CMG901, a Claudin18.2-specific antibody-drug conjugate, for the treatment of solid tumors.

Claudin18.2 has been recently recognized as a potential therapeutic target for gastric/gastroesophageal junction or pancreatic cancer. Here, we develop a Claudin18.2-directed antibody-drug conjugate (ADC), CMG901, with a potent microtubule-targeting agent MMAE (monomethyl auristatin E) and evaluate its preclinical profiles. In vitro studies show that CMG901 binds specifically to Claudin18.2 on the cell surface and kills tumor cells through direct cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and bystander killing activity. In vivo pharmacological studies show significant antitumor activity in patient-derived xenograft (PDX) models. Toxicity studies show that the major adverse effects related to CMG901 are reversible hematopoietic changes attributed to MMAE. The highest non-severely toxic dose (HNSTD) is 6 mg/kg in cynomolgus monkeys and 10 mg/kg in rats once every 3 weeks. CMG901's favorable preclinical profile supports its entry into the human clinical study. CMG901 is currently under phase 3 investigation in patients with advanced gastric/gastroesophageal junction adenocarcinoma expressing Claudin18.2 (NCT06346392).

Human umbilical cord mesenchymal stem cells-derived exosomes attenuate burn-induced acute lung injury via inhibiting ferroptosis.

Our previous study has shown that exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSCs-exo) alleviated burn-induced acute lung injury (ALI). In this study, we explored a novel mechanism by which hUCMSCs-exo contributed to the inhibition of burn-induced ALI. The ALI rat model with severe burn was established for the in vivo experiments, and rats PMVECs were stimulated with the serum from burn-induced ALI rats for the in vitro experiments. The pathological changes of lung tissues were evaluated by HE staining; the cell viability was measured using CCK-8; the iron level and Fe2+ concentration were assessed using Iron Assay Kit and Fe2+ fluorescence detection probe; the mRNA expression of SLC7A11 and GPX4 were measured by qRT-PCR; the protein levels of SLC7A11, GPX4, Nrf2 and HO-1 were detected by western blot. Both the in vivo and in vitro experiments revealed that ferroptosis was significantly induced in burn-induced ALI, which as verified by increased iron level and Fe2+ concentration, and decreased SLC7A11 and GPX4 mRNA and protein levels. Furthermore, both hUCMSCs-exo and Fer-1 (the inhibitor of ferroptosis) alleviated lung inflammation and up-regulated protein levels of Nrf2 and HO-1 in the lung tissues of burn-induced ALI rats. These results suggested that hUCMSCs-exo exhibited a protective role against burn-induced ALI by inhibiting ferroptosis, partly owing to the activation of Nrf2/HO-1 pathway, thus providing a novel therapeutic strategy for burn-induced ALI.

ZNF8 promotes progression of gastrointestinal cancers via a p53-dependent mechanism.

p53 is a critical tumor suppressor, and the disruption of its normal function is often a prerequisite for the development or progression of tumors. Our previous works revealed that multiple members of Krüppel-associated box (KRAB) domain zinc-finger proteins (KZFPs) family regulate p53 transcriptional activity by interacting with it. But the tumor biology functions of these members have not been fully elucidated. Here, the pan-cancer analysis related to gastrointestinal cancers (GICs) revealed that ZNF8, a p53-interacting protein, is an unfavorable prognostic factor for patients with malignancies. ZNF8 interacts with p53 and further depresses its transcriptional activity in colon cancer cells. The knockdown of ZNF8 or the overexpression of ZNF8 inhibits or facilitates the in vitro colony formation, migration, invasion, and angiogenesis of p53+/+ colon cancer HCT116 cells, HepG2 cells and EC109 cells rather than p53-/- colon cancer HCT116 cells and p53-knockout HepG2 cells, respectively. Xenograft experiments conducted in vivo also showed that the knockdown of ZNF8 in p53+/+ but not in p53-/- HCT116 cells curbs the tumor growth and metastasis to lung, leading to an extended life span for tumor-bearing mice. Clinically, two independent immunohistochemistry cohorts of colon cancer and esophageal cancer also indicated that ZNF8 is higher expression in carcinoma tissues than adjacent tissues and this is associated with worse overall survival outcomes in patients without harboring p53 mutation. Together, our results provide insight into the p53-specific tumor oncogenic function of ZNF8. ZNF8 may prove to be a potential target for GICs treatment.

