Rapid identification of early infections in febrile patients after CD19 target CAR-T cell therapy for B-cell malignancies.

BACKGROUND: CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy stands out as a revolutionary intervention, exhibiting remarkable remission rates in patients with refractory/relapsed (R/R) B-cell malignancies. However, the potential side effects of therapy, particularly cytokine release syndrome (CRS) and infections, pose significant challenges due to their overlapping clinical features. Promptly distinguishing between CRS and infection post CD19 target CAR-T cell infusion (CTI) remains a clinical dilemma. Our study aimed to analyze the incidence of infections and identify key indicators for early infection detection in febrile patients within 30 days post-CTI for B-cell malignancies. METHODS: In this retrospective cohort study, a cohort of 104 consecutive patients with R/R B-cell malignancies who underwent CAR-T therapy was reviewed. Clinical data including age, gender, CRS, ICANS, treatment history, infection incidence, and treatment responses were collected. Serum biomarkers procalcitonin (PCT), interleukin-6 (IL-6), and C-reactive protein (CRP) levels were analyzed using chemiluminescent assays. Statistical analyses employed Pearson's Chi-square test, t-test, Mann-Whitney U-test, Kaplan-Meier survival analysis, Cox proportional hazards regression model, Spearman rank correlation, and receiver operating characteristic (ROC) curve analysis to evaluate diagnostic accuracy and develop predictive models through multivariate logistic regression. RESULTS: In this study, 38 patients (36.5%) experienced infections (30 bacterial, 5 fungal, and 3 viral) within the first 30 days of CAR T-cell infusion. In general, bacterial, fungal, and viral infections were detected at a median of 7, 8, and 9 days, respectively, after CAR T-cell infusion. Prior allogeneic hematopoietic cell transplantation (HCT) was an independent risk factor for infection (Hazard Ratio [HR]: 4.432 [1.262-15.565], P = 0.020). Furthermore, CRS was an independent risk factor for both infection ((HR: 2.903 [1.577-5.345], P < 0.001) and severe infection (9.040 [2.256-36.232], P < 0.001). Serum PCT, IL-6, and CRP were valuable in early infection prediction post-CAR-T therapy, particularly PCT with the highest area under the ROC curve (AUC) of 0.897. A diagnostic model incorporating PCT and CRP demonstrated an AUC of 0.903 with sensitivity and specificity above 83%. For severe infections, a model including CRS severity and PCT showed an exceptional AUC of 0.991 with perfect sensitivity and high specificity. Based on the aforementioned analysis, we proposed a workflow for the rapid identification of early infection during CAR-T cell therapy. CONCLUSIONS: CRS and prior allogeneic HCT are independent infection risk factors post-CTI in febrile B-cell malignancy patients. Our identification of novel models using PCT and CRP for predicting infection, and PCT and CRS for predicting severe infection, offers potential to guide therapeutic decisions and enhance the efficacy of CAR-T cell therapy in the future.

Phosphoric Acid-Catalyzed Alkene Difunctionalization of 2-Vinylpyridines via HOMO/LUMO Biactivated Diels-Alder Reaction.

The difunctionalization of vinylpyridines based on the cyclization strategy remains rare and underdeveloped, in contrast to the well-developed hydrogen functionalization. Current exploration on [4 + 2] cyclization of vinylpyridines mainly relies on extremely high temperatures and the LUMO activation of vinylpyridines using boron trifluoride as a strong Lewis acid. Herein, we established a phosphoric acid-catalyzed [4 + 2] cyclization reaction of 3-vinyl-1H-indoles and 2-vinylpyridines by means of the LUMO/HOMO bifunctional activation model. This protocol features mild reaction conditions, high functional group tolerance, broad substrate compatibility, and high diastereoselectivity, enabling the efficient construction of various functionalized pyridine-substituted tetrahydrocarbazoles with prominent potential in drug discovery.

Accumulation of circulating myeloid-derived suppressor cell subsets: predicting poor clinical efficacy and prognosis through T cell suppression in non-Hodgkin's lymphoma.

