment for patients with type 2 diabetes in China.Keywords: diabetes treatment burden questionnaire, T2DM, reliability, validity

Eastern China (EC) suffered an extreme drought with long-lasting duration and record-breaking intensity in late summer–autumn 2019. Our diagnosed results show that the central Pacific (CP) El Niño, in tandem with warm sea surface temperature anomalies (SSTAs) over the Kuroshio Extension (KE) region, induces the meridionally elongated cyclonic circulation anomalies stretching from the western North Pacific (WNP) to the Yellow Sea. Its western flank corresponds to overwhelming low-level northerly wind anomalies over EC, which result in deficient moisture and anomalous descent over EC and hence cause the extreme drought in 2019. To investigate the relative contributions of SSTAs over different regions, we performed sensitivity experiments, and analyzed the relationship between extreme drought like what occurred in 2019 (a 2019Drought-like event) and the SSTAs in CMIP6 historical simulations. Modeling evidences reveal that both warm SSTAs over the central equatorial Pacific and the KE region are indispensable for shaping the meridionally elongated cyclone anomaly. Specifically, the cyclone anomaly over the WNP induced by CP El Niño aligns with the cyclone anomaly over the Yellow Sea induced by the warm SSTAs over the KE region, merging into a meridionally stretched cyclone anomaly to the east of EC. Consequently, the northerly anomalies stretch across EC, leading to unfavorable atmospheric conditions and the rainfall deficit there. Projection results show that the occurrence probability of a 2019Drought-like event will increase by 20% (decrease by 40%–50%) under a high (medium-low) emission scenario compared to present-day climate, indicating the nonlinear response of extreme drought to different emission scenarios and the urgency of carbon emission reduction. Significance Statement An extreme drought hit the Eastern China (EC) region in 2019 and caused tremendous losses. This study proposed that both the 2019 CP El Niño and the warm SST anomalies over the Kuroshio Extension (KE) region induce the meridionally elongated circulation anomalies and the resultant extreme drought. We showed that the typical circulation anomalies induced by central Pacific (CP) El Niño cannot totally explain the meridionally elongated circulation anomalies in 2019. Our modeling evidences confirmed the indispensable role of warm SST anomalies over KE region in the 2019 extreme drought’s formation. The projection results show that extreme drought like that in 2019 will occur more (less) frequently under a high (medium-low) emission scenario compared to modern-day level, indicating the urgency of carbon emission reduction.

Stirring-promoted piezo-photocatalysis based on a three-dimensional foam architecture has great potential applications in wastewater treatment and water splitting. However, the detailed mechanism of stirring-promoted piezo-photocatalysis has not been quantitatively studied, and the utilization of visible light needs to be further improved. In this work, the high solar-driven piezo-photocatalytic ability of graphite carbon nitride (g-C

Biomimetics plays an important role in cancer treatment since it can prolong the circulation of nanoparticles, enhance their delivery and retention in target tissues, and reduce the systemic toxicity of drugs and their carriers. In this study, we developed a biomimetic nanosystem consisting of chemotherapeutic and immunotherapeutic agents wrapped in cell membranes. Specifically, the anti-tumor drug doxorubicin (DOX) was loaded into a bacterial-derived immunomodulatory agent (low molecular weight curdlan, lCUR), and the lCUR-DOX was further wrapped in the red blood cell membrane for camouflage and prolonged circulation. The successful preparation of the lCUR-DOX@RBC nanosystem was supported by various optical and morphological characterizations. In vitro studies indicated that the nanosystem can escape uptake by macrophages, inhibit the invasion of tumor cells, and reprogram M2 macrophages with an immunosuppressive phenotype into M1 macrophages with an immunopromoting phenotype via the MAPK signaling pathway while promoting the phagocytosis of macrophages. In vivo studies showed that the nanosystem effectively inhibits tumor growth in the A-375 tumor-bearing mouse model. Taken together, the above results support further development of the lCUR-DOX@RBC platform for cancer immunochemotherapy in clinical applications.

