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ObjectiveThe aim of this study was to investigate the genotypic and clinical phenotypic characteristics of MAX germline mutation–associated pheochromocytoma (PCC) and paraganglioma (PGL).MethodsWe retrospectively analyzed the family investigation data and clinical genetic characteristics of six individuals from three independent families with PCC carrying MAX germline mutations from December 2005 to March 2024. A literature review was then conducted of the six carriers and another 103 carriers from the other 84 families with MAX germline mutations reported previously.ResultsThere were 109 patients in 87 families with all five exons and 53 types of MAX germline mutations. p.R33* (c.97C>T; 21.1%), p.R75* (c.223C>T; 13.8%), and p.A67D (c.200C>A; 7.3%), which accounted for 42.2% of mutations detected, were the most common mutations. Moreover, 101 (92.7%) patients developed PCCs, including 59 bilateral PCCs and 42 unilateral PCCs, and 19 (18.8%) patients showed metastasis. The mean age at diagnosis was 32.8 ± 12.6 (13-80) years. The male-to-female ratio was 1.3:1. In 11 (10.9%) patients, the PCC was accompanied by chest or abdominal PGL, and one other patient had sole head and neck PGL. Nine (8.3%) patients also had functional pituitary adenomas, 11 (10.9%) developed other neuroendocrine tumors (NETs), and 7 (6.4%) presented with concomitant non-NET. Meanwhile, MAX-p.Q82Tfs*89 and p.E158A mutations are reported for the first time in this study.ConclusionMAX germline mutations may cause new types of multiple endocrine neoplasia. A comprehensive baseline assessment of neural crest cell–derived diseases is recommended for all individuals with MAX germline mutations. The risk of bilateral and metastatic PCCs should also be considered.

IntroductionProstate cancer (PCa), one of the most prevalent malignant tumors in the genitourinary system, is characterized by distant metastasis and the development of castration-resistant prostate cancer (CRPC), which are major determinants of poor prognosis. Current treatment approaches for PCa primarily involve surgery and endocrine therapy, but effective strategies for managing distant metastasis and CRPC remain limited.MethodsWe utilized qPCR, WB, and other methods to measure the expression levels of respective proteins, concurrently assessing lipid metabolism to validate the role of FATP5 in lipid metabolism. Additionally, we employed bioinformatics analysis and WB techniques to explore the corresponding mechanisms.ResultsIn this study, we conducted an analysis of clinical samples and public databases to identify differential expression of FATP5 and further investigated its association with clinical outcomes. Through biochemical and functional experiments, we elucidated the potential underlying mechanisms by which FATP5 facilitates the progression of PCa. Our findings demonstrate that specific upregulation of FATP5 significantly enhances proliferation, migration, and invasion of PCa cell lines, while also modulating lipid metabolism in PCa. Mechanistically, the expression of FATP5 is closely associated with the Hippo signaling pathway, as it promotes the nuclear accumulation of YAP1 by inhibiting AMPK and facilitating the activation of β-catenin and RHOA. Furthermore, the transcription of FATP5 is mediated by TEAD4, and this transcriptional activation requires the involvement of YAP1.DiscussionFATP5 is highly expressed in prostate cancer and can enhance the biological activity and lipid metabolism of prostate cancer. We have also elucidated that FATP5 is regulated by the Hippo signaling pathway. This provides a new potential target for the treatment of prostate cancer.

The optimal treatment for patients with severe aplastic anemia (SAA) who fail an initial course of antithymocyte globulin (ATG) plus cyclosporine has not yet been established. We compared the effectiveness of allogeneic hematopoietic stem cell transplantation (allo-HSCT) (n = 36) with repeated immunosuppressive therapy (IST) (n = 33) for relapsed/refractory SAA between 2007 and 2022. In the IST group, patients were retreated with ATG (n = 16) or high-dose cyclophosphamide (n = 17). The overall response rate was 57.6% at 6 months and 60.6% at 12 months. In the allo-HSCT group, patients received a transplant from a matched sibling donor (n = 6), matched unrelated donor (n = 7), or haploidentical donor (n = 23). All patients achieved neutrophil engraftment, and there were no cases of primary graft failure. The cumulative incidences (CIs) of grades II–IV and III–IV acute graft-versus-host disease (GVHD) were 36.1% ± 0.7% and 13.9% ± 0.3% at day +100, respectively. The 4-year CI of chronic GVHD (cGVHD) was 36.2% ± 0.7%, with moderate to severe cGVHD at 14.9% ± 0.4%. Compared with IST, HSCT recipients showed much higher hematologic recovery rate at 3, 6, and 12 months (63.9%, 83.3%, and 86.1%, respectively, p < 0.001). The estimated 4-year overall survival (OS) (79.8% ± 6.8% vs. 80.0% ± 7.3%, p = 0.957) was similar; however, the failure-free survival (FFS) was significantly better in the HSCT group (79.8% ± 6.8% vs. 56.6% ± 8.8%, p = 0.049). Of note, children in the HSCT cohort were all alive without treatment failures, exhibiting superior OS (100% vs. 50.0% ± 17.7%, p = 0.004) and FFS (100% vs. 50.0% ± 17.7%, p = 0.004) than children in the IST cohort. Subgroup analysis revealed that younger patients (age ≤ 35 years), especially children, and those with refractory SAA benefited more from HSCT. Therefore, for these patients, salvage HSCT may be more preferable than a second course of IST.

Load models have a significant influence on power system simulation. However, current load modeling approaches can hardly satisfy the diversity and time-varying characteristics of loads [including electric vehicles (EVs) and battery storage] in terms of model accuracy and computing efficiency. An online modeling method for composite load models based on measurement information is proposed in this paper. Firstly, the dominant factors in load model output are analyzed based on the active subspace of parameter space. Then the clustering algorithm is applied to cluster the large number of underlying loads based on the characteristics of load daily output curves. Finally, the underlying loads are equivalently aggregated from the low voltage levels to the high voltage levels to construct the composite load model. Simulation results obtained based on PSCAD/EMTDC demonstrate that the load model constructed by the proposed approach can accurately reflect the actual load characteristics of a power system.

The Period (PER) gene family is one of the core components of the circadian clock, with substantial correlations between the PER genes and cancers identified in extensive researches. Abnormal mutations in PER genes can influence cell function, metabolic activity, immunity, and therapy responses, thereby promoting the initiation and development of cancers. This ultimately results in unequal cancers progression and prognosis in patients. This leads to variable cancer progression and prognosis among patients. In-depth studies on the interactions between the PER genes and cancers can reveal novel strategies for cancer detection and treatment. In this review, we aim to provide a comprehensive overview of the latest research on the role of the PER gene family in cancer.

Understanding the response of microbial communities and their potential functions is essential for sustainability of agroecosystems under long-term continuous cropping. However, limited research has focused on investigating the interaction between soil physicochemical factors and microbial community dynamics in agroecosystems under long-term continuous cropping. This study probed into the physicochemical properties, metabolites, and microbial diversity of tobacco rhizosphere soils cropped continuously for 0, 5, and 20 years. The relative abundance of bacterial genera associated with nutrient cycling (e.g., Sphingomonas) increased while potential plant pathogenic fungi and beneficial microorganisms showed synergistic increases with the duration of continuous cropping. Variations in soil pH, alkeline nitrogen (AN) content, and soil organic carbon (SOC) content drove the shifts in soil microbial composition. Metabolites such as palmitic acid, 3-hydroxypropionic acid, stearic acid, and hippuric acid may play a key role in soil acidification. Those results enhance our ability to predict shifts in soil microbial community structure associated with anthropogenic continuous cropping, which can have long-term implications for crop production.

Essential trace minerals play vital roles in maintaining human and animal health. However, an overdose of the existing inorganic trace minerals is prone to induce detrimental effects that outweigh positive benefits. In this study, an extracellular polymeric substances (EPS)-producing bacterium, identified as Bacillus licheniformis CCTCC M2020298, was isolated from marine using glutinous rice processing wastewater as enrichment medium. The EPS yield of Bacillus licheniformis CCTCC M2020298 could reach 8.62 g/L by using glutinous rice-processing wastewater containing medium. Furthermore, the potential of the EPS as a carrier for synthesizing EPS-iron (Fe) and EPS-copper (Cu) complex was explored. The results showed that the optimum condition for the synthesis EPS-Fe were the reaction temperature 70°C, pH 8.5–9.0 and mass ratio of EPS to trisodium citrate 2:1. The iron content of EPS-Fe reached 77.4 mg/g. Under the same condition, the copper content of EPS-Cu reached 90.7 mg/g. The elemental composition, functional groups and valence state of the mineral elements of EPS-Fe and EPS-Cu were well characterized. The EPS-Fe and EPS-Cu exhibited antioxidant activity in scavenging ·OH, DPPH and ·O2− free radicals, thereby leading to reduced oxidative stress and apoptosis levels in human colonic epithelial cells in vitro. They also inhibited the proliferation of mouse hepatocellular carcinoma H22 and the growth of intestinal pathogens in vitro. This study provided an effective avenue for EPS production from glutinous rice processing wastewater and proved the potential of EPS-Fe and EPS-Cu complexes as a new-type comprehensive essential trace mineral supplement.