Myeloid-derived suppressor cells (MDSCs) are implicated in the regulation of immune responses closely associated with poor clinical outcomes in cancer. However, the MDSC subtypes in non-Hodgkin's lymphoma (NHL) have not been systematically investigated. So, we investigated the percentage of MDSC subsets in 78 newly diagnosed NHL patients by flow cytometry. The results showed that all MDSC subsets increased in NHL patients compared with healthy donors. Notably, MDSCs, monocytic MDSCs, and CD14 + CD66b + MDSCs significantly increased in NHL patients compared with those with lymphadenitis donors. polymorphonuclear MDSCs (PMN-MDSCs), early-stage MDSCs (e-MDSCs), and the International Prognostic Index were independent risk factors for poor clinical efficacy and were involved in constructing the nomogram for predicting clinical efficacy. Progression-free survival (PFS) was significantly shorter in patients with high level of MDSC subsets, and PMN-MDSCs emerged as an independent prognostic factor for PFS. PMN-MDSCs, e-MDSCs, and the International Prognostic Index were involved in constructing the nomogram for predicting PFS. Patients with a higher percentage of MDSCs, PMN-MDSCs, e-MDSCs, and CD14 + CD66b + MDSCs experienced a shorter overall survival compared with those with lower percentages. In addition, research on mechanisms found that T cell function was suppressed and mediated by the expansion of MDSCs via involving arginase-1 and interleukin-10 in vitro and in vivo. In conclusion, our study demonstrates that the increased circulating MDSC subsets predict poor clinical efficacy and prognosis in NHL, potentially involving T cell suppression through MDSC subset expansion. These findings indicate the potential of MDSC subsets as comprehensive diagnostic, prognostic biomarkers, and therapeutic targets for NHL.

TBK1 upregulates the interferon response against virus by the TBK1-IRF3/7 axis in yellow catfish (Pelteobagrus fulvidraco).

Yellow catfish (Pelteobagrus fulvidraco) is an important economic species of freshwater fish, widely distributed in China. Recently, viral diseases of yellow catfish have been identified in Chian (Hubei province), arising more attention to the viral immunity in P. fulvidraco. Tumor necrosis factor (TNF) receptor-associated factor NF-κB activator (TANK)-binding kinase 1 (TBK1) plays an essential role in IFN production and innate antiviral immunity. In the present study, we characterized the P. fulvidraco TBK1 (PfTBK1) and reported its function in interferon response. The full-length open reading frame (ORF) is 2184 bp encoding a protein with 727 amino acids, which is composed of four conserved domains, including KD, ULD, CCD1, and CCD2, similar to TBK1 in other species. Pftbk1 was widely expressed in all detected tissues by qPCR and was not inducible by the spring viremia of carp virus (SVCV), a single-strand RNA virus. In addition, the cellular distribution indicated that PfTBK1 was only located in the cytoplasm. Moreover, PfTBK1 induced strong IFN promoter activities through the Jak-stat pathway, and PfTBK1 interacted with and significantly phosphorylated IFN regulatory factor 3/7 (IRF3/7) in P. fulvidraco, promoting the nuclear translocation of pfIRF3 and PfIRF7, and PfTBK1 upregulated IFN response by PfTBK1-PfIRF3/7 axis. Above all, PfTBK1 triggered IFN response and strongly inhibited the replication of SVCV in EPC cells through induction of IFN downstream IFN-stimulated genes (ISGs). Summarily, this work reveals that PfTBK1 plays a positive regulatory role in IFN induction through the TBK1-IRF3/7 axis, laying a foundation for further exploring the molecular mechanism of the antiviral process in P. fulvidraco.

[Differential Analysis of Macular Structure and Microcirculation in Both Eyes of Patients With Myopic Anisometropia].

Objective To compare the macular structure and microcirculation in both eyes of the patients with myopic anisometropia.Methods Optical coherence tomography angiography(OCTA)was employed to scan the macular areas in both eyes of 44 patients with myopic anisometropia.The patients were assigned into high and low groups based on the refractive diopter,and the parameters such as retinal thickness,choroidal thickness,vascular density,and perfusion density in the macular areas of both eyes were compared between the two groups.Results Other macular areas except the central and external nasal areas and the choroid of the fovea in the high group were thinner than those in the low group(all P<0.05).There was no statistically significant difference in retinal vascular density or perfusion density in different areas between the two groups(all P>0.05).Conclusion In the patients with myopic anisometropia,most areas of the retina in the case of high myopia is thinner than that in the case of low myopia,while there is no difference in retinal vascular density or perfusion density in both eyes.

