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Riemerella anatipestifer causes serious infections, characterized by septicemia and serositis, in ducks and geese. R. anatipestifer is mainly controlled through antimicrobial chemotherapy. This study investigated the pharmacokinetic/pharmacodynamic (PK/PD) integration of florfenicol (FF) against R. anatipestifer by establishing a systemic infection model in ducks. For PK studies, FF was administrated intramuscularly (i.m.) at single doses of 2.5, 10, 20, and 40 mg/kg body weight. The concentrations of FF in blood, lung, and liver were determined. FF was rapidly eliminated in R. anatipestifer-infected ducks with T 1/2kel values of 1.67, 2.2, and 1.62 h in the plasma, lung, and liver, respectively. For PD analysis, the infected ducks were administered FF via the i.m. route at doses of 5-80 mg/kg body weight, using 2 dosing regimens involving the administration of FF either once or twice over 24 h. The bacteria were counted 24 h after drug administration. Bactericidal effects in tissues (including those of the heart, liver, spleen, lung, kidney, and brain) were achieved at doses of ≥20 mg/kg following 2 i.m. injections of FF within 24 h. The data obtained were fitted to a sigmoidal E max model. The results demonstrated that AUC 24h /minimum inhibitory concentration (MIC) (R 2 = 0.930) and C max /MIC (R 2 = 0.930) were the optimal PK/PD parameters for describing the antibacterial activity of FF. The magnitudes of AUC 24h /MIC and C max /MIC required to produce a drop of 3 Log 10 CFU/mL in the bacterial count were 58.56 h and 15.10, respectively. The MIC distribution of 164 R. anatipestifer strains for FF ranged from 0.25 to 16 μg/mL. Both the values of CO WT derived from the ECOFFinder program and the CO PD based on a 10,000-subject Monte Carlo simulation of FF against R. anatipestifer were 1 μg/mL, confirming that infections caused by strains with MIC ≤ 1 μg/mL could be effectively treated. Our study results may prove useful in optimizing FF regimens to treat R. anatipestifer infections., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

This paper provides a novel approach using state-of-the-art generative Artificial Intelligence (AI) models to enhance the accuracy of machine learning methods in detecting AI-generated texts; the underlying generative capabilities are used along with ensemble-based learning methods for the exact characterization of created text attributes. Four basic steps are involved in the proposed methodology. The first step of the text process is the preprocessing stage itself consisting of several steps for the purification of irrelevant data. These stages include noise removal, text tokenization, removal of stop-words, word normalization, and handling uncommon words. In the next step, feature engineering and text representations are done whereby every preprocessed text is represented by a square matrix. This matrix encapsulates data about word correlations, cooccurrence, and word weights. The third step is Generative Adversarial Network (GAN)-based feature extraction, using a GAN model to extract efficient features in classifying the texts based on their creator type. After that, it turns the discriminator part into a strong feature extraction model. The fourth step is weighted Random Forest (RF)-based detection, with the features extracted by the discriminator of GAN serving as input to the RF-based detection model. This approach has covered the differences between texts generated by a human and that generated by Artificial Intelligence, with a significant improvement of 99.60% average accuracy, representing a 1.5% improvement against comparative methods., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Calcium is a vital trace element for the human body, and its deficiency can result in a range of pathological conditions, including rickets and osteoporosis. Despite the numerous types of calcium supplements currently available on the market, these products are afflicted with a number of inherent deficiencies, such as low calcium content, poor aqueous solubility, and low human absorption rate. Many microorganisms, particularly beneficial microorganisms, including edible fungi, lactic acid bacteria, and yeast, are capable of absorbing and enriching calcium, a phenomenon that has been widely documented. This opens the door to the potential utilization of microorganisms as novel calcium enrichment carriers. However, the investigation of calcium-rich foods from microorganisms still faces many obstacles, including a poor understanding of calcium metabolic pathways in microorganisms, a relatively low calcium enrichment rate, and the slow growth of strains. Therefore, in order to promote the development of calcium-rich products from microorganisms, this paper provides an overview of the impacts of calcium addition on strain growth, calcium enrichment rate, antioxidant system, and secondary metabolite production. Additionally, it highlights calcium transport and enrichment mechanisms in microorganism cells and offers a detailed account of the progress made on calcium-binding proteins, calcium transport pathways, and calcium storage and release. This paper offers insights for further research on the relevant calcium enrichment in microorganism cells.

Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer's disease (AD). We have recently conceptualized the design of hetero-bifunctional chimeras for selectively promoting the proximity between tau and phosphatase, thus specifically facilitating tau dephosphorylation and removal. Here, we sought to optimize the construction of tau dephosphorylating-targeting chimera (DEPTAC) and obtained a new chimera D14, which had high efficiency in reducing tau phosphorylation both in cell and tauopathy mouse models, while showing limited cytotoxicity. Moreover, D14 ameliorated neurodegeneration in primary cultured hippocampal neurons treated with toxic tau-K18 fragments, and improved cognitive functions of tauopathy mice. These results suggested D14 as a cost-effective drug candidate for the treatment of tauopathies., (© 2024. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Context: There is a significant challenge associated with the co-morbidity of mental and physical illnesses throughout the world. A classic example of mental/physical co-morbidity is diabetes-related depression (DD)., Objective: DD is treated with Zuogui Jiangtang Jieyu prescription (ZJJ). Diabetes and psychiatric disorders are associated with dysbiosis of the gut microbiota. In this study, the aim is to examine the effects of ZJJ on gut microbiota and neuroinflammation in DD., Methods: A model of DD was established and treated with medium and high doses of ZJJ as well as Metformin & Fluoxetine. A detection of depressive-like behavior was then conducted on the rats. Proinflammatory cytokines were measured in cerebrospinal fluid, and HPA axis-related proteins, glucose metabolism, and lipopolysaccharide (LPS) were measured in serum. Fecal samples from each group were collected and analyzed by 16S rRNA sequencing; TLR4 and MyD88 levels were detected by Western blot and immunohistochemistry (IHC) in the hippocampus., Results: High doses of ZJJ (ZJJ-H) were found to alleviate HPA axis hyperactivity and improve gut microbiota in rats with DD. Additionally, ZJJ treatment attenuated the inflammatory response in cerebrospinal fluid, e.g. a significant reduction in proinflammatory factors, a decrease in serum LPS levels, and an inhibition of TLR4/MyD88-related pathways in the hippocampus., Discussion and Conclusion: ZJJ improved DD glucose metabolism and alleviated depression-like behaviors by improving gut microbiota and inhibiting hippocampal TLR4/Myd88 signaling pathways., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks the expression of three receptors commonly targeted in breast cancer treatment. In this study, the research focused on investigating the role of centrosomal protein 55 (CEP55) in TNBC progression and its interaction with the transcription factor Spi-1 proto-oncogene (SPI1)., Methods: Various techniques including qRT-PCR, western blotting, and immunohistochemistry assays were utilized to examine gene expression patterns. Functional assays such as wound-healing assay, transwell invasion assay, 5-Ethynyl-2'-deoxyuridine assay, and metabolic assays were conducted to assess the impact of CEP55 on the behaviors of TNBC cells. CD163-positive macrophages were quantified by flow cytometry. The chromatin immunoprecipitation assay and dual-luciferase reporter assay were performed to assess the association of SPI1 with CEP55. A xenograft mouse model experiment was used to analyze the impact of SPI1 on tumor development in vivo., Results: CEP55 and SPI1 expression levels were significantly upregulated in TNBC tissues and cells. The depletion of CEP55 led to decreased TNBC cell migration, invasion, proliferation, glucose metabolism, and M2 macrophage polarization, indicating its crucial role in promoting TNBC progression. Moreover, SPI1 transcriptionally activated CEP55 in TNBC cells, and its overexpression was associated with accelerated tumor growth in vivo. Further, CEP55 overexpression relieved SPI1 silencing-induced inhibitory effects on TNBC cell migration, invasion, proliferation, glucose metabolism, and M2 macrophage polarization., Conclusion: SPI1-mediated transcriptional activation of CEP55 plays a key role in enhancing TNBC cell migration, invasion, proliferation, glucose metabolism, and M2 macrophage polarization. These insights provide valuable information for potential targeted therapies to combat TNBC progression by modulating the SPI1-CEP55 axis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Neural stem cells play a crucial role in maintaining brain homeostasis. Neural stem cells senescence can lead to the decline of nerve repair and regeneration, causing brain aging and neurodegenerative diseases. However, the mechanism underlying neural stem cells senescence remains poorly understood. In this study, we report a novel HO-1/PARP1 non-canonical pathway highlighting how oxidative stress triggers the DNA damage response, ultimately leading to premature cellular senescence in neural stem cells. HO-1 acts as a sensor for oxidative stress, while PARP1 functions as a sensor for DNA damage. The simultaneous expression and molecular interaction of these two sensors can initiate a crosstalk of oxidative stress and DNA damage response processes, leading to the vicious cycle. The persistent activation of this pathway contributes to the senescence of neural stem cells, which in turn plays a crucial role in the progression of neurodegenerative diseases. Consequently, targeting this novel signaling pathway holds promise for the development of innovative therapeutic strategies and targets aimed at mitigating neural stem cells senescence-related disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A pair of epimers of flavonoid alkaloids, with a pyrrolidone moiety, 2 S ,5'' R -eupodoratin A ( 1 ), 2 S ,5'' S -eupodoratin A ( 2 ), together with two known analogues, drahebephin A ( 3 ), drahebephin B ( 4 ), were isolated from the flowers of Chromolaena odorata (L.) R.M.King & H.Rob. Their structures were elucidated on the basis of HR-ESI-MS, 1D/2D NMR spectral analyses. The absolute configuration of compounds ( 1 ) and ( 2 ) was determined by its experimental and calculated electronic circular dichroism (ECD) spectra. All compounds were isolated from the Asteraceae family for the first time. The ABTS · + scavenging activity of compound ( 4 ) reached 93.56% at a concentration of 0.5 mM, while the scavenging capacity of positive control Trolox was 55.94%. In addition, all compounds show moderate antimicrobial activity against Escherichia coli (ATCC, 337304), Staphylococcus aureus (ATCC, 337371) and Candida albicans (ATCC, 186382) with a MIC value of more than 50 µg/mL.

