Short-Term Outcomes of Transcatheter Aortic Valve Replacement in Low-Risk Patients With Pure Severe Aortic Regurgitation.

Transcatheter aortic valve replacement (TAVR) has emerged as an alternative treatment for patients with pure severe aortic regurgitation (PSAR) who are contraindicated for surgery or have a high surgical risk. However, the therapeutic efficacy and safety of TAVR in low Society of Thoracic Surgeons (STS) score risk patients remain to be clarified. This study aimed to explore the feasibility of TAVR treatment in different STS-risk patients and to compare the adverse events between the groups. In this study, patients with PSAR who underwent TAVR at Zhongshan Hospital, Fudan University, China, during the inclusion period were included and categorized into 3 groups based on STS scores. The baseline data, imaging results, and follow-up data of the patients were documented. Therefore, of 75 TAVR patients, 38 (50.7%) were categorized as low risk (STS <4), and 37 (49.3%) patients were categorized as intermediate and high risk (STS ≥4). Compared with patients at intermediate and high risk, those in the low-risk group were younger, had a lower body mass index, had a lower prevalence of hypertension, chronic obstructive pulmonary disease, and previous percutaneous coronary intervention, and had better cardiac function (p all <0.05). In the hospital and at the 1-month follow-up, the degree of aortic regurgitation and cardiac function were significantly improved. No significant difference was found between the 2 groups in the hospital or during the 30-day follow-up. In conclusion, TAVR for PSAR in low-STS-risk patients is safe and efficient during 30 days of follow-up compared with intermediate- and high-STS-risk groups. TAVR for PSAR should not be limited to inoperable or STS-defined high-risk patients. Long-term follow-up is needed for further investigation.

Synthetic bacteria designed using ars operons: a promising solution for arsenic biosensing and bioremediation.

The global concern over arsenic contamination in water due to its natural occurrence and human activities has led to the development of innovative solutions for its detection and remediation. Microbial metabolism and mobilization play crucial roles in the global cycle of arsenic. Many microbial arsenic-resistance systems, especially the ars operons, prevalent in bacterial plasmids and genomes, play vital roles in arsenic resistance and are utilized as templates for designing synthetic bacteria. This review novelty focuses on the use of these tailored bacteria, engineered with ars operons, for arsenic biosensing and bioremediation. We discuss the advantages and disadvantages of using synthetic bacteria in arsenic pollution treatment. We highlight the importance of genetic circuit design, reporter development, and chassis cell optimization to improve biosensors' performance. Bacterial arsenic resistances involving several processes, such as uptake, transformation, and methylation, engineered in customized bacteria have been summarized for arsenic bioaccumulation, detoxification, and biosorption. In this review, we present recent insights on the use of synthetic bacteria designed with ars operons for developing tailored bacteria for controlling arsenic pollution, offering a promising avenue for future research and application in environmental protection.

Development of D-π-A organic dyes for discriminating HSA from BSA and study on dye-HSA interaction.

HSA (human serum albumin), a most abundant protein in blood serum, plays a key role in maintaining human health. Abnormal HSA level is correlated with many diseases, and thus has been used as an essential biomarker for therapeutic monitoring and biomedical diagnosis. Development of small-molecule fluorescent probes allowing the selective and sensitive recognition of HSA in in vitro and in vivo is of fundamental importance in basic biological research as well as medical diagnosis. Herein, we reported a series of new synthesized fluorescent dyes containing D-π-A constitution, which exhibited different optical properties in solution and solid state. Among them, dye M-H-SO3 with a hydrophilic sulfonate group at electron-acceptor part displayed selectivity for discrimination of HSA from BSA and other enzymes. Upon binding of dye M-H-SO3 with HSA, a significant fluorescence enhancement with a turn-on ratio about 96-fold was triggered. The detection limit was estimated to be âˆ¼ 40 nM. Studies on the interaction mechanism revealed that dye M-H-SO3 could bind to site III of HSA with a 1:1 binding stoichiometry. Furthermore, dye M-H-SO3 has been applied to determine HSA in real urine samples with good recoveries, which provided a useful method for HSA analysis in biological fluids.

Synergistic acceleration of machine learning and molecular docking for prostate-specific antigen ligand design.

