Cardiovascular events of Bruton's tyrosine kinase inhibitors: A real-world study based on the United States Food and Drug Administration Adverse Event Reporting System database.

AIMS: Bruton's tyrosine kinase inhibitors (BTKIs), including first-generation ibrutinib, second-generation acalabrutinib and zanubrutinib, may be involved in the mechanisms of action related to adverse events (AEs) of the cardiovascular system. We aimed to characterize the cardiovascular AEs of BTKIs reported in the US Food and Drug Administration (FDA) Adverse Event Reporting System, and to compare the cardiovascular risks of BTKIs. METHODS: Across all indications of three FDA-approved BTKIs, primary suspect drugs were extracted over two periods: from January 2013 to December 2022 (after the approval of the first BTKI), and from January 2020 to December 2022 (all three BTKIs on the market). Disproportionality was measured by reporting odds ratios (RORs) and information components. Additional analyses were performed without incorporating patients with underlying cardiovascular disease (CVD). RESULTS: A total of 10 353 cases included the uses of ibrutinib, acalabrutinib and zanubrutinib. Ibrutinib was significantly associated with 47 cardiovascular AEs. Acalabrutinib was associated with new signals, including cardiac failure (ROR = 1.82 [1.13-2.93]), pulmonary oedema (ROR = 2.15 [1.19-3.88]), ventricular extrasystoles (ROR = 5.18 [2.15-12.44]), heart rate irregular (ROR = 3.05 [1.53-6.11]), angina pectoris (ROR = 3.18 [1.71-5.91]) and cardiotoxicity (ROR = 25.22 [17.14-37.10]). In addition, cardiovascular events had an earlier onset in acalabrutinib users. Zanubrutinib was only associated with atrial fibrillation. Acalabrutinib and zanubrutinib had lower ROR values than ibrutinib. The AE signals were generally consistent between the population receiving and not receiving CVD medications. CONCLUSIONS: Potential cardiovascular risks identified in this study were not clearly noted on the label of marketed acalabrutinib. Caution should be paid to the cardiovascular risks of BTKIs having been or being developed.

Theoretical Investigations on the Rh(III)-Catalyzed Oxidative C-H Activation/Annulation of Salicylaldehydes with Masked Enynes: Mechanism Insights and Regioselectivity Origins.

The mechanism underlying the rhodium(III)-catalyzed reaction of the C-H alkenylation/annulation reaction of salicylaldehydes with enynes has been thoroughly investigated using DFT calculations. Based on mechanistic studies, our focus primarily lies on the regioselectivity of asymmetric alkynes inserting into the Rh-C bond and the involvement of the auxiliary group OAc- in these reactions. Our theoretical study uncovers that, with acetate assistance, a stepwise SN2' cyclization, 1,3-Rh migration, ß-H elimination, and reductive elimination process occur. Furthermore, we also explore the role of substitution at Cα (CH3 vs H) in the reaction. As demonstrated in this work, these findings are applicable to other related reactions.

[Characteristics of Municipal Solid Waste in Some Urban Agglomeration in the Past Five Years].

The treatment and disposal of municipal solid waste has increasingly become a common concern around the world, and the characteristics of municipal solid waste(MSW) are an important basis for the selection of terminal treatment methods. In this study, more than 400 MSW samples from over 30 cities across China were collected, and the basic physical and chemical properties, such as the physical composition, pollutant content, and calorific value, were analyzed. Shenzhen was taken as an example to analyze the influence of time and waste sorting measures on the physical and chemical characteristics of MSW. The correlation model between MSW composition and calorific value was established using partial least squares(PLS) regression, and the model was verified. The results showed that with per capita GDP increasing by 10,000 yuan, per capita MSW production and the low calorific value of MSW increased by 0.1 kg·(person·d)-1 and 373.8 kJ·kg-1, respectively. However, when per capita GDP was less than 60,000 yuan, the correlation between per capita GDP and per capita MSW production was relatively poor. Kitchen waste was still the most abundant component of MSW, and the content of most samples was between 40% and 60%. The combustible content of rubber/plastic and paper was relatively high, between 20%-30% and 10%-20%, respectively. The inorganic content did not usually exceed 5%, and the moisture content of the MSW was between 50% and 60%. After the implementation of waste classification in 2019, the content of kitchen waste in MSW had been significantly reduced, the content of rubber/plastic had increased, and other components had not changed much. Additionally, the calorific value of waste had been improved to a certain extent. The pollution element contents in MSW, S Cl, and N were all below 1%, and the average value was:N>Cl>S. The contents of Hg, As, Cr, Cd, and Pb in MSW samples did not change significantly with the composition and sampling time, and the content of Pb and Cr in MSW was affected by the environmental background value. The model analysis revealed that rubber/plastics and moisture content were the main variables that affected the calorific value of MSW. The deviation between the measured value and the predicted value was less than 20% for 85.96% of the samples. The model established in this study can meet the needs of the prediction of the calorific value of MSW.

