PCSK5 downregulation promotes the inhibitory effect of andrographolide on glioblastoma through regulating STAT3.

Proprotein convertase subtilisin/kexin type 5 (PCSK5) is a member of the proprotein convertase (PC) family, which processes immature proteins into functional proteins and plays an important role in the process of cell migration and transformation. Andrographolide is a non-peptide compound with PC inhibition and antitumor activity. Our research aimed to investigate the functional role of PCSK5 downregulation combined with Andro on GBM progression. Results from the cancer genome atlas (TCGA) and clinical samples revealed a significant upregulation of PCSK5 in GBM tissues than in non-tumor brain tissues. Higher expression of PCSK5 was correlated with advanced GBM stages and worse patient prognosis. PCSK5 knockdown attenuated the epithelial-mesenchymal transition (EMT)-like properties of GBM cells induced by IL-6. PCSK5 knockdown in combination with Andro treatment significantly inhibited the proliferation and invasion of GBM cells in vitro, as well as tumor growth in vivo. Mechanistically, PCSK5 downregulation reduced the expression of p-STAT3 and Matrix metalloproteinases (MMPs), which could be rescued by the p-STAT3 agonist. STAT3 silencing downregulated the expression of MMPs without affecting PCSK5. Furthermore, Andro in combination with PCSK5 silencing significantly inhibited STAT3/MMPs axis. These observations provided evidence that PCSK5 functioned as a potential tumor promoter by regulating p-STAT3/MMPs and the combination of Andro with PCSK5 silencing might be a good strategy to prevent GBM progression.

Assembling all-wood-derived carbon/carbon dots-assisted phase change materials for high-efficiency thermal-energy harvesters.

The collection and storage of renewable, sustainable and clean energy including wind, solar, and tidal energy has attracted considerable attention because of its promising potential to replace fossil energy sources. Advanced energy-storage materials are the core component for energy harvesters, affording the high-efficiency conversion of these new-style energy sources. Herein, originated from nature, a series of all-wood-derived carbon-assisted phase change materials (PCMs) were purposed by incorporating carbon dots-modified polyethylene glycol matrix into carbon skeletons via a vacuum-impregnation strategy. The resultant PCMs possessed desired anti-leakage capability and superior thermophysical behaviors. In particular, the optimum sample posed high latent heat (131.5 J/g) and well thermal stability, where the corresponding enthalpy still reserved 90 % over 100 heating/cooling cycles. More importantly, the as-fabricated thermal-energy harvester presented prominent capability to strorage and release multiple forms of thermal energy, as well as high-efficiency solar-energy utilization, corresponding to a photothermal conversion efficiency of 88 % in simulated sunlight irradiation, far exceeding some reported PCMs. Overall, with the introduction of wood-derived carbon dots and carbon skeletons, the assembled all-wood-derived carbon-assisted PCMs afforded trinity advantages on thermal performance, cycling stability, and energy conversion efficiency, which provide a promising potential for the practical application in thermal-energy harvesters.

Hematopoietic aging: cellular, molecular, and related mechanisms.

ABSTRACT: Aging is accompanied by significant inhibition of hematopoietic and immune system function and disruption of bone marrow structure. Aging-related alterations in the inflammatory response, immunity, and stem cell niches are at the root of hematopoietic aging. Understanding the molecular mechanisms underlying hematopoietic and bone marrow aging can aid the clinical treatment of aging-related diseases. In particular, it is unknown how the niche reprograms hematopoietic stem cells (HSCs) in an age-dependent manner to maintain normal hematopoiesis in elderly individuals. Recently, specific inhibitors and blood exchange methods have been shown to reshape the hematopoietic niche and reverse hematopoietic aging. Here, we present the latest scientific discoveries related to hematopoietic aging and hematopoietic system rejuvenation, discuss the relationships between hematopoietic niche aging and HSC aging, and describe related studies on stem cell-mediated regulation of hematopoietic aging, aiming to provide new ideas for further study.

Downregulation of MAL2 inhibits breast cancer progression through regulating ß-catenin/c-Myc axis.