Micro-macro SERS strategy for highly sensitive paper cartridge with trace-level molecular detection.

Surface-enhanced Raman Scattering (SERS) has become a powerful spectroscopic technology for highly sensitive detection. However, SERS is still limited in the lab because it either requires complicated preparation or is limited to specific compounds, causing poor applicability for practical applications. Herein, a micro-macro SERS strategy, synergizing polymer-assisted printed process with paper-tip enrichment process, is proposed to fabricate highly sensitive paper cartridges for sensitive practical applications. The polymer-assisted printed process finely aggregates nanoparticles with a discrete degree of 1.77, and SERS results are matched with theoretical enhancement, indicating small cluster-dominated hotspots at the micro-scale and thus 41-fold SERS increase compared to other aggregation methods. The paper-tip enrichment process moves molecules in a fluid into small tips filled with plasmonic clusters, and molecular localization at hotspots is achieved by the simulation and optimization of fluidic velocity at the macro-scale, generating a 39.5-fold SERS sensibility increase in comparison with other flow methods. A highly sensitive paper cartridge contains a paper-tip and a 3D-printed cartridge, which is simple, easy-to-operate, and costs around 2 US dollars. With a detection limit of 10 -12 M for probe molecules, the application of real samples and multiple analytes achieves single-molecule level sensitivity and reliable repeatability with a 30-min standardized procedure. The micro-macro SERS strategy demonstrates its potential in practical applications that require point-of-care detection.

Frailty trajectories and determinants in Chinese older adults: A longitudinal study.

OBJECTIVES: This study aimed to enrich the research on frailty trajectories by using FRAIL scale and frailty index (FI), and analyze the determinants of the different trajectories in older Chinese. METHODS: 2268 older adults from the Chinese Longitudinal Healthy Longevity Survey were included. The FRAIL scale was constructed from 5 items and FI was constructed from 39 deficits. Latent Class Trajectory Model was used to depict frailty trajectories. Lasso - logistic model was applied to exploration of influencing factors. RESULTS: Four FRAIL trajectories and three FI trajectories were identified. Women, smoking, illiteracy, more than two chronic diseases, and poor instrumental activities of daily living (all p < 0.05) were associated with frailty trajectories, regardless of the frailty instrument employed. CONCLUSIONS: Frailty trajectories of older Chinese adults are diverse and they are influenced by different frailty measurement tools. Long-term assessment and management of frailty are recommended as routine care in community healthcare centers.

Prevalence of Four Sexually Transmitted Infection Pathogens Detected in Urine and Genital Tract Secretion in Hangzhou, China.

BACKGROUND: Sexually transmitted infections (STIs) increase gradually and have become a public health problem in the world. UU, CT, NG, and MG are four common STI pathogens. Our retrospective study analyzed the clinical situation and the laboratory data of patients infected with the four pathogens. The prevalence of the four pathogens, detected in urine and genital tract secretion, was studied in Hangzhou, China. METHODS: A total of 3,168 male and female patients were randomly selected from February 2023 to February 2024. Urine and genital secretions were collected, and four STI pathogens were controlled for detection. Data were collected from the hospital's electronic medical records, and SPSS 25.0 software was used to perform a statistical analysis. RESULTS: Among 3,168 patients, a total of 1,527 were detected as positive, and the positive rate was 48.20%. The age of patients ranged from 13 - 98 years, with an average age of 45.6. The total of patients consisted of 2,191 males and 977 females, which had a significant difference (p < 0.05). Specimens were mainly collected from the Department of Dermatovenerology, Urological Surgery, Obstetrics and Gynecology, and so on. The positive rate was statistically different between male and female patients (p < 0.05). Single infection performed a main role and accounted for 79.57% of all of the positive patients. In the ≤ 20 age group, the positive rate was the highest and was as high as 77.65%. In detail, single infection caused by UU dominated, especially in the 21 - 30 age group. Double infection caused by UU and CT and triple infection caused by UU, CT, and NG were the majority, both especially in the 21 - 30 age group. There were significant differences in the positive rates in the different age groups and in the four pathogens (p < 0.05). Quadruple infection was very rare and had only been detected in one patient. CONCLUSIONS: The prevalence of the four pathogens in Hangzhou was different from other regions. More male than female patients, more single than multiple infections, and more single and multiple infections occurring in young people were the features in Hangzhou. The study would provide reference for prevention, diagnosis, and treatment of STI.