Prostate-specific antigen (PSA) serves as a critical biomarker for the early detection and continuous monitoring of prostate cancer. However, commercial PSA detection methods primarily rely on antigen-antibody interactions, leading to issues such as high costs, stringent storage requirements, and potential cross-reactivity due to PSA variant sequence homology. This study is dedicated to the precise design and synthesis of molecular entities tailored for binding with PSA. By employing a million-level virtual screening to obtain potential PSA compounds and effectively guiding the synthesis using machine learning methods, the resulting lead compounds exhibit significantly improved binding affinity compared to those developed before by researchers using high-throughput screening for PSA, substantially reducing screening and development costs. Unlike antibody detection, the design of these small molecules offers promising avenues for advancing prostate cancer diagnostics. Furthermore, this study establishes a systematic framework for the rapid development of customized ligands that precisely target specific protein entities.

Gamma-ray irradiation as an effective method for mitigating antibiotic resistant bacteria and antibiotic resistance genes in aquatic environments.

The prevalence of antibiotic resistance genes (ARGs) in municipal wastewater treatment plants (MWTPs) has emerged as a significant environmental concern. Despite advanced treatment processes, high levels of ARGs persist in the secondary effluent from MWTPs, posing ongoing environmental risks. This study explores the potential of gamma-ray irradiation as a novel approach for sterilizing antibiotic-resistant bacteria (ARB) and reducing ARGs in MWTP secondary effluent. Our findings reveal that gamma-ray irradiation at an absorbed dose of 1.6 kGy effectively deactivates all culturable bacteria, with no subsequent revival observed after exposure to 6.4 kGy and a 96-h incubation in darkness at room temperature. The removal efficiencies for a range of ARGs, including tetO, tetA, blaTEM-1, sulI, sulII, and tetW, were up to 90.5% with a 25.6 kGy absorbed dose. No resurgence of ARGs was detected after irradiation. Additionally, this study demonstrates a considerable reduction in the abundances of extracellular ARGs, with the transformation efficiencies of extracellular tetracycline and sulfadiazine resistance genes decreasing by 56.3-81.8% after 25.6 kGy irradiation. These results highlight the effectiveness of gamma-ray irradiation as an advanced and promising method for ARB sterilization and ARG reduction in the secondary effluent of MWTPs, offering a potential pathway to mitigate environmental risks associated with antibiotic resistance.

Disinfection of wastewater by a complete equipment based on a novel ultraviolet light source of microwave discharge electrodeless lamp: Characteristics of bacteria inactivation, reactivation and full-scale studies.

Ultraviolet (UV) light is widely used for wastewater disinfection. Traditional electrode-excited UV lamps, such as low-pressure mercy lamps (LPUV), encounter drawbacks like electrode aging and rapid light attenuation. A novel UV source of microwave discharge electrodeless lamp (MDEL) has aroused attention, yet its disinfection performance is unclear and still far from practical application. Here, we successfully developed a complete piece of equipment based on MDELs and achieved the application for disinfection in wastewater treatment plants (WWTPs). The light emitted by an MDEL (MWUV) shared a spectrum similar to that of LPUV, with the main emission wavelength at 254 nm. The inactivation rate of Gram-negative E. coli by MWUV reached 4.5 log at an intensity of 1.6 mW/cm2 and a dose of 20 mJ/cm2. For Gram-positive B. subtilis, an MWUV dose of 50 mJ/cm2 and a light intensity of 1.2 mW/cm2 reached an inactivation rate of 3.4 log. A higher MWUV intensity led to a better disinfection effect and a lower photoreactivation rate of E. coli. When inactivated by MWUV with an intensity of 1.2 mW/cm2 and a dose of 16 mJ/cm2, the maximum photoreactivation rate and reactivation rate constant Kmax of E. coli were 0.63 % and 0.11 % h-1 respectively. Compared with the photoreactivation, the dark repair of E. coli was insignificant. The full-scale application of the MDEL equipment was conducted in two WWTPs (10,000 m3/d and 15,000 m3/d). Generally 2-3 log inactivation rates of fecal coliforms in secondary effluent were achieved within 5-6 s contact time, and the disinfected effluent met the emission standard (1000 CFU/L). This study successfully applied MDEL for disinfection in WWTPs for the first time and demonstrated that MDEL has broad application prospects.

Fangji Fuling Decoction Alleviates Sepsis by Blocking MAPK14/FOXO3A Signaling Pathway.

