[Gualou Xiebai Banxia Decoction treats type 2 diabetes mellitus combined with acute myocardial infarction via chemerin/ CMKLR1/PPARα signaling pathway].

This study aims to investigate the effects of Gualou Xiebai Banxia Decoction(GXBD) on type 2 diabetes mellitus(T2DM) combined with acute myocardial infarction(AMI) in rats via chemerin/chemokine-like receptor 1(CMKLR1)/peroxisome proliferator-activated receptor α(PPARα) signaling pathway, and to explore the mechanism of GXBD in alleviating glucose and lipid metabolism disorders. The SD rats were randomized into control, model, positive control, and low-and high-dose GXBD groups. The rat model of T2DM was established by administration with high-fat emulsion(HFE) by gavage and intraperitoneal injection with streptozotocin, and then coronary artery ligation was performed to induce AMI. The control and model groups were administrated with the equal volume of normal saline, and other groups were administrated with corresponding drugs by gavage. Changes in relevant metabolic indicators were assessed by ELISA and biochemical assays, and the protein levels of chemerin, CMKLR1, and PPARα in the liver, abdominal fat, and heart were determined by Western blot. The results showed that GXBD alleviated the myocardial damage and reduced the levels of blood lipids, myocardial enzymes, and inflammatory cytokines, while it did not lead to significant changes in blood glucose. Compared with the model group, GXBD down-regulated the expression of chemerin in peripheral blood and up-regulated the expression of cyclic adenosine monophosphate(cAMP) and protein kinase A(PKA) in the liver. After treatment with GXBD, the protein levels of chemerin and CMKLR1 in the liver, abdominal fat, and heart were down-regulated, while the protein levels of PPARα in the liver and abdominal fat were up-regulated. In conclusion, GXBD significantly ameliorated the disorders of glycolipid metabolism in the T2DM-AMI model by regulating the chemerin/CMKLR1/PPARα signaling pathway to exert a protective effect on the damaged myocardium. This study provides a theoretical basis for further clinical study of GXBD against T2DM-AMI and is a manifestation of TCM treatment of phlegm and turbidity causing obstruction at the protein level.

Prediction of pCR based on clinical-radiomic model in patients with locally advanced ESCC treated with neoadjuvant immunotherapy plus chemoradiotherapy.

Background: The primary objective of this research is to devise a model to predict the pathologic complete response in esophageal squamous cell carcinoma (ESCC) patients undergoing neoadjuvant immunotherapy combined with chemoradiotherapy (nICRT). Methods: We retrospectively analyzed data from 60 ESCC patients who received nICRT between 2019 and 2023. These patients were divided into two cohorts: pCR-group (N = 28) and non-pCR group (N = 32). Radiomic features, discerned from the primary tumor region across plain, arterial, and venous phases of CT, and pertinent laboratory data were documented at two intervals: pre-treatment and preoperation. Concurrently, related clinical data was amassed. Feature selection was facilitated using the Extreme Gradient Boosting (XGBoost) algorithm, with model validation conducted via fivefold cross-validation. The model's discriminating capability was evaluated using the area under the receiver operating characteristic curve (AUC). Additionally, the clinical applicability of the clinical-radiomic model was appraised through decision curve analysis (DCA). Results: The clinical-radiomic model incorporated seven significant markers: postHALP, ΔHB, post-ALB, firstorder_Skewness, GLCM_DifferenceAverage, GLCM_JointEntropy, GLDM_DependenceEntropy, and NGTDM_Complexity, to predict pCR. The XGBoost algorithm rendered an accuracy of 0.87 and an AUC of 0.84. Notably, the joint omics approach superseded the performance of solely radiomic or clinical model. The DCA further cemented the robust clinical utility of our clinical-radiomic model. Conclusion: This study successfully formulated and validated a union omics methodology for anticipating the therapeutic outcomes of nICRT followed by radical surgical resection. Such insights are invaluable for clinicians in identifying potential nICRT responders among ESCC patients and tailoring optimal individualized treatment plans.

Photoinduced Decarboxylative Difluoroalkylation and Perfluoroalkylation of α-Fluoroacrylic Acids.