N-methyl-D-aspartate Receptor Subunits 2A and 2B Mediate Connexins and Pannexins in the Trigeminal Ganglion Involved in Orofacial Inflammatory Allodynia during Temporomandibular Joint Inflammation.

Temporomandibular joint osteoarthritis (TMJOA) is a severe form of temporomandibular joint disorders (TMD), and orofacial inflammatory allodynia is one of its common symptoms which lacks effective treatment. N-methyl-D-aspartate receptor (NMDAR), particularly its subtypes GluN2A and GluN2B, along with gap junctions (GJs), are key players in the mediation of inflammatory pain. However, the precise regulatory mechanisms of GluN2A, GluN2B, and GJs in orofacial inflammatory allodynia during TMJ inflammation still remain unclear. Here, we established the TMJ inflammation model by injecting Complete Freund's adjuvant (CFA) into the TMJ and used Cre/loxp site-specific recombination system to conditionally knock out (CKO) GluN2A and GluN2B in the trigeminal ganglion (TG). Von-frey test results indicated that CFA-induced mechanical allodynia in the TMJ region was relieved in GluN2A and GluN2B deficient mice. In vivo, CFA significantly up-regulated the expression of GluN2A and GluN2B, Gjb1, Gjb2, Gjc2 and Panx3 in the TG, and GluN2A and GluN2B CKO played different roles in mediating the expression of Gjb1, Gjb2, Gjc2 and Panx3. In vitro, NMDA up-regulated the expression of Gjb1, Gjb2, Gjc2 and Panx3 in satellite glial cells (SGCs) as well as promoted the intercellular communication between SGCs, and GluN2A and GluN2B knocking down (KD) altered the expression and function differently. NMDAR regulated Gjb1 and Panx3 through ERK1/2 pathway, and mediated Gjb2 and Gjc2 through MAPK, PKA, and PKC intracellular signaling pathways. These findings shed light on the distinct functions of GluN2A and GluN2B in mediating peripheral sensitization induced by TMJ inflammation in the TG, offering potential therapeutic targets for managing orofacial inflammatory allodynia.

Myeloid cell-expressed MNDA enhances M2 polarization to facilitate the metastasis of hepatocellular carcinoma.

Stable infiltration of myeloid cells, especially tumor-associated M2 macrophages, acts as one of the essential features of the tumor immune microenvironment by promoting the malignant progression of hepatocellular carcinoma (HCC). However, the factors affecting the infiltration of M2 macrophages are not fully understood. In this study, we found the molecular subtypes of HCC with the worst prognosis are characterized by immune disorders dominated by myeloid cell infiltration. Myeloid cell nuclear differentiation antigen (MNDA) was significantly elevated in the most aggressive subtype and exhibited a positively correlation with M2 infiltration and HCC metastasis. Moreover, MNDA functioned as an independent prognostic predictor and has a good synergistic effect with some existing prognostic clinical indicators. We further confirmed that MNDA was primarily expressed in tumor M2 macrophages and contributed to the enhancement of its polarization by upregulating the expression of the M2 polarization enhancers. Furthermore, MNDA could drive the secretion of M2 macrophage-derived pro-metastasis proteins to accelerate HCC cells metastasis both in vivo and in vitro. In summary, MNDA exerts a protumor role by promoting M2 macrophages polarization and HCC metastasis, and can serve as a potential biomarker and therapeutic target for HCC.