Upregulation of EphA4 deteriorate brain damage by shifting microglia M1-polarization via NF-κB signaling after focal cerebral ischemia in rats.

Ischemic stroke is the main reason of disability and mortality in many countries, and currently has limited treatments. The post-stroke inflammation characterized with microglia activation and polarization has been regarded as a promising therapeutic target for ischemic stroke. After ischemia, the activated microglia polarize to classical (M1) phenotype or alternative (M2) phenotype and exhibit biphasic function. Promoting microglia phenotype shift from deleterious M1 phenotype to neuroprotective M2 phenotype will be promising in stroke treatment. Increasing evidence indicates that the erythropoietin-producing human hepatocellular (Eph) receptor A4 (EphA4), a kind of abundant Eph receptor, distributes mainly in neuron and participates in multiple links of pathological changes after ischemia. This paper discussed the hypothesis that EphA4 receptor could affect ischemic brain injury through EphA4/ephrin bidirectional signaling between neuron and microglia, and then explored its underlying mechanisms. We manipulated EphA4/ephrin signaling with either EphA4 overexpression lentiviral vectors or the short hairpin RNA (shRNA) to upregulate or knock down neuronal EphA4 expression. NF-κB inhibitor pyrrolidine dithiocarbamate ammonium salt (PDTC) was applied to block NF-κB pathway. According to the experimental results, upregulated neuronal EphA4 induced by ischemia deteriorated neurological function as well as brain damage by shifting microglia M1-polarization via promoting NF-κB signaling.

Plasma microRNAs as potential biomarkers in diagnosis of acute venous thromboembolism.

OBJECTIVE: To assess the potential use of plasma microRNAs (miRNAs) in diagnosis of acute venous thromboembolism (VTE). METHODS: Using BGISEQ-500 sequencing technology, we analyzed the miRNA profile of paired plasma samples from the acute and chronic phases of four patients with unprovoked VTE. Using real-time quantitative polymerase chain reaction (RT-qPCR), we verified nine upregulated named miRNAs in the acute phase in the plasma samples of 54 patients with acute VTE and 39 controls. We then compared the relative expression of the 9 candidate miRNAs between the acute VTE and control group, and plotted the receiver operating characteristic (ROC) curves of the differentially expressed miRNAs. We chose the miRNA with the greatest area under curve (AUC) to evaluate the effect of miRNA on coagulation and platelet function in the plasma samples of 5 healthy volunteers. RESULTS: The plasma levels of miR-374b-3p, miR-660-5p, miR-378a-3p, miR-425-5p, miR-3613-5p, miR-130b-3p, miR-183-5p, and miR-103b were higher in patients with acute VTE than in the controls, with AUCs of 0.6776, 0.6614, 0.6648, 0.6885, 0.8048, 0.6871, 0.7298, and 0.7498, respectively, and P values of 0.0036, 0.0081, 0.0069, 0.0020,<0.0001, 0.0022, 0.0002, and < 0.0001, respectively. There were no significant differences in miR-193b-5p level between the acute VTE group and the control group. Fibrinogen (Fib), thrombin- antithrombin complex (TAT), tissue plasminogen activator-inhibitor complex (t-PAIC), and TAT/plasmin-α2-plasmin inhibitor complex (PIC) were decreased in the miR-3613-5p group when compared with the control group (P < 0.05) and the mean platelet aggregation rate was increased in the miR-3613 group (P < 0.05). CONCLUSION: miRNAs can be potential biomarkers for diagnosing acute VTE, and miR-3613-5p may be involved in the formation, coagulation, and platelet functions in acute VTE.

