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Abstract Background The function of hematopoietic stem cells (HSC) is regulated by HSC internal signaling pathways and their microenvironment. Chemokines and chemokine ligands play important roles in the regulation of HSC function. Yet, their functions in HSC are not fully understood. Methods We established Cxcr3 and Cxcl10 knockout mouse models (Cxcr3 −/− and Cxcl10 −/− ) to analyze the roles of Cxcr3 or Cxcl10 in regulating HSC function. The cell cycle distribution of LT-HSC was assessed via flow cytometry. Cxcr3 −/− and Cxcl10 −/− stem/progenitor cells showed reduced self-renewal capacity as measured in serial transplantation assays. To study the effects of Cxcr3 or Cxcl10 deficient bone marrow microenvironment, we transplanted CD45.1 donor cells into Cxcr3 −/− or Cxcl10 −/− recipient mice (CD45.2) and examined donor-contributed hematopoiesis. Results Deficiency of Cxcl10 and its receptor Cxcr3 led to decreased BM cellularity in mice, with a significantly increased proportion of LT-HSC. Cxcl10 −/− stem/progenitor cells showed reduced self-renewal capacity in the secondary transplantation assay. Notably, Cxcl10 −/− donor-derived cells preferentially differentiated into B lymphocytes, with skewed myeloid differentiation ability. Meanwhile, Cxcr3-deficient HSCs demonstrated a reconstitution disadvantage in secondary transplantation, but the lineage bias was not significant. Interestingly, the absence of Cxcl10 or Cxcr3 in bone marrow microenvironment did not affect HSC function. Conclusions The Cxcl10 and Cxcr3 regulate the function of HSC, including self-renewal and differentiation, adding to the understanding of the roles of chemokines in the regulation of HSC function.

Acute myeloid leukemia (AML) is a common hematological malignancy with overall poor prognosis. Exploring novel targets is urgent and necessary to improve the clinical outcome of relapsed and refractory (RR) AML patients. Through clinical specimens, animal models and cell-level studies, we explored the specific mechanism of 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1) in AML and the mechanism of targeting HMGCS1 to attenuate cell proliferation, increase chemotherapy sensitivity and improve the occurrence and development of AML. Here, we reveal that HMGCS1 is overexpressed in RR patients and negatively related to overall survival (OS). Knocking out HMGCS1 in AML cells attenuated cell proliferation and increased chemotherapy sensitivity, while stable overexpression of HMGCS1 had the opposite effects. Mechanistically, we identified that knockout of HMGCS1 suppressed mitogen-activated protein kinase (MAPK) pathway activity, while overexpression of HMGCS1 could remarkably enhance the pathway. U0126, a MEK1 inhibitor, offset the effects of HMGCS1 overexpression, indicating that HMGCS1 promotes RR AML through the MAPK pathway. Further, we verified that hymeglusin, a specific inhibitor of HMGCS1, decreases cell growth both in AML cell lines and primary bone marrow cells of AML patients. Furthermore, combination of hymeglusin and the common chemotherapeutic drug cytarabine and adriamycin (ADR) had synergistic toxic effects on AML cells. Our study demonstrates the important role of HMGCS1 in AML, and targeting this protein is promising for the treatment of RR AML.

Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy. Cannabidiol (CBD) is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects, including neuroprotective, antiemetic, anti-inflammatory, and antineoplastic activities. This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) technologies. Here, we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment (TME). Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity. Furthermore, CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages, thereby preventing tumor progression. Mechanistically, CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways. We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes. Furthermore, CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1 (PD-1) immunotherapy in xenografted mice. Taken together, we provide new insights into the anti-tumor effects of CBD.

The effect of drought stress on carbon metabolism in the leaves and roots of bermudagrass was investigated. Plants established in PVC tubes suffered from three water treatments for 10 days. C138 and Tifway (drought-tolerant) were found to have lower relative electrical conductivity and higher water use efficiency than C32 (drought-sensitive) under moderate drought by increasing carotenoid and soluble sugar content and rapidly decreasing leaf starch content. The sucrose synthase activity of leaves and roots, acid invertase and neutral invertase activity of C32 roots substantially decreased under severe drought, resulting in a slow sucrose decomposition rate and significantly lower fructose and glucose contents than C138 and Tifway. The activities of four carbon metabolism enzymes and sucrose content in the leaves were greater than those in the roots, while the fructose and glucose contents were on the contrary, indicating that bermudagrass transported fructose and glucose obtained from sucrose decomposition from leaves to roots under drought to reduce roots damage. The path analysis indicated that leaves neutral invertase activity, and roots soluble sugar content might be the key parameter of carbon metabolism in bermudagrass under drought.