Sonosensitizers that can increase the concentration of reactive oxygen species (ROS) within a tumor microenvironment is a high priority for sonodynamic therapy (SDT). In this study, a functionalized, smart nanosonosensitizer based on Au-RuO

Herein, we designed and constructed functional upconversion nanoparticles (UCNPs@SiO2-ThS), which can not only inhibit the aggregation of Aβ42 monomers, but also disassemble Aβ42 fibrils under the irradiation of near-infrared (NIR) light.

Loading rate and height–diameter ratio are important factors affecting mechanical properties of materials. In this paper, the effects of the two factors on the stress–strain curves and section deformation characteristics of titanium alloy and aluminum alloy were compared by uniaxial compression tests. The gray correlation coefficient between compressive strength and loading rate, height–diameter ratio, and high compression ratio of the two alloys was calculated by using the gray correlation theory, and multiple regression models of compressive strength of the two alloys were established based on the least squares method. The results show that ( i) the gray correlation coefficient of the two alloys is greater than 0.6, indicating that loading rate and height–diameter ratio have obvious effects on the compressive strengths of aluminum alloy; ( ii) of loading rate and height–diameter ratio, loading rate has more significant effect on compressive strength; and ( iii) the correlation coefficient of the regression model of titanium alloy compressive strength is 0.9, which is higher than that of the corresponding model of aluminum alloy (0.65), indicating that the reliability of the regression model of titanium alloy is higher than that of aluminum alloy, and the established model can better predict the uniaxial compressive strength of titanium alloy.

Porphyromonas gingivalis is a keystone pathogen for periodontitis. The function of the GntR family transcription factor is poorly studied in P. gingivalis. Numerous processes govern bacterial growth. The survival and pathogenicity of P. gingivalis depend heavily on its capacity to acquire amino acids as nutritional sources. In this investigation, a GntR transcription factor, pg1007, was identified in P. gingivalis, the deletion of which significantly inhibited bacterial growth. The mutant strain also exhibited an increased extracellular activity of gingipains and acylpeptidyl oligopeptidase (AOP). Global gene expression profiling revealed that the expression levels of 59 genes were significantly altered in the Δpg1007 mutant, with an upregulation in gene expression for AOP, ABC transporters, and some membrane proteins. In addition, His-PG1007 protein was purified as a recombinant protein from Escherichia coli, and the conserved DNA sequence bound by it was determined using electrophoretic mobility shift assays and DNase I footprinting assays. Consequently, this study demonstrated that pg1007 is a crucial transcription factor in P. gingivalis and regulates the bacterial growth and activity of gingipains and AOP. These findings may enhance our understanding of the regulation of bacterial proliferation and protease activity in P. gingivalis.

Long non-coding RNA (lncRNA) play vital regulatory roles in various biological processes. Intestine is one of the most sensitive organs to environmental and homeostatic disruptions for fish. However, systematic profiles of lncRNAs in the intestine of teleost in responses to pathogen infections is still limited. Turbot (Scophthalmus maximus L.), an important commercial fish species in China, has been suffering with Vibrio anguillarum infection, resulted in dramatic economic loss. Hereinto, the intestinal tissues of turbot were sampled at 0 h, 2 h, 12 h, and 48 h following V. anguillarum infection. The histopathological analysis revealed that the pathological trauma was mainly present in intestinal tunica mucosal epithelium. After high-throughput sequencing and bioinformatic analysis, a total of 9722 lncRNAs and 21,194 mRNAs were obtained, and the average length and exon number of lncRNAs were both less than those of mRNAs. Among which, a set of 158 lncRNAs and 226 mRNAs were differentially expressed (DE-lncRNAs and DEGs) in turbot intestine at three time points, related to many immune-related genes such as complement, interleukin, chemokine, lysosome, and macrophage, indicating their potential critical roles in immune responses. In addition, 2803 and 1803 GO terms were enriched for DEGs and co-expressed target genes of DE-lncRNAs, respectively. Moreover, 127 and 50 KEGG pathways including cell adhesion molecules (CAMs), phagosome, JAK-STAT signaling pathway, cytokine-cytokine receptor interaction, and intestinal immune network for IgA production, were enriched for DEGs and co-expressed target genes of DE-lncRNAs, respectively. Finally, qRT-PCR was conducted to confirm the reliability of sequencing data. The present study will set the foundation for the future exploration of lncRNA functions in teleost in response to bacterial infection.