PURPOSE: Myelin and lymphocyte protein 2 (MAL2) is mainly involved in endocytosis under physiological conditions and mediates the transport of materials across the membranes of cell and organelle. It has been reported that MAL2 is significantly upregulated in diverse cancers. This study aimed to investigate the role of MAL2 in breast cancer (BC). METHODS: Bioinformatics analysis and Immunohistochemical assay were applied to detect the correlation between MAL2 expression in breast cancer tissues and the prognosis of breast cancer patients. Functional experiments were carried out to investigate the role of MAL2 in vitro and in vivo. The molecular mechanisms involved in MAL2-induced ß-catenin and c-Myc expression and ß-catenin/c-Myc-mediated enhancement of BC progression were confirmed by western blot, ß-catenin inhibitor and agonist, Co-IP and immunofluorescence colocalization assays. RESULTS: Results from the cancer genome atlas (TCGA) and clinical samples confirmed a significant upregulation of MAL2 in BC tissues than in adjacent non-tumor tissues. High expression of MAL2 was associated with worse prognosis. Functional experiments demonstrated that MAL2 knockdown reduced the migration and invasion associating with EMT, increased the apoptosis of BC cells in vitro and reduced the metastatic capacity in vivo. Mechanistically, MAL2 interacts with ß-catenin in BC cells. MAL2 silencing reduced the expression of ß-catenin and c-Myc, while the ß-catenin agonist SKL2001 partially rescued the downregulation of c-Myc and inhibition of migration and invasion caused by MAL2 knockdown in BC cells. CONCLUSION: These observations provided evidence that MAL2 acted as a potential tumor promoter by regulating EMT and ß-catenin/c-Myc axis, suggesting potential implications for anti-metastatic therapy for BC.

Nodal coordinates the anterior-posterior patterning of germ layers and induces head formation in zebrafish explants.

Much progress has been made toward generating analogs of early embryos, such as gastruloids and embryoids, in vitro. However, methods for how to fully mimic the cell movements of gastrulation and coordinate germ-layer patterning to induce head formation are still lacking. Here, we show that a regional Nodal gradient applied to zebrafish animal pole explant can generate a structure that recapitulates the key cell movements of gastrulation. Using single-cell transcriptome and in situ hybridization analysis, we assess the dynamics of the cell fates and patterning of this structure. The mesendoderm differentiates into the anterior endoderm, prechordal plate, notochord, and tailbud-like cells along an anterior-posterior axis, and an anterior-posterior-patterned head-like structure (HLS) progressively forms during late gastrulation. Among 105 immediate Nodal targets, 14 genes contain axis-induction ability, and 5 of them induce a complete or partial head structure when overexpressed in the ventral side of zebrafish embryos.

An engineered abcb4 expression model reveals the central role of NF-κB in the regulation of drug resistance in zebrafish.

Multi-drug resistance (MDR) is a phenomenon that tumor cells are exposed to a chemotherapeutic drug for a long time and then develop resistance to a variety of other anticancer drugs with different structures and different mechanisms. The in vitro studies of tumor cell lines cannot systematically reflect the role of MDR gene in vivo, and the cost of in vivo studies of transgenic mice as animal models is high. Given the myriad merits of zebrafish relative to other animal models, we aimed to establish a screening system using zebrafish stably expressing ATP-binding cassette (ATP-cassette) superfamily transporters and unveil the potential regulatory mechanism. We first used the Tol2-mediated approach to construct a Tg (abcb4:EGFP) transgenic zebrafish line with ATP-binding cassette (ABC) subfamily B member 4 (abcb4) gene promoter to drive EGFP expression. The expression levels of abcb4 and EGFP were significantly increased when Tg(abcb4:EGFP) transgenic zebrafish embryos were exposed to doxorubicin (DOX) or vincristine (VCR), and the increases were accompanied by a marked decreased accumulation of rhodamine B (RhB) in embryos, indicating a remarkable increase in DOX or VCR efflux. Mechanistically, Akt and Erk signalings were activated upon the treatment with DOX or VCR. With the application of Akt and Erk inhibitors, drug resistance was reversed with differing responsive effects. Notably, downstream NF-κB played a central role in the regulation of abcb4-mediated drug resistance. Taken together, the data indicate that the engineered Tg(abcb4:EGFP) transgenic zebrafish model is a new platform for screening drug resistance in vivo, which may facilitate and accelerate the process of drug development.

GATA4 regulates osteogenic differentiation by targeting miR-144-3p.

Numerous studies have demonstrated that microRNAs (miRNAs or miRs) play an important role in regulating osteogenic differentiation, but their specific regulatory mechanism requires further investigation. In the present study, it was revealed that during osteogenic differentiation of rat bone marrow mesenchymal stem cells (BMSCs), the expression level of miR-144-3p was decreased with increased osteogenic induction duration and was negatively associated with osteogenic marker gene expression. Overexpression of miR-144-3p inhibited osteogenic differentiation, while inhibition of miR-144-3p expression promoted osteogenic differentiation. In addition, dual-luciferase activity analysis and adenovirus infection experiments revealed that GATA binding protein 4 targeted miR-144-3p for regulation and that overexpression of GATA4 promoted the expression of miR-144-3p. These data indicated that miR-144-3p plays a role in inhibiting BMSC osteogenic differentiation and that GATA4 inhibits osteogenic differentiation by targeting miR-144-3p expression.

A natural acylphloroglucinol triggered antiproliferative possessions in HEL cells by impeding STAT3 signaling and attenuating angiogenesis in transgenic zebrafish model.