IntroductionRetrospective studies have suggested that Ursodeoxycholic Acid (UDCA) provide a protective effect against SARS-CoV-2 infection, particularly in patients with liver disease. However, it is uncertain whether this finding can be extended to the allogeneic hematopoietic stem cell transplantation (allo-HSCT) cohort. Therefore, we aim to examine the protective potential of UDCA against SARS-CoV-2 infection in recently received allo-HSCT patients.MethodsDuring the initial Omicron variant wave in China (December 2022 to February 2023), we conducted a prospective observational study involving 91 hospitalized patients who had undergone allo-HSCT within the previous 6 months as part of the National Longitudinal Cohort of Hematological Diseases (NICHE). Throughout hospitalization, we continuously monitored the status of COVID-19 using SARS-CoV-2 PCR kits or SARS-CoV-2 Antigen Rapid Tests.ResultsAmong these patients, 67.0% (n = 61) were confirmed to have contracted SARS-CoV-2 infection. For the 52 patients evaluated, 23.1% experienced a severe or critical clinical course. There was no difference in the infection rate or severity of COVID-19 between the UDCA group and the non-UDCA group. We found that only patients transplanted between 3 and 6 months ago demonstrated a higher risk of SARS-CoV-2 infection compared to those who received allo-HSCT within 3 months (Odds Ratio [OR]: 3.241, 95% Confidence Interval [CI]: 1.287-8.814, P = 0.016). But other clinical factors, such as administration of UDCA, showed no difference. Notably, only age ≥38 years old remained as an independent risk factor for a severe clinical course of SARS-CoV-2 infection (OR: 3.664, 95% CI: 1.129-13.007, P = 0.035).ConclusionThe effectiveness of UDCA in protecting newly allo-HSCT recipients against SARS-CoV-2 infection remains unconfirmed. Presently, the most effective strategy appears to be minimizing exposure to SARS-CoV-2.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT04645199, identifier NCT04645199.

ObjectiveThis study aimed to investigate the relationship between intraoperative hip arthrogram parameters and residual acetabular dysplasia (RAD) and avascular necrosis of the femoral head (AVN) in children with developmental dysplasia of the hip (DDH) treated by closed reduction.MethodsWe retrospectively analyzed the data of 102 patients (110 hips; mean age, 14.6 months ± 4.7 months) with DDH treated by closed reduction. A hip arthrogram was routinely performed during the operation. The femoral head coverage rate (FHC), medial pool distance of the hip (MPD), labral inversion, and reduction quality classification were evaluated under the hip arthrogram. The presence of RAD and AVN was assessed on radiographs at the last follow-up. The relationship between each arthrogram parameter and RAD as well as AVN was investigated using a t-test, chi-square test, and logistic regression.ResultsThe overall FHC and medial pool distance of the hip (MDP) averaged 42.2% ± 12% and 8.1% ± 11.7%, respectively. There were 80 hips (72.7%) with labral inversion and 30 hips (27.2%) without. The reduction quality was type A in 57 hips (51.8%), type B in 28 hips (25.4%), and type C in 25 hips (22.7%). A total of 32 hips (29%) were in the RAD group, and 78 hips (71%) were in the recovered group according to whether pelvic osteotomy was performed or not and according to the last Severin grade. The FHC was significantly higher in the recovered group than that in the RAD group (P = 0.014). No significant difference was observed in sex, age at reduction, side, preoperative acetabular index, International Hip Dysplasia Institute classification, follow-up time, quality of reduction, MDP, and proportion of labral inversion between the recovered and RAD groups. Logistic regression analysis showed that only the FHC was a risk factor for RAD. The incidence of AVN above type II was 11.8% in this group of patients, and the incidence of AVN was significantly higher in patients with labral inversion (23.2%) than that in those without (7.5%; P = 0.041). Logistic regression analysis showed that labral inversion was a risk factor for AVN.ConclusionThe FHC measured under arthrogram can predict the occurrence of RAD after closed reduction of DDH, whereas MDP, reduction quality classification, and labral inversion are of little significance. Labral inversion is a risk factor for AVN.

Plant height is an important agronomic trait. Dwarf varieties present several advantages, such as lodging resistance, increased yield, and suitability for mechanized harvesting, which are crucial for crop improvement. However, limited research is available on dwarf tomato varieties suitable for production. In this study, we report a novel short internode mutant named “short internode and pedicel (sip)” in tomato, which exhibits marked internode and pedicel shortening due to suppressed cell elongation. This mutant plant has a compact plant structure and compact inflorescence, and has been demonstrated to produce more fruits, resulting in a higher harvest index. Genetic analysis revealed that this phenotype is controlled by a single recessive gene, SlSIP. BSA analysis and KASP genotyping indicated that ERECTA (ER) is the possible candidate gene for SlSIP, which encodes a leucine-rich receptor-like kinase. Additionally, we obtained an ER functional loss mutant using the CRISPR/Cas9 gene-editing technology. The 401st base A of ER is substituted with T in sip, resulting in a change in the 134th amino acid from asparagine (N) to isoleucine (I). Molecular dynamics(MD) simulations showed that this mutation site is located in the extracellular LRR domain and alters nearby ionic bonds, leading to a change in the spatial structure of this site. Transcriptome analysis indicated that the genes that were differentially expressed between sip and wild-type (WT) plants were enriched in the gibberellin metabolic pathway. We found that GA3 and GA4 decreased in the sip mutant, and exogenous GA3 restored the sip to the height of the WT plant. These findings reveal that SlSIP in tomatoes regulates stem elongation by regulating gibberellin metabolism. These results provide new insights into the mechanisms of tomato dwarfing and germplasm resources for breeding dwarfing tomatoes.

Woody plants play a vital role in global ecosystems and serve as valuable resources for various industries and human needs. While many woody plant genomes have been fully sequenced, gene function research and biotechnological breeding advances have lagged behind. As a result, only a limited number of genes have been elucidated, making it difficult to use newer tools such as CRISPR-Cas9 for biotechnological breeding purposes. The use of Agrobacterium rhizogenes as a transformative tool in plant biotechnology has received considerable attention in recent years, particularly in the research field on woody plants. Over the past three decades, numerous woody plants have been effectively transformed using A. rhizogenes-mediated techniques. Some of these transformed plants have successfully regenerated. Recent research on A. rhizogenes-mediated transformation of woody plants has demonstrated its potential for various applications, including gene function analysis, gene expression profiling, gene interaction studies, and gene regulation analysis. The introduction of the Ri plasmid has resulted in the emergence of several Ri phenotypes, such as compact plant types, which can be exploited for Ri breeding purposes. This review paper presents recent advances in A. rhizogenes-mediated basic research and Ri breeding in woody plants. This study highlights various aspects of A. rhizogenes-mediated transformation, its multiple applications in gene function analysis, and the potential of Ri lines as valuable breeding materials

As the promotive/complementary mechanism of the microbe–soil–tobacco (Nicotiana tabacum L.) interaction remains unclear and the contribution of this triple interaction to tobacco growth is not predictable, the effects of intercropping on soil nutrients, enzymatic activity, microbial community composition, plant growth, and plant quality were studied, and the regulatory mechanism of intercropping on plant productivity and soil microenvironment (fertility and microorganisms) were evaluated. The results showed that the soil organic matter (OM), available nitrogen (AN), available phosphorus (AP), available potassium (AK), the urease activity (UE) and sucrase activity (SC), the diversity, abundance, and total and unique operational taxonomic units (OTUs) of bacteria and fungi as well as plant biomass in T1 (intercropping onion), T2 (intercropping endive), and T3 (intercropping lettuce) treatments were significantly higher than those of the controls (monocropping tobacco). Although the dominant bacteria and fungi at the phylum level were the same for each treatment, LEfSe analysis showed that significant differences in community structure composition and the distribution proportion of each dominant community were different. Proteobacteria, Acidobacteria, and Firmicutes of bacteria and Ascomycota and Basidiomycetes of fungi in T1, T2, and T3 treatments were higher than those of the controls. Redundancy analysis (RDA) suggested a close relation between soil characteristic parameters and microbial taxa. The correlation analysis between the soil characteristic parameters and the plant showed that the plant biomass was closely related to soil characteristic parameters. In conclusion, the flue-cured tobacco intercropping not only increased plant biomass and improved chemical quality but also significantly increased rhizospheric soil nutrient and enzymatic activities, optimizing the microbial community composition and diversity of rhizosphere soil. The current study highlighted the importance of microbe–soil–tobacco interactions in maintaining plant productivity and provided the potential fertilization practices in flue-cured tobacco production to maintain ecological sustainability.

SET-NUP214 fusion gene, also known as TAF-1-CAN and SET-CAN, is observed in acute myeloid leukemia (AML) and T-cell lymphoblastic leukemia (T-ALL). SET-NUP214 fusion in T-cell lymphoblastic leukemia is associated with chemotherapy resistance, but the prognosis of patients with AML with SET-NUP214 has rarely been reported. In the present study, we retrospectively analyzed all patients with acute leukemia including AML and T-ALL patients with SET-NUP214 fusion who underwent allogeneic stem cell transplantation (alloHSCT) in our center from July 2017 to November 2022. Of the total 11 patients, 5 patients were diagnosed with AML and 6 patients were diagnosed with T-ALL de novo. All patients received myeloablative regimens in CR1, and there were three (60%) AML patients who relapsed post-alloHSCT and three T-ALL (50%) patients who relapsed post-alloHSCT. Only one patient with AML who relapsed post-alloHSCT responded to subsequent chemotherapy plus donor lymphocyte infusion and survived the last follow-up. The estimated 1-year overall survival and 3-year overall survival for all these 11 patients were 69.3% and 38.5%, respectively. The estimated 1-year leukemia-free survival and 3-year leukemia-free survival for all patients were 69.3% and 38.5%, respectively. The research shows a high incidence of relapse for patients with acute leukemia with the SET-NUP214 fusion gene, even after alloHSCT. More clinical trials or research with larger samples are urgently needed for this group of patients.