Summary: Tumors maintain an alkaline intracellular environment to enable rapid growth. The proton exporter NHE1 participates in maintenance of this pH gradient. However, whether targeting NHE1 could inhibit the growth of tumor cells remains unknown. Here, we report that the NHE1 inhibitor Hexamethylene amiloride (HA) efficiently suppresses the growth of AML cell lines. Moreover, HA combined with venetoclax synergized to efficiently inhibit the growth of AML cells. Interestingly, lysosomes are the main contributors to the synergism of HA and venetoclax in inhibiting AML cells. Most importantly, the combination of HA and venetoclax also had prominent anti-leukemia effects in both xenograft models and bone marrow samples from AML patients. In summary, our results provide evidence that the NHE1 inhibitor HA or its combination with venetoclax efficiently inhibits the growth of AML in vitro and in vivo.

Ginger (Zingiber officinale Roscoe) is an important vegetable with medicinal value. Rhizome development determines ginger yield and quality. However, little information is available about the molecular features underlying rhizome expansion and maturation. In this study, we investigated anatomy characteristics, lignin accumulation and transcriptome profiles during rhizome development. In young rhizomes, the vascular bundle (VB) was generated with only vessels in it, whereas in matured rhizomes, three to five layers of fibre bundle in the xylem were formed, resulting in VB enlargement. It indicates VB development favouring rhizome swelling. With rhizome matured, the lignin content was remarkably elevated, thus facilitating tissue lignification. To explore the regulators for rhizome development, nine libraries including ginger young rhizomes (GYR), growing rhizomes (GGR), and matured rhizomes (GMR) were established for RNA-Seq, a total of 1264 transcription factors (TFs) were identified. Among them, 35, 116, and 14 differentially expressed TFs were obtained between GYR and GGR, GYR and GMR, and GGR and GMR, respectively. These TFs were further divided into three categories. Among them, three ZobHLHs (homologs of Arabidopsis LHW and AtbHLH096) as well as one DIVARICATA homolog in ginger might play crucial roles in controlling VB development. Four ZoWRKYs and two ZoNACs might be potential regulators associated with rhizome maturation. Three ZoAP2/ERFs and one ZoARF might participate in rhizome development via hormone signalling. This result provides a molecular basis for rhizome expansion and maturation in ginger.

Wheat bran-based food is rich in bioactive compounds, and steam explosion enhances the nutritional properties of wheat bran. This study examined the potential utilization of steam-exploded wheat bran (SWB) in cookie formulation. The influence of steam explosion on the chemical compounds in wheat bran and the effects of SWB on the physical properties, antioxidant capacity, and starch digestibility of cookies were investigated. The results showed that steam explosion facilitated the release of reducing sugar, flavonoids, phenolic substances, and amino acid nitrogen in wheat bran, thereby improving its nutritional properties. The reduction of sugar, total flavonoids, total phenolics, and amino acid nitrogen contents of wheat bran after steam explosion increased by 34.22, 183.02, 284.09, and 93.39%, respectively, compared with those of native wheat bran. Substitution of SWB for wheat flour mainly induced higher water, sodium carbonate, and sucrose solvent retention capacities, which were positively related to the spread ratio and hardness of cookies. The cookies with more SWB substitution (30–50%) expressed a higher spread ratio and harder texture than the others. The substitution of SWB caused changes in the antioxidant properties of cookies, which were related to the phenolic content. The cookies with SWB showed a higher DPPH radical scavenging activity (16.30–30.93%) than that of the control (14.74%). SWB might form a matrix barrier to hinder starch digestion, thus reducing the digestibility of cookies. The cookies enriched with 30–50% of the SWB exhibited greater physical properties and antioxidant capacity but lower starch digestibility than those of other cookies. The results will contribute to expanding the application range and improving the quality of bran-rich flour products.