The discovery of novel imidazo[1,2-a]pyridine derivatives as covalent anticancer agents.

The success of targeted covalent inhibitors (TCIs) for treating cancers has spurred the search for novel scaffolds to install covalent warheads. In our endeavour, using a scaffold hopping strategy, we managed to utilize imidazo[1,2-a]pyridine as the core backbone and explored its potential for the development of covalent inhibitors, therefore, synthesizing a series of novel KRAS G12C inhibitors facilitated by the Groebke-Blackburn-Bienaymè reaction (GBB reaction). Preliminary bio-evaluation screening delivered compound I-11 as a potent anticancer agent for KRAS G12C-mutated NCI-H358 cells, whose effects were further clarified by a series of cellular, biochemical, and molecular docking experiments. These results not only indicate the potential of compound I-11 as a lead compound for the treatment of intractable cancers, but also validate the unique role of imidazo[1,2-a]pyridine as a novel scaffold suitable for the discovery of covalent anticancer agents.

Prevalence and Genotype Distribution of HPV in Hangzhou, China.

BACKGROUND: For women, cervical cancer is the most prevalent cancer and the most common cause of cancer-related deaths worldwide. Human papillomavirus (HPV) is causatively linked to over 90% of cervical cancer cases. Our retrospective study explored the clinical and laboratory data of outpatients with HPV infection to analyze the prevalence and genotype distribution of 3,793 outpatients in the Hangzhou area by using HPV genotype tests. It could provide value for an effective prevention and treatment of HPV infection. METHODS: In total, 3,793 female outpatients were randomly selected from January 2022 to December 2023. Exfoliated cervical cells were collected using a cytobrush and HPV genotype screening was conducted for testing. Data of all outpatients were collected from the hospital's electronic medical records, and SPSS 26.0 software was used to perform the statistical analysis. RESULTS: Out of 3,793 outpatients, 953 were detected as positive, and the positive rate was 25.13%. The age of the outpatients ranged from 15 - 97, with an average age of 39.91. All outpatients were divided into six age groups. Among the six age groups, the HPV positive rates were, with ascending age, 43.90%, 33.27%, 21.49%, 16.99%, 27.30%, and 25.48%, and the highest positive rate was observed in those aged  20 with a rate of 43.90%. There were significant differences in the positive rates among different age groups (p < 0.05). There were more outpatients with a single infection than with multiple infection (p < 0.05). The positive rate of single infection was the highest in the 31 - 40 and 41 - 50 age groups (74.32% for both) and the positive rate of multiple infection was the highest in the  20 age group (66.67%). Among 24 genotypes, HPV 52, 58, and 51 were the most commonly detected. All three were high-risk genotypes, and HPV 52 was the most dominant in all age groups. As distribution according to quarter, more HPV infection occurred in the fourth quarter, which had a significant difference (p < 0.05). And in the first quarter, the number of HPV positive infections was the lowest. CONCLUSIONS: Prevalence and genotype distribution of HPV in the Hangzhou area were different from those of other regions. More single infection, and more multiple infection occurring in low age and in the fourth quarter were the characteristics of HPV infection in the Hangzhou area. It was suggested that vaccine containing HPV 52 might be a better choice for this region.

Mortality prediction and influencing factors for intensive care unit patients with acute tubular necrosis: random survival forest and cox regression analysis.

