Evaluating the predictive efficacy of real-time 3D echocardiography in cardiac resynchronization therapy.

BACKGROUND: The aim of this study is to assess the predictive efficacy of real-time three-dimensional echocardiography (RT-3DE) and QRS wave duration in determining the response to cardiac resynchronization therapy (CRT) and assessing left ventricular systolic function pre- and post-CRT device implantation. METHOD: A total of 51 patients with heart failure undergoing CRT at the Second Affiliated Hospital of Nantong University between January 1, 2013, and October 31, 2020, were enrolled in this study. Traditional two-dimensional echocardiography and RT-3DE were performed pre and post-CRT, with QRS wave width data from electrocardiograms and additional clinical information collected. Patients were categorized into CRT responder (n = 36) and CRT non-responder (n = 15) groups based on their response to CRT device implantation. Comparative analyses were conducted on the general characteristics of both groups, as well as the predictive efficacy of RT-3DE and QRS wave width for CRT responsiveness and left ventricular systolic function. Data on the standard deviation (Tmsv16-SD, Tmsv12-SD, Tmsv6-SD) and maximum difference (Tmsv16-Dif, Tmsv12-Dif, Tmsv6-Dif) of left ventricular end-systolic volume (LVESV) at segments 16, 12, and 6, as well as QRS wave width, were collected and analyzed. RESULTS: The indicators Tmsv6-Dif, Tmsv12-Dif, Tmsv16-Dif, Tmsv6-SD, Tmsv12-SD, Tmsv16-SD, and QRS wave width exhibited significantly higher values in the CRT responder group when compared to the CRT non-responder group (P < 0.05). Among these, Tmsv16-SD demonstrated superior predictive performance for post-CRT response, with a sensitivity of 88.9%, specificity of 80.0%, and a diagnostic cut-off value of 6.19%. This predictive capability exceeded that of the conventional indicator, QRS wave width. CONCLUSION: RT-3DE enables accurate prediction of post-CRT patient response and significantly facilitates quantitative assessment of CRT therapy efficacy.

Perioperative systemic and prophylactic intraperitoneal chemotherapy for type 4/large type 3 gastric cancer: DRAGON-10.

Large type 3 and type 4 gastric cancers (GC) have a significantly poor prognosis, primarily due to their high predisposition for peritoneal dissemination. The application of intraperitoneal chemotherapy has emerged as a viable therapeutic strategy for managing GC patients with peritoneal metastasis. This study is planned to enroll 37 resectable large type 3 or type 4 GC patients. These patients are scheduled to undergo a treatment comprising preoperative chemotherapy with paclitaxel, oxaliplatin and S-1, followed by D2 gastrectomy, and concluding with postoperative treatments that include prophylactic intraperitoneal chemotherapy. The study's primary objective is to evaluate the 3-year peritoneal recurrence rate. Secondary objectives are to assess the 3-year disease-free survival, 3-year overall survival and to monitor the adverse events.Clinical trial registration number: ChiCTR2400083253 (https://www.chictr.org.cn).

Gastric cancer (GC), specifically the large type 3 and type 4 kinds, is a serious health condition that often leads to a very poor chance of survival. This is mainly because these types of cancer easily spread to the lining of the abdomen, a process known as peritoneal dissemination. One way to tackle this issue is through a treatment known as intraperitoneal chemotherapy, which directly targets the abdominal lining to kill cancer cells. In our study, 37 resectable large type 3 and type 4 GC patients will receive a combination of chemotherapy drugs before undergoing surgery to remove the cancer. After surgery, they will receive additional treatment that combines chemotherapy into the abdomen with standard chemotherapy. The main goal of our study is to see if this treatment approach can reduce the chance of cancer returning to the abdominal lining within 3 years. We are also looking at how long patients remain free from cancer, their overall survival after 3 years, and any side effects they may experience from the treatment. This study aims to provide a clearer understanding of how effective this combined treatment is for patients with these aggressive types of GC, with the hope of improving their chances of survival and quality of life.