Individuals' continuous success in competitive interactions with conspecifics strongly affects their social hierarchy. Medial prefrontal cortex (mPFC) is the key brain region mediating both social competition and hierarchy. However, the molecular regulatory mechanisms underlying the neural ensemble in the mPFC remains unclear. Here, we demonstrate that in excitatory neurons of prelimbic cortex (PL), lncRNA Sera remodels the utilization of Pkm Exon9 and Exon10, resulting in a decrease in the Pkm1/2 ratio in highly competitive mice. By employing a tet-on/off system, we disrupt or rebuild the normal Pkm1/2 ratio by controlling the expression of Pkm2 in PL excitatory neurons. We find that long-term Pkm2 modulation induces timely competition alteration and hysteretic rank change, through phosphorylating the Ser845 site of GluA1. Together, this study uncovers a crucial role of lncRNA Sera/Pkm2 pathway in the transition of social competition to rank by remodeling neural ensemble in mPFC., (© 2024. The Author(s).)

Objective: To investigate the effects of luteolin on chronic unpredictable mild stress (CUMS)-induced depressive rats and corticosterone (CORT)-induced depressive primary hippocampal neurons, and to elucidate the mechanism behind the action., Methods: The antidepressant mechanism of luteolin was studied by using CUMS rat model and primary hippocampal neurons in fetal rats. In vivo , novelty suppressed feeding, open-field and sucrose preference tests as well as Morris water maze were evaluated. The content of brain derived neurotrophic factor (BDNF), 5-hydroxytryptamine (5-HT), norepinephrine (NE), and dopamine (DA) in serum were detected by enzyme-linked immunosorbent assay. The mechanisms of luteolin were explored based on neurotrophin and hippocampal neurogenesis, and proliferation. Survival of the septo-temporal axis in hippocampus was assayed using the 5-bromo-2-deoxyuridine (BrdU), the expression of BDNF, neurotrophin-3 (NT-3), and nerve growth factor (NGF) in hippocampus dentate gyrus region were measured by Western-blotting. In vitro , BDNF, NT-3, tropomyosin receptor kinase B (TrkB), and phosphorylated cyclic adenosine monophosphate responsive element binding protein (p-CREB) were detected through the high content analysis (HCA) to investigate neurotrophin and apoptosis., Results: Induction of CUMS in rats induced depressive symptoms, while luteolin significantly enhanced sucrose consumption, decreased feeding latency, increased locomotor activity, escape latency, distance of target quadrant and regulated the content of depressive-like biomarkers. Histology analysis revealed that luteolin increased the abundance of new born neurons that had been labeled with BrdU, BrdU + neuronal nuclear antigen, and BrdU + doublecortin in septo-temporal axis of S2 (mid-septal) and T3 (mid-temporal). Moreover, expression of BDNF, NT-3, and NGF increased significantly in the septo-temporal axis of S2 and T3. HCA showed increased expression of BDNF, NT-3, TrkB and p-CREB in primary hippocampal neurons., Conclusion: The results provided direct evidence that luteolin has an antidepressant effect and could effectively promote the regeneration of the septotemporal axis nerve and hippocampal neuronutrition, which suggested that the antidepressant effect of luteolin may be related to hippocampal neurogenesis.