Herein, a novel and practical methodology for the photoinduced decarboxylative difluoroalkylation and perfluoroalkylation of α-fluoroacrylic acids is reported. A wide range of α-fluoroacrylic acids can be used as applicable feedstocks, allowing for rapid access to structurally important difluoroalkylated and polyfluoroalkylated monofluoroalkenes with high Z-stereoselectivity under mild conditions. The protocol demonstrates excellent functional group compatibility and provides a platform for modifying complex biologically active molecules.

Neutrophil extracellular traps promote acetaminophen-induced acute liver injury in mice via AIM2.

Excessive acetaminophen (APAP) can induce neutrophil activation and hepatocyte death. Along with hepatocyte dysfunction and death, NETosis (a form of neutrophil-associated inflammation) plays a vital role in the progression of acute liver injury (ALI) induced by APAP overdose. It has been shown that activated neutrophils tend to migrate towards the site of injury and participate in inflammatory processes via formation of neutrophil extracellular traps (NETs). In this study we investigated whether NETs were involved in hepatocyte injury and contributed to APAP-induced ALI progression. ALI mouse model was established by injecting overdose (350 mg/kg) of APAP. After 24 h, blood and livers were harvested for analyses. We showed that excessive APAP induced multiple programmed cell deaths of hepatocytes including pyroptosis, apoptosis and necroptosis, accompanied by significantly increased NETs markers (MPO, citH3) in the liver tissue and serum. Preinjection of DNase1 (10 U, i.p.) for two consecutive days significantly inhibited NETs formation, reduced PANoptosis and consequently alleviated excessive APAP-induced ALI. In order to clarify the communication between hepatocytes and neutrophils, we induced NETs formation in isolated neutrophils, and treated HepaRG cells with NETs. We found that NETs treatment markedly increased the activation of GSDMD, caspase-3 and MLKL, while pre-treatment with DNase1 down-regulated the expression of these proteins. Knockdown of AIM2 (a cytosolic innate immune receptor) abolished NETs-induced PANoptosis in HepaRG cells. Furthermore, excessive APAP-associated ALI was significantly attenuated in AIM2KO mice, and PANoptosis occurred less frequently. Upon restoring AIM2 expression in AIM2KO mice using AAV9 virus, both hepatic injury and PANoptosis was aggravated. In addition, we demonstrated that excessive APAP stimulated mtROS production and mitochondrial DNA (mtDNA) leakage, and mtDNA activated the TLR9 pathway to promote NETs formation. Our results uncover a novel mechanism of NETs and PANoptosis in APAP-associated ALI, which might serve as a therapeutic target.

Non-thyroidal disease syndrome in patients with systemic lupus erythematosus: relation to disease inflammatory activity.

OBJECTIVE: To identify risk factors for the development of non-thyroidal illness syndrome (NTIS) in patients with systemic lupus erythematosus (SLE). METHODS: A retrospective analysis of 517 SLE patients and 1034 age-and sex-matched healthy population was conducted to compare the prevalence of NTIS in these two groups, and to analyze the laboratory and clinical characteristics of SLE patients with NTIS. Finally Logistic regression analysis was used to determine the risk factors for NTIS in SLE patients. RESULTS: The prevalence of NTIS in the SLE patients was significantly higher than that in controls (39.7% vs. 1.0%, P < 0.001). In SLE patients, compared with euthyroidism patients, NTIS patients exhibited higher levels of neutrophils, hepatic enzymes, kidney damage markers, inflammatory markers and SLE disease activity index (SLEDAI). They also had a higher incidence of organ insufficiency and positive antibodies such as anti-ds-DNA antibodies and anti-SSA antibodies. However, NTIS patients had lower levels of hemoglobin, lymphocytes, platelets, serum albumin, and complement. Additionally, NTIS patients had a shorter duration of lupus and lower utilization of disease-modifying antirheumatic drugs (DMARDs) (P < 0.05). Logistic regression analysis showed that elevated SLEDAI (OR = 1.060, 95%CI 1.022-1.099, P = 0.002), elevated systemic immune-inflammation index (SII) (OR = 1.003, 95%CI 1.001-1.007, P = 0.026), elevated erythrocyte sedimentation rate (ESR) (OR = 1.019, 95%CI 1.010-1.028, P < 0.001), and hepatic insufficiency (OR = 1.916, 95% CI 1.173-3.131, P = 0.009) were independent risk factors for the development of NTIS in SLE. DMARDs treatment (OR = 0.495, 95% CI 0.306-0.799, P < 0.001) was an independent protective factor for NTIS. CONCLUSIONS: Inflammatory activity in SLE patients is associated with the development of NTIS. Key Points • Inflammatory activity indexes such as SLEDAI, SII, and ESR are independent risk factors for NTIS in SLE patients.