Temporal enrichment of comammox Nitrospira and Ca. Nitrosocosmicus in a coastal plastisphere.

Plastic marine debris is known to harbor a unique microbiome (termed the "plastisphere") that can be important in marine biogeochemical cycles. However, the temporal dynamics in the plastisphere and their implications for marine biogeochemistry remain poorly understood. Here, we characterized the temporal dynamics of nitrifying communities in the plastisphere of plastic ropes exposed to a mangrove intertidal zone. The 39-month colonization experiment revealed that the relative abundances of Nitrospira and Candidatus Nitrosocosmicus representatives increased over time according to 16S rRNA gene amplicon sequencing analysis. The relative abundances of amoA genes in metagenomes implied that comammox Nitrospira were the dominant ammonia oxidizers in the plastisphere, and their dominance increased over time. The relative abundances of two metagenome-assembled genomes of comammox Nitrospira also increased with time and positively correlated with extracellular polymeric substances content of the plastisphere but negatively correlated with NH4+ concentration in seawater, indicating the long-term succession of these two parameters significantly influenced the ammonia-oxidizing community in the coastal plastisphere. At the end of the colonization experiment, the plastisphere exhibited high nitrification activity, leading to the release of N2O (2.52 ng N2O N g-1) in a 3-day nitrification experiment. The predicted relative contribution of comammox Nitrospira to N2O production (17.9%) was higher than that of ammonia-oxidizing bacteria (4.8%) but lower than that of ammonia-oxidizing archaea (21.4%). These results provide evidence that from a long-term perspective, some coastal plastispheres will become dominated by comammox Nitrospira and thereby act as hotspots of ammonia oxidation and N2O production.

Discovery and evaluation of novel SHIP-1 inhibitors.

Src Homology 2-containing Inositol 5'-Phosphatase-1 (SHIP-1), encoded by INPP5D, has been identified as an Alzheimer's disease (AD) risk-associated gene through recent genetic and epigenetic studies. SHIP-1 confers AD risk by inhibiting the TREM2 cascade and reducing beneficial microglial cellular processes, including phagocytosis. While several small molecules have been reported to modulate SHIP-1 activity, their limited selectivity and efficacy in advanced models restricted their potential as therapeutic agents or probes for biological studies. Herein, we validated and implemented a high-throughput screening platform to explore new chemotypes that can modulate the phosphatase activity of SHIP-1. We screened 49,260 central nervous system (CNS)-penetrate compounds sourced from commercial vendors using the malachite green-based assay for anti-SHIP-1 activity. Through analysis, prioritization, and validation of the screening hits, we identified three novel types of scaffolds that inhibit the SHIP-1 phosphatase activity with IC50s as low as 46.6 µM. To improve the inhibitory activity of these promising hits, we carried out structure-activity relationship (SAR) studies, resulting in a lead molecule SP3-12 that inhibits SHIP-1 with an IC50 value of 6.1 µM. Kinetic analyses of SP3-12 revealed that its inhibition mechanism is competitive, with a Ki value of 3.2 µM for SHIP-1 and a 7-fold selectivity over SHIP-2. Furthermore, results from testing in a microglial phagocytosis/cell health high content assay indicated that SP3-12 could effectively activate phagocytosis in human microglial clone 3 (HMC3) cells, with an EC50 of 2.0 µM, without cytotoxicity in the dose range. Given its potency, selectivity, and cellular activity, SP3-12 emerges as a promising small molecule inhibitor with potential for investigating the biological functions of SHIP-1.

Customizable Three-Dimensional Printed Zerovalent Iron: An Efficient and Reusable Fenton-like Reagent for Florfenicol Degradation.