Integrated analysis of the microbiome and transcriptome in stomach adenocarcinoma.

We aimed to characterize the stomach adenocarcinoma (STAD) microbiota and its clinical value using an integrated analysis of the microbiome and transcriptome. Microbiome and transcriptome data were downloaded from the Cancer Microbiome Atlas and the Cancer Genome Atlas databases. We identified nine differentially abundant microbial genera, including Helicobacter, Mycobacterium, and Streptococcus, which clustered patients into three subtypes with different survival rates. In total, 74 prognostic genes were screened from 925 feature genes of the subtypes, among which five genes were identified for prognostic model construction, including NTN5, MPV17L, MPLKIP, SIGLEC5, and SPAG16. The prognostic model could stratify patients into different risk groups. The high-risk group was associated with poor overall survival. A nomogram established using the prognostic risk score could accurately predict the 1, 3, and 5 year overall survival probabilities. The high-risk group had a higher proportion of histological grade 3 and recurrence samples. Immune infiltration analysis showed that samples in the high-risk group had a higher abundance of infiltrating neutrophils. The Notch signaling pathway activity showed a significant difference between the high- and low-risk groups. In conclusion, a prognostic model based on five feature genes of microbial subtypes could predict the overall survival for patients with STAD.

Comparative Transcriptome Analysis Reveals the Effect of miR156a Overexpression on Mineral Nutrient Homeostasis in Nicotiana tabacum.

Mineral nutrition plays an important role in crop growth, yield and quality. MiR156 is a regulatory hub for growth and development. To date, the understanding of miR156-mediated mineral homeostasis is limited. In this study, we overexpressed Nta-miR156a in the tobacco cultivar TN90 and analyzed the effects of miR156 on mineral element homeostasis in tobacco by comparative transcriptome analysis. The results showed that the overexpression of miR156a caused significant morphological changes in transgenic tobacco. Chlorophyll and three anti-resistance markers, proline, total phenolics, and total flavonoids, were altered due to increased miR156 expression levels. Interestingly, the distribution of Cu, Mn, Zn, and Fe in different tissues of transgenic tobacco was disordered compared with that of the wild type. Comparative transcriptome analysis showed that the overexpression of miR156 resulted in 2656 significantly differentially expressed genes. The expression levels of several metal-transport-related genes, such as NtABC, NtZIP, NtHMA, and NtCAX, were significantly increased or decreased in transgenic tobacco. These results suggest that miR156 plays an essential role in regulating mineral homeostasis. Our study provides a new perspective for the further study of mineral nutrient homeostasis in plants.

Zebrafish MARCH7 negatively regulates IFN antiviral response by degrading TBK1.

Membrane-associated RING-CH-type finger (MARCH) proteins have been reported to regulate type I IFN production during host antiviral innate immunity. The present study reported the zebrafish MARCH family member, MARCH7, as a negative regulator in virus-triggered type I IFN induction via targeting TANK-binding kinase 1 (TBK1) for degradation. As an IFN-stimulated gene (ISG), we discovered that MARCH7 was significantly induced by spring viremia of carp virus (SVCV) or poly(I:C) stimulation. Ectopic expression of MARCH7 reduced the activity of IFN promoter and dampened the cellular antiviral responses triggered by SVCV and grass carp reovirus (GCRV), which concomitantly accelerated the viral replication. Accordingly, the knockdown of MARCH7 by siRNA transfection significantly promoted the transcription of ISG genes and inhibited SVCV replication. Mechanistically, we found that MARCH7 interacted with TBK1 and degraded it via K48-linked ubiquitination. Further characterization of truncated mutants of MARCH7 and TBK1 confirmed that the C-terminal RING of MARCH7 is essential in the MARCH7-mediated degradation of TBK1 and the negative regulation of IFN antiviral response. This study reveals a molecular mechanism by which zebrafish MARCH7 negatively regulates the IFN response by targeting TBK1 for protein degradation, providing new insights into the essential role of MARCH7 in antiviral innate immunity.

A practical application of front-face synchronous fluorescence spectroscopy to rapid, simultaneous and non-destructive determination of piperine and multiple adulterants in ground black and white pepper (Piper nigrum L.).