Mechanistic Study on CpRh(III)-Catalyzed [3 + 2] Annulation of Aniline Derivatives with Vinylsilanes: A DFT Study.

The rhodium(III)-catalyzed reaction of aniline derivatives that contain a pyrimidine-directing group with vinylsilanes results in the formation of C3-substituted indoline derivatives. The reaction path and formation of the indoline product with density functional theory calculations were analyzed. This study reveals that the whole catalysis can be characterized in the following stages: (I) C-H activation via concerted metalation deprotonation, (II) 2,1-vinylsilane insertion, (III) deprotonation of the NH amide proton, (IV) the oxidation of Ag+, and (V) reductive elimination. These steps are kinetically and thermodynamically feasible for experimental realization under mild conditions, and the insertion step with a barrier of 22.0 kcal/mol should not only be the critical step of regioselectivity but also the rate-determining step during the whole catalysis. Computations reveal that the Ag+ oxidation can accelerate the reductive elimination step after the formation of natural intermediate, thus highlighting the role of Ag+ as a catalytic promoter for the oxidatively induced reactivity of the Rh catalyst in C3-substituted indoline synthesis.

Chronic high­salt intake induces cardiomyocyte autophagic vacuolization during left ventricular maladaptive remodeling in spontaneously hypertensive rats.

The role of autophagy in high-salt (HS) intake associated hypertensive left ventricular (LV) remodeling remains unclear. The present study investigated the LV autophagic change and its association with the hypertensive LV remodeling induced by chronic HS intake in spontaneously hypertensive rats (SHR). Wistar Kyoto (WKY) rats and SHR were fed low-salt (LS; 0.5% NaCl) and HS (8.0% NaCl) diets and were subjected to invasive LV hemodynamic analysis after 8, 12 and 16 weeks of dietary intervention. Reverse transcription-quantitative PCR and western blot analysis were performed to investigate the expression of autophagy-associated key components. The LV morphologic staining was performed at the end of the study. The rat H9c2 ventricular myoblast cell-associated experiments were performed to explore the mechanism of HS induced autophagic change. A global autophagy-associated key component, as well as increased cardiomyocyte autophagic vacuolization, was observed after 12 weeks of HS intake. During this period, the heart from HS-diet-fed SHR exhibited a transition from compensated LV hypertrophy to decompensation, as shown by progressive impairment of LV function and interstitial fibrosis. Myocardial extracellular [Na+] and the expression of tonicity-responsive enhancer binding protein (TonEBP) was significantly increased in HS-fed rats, indicating myocardial interstitial hypertonicity by chronic HS intake. The global autophagic change and overt deterioration of LV function were not observed in LS-fed SHR and HS-fed WKY rats. The study of rat H9c2 cardiomyocytes demonstrated a cytosolic [Na+] elevation-mediated, reactive oxygen species-dependent the autophagic change occurred when exposed to an increased extracellular [Na+]. The present findings demonstrated that a myocardial autophagic change participates in the maladaptive LV remodeling induced by chronic HS intake in SHR, which provides a possible target for future intervention studies on HS-induced hypertensive LV remodeling.

Determinants and Assembly Mechanism of Bacterial Community Structure in Ningxia Section of the Yellow River.

The Yellow River is a valuable resource in the Ningxia Hui Autonomous Region and plays a vital role in local human activities and biodiversity. Bacteria are a crucial component of river ecosystems, but the driving factors and assembly mechanisms of bacterial community structure in this region remain unclear. Herein, we documented the bacterial community composition, determinants, co-occurrence pattern, and assembly mechanism for surface water and sediment. In comparison to sediment, the bacterioplankton community showed significant seasonal variation, as well as less diversity and abundance. The network topology parameters indicated that the sediment bacterial network was more stable than water, but the bacterioplankton network had higher connectivity. In this lotic ecosystem, CODMn, Chl a, and pH affected the structure of the bacterioplankton community, while TP was the primary factor influencing the structure of the sediment bacterial community. The combined results of the neutral community model and the phylogenetic null model indicate that Bacterial communities in both habitats were mainly affected by stochastic processes, with ecological processes dominated by ecological drift for bacterioplankton and dispersal limitation for sediment bacteria. These results provide essential insights into future research on microbial ecology, environmental monitoring, and classified management in the Ningxia section of the Yellow River.