BackgroundTo investigate the diagnostic value of shear wave elastography (SWE) and super microvascular imaging (SMI) integrated with the traditional ultrasound breast imaging reporting and data system (BI-RADS) classification in differentiating between benign and malignant breast nodules.MethodsFor analysis, 88 patients with 110 breast nodules assessed as BI-RADS 3-5 by conventional ultrasound were selected. SWE and SMI evaluations were conducted separately, and all nodules were verified as benign or malignant ones by pathology. Receiver operating characteristic (ROC) curves were plotted after obtaining quantitative parameters of different shear waves of nodules, including maximum (Emax), mean (Emean), minimum (Emin) Young’s modulus, modulus standard deviation (SD), and modulus ratio (Eratio). The best cut-off value, specificity, sensitivity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) for diagnosing malignant nodules employing Emax were obtained, and the diagnostic value of combining Emax and BI-RADS classification was compared. SMI graded nodule based on the Alder blood flow grading standard, whereas the BI-RADS classification was based on microvascular morphology. We assessed the diagnostic value of SMI for breast nodules and investigated the diagnostic efficacy of SWE combined with SMI in differentiating benign and malignant breast nodules with BI-RADS classification 3–5.ResultsThe adjusted the BI-RADS classification using SMI and SWE technologies promoted the sensitivity, specificity, and accuracy of discriminating benign and malignant breast nodules (P < 0.05). The combination of traditional ultrasound BI-RADS classification with SWE and SMI technologies offered high sensitivity, specificity, accuracy, PPV, and NPV for identifying benign and malignant breast lesions. Moreover, combining SWE and SMI technologies with the adjusted BI-RADS classificationhad the best diagnostic efficacy for distinguishing benign and malignant breast nodules with BI-RADS 3–5.ConclusionThe combination of SWE and SMI with the adjusted BI-RADS classification is a promising diagnostic method for differentiating benign and malignant breast nodules.

Malformed tomato fruit with multiple locules is a common physiological disorder that significantly affects the quality of tomatoes. Research has shown that the occurrence of malformed fruit in tomatoes is closely linked to the number of locules, and two key QTLs, lc and fas, are involved in controlling this trait. It has been observed that lc has a relatively weaker effect on increasing locule number, which is associated with two SNPs in the CArG repressor element downstream of the SlWUS. However, the precise molecular mechanism underlying lc is not yet fully understood. In this study, we investigated the role of lc in tomato locule development. We found that the number of floral organs and fruit locules significantly increased in tomato lc knockout mutants. Additionally, these mutants showed higher expression levels of the SlWUS during carpel formation. Through cDNA library construction and yeast one-hybrid screening, we identified the MADS-box transcription factor SlSEP3, which was found to bind to lc. Furthermore, we observed an increase in floral organs and fruit locules similar to the lcCR plant on SlSEP3 silencing plants. However, it should be noted that the lc site is located after the 3′ untranslated region (UTR) of SlWUS in the tomato genome. As a result, SlSEP3 may not be able to exert regulatory functions on the promoter of the gene like other transcription factors. In the yeast two-hybrid assay, we found that several histone deacetylases (SlHDA1, SlHDA3, SlHDA4, SlHDA5, SlHDA6, SlHDA7, and SlHDA8) can interact with SlSEP3. This indicated that SlSEP3 can recruit these proteins to repress nucleosome relaxation, thereby inhibiting SlWUS transcription and affecting the number of locules in tomato fruit. Therefore, our findings reveal a new mechanism for lc playing a significant role in the genetic pathway regulating tomato locule development.

BackgroundSilicosis, a severe lung disease caused by inhaling silica dust, predominantly affects workers in industries such as mining and construction, leading to a significant global public health challenge. The purpose of this study is to analyze the current disease burden of silicosis and to predict the development trend of silicosis in the future the world by extracting data from the GBD database.MethodsWe extracted and analyzed silicosis prevalence, incidence, mortality, and disability-adjusted life years (DALYs) data from the Global Burden of Disease 2019 program for 204 countries and territories from 1990 to 2019. The association between the Sociodemographic Index (SDI) and the burden of age-standardized rates (ASRs) of DALYs has been examined at the regional level. Jointpoint regression analysis has been also performed to evaluate global burden trends of silicosis from 1990 to 2019. Furthermore, Nordpred age-period-cohort analysis has also been projected to predict future the burden of silicosis from 2019 to 2044.ResultsIn 2019, global ASRs for silicosis prevalence, incidence, mortality, and DALYs were 5.383, 1.650, 0.161, and 7.872%, respectively which are lower than that in 1990. The populations of 45–59 age group were more susceptible to silicosis, while those aged 80 or above suffered from higher mortality and DALY risks. In 2019, the most impacted nations by the burden of silicosis included China, the Democratic People’s Republic of Korea, and Chile. From 1990 to 2019, most regions observed a declining burden of silicosis. An “M” shaped association between SDI and ASRs of DALYs for silicosis was observed from 1990 to 2019. The age-period-cohort analysis forecasted a decreasing trend of the burden of silicosis from 2019 to 2044.ConclusionDespite the overall decline in the global silicosis burden from 1990 to 2019, some regions witnessed a notable burden of this disease, emphasizing the importance of targeted interventions. Our results may provide a reference for the subsequent development of appropriate management strategies.

BackgroundInactivated SARS-CoV-2 vaccination has recently been approved for children aged 3-17 years in China. However, data on long-term humoral responses to inactivated vaccines in children with chronic hepatitis B (CHB) are still limited.MethodsIn this prospective observational study, CHB children after primary inactivated SARS-CoV-2 vaccines were recruited consecutively and followed up for 1 year. CHB adults from another cohort study (NCT05007665) were used as a control. The receptor-binding domain IgG antibody (anti-RBD-IgG), neutralizing antibody (NAb), neutralization against Omicron (BA2.12.1, BA.4 and BA.5), and memory B -cell (MBC) responses were evaluated.ResultsOverall, 115 CHB children and 351 CHB adults were included in this analysis. The antibody titers decreased over the first ~180 days and then plateaued up to 1 year in CHB children. However, lower and faster declines in antibody responses were observed in CHB adults. Interestingly, the seroprevalence of antibodies was still high after over 8 months in CHB children (anti-RBD-IgG [90%] and NAbs [83%]). However, neutralization against Omicron subvariants was significantly reduced in CHB children (-3.68-fold to -8.60-fold). Notably, neutralization against the BA.5 subvariant was obviously diminished in CHB children compared with adults. Moreover, CHB children had similar RBD-specific MBCs but higher RBD-specific atypical MBCs compared with adults.ConclusionInactivated vaccination could elicit more robust and durable antibody responses to the wild-type SARS-CoV-2 strain in CHB children than in CHB adults but showed inferior responses to Omicron subvariants (especially to the BA.5 strain). Hence, new Omicron-related or all-in-one vaccines are needed immediately for CHB children.

IntroductionSatellite observations of sun-induced chlorophyll fluorescence (SIF) are increasingly considered a “probe” for photosynthesis. In recent years the emergence of SIF has facilitated regional and global monitoring of vegetation photosynthesis. On the one hand, there is still controversy about the liner or non-linear SIF-GPP relationship and whether high-temperature events will change the linear relationship. On the other hand, it is unclear whether different vegetation types will affect the SIF-GPP. We used GOSIF and MOD17A2 GPP to study the different relationships under five vegetation types during the long-term climate change period and the extreme drought in 2009/2010 in southwest China.MethodsIn this study, curve fitting was used to explore the relationship of SIF and GPP under long time series and extreme drought period.ResultsWe found that during the long-term climate change period, there was a generally linear SIF-GPP relationship under five vegetation types. The correlation is almost universally maintained at the r2 = 0.92 level. During the drought, the extremely high temperature did not change the linear relationship. Besides the farmland ecosystem, the correlation remained at the r2 = 0.85.DiscussionOur study shows that the linear relationship of SIF-GPP is not influenced by drought on a large scale, and there is a general SIF-GPP relationship in different vegetation types. In the case of extreme drought, irrigation measures adopted by farmers in response to heat conditions may affect the SIF-GPP relationship of farmland.