As a typical dioecious species, Zanthoxylum armatum establishes apomictic reproduction, hence only female trees are cultivated. However, male and hermaphrodite flowers have recently appeared in female plants, resulting in a dramatic yield reduction. To date, the genetic basis underlying sex determination and apomixis in Z. armatum has been largely unknown. Here, we observed abortion of the stamen or carpel prior to primordium initiation, thus corroborating the potential regulation of MADS-box in sex determination. In Z. armatum, a total of 105 MADS-box genes were identified, harboring 86 MIKC-type MADSs with lack of FLC orthologues. Transcriptome analysis revealed candidate MADSs involved in floral organ identity, including ten male-biased MADSs, represented by ZaMADS92/81/75(AP3/PI-like), and twenty-six female-specified, represented by ZaMADS80/49 (STK/AGL11-like) and ZaMADS42 (AG-like). Overexpressing ZaMADS92 resulted in earlier flowering, while ZaMADS80 overexpression triggered precocious fruit set and parthenocarpy as well as dramatic modifications in floral organs. To characterize their regulatory mechanisms, a comprehensive protein-protein interaction network of the represented MADSs was constructed based on yeast two-hybrid and bimolecular fluorescence complementation assays. Compared with model plants, the protein interaction patterns in Z. armatum exhibited both conservation and divergence. ZaMADS70 (SEP3-like) interacted with ZaMADS42 and ZaMADS48 (AP3-like) but not ZaMADS40 (AP1-like), facilitating the loss of petals in Z. armatum. The ZaMADS92/ZaMADS40 heterodimer could be responsible for accelerating flowering in ZaMADS92-OX lines. Moreover, the interactions between ZaMADS80 and ZaMADS67(AGL32-like) might contribute to apomixis. This work provides new insight into the molecular mechanisms of MADS-boxes in sex organ identity in Z. armatum.

Background The loss of tumor antigens and depletion of CD8 T cells caused by the PD-1/PD-L1 pathway are important factors for tumor immune escape. In recent years, there has been increasing research on traditional Chinese medicine in tumor treatment. Cycloastragenol (CAG), an effective active molecule in Astragalus membranaceus, has been found to have antiviral, anti-aging, anti-inflammatory, and other functions. However, its antitumor effect and mechanism are not clear.Methods The antitumor effect of CAG was investigated in MC38 and CT26 mouse transplanted tumor models. The antitumor effect of CAG was further analyzed via single-cell multiomics sequencing. Target responsive accessibility profiling technology was used to find the target protein of CAG. Subsequently, the antitumor mechanism of CAG was explored using confocal microscopy, coimmunoprecipitation and transfection of mutant plasmids. Finally, the combined antitumor effect of CAG and PD-1 antibodies in mice or organoids were investigated.Results We found that CAG effectively inhibited tumor growth in vivo. Our single-cell multiomics atlas demonstrated that CAG promoted the presentation of tumor cell-surface antigens and was characterized by the enhanced killing function of CD8+ T cells. Mechanistically, CAG bound to its target protein cathepsin B, which then inhibited the lysosomal degradation of major histocompatibility complex I (MHC-I) and promoted the aggregation of MHC-I to the cell membrane, boosting the presentation of the tumor antigen. Meanwhile, the combination of CAG with PD-1 antibody effectively enhanced the tumor killing ability of CD8+ T cells in xenograft mice and colorectal cancer organoids.Conclusion Our data reported for the first time that cathepsin B downregulation confers antitumor immunity and explicates the antitumor mechanism of natural product CAG.

Ground moving targets with slow velocity and low radar cross-section (RCS) are usually embedded in the clutter Doppler spectrum. To achieve the detection and estimation of such targets, a novel method operating in the range-Doppler domain is developed for airborne multichannel radar systems. The interferometric phases that are sensitive to moving targets are obtained by coherent difference processing (CDP) for target detection. Moreover, the amplitude is utilized as complementary information to improve the detection performance. Then, a matched filter bank is designed and applied to the CDP processed data to complete the parameter estimation. The proposed method provides the benefits of high efficiency and robustness, since it does not involve matrix inversion, and it does not require homogeneous clutter assumption unlike adaptive algorithms. Experiments on real data acquired by an airborne X-band four-channel radar system demonstrate its effectiveness.