Objective: To explore the mechanism of acupuncture to relieve diabetic proteinuria in Diabetic Kidney Disease (DKD)., Methods: A total of 10 male Sprague-Dawley rats were randomly selected as the negative control group (NC), and a further 30 rats were fed a high-fat diet (HFD) and intraperitoneal streptozotocin (STZ). The DKD model rats in the model group (DKD) and the acupuncture group (DKD + Acu) were randomly assigned. After 4 weeks of intervention, collected urine, peripheral blood, and renal tissues from all rats, and assessed blood urea nitrogen, serum creatinine, triglyceride, 24-h urine protein quantification, and blood glucose, left kidney weight, kidney body ratio index, then observe changes in renal histology in the rats. The renal cortex tissues of three rats from each group were sent for transcriptomic analysis. According to the results of transcriptomic analysis, various kits were used to detect SOD, MDA, GSH, GSH-px, and iron concentration. The expression levels of GPX4 and System Xc-, members of the antioxidative stress pathway, and TfR 1, SLC39A14, FTH 1, and SLC40A1, involved in iron metabolism, in the kidney tissues were measured by western blotting and reverse transcription-quantitative PCR. The expression of mesenchymal phenotype markers and podocyte-specific markers were evaluated by immunofluorescence., Results: Acupuncture promoted the levels of GSH, GSH-px, and SOD, decreased the level of MDA (P < 0.05), promoted the expression of GPX4 and System Xc- ( P  < 0.05), decreased the expression of TfR1 and SLC39A14 ( P  < 0.01), and increased the expression of FTH 1 and SLC40A1 ( P  < 0.05), inhibited the expression of TGF-β1, desmin, FSP-1, and α-SMA ( P  < 0.05), promoted the expression of Nephrin, Podocin, and CD2AP (P < 0.05)., Conclusion: Improving the ability of podocytes to prevent oxidative stress and restoring iron ion homeostasis, can improve Ferroptosis and block epithelial-mesenchymal transition, improve podocyte injury, restore filtration function, and reduce proteinuria in DKD rats., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Purpose: To characterize and compare clinical and immunological features of para(p)-autoimmune retinopathy (AIR) and non-para(np)-AIR and to assess the clinical significance of the presence of serum anti-retinal antibodies (ARAs)., Methods: We retrospectively reviewed 48 Chinese patients with p-AIR or np-AIR who took comprehensive ophthalmic examinations and lab tests of the presence of serum ARAs., Results: p-AIR patients differed from np-AIR patients in terms of disease progression, ocular inflammation, findings of OCT, FFA, and presence of ARAs. No significant difference was found in the band number of serum ARAs between AIR patients and healthy controls. The prevalence of antibodies to recoverin and ɑ-enolase in the sera of p-AIR was significantly higher than that of the healthy individuals., Conclusion: While having many similar clinical signs, patients with p-AIR or np-AIR nevertheless displayed unique characteristics. Detection of ARAs subtypes, rather than their quantity, may be helpful in evaluating the conditions in the verified instances.

Sterigmatocystins and aflatoxins are a group of mycotoxins mainly isolated from fungi of the genera Aspergillus . Since the discovery of sterigmatocystins in 1954 and aflatoxins in 1961, many scholars have conducted a series of studies on their structural identification, synthesis and biological activities. Studies have shown that sterigmatocystins and aflatoxins have a wide range of biological activities such as antitumour, antibacterial, anti-inflammatory, antiplasmodial, etc. The sterigmatocystins and aflatoxins had been shown to be hepatotoxic and nephrotoxic in animals. This review attempts to give a comprehensive summary of progress on the chemical structural features, synthesis, and bioactivity of sterigmatocystins and aflatoxins reported from 1954 to April 2024. A total of 72 sterigmatocystins and 20 aflatoxins are presented in this review. This paper reviews the chemical diversity and potential activity and toxicity of sterigmatocystins and aflatoxins, enhances the understanding of sterigmatocystins and aflatoxins that adversely affect humans and animals, and provides ideas for their prevention, research and development.

Objectives: To explore how the circular non-coding RNA circ&#95;0072088 influences the progression of breast carcinoma (BC) by affecting cell behavior., Methods: We measured the levels of circ&#95;0072088, microRNA-607 (miR-607), and ring finger protein 2 (RNF2) mRNA levels in BC tissues and cell lines using quantitative real-time PCR. We also conducted cell counting kit-8 (CCK-8), BrdU incorporation, and flow cytometry assays to assess cell viability, cell cycle, and apoptosis, respectively., Results: We observed increased levels of circ&#95;0072088 and RNF2, and decreased levels of miR-607 in BC tissues. Overexpressing circ&#95;0072088 promoted BC cell proliferation and cell cycle progression while inhibiting apoptosis. Conversely, silencing circ&#95;0072088 had the opposite effects. Our data suggest that circ&#95;0072088 directly targets and downregulates miR-607, which in turn upregulates RNF2, a target of miR-607. Moreover, miR-607 overexpression could mitigate the pro-proliferative and anti-apoptotic effects of circ&#95;0072088 on BC cells., Conclusion: Circ&#95;0072088 drives BC progression by downregulating miR-607 and upregulating RNF2, thereby promoting cell proliferation and cycle progression while reducing apoptosis., Competing Interests: None., (AJTR Copyright © 2024.)

Background: Episodic memory loss is a prominent clinical manifestation of Alzheimer's disease (AD), which is closely related to tau pathology and hippocampal impairment. Due to the heterogeneity of brain neurons, the specific roles of different brain neurons in terms of their sensitivity to tau accumulation and their contribution to AD-like social memory loss remain unclear. Therefore, further investigation is necessary., Methods: We investigated the effects of AD-like tau pathology by Tandem mass tag proteomic and phosphoproteomic analysis, social behavioural tests, hippocampal electrophysiology, immunofluorescence staining and in vivo optical fibre recording of GCaMP6f and iGABASnFR. Additionally, we utilized optogenetics and administered ursolic acid (UA) via oral gavage to examine the effects of these agents on social memory in mice., Results: The results of proteomic and phosphoproteomic analyses revealed the characteristics of ventral hippocampal CA1 (vCA1) under both physiological conditions and AD-like tau pathology. As tau progressively accumulated, vCA1, especially its excitatory and parvalbumin (PV) neurons, were fully filled with mislocated and phosphorylated tau (p-Tau). This finding was not observed for dorsal hippocampal CA1 (dCA1). The overexpression of human tau (hTau) in excitatory and PV neurons mimicked AD-like tau accumulation, significantly inhibited neuronal excitability and suppressed distinct discrimination-associated firings of these neurons within vCA1. Photoactivating excitatory and PV neurons in vCA1 at specific rhythms and time windows efficiently ameliorated tau-impaired social memory. Notably, 1 month of UA administration efficiently decreased tau accumulation via autophagy in a transcription factor EB (TFEB)-dependent manner and restored the vCA1 microcircuit to ameliorate tau-impaired social memory., Conclusion: This study elucidated distinct protein and phosphoprotein networks between dCA1 and vCA1 and highlighted the susceptibility of the vCA1 microcircuit to AD-like tau accumulation. Notably, our novel findings regarding the efficacy of UA in reducing tau load and targeting the vCA1 microcircuit may provide a promising strategy for treating AD in the future., (© 2024. The Author(s).)

Sestrins are metabolic regulators that respond to stress by reducing the levels of reactive oxygen species (ROS) and inhibiting the activity of target of rapamycin complex 1 (mTORC1). Previous research has demonstrated that Sestrin2 mitigates ischemia-reperfusion (IR) injury in the heart, liver, and kidneys. However, its specific role in intestinal ischemia-reperfusion (IIR) injury remains unclear. To elucidate the role of Sestrin2 in IIR injury, we conducted an experimental study using a C57BL/6J mouse model of IIR. We noticed an increase in the levels of Sestrin2 expression and indicators associated with ferroptosis. Our study revealed that manipulating Sestrin2 expression in Caco-2 cells through overexpression or knockdown resulted in a corresponding decrease or increase, respectively, in ferroptosis levels. Furthermore, our investigation revealed that Sestrin2 alleviated ferroptosis caused by IIR injury through the activation of the Keap1/Nrf2 signal pathway. This finding highlights the potential of Sestrin2 as a therapeutic target for alleviating IIR injury. These findings indicated that the modulation of Sestrin2 could be a promising strategy for managing prolonged IIR injury., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Trilobolide-6-O-isobutyrate exhibits significant antitumor effects on cholangiocarcinoma (CCA) cells by effectively inhibiting the JAK/STAT3 signaling pathway. This study aims to investigate the mechanisms underlying the antitumor properties of trilobolide-6-O-isobutyrate, and to explore its potential as a therapeutic agent for CCA. This study illustrates that trilobolide-6-O-isobutyrate efficiently suppresses CCA cell proliferation in a dose- and time-dependent manner. Furthermore, trilobolide-6-O-isobutyrate stimulates the production of reactive oxygen species, leading to oxidative stress and initiation of apoptosis via the activation of the mitochondrial pathway. Data from xenograft tumor assays in nude mice confirms that TBB inhibits tumor growth, and that there are no obvious toxic effects or side effects in vivo . Mechanistically, trilobolide-6-O-isobutyrate exerts antitumor effects by inhibiting STAT3 transcriptional activation, reducing PCNA and Bcl-2 expression, and increasing P21 expression. These findings emphasizes the potential of trilobolide-6-O-isobutyrate as a promising therapeutic candidate for the treatment of CCA., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