Kinetic Resolution of ß-Alkyl Phenylethylamine Derivatives through Palladium-Catalyzed, Nosylamide-Directed C-H Olefination.

Palladium-catalyzed C-H activation reactions have attracted the attention of organic researchers due to their unique high selectivity, broad functional group tolerance, and high efficiency, and they are widely used in natural products and asymmetric synthesis. Here, we report an example of enantioselective C-H alkenylation between ß-alkyl phenylethylamine compounds and styrenes with Boc-L-lle-OH as the ligand and nosylamide as the directing group. This reaction is applicable to styrene containing various electron-deficient and electron-donating substitutions and may be utilized for the synthesis of benzoazepine compounds.

Crizotinib-based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation.

As one of the common malignant cancer types, gastric cancer (GC) is known for late-stage diagnosis and poor prognosis. Overexpression of the receptor tyrosine kinase MET is associated with poor prognosis among patients with advanced stage GC. However, no MET inhibitor has been used for GC treatment. Like other tyrosine kinase inhibitors that fit the "occupancy-driven" model, current MET inhibitors are prone to acquired resistance. The emerging proteolysis targeting chimera (PROTAC) strategy could overcome such limitations through direct degradation of the target proteins. In this study, we successfully transformed the MET-targeted inhibitor crizotinib into a series of PROTACs, recruiting cereblon/cullin 4A E3 ubiquitin ligase to degrade the MET proteins. The optimized lead PROTAC (PRO-6 E) effectively eliminated MET proteins in vitro and in vivo, inhibiting proliferation and motility of MET-positive GC cells. In the MKN-45 xenograft model, PRO-6 E showed pronounced antitumor efficacy with a well-tolerated dosage regimen. These results validated PRO-6 E as the first oral PROTAC for MET-dependent GC.

A Music-Driven Deep Generative Adversarial Model for Guzheng Playing Animation.

To date relatively few efforts have been made on the automatic generation of musical instrument playing animations. This problem is challenging due to the intrinsically complex, temporal relationship between music and human motion as well as the lacking of high quality music-playing motion datasets. In this article, we propose a fully automatic, deep learning based framework to synthesize realistic upper body animations based on novel guzheng music input. Specifically, based on a recorded audiovisual motion capture dataset, we delicately design a generative adversarial network (GAN) based approach to capture the temporal relationship between the music and the human motion data. In this process, data augmentation is employed to improve the generalization of our approach to handle a variety of guzheng music inputs. Through extensive objective and subjective experiments, we show that our method can generate visually plausible guzheng-playing animations that are well synchronized with the input guzheng music, and it can significantly outperform the state-of-the-art methods. In addition, through an ablation study, we validate the contributions of the carefully-designed modules in our framework.

Small-molecule PROTAC mediates targeted protein degradation to treat STAT3-dependent epithelial cancer.

The aberrant activation of STAT3 is associated with the etiology and progression in a variety of malignant epithelial-derived tumors, including head and neck squamous cell carcinoma (HNSCC) and colorectal cancer (CRC). Due to the lack of an enzymatic catalytic site or a ligand-binding pocket, there are no small-molecule inhibitors directly targeting STAT3 that have been approved for clinical translation. Emerging proteolysis targeting chimeric (PROTAC) technology-based approach represents a potential strategy to overcome the limitations of conventional inhibitors and inhibit activation of STAT3 and downstream genes. In this study, the heterobifunctional small-molecule-based PROTACs are successfully prepared from toosendanin (TSN), with 1 portion binding to STAT3 and the other portion binding to an E3 ubiquitin ligase. The optimized lead PROTAC (TSM-1) exhibits superior selectivity, potency, and robust antitumor effects in STAT3-dependent HNSCC and CRC - especially in clinically relevant patient-derived xenografts (PDX) and patient-derived organoids (PDO). The following mechanistic investigation identifies the reduced expression of critical downstream STAT3 effectors, through which TSM-1 promotes cell cycle arrest and apoptosis in tumor cells. These findings provide the first demonstration to our knowledge of a successful PROTAC-targeting strategy in STAT3-dependent epithelial cancer.