IntroductionThe Danjiang River Basin has experienced significant alterations to its runoff patterns in recent years, primarily as a result of climate change and anthropogenic activities.MethodsThis study aims to investigate these factors’ influence on the basin’s runoff between 1960 and 2016 using the Mann–Kendall (M-K) test and Accumulative Anomaly Curve (AAC) to assess the abrupt change characteristics of runoff. Furthermore, the study evaluates the effects of climate and anthropogenic factors on runoff evolution using eight independent Budyko hypotheses.ResultsThe findings indicate that annual precipitation in the basin remained stable (P > 0.1), while annual runoff decreases significantly to −4.08 mm/a (P < 0.05) and the annual potential evapotranspiration slightly decreases to −1.76 mm/a (P < 0.05). The study also reveales that the reduction of runoff is primarily attributable to anthropogenic activities, contributing between 133.66 and 147.50%, while climate change contributes between −33.66 and −47.50%.DiscussionThe increased vegetation cover in the basin is identified as the primary cause of the reduction in runoff production and increase in evapotranspiration. Additionally, the construction of hydraulic engineering facilities in the basin is found to have had some impact on reducing runoff. These findings have significant implications for water resource management and soil and water conservation in the Danjiang River Basin.

ObjectiveWe conducted this cross-sectional study to explore the mediating and predicting role of somatic symptom disorder (SSD) between psychological measures and quality of life (QOL) among Chinese breast cancer patients.MethodsBreast cancer patients were recruited from three clinics in Beijing. Screening tools included the Patient Health Questionnaire-15 (PHQ-15), the Patient Health Questionnaire-9 (PHQ-9), the General Anxiety Disorder-7 scale (GAD-7), the Health Anxiety Scale (Whiteley Index-8, WI-8), the Somatic Symptom Disorder B-Criteria Scale (SSD-12), the Fear of Cancer Recurrence scale (FCR-4), the Brief Illness Perception Questionnaire (BIPQ-8), and the Functional Assessment of Cancer Therapy-Breast (FACT-B). Chi-square tests, nonparametric tests, mediating effect analysis, and linear regression analysis were used for the data analysis.ResultsAmong the 264 participants, 25.0% were screened positive for SSD. The patients with screened positive SSD had a lower performance status, and a greater number of patients with screened positive SSD received traditional Chinese medicine (TCM) (p

IntroductionAtrial fibrillation (AF) is a challenging cardiovascular disease worldwide. Wearable electrocardiograph devices (WEDs) have great potential to improve the detection rate of AF in primary care. However, the factors that influence general practitioners’ (GPs) perception and acceptance of WEDs are not well understood. To identify factors that influence the intention of GPs to utilize WEDs in a clinical setting to screen patients for AF.MethodThe research hypotheses and questionnaire items were designed and developed based on the unified theory of acceptance and technology (UTAUT) framework. We used stratified sampling and obtained the data through an online survey. Structural equation modeling was used to analyze the collected data.Results: A total of 1,004 valid questionnaires from GPs across Sichuan province in China were collected. Three factors increased GPs’ intention to utilize WEDs to screen patients for AF, including performance expectancy (β = 0.121, p = 0.004), social influence (β = 0.356, p

CD19 chimeric antigen receptor (CAR) engineered NK cells have been used for treating patients with relapsed and/or refractory B cell malignancies and show encouraging outcomes and safety profile. However, the poor persistence of NK cells remains a major challenge for CAR NK cell therapy. Memory-like NK cells (MLNK) induced by IL-12, IL-15, and IL-18 have shown enhanced and prolonged responses to tumor re-stimulation, making them an attractive candidate for adoptive cellular immunotherapy. Here, we show efficient and stable gene delivery of CD19 CAR to memory-like NK cells using retroviral vectors with transduction efficiency comparable to those achieved with conventional NK cells. Analysis of surface molecules revealed a distinct phenotypic profile in CAR engineered memory-like NK cells (CAR MLNK), as evidenced by increased expression of CD94 and downregulation of NKp30 as well as KIR2DL1. Compared to conventional CAR NK cells, CAR MLNK cells exhibited significantly increased IFN-γ production and degranulation in response to CD19+ target cells, resulting in enhanced cytotoxic activity against CD19+ leukemia cells and lymphoma cells. Furthermore, memory properties induced by IL-12/-15/-18 improved the in vivo persistence of CAR MLNK cells and significantly suppressed tumor growth in a exnograft mouse model of lymphoma, leading to prolonged survival of CD19+ tumor-bearing mouse. Altogether, our data indicate that CD19 CAR engineered memory-like NK cells exhibited superior persistence and antitumor activity against CD19+ tumors, which might be an attractive approach for treating patient with relapse or refractory B cell malignancies.

Fighting intracellular bacteria with strong antibiotics evading remains a long-standing challenge. Responding to and regulating the infectious microenvironment is crucial for treating intracellular infections. Sophisticated nanomaterials with unique physicochemical properties exhibit great potential for precise drug delivery towards infection sites, along with modulating infectious microenvironment via their instinct bioactivity. In this review, we first identify the key characters and therapeutic targets of intracellular infection microenvironment. Next, we illustrate how the nanomaterials physicochemical properties, such as size, charge, shape and functionalization affect the interaction between nanomaterials, cells and bacteria. We also introduce the recent progress of nanomaterial-based targeted delivery and controlled release of antibiotics in intracellular infection microenvironment. Notably, we highlight the nanomaterials with unique intrinsic properties, such as metal toxicity and enzyme-like activity for the treatment of intracellular bacteria. Finally, we discuss the opportunities and challenges of bioactive nanomaterials in addressing intracellular infections.

Fusarium head blight (FHB), caused mainly by the fungus Fusarium graminearum, is one of the most devastating diseases in wheat, which reduces the yield and quality of grain. Fusarium graminearum infection of wheat cells triggers dynamic changes of gene expression in both F. graminearum and wheat, leading to molecular interactions between pathogen and host. The wheat plant in turn activates immune signaling or host defense pathways against FHB. However, the mechanisms by which F. graminearum infects wheat varieties with different levels of host resistance are largely limited. In this study, we conducted a comparative analysis of the F. graminearum transcriptome in planta during the infection of susceptible and resistant wheat varieties at three timepoints. A total of 6,106 F. graminearum genes including those functioning in cell wall degradation, synthesis of secondary metabolites, virulence, and pathogenicity were identified during the infection of different hosts, which were regulated by hosts with different genetic backgrounds. Genes enriched with metabolism of host cell wall components and defense response processes were specifically dynamic during the infection with different hosts. Our study also identified F. graminearum genes that were specifically suppressed by signals derived from the resistant plant host. These genes may represent direct targets of the plant defense against infection by this fungus. Briefly, we generated databases of in planta-expressed genes of F. graminearum during infection of two different FHB resistance level wheat varieties, highlighted their dynamic expression patterns and functions of virulence, invasion, defense response, metabolism, and effector signaling, providing valuable insight into the interactions between F. graminearum and susceptible/resistant wheat varieties.

Background: Elevated expression of Copine-1 (CPNE1) has been proved in various cancers; however, the underlying mechanisms by which it affects clear cell renal cell carcinoma (ccRCC) are unclear.Methods: In this study, we applied multiple bioinformatic databases to analyze the expression and clinical significance of CPNE1 in ccRCC. Co-expression analysis and functional enrichment analysis were investigated by LinkedOmics, cBioPortal and Metascape. The relationships between CPNE1 and tumor immunology were explored using ESTIMATE and CIBERSORT method. In vitro experiments, CCK-8, wound healing, transwell assays and western blotting were conducted to investigate the effects of gain- or loss-of-function of CPNE1 in ccRCC cells.Results: The expression of CPNE1 was notably elevated in ccRCC tissues and cells, and significantly correlated with grade, invasion range, stage and distant metastasis. Kaplan–Meier and Cox regression analysis displayed that CPNE1 expression was an independent prognostic factor for ccRCC patients. Functional enrichment analysis revealed that CPNE1 and its co-expressed genes mainly regulated cancer-related and immune-related pathways. Immune correlation analysis showed that CPNE1 expression was significantly related to immune and estimate scores. CPNE1 expression was positively related to higher infiltrations of immune cells, such as CD8+ T cells, plasma cells and regulatory T cells, exhibited lower infiltrations of neutrophils. Meanwhile, elevated expression of CPNE1 was characterized by high immune infiltration levels, increased expression levels of CD8+ T cell exhaustion markers (CTLA4, PDCD1 and LAG3) and worse response to immunotherapy. In vitro functional studies demonstrated that CPNE1 promoted proliferation, migration and invasion of ccRCC cells through EGFR/STAT3 pathway.Conclusion: CPNE1 is a reliable clinical predictor for the prognosis of ccRCC and promotes proliferation and migration by activating EGFR/STAT3 signaling. Moreover, CPNE1 significantly correlates with immune infiltration in ccRCC.

IntroductionSince allogeneic stem cell transplantation (allo-HSCT) is considered one of the curative treatments for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), hematological relapse following allo-HSCT remained a crucial concern for patients’ survival. MethodsWe retrospectively compared patients who received venetoclax plus hypomethylating agents (VEN+HMA, n=23) or intensive chemotherapy (IC, n=42) for hematological relapse of myeloid malignancies after allo-HSCT. HMA selection included decitabine (n=2) and azacitidine (n=21), and combined donor lymphocyte infusion was administered to 21 and 42 patients in VEN+HMA and IC groups, respectively. ResultsMedian age of all patients was 39 (16-64) years old. Overall response rates, including complete response (CR), CR with incomplete recovery of normal neutrophil or platelet counts (CRi) and partial response (PR), were not significantly different between VEN+HMA and IC groups (60.1% versus 64.3%, P=0.785). CR/CRi rate was 52.2% in VEN+HMA and 59.5% in IC group (P=0.567). The rate of relapse after response was 66.7% in VEN+HMA group and 40.7% in IC group (P=0.176). Median overall survival was 209.0 (95%CI 130.9-287.1) days for VEN+HMA group versus 211.0 (95%CI 28.7-393.3) days for IC group (P=0.491). The incidence of lung infection (17.4% versus 50.0%, P=0.010), thrombocytopenia (73.9% versus 95.2%, P=0.035) and acute graft-versus-host disease (aGvHD) (50.0% versus 13.0%, P=0.003) was significantly higher in IC group. DiscussionIn conclusion, VEN+HMA is not inferior to IC regimen in terms of improving response and survival, and is associated with a lower incidence of adverse events and aGvHD. However, further research is required to enhance long-term survival.