This research establishes an emergency evacuation time model specifically designed for subway stations with complex structures. The model takes into account multiple factors, including passenger flow rate, subway facility parameters, and crowd density, to accurately assess evacuation times. It considers the impact of horizontal walking distance, flow rate, subway train size, and stair parameters on the overall evacuation process. By identifying bottleneck points such as gates, car doors, and stairs, the model facilitates the evaluation of evacuation capacity and the formulation of effective evacuation plans, particularly in multiline subway transfer stations. The good consistency is achieved between the calculated evacuation time and simulated results using the Pathfinder software (with the relative error of 5.4%). To address urban traffic congestion and enhance subway station safety, the study recommends implemented measures for emergency diversion and passenger flow control. Additionally, the research presents characteristic mathematical models for various evacuation routes by considering the structural and temporal characteristics of metro systems. These models provide valuable guidance for conducting large-scale passenger evacuation simulations in complex environments. Future research can further enhance the model by incorporating psychological factors, evacuation signage, and strategies for vulnerable populations. Overall, this study contributes to a better understanding of evacuation dynamics and provides practical insights to improve safety and efficiency in subway systems., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hui et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Hirschsprung's disease (HSCR) is the leading cause of neonatal functional intestinal obstruction, which has been identified in many familial cases. HSCR, a multifactorial disorder of enteric nervous system (ENS) development, is associated with at least 24 genes and seven chromosomal loci, with RET and EDNRB as its major genes. We present a genetic investigation of familial HSCR to clarify the genotype-phenotype relationship., Methods: We performed whole exome sequencing (WES) on Illumina HiSeq X Ten platform to investigate genetic backgrounds of core family members, and identified the possibly harmful mutation genes. Mutation carriers and pedigree relatives were validated by Sanger sequencing for evaluating the gene penetrance., Results: Four familial cases showed potential disease-relative variants in EDNRB and RET gene, accounting for all detection rate of 57.1%. Three familial cases exhibited strong pathogenic variants as frameshift or missense mutations in EDNRB gene. A novel c.367delinsTT mutation of EDNRB was identified in one family member. The other two EDNRB mutations, c.553G>A in family 2 and c.877delinsTT in family 5, have been reported in previous literatures. The penetrance of EDNRB variants was 33-50% according mutation carries. In family 6, the RET c.1858T>C (C620R) point mutation has previously been reported to cause HSCR, with 28.5% penetrance., Conclusion: We identified a novel EDNRB (deleted C and inserted TT) mutation in this study using WES. Heterozygote variations in EDNRB gene were significantly enriched in three families and RET mutations were identified in one family. EDNRB variants showed an overall higher incidence and penetrance than RET in southern Chinese families cases., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Two new sesquiterpene glycosides, 8 α ,12,15 β -trihydroxycopacamphan-15- O - β -D-glucopyranoside ( 1 ) and dendrobiumane C-11- O - β -D-glucopyranoside ( 2 ), along with three known terpenoids ( 3-5 ) were isolated from the aerial stems of Dendrobium henanense . Their structures were elucidated based on NMR-spectroscopic and HR-MS analyses. All compounds could reduce the levels of NO, TNF- α and IL-1 β in LPS-induced RAW264.7 cells with IC 50 values ranging from 10.37 to 34.55 µ Μ.

Hepatocellular carcinoma (HCC), one of the most common malignant cancers with a low 5-year survival rate, is the third leading cause of cancer-related deaths worldwide. The finding of novel agents and strategies for the treatment of HCC is an urgent need. Sesquiterpene lactones (SLs) have attracted extensive attention because of their potent antitumor activity. In this study, a new series of SL derivatives ( 3 - 18 ) were synthesized using epimers 1 and 2 as parent molecules, isolated from Sphagneticola trilobata , and evaluated for their anti-HCC activity. Furthermore, the structures of 4 , 6 , and 14 were confirmed by X-ray single-crystal diffraction analyses. The cytotoxic activities of 3 - 18 on two HCC cell lines, including HepG2 and Huh7, were evaluated using the CCK-8 assay. Among them, compound 10 exhibited the best activity against the HepG2 and Huh7 cell lines. Further studies showed that 10 induced cell apoptosis, arrested the cell cycle at the S phase, and induced the inhibition of cell proliferation and migration in HepG2 and Huh7. In addition, absorption, distribution, metabolism, and excretion (ADME) properties prediction showed that 10 may possess the properties to be a drug candidate. Thus, 10 may be a promising lead compound for the treatment of HCC.

A new bicyclic lactam derivatives penicilactam B ( 1 ) and a new monocyclic amide penicillamide D ( 2 ), along with four known compounds ( 3-6 ), were isolated from the fermentation broth of the derived fungus Penicillium rubens PQJ-2. Their structures and stereochemistry were elucidated by comprehensive spectroscopic analyses and quantum ECD calculations. All the compounds were evaluated for their antibacterial activities against Staphylococcus aureus subsp , Candida albicans, Escherichia coli and insecticidal activity against Helicoverpa armigera Hubner. Compounds 1-3 exhibited modest insecticidal activity against H. armigera Hubner.

Poly (ADP-ribose) polymerase inhibitors (PARPis) are approved for cancer therapy according to their synthetic lethal interactions, and clinical trials have been applied in non-small cell lung cancer. However, the therapeutic efficacy of PARPis in lung adenocarcinoma (LUAD) is still unknown. We explored the effect of a mutated retinoblastoma gene (RB1) on PARPi sensitivity in LUAD. Bioinformatic screening was performed to identify PARPi-sensitive biomarkers. Here, we showed that viability of LUAD cell lines with mutated RB1 was significantly decreased by PARPis (niraparib, rucaparib, and olaparib). RB1 deficiency induced genomic instability, prompted cytosolic double-stranded DNA (dsDNA) formation, activated the cGAS/STING pathway, and upregulated downstream chemokines CCL5 and CXCL10, triggering immune cell infiltration. Xenograft experiments indicated that PARPi treatment reduced tumorigenesis in RB1-KO mice. Additionally, single-cell RNA sequencing analysis showed that malignant cells with downregulated expression of RB1 had more communications with other cell types, exhibiting activation of specific signaling such as GAS, IFN response, and antigen-presenting and cytokine activities. Our findings suggest that RB1 mutation mediates the sensitivity to PARPis through a synthetic lethal effect by triggering the cGAS/STING pathway and upregulation of immune infiltration in LUAD, which may be a potential therapeutic strategy.