Based on the distinct fluorescence of piperine and tryptophan, and their different profiles in pepper and several possible adulterants, front-face synchronous fluorescence spectroscopy (FFSFS) was applied for the fast and non-invasive authentication of ground black pepper adulterated with papaya seed powder and buckwheat flour, and ground white pepper adulterated with whole wheat and maize flours. For either single adulterant or dual adulterants in the range of 10-40% w/w, prediction models were constructed based on the combination of unfolded total synchronous fluorescence spectra and partial least square (PLS) regression, and were validated by both five-fold cross-validation and external validation. The built PLS2 models produced suitable results, with most of the determination coefficients of prediction (Rp2) greater than 0.8, the root mean square error of prediction (RMSEP) < 5% and residual predictive deviation (RPD) greater than 2. The limits of detection (LODs) were 11.1, 5.5, 10.6 and 12.0% for papaya seed powder, buckwheat, whole wheat and maize flours, respectively. Most relative prediction errors for simulated blind samples were within ± 30%. Besides, piperine in ground black and white pepper was also determined with acceptable PLS results.

[Chemical constituents from fruits of Morinda citrifolia and their inhibitory effects on proliferation of synoviocytes in vitro].

The chemical constituents from the fruits of Morinda citrifolia were systematically explored by chromatographic fractionation methods including silica gel, octadecylsilyl(ODS) gel, Sephadex LH-20 gel, and preparative high performance liquid chromatography(pre-HPLC). The chemical structures of all isolated compounds were identified on the basis of their physicochemical properties, spectroscopic analyses, as well as the comparisons of their physicochemical and spectroscopic data with the reported data in literature. As a result, 22 isolated compounds from the 90% ethanol extract of the fruits of M. citrifolia were identified, which were moricitritone(1), 2'-deoxythymidine(2), cyclo-(L-Pro-L-Tyr)(3), methyl-5-hydroxy-2-pyridinecarboxylate(4), methyl pyroglutamate(5), bisbenzopyran(6), epipinoresinol(7), 3, 3'-bisdemethyl pinoresinol(8), 3, 3'-bisdemethyltanegool(9), trimesic acid(10), crypticin B(11), kojic acid(12), vanillic acid(13), protocatechoic acid(14), 5-hydroxymethyl furfural(15), blumenol A(16), 1-O-(9Z, 12Z-octadecadienoyl) glycerol(17), mucic acid dimethylester(18), methyl 2-O-ß-D-glucopyranosylbenzoate(19), 2-phenylethyl-O-ß-D-glucoside(20), scopoletin(21), and quercetin(22). Among them, compound 1 was a new pyrone derivative, compounds 2, 4-7, 10-12, and 17 were isolated from the plants belonging to Morinda genus for the first time, and compound 18 was obtained from M. citrifolia for the first time. Moreover, on the basis of testing the activities of all isolated compounds on inhibiting the proliferation of synovial fibroblasts in vitro by MTS assay, the anti-rheumatoid arthritis activities of all isolated compounds were initially evaluated. The results showed that compounds 1-6, 9, 19, and 20 exhibited remarkable anti-rheumatoid arthritis activities, which displayed the inhibitory effects on the proliferation of MH7A synovial fibroblast cells with the IC_(50) values in the range of(3.69±0.08) to(168.96±0.98) µmol·L~(-1).

[Chemical constituents from Artocarpus incisus and their inhibitory effects on proliferation of synoviocytes in vitro].