Ion-Concentration-Hopping Heterolayer Gel for Ultrahigh Gradient Energy Conversion.

Conventional solid ion channel systems relying on single one- or two-dimensional confined nanochannels enabled selective and ultrafast convective ion transport. However, due to intrinsic solid channel stacking, these systems often face pore-pore polarization and ion concentration blockage, thereby restricting their efficiency in macroscale ion transport. Here, we constructed a soft heterolayer-gel system that integrated an ion-selective hydrogel layer with a water-barrier organogel layer, achieving ultrahigh cation selectivity and flux and effectively providing high-efficiency gradient energy conversion on a macroscale order of magnitude. Specifically, the hydrogel layer featured an unconfined 3D network, where the fluctuations of highly hydrated polyelectrolyte chains driven by thermal dynamics enhanced cation selectivity and mitigated transfer energy barriers. Such chain fluctuation mechanisms facilitated ion-cluster internal transmission, thereby enhancing ion concentration hopping for more efficient ion-selective transport. Compared to the existing rigid nanochannel-based gradient energy conversion systems, such a heterogel-based power generator exhibited a record power density of 192.90 and 1.07 W/m2 at the square micrometer scale and square centimeter scale, respectively (under a 500-fold artificial solution). We anticipate that such heterolayer gels would be a promising candidate for energy separation and storage applications.

Clinical difference on the variants and co-mutation in a Chinese cohort with ALK-positive advanced non-small cell lung cancer.

PURPOSE: Despite the generally favourable prognoses observed in patients with ALK-positive non-small cell lung cancer (NSCLC), there remains significant variability in clinical outcomes. The objective of this study is to enhance patient stratification by examining both the specific sites of gene fusion and the presence of co-occurring mutations. METHODS: We collected retrospective clinical and pathological data on ALK-positive patients with locally advanced or metastatic disease. ALK fusion variants and concomitant mutations were identified through next-generation sequencing technology. We then assessed treatment efficacy via tumor response and survival metrics. RESULTS: This study included a total of 59 patients, with 49 harboring echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusions and 10 presenting with rare fusions. The median follow-up period was 33 months. Clinical outcomes between non-EML4-ALK and EML4-ALK patients were comparable. Among the EML4-ALK cohort, patients with longer variants (v1, v2, v8) demonstrated superior progression-free survival (PFS) (median PFS: 34 months vs. 11 months; hazard ratio [HR]: 2.28; P = 0.05) compared to those with shorter variants (v3, v5). Furthermore, patients treated with second-generation ALK inhibitors (ALKi) displayed a progression-free survival advantage (median PFS: not reached [NR] vs. 9 months; HR: 5.37; P = 0.013). Baseline TP53 co-mutation were linked with a substantially shorter OS (median OS,37 months vs. NR; HR 2.74; P = 0.047). CONCLUSIONS: In ALK+ NSCLC, longer EML4-ALK variants correlate with improved prognosis and enhanced response to second-generation ALKi, while TP53 co-mutations indicate a negative prognosis.

Biomedical Applications of Sulfonylcalix[4]arene-Based Metal-Organic Supercontainers.

Coordination cages sustained by metal-ligand interactions feature polyhedral architectures and well-defined hollow structures, which have attracted significant attention in recent years due to a variety of structure-guided promising applications. Sulfonylcalix[4]arenes-based coordination cages, termed metal-organic supercontainers (MOSCs), that possess unique multi-pore architectures containing an endo cavity and multiple exo cavities, are emerging as a new family of coordination cages. The well-defined built-in multiple binding domains of MOSCs allow the efficient encapsulation of guest molecules, especially for drug delivery. Here, we critically discuss the design strategy, and, most importantly, the recent advances in research surrounding cavity-specified host-guest chemistry and biomedical applications of MOSCs.