Zerovalent iron (Fe0)-based Fenton-like technology has great potential for treating recalcitrant organic pollutants (ROPs) in wastewater. However, rapidly and precisely manufacturing Fe0-based materials with the desired geometries is challenging. Herein, novel three-dimensional printed Fe0 (3DP-Fe0) and bimetallic 3DP-Ni/Fe0 were customized by 3D printing for efficient Fenton-like degradation of florfenicol (FLO), a typical antibiotic in wastewater. 3DP-Ni/Fe0 with hydrogen peroxide (H2O2) exhibited superior reactivity toward FLO than 3DP-Fe0, generating hydroxyl radicals (·OH) and atomic hydrogen to achieve >90% dehalogenation and >70% total organic carbon removal within 10 min. The resulting degradation intermediates possessed lower antibacterial activity than FLO and did not cause resistance gene proliferation in activated sludge. The Fenton-like activity of 3DP-Ni/Fe0 was similar across different shapes but increased with increasing porosity and size. Compared with powdered Ni/Fe0, 3DP-Ni/Fe0 exhibited faster electron transfer during Fe(II)/Fe(III) cycling, which increased the utilization efficiency of dissolved Fe2+ and H2O2 for ·OH production. Moreover, 3DP-Ni/Fe0 could be reused >150 times, 5-fold more than powdered Ni/Fe0, owing to its lower metal ion release and Fe0 depletion. 3DP-Ni/Fe0 with H2O2 can also efficiently remove chemical oxygen demand from real wastewater and other ROPs (e.g., acetaminophen, carbamazepine, thiamphenicol, and tetrabromobisphenol A).

[Global quantification of the spatial variability and temporal stability of throughfall]. / æž—å† ç©¿é€é›¨ç©ºé—´å¼‚è´¨æ€§åŠå ¶æ—¶é—´ç¨³å®šæ€§ç‰¹å¾çš„å ¨çƒé‡åŒ–.

Spatial variability of throughfall (i.e. the non-uniform characteristics of throughfall at different canopy positions) and its temporal persistence (i.e. time stability) are related to the quantity and efficiency of soil moisture replenishment, and affect plant competition and community succession dynamics by affecting resource availability. We carried out a meta-analysis with 554 papers (from 2000 to 2022) retrieved from Web of Science and China National Knowledge Infrastructure (CNKI) based on keyword search, quantified and compared the amount, spatial heterogeneity, and temporal stability characteristics of penetrating rain in different climate zones and plant functional types. Our results that throughfall proportion was lower in arid regions (72.0%±13.6%) than humid (75.1%±9.3%) and semi-humid areas (79.9%±10.4%). Cold climates had lower values (74.1%±14.6%) than temperate (74.2%±7.5%) and tropical climates (80.9%±14.6%). Shrubs (68.9%±14.9%) generally had lower throughfall proportion than trees (76.7%±9.1%). Broad-leaved trees (75.2%±11.1%) and conifers (75.1%±9.9%) showed similar throughfall proportions, as did evergreen (76.7%±10.0%) and deciduous species (74.7%±11.9%). Additionally, spatial variability (coefficient of variation) did not significantly differ across rainfall zones, temperature zones, or vegetation types. The spatial distribution of throughfall was relatively stable. Canopy structure was the dominant factor affecting temporal stability of throughfall. However, there was a lack of comparison between typical geographic units (i.e. spatial units with basically consistent geographical environmental conditions) at various temporal scales. Future research should expand upwards to the summary of global spatial scale rules and downwards to the analysis of process based temporal scale mechanisms, to depict the dynamic distribution of penetrating rain and unify observation standards to enhance comparability of different studies, in order to efficiently promote research on canopy penetrating rain and provide ecological and hydrological basis for protecting nature, managing artificial activities, and restoring degraded ecosystems.

Correlative Imaging for Comprehensive Molecular Mapping of Individual Cell Types in Biological Tissues.