Mitochondrial dysfunction and oxidative damage represent important pathological mechanisms of myocardial ischemia-reperfusion injury (MI/RI). Searching for potential antioxidant agents to attenuate MI/RI is of great significance in clinic. Herein, gold-selenium core-shell nanostructures (AS-I/S NCs) with good near-infrared (NIR)-II photoacoustic imaging were designed for MI/RI treatment. The AS-I/S NCs after ischemic myocardium-targeted peptide (IMTP) and mitochondrial-targeted antioxidant peptide SS31 modification achieved cardiomyocytes-targeted cellular uptake and enhanced antioxidant ability and significantly inhibited oxygen-glucose deprivation-recovery (OGD/R)-induced cardiotoxicity of H9c2 cells by inhibiting the depletion of mitochondrial membrane potential (MMP) and restoring ATP synthase activity. Furthermore, the AS-I/S NCs after SS31 modification achieved mitochondria-targeted inhibition of reactive oxygen species (ROS) and subsequently attenuated oxidative damage in OGD/R-treated H9c2 cells by inhibition of apoptosis and oxidative damage, regulation of MAPKs and PI3K/AKT pathways. The

Developing smart fluorescent materials having very advanced levels, showing dynamic displays of encrypted messaging, remains a huge challenge. In this paper, we present a unique method based on combining a common photochromic molecule spiropyran (SP) with hydrogen-bonded organic frameworks (HOFs), which allows for reversible switching of SP in solid states and shows dynamic displays of encrypted information. With the irradiation time extended, the fluorescence emission undergo an evident transformation from yellow-green to orange to red, because of the fluorescence resonance energy transfer (FRET) process between the unique HOFs and merocyanine (MC) isomer. By doping with polydimethylsiloxane (PDMS), we obtained free-standing membranes with high flexibility and mechanical strength, which can be reversibly and repeatedly bent and folded at angles of90°. Notably, the comparison of fatigue resistance between SP2/PDMS (can be used for no more than 5 times) and SP2 ⊂ HOF2/PDMS (can be used for more than 100 times) further proved the importance of HOFs. This composite system has many advantages: (1) it has diverse dynamic fluorescence emission and visible colors regulated by ultraviolet radiation with high contrast and can be reversibly converted; (2) these changes in behavior can be achieved by simple UV illumination; and (3) compared with previous work, this work not only shows the dynamic fluorescence emission, but also shows the dynamic information during the decryption.

Turbot (Scophthalmus maximus) is an important cold-water economic fish. However, the production and development of turbot industry has been constantly hindered by the frequent occurrence of some diseases. Lacking full-length transcriptome for turbot limits immune gene discoveries and gene structures analysis. Therefore, we generated a full-length transcriptome using mixed immune-related tissues of turbot with PacBio Sequel platform. In this study, a total of 31.7 Gb high quality data were generated with the average subreads length of 2618 bp. According to the presence of 5' and 3' primers as well as poly (A) tails, FL (Full-length) and NFL (Non-full-length) isoforms were obtained. Meanwhile, we identified 32,003 non-redundant transcripts, 76.02% of which was novel isoforms of known genes. In addition, 12,176 alternative splicing (AS) events, 6614 polyadenylation (APA) events, 1905 transcription factors, and 2703 lncRNAs were identified. This work is a comprehensive report on the full-length transcriptome of immune-related tissues of turbot, and it also provides valuable molecular resources for future research on the adaptation mechanisms and functional genomics of turbot.

Mobile edge computing enables resource-limited edge clouds (ECs) in federation to help each other with resource-hungry yet delay-sensitive service requests. Contrary to common practice, we acknowledge that mobile services are heterogeneous and the limited storage resources of ECs allow only a subset of services to be placed at the same time. This paper presents a jointly optimized design of cooperative placement and scheduling framework, named JCPS, that pursues social cost minimization over time while ensuring diverse user demands. Our main contribution is a novel perspective on cost reduction by exploiting the spatial-temporal diversities in workload and resource cost among federated ECs. To build a practical edge cloud federation system, we have to consider two major challenges: user deadline preference and ECs strategic behaviors. We first formulate and solve the problem of spatially strategic optimization without deadline awareness, which is proved NP -hard. By leveraging user deadline tolerance, we develop a Lyapunov-based deadline-driven joint cooperative mechanism under the scenario where the workload and resource information of ECs are known for one-shot global cost minimization. The service priority imposed by deadline urgency drives time-critical placement and scheduling, which, combined with cooperative control, enables workloads migrated across different times and ECs.