Two new indole diterpene derivatives, 5 S -hydroxy- β -aflatrem ( 1 ) and 14 R -hydroxy- β -aflatrem ( 2 ), along with one known analogue, 14-( N , N -dimethl- L -valyloxy)paspalinine ( 3 ), were isolated from the fermentation broth of the fungus Aspergillus sp. PQJ-1 derived from Sphagneticola trilobata . The structures of the new compounds were elucidated from spectroscopic data and ECD spectroscopic analyses. All the compounds ( 1 - 3 ) were evaluated for their cytotoxicity against A549, Hela, Hep G2, and MCF-7 cell lines. Compounds 1 and 2 exhibited selective inhibition against Hela cells. Further studies showed that 1 significantly induced apoptosis and suppressed migration and invasion in Hela cells. Moreover, 1 could up-regulate pro-apoptotic genes BAX and Caspase-3 and down-regulate anti-apoptotic genes Bcl-xL and XIXP.

Background: Immune checkpoint inhibitors (ICI) have revolutionized the treatment for multiple cancers. However, most of patients encounter resistance. Synthetic viability (SV) between genes could induce resistance. In this study, we established SV signature to predict the efficacy of ICI treatment for melanoma., Methods: We collected features and predicted SV gene pairs by random forest classifier. This work prioritized SV gene pairs based on CRISPR/Cas9 screens. SV gene pairs signature were constructed to predict the response to ICI for melanoma patients., Results: This study predicted robust SV gene pairs based on 14 features. Filtered by CRISPR/Cas9 screens, we identified 1,861 SV gene pairs, which were also related with prognosis across multiple cancer types. Next, we constructed the six SV pairs signature to predict resistance to ICI for melanoma patients. This study applied the six SV pairs signature to divide melanoma patients into high-risk and low-risk. High-risk melanoma patients were associated with worse response after ICI treatment. Immune landscape analysis revealed that high-risk melanoma patients had lower natural killer cells and CD8 + T cells infiltration., Conclusions: In summary, the 14 features classifier accurately predicted robust SV gene pairs for cancer. The six SV pairs signature could predict resistance to ICI., (© 2023. The Author(s).)

Purpose: Autoimmune retinopathy (AIR) is a group of autoimmune retinal diseases that can cause blindness. The purpose of this study is to investigate the profiles of serum antiretinal antibodies (ARAs) and cytokines and their association with disease diagnosis as well as clinical features in AIR., Methods: The patients with presumed para (p) and non-paraneoplastic (np) AIR diagnosis, the patients with retinitis pigmentosa and bilateral uveitis as disease controls, and healthy subjects were prospectively enrolled. Western blotting and Luminex multiple cytokine assay/enzyme linked immunosorbent assay were used to determine the presence of serum ARAs and the concentration of cytokines, respectively. Kruskal-Wallis or chi square test was applied to compare the profiles of ARA and cytokines among various groups. The multilevel mixed-effect regression was used to investigate the association of ARA or cytokines with clinical features., Results: No significant difference in the band number and subtypes of serum ARAs was found between AIR patients and their controls. AIR patients had higher concentration of serum IFN-ɤ, CXCL9, or CXCL10 than non-AIR controls. A positive correlation was found between increased number of ARAs and elevated TNF-α in np-AIR patients. Elevated pro-inflammatory cytokines or ARA subtypes (antibody against recoverin and α-enolase) were associated with worse retinal functions or anatomy, including visual acuity, visual field, ERG parameters, and central retinal thickness., Conclusions: The data of our study demonstrate that detection of serum ARAs has limited value in the diagnosis of AIR. Th1-type cytokines/chemokines or specific ARA subtypes are associated with pathogenesis and disease severity of the AIR., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ziziphi Spinosae Semen(ZSS) is an edible TCM derived from the dried ripe seeds of Ziziphus jujube Mill. var. spinosa(Bunge)Hu ex H. F. Chou(Rhamnaceae), which has the effects of nourishing the heart, tonifying the liver, calming the heart, tranquilizing the mind, arresting sweating, and promoting fluid production, and is widely used in the treatment and health care of diseases related to cardiovascular, nervous, and immune systems. Jujuboside B(JuB), one of the main active ingredients of ZSS, possesses various pharmacological effects with application values. This paper reviewed the chemical structure and pharmacological effects of JuB. JuB has sedative, hypnotic, antitumor, anti-platelet, anti-inflammatory, and other biological activities, which shows the potential thera-peutic effects on insomnia, tumors, coronary artery disease, airway inflammation, and liver injury. However, there are some limitations to the results of current studies. More comprehensive studies, including basic research and clinical trials, need to be carried out to provide more reliable evidence.

Objectives. To examine the global prevalence of and factors associated with tobacco dependence among adolescents who are currently smoking. Methods. We obtained 2012 to 2019 Global Youth Tobacco Survey data on 67 406 adolescents aged 12 to 16 years from 125 countries or territories (hereafter countries). Those with tobacco dependence were defined as current smokers who felt a strong desire to smoke again within 24 hours after smoking or who had ever smoked or felt like smoking first thing in the morning. Results. The global prevalence of tobacco dependence among adolescents who were currently smoking was 38.4% (95% confidence interval [CI] = 34.0, 42.7). The prevalence was highest in high-income countries (49.8%; 95% CI = 47.0, 52.6) and lowest in lower-middle-income countries (31.2%; 95% CI = 26.9, 35.4). Secondhand smoke exposure, parental smoking, smoking among closest friends, tobacco advertisement exposure, and offers of free tobacco products were positively associated with tobacco dependence. Conclusions. Nearly 40% of adolescents who are currently smoking have tobacco dependence worldwide. Public Health Implications. Our findings emphasize the need to develop tobacco control interventions to prevent experimentation from progressing to regular smoking among adolescents who are currently smoking tobacco. ( Am J Public Health. 2023;113(8):861-869. https://doi.org/10.2105/AJPH.2023.307283).

Gastric cancer stem cells (GCSCs) play critical roles in gastric cancer (GC) initiation and development. Circular RNAs (circRNAs) participate in diverse cancer biological processes and function as tumor suppressors or oncogenes. This study aims to discover the expression profile and functional roles of circRNAs in GCSCs. A spheroid formation assay was conducted to enrich GCSCs. Genome-wide sequencing of circRNAs showed that a novel circRNA, circSLC4A7, was one of the most upregulated circRNAs in GCSCs. CircSLC4A7 was localized to the nucleus, and its level was elevated in GC cells and tissues. Furthermore, circSLC4A7 increased CSC-like properties and drove cell proliferation, migration, and invasion, which were determined by gain- and loss-of-function experiments. Specific circRNA pull-down assays followed by mass spectrometry analysis, RNA immunoprecipitation, and dual RNA-fluorescence in situ hybridization and immunofluorescence assay were conducted and HSP90 was detected to interact with circSLC4A7 and mediate the oncogenic function of circSLC4A7 by activating the Notch1 signaling pathway in GC. This study highlights a novel oncogenic function of circSLC4A7 mediated by its binding with HSP90 and thus activating the Notch1 signaling pathway., (© 2023. The Author(s).)

Four undescribed pyranone derivatives, named ascomycopyrones A-D ( 1 - 4 ), as well as one known analogue simplicilopyrone ( 5 ) (this is the first study to report the absolute configuration), were isolated from the endophytic fungus Ascomycota sp. FAE17 derived from the flowers of Scutellaria formosa . The structures of these pyranones were identified by comprehensive spectroscopic and MS analyses, and the absolute configurations were determined by their experimental and quantum chemical electronic circular dichroism (ECD) calculations. All isolated compounds were tested for various bioactivities, including antibacterial, cytotoxic activity, and NO inhibitory activity. Unfortunately, none of the compounds showed significant bioactivities.