Background: Patients with acute tubular necrosis (ATN) not only have severe renal failure, but also have many comorbidities, which can be life-threatening and require timely treatment. Identifying the influencing factors of ATN and taking appropriate interventions can effectively shorten the duration of the disease to reduce mortality and improve patient prognosis. Methods: Mortality prediction models were constructed by using the random survival forest (RSF) algorithm and the Cox regression. Next, the performance of both models was assessed by the out-of-bag (OOB) error rate, the integrated brier score, the prediction error curve, and area under the curve (AUC) at 30, 60 and 90 days. Finally, the optimal prediction model was selected and the decision curve analysis and nomogram were established. Results: RSF model was constructed under the optimal combination of parameters (mtry = 10, nodesize = 88). Vasopressors, international normalized ratio (INR)_min, chloride_max, base excess_min, bicarbonate_max, anion gap_min, and metastatic solid tumor were identified as risk factors that had strong influence on mortality in ATN patients. Uni-variate and multivariate regression analyses were used to establish the Cox regression model. Nor-epinephrine, vasopressors, INR_min, severe liver disease, and metastatic solid tumor were identified as important risk factors. The discrimination and calibration ability of both predictive models were demonstrated by the OOB error rate and the integrated brier score. However, the prediction error curve of Cox regression model was consistently lower than that of RSF model, indicating that Cox regression model was more stable and reliable. Then, Cox regression model was also more accurate in predicting mortality of ATN patients based on the AUC at different time points (30, 60 and 90 days). The analysis of decision curve analysis shows that the net benefit range of Cox regression model at different time points is large, indicating that the model has good clinical effectiveness. Finally, a nomogram predicting the risk of death was created based on Cox model. Conclusion: The Cox regression model is superior to the RSF algorithm model in predicting mortality of patients with ATN. Moreover, the model has certain clinical utility, which can provide clinicians with some reference basis in the treatment of ATN and contribute to improve patient prognosis.

Preclinical characterization of a novel investigational monoclonal antibody CM313 with potent CD38-positive cell killing activity.

Introduction: CM313 is currently under clinical investigation for treatments of multiple myeloma, systemic lupus erythematosus, and immune thrombocytopenia. We aimed to report the preclinical profile of the novel therapeutic anti-CD38 monoclonal antibody (mAb) CM313, with an emphasis on the difference with other CD38-targeting mAb. Methods: The binding of CM313 to CD38 recombinant protein across species was assessed using ELISA. The binding of CM313 to CD38-positive (CD38+) cells was detected using flow cytometry assays. CM313-induced complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and apoptosis on different CD38+ cells were assessed by LDH release assays or flow cytometry assays. The effect of CM313 on CD38 enzymatic activity was measured using fluorescence spectroscopy. CM313 immunotoxicity in human blood was assessed using flow cytometry assays, ELISA, and LDH release assays. Anti-tumor activity of CM313 was assessed in multiple mouse xenograft models. Safety profile of CM313 were evaluated in cynomolgus monkeys and human CD38 transgenic (B-hCD38) mice. Results: There exist unique sequences at complementarity-determining regions (CDR) of CM313, which facilitates its affinity to CD38 is consistently higher across a spectrum of CD38+ cell lines than daratumumab. In vitro studies showed that CM313 induces comparable killing activity than daratumumab, including ADCC, CDC, ADCP, apoptosis induced by Fc-mediated cross-linking, and effectively inhibited the enzymatic activity of CD38. However, CM313 showed more potent CDC than isatuximab. In vivo, CM313 dose-dependently inhibited xenograft tumor growth, both as a monotherapy and in combination with dexamethasone or lenalidomide. Furthermore, CM313 was well tolerated with no drug-related clinical signs or off-target risks, as evidenced by 4-week repeat-dose toxicology studies in cynomolgus monkeys and B-hCD38 mice, with the later study showing no observed adverse effect level (NOAEL) of 300mg/kg once weekly. Discussion: CM313 is a novel investigational humanized mAb with a distinct CDR sequence, showing comparable killing effects with daratumumab and stronger CDC activity than isatuximab, which supports its clinical development.

Molecularly imprinted polymer-based SERS sensing of transferrin in human serum.