Microstructure and magnetic properties were studied for the commercial Sm(CoFeCuZr)z magnets before and after post annealing treatment. The results show that the phases composition and orientation of the magnet do not change after post annealing treatment, but the substantial redistribution of Cu element within multiscale (the microscale crystal grain and the nanoscale cellular structure) had been observed simultaneously. In detail, as the Cu redistribution, the thickness of the Cu-rich Sm(Co,Cu)5 cell boundary becomes thinner, and the Cu concentration in the boundary increases sharply. The pinning field of domain walls and corresponding coercivity increases remarkably with slight remanence and maximum energy product loss, and the overall magnetic performance of (BH)max (MGOe)+Hcj (kOe) increases by 54.3% as a result. Moreover, the thermal stability of the magnet improves as well. On the other hand, Cu-lean phenomenon was observed along the grain boundary region, triggering to magnetic domain reversal process and slightly undermining the squareness of the demagnetization curve of the magnet.

Currently, as shown by large-scale research on two-dimensional materials in the field of nanoelectronics and catalysis, the construction of large-area two-dimensional materials is crucial for the development of devices and their application in photovoltaics, sensing, optoelectronics, and energy generation/storage. Here, using atmospheric-pressure chemical vapor deposition, we developed a method to regulate growth conditions according to the growth mechanism for WSe2 and MoSe2 materials. By accurately controlling the hydrogen flux within the range of 1 sccm and the distance between the precursor and the substrate, we obtained large-size films of single atomic layers with thicknesses of only about 1 nm. When growing the samples, we could not only obtain a 100 percent proportion of samples with the same shape, but the samples could also be glued into pieces of 700 μm and above in size, changing the shape and making it possible to reach the millimeter/submillimeter level visible to the naked eye. Our method is an effective method for the growth of large-area films with universal applicability.

Cutting heat and cutting vibration are important basic research topics in the field of machining. Many factors affect cutting heat and cutting vibration, and cutting heat and cutting vibration also affect each other. This paper mainly studied the coupling characteristics between cutting vibration and cutting heat from the perspective of energy power density. A measurement system was built to collect the time-domain signals of cutting temperature and three-dimensional cutting vibration. Through Stefan–Boltzmann's law, the cutting thermal power density represented by the cutting temperature was obtained. Frequency domain analysis dealing with the self-power spectrum density was carried out on the three-dimensional vibration acceleration, and the operation of reducing the vibration dimension was carried out by principal component analysis. Based on the particle swarm optimization algorithm, two coupling models between cutting heat and cutting vibration were established. The research showed that the coupling correlation coefficient between cutting heat and cutting vibration was above 0.6. The coupling characteristics of cutting heat and cutting vibration were strong, and the impact of cutting vibration on cutting heat was more significant. The conclusions provide theoretical guidance for studying the coupling characteristics of cutting heat and cutting vibration from the energy perspective.

Chemokines are a superfamily of structurally related cytokines, which exert essential roles in guiding cell migration in development, homeostasis, and immunity. CC and CXC chemokines are the two major subfamilies in teleost species. In this study, a total of seventeen CC and CXC chemokines, with inclusion of twelve CC and five CXC chemokines, were systematically identified from the turbot genome, making turbot the teleost harboring the least number of CC and CXC chemokines among all teleost species ever reported. Phylogeny, synteny, and genomic organization analyses were performed to annotate these genes, and multiple chemokine genes were identified in the turbot genome, due to the tandem duplications (CCL19 and CCL20), the whole genome duplications (CCL20, CCL25, and CXCL12), and the teleost-specific members (CCL34-36, CCL44, and CXCL18). In addition, chemokines were ubiquitously expressed in nine examined healthy tissues, with high expression levels observed in liver, gill, and spleen. Moreover, most chemokines were significantly differentially expressed in gill and spleen after Aeromonas salmonicida infection, and exhibited tissue-specific and time-dependent manner. Finally, protein-protein interaction network (PPI) analysis indicated that turbot chemokines interacted with a few immune-related genes such as interleukins, cathepsins, stats, and TLRs. These results should be valuable for comparative immunological studies and provide insights for further functional characterization of chemokines in teleost.