Broadband Terahertz Detection by Laser Plasma with Balanced Optical Bias.

Using a controlled optical bias and balanced geometry, we propose a new scheme for broadband terahertz detection by laser-gas interaction without high-voltage manipulation. Compared to the conventional optical bias scheme, the common noise is reduced and the dynamic range as well as the signal-to-noise ratio are doubled. It provides a simple alternative for coherent broadband terahertz detection. The influence of optical bias on terahertz waveform is also investigated, and the evolution of the terahertz-induced second harmonic with probe delay is further revealed. This new detection scheme for broadband terahertz will boost the application of terahertz time-domain spectroscopy for its miniaturization and integrability.

A Preliminary Study of Bacterioplankton Community Structure in the Taiyangshan Wetland in Ningxia and Its Driving Factors.

The Taiyangshan Wetland, a valuable wetland resource in the arid zone of central Ningxia, is critical for flood storage and drought resistance, climate regulation, and biodiversity protection. Nevertheless, the community structure and diversity of bacterioplankton in the Taiyangshan Wetland remains unclear. High-throughput sequencing was used to analyze the differences in bacterioplankton structure and major determinants in the Taiyangshan Wetland from April to October 2020. The composition and diversity of the bacterioplankton community varied significantly in different sampling periods but showed negligible differences across lake regions. Meanwhile, the relative abundances of bacterioplankton Bacteroidetes, Actinobacteria, Firmicutes, Chloroflexi, Tenericutes, Epsilonbacteraeota, and Patescibacteria were significantly different in different sampling periods, while the relative abundances of Cyanobacteria in different lake regions were quite different. Network analysis revealed that the topological attributes of co-occurrence pattern networks of bacterioplankton were high, and bacterioplankton community compositions were complicated in the month of July. A mantel test revealed that the bacterioplankton community in the entire wetland was affected by water temperature, electrical conductivity, dissolved oxygen, salinity, total nitrogen, ammonia nitrogen, chemical oxygen demand, fluoride, and sulfate. The bacterioplankton community structure was affected by ten environmental parameters (e.g., water temperature, dissolved oxygen, salinity, and permanganate index) in April, while the bacterioplankton community was only related to 1~2 environmental parameters in July and October. The bacterioplankton community structure in Lake Region IV was related to seven environmental parameters, including dissolved oxygen, pH, total nitrogen, and chemical oxygen demand, whereas the bacterioplankton community structures in the other three lake regions were related to two environmental parameters. This study facilitates the understanding of the bacterioplankton community in wetlands in arid areas and provides references to the evaluation of aquatic ecological management of the Taiyangshan Wetland.

A theoretical study based on DFT calculations on the different influence of functional groups on the C-H activation process via Pd-catalysed ß-X elimination.

We have performed a series of theoretical calculations for palladium-catalyzed ß-X elimination reactions. The DFT calculation combined with energy decomposition analysis shows the determining factors of reactivity. Such as, the elemental composition, the structure of different functional groups and the stronger steric repulsions contribution.

Theoretical analysis of expanded porphyrins: Aromaticity, stability, and optoelectronic properties.

Expanded porphyrin systems are capable of binding a variety of substrates due to their increased cavity size and aromatic nature, holding important applications as magnetic resonance imaging contrast agents and as sensitizers for photodynamic therapy. It is there of fundamental interest to know the photoelectrical properties of expanded porphyrins using quantum chemistry calculations. In this work, we theoretically designed and screened a series of expanded porphyrins by incorporating terthiophene (TTH) and dithienothiophene (DTT) moieties. Our calculations showed that all the designed molecules exhibit excellent optoelectronic performance than the reference molecule. It is suggested that the porphyrin molecule with TTH moiety has better stability than the one with DTT moiety. Finally, we demonstrated that molecule 2 features with TTH moiety and the inverted selenophene ring outperform other molecules because it exhibits increased HOMO-LUMO gap, planar geometry, and strengthened aromaticity. We expect that this work can provide theoretical guidelines for the design of novel porphyrin materials.