Specific detection of glycoproteins such as transferrin (TRF) related to neurological diseases, hepatoma and other diseases always plays an important role in the field of disease diagnosis. We designed an antibody-free immunoassay sensing method based on molecularly imprinted polymers (MIPs) formed by the polymerization of multiple functional monomers for the sensitive and selective detection of TRF in human serum. In the sandwich surface-enhanced Raman spectroscopy (SERS) sensor, the TRF-oriented magnetic MIP nanoparticles (Fe3O4@SiO2-MIPs) served as capture units to specifically recognize TRF and 4-mercaptophenylboronic acid-functionalized gold nanorods (MPBA-Au NRs) served as SERS probes to label the targets. In order to achieve stronger interaction between the recognition cavities of the prepared MIPs and the different amino acid fragments that make up TRF, Fe3O4@SiO2-MIPs were obtained through polycondensation reactions between more silylating reagents, enhancing the specific recognition of the entire TRF protein and achieving high IF. This sensing method exhibited a good linear response to TRF within the TRF concentration range of 0.01 ng mL-1 to 1 mg mL-1 (R2 = 0.9974), and the LOD was 0.00407 ng mL-1 (S/N = 3). The good stability, reproducibility and specificity of the resulting MIP based SERS sensor were demonstrated. The determination of TRF in human serum confirmed the feasibility of the method in practical applications.

Clinical Situation, Species Distribution, and Antibiotic Resistance of Pathogenic Bacteria and Fungi in 626 Cases of Vulvovaginitis in Hangzhou, China.

BACKGROUND: Female vulvovaginitis was one of the most common gynecological diseases. It had a great negative impact on their work and quality of life. This retrospective study evaluated the clinical and laboratory data of patients with vulvovaginitis in Hangzhou, China. To analyze the clinical situation, species distribution and antibiotic resistance of pathogenic fungi and bacteria in 626 cases of vulvovaginitis in Hangzhou. Microorganism culture, identification, and antibiotic susceptibility testing were conducted. The study aimed to provide a theoretical value for an effective treatment of vulvovaginitis. METHODS: In total, 626 outpatients and inpatients diagnosed with vulvovaginitis were selected from January 2018 to January 2023. Data of all the patients were collected from the hospital's electronic medical records. Vaginal secretion was collected for testing and SPSS 25.0 software was used to perform statistical analysis. RESULTS: A total of 626 strains of fungi, Gram-positive, and -negative bacteria were detected. Clinical situations of patients infected with the top five pathogenic fungi and bacteria were analyzed. Pathogenic fungi and bacteria were slightly different in each age group and in each onset time group. The results of antibiotic susceptibility testing showed that the resistance rates of itraconazole and fluconazole were high and Gram- negative and -positive bacteria were multidrug resistant. Gram-negative bacteria were more sensitive to carbenicillins and compound antibiotics, while Gram-positive bacteria were sensitive to rifampicin and daptomycin. MRSA and non vancomycin-resistant strains were detected. CONCLUSIONS: Fungi and bacteria were usually detected as pathogenes in patients with vulvovaginitis in Hangzhou. Some factors, such as age and onset time, often affected the incidence. Pathogenic fungi and bacteria were resistant to some common antibiotics, and clinical treatments should be carried out in a timely and reasonable manner according to the results of antibiotic susceptibility testing.

Unraveling transcriptomic signatures and dysregulated pathways in systemic lupus erythematosus across disease states.

OBJECTIVES: This study aims to elucidate the transcriptomic signatures and dysregulated pathways in patients with Systemic Lupus Erythematosus (SLE), with a particular focus on those persisting during disease remission. METHODS: We conducted bulk RNA-sequencing of peripheral blood mononuclear cells (PBMCs) from a well-defined cohort comprising 26 remission patients meeting the Low Lupus Disease Activity State (LLDAS) criteria, 76 patients experiencing disease flares, and 15 healthy controls. To elucidate immune signature changes associated with varying disease states, we performed extensive analyses, including the identification of differentially expressed genes and pathways, as well as the construction of protein-protein interaction networks. RESULTS: Several transcriptomic features recovered during remission compared to the active disease state, including down-regulation of plasma and cell cycle signatures, as well as up-regulation of lymphocytes. However, specific innate immune response signatures, such as the interferon (IFN) signature, and gene modules involved in chromatin structure modification, persisted across different disease states. Drug repurposing analysis revealed certain drug classes that can target these persistent signatures, potentially preventing disease relapse. CONCLUSION: Our comprehensive transcriptomic study revealed gene expression signatures for SLE in both active and remission states. The discovery of gene expression modules persisting in the remission stage may shed light on the underlying mechanisms of vulnerability to relapse in these patients, providing valuable insights for their treatment.