OBJECTIVE: To examine the therapeutic effect of Fangji Fuling Decoction (FFD) on sepsis through network pharmacological analysis combined with in vitro and in vivo experiments. METHODS: A sepsis mouse model was constructed through intraperitoneal injection of 20 mg/kg lipopolysaccharide (LPS). RAW264.7 cells were stimulated by 250 ng/mL LPS to establish an in vitro cell model. Network pharmacology analysis identified the key molecular pathway associated with FFD in sepsis. Through ectopic expression and depletion experiments, the effect of FFD on multiple organ damage in septic mice, as well as on cell proliferation and apoptosis in relation to the mitogen-activated protein kinase 14/Forkhead Box O 3A (MAPK14/FOXO3A) signaling pathway, was analyzed. RESULTS: FFD reduced organ damage and inflammation in LPS-induced septic mice and suppressed LPS-induced macrophage apoptosis and inflammation in vitro (P<0.05). Network pharmacology analysis showed that FFD could regulate the MAPK14/FOXO signaling pathway during sepsis. As confirmed by in vitro cell experiments, FFD inhibited the MAPK14 signaling pathway or FOXO3A expression to relieve LPS-induced macrophage apoptosis and inflammation (P<0.05). Furthermore, FFD inhibited the MAPK14/FOXO3A signaling pathway to inhibit LPS-induced macrophage apoptosis in the lung tissue of septic mice (P<0.05). CONCLUSION: FFD could ameliorate the LPS-induced inflammatory response in septic mice by inhibiting the MAPK14/FOXO3A signaling pathway.

Research Progress on the Antidepressant Effects of Baicalin and Its Aglycone Baicalein: A Systematic Review of the Biological Mechanisms.

Depression is the most prevalent mental disorder, affecting more than 300 million adults worldwide each year, which can lead to serious economic and social problems. Antidepressants are usually the first-line treatment for depression, however, traditional antidepressants on the market have the disadvantage of low remission rates and may cause side effects to patients, therefore, the current focus in the field of depression is to develop novel therapeutic agents with high remission rates and few side effects. In this context, the antidepressant effects of natural compounds have received attention. Baicalin (baicalein-7-O-glucuronide) and its aglycone baicalein (5,6,7-trihydroxyflavone) are flavonoid compounds extracted from the root of Scutellaria baicalensis. Although lacking the support of clinical data, they have been shown to have significantly promising antidepressant activity in many preclinical studies through various rodent models of depression. This paper reviews the antidepressant effects of baicalin and baicalein in experimental animal models, with emphasis on summarizing the molecular mechanisms of their antidepressant effects including regulation of the HPA axis, inhibition of inflammation and oxidative stress, reduction of neuronal apoptosis and promotion of neurogenesis, as well as amelioration of mitochondrial dysfunction. Controlled clinical trials should be conducted in the future to examine the effects of baicalin and baicalein on depression in humans.

Mitoguardin 1 and 2 promote granulosa cell proliferation by activating AKT and regulating the Hippo-YAP1 signaling pathway.

Mitochondria have been identified to be involved in oxidative phosphorylation, lipid metabolism, cell death, and cell proliferation. Previous studies have demonstrated that mitoguardin (Miga), a mitochondrial protein that governs mitochondrial fusion, mitochondria-endoplasmic reticulum (ER) contacts, lipid formation, and autophagy, is crucial for ovarian endocrine and follicular development. Nevertheless, whether mammalian MIGA1 or MIGA2 (MIGA1,-2) regulates ovarian granulosa cell proliferation remains unclear. This study revealed that mammalian MIGA1,-2 promotes cell proliferation and regulates the phosphorylation and localization of Yes-associated protein 1 (YAP1) in ovarian granulosa cells. MIGA2 upregulation resulted in reduced YAP1 activity, while MIGA2 removal led to increased YAP1 activity. Further analysis indicated that MIGA1,-2 regulated YAP1 via the Hippo signaling pathway and regulated protein kinase B (AKT) activity in collaboration with YAP1. In addition, lysophosphatidic acid (LPA) regulated MIGA2 expression and AKT activity by activating YAP1. Briefly, we demonstrated that the mitochondrial MIGA1 and MIGA2, especially MIGA2, promoted cellular proliferation by activating AKT and regulating the Hippo/YAP1 signaling pathway in ovarian granulosa cells, which may contribute to the molecular pathogenesis of reproductive endocrine diseases, such as polycystic ovary syndrome (PCOS).