Background: Ovarian cancer (OVCA) has unique epigenetic alterations and defects in homologous recombination (HR). Despite initial sensitivity to platinum-based chemotherapy, HR dysfunctional tumors eventually acquire drug resistance. Fanconi anemia (FA) is characterized by bone marrow failure (BMF) and a reduced ability to eradicate DNA interstrand cross-links (ICL). However, the mechanism of chemoresistance mediated by FANCI was unclear in OVCA. Objective: We explore to identify whether FANCI was involved in chemoresistance in OVCA. Methods: FANCI expression and epigenetic alterations were analyzed, respectively, using TIMER and cBioPortal. The correlation between FANCI expression and the survival of OVCA patients was analyzed using Kaplan-Meier Plotter, GSE63885, and TCGA-OVCA dataset. FANCI expression in OVCA was detected by immunohistochemistry. Cell proliferation, migration, and invasion in FANCI inhibiting cells were assessed by CCK-8 and Transwell. Apoptosis and DNA damage were examined by flow cytometry and immunofluorescence. Meanwhile, the activity of caspase 3/7 was detected by Caspase-Glo® 3/7 kit. In addition, the expression of FANCI, γH2AX, and apoptosis effectors was examined by Western blot. Results: FANCI has copy number variations (CNVs) in OVCA. The high expression of FANCI in OVCA patients was associated with poor survival. Moreover, FANCI expression was correlated with the response to chemotherapy in OVCA. FANCI expression in OVCA cells was induced by carboplatin in a time-dependent manner. Silencing of FANCI had no effect on cell proliferation, but hindered OVCA cell migration and invasion. Mechanically, knockdown of FANCI enhanced DNA damage-induced apoptosis through the CHK1/2-P53-P21 pathway. Conclusion: FANCI may be a potential therapeutic target for OVCA patients.

Practical applications of CsPbX3 nanocrystals (NCs) are limited by their poor stability. The formation of a heterojunction between CsPbX3 NCs and oxides is an effective means to protect perovskite from polar solvents and other external factors. Significantly improving the stability and photocatalytic properties of the core/shell perovskite is very important for its application in photoelectric and photocatalytic technology. Here, we report the synthesis of asymmetrical CsPbBr3/TiO2 core–shell heterostructure NCs at the single-particle level by hot-injection liquid-phase synthesis and sol–gel method, where each CsPbBr3 NCs is partially covered by titanium dioxide. We tested not only the optical properties of the material but also the electrochemical impedance and photocurrent density of the material in sodium sulfate solution. It is shown that the type II arrangement is generated at the heterogeneous interface, which greatly facilitates the separation of electron–hole pairs and increases the carrier transport efficiency. Compared with CsPbBr3 NCs, CsPbBr3/TiO2 has higher photocatalytic efficiency. More crucially, due to the protection of the titanium dioxide shell, the product has higher long-term stability in humid air compared with bare CsPbBr3 NCs. The asymmetrical core–shell heterostructure prepared in this study not only improves the stability of CsPbX3 NCs but also provides some ideas for optoelectronic device applications and TiO2-based photocatalysts.

Compared with conventional semiconductors, halide perovskite nanocrystals (NCs) have a unique crystal structure and outstanding optoelectronic properties, offering wide potential for applications in optoelectronic devices such as solar cells, photodetectors, light-emitting diodes, lasers, and displays. Rational technological design is providing vital support for the development of perovskite optoelectronics. Herein, monodisperse all-inorganic halide perovskite nanocrystals with consistent morphology and cubic crystal phase were synthesized employing a modified one-pot hot injection method to independently modulate the stoichiometric ratios of three precursors involving cesium salt, lead source, and halide. In combination with an anion exchange reaction, mixing two kinds of perovskite NCs with different halogens enables a transition from violet emission to green and finally to red emission over the entire visible region. Additionally, optical and electrochemical tests suggested that the as-synthesized halide perovskite NCs are promising for photoelectric catalysis applications.