Spatiotemporal pattern of coastal water pollution and its driving factors: implications for improving water environment along Hainan Island, China.

In the context of human activities and climate change, the gradual degradation of coastal water quality seriously threatens the balance of coastal and marine ecosystems. However, the spatiotemporal patterns of coastal water quality and its driving factors were still not well understood. Based on 31 water quality parameters from 2015 to 2020, a new approach of optimizing water quality index (WQI) model was proposed to quantitatively assess the spatial and temporal water quality along tropical Hainan Island, China. In addition, pollution sources were further identified by factor analysis and the effects of pollution source on water quality was finally quantitatively in our study. The results showed that the average water quality was moderate. Water quality at 86.36% of the monitoring stations was good while 13.53% of the monitoring stations has bad or very bad water quality. Besides, the coastal water quality had spatial and seasonal variation, along Hainan Island, China. The water quality at "bad" level was mainly appeared in the coastal waters along large cities (Haikou and Sanya) and some aquaculture regions. Seasonally, the average water quality in March, October and November was worse than in other months. Factor analysis revealed that water quality in this region was mostly affected by urbanization, planting and breeding factor, industrial factor, and they played the different role in different coastal zones. Waters at 10.23% of monitoring stations were at the greatest risk of deterioration due to severe pressure from environmental factors. Our study has significant important references for improving water quality and managing coastal water environment.

Dual-Responsive Near-Infrared BODIPY-Based Fluorescent Probe for the Detection of F- and HClO in Organisms.

Fluoride anions (F-) play a crucial role in human physiological processes. However, excessive intake of F- would affect oxygen metabolism and promote the generation of oxygen-free radicals. Hence, it is essential to develop a precise and efficient fluorescent probe for visualizing F--induced oxidative stress. In this work, we developed the first bifunctional BODIPY-based fluorescent probe dfBDP with p-tert-butyldimethylsilanolate benzyl thioether as the sensing site for the detection of F- and HClO via two distinct reactions, the self-immolative removal and the thioether oxidation, which generate the sensing products with two nonoverlap fluorescence bands: 800-1200 and 500-750 nm, respectively. The probe dfBDP displays rapid response, high specificity, and sensitivity for the detection of F- (LOD, 316.2 nM) and HClO (LOD, 33.9 nM) in vitro. Cellular imaging reveals a correlation between F--induced oxidative stress and the upregulation of HClO. Finally, probe dfBDP was employed to detect F- and HClO in mice under the stimulation of F-. The experimental results display that the level of HClO elevates in the liver of mice.

Visible-light-promoted difluoroamidated oxindole synthesis via electron donor-acceptor complexes.

A method involving a metal-free visible-light-promoted synthesis was developed for the construction of difluoroalkylated oxindoles with N-phenylacrylamides and bromodifluoroacetamides as starting materials in the presence of N,N,N',N'-tetramethylethylenediamine (TMEDA). Twenty-four examples of the photochemical reaction were successfully performed, with good yields (44-99%) and excellent substrate adaptability. Mechanistic studies showed that the visible-light-promoted reaction involved a radical addition to N-phenylacrylamide, intramolecular cyclization, dehydrogenation, and rearomatization. The difluoroacetamide radical was produced as a result of electron transfer to bromodifluoroacetamides from the electron donor TMEDA in their electron-donor-acceptor (EDA) complexes under visible light irradiation. This protocol is a promising photochemical method due to its advantages of mild conditions, simple operation, wide substrate scope and high yields. And the obtained products may have great potential in the field of medicine.

The IAA17.1/HSFA5a module enhances salt tolerance in Populus tomentosa by regulating flavonol biosynthesis and ROS levels in lateral roots.