Introduction Severe hyperbilirubinaemia in newborns can be easily complicated by acute bilirubin encephalopathy or even kernicterus, which could lead to neurological sequelae or death. However, there is no systematic study of the management of severe hyperbilirubinaemia in China. The Neonatal Severe Hyperbilirubinemia Online Registry study aims to investigate the management of jaundice before admission, risk factors and outcomes of severe hyperbilirubinaemia in a real-world setting in China.Methods and analysis This is a prospective, multicentre, open, observational cohort study. From May 2020 to April 2023, more than 2000 patients with neonatal severe hyperbilirubinaemia from 13 tertiary hospitals in Jiangsu Province will join the study. Demographic data and treatment information will be collected from their clinical data. Management measures for jaundice before admission will be collected by the WeChat applet (called ‘Follow-up of jaundice’) after being provided by the patient’s guardian using a mobile phone. Follow-up data will include cranial MRI examination results, brainstem auditory-evoked potential or automatic auditory brainstem response, physical examination results and Griffiths Development Scales-Chinese at the corrected ages of 3–6 months and 1 and 2 years. Results and conclusions will be recorded using ‘Follow-up of jaundice.’ In-hospital outcomes, including severity of hyperbilirubinaemia (severe, extreme, hazardous), acute bilirubin encephalopathy (mild, moderate, severe) and survival status (death or survival), will be collected at discharge. Follow-up outcomes will include loss to follow-up, survival status and kernicterus (yes or no) at 2 years. The research will enhance our comprehensive knowledge of jaundice management before admission, risk factors and outcomes of severe hyperbilirubinaemia in China, which will ultimately help to reduce the incidence of neonatal severe hyperbilirubinaemia.Ethics and dissemination Our protocol has been approved by the Medical Ethics Committee of Nanjing Maternity and Child Health Care Hospital. We will present our findings at national conferences and peer-reviewed paediatrics journals.Trial registration number NCT04251286.

Introduction Thoracic endovascular aortic repair (TEVAR) has gradually become the mainstream therapy for aortic arch pathologies (AAP). Our centre developed the in situ fenestration (ISF) system according to years of clinical experience and technological innovation. This study aims to evaluate the safety and effectiveness of the innovative, self-developed ISF system in TEVAR for AAP.Methods and analysis The study is a prospective, multicentre and single-arm study. Patients diagnosed with AAPs in five centres on 1 January 2021 will be recruited and general TEVAR with ISF system will be performed. Clinical information and CT angiography images will be collected and recorded. Patients will be followed up for 5 years. Safety and efficacy endpoints are planned to be reported to evaluate this self-developed ISF system.Ethics and dissemination The study is a registry. We have registered the study on the Chinese Clinical Trial Registry website (http://www.chictr.org.cn/). This study has been approved by the Ethics Committee of Zhongshan Hospital Fudan University (B2020-371) and individual consents will be signed at the time of enrolment. We anticipate that this self-developed ISF system will result in favourable social and economic benefits. Findings will be disseminated in peer-reviewed journals to provide reference for future clinical practice.Trial registration number ChiCTR1900026696.

Background: Newborn infants who are risk for severe hyperbilirubinemia and cared at home should be monitored for progression of jaundice. We aimed to verify if a smart phone application (BiliScan Inc), which uses automated imaging for bilirubin (AIB), can be used to estimate total serum bilirubin (TSB) levels at home. Methods: A convenience sample of 1038 “healthy” infants in China were prospectively enrolled to a single-center study in 2016. Correlations between AIB and TcB measurements were correlated to TB measurements. Bias and imprecision of AIB measurements were determined using Bland-Altman analysis. The diagnostic value of AIB was compared by the area-under-curve (AUC) values of receiver operator characteristic (ROC) curves. Results: The best correlation and AUC for AIB were at the sternum, both with values of 0.76. We truncated performances to 369 TB values >5 and 13.5 mg/dL (n=369 babies), the sensitivity and negative predictive value (NPV) were 100% with a specificity of 50%. Furthermore, Bland-Altman analyses showed a bias and imprecision of AIB and TcB when TB was >13.5 and

The post-Doppler adaptive matched filter (PD-AMF) with constant false alarm rate (CFAR) property was developed for adaptive detection of moving targets, which is a standardized version of the post-Doppler space–time adaptive processing (PD-STAP) in practical applications. However, its detection performance is severely constrained by the training data, especially in a dense signal environment. Improper training data and contamination of moving target signals remarkably degrade the performance of disturbance suppression and result in target cancellation by self-whitening. To address these issues, a novel post-Doppler parametric adaptive matched filter (PD-PAMF) detector is proposed in the range-Doppler domain. Specifically, the detector is introduced via the post-Doppler matched filter (PD-MF) and the lower-diagonal-upper (LDU) decomposition of the disturbance covariance matrix, and the disturbance signals of the spatial sequence are modelled as an auto-regressive (AR) process for filtering. The purpose of detecting ground moving targets as well as for estimating their geographical positions and line-of-sight velocities is achieved when the disturbance is suppressed. The PD-PAMF is able to reach higher performances by using only a smaller training data size. More importantly, it is tolerant to moving target signals contained in the training data. The PD-PAMF also has a lower computational complexity. Numerical results are presented to demonstrate the effectiveness of the proposed detector.