Antimicrobial and immunomodulatory activity of beta-defensin from the Chinese spiny frog (Quasipaa spinosa).

The ß-defensins are important components of the vertebrate innate immune system. While mammalian ß-defensins have wide-ranging antibacterial and immunomodulatory activities, those of amphibians remain largely uncharacterised. In this study, ß-defensin cDNA was identified from the skin transcriptome of the Chinese spiny frog Quasipaa spinosa. This ß-defensin (QS-BD) consists of a signal and a mature peptide. Sequence alignments with other amphibian ß-defensins showed conservation of the functional mature peptide and that its closest relative is ß-defensin from Zhangixalus puerensis. Synthetic QS-BD showed antibacterial activity against Vibrio vulnificus, Vibrio harveyi, Streptococcus iniae, and Aeromonas hydrophila. QS-BD showed bactericidal activity by destroying the cell membrane integrity, but did not hydrolyse genomic DNA. QS-BD treatment promoted respiratory bursts and upregulated the expression of interleukin-1ß and tumour necrosis factor-α in the murine leukemic monocyte/macrophage cell line RAW264.7. This is the first demonstration of immunomodulatory activity by an amphibian ß-defensin.

Synergistic effects of Rapamycin and Fluorouracil to treat a gastric tumor in a PTEN conditional deletion mouse model.

The tumor suppressor gene phosphatase and tensin homolog (PTEN) in PI3K/Akt/mTOR pathway is essential in inhibiting tumor growth and metastasis. However, whether the mutation of PTEN gene could induce tumorigenesis and impact the treatment of gastric cancer is still unclear. The purpose of the study was to investigate the combined treatment of gastric tumorigenesis using Rapamycin and Fluorouracil (5-Fu) through interfering with the Akt/mTOR pathway in a mouse model with PTEN conditional deletion. Three groups of mice were exposed for 5 days to Rapamycin and 5-Fu separately and together. The gene expression of the Akt/mTOR pathway, the protein expression of caspase-3 and p-Akt, p-S6K and p-4EBP1, and the pathological changes in stomachs were analyzed. Our study demonstrates that the conditional PTEN deletion in the cells of glandular stomach induces hyperplastic gastric tumors in mice. The combined Rapamycin administration with 5-Fu resulted in better outcomes than their separate administration for the treatment of gastric cancer by inhibiting the mTOR signal pathway. Our study indicates that Rapamycin has a synergistic interaction with chemotherapeutic 5-Fu, and demonstrates a potential therapeutic combination treatment on glandular stomach tumor with PTEN functional absence or aberrantly activated Akt/mTOR pathway. It provides important insights into the inhibition of the Akt/mTOR pathway in gastric cancer clinical therapy.

First record of Bursaphelenchus hildegardae Braasch et al., 2006 (Nematoda) in New Zealand with updated information on morphology, sequencing and a key to species of the eggersi-group.

Bursaphelenchus hildegardae Braasch et al., 2006 was collected from pine wood (Pinus radiata) growing in Kaingaroa Timberlands, and a bark beetle, Hylastes ater Paykull, 1800 in New Zealand. This is a new record for B. hildegardae, occuring in New Zealand, and the second report from the southern hemisphere in addition to Australia. In general, the New Zealand isolate of B. hildegardae corresponds well with the description of B. hildegardae given by Braasch et al. (2006) from Germany. The New Zealand isolate is characterized by having an adult body length of 8071190 m, medium a ratios (47.558.5 for female and 44.660.1 for male), b ratios of 9.814.5 (female) and 10.212.7 (male), c ratios of 18.825.2 (female) and 21.632.4 (male), c ratios of 4.04.4 (female) and 2.12.7 (male), and is characterised by having three incisures in the lateral fields, thorn-shaped spicules with a distinctly dorsally-bent thin hook-like condylus, and a dorso-ventally visible terminal bursa. In addition, molecular phylogeny using near full length small subunit (SSU), D2/D3 expansion segments of the large subunit (LSU) and the internal transcribed spacer region (ITS1 and 2) of the ribosomal rDNA supports the identification. A key to Bursaphelenchus species in the eggersi-group is given.