Myocardial edema mediated by endothelial dysfunction plays an important role in sepsis-induced cardiomyopathy (SIC); however, its mechanism is unclear. The current study aimed to provide evidence on the cardioprotection of CD1d-dependent natural killer T (NKT) cells and clarify the possible mechanism in a mouse model of sepsis. Wild-type (WT) and CD1d-dependent NKT-cells inactivation (CD1dko) mice were subjected to sepsis induced by intraperitoneal injection of lipopolysaccharide (LPS). The NKT-cells number and CD1d expression were both increased in the hearts and blood of WT mice after LPS treatment. Compared with WT mice, CD1dko mice exhibited remarkably accelerated LPS-induced mortality, cardiac dysfunction, myocardial injury, endothelial apoptosis, microvascular damage, microvascular permeability and cardiac edema. Mechanistically, CD1d deficiency further increased LPS-induced accumulation of T lymphocytes in the myocardium and upregulation of IL-6 protein levels. Administration of an IL-6 neutralizing antibody to CD1dko mice improved cardiac dysfunction, myocardial injury and edema induced by LPS. Our study identified that CD1d-dependent NKT-cells inactivation exacerbated SIC via T lymphocytes infiltration and IL-6 production. Hence, activation of CD1d-dependent NKT cells may be a potential candidate strategy for SIC treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The solid-electrolyte interphase (SEI) plays crucial roles for the reversible operation of lithium metal batteries. However, fundamental understanding of the mechanisms of SEI formation and evolution is still limited. Herein, we develop a depth-sensitive plasmon-enhanced Raman spectroscopy (DS-PERS) method to enable in-situ and nondestructive characterization of the nanostructure and chemistry of SEI, based on synergistic enhancements of localized surface plasmons from nanostructured Cu, shell-isolated Au nanoparticles and Li deposits at different depths. We monitor the sequential formation of SEI in both ether-based and carbonate-based dual-salt electrolytes on a Cu current collector and then on freshly deposited Li, with dramatic chemical reconstruction. The molecular-level insights from the DS-PERS study unravel the profound influences of Li in modifying SEI formation and in turn the roles of SEI in regulating the Li-ion desolvation and the subsequent Li deposition at SEI-coupled interfaces. Last, we develop a cycling protocol that promotes a favorable direct SEI formation route, which significantly enhances the performance of anode-free Li metal batteries., (© 2023. The Author(s).)

Purpose: The purpose of this study is to evaluate clinical outcomes of autoimmune retinopathy (AIR) in the patients treated with intravitreal dexamethasone implant (IDI)., Method: Twenty-one eyes of 11 AIR patients treated with at least 1 injection of IDI were retrospectively reviewed. Clinical outcomes before and after treatment, including best corrected visual acuity (BCVA), optic coherence tomography (OCT), fundus autofluorescence (FAF), full-field electroretinography (ff-ERG), and visual field (VF) at last visit within 6 and/or 12 months, were recorded., Results: Among all the patients, 3 had cancer-associated retinopathy (CAR) and 8 had non-paraneoplastic-AIR (npAIR) with mean followed up of 8.52 ± 3.03 months (range 4-12 months). All patients achieved improved or stable BCVA within 6 and/or 12 months after the treatment. Cystoid macular edema (CME) in 2 eyes and significant retinal inflammation in 4 eyes were markedly resolved after single injection. Central retinal thickness (CFT) in all eyes without CME, ellipsoid zone (EZ) on OCT in 71.4% of eyes, ERG response in 55% of eyes, and VF in 50% of eyes were stable or improved within 6 months after treatment. At last visit within 12 months, both BCVA and CFT remained stable in the eyes treated with either single or repeated IDI; however, progression of EZ loss and damage of ERG response occurred in some patients with single IDI., Conclusion: Clinical outcomes, including BCVA and parameters of OCT, ERG, and VF, were stable or improved after IDI in a majority of AIR patients. Local treatment of AIR with IDI was a good option to initiate the management or an alternative for the patients' refractory to the systemic therapy but with limited side effect., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Stem cell therapy mainly uses natural stem cells for transplantation, and the use of genetic engineering to optimize stem cell products is a very important process. This article reviews successful gene modification methods in the field of immune cell therapy and summarizes some attempts at stem cell gene editing in current research. Cell bridging is an innovative cutting-edge strategy that includes the specific recognition and signal transduction of artificial receptors. The "off-the-shelf" cell strategies mainly introduce the advantages of allogeneic cell therapy and how to overcome issues such as immunogenicity. Gene regulatory systems allow us to manipulate cells with small molecules to control cellular phenotypes. In addition, we also summarize some important genes that can provide a reference for cell genetic engineering. In conclusion, we summarize a variety of technical strategies for gene editing cells to provide useful ideas and experiences for future stem cell therapy research., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Vascular dementia (VD), associated with cerebrovascular injury, is characterized by severe cognitive impairment. Jianpi Tianjing Decoction (JTD) has been widely used to treat VD. However, its molecular targets and mechanisms of action in this treatment remain unclear. This study integrated network pharmacology and proteomics to identify targets and mechanisms of JTD in the treatment of VD and to provide new insights and goals for clinical treatments., Methods: Systematic network pharmacology was used to identify active chemical compositions, potential targets, and mechanisms of JTD in VD treatment. Then, a mouse model of VD was induced via transient bilateral common carotid artery occlusion to verify the identified targets and mechanisms of JTD against VD using 4D label-free quantitative proteomics., Results: By screening active chemical compositions and potential targets in relevant databases, 187 active chemical compositions and 416 disease-related compound targets were identified. In vivo experiments showed that JTD improved learning and memory in mice. Proteomics also identified 112 differentially expressed proteins in the model and sham groups and the JTD and model groups. Integrating the network pharmacology and proteomics results revealed that JTD may regulate expressions of cytochrome c oxidase subunit 7C, metabotropic glutamate receptor 2, Slc30a1 zinc transporter 1, and apolipoprotein A-IV in VD mice and that their mechanisms involve biological processes like oxidative phosphorylation, regulation of neuron death, glutamate secretion, cellular ion homeostasis, and lipoprotein metabolism., Conclusions: JTD may suppress VD development via multiple components, targets, and pathways. It may thus serve as a complementary treatment option for patients with VD., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Jidan Liu et al.)

Quantification of steroids possesses a crucial clinical value in early diagnosis and prognosis evaluation of various endocrine diseases. However, it is still challenging to realize feasible analysis of estrogens, androgens, progestogens, and corticoids within one single workflow. In this study, two derivatization reactions were newly designed for improvement: (1) acylation of phenolic hydroxyl on estrogens with isonicotinoyl chloride (INC) under the catalysis of 4-dimethylaminopyridine and (2) post-modification of oxime hydroxyl on hydroxylamine-pretreated ketosteroids with INC. Both reactions could conduct instantaneously at room temperature under aqueous conditions. Moreover, the resulting phenolic-INC and oxime-INC esters exhibited favorable MS responses. Through integrating these derivatization strategies with cold-induced phase separation technology, a feasible LC-MS/MS method was developed for simultaneous quantification of 15 multiclass steroids with proper sample consumption (50 μL serum), satisfying sensitivity (lower limit of quantitation at 0.01-5.00 ng/mL) and high throughput (40 min for sample-preparation). The practical applicability was tested by detecting 30 real samples from pregnant and non-pregnant women. The obtained results showed a good agreement with a previous validated methodology.