Mass spectrometry imaging (MSI) is a powerful technique for label-free spatial mapping of multiple classes of biomolecules in tissue sections. However, differences in desorption and ionization efficiency of different classes of molecules make it challenging to simultaneously map biomolecules at each omics layer in the same tissue sample. Herein, we present a correlative imaging method using nanospray desorption electrospray ionization (nano-DESI) MSI, which enables the spatial mapping of lipids, metabolites, peptides, and proteins with cellular-level spatial resolution in a single tissue section. We demonstrate the molecular profiling of specific cell types and identify truncated peptides in mouse pancreatic tissue. Distinct chemical gradients of peptides and lipids extending from endocrine cells to exocrine cells indicate their different roles in endocrine-exocrine crosstalk and intracellular signaling. The results underscore the power of the developed imaging approach for spatial multi-omics analysis that provides deep insights into cellular diversity and the intricate molecular interactions that occur within heterogenous biological tissues.

Valosin-Containing Protein (VCP)/p97 Oligomerization.

Valosin-containing protein (VCP), also known as p97, is an evolutionarily conserved AAA+ ATPase essential for cellular homeostasis. Cooperating with different sets of cofactors, VCP is involved in multiple cellular processes through either the ubiquitin-proteasome system (UPS) or the autophagy/lysosomal route. Pathogenic mutations frequently found at the interface between the NTD domain and D1 ATPase domain have been shown to cause malfunction of VCP, leading to degenerative disorders including the inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS), and cancers. Therefore, VCP has been considered as a potential therapeutic target for neurodegeneration and cancer. Most of previous studies found VCP predominantly exists and functions as a hexamer, which unfolds and extracts ubiquitinated substrates from protein complexes for degradation. However, recent studies have characterized a new VCP dodecameric state and revealed a controlling mechanism of VCP oligomeric states mediated by the D2 domain nucleotide occupancy. Here, we summarize our recent knowledge on VCP oligomerization, regulation, and potential implications of VCP in cellular function and pathogenic progression.

Lnc PVT1 facilitates TGF-ß1-induced human cardiac fibroblast activation in vitro and ISO-induced myocardial fibrosis in vivo through regulating MYC.

Cardiac fibrosis is a commonly seen pathophysiological process in various cardiovascular disorders, such as coronary heart disorder, hypertension, and cardiomyopathy. Cardiac fibroblast trans-differentiation into myofibroblasts (MFs) is a key link in myocardial fibrosis. LncRNA PVT1 participates in fibrotic diseases in multiple organs; however, its role and mechanism in cardiac fibrosis remain largely unknown. Human cardiac fibroblasts (HCFs) were stimulated with TGF-ß1 to induce myofibroblast; Immunofluorescent staining, Immunoblotting, and fluorescence in situ hybridization were used to detect the myofibroblasts phenotypes and lnc PVT1 expression. Cell biological phenotypes induced by lnc PVT1 knockdown or overexpression were detected by CCK-8, flow cytometry, and Immunoblotting. A mouse model of myocardial fibrosis was induced using isoproterenol (ISO), and the cardiac functions were examined by echocardiography measurements, cardiac tissues by H&E, and Masson trichrome staining. In this study, TGF-ß1 induced HCF transformation into myofibroblasts, as manifested as significantly increased levels of α-SMA, vimentin, collagen I, and collagen III; the expression level of lnc PVT1 expression showed to be significantly increased by TGF-ß1 stimulation. The protein levels of TGF-ß1, TGFBR1, and TGFBR2 were also decreased by lnc PVT1 knockdown. Under TGF-ß1 stimulation, lnc PVT1 knockdown decreased FN1, α-SMA, collagen I, and collagen III protein contents, inhibited HCF cell viability and enhanced cell apoptosis, and inhibited Smad2/3 phosphorylation. Lnc PVT1 positively regulated MYC expression with or without TGF-ß1 stimulation; MYC overexpression in TGF-ß1-stimulated HCFs significantly attenuated the effects of lnc PVT1 knockdown on HCF proliferation and trans-differentiation to MFs. In the ISO-induced myocardial fibrosis model, lnc PVT1 knockdown partially reduced fibrotic area, improved cardiac functions, and decreased the levels of fibrotic markers. In addition, lnc PVT1 knockdown decreased MYC and CDK4 levels but increased E-cadherin in mice heart tissues. lnc PVT1 is up-regulated in cardiac fibrosis and TGF-ß1-stimulated HCFs. Lnc PVT1 knockdown partially ameliorates TGF-ß1-induced HCF activation and trans-differentiation into MFs in vitro and ISO-induced myocardial fibrosis in vivo, potentially through interacting with MYC and up-regulating MYC.