Pb(II)-inducible proviolacein biosynthesis enables a dual-color biosensor toward environmental lead.

With the rapid development of synthetic biology, various whole-cell biosensors have been designed as valuable biological devices for the selective and sensitive detection of toxic heavy metals in environmental water. However, most proposed biosensors are based on fluorescent and bioluminescent signals invisible to the naked eye. The development of visible pigment-based biosensors can address this issue. The pbr operon from Klebsiella pneumoniae is selectively induced by bioavailable Pb(II). In the present study, the proviolacein biosynthetic gene cluster was transcriptionally fused to the pbr Pb(II) responsive element and introduced into Escherichia coli. The resultant biosensor responded to Pb(II) in a time- and dose-dependent manner. After a 5-h incubation with Pb(II), the brown pigment was produced, which could be extracted into n-butanol. Extra hydrogen peroxide treatment during n-butanol extract resulted in the generation of a stable green pigment. An increased brown signal was observed upon exposure to lead concentrations above 2.93 nM, and a linear regression was fitted from 2.93 to 3,000 nM. Extra oxidation significantly decreased the difference between parallel groups. The green signal responded to as low as 0.183 nM Pb(II), and a non-linear regression was fitted in a wide concentration range from 0.183 to 3,000 nM. The specific response toward Pb(II) was not interfered with by various metals except for Cd(II) and Hg(II). The PV-based biosensor was validated in monitoring bioaccessible Pb(II) spiked into environmental water. The complex matrices did not influence the regression relationship between spiked Pb(II) and the dual-color signals. Direct reading with the naked eye and colorimetric quantification enable the PV-based biosensor to be a dual-color and low-cost bioindicator for pollutant heavy metal.

Diagnosis and treatment of biliary mucinous cystic neoplasms: A single-center experience.

BACKGROUND: Biliary mucinous cystic neoplasms (BMCNs) are rare hepatobiliary cystic tumors, which can be divided into noninvasive and invasive types. This study aimed to investigate the diagnosis, treatment, and prognosis of BMCNs in a large single center. METHODS: We analyzed 49 patients with BMCNs confirmed by postoperative pathology at the First Affiliated Hospital, Zhejiang University School of Medicine between January 2007 and December 2021. RESULTS: Among the 49 patients, 37 were female (75.5%), and the average age was 57.04 years. Common symptoms included abdominal discomfort, jaundice and fever, while 22 patients (44.9%) had no symptoms. Serum carbohydrate antigen (CA) 19-9 and CA125 concentrations were elevated in 34.8% and 19.6% of patients, respectively. Forty-eight patients had tumors in the intrahepatic bile ducts and only one had a tumor in the extrahepatic bile duct. Forty-eight patients with noninvasive intrahepatic BMCNs were further analyzed in terms of pathological features: 34 (70.8%) had low-grade intraepithelial neoplasms (LGINs), and 14 (29.2%) had high-grade intraepithelial neoplasms (HGINs). The potential immunohistochemical markers of BMCNs were cytokeratin (CK) 19, CK7, estrogen receptor and progesterone receptor. Follow-up data for 37 patients with intrahepatic BMCNs were obtained. The median overall survival (OS) of BMCNs was not reached. The longest survival time was 137 months.The 5- and 10-year OS rates were 100% and 85.4%, respectively. The 5- and 10-year recurrence-free survival (RFS) rates were 93.9% and 80.2%, respectively. CONCLUSIONS: BMCNs are rare cystic neoplasms that commonly occur in middle-aged females. BMCNs can only be diagnosed and classified by postoperative pathology, as there are no specific clinical presentations, serological indicators or imaging modalities for preoperative diagnosis. Complete surgical resection is necessary for BMCNs, and the postoperative prognosis is favorable.

GlycoNote with Iterative Decoy Searching and Open-Search Component Analysis for High-Throughput and Reliable Glycan Spectral Interpretation.