The chemical constituents from the branches and leaves of Artocarpus incisus were isolated and purified via silica gel, ODS, and Sephadex LH-20 column chromatography as well as preparative HPLC. The chemical structures of all isolated compounds were identified in the light of their physicochemical properties, spectroscopic analyses, and comparisons of their physicochemical and spectroscopic data with the reported data in literature. As a result, 20 compounds were isolated and characterized from the 90% ethanol extract of the branches and leaves of A. incisus, which were identified as tephrosin(1), 6-hydroxy-6 a, 12 a-dehydrodeguelin(2), sarcolobin(3), lupiwighteone(4), 12-deoxo-12α-methoxyelliptone(5), 6 aα,12 aα-12 a-hydroxyelliptone(6), homopterocarpin(7), 3-hydroxy-8,9-dimethoxypterocarpan(8), pterocarpin(9), maackiain(10), medicarpin(11), calycosin(12), genistein(13), formononetin(14), 5-hydroxy-4',7-dimethoxy isoflavone(15), liquiritigenin(16), 4(15)-eudesmene-1ß,7α-diol(17), ent-4(15)-eudesmene-1ß,6α-diol(18), 1α-hydroxyisodauc-4-en-15-al(19), and guaianediol(20). Except compounds 13 and 16, all other compounds were isolated from the Artocarpus plants for the first time. Additionally, using MTS assay, compounds 1-20 were eva-luated for their anti-rheumatoid arthritis activities by measuring their anti-proliferative effects on synoviocytes in vitro. As a consequence, compounds 1-16 showed notable anti-rheumatoid arthritis activities, which displayed inhibitory effects on the proliferation of MH7 A synovial fibroblast cells, with the IC_(50) values in range of(9.86±0.09)-(218.07±1.96) µmol·L~(-1).

[Effects of irrigation at flowering stage on soil nutrient and root distribution in wheat field]. / å°éº¦å¼€èŠ±æœŸçŒæ°´å¯¹åœŸå£¤å »åˆ†åŠæ ¹ç³»åˆ†å¸ƒçš„å½±å“.

To provide theoretical support the full use of water and fertilizer resources for wheat, we explored the effects of irrigation on wheat yield, plant and soil nutrient distribution during flowering period and its relationship with root characteristics. We set up two treatments by using the 2 m deep soil column cultivation method with irrigation during flowering (T1) and no irrigation during flowering (T2), with the drought-resistant and high-yield cultivar Luomai 28 (LM28) and the high photosynthetic efficiency cultivar Bainong 207 (BN207) as materials. We measured contents of nitrogen, phosphorus and potassium in plants and soils, as well as the characteristics of soil roots. The results showed that ammonium, available phosphorus, and available potassium were mainly distributed in 0-80 cm soil layer, and that nitrate was mainly distributed in soil layer below 80 cm during wheat harvest. Irrigation at anthesis stage promoted wheat to absorb ammonium, available phosphorus and available potassium from the upper layer of soil and nitrate nitrogen from the lower layer but did not aggravate the deep leaching of nitrate. The root of wheat mainly concentrated in 0-60 cm soil layer and decreased with increasing soil depth. Dry matter accumulation, total nitrogen and total phosphorus were mainly distributed in wheat grains at maturity, while total potassium was mainly distributed in stems. Irrigation at anthesis stage significantly increased the 100-grain weight of wheat, and consequently the yield. Root morphology was negatively correlated with soil nitrate in 0-40 cm soil layer, positively correlated with soil ammonium in 80-100 cm soil layer and soil available phosphorus in 0-100 cm soil layer. Irrigation at anthesis stage promoted the full absorption of soil nutrients by roots at late filling stage, delayed the senescence of flag leaves after flowering, prolonged the functional period of transporting nutrients from vegetative organs to reproductive organs, leading nutrients in vegetative organs more fully transported to grains, increasing grain weight and yield.

Effect of Carbon Fiber Surface Microstructure on Composite Interfacial Property Based on Image Quantitative Characterization Technique.

The surface roughness (Ra) and composite interfacial property of carbon fiber (CF) are considered to be mainly affected by the microstructure of the CF surface. However, quantitative characterization of the CF surface microstructure is always a difficulty. How the CF surface microstructure affects the interfacial property of CF composites is not entirely clear. A quantitative characterization technique based on images was established to calculate the cross-section perimeter and area of five types of CFs, as well as the number (N), width (W) and depth (D) of grooves on these CF surfaces. The CF composite interfacial shear strength (IFSS) was tested by the micro-droplet debonding test and modified by the realistic perimeter. The relationship between the groove structure parameter and the Ra, specific surface area and composite interfacial property was discussed in this article. The results indicated that the CF cross-section perimeter calculated by this technique showed strong consistency with the CF specific surface area and composite interfacial property. At last, the composite interface bonding mechanism based on defect capture was put forward. This mechanism can be a guiding principle for CF surface modification and help researchers better understand and establish interface bonding theories.

Effect of Sizing Agents on Surface Properties of Carbon Fibers and Interfacial Adhesion of Carbon Fiber/Bismaleimide Composites.