Flower scent is one of the main ornamental characteristics of herbaceous peony, and the improvement of flower fragrance is a vital objective of herbaceous peony breeding. In this study, 87 herbaceous peony cultivars were divided into three groups (no/light fragrance, medium fragrance, and strong fragrance) based on their sensory evaluation scores, and 16 strong fragrance cultivars and one no fragrance cultivar were selected for subsequent analysis. Sixty-eight volatile components were detected in these 17 cultivars based on solid-phase microextraction (SPME) and gas chromatography/mass spectrometry (GC/MS), and 26 types were identified as important scent components. They were composed of terpenoids, benzenoids/phenylpropanoids, and fatty acid derivatives. According to the content and odor threshold of these main aroma components, the characteristic aroma substances of herbaceous peony were identified, including linalool, geraniol, citronellol, and phenylethyl alcohol (2-PE). The cultivars of strong scented herbaceous peony were divided into three types: rose scent, lily scent, and mixed scent. We explored the possible key genes of characteristic aroma substances in herbaceous peony petals with different odors through the qRT-PCR. The key genes encoding monoterpene biosynthesis were found to be PlDXS2, PlDXR1, PlMDS1, PlHDR1, PlGPPS3, and PlGPPS4. In addition, the linalool synthase (LIS) gene and the geraniol synthase (GES) gene were also found. PlAADC1, PlPAR1, and PlMAO1, related to the biosynthesis of 2-PE were detected, and the synthetic pathway of 2-PE was speculated. In conclusion, these findings revealed that the difference in gene expression of monoterpene and 2-PE synthesis pathway was related to the difference in the fragrance of herbaceous peony. This study explored the releasing pathway of herbaceous peony characteristic aroma substances and provided key genetic resources for fragrance improvement.

Cyclic peptide natural products represent an important class of bioactive compounds and clinical drugs. Enzymatic side-chain macrocyclization of ribosomal peptides is a major strategy developed by nature to generate these chemotypes, as exemplified by the superfamily of ribosomally synthesized and post-translational modified peptides. Despite the diverse types of side-chain crosslinks in this superfamily, the participation of histidine residues is rare. Herein, we report the discovery and biosynthesis of bacteria-derived tricyclic lanthipeptide noursin, which is constrained by a tri amino acid labionin crosslink and an unprecedented histidine-to-butyrine crosslink, named histidinobutyrine. Noursin displays copper-binding ability that requires the histidinobutyrine crosslink and represents the first copper-binding lanthipeptide. A subgroup of lanthipeptide synthetases, named LanKCHbt, were identified to catalyze the formation of both the labionin and the histidinobutyrine crosslinks in precursor peptides and produce noursin-like compounds. The discovery of the histidinobutyrine-containing lanthipeptides expands the scope of post-translational modifications, structural diversity and bioactivity of ribosomally synthesized and post-translational modified peptides.