Hepatitis-associated aplastic anemia (HAAA) is a rare variant of acquired aplastic anemia characterized with a syndrome of bone marrow failure after hepatitis. We retrospectively analyzed the outcomes of consecutive severe HAAA patients who received immunosuppressive therapy (IST, n = 70), matched-sibling donor hematopoietic stem cell transplantation (MSD-HSCT, n = 26) or haploidentical-donor (HID) HSCT (n = 11) as the first-line treatment. In the IST group, the hematologic response (HR) rate was 55.71% at 6 months. In contrast, HSCT recipients exhibited significantly more rapid and sustained hematopoiesis (HR 76.92%, 96.15% and 96.15% at 3, 6 and 12months, respectively). The 5-year overall survival (OS) was not different among IST (83.7 ± 4.9%), MSD-HSCT (93.3 ± 6.4%) and HID-HSCT group (80.8 ± 12.3%). Compared with IST, MSD and HID-HSCT demonstrated a trend of superiority in the estimated 5-year failure-free survival rates (93.3 ± 6.4% vs 64.3 ± 6.0%, p = 0.05; 80.8 ± 12.3% vs 64.3 ± 6.0%, p = 0.57). In subsequent stratified analysis on age, we found that HID-HSCT showed its efficacy and safety among young patients. In sum, MSD-HSCT remains first-line treatment choice for HAAA, whereas HID-HSCT represents an alternative treatment choice in addition to IST for young patients (< 40 years) without a matched sibling donor.

The highly efficient capture of circulating tumor cells (CTCs) in the blood is essential for the screening, treatment, and assessment of the risk of metastasis or recurrence of cancer. Immobilizing specific antibodies, such as EpCAM antibodies, on the material’s surface is currently the primary method for efficiently capturing CTCs. However, the strategies for immobilizing antibodies usually have the disadvantages of requiring multiple chemical reagents and a complex pre-treatment process. Herein we developed a simple strategy for the immobilization of EpCAM antibodies without additional chemical reagents. By utilizing the positive charge property of the photo-functionalized titanium dioxide (TiO2), the negatively charged carboxyl terminal of EpCAM antibodies was immobilized by electrostatic interaction, allowing the antibodies to expose the antigen binding site fully. The experimental results showed that the photo-functionalized TiO2 surface had a marked positive charge and super-hydrophilic properties that could immobilize large amounts of EpCAM antibodies and keep excellent activity. CTCs capture experiments in vitro showed that the EpCAM antibodies-modified photo-functionalized TiO2 could efficiently capture CTCs. The results of blood circulation experiments in rabbits showed that the EpCAM antibodies-modified photo-functionalized TiO2 could accurately capture CTCs from the whole body’s blood. It was foreseen that the strategy of simple immobilization of EpCAM antibodies based on photo-functionalized TiO2 is expected to serve in the efficient capture of CTCs in the future.

IntroductionPsoriasis is a chronic inflammatory disease of the skin. A few studies have shown that psoriasis is an immune-mediated disease in which multiple immune cells play crucial roles. However, the association between circulating immune cells and psoriasis remains elusive.MethodsTo explore the role of circulating immune cells in psoriasis, 361,322 individuals from the UK Biobank (UKB) and 3,971 patients with psoriasis from China were included to investigate the association between white blood cells and psoriasis via an observational study. Genome-wide association studies (GWAS) and Mendelian randomization (MR) were used to evaluate the causal relationship between circulating leukocytes and psoriasis.ResultsThe risk of psoriasis increased with high levels of monocytes, neutrophils, and eosinophils (relative risks and 95% confidence intervals, respectively: 1.430 (1.291–1.584) for monocytes, 1.527 (1.379–1.692) for neutrophils, and 1.417 (1.294–1.551) for eosinophils). Upon further MR analysis, eosinophils showed a definite causal relationship with psoriasis (odds ratio of inverse-variance weighted: 1.386, 95% confidence intervals: 1.092–1.759) and a positive correlation with the psoriasis area and severity index (PASI) score (P = 6.6 × 10-5). The roles of the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR) in psoriasis were also assessed. More than 20,000 genetic variations associated with NLR, PLR, and LMR were discovered in a GWAS analysis using the UKB data. Following adjustment for covariates in the observational study, NLR and PLR were shown to be risk factors for psoriasis, whereas LMR was a protective factor. MR results indicated that there was no causal relationship between these three indicators and psoriasis; however, NLR, PLR, and LMR correlated with the PASI score (NLR: rho = 0.244, P = 2.1 × 10-21; PLR: rho = 0.113, P = 1.4 × 10-5; LMR: rho = -0.242, P = 3.5×10-21).DiscussionOur findings revealed an important association between circulating leukocytes and psoriasis, which is instructive for the clinical practice of psoriasis treatment.

Breast cancer (BRCA) remains the most prevalent cancer worldwide and the tumor microenvironment (TME) has been discovered to exert a wide influence on the overall survival and therapeutic response. Numerous lines of evidence reported that the effects of immunotherapy of BRCA were manipulated by TME. Immunogenic cell death (ICD) is a form of regulated cell death (RCD) that is capable of fueling adaptive immune responses and aberrant expression of ICD-related genes (ICDRGs) can govern the TME system by emitting danger signals or damage-associated molecular patterns (DAMPs). In the current study, we obtained 34 key ICDRGs in BRCA. Subsequently, using the transcriptome data of BRCA from the TCGA database, we constructed a risk signature based on 6 vital ICDRGs, which had a good performance in predicting the overall survival of BRCA patients. We also examined the efficacy of our risk signature in the validation dataset (GSE20711) in the GEO database and it performed excellently. According to the risk model, patients with BRCA were divided into high-risk and low-risk groups. Also, the unique immune characteristics and TME between the two subgroups and 10 promising small molecule drugs targeting BRCA patients with different ICDRGs risk have been investigated. The low-risk group had good immunity indicated by T cell infiltration and high immune checkpoint expression. Moreover, the BRCA samples could be divided into three immune subtypes according to immune response severity (ISA, ISB, and ISC). ISA and ISB predominated in the low-risk group and patients in the low-risk group exhibited a more vigorous immune response. In conclusion, we developed an ICDRGs-based risk signature that can predict the prognosis of BRCA patients and offer a novel therapeutic strategy for immunotherapy, which would be of great significance in the BRCA clinical setting.

Background: RNA-editing refers to post-transcriptional transcript alterations that lead to the formation of protein isoforms and the progression of various tumors. However, little is known about its roles in gliomas.Aim: The aim of this study is to identify prognosis-related RNA-editing sites (PREs) in glioma, and to explore their specific effects on glioma and potential mechanisms of action.Methods: Glioma genomic and clinical data were obtained from TCGA database and SYNAPSE platform. The PREs was identified with regression analyses and the corresponding prognostic model was evaluated with survival analysis and receiver operating characteristic curve. Functional enrichment of differentially expressed genes between risk groups was performed to explore action mechanisms. The CIBERSORT, ssGSEA, gene set variation analysis, and ESTIMATE algorithms were employed to assess the association between PREs risk score and variations of tumor microenvironment, immune cell infiltration, immune checkpoints, and immune responses. The maftools and pRRophetic packages were used to evaluate tumor mutation burden and predict drug sensitivity.Results: A total of thirty-five RNA-editing sites were identified as prognosis-related in glioma. Functional enrichment implied variation of immune-related pathways between groups. Notably, glioma samples with higher PREs risk score exhibited higher immune score, lower tumor purity, increased infiltration of macrophage and regulatory T cells, suppressed NK cell activation, elevated immune function score, upregulated immune checkpoint gene expression, and higher tumor mutation burden, all of which implied worse response to immune therapy. Finally, high-risk glioma samples are more sensitive to Z-LLNle-CHO and temozolomide, while the low-risk ones respond better to Lisitinib.Conclusion: We identified a PREs signature of thirty-five RNA editing sites and calculated their corresponding risk coefficients. Higher total signature risk score indicates worse prognosis and worse immune response and lower sensitivity to immune therapy. The novel PREs signature could help risk stratification, immunotherapy response prediction, individualized treatment strategy-making for glioma patients, and development of novel therapeutic approaches.