Bicontinuous vitrimer heterogels with wide-span switchable stiffness-gated iontronic coordination.

Currently, it remains challenging to balance intrinsic stiffness with programmability in most vitrimers. Simultaneously, coordinating materials with gel-like iontronic properties for intrinsic ion transmission while maintaining vitrimer programmable features remains underexplored. Here, we introduce a phase-engineering strategy to fabricate bicontinuous vitrimer heterogel (VHG) materials. Such VHGs exhibited high mechanical strength, with an elastic modulus of up to 116 MPa, a high strain performance exceeding 1000%, and a switchable stiffness ratio surpassing 5 × 103. Moreover, highly programmable reprocessing and shape memory morphing were realized owing to the ion liquid-enhanced VHG network reconfiguration. Derived from the ion transmission pathway in the ILgel, which responded to the wide-span switchable mechanics, the VHG iontronics had a unique bidirectional stiffness-gated piezoresistivity, coordinating both positive and negative piezoresistive properties. Our findings indicate that the VHG system can act as a foundational material in various promising applications, including smart sensors, soft machines, and bioelectronics.

Design, synthesis and biological evaluation of rhein-piperazine-furanone hybrids as potential anticancer agents.

Novel rhein-piperazine-furanone hybrids, 5, were designed and synthesized efficiently from rhein. Cytotoxicity of all hybrids 5a-j against A549 human lung cancer cells was superior to the parent rhein and the reference cytarabine (CAR). Hybrid 5e (IC50 = 5.74 µM), the most potent compound, was 46- and 35-fold more toxic against A549 cells than rhein (IC50 = 265.59 µM) and CAR (IC50 = 202.57 µM), respectively. Moreover, hybrid 5e (IC50 = 69.28 µM) was less toxic to normal WI-38 human lung fibroblast cells with good selectivity (WI-38/A549, SI ≈ 12), being much higher than rhein (SI ≈ 1) and CAR (SI ≈ 2). Structure-activity relationship (SAR) analysis showed that cytotoxicity and selectivity against A549 lung cancer cells were greatly enhanced when methoxy-containing furanone was introduced to the hybrids (5e and 5h). Further, hybrid 5e showed better cytotoxicity against four types of human lung cancer cells (H460, A549, PC-9, and Calu-1; IC50 = 4.35-15.39 µM) than six other types of human cancer cells (SK-BR-3, SK-OV-3, 786-O, Huh-7, HCT116, and HeLa; IC50 = 13.77-60.45 µM), showing specificity. In particular, hybrid 5e showed the highest cytotoxicity (IC50 = 4.35 µM) and the highest selectivity (WI-38/H460, SI ≈ 16) against H460 human lung cancer cells. Flow cytometric analysis showed that hybrid 5e induced apoptosis in a concentration-dependent manner in H460 cells. The results show that the cytotoxicity and selectivity of rhein can be greatly enhanced by hybridization with furanone. Hybrid 5e is expected to be a leading candidate for anti-lung cancer drugs.

The miR6445-NAC029 module regulates drought tolerance by regulating the expression of glutathione S-transferase U23 and reactive oxygen species scavenging in Populus.

MicroRNAs are essential in plant development and stress resistance, but their specific roles in drought stress require further investigation. Here, we have uncovered that a Populus-specific microRNAs (miRNA), miR6445, targeting NAC (NAM, ATAF, and CUC) family genes, is involved in regulating drought tolerance of poplar. The expression level of miR6445 was significantly upregulated under drought stress; concomitantly, seven targeted NAC genes showed significant downregulation. Silencing the expression of miR6445 by short tandem target mimic technology significantly decreased the drought tolerance in poplar. Furthermore, 5' RACE experiments confirmed that miR6445 directly targeted NAC029. The overexpression lines of PtrNAC029 (OE-NAC029) showed increased sensitivity to drought compared with knockout lines (Crispr-NAC029), consistent with the drought-sensitive phenotype observed in miR6445-silenced strains. PtrNAC029 was further verified to directly bind to the promoters of glutathione S-transferase U23 (GSTU23) and inhibit its expression. Both Crispr-NAC029 and PtrGSTU23 overexpressing plants showed higher levels of PtrGSTU23 transcript and GST activity while accumulating less reactive oxygen species (ROS). Moreover, poplars overexpressing GSTU23 demonstrated enhanced drought tolerance. Taken together, our research reveals the crucial role of the miR6445-NAC029-GSTU23 module in enhancing poplar drought tolerance by regulating ROS homeostasis. This finding provides new molecular targets for improving the drought resistance of trees.