BackgroundTelofiban is a class of small molecule non-peptide tyrosine derivatives containing RGD sequences. It is the only platelet surface glycoprotein (GP) IIb/IIIa receptor antagonist (GPI) currently marketed in China. In patients with ST-segment elevation myocardial infarction(STEMI) who receive percutaneous coronary intervention (PCI) with a heavy thrombotic load, postoperative intravenous tirofiban can prevent complications of myocardial ischemia due to sudden coronary artery occlusion. With the increase in the clinical use of tirofiban, the number of adverse reactions related to thrombocytopenia induced by tirofiban has gradually increased. Still, most of them have thrombocytopenia after the first use. We report one case of very severe thrombocytopenia following the reuse of tirofiban.Case summaryA 65-year-old man of Han nationality, 170 cm in height, 85 kg in weight, and 29.4 BMI, suffered from cerebral infarction 13 years ago and left with right limb movement disorder. Five days before this hospitalization, the patient underwent PCI, and three stents were implanted. After the operation, anti-platelet tirofiban and nadroparin calcium were given, and no thrombocytopenia was found. The patient still retains 80% stenosis due to anterior descending branches and plans to undergo PCI again half a month later. The patient with a history of hypertension, type 2 diabetes, diabetic nephropathy, and cerebral infarction usually took 100 mg of aspirin and 75 mg of clopidogrel, antiplatelet therapy, and had no history of food and drug allergy. One day after discharge, the patient suddenly felt chest tightness and wheezing. The laboratory showed hypersensitivity troponin 2.85 ng/ml (normal 0–0.0268 ng/ml), and the admission ECG showed ST-T changes in leads I, aVL, V5-V6. On the 6th day of hospitalization, PCI was performed, a stent was implanted in the proximal section of the anterior descending branch opening, and tirofiban(10 ug/kg, 3 min bolus, then 0.1 ug/kg/min) antiplatelet therapy was given after surgery. About 10 min after the tirofiban infusion, the patient suddenly shivered, accompanied by convulsions, accompanied by elevated body temperature (up to 39.4°C), accompanied by epistaxis and microscopic hematuria. An urgent blood test showed that the platelets dropped to 1 × 109/L, tirofiban and aspirin stopped immediately, and the antiplatelet therapy of clopidogrel was retained. After infusion of methylprednisolone sodium succinate and gamma globulin, the patient's platelets gradually recovered, and the patient was successfully discharged seven days later in stable condition.ConclusionThis case is typical of severe thrombocytopenia caused by reusing tirofiban. This case may provide new insights into: 1. Patients who did not have thrombocytopenia after the first use of tirofiban may still have extremely severe thrombocytopenia after re-exposure to tirofiban. Routine platelet count monitoring and early identification of thrombocytopenia are the essential links. 2. Thrombocytopenia caused by re-exposure to tirofiban may have a faster onset, deeper degree, and slower recovery due to antibodies retained after the first exposure to tirofiban; 3. Platelet transfusions may not be necessary for patients with severe thrombocytopenia; 4. Immunosuppressants help suppress the body's immune response, promote platelet recovery, and can be reduced or discontinued when platelets rise and may be safe; 5. After tirofiban for PCI, continuing the maintenance dose of clopidogrel may be safe if the patient has no significant bleeding events.

N6-Methyladenosine (m6A) is the most prevalent internal modification of mammalian mRNAs. Recent studies have shown that m6A methyltransferases METTL3 and METTL14 play important roles in urothelial bladder carcinoma (BLCA). To provide a more comprehensive understanding of the m6A regulatory landscape in bladder cancer, we investigated the role of YTHDF2, a crucial m6A reader, in BLCA. YTHDF2 was frequently upregulated at both the RNA and protein level in BLCA. Functionally, YTHDF2 promoted the proliferation and tumor growth of BLCA cells in vitro and in vivo, respectively. Integrative RNA sequencing and m6A sequencing analyses identified RIG-I as a downstream target of YTHDF2. Mechanistically, YTHDF2 bound to the coding sequence of DDX58 mRNA, which encodes RIG-I, and mediated its degradation in an m6A-dependent manner. Knockdown of RIG-I inhibited apoptosis and promoted the proliferation of BLCA cells. Depleting RIG-I was also able to reverse the effects of YTHDF2 deficiency. YTHDF2-deficient BLCA cells implanted orthotopically in recipient mice activated an innate immune response and promoted recruitment of CD8+ T lymphocytes into the tumor bed and the urothelium. Moreover, YTHDF2 deficiency enhanced the efficacy of Bacillus Calmette-Guérin immunotherapy treatment. This study reveals that YTHDF2 acts as an oncogene in BLCA. YTHDF2 inhibits RIG-I to facilitate immune evasion, supporting testing YTHDF2 inhibition in combination with immunotherapy.Significance:YTHDF2 regulates RIG-I–mediated innate immune signaling to support bladder cancer progression, highlighting the functional importance of m6A modifications in bladder cancer and uncovering therapeutic opportunities to improve patient outcomes.