This is a small phase I study examining the safety and efficacy of a cladribine (CLAD)-containing conditioning regimen prior to autologous hematopoietic stem cell transplantion (auto-HSCT) for patients with acute myeloid leukemia (AML). All patients, aged 15–54 years (median 32 years), had favorable/intermediate risk AML (n = 20) or acute promyelocytic leukemia (APL; n = 2) and no evidence of minimal residual disease (MRD) prior to transplantation. Fourteen of the 22 patients received the conditioning regimen as follows: busulfan (Bu) + cyclophosphamide (Cy) + CLAD + cytarabine (Ara-c) or idarubicin. The conditioning regimen of 8 patients was without Cy nor idarubicin to reducing adverse cardiac reaction: the regimen of Bu + CLAD+ Ara-c for 6 patients; and the regimen of Bu + melphalan + CLAD + Ara-c for the other 2 patients. All 22 AML patients received peripheral blood stem cell transplantation. The number of infused mononuclear cells and CD34+ cells was 10.00 (2.88–20.97) × 108/kg and 1.89 (1.52–10.44) × 106/kg, respectively. Hematopoietic reconstitution was achieved in all patients, with a median time of 13 (10–34) days for neutrophils and 28 (14–113) days for platelets. Two patients suffered from pulmonary infection, 4 patients suffered from septicemia during the neutropenic stage, and the others suffered from infection or gastrointestinal reaction without exceeding grade 3 after conditioning, which were all alleviated by anti-infection and other supportive treatment. None of the patients died of transplantation-related complications. At a median follow-up of 29.5 (ranging from 4.0 to 60.0) months, three patients relapsed after auto-HSCT at a median time of 6 (ranging from 0.5 to 10.0) months. One patient died due to relapse at 18 months after auto-HSCT. The remaining 21 patients were all alive, including 19 patients with negative MRD. The other 2 patients achieved negative MRD after allogeneic HSCT or chemotherapy. The estimated 2-year survival, relapse, and Leukemia-free survival rates were 94.1 ± 5.7%, 14.7 ± 7.9% and 85.3 ± 7.9%, respectively. A CLAD-combination conditioning regimen is efficient and safe for auto-HSCT, indicating an effective approach for AML treatment.

Winterberry (Ilex verticillata (L.) A. Gray) is a recently introduced ornamental tree species in China that has not been closely investigated for its drought resistance. In this study, we used two-year-old cuttings from I. verticillata (L.) A. Gray and two representative varieties derived from it, I. verticillata ‘Oosterwijk’ and I. verticillata ‘Jim Dandy’, as materials to investigate how this plant responds to drought stress and whether exogenous spermidine (SPD) can alleviate the negative effects caused by drought stress. The results showed that as the degree of drought stress increased, the leaves of winterberry seedlings became chlorotic, and their edges became dry. Similarly, the relative water content, specific leaf weight, chlorophyll content, leaf nitrogen content, net photosynthetic rate, stomatal conductance and transpiration rate were significantly reduced, whereas the content of malondialdehyde continuously increased with the degree of drought stress. The activities of superoxide dismutase, peroxidase, and catalase increased under moderate drought stress and then decreased under severe drought stress. The levels of soluble sugar and abscisic acid continued to increase, while those of auxin and gibberellic acid decreased. When compared with individual drought stress, an increase in the amount of external SPD clearly alleviated the effect of drought stress on winterberry seedlings. The combined phenotypes and physiological indices of the winterberry leaves under drought stress conditions revealed that the drought resistance of the native species was significantly higher than its two varieties. This finding serves as an important theoretical foundation for the popularization and application of I. verticillata (L.) A. Gray and the two varieties.

Cardiac involvement in hematological malignancies is uncommon, with only a few cases reported to date, and it often leads to a poor prognosis. Here, we report a case of a 42-year-old woman with a history of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for B-cell lymphoblastic lymphoma/acute lymphoblastic leukemia in whom cardiac mass and myocardial infiltration were detected. Prior to this presentation, massive pericardial effusion had occurred 6 months after CAR T-cell therapy, which was improved via ultrasound-guided pericardiocentesis. We observed elevated cytokine levels and increased copy number of CAR DNA in both pericardial effusion and serum. Upon detecting cardiac mass and myocardial infiltration, the patient was administered tocilizumab (a humanized monoclonal antibody against IL-6 receptor), which controlled the serum cytokine levels, and reduced intensity chemotherapy, including vindesine, cyclophosphamide, and prednisolone. However, the patient finally died of multiple organ failure. To the best of our knowledge, this is the first report on the development of a cardiac mass and occurrence of myocardial infiltration after allo-HSCT and CAR T-cell therapy. This report may provide supporting data for the early diagnosis and immediate treatment of patients with cardiac involvement.

Auxin is essential for regulating plant growth and development as well as the response of plants to abiotic stresses. AUX/LAX proteins are auxin influx transporters belonging to the amino acid permease family of proton-driven transporters, and are involved in the transport of indole-3-acetic acid (IAA). However, how AUX/LAX genes respond to abiotic stresses in Chinese hickory is less studied. For the first time identification, structural characteristics as well as gene expression analysis of the AUX/LAX gene family in Chinese hickory were conducted by using techniques of gene cloning and real-time fluorescent quantitative PCR. Eight CcAUX/LAXs were identified in Chinese hickory, all of which had the conserved structural characteristics of AUX/LAXs. CcAUX/LAXs were most closely related to their homologous proteins in Populus trichocarpa , which was in consistence with their common taxonomic character of woody trees. CcAUX/LAXs exhibited different expression profiles in different tissues, indicating their varying roles during growth and development. A number of light-, hormone-, and abiotic stress responsive cis-acting regulatory elements were detected on the promoters of CcAUX/LAX genes. CcAUX/LAX genes responded differently to drought and salt stress treatments to varying degrees. Furthermore, CcAUX/LAX genes exhibited complex expression changes during Chinese hickory grafting. These findings not only provide a valuable resource for further functional validation of CcAUX/LAXs, but also contribute to a better understanding of their potential regulatory functions during grafting and abiotic stress treatments in Chinese hickory.

Airborne lidar is a technology for mapping surface spatial information and has been widely used in many areas of geospatial information disciplines. The filtering process of removing non-ground points has always been the focus of research. PTD (Progressive Triangular Irregular Network Densification) filtering algorithm is a widely used filtering algorithm for airborne lidar data. However, this algorithm has shortcomings in retaining ground points in steep areas, leading to large type Ⅰ errors. Therefore, this paper proposes an improved PTD algorithm. The improvement is the addition of the seed points filtering. Specifically, after the potential seed points are obtained by the progressive morphological filter, the seed points filtering is performed on it to remove the non-ground points, so that the obtained seed points are more accurate. The benchmark dataset of ISPRS (International Society for Photogrammetry and Remote Sensing) Working Group III is used to assess the proposed method. Results show that the method is effective in decreasing type Ⅰ error in steep areas. Comparing with the classic PTD algorithm, the type Ⅰ error and total error are decreased by 8.46% and 5.06% respectively. In addition, the proposed method shows a great advantage in computational efficiency, that is eight times more efficient than the classic PTD algorithm.

ObjectiveThis study aims to compare the characteristics of early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) and non-ETP ALL patients and the outcomes of these patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT).MethodA total of 57 patients with T-cell acute lymphoblastic leukemia/lymphoma receiving allo-HSCT at our center between January 2016 and March 2022 were enrolled in the study. Twenty-eight patients were diagnosed as ETP-ALL/LBL (28/57, 49.12%) in the cohort.ResultsThe baseline characteristic was not significantly different between the two groups. The median time for myeloid engraftment was 14 days (ranged from 11 to 21) versus 14 days (ranged from 10 to 20) (P = 0.067) and 18 days (ranged from 12 to 27) versus 15.5 days (ranged from 12 to 72) (P = 0.183) for platelet engraftment in the ETP-ALL/LBL and non-ETP ALL groups, respectively. There was no significant difference in 5-year overall survival (54.74% ± 10.33% vs. 64.20% ± 10.30%, P = 0.786), relapse-free survival (56.22% ± 10.11% vs. 57.17% ± 12.71%, P = 0.841), cumulative incidence of relapse (30.14% ± 9.85% vs. 22.79% ± 8.24%, P = 0.774), and non-relapse mortality (19.52% ± 8.99% vs. 25.95% ± 14.44%, P = 0.967) between the two groups. The incidence of acute graft versus host disease (aGVHD) (P = 0.922), II–IV aGVHD (P = 0.940), III–IV aGVHD (P = 0.664), cytomegalovirus infection (P = 0.862), Epstein–Barr virus infection (P = 0.610), and severe bacterial infection (P = 0.145) was also similar.ConclusionThe prognosis of patients with ETP-ALL/LBL was similar to non-ETP ALL patients when they received allo-HSCT.