Off-target autophagy inhibition by SHP2 allosteric inhibitors contributes to their antitumor activity in RAS-driven cancers.

Aberrant activation of RAS/MAPK signaling is common in cancer, and efforts to inhibit pathway components have yielded drugs with promising clinical activities. Unfortunately, treatment-provoked adaptive resistance mechanisms inevitably develop, limiting their therapeutic potential. As a central node essential for receptor tyrosine kinase-mediated RAS activation, SHP2 has emerged as an attractive cancer target. Consequently, many SHP2 allosteric inhibitors are now in clinical testing. Here we discovered a previously unrecognized off-target effect associated with SHP2 allosteric inhibitors. We found that these inhibitors accumulate in the lysosome and block autophagic flux in an SHP2-independent manner. We showed that off-target autophagy inhibition by SHP2 allosteric inhibitors contributes to their antitumor activity. We also demonstrated that SHP2 allosteric inhibitors harboring this off-target activity not only suppress oncogenic RAS signaling but also overcome drug resistance such as MAPK rebound and protective autophagy in response to RAS/MAPK pathway blockage. Finally, we exemplified a therapeutic framework that harnesses both the on- and off-target activities of SHP2 allosteric inhibitors for improved treatment of mutant RAS-driven and drug-resistant malignancies such as pancreatic and colorectal cancers.

Development of Novel Phosphonodifluoromethyl-Containing Phosphotyrosine Mimetics and a First-In-Class, Potent, Selective, and Bioavailable Inhibitor of Human CDC14 Phosphatases.

Together with protein tyrosine kinases, protein tyrosine phosphatases (PTPs) control protein tyrosine phosphorylation and regulate numerous cellular functions. Dysregulated PTP activity is associated with the onset of multiple human diseases. Nevertheless, understanding of the physiological function and disease biology of most PTPs remains limited, largely due to the lack of PTP-specific chemical probes. In this study, starting from a well-known nonhydrolyzable phosphotyrosine (pTyr) mimetic, phosphonodifluoromethyl phenylalanine (F2Pmp), we synthesized 7 novel phosphonodifluoromethyl-containing bicyclic/tricyclic aryl derivatives with improved cell permeability and potency toward various PTPs. Furthermore, with fragment- and structure-based design strategies, we advanced compound 9 to compound 15, a first-in-class, potent, selective, and bioavailable inhibitor of human CDC14A and B phosphatases. This study demonstrates the applicability of the fragment-based design strategy in creating potent, selective, and bioavailable PTP inhibitors and provides a valuable probe for interrogating the biological roles of hCDC14 phosphatases and assessing their potential for therapeutic interventions.

Targeting PRL phosphatases in hematological malignancies.

INTRODUCTION: Phosphatase of regenerating liver (PRL) family proteins, also known as protein tyrosine phosphatase 4A (PTP4A), have been implicated in many types of cancers. The PRL family of phosphatases consists of three members, PRL1, PRL2, and PRL3. PRLs have been shown to harbor oncogenic potentials and are highly expressed in a variety of cancers. Given their roles in cancer progression and metastasis, PRLs are potential targets for anticancer therapies. However, additional studies are needed to be performed to fully understand the roles of PRLs in blood cancers. AREAS COVERED: In this review, we will summarize recent studies of PRLs in normal and malignant hematopoiesis, the role of PRLs in regulating various signaling pathways, and the therapeutic potentials of targeting PRLs in hematological malignancies. We will also discuss how to improve current PRL inhibitors for cancer treatment. EXPERT OPINION: Although PRL inhibitors show promising therapeutic effects in preclinical studies of different types of cancers, moving PRL inhibitors from bench to bedside is still challenging. More potent and selective PRL inhibitors are needed to target PRLs in hematological malignancies and improve treatment outcomes.