A retrospective analysis of optimal timing of thoracic radiotherapy for driver gene-negative metastatic non-small cell lung cancer.

BACKGROUND: The optimal timing of thoracic radiotherapy (TRT) in driver-gene-negative metastatic non-small cell lung cancer (mNSCLC) patients was retrospectively investigated based on survival and safety profile. METHODS: The efficacy and safety data of driver-gene-negative mNSCLC patients treated with TRT during maintenance after first-line therapy was collected. Patients whose primary tumor and metastatic lesions remained no progression during maintenance and then received TRT were categorized as the NP (no progression) group, while patients who experienced slow progression during maintenance without reaching progressive disease and then received TRT were categorized as the SP (slow progression) group. The efficacy and adverse events of TRT were analyzed. RESULTS: In total, 149 driver-gene-negative mNSCLC patients treated with TRT during maintenance were enrolled into the study, with 119 in the NP group and 30 in the SP group. After a median follow-up of 30.83 (range: 26.62-35.04) months, the median progression-free survival (PFS) in the NP group was 11.13 versus 9.53 months in the SP group (HR 0.599, p = 0.017). The median overall survival (OS) in the NP group was 32.27 versus 25.57 months in the SP group (HR 0.637, p = 0.088). The median PFS after radiotherapy (rPFS) was 6.33 versus 3.90 months (HR 0.288, p < 0.001). The adverse events were tolerable and manageable in both groups without significant difference (p > 0.05). CONCLUSION: The addition of TRT during the pre-emptive no progression phase was associated with a significantly longer PFS than during the delayed slow progression phase and had an acceptable safety profile. Our results might support the earlier initiation of TRT after induction therapy for some patients with driver-gene-negative mNSCLC.

First Reports of Cladosporium tenuissimum Causing Leaf spots on Hydrangea macrophylla in Anhui province in China.

Forever Summer Hydrangea (Hydrangea macrophylla) is a common flowering plant in the Yangtze River Valley area of China, and it is widely cultivated globally (Chen et al. 2015). In July 2023, H. macrophylla leaves exhibiting visible diseased lesions were reported in a nursery in Wuhu, Anhui Province, China. The incidence reached 40% in a 0.2 ha area. The primary disease symptom was multiple irregular necrotic spots (0.5 to 1 mm in diameter) appearing on the leaves. These spots on the leaves were faded yellow around the perimeter and grayish brown in the center.). 15 leaf samples were sterilized with 75% alcohol and rinsed three times in sterile distilled water, then transferred to antibiotic-added potato dextrose agar (PDA) for incubation at 27°C. The colonies were fluffy, flocculent, or hairy, dark green, gray-green to gray-brown in color, and spreading or protruding punctate with a colorless halo on PDA. The conidiophores were brown to dark brown, smooth or rough surface, mostly unbranched, clearly differentiated, erect or curved. The conidia displayed a light brown to brown hue, lemon shape, fusiform, elongated ellipsoid or others with obvious spore markings and spore umbilicus. Genomic DNA was extracted from fungal colonies on infected leaves of three collections separately (Braun et al. 2003) and the internal transcribed spacer regions (ITS), actin (ACT) genes and partial translation elongation factor-l-alpha (EF) were amplified and sequenced using the primers ITS1/4 (Yin et al. 2012), ACT-512F/ACT-783R and EF 1-728F/986R (Carbone and Kohn 1999), respectively. DNA sequences of isolates were identical and deposited in GenBank (accession no. OR362754 for ITS, OR611929 for ACT and PP209106 for EF). The consensus sequences from ITS, EF and ACT showed 100%, 98.98% and 100% identical to Cladosporium strains (accession no. OQ186140.1, MT154169.1 and OL322092.1), respectively. To confirm the pathogenicity of the isolates, hydrangeas were planted in 15-cm pots containing commercial potting mix (one plant/pot). Three healthy plants were inoculated at the five to eight leaf stage by spraying 50 µL of the isolate conidial suspension (4 × 106 spores/mL) on healthy leaves. Three plants treated with sterile distilled water were used as controls. After inoculation, all plants were placed in a humidity chamber (>95% relative humidity, 26°C) for 48 h and then transferred to a greenhouse at 22/27°C. All inoculated leaves exhibited symptoms similar to those observed in the nursery 10 days after inoculation, while no symptoms were observed for control leaves. The fungus was re-isolated and confirmed to be C. tenuissimum. Based on the above morphological characterization and molecular identification, the causal agent for this leaf spot disease was identified as C. tenuissimum. Although C. tenuissimum has been reported to cause disease on H. paniculata in northern China (Li et al.2021), this is the first time that C. tenuissimum has been found on H. macrophylla in southern China. This new disease of H. macrophylla caused by C. tenuissimum is a threat to urban greening and is worth further investigation.