Mass spectrometry-based glycome analysis is a viable strategy for the compositional and functional exploration of glycosylation. However, the lack of generic tools for high-throughput and reliable glycan spectral interpretation largely hampers the broad usability of glycomic research. Here, we developed a generic and reliable glycomic tool, GlycoNote, for comprehensive and precise glycome analysis. GlycoNote supports interpretation of tandem-mass spectrometry glycomic data from any sample source, uses a novel target-decoy method with iterative decoy searching for highly reliable result output, and embeds an open-search component analysis mode for heterogeneity analysis of monosaccharides and modifications. We tested GlycoNote on several different large-scale glycomic datasets, including human milk oligosaccharides, N- and O-glycome from human cell lines, plant polysaccharides, and atypical glycans from Caenorhabditis elegans, demonstrating its high capacity for glycome analysis. An application of GlycoNote to the analysis of labeled and derived glycans further demonstrates its broad usability in glycomic studies. By enabling generic characterization of various glycan types and elucidation of component heterogeneity in glycomic samples, the freely available GlycoNote is a promising tool for facilitating glycomics in glycobiology research.

Heat shock protein: a double-edged sword linking innate immunity and hepatitis B virus infection.

Heat shock proteins (HSPs), which have a variety of functions, are one of the stress protein families. In recent years, They have been reported to play a dual role in hepatitis B virus (HBV) which as persistent infection which is associated with, cirrhosis and liver cancer. In this article, we have summarized the regulatory mechanisms between HSPs and viruses, especially HBV and associated diseases based on HSP biological functions of in response to viral infections. In view of their potential as broad-spectrum antiviral targets, we have also discuss current progress and challenges in drug development based on HSPs, as well as the potential applications of agents that have been evaluated clinically in HBV treatment.

Effects of Tanreqing Injection on ICU Mortality among ICU Patients Receiving Mechanical Ventilation: Time-Dependent Cox Regression Analysis of A Large Registry.

OBJECTIVE: To assess whether the use of Tanreqing (TRQ) Injection could show improvements in time to extubation, intensive care unit (ICU) mortality, ventilator-associated events (VAEs) and infection-related ventilator associated complication (IVAC) among patients receiving mechanical ventilation (MV). METHODS: A time-dependent cox-regression analysis was conducted using data from a well-established registry of healthcare-associated infections at ICUs in China. Patients receiving continuous MV for 3 days or more were included. A time-varying exposure definition was used for TRQ Injection, which were recorded on daily basis. The outcomes included time to extubation, ICU mortality, VAEs and IVAC. Time-dependent Cox models were used to compare the clinical outcomes between TRQ Injection and non-use, after controlling for the influence of comorbidities/conditions and other medications with both fixed and time-varying covariates. For the analyses of time to extubation and ICU mortality, Fine-Gray competing risk models were also used to measure competing risks and outcomes of interest. RESULTS: Overall, 7,685 patients were included for the analyses of MV duration, and 7,273 patients for the analysis of ICU mortality. Compared to non-use, patients with TRQ Injection had a lower risk of ICU mortality (Hazards ratios (HR) 0.761, 95% CI, 0.581-0.997), and was associated with a higher hazard for time to extubation (HR 1.105, 95% CI, 1.005-1.216), suggesting a beneficial effect on shortened time to extubation. No significant differences were observed between TRQ Injection and non-use regarding VAEs (HR 1.057, 95% CI, 0.912-1.225) and IVAC (HR 1.177, 95% CI, 0.929-1.491). The effect estimates were robust when using alternative statistic models, applying alternative inclusion and exclusion criteria, and handling missing data by alternative approaches. CONCLUSION: Our findings suggested that the use of TRQ Injection might lower mortality and improve time to extubation among patients receiving MV, even after controlling for the factor that the use of TRQ changed over time.

An environmentally insensitive fluorescent probe for G4 DNA detection: Design, synthesis, and mechanism studies.

G4 DNA structure highly localized to functionally important sites within the human genome, has been identified as a biomarker for regulation of multiple biological processes. Identification G4-responsive fluorescence probes has broad application prospects for addressing G4 biological functions, as well as developing of new families of anticancer drugs. However, some currently designed G4 DNA probes may suffer from serious solvent-dependent effect, and cause unspecific fluorescence that masks the specific signal from G4 DNA. Herein, with a bulky imidazole-cored molecular rotor fusing in D-A building block of carbazole-pyridinium, we constructed a new probe ACPS. This new probe with desirable environmentally insensitive property exhibited a "fluorescence-off" state in various polarity solvents. In the presence of G4 DNA, the intra-molecular rotations would be restricted, triggering intense fluorescence enhancement. Especially, probe ACPS bound to G4 DNA structures with superior selectivity, exhibiting much weaker fluorescence response in the presence of non-G4 DNA structures. This probe was also able to realize fluorescence visualization in cell imaging. Collectively, the probe design strategy eliminates the background fluorescence caused by uncontrollable environmental polarity change, thereby achieving high-fidelity sensing G4 DNA structures in complicated systems.