Making the Unseen Seen: The Role of Signaling and Novelty in Rating Metaphors.

Comprehension of metaphorical expressions differs with their degree of novelty. Conventional metaphors are typically comprehended as easily as literal sentences, while novel metaphors are responded to less quickly than their conventional counterparts. However, the influence of metaphor signals on the interpretability and acceptability of sentences with metaphors, especially their potential interaction with novelty, remains an open question. We conducted six online experiments among 1,694 native speakers of American English to examine how interpretability and acceptability ratings of individually presented sentences were affected by metaphor novelty and different types of metaphor signals. Across all six experiments, we consistently found that novel metaphors decreased the interpretability and acceptability of sentences compared to both conventional metaphors and literal controls. Signals, on the contrary, did not impact the interpretability or acceptability of the sentences. Moreover, only in experiment 3b did we find an interaction between metaphor type and signals. Specifically, when a metaphor was marked by double signals (i.e., both lexical signals and a typographical signal were added around the metaphorical keywords) vs. no signals, acceptability of novel metaphors increased, but acceptability of conventional metaphors decreased. We hypothesize that the double signaling of novel metaphors marks their novelty, making them more acceptable. By contrast, the double signaling of conventional metaphors may have been perceived as redundant, leading to a lower acceptability.

CD32 captures committed haemogenic endothelial cells during human embryonic development.

During embryonic development, blood cells emerge from specialized endothelial cells, named haemogenic endothelial cells (HECs). As HECs are rare and only transiently found in early developing embryos, it remains difficult to distinguish them from endothelial cells. Here we performed transcriptomic analysis of 28- to 32-day human embryos and observed that the expression of Fc receptor CD32 (FCGR2B) is highly enriched in the endothelial cell population that contains HECs. Functional analyses using human embryonic and human pluripotent stem cell-derived endothelial cells revealed that robust multilineage haematopoietic potential is harboured within CD32+ endothelial cells and showed that 90% of CD32+ endothelial cells are bona fide HECs. Remarkably, these analyses indicated that HECs progress through different states, culminating in FCGR2B expression, at which point cells are irreversibly committed to a haematopoietic fate. These findings provide a precise method for isolating HECs from human embryos and human pluripotent stem cell cultures, thus allowing the efficient generation of haematopoietic cells in vitro.

Identification of miRNAs that target Fcγ receptor-mediated phagocytosis during macrophage activation syndrome.

Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile arthritis, accompanied by cytokine storm and hemophagocytosis. In addition, COVID-19-related hyperinflammation shares clinical features of MAS. Mechanisms that activate macrophages in MAS remain unclear. Here, we identify the role of miRNA in increased phagocytosis and interleukin-12 (IL-12) production by macrophages in a murine model of MAS. MAS significantly increased F4/80+ macrophages and phagocytosis in the mouse liver. Gene expression profile revealed the induction of Fcγ receptor-mediated phagocytosis (FGRP) and IL-12 production in the liver. Phagocytosis pathways such as High-affinity IgE receptor is known as Fc epsilon RI -signaling and pattern recognition receptors involved in the recognition of bacteria and viruses and phagosome formation were also significantly upregulated. In MAS, miR-136-5p and miR-501-3p targeted and caused increased expression of Fcgr3, Fcgr4, and Fcgr1 genes in FGRP pathway and consequent increase in phagocytosis by macrophages, whereas miR-129-1-3p and miR-150-3p targeted and induced Il-12. Transcriptome analysis of patients with MAS revealed the upregulation of FGRP and FCGR gene expression. A target analysis of gene expression data from a patient with MAS discovered that miR-136-5p targets FCGR2A and FCGR3A/3B, the human orthologs of mouse Fcgr3 and Fcgr4, and miR-501-3p targets FCGR1A, the human ortholog of mouse Fcgr1. Together, we demonstrate the novel role of miRNAs during MAS pathogenesis, thereby suggesting miRNA mimic-based therapy to control the hyperactivation of macrophages in patients with MAS as well as use overexpression of FCGR genes as a marker for MAS classification.