[Advances in the applications of exposomics in the identification of environmental pollutants and their health hazards].

Environmental pollution has become a prominent global problem, and the potential health hazards of pollutants have caused widespread concern. However, revealing the relationship between complex-pollutant exposure and disease development remains an immense challenge. The core of environmental-health research and risk assessment is the identification of contaminants and their effects. Exposomics provides a new approach in the study of the relationship between environmental factors and human health. Both "top-down" and "bottom-up" strategies are employed in exposomics research. The development of new technologies for chemical detection and "multi-omics" has greatly facilitated the implementation of these strategies. Exposomics focuses on the measurement of an individual's lifelong exposure and aims to identify the health effects of such exposure. It involves the dynamic monitoring of external and internal exposure levels at different stages of life through traditional biomonitoring and exposomic methods. It also includes the identification of biomarkers, which indicate specific environmental exposures and the adverse effects of these exposures on health. Compared with traditional environmental-health studies, exposomics can more accurately reflect the diversity of exposure factors such as pollutants, natural factors, and lifestyles in the real environment, as well as the complexity of their in vivo processes and the responses they trigger in an organism. Powerful chemical analytical tools such as high-resolution mass spectrometry (HRMS) are widely used in studies related to the field of exposomics. Liquid chromatography-mass spectrometry (LC-MS) has been applied in the detection and analysis of environmental pollutants. Proteomics and metabolomics, as two important tools for biomarker identification and effects analysis, are widely used to explore the relationship between environmental factors and diseases. Pollutants can lead to pathological changes and even toxic effects by interacting with proteins. In the case of mixed exposure, some contaminants may present joint toxicity. The interaction between contaminants may change their environmental behavior or the amount of each contaminant that enters the human body, which, in turn, affects their health effects.

Survival outcomes of targeted and immune consolidation therapies in locally advanced unresectable lung adenocarcinoma.

BACKGROUND: Locally advanced non-small cell lung cancer (LA-NSCLC) presents unique challenges due to its progression and tumor heterogeneity. The effectiveness of consolidation therapies, particularly in patients with gene mutations, remains an area of active investigation. METHODS: In this retrospective cohort study, we examined data from 3,454 patients with unresectable lung adenocarcinoma (LUAD), narrowing our focus to 242 individuals with stage II/III. We gathered patient data, such as demographics, ECOG status, histology, treatment specifics, and gene expression, from patients in China. The study's primary outcome was overall survival (OS), while progression-free survival (PFS) served as the secondary outcome. RESULTS: In this study, 50 % of the 242 patients underwent only radical chemoradiotherapy, with 45.87 % (111/242) exhibiting driver gene mutations, predominantly EGFR (58.57 %), followed by KRAS and ALK. Patients with mutations who received either targeted or immune consolidation therapy demonstrated a significantly longer median PFS (42.97 months vs. 24.87 months, p = 0.014) and improved OS (not reached vs. 24.37 months, p = 0.006), compared to those without consolidation therapy. Targeted therapy in mutant patients resulted in an extended median PFS (42.87 months) compared to immune therapy (27.03 months, p = 0.029), with no significant difference in OS. Median PFS and OS were similar between mutant and wild-type patients receiving immune therapy (p = 0.380 and p = 0.928, respectively). CONCLUSION: This study underscores the efficacy of targeted consolidation therapy in enhancing PFS in LUAD patients with genetic mutations. It also shows that immune consolidation therapy provides similar survival benefits to mutant and wild-type patients. Future research should focus on optimizing these therapies for improved patient outcomes.