Mitoguardin2 Is Associated With Hyperandrogenism and Regulates Steroidogenesis in Human Ovarian Granulosa Cells.

Polycystic ovary syndrome (PCOS) is an endocrinopathy characterized by hyperandrogenism, anovulation, and polycystic ovaries, in which hyperandrogenism manifests by excess androgen and other steroid hormone abnormalities. Mitochondrial fusion is essential in steroidogenesis, while the role of mitochondrial fusion in granulosa cells of hyperandrogenic PCOS patients remains unclear. In this study, mRNA expression of mitochondrial fusion genes mitoguardin1, -2 (MIGA 1, -2) was significantly increased in granulosa cells of hyperandrogenic PCOS but not PCOS with normal androgen levels, their mRNA expression positively correlated with testosterone levels. Dihydrotestosterone (DHT) treatment in mice led to high expression of MIGA2 in granulosa cells of ovulating follicles. Testosterone or forskolin/ phorbol 12-myristate 13-acetate treatments increased expression of MIGA2 and the steroidogenic acute regulatory protein (StAR) in KGN cells. MIGA2 interacted with StAR and induced StAR localization on mitochondria. Furthermore, MIGA2 overexpression significantly increased cAMP-activated protein kinase A (PKA) and phosphorylation of AMP-activated protein kinase (pAMPK) at T172 but inhibited StAR protein expression. However, MIGA2 overexpression increased CYP11A1, HSD3B2, and CYP19A1 mRNA expression. As a result, MIGA2 overexpression decreased progesterone but increased estradiol synthesis. Besides the androgen receptor, testosterone or DHT might also regulate MIGA2 and pAMPK (T172) through LH/choriogonadotropin receptor-mediated PKA signaling. Taken together, these findings indicate that testosterone regulates MIGA2 via PKA/AMP-activated protein kinase signaling in ovarian granulosa cells. It is suggested mitochondrial fusion in ovarian granulosa cells is associated with hyperandrogenism and potentially leads to abnormal steroidogenesis in PCOS.

Overlooked Cytotoxicity and Genotoxicity to Mammalian Cells Caused by the Oxidant Peroxymonosulfate during Wastewater Treatment Compared with the Sulfate Radical-Based Ultraviolet/Peroxymonosulfate Process.

Byproduct formation (chlorate, bromate, organic halogen, etc.) during sulfate radical (SO4•-)-based processes like ultraviolet/peroxymonosulfate (UV/PMS) has aroused widespread concern. However, hypohalous acid (HOCl and HOBr) can form via two-electron transfer directly from PMS, thus leading to the formation of organic halogenated byproducts as well. This study found both PMS alone and UV/PMS can increase the toxicity to mammalian cells of wastewater, while the UV/H2O2 decreased the toxicity. Cytotoxicity of two wastewater samples increased from 5.6-8.3 to 15.7-29.9 mg-phenol/L, and genotoxicity increased from 2.8-3.1 to 5.8-12.8 µg 4-NQO/L after PMS treatment because of organic halogen formation. Organic halogen formation from bromide rather than chloride was found to dominate the toxicity increase. The SO4•--based process UV/PMS led to the formation of both organic halogen and inorganic bromate and chlorate. However, because of the very low concentration (<20 µg/L) and relatively low toxicity of bromate and chlorate, contributions of inorganic byproducts to toxicity increase were negligible. PMS would not form chlorate and bromate, but it generated a higher concentration of total organic halogen, thus leading to a more toxic treated wastewater than UV/PMS. UV/PMS formed less organic halogen and toxicity because of the destruction of byproducts by UV irradiation and the removal of byproduct precursors. Currently, many studies focused on the byproducts bromate and chlorate during SO4•--based oxidation processes. This work revealed that the oxidant PMS even needs more attention because it caused higher toxicity due to more organic halogen formation.

Two new alkaloids from a strain of endophytic fungus Aspergillus sp.