Physicochemical, surface, and mechanical properties of three batches of T800 grade carbon fibers (CFs) treated with three kinds of sizing agents and Toray T800H CFs were characterized to study the effect of sizing agents on surface properties. Scanning electron microscopy for morphology, atomic force microscopy calculations, and results for the content of sizing agents showed that sizing agent B improved the surface roughness and CFs with high content of sizing agent always presented small surface roughness in a certain content range 1.2-1.6%. Surface energy of CFs was calculated by Young's contact angle using the test results with water and glycol, and contact angles with LY-1 and modified-AC531 were also acquired. The results proved that CFs of sizing agent group B had the highest average surface energy and the lowest average contact angles with both LY-1 and modified-AC531. From both single-filament and tensile strength test results, the average strength of CFs of sizing agent group B was found to be the lowest, which indicated that sizing agent B had an influence on tensile strength decrease of T800 grade CFs. Comparing the results of interfacial shear strength both in a natural dry state and after hygrothermal treatment, high surface energy was found to be the key element to obtain high interfacial adhesion between T800 grade CFs and bismaleimide, and high surface roughness and low contact angle also played important roles. Among sizing agents A, B, and C, A had an effect on the interfacial shear strength decrease of CFs in the natural dry state, while C had that after hygrothermal treatment.

[Effects of row spacing and sowing rate on vertical distribution of photosynthetically active radiation, biomass, and grain yield in winter wheat canopy.] / è¡Œè·å’Œæ’­ç§é‡å¯¹å†¬å°éº¦å† å±‚å ‰åˆæœ‰æ•ˆè¾å°„åž‚ç›´åˆ†å¸ƒã€ç”Ÿç‰©é‡å’Œç±½ç²’äº§é‡çš„å½±å“.

To clarify the effects of row spacing and sowing rate on the vertical distribution of canopy PAR, biomass, and grain yield in winter wheat, a field experiment was conducted without increa-sing water and fertilizer input. There were two row spacing modes, R1 (equal spacing, 20 cm+20 cm) and R2(wide and narrow row spacing, 12 cm+12 cm+12 cm+24 cm), and three sowing rates, D1 (low, 120 kg·hm-2), D2 (medium, 157.5 kg·hm-2), D3 (high, 195 kg·hm-2). The canopy photosynthetically active radiation (PAR) interception and utilization rate in different heights, population photosynthetic capacity, biomass, and grain yield were measured during the main growth stages of winter wheat. The results showed that both total PAR interception and upper layer PAR interception of winter wheat canopy under R1 treatment were significantly higher than those in R2 treatment, but those of the middle layer and lower layer were higher in R2 than in R1, and with significant difference in the middle layer. From flowering to maturity, the photosynthetic potential (LAD), population photosynthetic rate (CAP), PAR conversion rate, and utilization rate in R2 were all significantly higher than those in R1 under the same sowing rate, with the highest value under R2D2 treatment. With the increasing sowing rate, the population biomass (BA) and leaf biomass (BL) at different layers increased, but the individual biomass (BP) showed an opposite trend. Under the same sowing rate, BA, BL and BP in R2 were higher than that in R1 after the flowering stage. Among them, BA and BP had significant difference in row spacing treatments at the maturity stage, with significant difference between the two row spacing treatments being observed in BL of the middle and lower layers under D2 and D3 sowing rates. The spike number, grain number per spike, 1000-kernel weight, and grain yield of winter wheat among different treatments were the highest in R2D3, R2D1, R2D1, and R2D2, respectively. The 1000-kernel weight, grain number per spike and grain yield in R2 treatment were significantly higher than R1. In summary, the PAR interception in the middle and lower layers of winter wheat canopy was improved by changing row spacing, with positive consequence on the photosynthetic capacity of individual plant and population, PAR utilization and transformation efficiency, which finally increased biomass and grain yield. Therefore, optimizing the field structure and shaping the ideal population photosynthetic structure should pay more attention during the high-yield cultivation of winter wheat. Making full use of light resources per unit land area and excavating the photosynthetic production potential of crops were also critical to achieve high yield and efficiency. In this experiment, the population photosynthetic capacity, photosynthetic effective radiation utilization rate, and yield were the highest under the treatment of R2D2.