IntroductionTumor microenvironment (TME) has been shown to be extensively involved in tumor development. However, the dynamic change of TME components and their effects are still unclear. Here, we attempted to identify TME-related genes that could help predict survival and may be potential therapeutic targets.MethodsData was collected from UCSC Xena and GEO database. ESTIMATE and CIBERSORT algorithms were applied to estimate the components and the proportions of TIICs in TME. We analyzed the gene expression differences of immune components and stromal components, respectively, and finally got the overlapped DEGs. Through protein-protein interaction (PPI) network and univariate Cox regression analysis based on shared DEGs, we screened out and validated the TME-related genes. Focusing on this gene, we analyzed the expression and prognostic value of this gene, and investigated its relationship with immune cells by correlation analysis, single cell analysis, immunohistochemistry and immunofluorescence analysis.ResultsThrough a series analysis, we found that the proportion of immune and stromal components was an important prognostic factor, and screened out a key gene, LPAR5, which was highly correlated with prognosis and metastasis. And the expression of LPAR5 was positively correlated with immune cells, especially macrophages, indicating LPAR5+ macrophages played an important role in tumor microenvironment of osteosarcoma. Meanwhile, the genes in LPAR5 high expression group were enriched in immune-related activities and pathways, and differentially expressed genes between LPAR5+ macrophages and LPAR5- macrophages were enriched in the biological processes associated with phagocytosis and antigen presentation. What’ more, we found that LPAR5 was mainly expressed in TME, and high LPAR5 expression predicting a better prognosis.ConclusionWe identified a TME-related gene, LPAR5, which is a promising indicator for TME remodeling in osteosarcoma. Particularly, LPAR5+ macrophages might have great potential to be a prognostic factor and therapeutic target for osteosarcoma.

BackgroundHeart failure is a chronic progressive condition that significantly affects the quality of life of patients with high hospitalization and mortality rates. Jiashen tablets (JST), a Chinese herbal formula, have been reported to be an effective treatment against heart failure, however the underlying mechanisms remain obscure. This study was designed to determine the effect of JST on the treatment of heart failure and delineate the underlying mechanisms by an untargeted metabolomics approach.Materials and methodsThe chronic heart failure model was established by the permanent ligation of the left anterior descending coronary artery in rats. The cardiac functions of rats, including left ventricular ejection fraction (LVEF) and fractional shortening (LVFS), left ventricular internal diameter end diastole (LVIDd) and end systole (LVIDs), and interventricular septum thickness in diastole (IVSd) and in systole (IVSs), were measured by echocardiography. Biochemical analysis and histopathological examination were also performed to evaluate therapeutic effects of JST for treating heart failure. UHPLC-QTOF-MS/MS coupled with multivariate statistical analyses were applied for plasma metabolic profiling to identify biomarkers and potential mechanisms of JST in the treatment of heart failure.ResultsJiashen tablets could improve the cardiac function of heart failure rats and thus ameliorate heart failure via enhancing rat LVEF and LVFS and decreasing LVIDd, LVIDs, IVSd, and IVSs. Results of biochemical analysis and histopathological examination revealed that JST could reduce the serum lactate dehydrogenase (LDH) activity and the level of NT-pro BNP, markers of heart failure and myocardial damage, and inhibit myocardial fibrosis. Furthermore, in metabolomics analysis, a total of 210 metabolites with significant differences were identified between heart failure rats and normal rats, among which 29 metabolites were significantly restored after JST treatment. These metabolites were primarily involved in tryptophan metabolism, branched-chain amino acid metabolism, fatty acids β-oxidation, and glycerophospholipid metabolism.ConclusionThe present study illustrated the therapeutic effect of JST for the treatment of heart failure and delineated the underlying mechanisms mainly relating to the regulation of amino acid metabolism and lipid metabolism in heart failure rats.

IntroductionMultiple myeloma (MM) is still an incurable plasma cell malignancy. The efficacy of immunotherapy on MM remains unsatisfactory, and the underlying molecular mechanisms still are not fully understood.MethodsIn this study, we delineated the dynamic features of immune cell in MM bone marrow (BM) along with elevated tumor cell infiltration by single-cell RNA sequencing (scRNA-seq), and investigated the underlying mechanisms on dysfunction of immune cells associated with myelomagenesis.ResultsWe found that immune cells were activated in those patients with low infiltration of tumor cells, meanwhile suppressed with elevated infiltration of MM cells, which facilitated MM escaping from immune surveillance. Besides PD-1, abnormal expression of PIM kinases, KLRB1 and KLRC1 were involved in the defect of immune cells in MM patients. Importantly, we found aberrant metabolic processes were associated with the immunosuppressive microenvironment in MM patients. Disordered amino acid metabolism promoted the dysfunction of cytotoxicity CD8 T cells as well as lipid metabolism disorder was associated with the dysregulation of NK and DCs in MM. As metabolic checkpoints, PIM kinases would be potential effective strategies for MM immunotherapy.DiscussionIn summary, redressing the disordered metabolism should be the key points to get promising effects in immune-based therapies.

BackgroundCardiovascular disease (CVD) is a constellation of heart, brain, and peripheral vascular diseases with common soil hypothesis of etiology, and its subtypes have been well-established in terms of the albumin-mortality association. However, the association between albumin and the mortality of CVD as a whole remains poorly understood, especially the non-linear association. We aimed to investigate the association of albumin levels with long-term mortality of CVD as a whole.Materials and methodsThis study included all CVD patients who participated in the National Health and Nutrition Examination Survey (NHANES 2011–2014). CVD was defined as coronary heart disease, stroke, heart failure, or any combination of these two or three diseases. Serum albumin was tertile partitioned: tertile 1, 4.3 g/dl. COX proportional hazards model was used to assess the association between the serum albumin levels and CVD mortality. Restricted cubic spline (RCS) curves were used to explore the non-linear relationship.ResultsA total of 1,070 patients with CVD were included in the analysis, of which 156 deaths occurred during a median 34 months of follow-up. On a continuous scale, per 1 g/dl albumin decrease was associated with an adjusted HR (95% CI) of 3.85 (2.38–6.25). On a categorical scale, as compared with tertile 3, the multivariable adjusted hazard ratio (95% CI) was 1.42 (0.74–2.71) for the tertile 2, and 2.24 (1.20–4.16) for the tertile 1, respectively, with respect to mortality. RCS curve analysis revealed a J-shaped association between albumin and CVD mortality.ConclusionA J-shaped association between low serum albumin levels and increased long-term mortality of CVD has been revealed. This J-shaped association’s implications for CVD prevention and treatment are deserving of being further studied.

Smartphone technology has been recently applied for biomedical image acquisition and data analysis due to its high-quality imaging capability, and flexibility to customize multi-purpose apps. In this work, we developed and characterized a smartphone-microfluidic fluorescence imaging system for studying the physiology of pancreatic islets. We further evaluated the system capability by performing real-time fluorescence imaging on mouse islets labeled with either chemical fluorescence dyes or genetically encoded fluorescent protein indicators (GEFPIs). Our results showed that the system was capable of analyzing key beta-cell insulin stimulator-release coupling factors in response to various stimuli with high-resolution dynamics. Furthermore, the integration of a microfluidics allowed high-resolution detection of insulin secretion at single islet level. When compared to conventional fluorescence microscopes and macro islet perifusion apparatus, the system has the advantages of low cost, portable, and easy to operate. With all of these features, we envision that this smartphone-microfluidic fluorescence imaging system can be applied to study islet physiology and clinical applications.

BackgroundRosai–Dorfman disease (RDD) is a rare benign non-Langerhans cell histiocytic proliferative disease. RDD with central nervous system (CNS) involvement (CNS-RDD) is extremely rare. Its etiology is unclear, and there are no consensus recommendations for its treatment. More studies are needed to elucidate the clinical and radiological manifestations and prognosis of CNS-RDD.MethodsFrom January 2012 to June 2022, 12 patients with CNS-RDD (intracranial or spinal) were retrospectively evaluated, including collecting clinical data, imaging data, and pathological findings; summarizing imaging characteristics; and conducting follow-up studies on CND-RDD patient treatment and prognosis.ResultsTwelve CNS-RDD patients (nine male and three female patients, aged 12–67 years) were enrolled in this study. Nine patients represented convex and/or skull base RDD (eight with edema, six with lobulation and/or pseudopodium sign, four with multiple intracranial lesions), two patients had parenchymal RDD, and one patient had spinal cord subdural lesions. Symptoms of patients would vary according to the locations of the lesion, including but not limited to headaches, dizziness, seizures, cranial nerve dysfunction, and visual impairment. The immunohistochemistry of RDD showed positive expression of S100 and CD68 but not CD1a. Total resection (n = 7), subtotal resection (n = 3), partial resection (n = 1), and stereotaxic biopsy (n = 1) were achieved, respectively. A combination of chemotherapy plus steroid therapy was performed on two patients (relapsing case and residual lesion) and showed a remarkable effect.ConclusionCNS-RDD, as a rare disease, presents a significant diagnostic challenge for clinicians. Solitary CNS-RDD are easily misdiagnosed as meningioma. However, when the MRI imaging of the disease represents dura-based masses with significant edema, homogeneous enhancement, lobulation, and/or pseudopodium sign, we should consider it might be the CNS-RDD. Surgery is an important and effective therapy for CNS-RDD. Steroids and chemotherapy are safe and effective for the postoperative treatment of relapsing cases or residual lesions.