Objective: On the basis of sodium hyaluronate eye drops, to observe the clinical efficacy of acupuncture on dry eye and explore the effect mechanism of ocular surface protection., Methods: A total of 80 patients with dry eye were randomly divided into an observation group and a control group, 40 cases in each group. The control group was treated with routine cleaning of eyelid margin, hot compress of eyes with warm towel, and external application of sodium hyaluronate eye drops for 5 weeks. On the basis of the treatment as the control group, the observation group was treated with acupuncture at Jingming (BL 1), Cuanzhu (BL 2), Chengqi (ST 1), Hegu (LI 4), Zusanli (ST 36), Sanyinjiao (SP 6), etc., once a day, 6 times a week for 5 weeks (30 times totally). Before and after treatment, SchirmerⅠtest (SⅠT), breaking up time (BUT), corneal fluorescent (FL) score, ocular surface disease index (OSDI) score, and the contents of IL-6 and TNF-α in tears were evaluated and the therapeutic effect was compared between the two groups., Results: Compared with before treatment, SⅠT and BUT after treatment in the observation group were prolonged ( P <0.05), the scores of FL and OSDI and the contents of IL-6 and TNF-α in tears were decreased ( P <0.05). After treatment, SⅠT and BUT in the observation group were longer than the control group ( P <0.05), and the scores of FL and OSDI and the contents of IL-6 and TNF-α in tears in the observation group were lower than the control group ( P <0.05). The total effective rate in the observation group was 87.5% (35/40), which was higher than 45.0% (18/40) in the control group ( P <0.05)., Conclusion: On the basis of sodium hyaluronate eye drops, acupuncture could improve the clinical symptoms of dry eye, promote the secretion of tears, prolong the tear film breaking up time, and reduce corneal damage, and effect mechanism may be related to the reduction of inflammatory response.

Ex-situ stabilization for As and Sb co-contaminated soil was conducted through an iron-based stabilizer, PFSC (a mixture of polymerized ferric sulfate (PFS) and hydrated lime (Ca(OH 2 )) with a dry mass ratio of 2:1). After field aging for one week, the stabilized contaminated soil was subjected to a horizontal vibration leaching test (HJ 557), Wenzel's sequential extraction, and a semi-dynamic leaching test (ANS 16.1). By assessing the cumulative fractions of As and Sb, the observed diffusion coefficients (D obs ) and leachability indices (LX) of metalloids released from the soil specimens were calculated. The PFSC ex-situ stabilization was effective to immobilize metalloids, and the As and Sb leached concentrations of stabilized contaminated soil samples were lower than remediation targets. Nonspecifically bound As and Sb in the stabilized contaminated soil samples decreased from 4.5 - 9.2 % to 1.5-2.5 % and from 2.2 - 5.8 % to 1.1-1.5 %, respectively. The mechanisms controlling the leaching behaviors of As and Sb included wash-off and diffusion and they were changed with the leaching interval. The mean D obs of As and Sb released from stabilized contaminated soil specimen were 3.46 × 10 -12 and 2.99 × 10 -13 cm 2 s -1 , in the which were two orders of magnitude lower than that of untreated contaminated soil specimen. The mean LX of stabilized contaminated soil specimen for As and Sb releases were 11.40 and 12.83, respectively, indicating that the stabilized contaminated soil was acceptable for "controlled utilization"., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Abnormal cell apoptosis is closely related to the occurrence of hematologic tumors, B-cell lymphoma-2 (BCL-2), as a key anti-apoptotic protein in intrinsic programmed cell death, has become a hot spot in the treatment of hematologic tumors in recent years. Venetoclax is an oral small-molecule selective BCL-2 inhibitor approved by the Food and Drug Administration (FDA） for the treatment of chronic lymphocytic leukemia (CLL) patients or small lymphocytic lymphoma (SLL) patients and for the treatment of elderly acute myeloid leukemia (AML) patients that is not suitable for aggressive chemotherapy. In addition, it also showed a promising clinical application in treatment of non-Hodgkin's lymphoma (NHL) patients, which is a new expansion of the clinical indications for venetoclax. In this review, the role of BCL-2 protein family played in the regulation of NHL cell apoptosis, the development of BCL-2 inhibitors and the recent research progress of venetoclax in the treatment of NHL are reviewed.

The final stadium larvae of Huosoma latiloba (Yu, Yang Bu, 2008) and Huosoma tinctipenne (McLachlan, 1894) from Yunnan Province, China are described and illustrated for the first time, with diagnostic differences between the two species identified. While no morphological characters separating the adults of this genus, and the closely related western Palaearctic Pyrrhosoma Charpentier, 1840 have been found, the larvae of these two genera do show differences which are discussed here.

With the rapid development of global economy, the industrial cluster has become the new trend of world economic development. So far, the industrial cluster mode with space as the main division has been formed. The cooperation of industrial clusters is dynamic. The industries in the cluster cooperate with each other for mutual benefit and win-win, occupying a place in the fierce market competition. In addition, the industrial cluster is also conducive to strengthen the international economic division of labor and points out the direction of regional industrial transfer. China is now in a critical period of economic development; the industrial cluster plays an important role in China's industrial transformation and economic development. At present, the most common regional development mode in China is industrial cluster. The emergence of industrial cluster accelerates the development of industrial regional economy and the balance of industrial layout. Industrial clusters occupy a key position in China's economic industry chain, and the development and change in industrial clusters will directly affect the development of the entire industrial chain. This study first simulates the evolution path of industrial cluster and then establishes the relevant data model. Finally, through repast simulation, it puts forward conclusions and suggestions according to the verification results. The construction of dynamic model can realize the simulation of industrial cluster theory. According to the simulation results, we can find that the ecosystem in different stages will produce different characteristics; the formation and evolution of industrial clusters are actually the epitome of market development. In this process, the government guidance and market regulation are needed to accelerate the formation of industrial cluster ecosystem and increase the scale of industrial cluster., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Yang Hui et al.)

Background: Patients with relapsed/refractory acute myeloid leukaemia (AML) with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) have limited treatment options and poor prognosis. Therefore, novel treatment modalities are needed. Since high expression of natural killer group 2 member D ligands (NKG2DLs) can be induced by FLT3 inhibitors, we constructed dual-target FLT3 single-chain fragment variable (scFv)/NKG2D-chimeric antigen receptor (CAR) T cells, and explored whether FLT3 inhibitors combined with FLT3scFv/NKG2D-CAR T cells could have synergistic anti-leukaemia effects., Methods: FLT3scFv and NKG2D expression in CAR T cells, FLT3 and NKG2DL expression in AML cells, and the in vitro cytotoxicity of combining CAR T cells with gilteritinib were assessed by flow cytometry. The therapeutic effect was evaluated in a xenograft mouse model established by injection of MOLM-13 cells. Mechanisms underlying the gilteritinib-induced NKG2DL upregulation were investigated using siRNA, ChIP-QPCR and luciferase assays., Results: The FLT3scFv/NKG2D-CAR T cells specifically lysed AML cells both in vitro and in the xenograft mouse model. The efficacy of FLT3scFv/NKG2D-CAR T cells was improved by gilteritinib-pretreatment. The noncanonical NF-κB2/Rel B signalling pathway was found to mediate gilteritinib-induced NKG2DL upregulation in AML cells., Conclusions: Bispecific FLT3scFv/NKG2D-CAR T cells can effectively eradicate AML cells. The FLT3 inhibitor gilteritinib can synergistically improve this effect by upregulating NF-κB2-dependent NKG2DL expression in AML cells., (© 2022. The Author(s).)