Coarse particles compensate for missing daytime sources of nitrous acid and enhance atmospheric oxidation capacity in a coastal atmosphere.

Large missing sources of daytime atmospheric nitrous acid (HONO), a vital source of hydroxyl radicals (OH) through its photolysis, frequently exist in global coastal regions. In this study, ambient HONO and relevant species were measured at a coastal site in the Pearl River Delta (PRD), China, during October 2019. Relatively high concentrations (0.32 ± 0.19 ppbv) and daytime peaks at approximately 13:00 of HONO were observed, and HONO photolysis was found to be the dominant (55.5 %) source of the primary OH production. A budget analysis of HONO based on traditional sources suggested large unknown sources during the daytime (66.4 %), which had a significant correlation with the mass of coarse particles (PM2.5-10) and photolysis frequency (J(NO2)). When incorporating photolysis of the abundant nitrate measured in coarse particles with a reasonable enhancement factor relative to fine particles due to favorable aerosol conditions, the missing daytime sources of HONO could be fully compensated by coarse particles serving as the largest source at this coastal site. Our study revealed great potential of coarse particles as a strong daytime HONO source, which has been ignored before but can efficiently promote NOx recycling and thus significantly enhance atmospheric oxidation capacity.

Comprehensive assessment of fine motor movement and cognitive function among older adults in China: a cross-sectional study.

BACKGROUND: Fine motor skills are closely related to cognitive function. However, there is currently no comprehensive assessment of fine motor movement and how it corresponds with cognitive function. To conduct a complete assessment of fine motor and clarify the relationship between various dimensions of fine motor and cognitive function. METHODS: We conducted a cross-sectional study with 267 community-based participants aged ≥ 60 years in Beijing, China. We assessed four tests performance and gathered detailed fine motor indicators using Micro-Electro-Mechanical System (MEMS) motion capture technology. The wearable MEMS device provided us with precise fine motion metrics, while Chinese version of the Montreal Cognitive Assessment (MoCA) was used to assess cognitive function. We adopted logistic regression to analyze the relationship between fine motor movement and cognitive function. RESULTS: 129 (48.3%) of the participants had cognitive impairment. The vast majority of fine motor movements have independent linear correlations with MoCA-BJ scores. According to logistic regression analysis, completion time in the Same-pattern tapping test (OR = 1.033, 95%CI = 1.003-1.063), Completion time of non-dominant hand in the Pieces flipping test (OR = 1.006, 95%CI = 1.000-1.011), and trajectory distance of dominant hand in the Pegboard test (OR = 1.044, 95%CI = 1.010-1.068), which represents dexterity, are related to cognitive impairment. Coordination, represented by lag time between hands in the Same-pattern tapping (OR = 1.663, 95%CI = 1.131-2.444), is correlated with cognitive impairment. Coverage in the Dual-hand drawing test as an important indicator of stability is negatively correlated with cognitive function (OR = 0.709, 95%CI = 0.6501-0.959). Based on the above 5-feature model showed consistently high accuracy and sensitivity at the MoCA-BJ score (ACU = 0.80-0.87). CONCLUSIONS: The results of a comprehensive fine-motor assessment that integrates dexterity, coordination, and stability are closely related to cognitive functioning. Fine motor movement has the potential to be a reliable predictor of cognitive impairment.

A strategy of accuracy quantification by extending the concentration monitoring coverage based on online double collision energy of ultra-high performance liquid chromatography tandem mass spectrometry: The pharmacokinetics of Toddalia asiatica as a case study.