ObjectiveThe aim of this study is to explore efficacy and safety for radiofrequency ablation (RFA) among cases attacked by large benign solid thyroid nodules, mainly focusing on volume reduction, complication rate, and thyroid function.Methods and materialsFrom June 2015 to November 2019, 24 patients with 25 large benign solid thyroid nodules (more than 25 ml) underwent single or sequential RFA in our institution. Eleven nodules achieved complete ablation after single RFA, whereas the other 14 nodules received sequential RFA. Volume reduction in large nodules was evaluated. Following single or sequential RFA, all patients received clinical and ultrasound evaluations, and the median follow-up duration among them was 23.5 months. Technical success, complication rate, and recurrence rate were assessed as well.ResultsIn single RFA group, volume reduction ranged from 62.6% to 99.4% (mean ± SD, 93.6 ± 9.9%) 6 months after RFA. In sequential RFA group, volume reduction ranged from 30.6% to 92.9% (mean ± SD, 67.4 ± 17.8%) after the first RFA and was between 83.4% and 98.4% (mean ± SD, 94.8± 3.8%) 6 months after the second RFA. The concentrations of FT3 and FT4 increased slightly 1 day after RFA and returned to normal level 1 month after.ConclusionsSingle or sequential RFA is safe and effective in treating large benign solid thyroid nodules (more than 25 ml) that cause obvious compressive symptoms. Hence, compression symptoms and cosmetic conditions could be effectively improved through single or sequential RFA without marginal recurrence.

ObjectiveTo search for significant biomarkers associated with sudden death (SD).MethodsDifferential genes were screened by comparing the whole blood samples from 15 cases of accidental death (AD) and 88 cases of SD. The protein-protein interaction (PPI) network selects core genes that interact most frequently. Machine learning is applied to find characteristic genes related to SD. The CIBERSORT method was used to explore the immune-microenvironment changes.ResultsA total of 10 core genes (MYL1, TNNC2, TNNT3, TCAP, TNNC1, TPM2, MYL2, TNNI1, ACTA1, CKM) were obtained and they were mainly related to myocarditis, hypertrophic myocarditis and dilated cardiomyopathy (DCM). Characteristic genes of MYL2 and TNNT3 associated with SD were established by machine learning. There was no significant change in the immune-microenvironment before and after SD.ConclusionDetecting characteristic genes is helpful to identify patients at high risk of SD and speculate the cause of death.

Objectives: .Asthma is a highly heterogeneous disease, and T-helper cell type 17 (Th17) cells play a pathogenic role in the development of non-T2 severe asthma. Misshapen like kinase 1 (MINK1) is involved in the regulation of Th17 cell differentiation, but its effect on severe asthma remains unclear. Our previous studies showed that methyl-CpG binding domain protein 2 (MBD2) expression was significantly increased in patients with Th17 severe asthma and could regulate Th17 cell differentiation. The aim of this study was to investigate how MBD2 interacts with MINK1 to regulate Th17 cell differentiation in Th17-dominant asthma.Materials and methods: Female C57BL/6 mice and bronchial epithelial cells (BECs) were used to establish mouse and cell models of Th17-dominant asthma, respectively. Flow cytometry was used to detect Th17 cell differentiation, and the level of IL-17 was detected by enzyme-linked immunosorbent assay (ELISA). Western blot and quantitative real-time PCR (qRT-PCR) were used to detect MBD2 and MINK1 expression. To investigate the role of MBD2 and MINK1 in Th17 cell differentiation in Th17-dominant asthma, the MBD2 and MINK1 genes were silenced or overexpressed by small interfering RNA and plasmid transfection.Results: Mouse and BEC models of Th17-dominant asthma were established successfully. The main manifestations were increased neutrophils in BALF, airway hyperresponsiveness (AHR), activated Th17 cell differentiation, and high IL-17 levels. The expression of MBD2 in lung tissues and BECs from the Th17-dominant asthma group was significantly increased, while the corresponding expression of MINK1 was significantly impaired. Through overexpression or silencing of MBD2 and MINK1 genes, we have concluded that MBD2 and MINK1 regulate Th17 cell differentiation and IL-17 release. Interestingly, MBD2 was also found to negatively regulate the expression of MINK1.Conclusion: Our findings have revealed new roles for MBD2 and MINK1, and provide new insights into epigenetic regulation of Th17-dominant asthma, which is dominated by neutrophils and Th17 cells. This study could lead to new therapeutic targets for patients with Th17-dominant asthma.

BackgroundWe have recently developed the Coronary Artery Tree description and Lesion EvaluaTion (CatLet©) angiographic scoring system, which is capable of accounting for the variability in coronary anatomy, and risk-stratifying patients with coronary artery disease. This study aimed to clarify whether the CatLet score had a predictive value for long-term prognosis in patients with acute myocardial infarction (AMI) presenting > 12 h after symptom onset.Materials and methodsThe CatLet score was calculated for 1,018 consecutively enrolled AMI patients, who were divided into 3 groups according to the CatLet score tertiles. The primary endpoint was major adverse cardiac events (MACEs), defined as a composite of myocardial infarction, cardiac death, and ischemia-driven revascularization; secondary endpoints were all-cause death, cardiac death, myocardial infarction, and ischemia-driven revascularization.ResultsThe CatLet score was capable of predicting long-term prognosis at a median 4.9-year follow-up alone or after adjustment for risk factors. Multivariable-adjusted hazard ratios (95% CI)/unit higher score were 1.06 (1.05–1.08) for MACEs, 1.05 (1.03–1.07) for all-cause death, 1.06 (1.04–1.09) for cardiac death, 1.06 (1.04–1.08) for myocardial infarction, and 1.06 (1.04–1.08) for revascularization. The univariate model showed good calibration (χ2 = 8.25, P = 0.4091) and good discrimination (area under ROC curve = 0.7086) for MACEs.ConclusionThe CatLet score is an independent predictor of long-term clinical outcomes of patients with AMI presenting > 12 h after symptom onset (http://www.chictr.org.cn; Registry Number: ChiCTR2000033730).

Background: Previous observational studies have suggested the involvement of 25-hydroxyvitamin D [25(OH)D] in chronic pain. However, whether the 25(OH)D is a novel target for management, the causality remains unclear.Methods: A two-sample Mendelian randomization (MR) study was conducted to identify the causal association between 25(OH)D and low back pain (LBP). The primary analysis was revealing causality from serum 25(OH)D level (n = 417,580) on LBP (21,140 cases and 227,388 controls). The replicated analysis was performing MR estimates from circulating 25(OH)D concentration (n = 79,366) on LBP experienced last month (118,471 cases and 343,386 controls). Inverse variance weighted (IVW) was used as the main analysis. In addition, we used weighted median and MR-Egger to enhance the robustness. Sensitivity analysis was conducted to evaluate the robustness of MR results.Results: IVW estimation indicated strong evidence that higher serum 25(OH)D levels exerted a protective effect on LBP (OR = 0.89, 95% CI = 0.83–0.96, p = 0.002). Similar trends were also found in replicate analysis (OR = 0.98, 95% CI = 0.96–1.00, p = 0.07). After meta-analysis combining primary and replicated analysis, the causal effect is significant (p = 0.03). Sensitivity analysis supported that the MR estimates were robust.Conclusion: In our MR study, genetically increased serum 25(OH)D levels were associated with a reduced risk of LBP in the European population. This might have an implication for clinicians that vitamin D supplements might be effective for patients with LBP in clinical practice.

There is a positive association between air pollution and lung cancer burden. This study aims to identify and examine lung cancer risks and mortality burdens associated with air pollutants, including PM10, NO2 and SO2, in seven eastern metropolises of China. The study population comprised a population from seven eastern metropolises of China. The yearly average values (YAV, μg/m3) of the PM10, NO2 and SO2 levels were extracted from China Statistical Yearbook (CSYB) for each selected city from 2006 to 2014. Data collected in the China Cancer Registry Annual Report (CCRAR) provide lung cancer incidence and mortality information. A two-level normal random intercept regression model was adopted to analyze the association between the lung cancer rates and individual air pollutant concentration within a five-year moving window of past exposure. The yearly average values of PM10, SO2 and NO2 significantly decreased from 2006 to 2014. Consistently, the male age-adjusted incidence rate (MAIR) and male age-adjusted mortality rate (MAMR) decreased significantly from 2006 to 2014.Air pollutants have a lag effect on lung cancer incidence and mortality for 2-3 years. NO2 has the significant association with MAIR (RR=1.57, 95% CI: 1.19-2.05, p=0.002), MAMR (RR=1.70, 95% CI: 1.32-2.18, p=0.0002) and female age-adjusted mortality rate (FAMR) (RR=1.27, 95% CI: 1.08-1.49, p=0.003). Our findings suggested that air pollutants may be related to the occurrence and mortality of lung cancer. NO2 was significantly associated with the risk of lung cancer, followed by SO2. Air pollutants have the strongest lag effect on the incidence and mortality of lung cancer within 2-3 years.

BackgroundWe aimed to assess the differences in the gut microbiome among participants with different uric acid levels (hyperuricemia [HUA] patients, low serum uric acid [LSU] patients, and controls with normal levels) and to develop a model to predict HUA based on microbial biomarkers.MethodsWe sequenced the V3-V4 variable region of the 16S rDNA gene in 168 fecal samples from HUA patients (n=50), LSU patients (n=61), and controls (n=57). We then analyzed the differences in the gut microbiome between these groups. To identify gut microbial biomarkers, the 107 HUA patients and controls were randomly divided (2:1) into development and validation groups and 10-fold cross-validation of a random forest model was performed. We then established three diagnostic models: a clinical model, microbial biomarker model, and combined model.ResultsThe gut microbial α diversity, in terms of the Shannon and Simpson indices, was decreased in LSU and HUA patients compared to controls, but only the decreases in the HUA group were significant (P=0.0029 and P=0.013, respectively). The phylum Proteobacteria (P