The Gaussian vertical backscatter (GVB) model has a pivotal role in describing the forest vertical structure more accurately, which is reflected by P-band polarimetric interferometric synthetic aperture radar (Pol-InSAR) with strong penetrability. The model uses a three-dimensional parameter space (forest height, Gaussian mean representing the strongest backscattered power elevation, and the corresponding standard deviation) to interpret the forest vertical structure. This paper establishes a two-dimensional GVB model by simplifying the three-dimensional one. Specifically, the two-dimensional GVB model includes the following three cases: the Gaussian mean is located at the bottom of the canopy, the Gaussian mean is located at the top of the canopy, as well as a constant volume profile. In the first two cases, only the forest height and the Gaussian standard deviation are variable. The above approximation operation generates a two-dimensional volume only coherence solution space on the complex plane. Based on the established two-dimensional GVB model, the three-baseline inversion is achieved without the null ground-to-volume ratio assumption. The proposed method improves the performance by 18.62% compared to the three-baseline Random Volume over Ground (RVoG) model inversion. In particular, in the area where the radar incidence angle is less than 0.6 rad, the proposed method improves the inversion accuracy by 34.71%. It suggests that the two-dimensional GVB model reduces the GVB model complexity while maintaining a strong description ability.

This paper investigates the potential of the time-frequency optimization on the basis of the sublook decomposition for forest height estimation. The optimization is deemed to be capable of extracting a relatively accurate volume contribution when P-band polarimetric interferometric synthetic aperture radar (Pol-InSAR) systems are adopted to observe forest-covered areas. The highest and the lowest phase centers acquired by the time-frequency optimization modify the conventional three-stage inversion process. This paper presents, for the first time, a performance assessment of the time-frequency optimization on P-band Pol-InSAR data over boreal forests. Simultaneously, to alleviate the model inversion errors caused by topographic fluctuations, forest height is estimated based on the sloped Random Volume over Ground (S-RVoG) model in which the incidence angle is corrected with the terrain slope. The E-SAR P-band Pol-InSAR data acquired during the BIOSAR 2008 campaign in Northern Sweden is utilized to evaluate the performance of the proposed method. From the results of the forest height estimation preprocessed with time-frequency optimization, the root mean square error (RMSE) of Random Volume over Ground (RVoG) and S-RVoG model on negative slope are 5.09 m and 4.71 m, respectively. It is concluded that the time-frequency processing and negative terrain slope compensation improve the inversion performance by 41 . 49 % and 11 . 96 % , respectively.

Overweight/obesity in women of childbearing age is a serious public-health problem. In China, the incidence of maternal overweight/obesity has been increasing. However, there is not a meta-analysis to determine if pre-pregnancy body mass index (BMI) is related to infant birth weight (BW) and offspring overweight/obesity.Three electronic bibliographic databases (MEDLINE, EMBASE and CINAHL) were searched systematically from January 1970 to November 2012. The dichotomous data on pre-pregnancy overweight/obesity and BW or offspring overweight/obesity were extracted. Summary statistics (odds ratios, ORs) were used by Review Manager, version 5.1.7.After screening 665 citations from three electronic databases, we included 45 studies (most of high or medium quality). Compared with normal-weight mothers, pre-pregnancy underweight increased the risk of small for gestational age (SGA) (odds ratios [OR], 1.81; 95% confidence interval [CI], 1.76-1.87); low BW (OR, 1.47; 95% CI, 1.27-1.71). Pre-pregnancy overweight/obesity increased the risk of being large for gestational age (LGA) (OR, 1.53; 95% CI, 1.44-1.63; and OR, 2.08; 95% CI; 1.95-2.23), high BW (OR, 1.53; 95% CI, 1.44-1.63; and OR, 2.00; 95% CI; 1.84-2.18), macrosomia (OR, 1.67; 95% CI, 1.42-1.97; and OR, 3.23; 95% CI, 2.39-4.37), and subsequent offspring overweight/obesity (OR, 1.95; 95% CI, 1.77-2.13; and OR, 3.06; 95% CI, 2.68-3.49), respectively. Sensitivity analyses revealed that sample size, study method, quality grade of study, source of pre-pregnancy BMI or BW had a strong impact on the association between pre-pregnancy obesity and LGA. No significant evidence of publication bias was observed.Pre-pregnancy underweight increases the risk of SGA and LBW; pre-pregnancy overweight/obesity increases the risk of LGA, HBW, macrosomia, and subsequent offspring overweight/obesity. A potential effect modification by maternal age, ethnicity, gestational weight gain, as well as the role of gestational diseases should be addressed in future studies.