19-Hydroxybrevianamide M (1) and 6 R-methoxybrevianamide V (2), two new alkaloids, were isolated from an extract of the endophytic fungus Aspergillus sp. JNU18HC0517J, together with six known analogues (3- 8). Their structures were elucidated by extensive spectroscopic analyses, NMR calculations, and ECD calculations. 6 R-methoxybrevianamide V (2) was the first L-proline indole DKP alkaloid with substitution at C-6 on the proline ring. Furthermore, the cytotoxities and antimicrobial activities of these isolated compounds were also evaluated. Compound 8 exhibited moderate antibacterial activity against Staphylococcus aureus 209 P with a minimal inhibitory concentration (MIC) value of 16 µg/ml.[Figure: see text].

Transcriptome and metabolome reveal the effects of three canopy types on the flavonoids and phenolic acids in 'Merlot' (Vitis vinifera L.) berry pericarp.

The flavonoids and phenolic acids in grape berries greatly influence the quality of wine. Various methods are used to shape and prune grapevines, but their effects on the flavonoids and phenolic acids remain unclear. The flavonoids and phenolic acids in the berry pericarps from grapevines pruned using three types of leaf canopy, namely, V-shaped, T-shaped, and vertical shoot-positioned (VSP) canopies, were compared in this study. Results showed that the V-shaped canopy was more favorable for the accumulation of flavonoids and phenolic acids. Transcriptome and metabolome analyses revealed that the differentially expressed genes (DEGs) and differentially regulated metabolites (DRMs) were significantly enriched in the flavonoid and phenylpropanoid biosynthesis pathways. A total of 96 flavonoids and 32 phenolic acids were detected among the DRMs. Their contents were higher in the V-shaped canopy than in the T-shaped and VSP canopies. Conjoint analysis of transcriptome and metabolome showed that nine DEGs (e.g., cytochrome P450 98A9 and 98A2) were significantly correlated to nine phenolic acids (e.g., gentisic acid and neochlorogenic acid) and three genes (i.e., chalcone isomerase, UDP-glycosyltransferase 88A1, and caffeoyl-CoA O-methyltransferase) significantly correlated to 15 flavonoids (e.g., baimaside and tricin-7-O-rutinoside). These genes may be involved in the regulation of various flavonoids and phenolic acids in grape berries, but their functions need validation. This study provides novel insights into the effects of leaf canopy on flavonoids and phenolic acids in the skin of grape berries and reveals the potential regulatory networks involved in this phenomenon.

Granulocyte-macrophage colony stimulating factor enhances efficacy of nimustine rendezvousing with temozolomide plus irradiation in patients with glioblastoma.

BACKGROUND: Glioblastoma is the most common and most aggressive type of primary brain tumor. OBJECTIVE: The aim of this study was to investigate the efficacy and safety of intranasal granulocyte-macrophage colony stimulating factor (GM-CSF) administration combined with chemoradiotherapy in patients with glioblastoma who underwent surgery. METHODS: Ninety-two patients were randomly divided into two groups: a control group (n= 46), who received radiotherapy with adjuvant local delivery of nimustine hydrochloride (ACNU) and systemic administration of temozolomide, and an intervention group (n= 46), who received intranasal GM-CSF prior to each cycle of adjuvant chemotherapy in addition to the treatment of the control group. Karnofsky performance status (KPS) scores, progression-free survival (PFS), overall survival (OS), and adverse effects were calculated and compared between the two groups. RESULTS: Compared with the control group, the intervention group had longer PFS (7.8 vs. 6.9 months, P= 0.016) and OS (19.2 vs. 17.1 months, P= 0.045, without adjustment for interim analyses). The KPS scores were also higher in the intervention group than in the control group after 6 months (84.35 ± 8.86 vs. 80.65 ± 7.72; t= 4.552, P= 0.036). Furthermore, the patients in the intervention group had lower incidence of neutropenia and thrombocytopenia (8.7% vs. 29.5%, P= 0.012; 8.7% vs. 18.2%, P= 0.186). Other adverse events were similar in both groups, and most adverse events were grade I/II and resolved spontaneously. CONCLUSION: Intranasal GM-CSF enhances the efficacy of the local ACNU administration combined with oral temozolomide chemotherapy. The survival and performance status were significantly improved in patients with glioblastoma after surgery. Additionally, the GM-CSF therapy was able to reduce the occurrence of chemotherapy-related neutropenia and thrombocytopenia.