To facilitate the safety, efficacy and rationality of clinical application of traditional Chinese medicines (TCMs), pharmacokinetic research played an indispensable role. The key challenge during pharmacokinetic investigation lied at the substantial fluctuation of compound concentrations in the plasma over the course of absorption. Taking the pharmacokinetics of six compounds after administration of Toddalia asiatica (TA) as an example, an efficient strategy was established by introducing the online double collision energy (ODCE) into the quantification process applying ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). During the analytical program, double collision energy (DCE) was optimized to establish the dual calibration curve (DCC) with large concentration monitoring coverage (CMC) for meeting the wide content range of certain target compounds. Method validation test was performed in terms of linearity, precision, sensitivity, matrix effect, recovery, etc. The results displayed that the CMC of todarolactone with high exposure in plasma was extended from 1.25-2,500 ng/mL to 1.25-125,000 ng/mL. Furthermore, a rapid UHPLC-MS/MS method integrated with ODCE was successfully applied to the determination of six compounds in rat plasma, revealing an extremely high plasma concentration of todarolactone (16,662 ng/mL). This strategy could expand the range of quantification while retaining extraordinary sensitivity. Consequently, it could be a fit-for-purpose strategy to quantify compounds over a wide concentration range for in vivo process monitoring.

The causal relationship between autoimmune thyroid disorders and telomere length: A Mendelian randomization and colocalization study.

This study aimed to evaluate whether there is a causal relationship between autoimmune thyroid disorders (AITDs) and telomere length (TL) in the European population and whether there is reverse causality. In this study, Mendelian randomization (MR) and colocalization analysis were conducted to assess the potential causal relationship between AITDs and TL using summary statistics from large-scale genome-wide association studies, followed by analysis of the relationship between TL and thyroid stimulating hormone and free thyroxine (FT4) to help interpret the findings. The inverse variance weighted (IVW) method was used to estimate the causal estimates. The weighted median, MR-Egger and leave-one-out methods were used as sensitivity analyses. The IVW method results showed a significant causal relationship between autoimmune hyperthyroidism and TL (ß = -1.93 × 10-2 ; p = 4.54 × 10-5 ). There was no causal relationship between autoimmune hypothyroidism and TL (ß = -3.99 × 10-3 ; p = 0.324). The results of the reverse MR analysis showed that genetically TL had a significant causal relationship on autoimmune hyperthyroidism (IVW: odds ratio (OR) = 0.49; p = 2.83 × 10-4 ) and autoimmune hypothyroidism (IVW: OR = 0.86; p = 7.46 × 10-3 ). Both horizontal pleiotropy and heterogeneity tests indicated the validity of our bidirectional MR study. Finally, colocalization analysis suggested that there were shared causal variants between autoimmune hyperthyroidism and TL, further highlighting the robustness of the results. In conclusion, autoimmune hyperthyroidism may accelerate telomere attrition, and telomere attrition is a causal factor for AITDs.

Primary versus acquired epidermal growth factor receptor Thr790Met mutant non-small cell lung cancer: clinical features and prognoses.

PURPOSE: This study aimed to identify the impact of epidermal growth factor receptor (EGFR) T790M mutations on clinical characteristics and prognosis. METHODS: Retrospective analyses were conducted on the differences on clinicopathological features and prognosis between primary and acquired T790M mutations. Subgroup analyses were performed for primary T790M coexisting with other mutations. RESULTS: Patients with primary T790M mutations showed a 60.53% (23/38) incidence of concurrent L858R mutations, 18.42% (7/38) for 19del mutations and a 21.05% (8/38) occurrence of brain metastases. Conversely, those with acquired T790M mutations demonstrated respective frequencies of 36.53% (61/167), 58.68% (98/167) and 44.31% (74/167), with all comparisons yielding p < 0.05. The median overall survival differed significantly between the two groups, with a duration of 33 months for patients with primary T790M mutations as compared to 48 months for those with acquired mutations (p = 0.030). Notably, among patients with L858R co-mutations, when treated with third-generation EGFR-TKIs, those with acquired T790M mutations experienced a significantly prolonged median time to treatment failure compared to those with primary mutations (17 months vs. 9 months, p = 0.009). CONCLUSION: Patients with primary T790M have unique molecular features and had worse prognosis compared with acquired T790M. Resistance to third-generation EGFR-TKIs seems to be associated with the presence of EGFR co-mutations.