Natural Product-Inspired Molecules for Covalent Inhibition of SHP2 Tyrosine Phosphatase.

Natural products have been playing indispensable roles in the development of lifesaving drug molecules. They are also valuable sources for covalent protein modifiers. However, they often are scarce in nature and have complex chemical structures, which are limiting their further biomedical development. Thus, natural product-inspired small molecules which still contain the essence of the parent natural products but are readily available and amenable for structural modification, are important and desirable in searching for lead compounds for various disease treatment. Inspired by the complex and diverse ent-kaurene diterpenoids with significant biological activities, we have created a synthetically accessible and focused covalent library by incorporating the bicyclo[3.2.1]octane α-methylene ketone, which is considered as the pharmacophore of ent-kaurene diterpenoids, as half of the structure, and replacing the other half with much less complex but more druglike scaffolds. From this library, we have identified and characterized selective covalent inhibitors of protein tyrosine phosphatase SHP2, an important anti-cancer therapeutic target. The success of this study demonstrated the importance of creating and evaluating natural product-inspired library as well as their application in targeting challenging disease targets.

Review: The application of source analysis methods in tracing urban non-point source pollution: categorization, hotspots, and future prospects.

The contribution of urban non-point source (NPS) pollution to surface water pollution has gradually increased, analyzing the sources of urban NPS pollution is of great significance for precisely controlling surface water pollution. A bibliometric analysis of relevant research literature from 2000 to 2021 reveals that the main methods used in the source analysis research of urban NPS pollution include the emission inventory approach, entry-exit mass balance approach, principal component analysis (PCA), positive matrix factorization (PMF) model, etc. These methods are primarily applied in three aspects: source analysis of rainfall-runoff pollution, source analysis of wet weather flow (WWF) pollution in combined sewers, and analysis of the contribution of urban NPS to the surface water pollution load. The application of source analysis methods in urban NPS pollution research has demonstrated an evolution from qualitative to quantitative, and further towards precise quantification. This progression has transitioned from predominantly relying on on-site monitoring to incorporating model simulations and employing mathematical statistical analyses for traceability. This paper reviews the principles, advantages, disadvantages, and the scope of application of these methods. It also aims to address existing problems and analyze potential future development directions, providing valuable references for subsequent related research.

A novel micellular fluorogenic substrate for quantitating the activity of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma (PLCγ) enzymes.

The activities of the phospholipase C gamma (PLCγ) 1 and 2 enzymes are essential for numerous cellular processes. Unsurprisingly, dysregulation of PLCγ1 or PLCγ2 activity is associated with multiple maladies including immune disorders, cancers, and neurodegenerative diseases. Therefore, the modulation of either of these two enzymes has been suggested as a therapeutic strategy to combat these diseases. To aid in the discovery of PLCγ family enzyme modulators that could be developed into therapeutic agents, we have synthesized a high-throughput screening-amenable micellular fluorogenic substrate called C16CF3-coumarin. Herein, the ability of PLCγ1 and PLCγ2 to enzymatically process C16CF3-coumarin was confirmed, the micellular assay conditions were optimized, and the kinetics of the reaction were determined. A proof-of-principle pilot screen of the Library of Pharmacologically Active Compounds 1280 (LOPAC1280) was performed. This new substrate allows for an additional screening methodology to identify modulators of the PLCγ family of enzymes.

Effectiveness and safety of Moluodan in the treatment of precancerous lesions of gastric cancer: A randomized clinical trial.