Protective effects of curcumin against rat intestinal inflammation­related motility disorders.

Intestinal inflammation frequently occurs alongside dysmotility, which is characterized by altered myosin light chain phosphorylation levels. Curcumin, an active component from the ginger family, is reported to confer anti­inflammatory effects. However, the effects of curcumin on both diarrhea and constipation associated inflammation remains to be elucidated. The present study was designed to investigate the effects of curcumin on diarrhea and constipation and to determine the related mechanisms. Sprague­Dawley rats were used to establish diarrhea and constipation models via intracolonic acetic acid (4%) instillation or cold water gavage for 2 weeks, respectively. Blood samples were collected to measure the serum levels of the cytokines TNF­α and IL­1ß using ELISA kits. Western blotting was performed to measure NF­κB, RhoA, Rho­related kinase 2, phosphorylated MLC20, phosphorylated myosin phosphorylated target subunit 1, 130k Da­MLC kinase (MLCK), c­kit tyrosine kinase protein expression, and reverse transcription­quantitative PCR was conducted to measure MLCK expression levels. The results indicated that curcumin reversed the elevations in the pro­inflammatory cytokines IL­1ß and TNF­α by inhibiting the NF­κB pathway in rats with diarrhea and constipation. The results also indicated that myosin light chain (MLC) phosphorylation in intestinal smooth muscle was positively and negatively associated with the motility of inflammation­related diarrhea and constipation in rats, respectively. Curcumin significantly reversed the increased MLC phosphorylation in the jejunum of the rats with diarrhea, significantly enhanced the reductions in inflammatory mediators, including TNF­α and IL­1ß, of rats with constipation and significantly ameliorated the related hyper­motility and hypo­motility in rats with both diarrhea and constipation. In conclusion, the potential roles of the MLC kinase, c­kit tyrosine and Rho A/Rho­associated kinase 2 pathways, which are involved in curcumin­induced amelioration of inflammation­related diarrhea and constipation, were explored in the present study. Results from the present study suggested that curcumin has potential therapeutic value for treating intestinal inflammation and inflammation­related motility disorders.

The Influence of COVID-19 on Community Disaster Resilience.

Global pandemics, such as the Coronavirus Disease 2019 (COVID-19), have serious harmful effects on people's physical health and mental well-being. It is imperative therefore that we seek to understand community resilience and identify ways to enhance this, especially within our cities and communities. Therefore, great emphasis is now placed on how cities prepare for and recover from such disasters, and community resilience has emerged as a key consideration. Drawing upon research on the theory of resilience, this study seeks to identify the factors that influence community resilience and to analyze their causation toward helping to manage the risks associated with the COVID-19 pandemic. Seventeen factors from the five dimensions of social capital, economic capital, physical environment, demographic characteristics, and institutional factors are used to construct an index system. This is used to establish the structural level and importance of each factor. Data were collected using a questionnaire survey involving 12,000 members of key community groups in the city of Wuhan. An interpretative structural model (ISM) combining the analytic hierarchy process (AHP) method was then used to obtain the multi-level hierarchical structure composed of direct factors, indirect factors, and fundamental factors. The results show that the income level, vulnerability of the population, and the built environment are the main factors that affect the resilience of communities affected by COVID-19. These findings provide useful guidance toward the effective planning and design of urban construction and infrastructure. The results are expected to be useful to inform future decision-making and toward the long term, sustainable management of the risks posed by COVID-19.

Overview on new progress of hereditary diffuse gastric cancer with CDH1 variants.

Hereditary diffuse gastric cancer (HDGC), comprising 1%-3% of gastric malignances, has been associated with CDH1 variants. Accumulating evidence has demonstrated more than 100 germline CDH1 variant types. E-cadherin encoded by the CDH1 gene serves as a tumor suppressor protein. CDH1 promoter hypermethylation and other molecular mechanisms resulting in E-cadherin dysfunction are involved in the tumorigenesis of HDGC. Histopathology exhibits characteristic signet ring cells, and immunohistochemical staining may show negativity for E-cadherin and other signaling proteins. Early HDGC is difficult to detect by endoscopy due to the development of lesions beneath the mucosa. Prophylactic gastrectomy is the most recommended treatment for pathogenic CDH1 variant carriers. Recent studies have promoted the progression of promising molecular-targeted therapies and management strategies. This review summarizes recent advances in CDH1 variant types, tumorigenesis mechanisms, diagnosis, and therapy, as well as clinical implications for future gene therapies.