Background: Venetoclax, a selective B-cell lymphoma-2 (BCL2) inhibitor, has a potential therapeutic effect when combined with demethylating agents in the first-line setting of unfit elderly patients with acute myeloid leukaemia (AML); however, efficacy is still limited in refractory/recurrent AML. Therefore, exploration of a suitable novel treatment scheme is urgently needed.However, combining venetoclax with NK cell-based immunotherapy has not been studied., Methods: The cytotoxicity of NK cell combined with venetoclax was assessed in vitro using flow cytometry. Venetoclax-induced natural killer group 2 member D (NKG2D) ligand (NKG2DL) expression was detected by flow cytometry and western blotting. Mechanisms underlying venetoclax-induced NKG2DL expression were found by GSE127200 analysis and investigated using real-time PCR (Q-PCR) and western blotting., Results: Flow cytometric analysis showed that combining venetoclax with NK cells produced synergistic anti-leukaemia effects similar to those of venetoclax + azacitidine. Venetoclax could render AML cell lines and primary AML cells sensitive to NK cell killing by promoting NK cell degranulation, NK-AML cell recognition and NK cell secretion of interferon (IFN)-γ and granzyme B. The synergistic effect resulted from venetoclax-induced NKG2DL upregulation in AML cells and could be undermined by blocking NKG2D on NK cells. This finding suggests that venetoclax enhances NK cell killing activity by activating the NKG2D/NKG2DL ligand-receptor pathway. Furthermore, the nuclear factor-kappa-B (NFKB) signalling pathway was involved in venetoclax-induced NKG2DL upregulation., Conclusions: Collectively, our data confirm that venetoclax combined with NK cells induces synergistic AML cell cytolysis and preliminarily revealed that venetoclax could selectively induce NKG2DLs on AML cells via NFKB signalling pathway., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To investigate the efficacy, safety and the risk factors affecting prognosis of high-risk acute myeloid leukemia (AML) patients treated by cladribine-based intensified conditioning regimen., Methods: The clinical data of 28 patients with high-risk AML treated by cladribine in combination with busulfan plus cyclophosphamide (BuCy) intensified conditioning regimen before allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Zhujiang Hospital, Southern Medical University from October 2016 to June 2020 were analyzed retrospectively. The overall survival (OS) rate, cumulative progression-free survival (PFS) rate, relapse rate, non-relapse mortality (NRM), regimen related toxicity (RRT) and risk factors affecting prognosis of the patients were analyzed., Results: The 1-year OS and PFS of the patients after implantation was (78.8±8.6)% and (79.8±8.1)%, while the 1-year cumulative relapse rate and NRM of the patients was 9.3% and 22.0%, respectively. The 1-year expected OS of MRD - high-risk patients before HSCT was 100%. The 1-year expected OS and PFS of the patients in pre-transplant relapse group was (46.9±18.7)% and (50.0±17.7)%, respectively. The incidence of I/II grade RRT was 39.3%. NO III/IV grade RRT were found in 28 patients. Multivariate analysis showed that pre-transplant relapse was the independent risk factor affecting OS and PFS of the patients., Conclusion: The intensified conditioning regimen of cladribine in combination with BuCy can reduce the relapse rate of high-risk AML transplantation, and its RRT is mild, exhibiting good safety. MRD - high-risk patients before HSCT can achieve better transplant benefits, but the prognosis of patients with relapse before transplantation is not significantly improved. Therefore, for non-relapsed high-risk AML patients, this intensified conditioning regimen deserves to be considered.

Sixteen oligosaccharide monomers with the degree of polymerization 3 to 18 (DP 3 to DP 18) and three active fractions (DP 3-9, DP 8-11, and DP 11-17) were separated from Atractylodes lancea (Thunb.) DC. by optimized fast protein liquid chromatography coupled with refractive index detector (FPLC-RID) and preparation hydrophilic interaction chromatography (Pre-HILIC). Gas chromatography-mass spectrometer (GC-MS), liquid chromatography tandem mass spectrometry (LC-MS/MS), nuclear magnetic resonance (NMR) spectroscopy, and methylation analysis showed that the oligosaccharide in A. lancea was 1-kestose [β-D-fructofuranosyl-(2 → 1)-β-D-fructofuranosyl-(2 → 1)-α-D-glucopyranoside] (inulin-type fructooligosaccharides, FOS). Particularly, DP 3-9 showed the best capacity in stimulating phagocytic, NO, and cytokines production on RAW264.7 cells than any other purified oligosaccharide monomers and active fractions. It could also activate T-cells in Peyer's patch cells and enhance the production of colony stimulation factors. Besides, FPLC-RID showed a good capacity for large-scale preparation of DP 3-9 with the recovery of more than 93%. The bioactivity of sixteen FOS monomers (DP 3 to DP 18) and three FOS fractions (DP 3-9, DP 8-11, and DP 11-17) investigated in this study are beneficial for the utilization of FOS as a functional ingredient in novel product development., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Patients with gastric cancer after gastrectomy often suffer from a decline in their quality of life (QoL), but the relationship between body composition (BC) and physical function on QoL has rarely been studied. This study aims to evaluate and determine the changes in QoL after gastrectomy and the impact of BC and physical function on QoL., Methods: A total of 311 gastric cancer patients completed EORTC QLQ-C30 and EORTC QLQ-STO22 questionnaires before and 1, 3, 6 months post-surgery. Data including BC, handgrip strength (HGS) and 6-m gait speed (GS) were collected prospectively. Multiple linear regression analysis was used to determine the correlation between QoL and BC, HGS and GS., Results: Patients had significantly worse scores after surgery on most function and symptom scales ( p < 0.001), but most of these scales recovered within 6 months after surgery. A higher subcutaneous fat area (SFA)was associated with increased symptom scores 1 month after surgery. A higher GS is associated with a better global health status symptom., Conclusion: Patients suffer from a decline in their QoL after gastrectomy for gastric cancer. Intervention strategies aiming at reducing SFA and improving GS may improve the QoL in patients underwent gastrectomy for gastric cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Song, Huang, Luo, Cai, Yan, Chen, Xing, Dong and Chen.)

Aim: Rectal stenosis is a relatively rare complication after transanal endoscopic microsurgery (TEM). This study aims to identify the predictive parameters for stenosis and the application of TEM in the treatment., Method: The clinical data of patients who underwent TEM for rectal adenoma and early cancer from 2008 to 2019 were retrospectively reviewed. We compared the clinicopathological characteristics of patients with stenosis and those without stenosis and analysed the risk factors for stenosis. Treatment outcomes of stenosis with TEM were evaluated., Results: A total of 230 patients were enrolled in this study. Overall, the postoperative complication rate was 11.7% (27/230), including eight (3.5%) patients with stenosis. Patients with stenosis exhibited a higher rate of tumour showing a laterally spreading morphology (P = 0.048), a wider circumferential extent of mucosal defect (P < 0.001), a shorter distance of the tumour from the anal verge (P = 0.001) and a wider longitudinal extent of mucosal defect (P = 0.027). A circumferential extent of mucosal defect >3/4 (OR 94.945, 95% CI 3.611-2496.41, P = 0.006) was identified as the only independent risk factor for stenosis. The four patients with both stenosis and clinical symptoms were treated by incising the stenosis ring using the TEM platform; the stenosis was cured, and symptoms disappeared after one to four courses of treatment., Conclusions: Circumferential extent of mucosal defect ≥3/4 was an independent risk factor for stenosis in treating rectal adenoma and early cancer with TEM. Incision of the stenosis ring using the TEM platform is an effective strategy for treating stenosis., (© 2021 The Association of Coloproctology of Great Britain and Ireland.)