Auxin signaling provides a promising approach to controlling root system architecture and improving stress tolerance in plants. However, how the auxin signaling is transducted in this process remains unclear. The Aux indole-3-acetic acid (IAA) repressor IAA17.1 is stabilized by salinity, and primarily expressed in the lateral root (LR) primordia and tips in poplar. Overexpression of the auxin-resistant form of IAA17.1 (IAA17.1m) led to growth inhibition of LRs, markedly reduced salt tolerance, increased reactive oxygen species (ROS) levels, and decreased flavonol content. We further identified that IAA17.1 can interact with the heat shock protein HSFA5a, which was highly expressed in roots and induced by salt stress. Overexpression of HSFA5a significantly increased flavonol content, reduced ROS accumulation, enhanced LR growth and salt tolerance in transgenic poplar. Moreover, HSFA5a could rescue the defective phenotypes caused by IAA17.1m. Expression analysis showed that genes associated with flavonol biosynthesis were altered in IAA17.1m- and HAFA5a-overexpressing plants. Furthermore, we identified that HSFA5a directly activated the expression of key enzyme genes in the flavonol biosynthesis pathway, while IAA17.1 suppressed HSFA5a-mediated activation of these genes. Collectively, the IAA17.1/HSFA5a module regulates flavonol biosynthesis, controls ROS accumulation, thereby modulating the root system of poplar to adapt to salt stress.

Evaluation of analgesic effect of nalbuphine in patients with non-mechanical ventilation in intensive care unit: a multi-center randomized controlled trail / 中华急诊医学杂志

Objective:To analyze the efficacy and safety of nalbuphine for analgesia in patients with non-mechanical ventilation in intensive care unit (ICU).Methods:From December 2018 to August 2021, a multicenter randomized controlled clinical study was conducted to select non-mechanical ventilation patients with analgesic needs admitted to ICU of four hospitals in Henan Province and Guizhou Province. Patients were randomly assigned to nalbuphine group and fentanyl group. The nalbuphine group was given continuous infusion of nalbuphine [0.05~0.20 mg/(kg·h)], and the fentanyl group was given continuous infusion of fentanyl [0.5~2.0 μg/(kg·h)]. The analgesic target was critical-care pain observation tool (CPOT) score<2. The observation time was 48 hours. The primary endpoint was CPOT score, the secondary endpoints were Richmond agitation-sedation score (RASS), ICU length of stay, adverse events, and proportion of mechanical ventilation. The quantitative data of the two groups were compared by t test or Mann-Whitney U test. The enumeration data were compared by chi square test or Fisher exact probability method. The data at different time points between groups were compared by repeated measures analysis of variance. Results:A total of 210 patients were enrolled, including 105 patients in the nalbuphine group and 105 patients in the fentanyl group. There was no significant difference in baseline data between the two groups (all P>0.05). There was no significant difference in CPOT score between nalbuphine group and fentanyl group at each time point after medication ( P>0.05), the CPOT score of both groups at each time point after medication was significantly lower than that before medication, and the analgesic target could be achieved and maintained 2 hours after medication. There was no significant difference in RASS between the two groups at each time point after medication ( P>0.05), which was significantly lower than that before medication, and the target sedative effect was achieved 2 hours after medication. There was no significant difference in ICU length of stay between nalbuphine group and fentanyl group [5.0(4.0,7.5) d vs. 5.0(4.0,8.0) d, P=0.504]. The incidence of delirium, nausea and vomiting, abdominal distension, pruritus, vertigo and other adverse events in the nalbuphine group was lower than that in the fentanyl group (all P<0.05). There was no significant difference in the incidence of other adverse events such as deep sedation, hypotension and bradycardia between the two groups (all P>0.05). The incidence of respiratory depression in nalbuphine group was not significantly different from that in fentanyl group ( P>0.05), but the proportion of mechanical ventilation was significantly lower than that in the fentanyl group [1.9% (2/105) vs. 8.6%(9/105), P=0.030]. Conclusions:Nalbuphine could be used for analgesia in ICU patients with non-mechanical ventilation. The target analgesic effect could be achieved within 2 hours, and it had a certain sedative effect with a low incidence of adverse reactions.