Multidimensional study of the heterogeneity of leukemia cells in t(8;21) acute myelogenous leukemia identifies the subtype with poor outcome.

t(8;21)(q22;q22) acute myelogenous leukemia (AML) is morphologically characterized by a continuum of heterogeneous leukemia cells from myeloblasts to differentiated myeloid elements. Thus, t(8;21) AML is an excellent model for studying heterogeneous cell populations and cellular evolution during disease progression. Using integrative analyses of immunophenotype, RNA-sequencing (RNA-seq), and single-cell RNA-sequencing (scRNA-seq), we identified three distinct intrapatient leukemic cell populations that were arrested at different stages of myeloid differentiation: CD34+CD117dim blasts, CD34+CD117bri blasts, and abnormal myeloid cells with partial maturation (AM). CD117 is also known as c-KIT protein. CD34+CD117dim cells were blocked in the G0/G1 phase at disease onset, presenting with the regular morphology of myeloblasts showing features of granulocyte-monocyte progenitors (GMP), and were drug-resistant to chemotherapy. Genes associated with cell migration and adhesion (LGALS1, EMP3, and ANXA2) were highly expressed in the CD34+CD117dim population. CD34+CD117bri blasts were blocked a bit later than the CD34+CD117dim population in the hematopoietic differentiation stage and displayed high proliferation ability. AM cells, which bear abnormal myelocyte morphology, especially overexpressed granule genes AZU1, ELANE, and PRTN3 and were sensitive to chemotherapy. scRNA-seq at different time points identified CD34+CD117dim blasts as an important leukemic cluster that expanded at postrelapse refractory stage after several cycles of chemotherapy. Patients with t(8;21) AML with a higher proportion of CD34+CD117dim cells had significantly worse clinical outcomes than those with a lower CD34+CD117dim proportion. Univariate and multivariate analyses identified CD34+CD117dim proportion as an independent factor for poor disease outcome. Our study provides evidence for the multidimensional heterogeneity of t(8;21)AML and may offer new tools for future disease stratification.

Paclitaxel induces apoptosis through the TAK1-JNK activation pathway.

Paclitaxel (PTX) has previously been used to treat tumours of various tissue origins, such as lung, breast, ovarian, prostate cancers and leukemia. PTX-induced apoptosis is associated with p38 mitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated kinase (ERK), nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase or stress-activated protein kinase (JNK/ SAPK) pathways. Transforming growth factor-beta-activated kinase 1 (TAK1) and TAK1-binding protein 1 (TAB1) play an important role in cell apoptosis through the p38, ERK, NF-κB and JNK signal transduction pathways. To investigate the role of TAK1 in PTX-induced cell apoptosis, we treated HEK293 and 8305C cells with 0-20 µM PTX for 6, 12 or 24 h. To investigate whether TAK1 can cooperate with PTX for cancer treatment, we transfected cells with TAK1, TAB1 or control plasmid and treated them with PTX (3-10 µM) for 9-24 h. Apoptosis rates were analysed by flow cytometry (Annexin V/PI). Endogenous TAK1 and TAB1, caspase-7 cleavage, poly ADP-ribose polymerase (PARP) cleavage, Bcl-xL level, phospho-p44/42, phospho-JNK and phospho-p38 were detected by western blot. We show that in HEK293 and 8305C cells, PTX enhanced the endogenous TAK1/TAB1 level and induced cell apoptosis in a dose- and time-dependent manner. Upon TAK1 overexpression in HEK293 cells treated with PTX, apoptosis rate, JNK phosphorylation and PARP cleavage increased contrary to heat-shocked or untreated cells. CRISPR editing of the tak1 gene upon PTX treatment resulted in lower phospho-JNK and PARP cleavage levels than in cells transfected with the control or the TAK1- or TAB1 + TAK1-containing plasmids. TAK1-K63A could not induce JNK phosphorylation or PARP cleavage. We conclude that PTX induces HEK293 and 8305C cell apoptosis through the TAK1-JNK activation pathway, potentially highlighting TAK1's role in chemosensitivity.