OBJECTIVE: To investigate the clinical potential and safety of Moluodan to reverse gastric precancerous lesions. METHODS: Patients aged 18-70 years diagnosed with moderate-to-severe atrophy and/or moderate-to-severe intestinal metaplasia, with or without low-grade dysplasia, and negative for Helicobacter pylori were recruited in this randomized, double-blind, parallel-controlled trial. The primary outcome was the improvement of global histological diagnosis at 1-year follow-up endoscopy using the operative link for gastritis assessment, the operative link for gastric intestinal metaplasia assessment, and the disappearance rate of dysplasia. RESULTS: Between November 3, 2017 and January 27, 2021, 166 subjects were randomly assigned to the Moluodan group, 168 to the folic acid group, 84 to the combination group, and 84 to the high-dose Moluodan group. The improvement in global histological diagnosis was achieved in 60 (39.5%) subjects receiving Moluodan, 59 (37.8%) receiving folic acid, 26 (32.1%) receiving the combined drugs, and 36 (47.4%) receiving high-dose Moluodan. Moluodan was non-inferior to folic acid (95% confidence interval: -9.2 to 12.5; P = 0.02). High-dose Moluodan had a trend for better protective efficacy, though there was no statistical significance. The disappearance rate of dysplasia was 82.8% in the Moluodan group, which was superior to folic acid (53.9%; P = 0.006). No drug-related serious adverse events were observed. CONCLUSIONS: One pack of Moluodan three times daily for 1 year was safe and effective in reversing gastric precancerous lesions, especially dysplasia. Doubling its dose showed a better efficacy trend.

Effect of acupoint catgut embedding on p38 MAPK pathway in the lung tissue of asthmatic rats. / 穴位埋线通过调节p38ä¸è£‚åŽŸæ´»åŒ–è›‹ç™½æ¿€é ¶é€šè·¯å¯¹å“®å–˜å¤§é¼ æ°”é“ä¸Šçš®çš„å½±å“.

OBJECTIVES: To observe the effect of catgut embedding at "Feishu"(BL13), "Dingchuan" (EX-B1) and "Danzhong" (CV17) on expression of phosphorylated p38 mitogen activated protein kinase (p-p38 MAPK), interleukin-4 (IL-4), interferon-γ (IFN-γ) and changes of airway epithelial cells (AEC) in the lung tissue of bronchial asthma (BA) rats, so as to explore its mechanisms underlying improvement of BA. METHODS: Forty male Wistar rats were randomly and equally divided into blank control, model, dexamethasone (DEX) and catgut embedding groups. The BA model was established by intraperitoneal injection of suspension of ovalbumin and aluminum hydroxide. Rats of the DEX group received intraperitoneal injection of DEX (1.5 mg/kg), once daily for 2 weeks, and those of the catgut embedding group received catgut embedding at BL13, EX-B1 and CV17 only one time. The rats' sneezing times per miniute in each group were recorded. H.E. staining was used to observe the histopathological changes of the lung tissue under light microscope. A transmission electron microscope (TEM) was used to observe the ultrastructural changes of AEC in the lung tissue, including the thickness of bronchial wall and bronchial smooth muscle by using an image analysis software. The protein expressions of p-p38 MAPK, IL-4 and INF-γ in the lung tissue were determined using Western blot. RESULTS: Morphological observation revealed that in the model group, light microscope showed deformed and swollen bronchial tube wall with increased folds and thickened bronchial smooth muscle；and TEM showed a large number of autophagy vesicles containing swollen and deformed organelles in the AEC, and apparent reduction of intracellular mitochondria, these situations were obviously milder in both DEX and catgut embedding groups. Compared with the blank control group, the sneezing times, thickness of bronchial wall and bronchial smooth muscle in the model group were significantly increased (P<0.01), and the expressions of p-p38 MAPK and IL-4 in lung tissue were significantly increased (P<0.01), while the expression of IFN-γ was significantly decreased (P<0.01) in the model group. In comparison with the model group, the sneezing times, thickness of bronchial wall and bronchial smooth muscle, protein expressions of p-p38 MAPK and IL-4 were significantly decreased (P<0.01), while the expression of IFN-γ was obviously increased (P<0.01) in both the DEX and catgut embedding groups. CONCLUSIONS: Acupoint catgut embedding can reduce the expression of IL-4 and increase the expression of IFN-γ by inhibiting p38 MAPK signal pathway of lung tissues in BA rats, which may contribute to its effect in alleviating the degree of airway epithelial cells damage.