Leukemia is responsible for a reason of death, globally. Even though there are several treatment regimens available in the clinics against this disease, a perfect chemotherapeutic agent for the same is still under investigation. Natural plant-derived secondary metabolites are used in clinics to treat leukemia for better benefits with reduced side-effects. Likely, several bioactive compounds from Callistemon sp. were reported for their bioactive benefits. Furthermore, acylphloroglucinol derivatives from Callistemon salignus, showed both antimicrobial and cytotoxic activities in various adherent human cancer cell lines. Thus, in the present study, a natural acylphloroglucinol (2,6-dihydroxy-4-methoxyisobutyrophenone, L72) was tested for its antiproliferative efficacy in HEL cells. The MTT and the cell cycle analysis study revealed that L72 treatment can offer antiproliferative effects, both time and dose-dependent manner, causing G2/M cell cycle arrest. The western blot analysis revealed that L72 treatment triggered intrinsic apoptotic machinery and activated p21. Likewise, L72 could downregulate the gene expressions of XIAP, FLT3, IDH2, and SOD2, which was demonstrated by qPCR analysis, thus promoting its antiproliferative action. The L72 could impede STAT3 expression, which was evidenced by insilico autodock analysis and western blot analysis using STAT3 inhibitor, Pimozide. The treatment of transgenic (Flk-1+/egfr+) zebrafish embryos resulted in the STAT3 gene inhibition, proving its anti-angiogenic effect, as well. Thus, the study revealed that L72 could act as an antiproliferative agent, by triggering caspase-dependent intrinsic apoptosis, reducing cell proliferation by attenuating STAT3, and activating an anti-angiogenic pathway via Flk-1inhibition.

Tanshinone I, a new EZH2 inhibitor restricts normal and malignant hematopoiesis through upregulation of MMP9 and ABCG2.

Rationale: Tanshinone, a type of diterpenes derived from salvia miltiorrhiza, is a particularly promising herbal medicine compound for the treatment of cancers including acute myeloid leukemia (AML). However, the therapeutic function and the underlying mechanism of Tanshinone in AML are not clear, and the toxic effect of Tanshinone limits its clinical application. Methods: Our work utilizes human leukemia cell lines, zebrafish transgenics and xenograft models to study the cellular and molecular mechanisms of how Tanshinone affects normal and abnormal hematopoiesis. WISH, Sudan Black and O-Dianisidine Staining were used to determine the expression of hematopoietic genes on zebrafish embryos. RNA-seq analysis showed that differential expression genes and enrichment gene signature with Tan I treatment. The surface plasmon resonance (SPR) method was used with a BIAcore T200 (GE Healthcare) to measure the binding affinities of Tan I. In vitro methyltransferase assay was performed to verify Tan I inhibits the histone enzymatic activity of the PRC2 complex. ChIP-qPCR assay was used to determine the H3K27me3 level of EZH2 target genes. Results: We found that Tanshinone I (Tan I), one of the Tanshinones, can inhibit the proliferation of human leukemia cells in vitro and in the xenograft zebrafish model, as well as the normal and malignant definitive hematopoiesis in zebrafish. Mechanistic studies illustrate that Tan I regulates normal and malignant hematopoiesis through direct binding to EZH2, a well-known histone H3K27 methyltransferase, and inhibiting PRC2 enzymatic activity. Furthermore, we identified MMP9 and ABCG2 as two possible downstream genes of Tan I's effects on EZH2. Conclusions: Together, this study confirmed that Tan I is a novel EZH2 inhibitor and suggested MMP9 and ABCG2 as two potential therapeutic targets for myeloid malignant diseases.

Efficacy of mesenchymal stem cell transplantation therapy for type 1 and type 2 diabetes mellitus: a meta-analysis.

BACKGROUND: This meta-analysis was first conducted to evaluate the efficacy and safety of transplantation of mesenchymal stem cells in the treatment of type 1 and type 2 diabetes mellitus (T1DM and T2DM). METHODS: We systematically searched PubMed, ScienceDirect, Google Scholar, CNKI, EMBASE, Web of Science, MEDLINE, and the Cochrane Library for studies published from the establishment of the databases to November 2020. Two researchers independently screened the identified studies, based on inclusion and exclusion criteria. The combined standard mean difference (SMD) and 95% confidence interval (CI) of data from the included studies were calculated using fixed- or random-effects models. RESULTS: We included 10 studies in our meta-analysis (4 studies on T1DM and 6 on T2DM, with 239 participants) to examine the efficacy of mesenchymal stem cells (MSCs) therapy in the treatment of diabetes mellitus. According to the pooled estimates, the glycated hemoglobin (HbA1c) level of the MSC-treated group was significantly lower than it was at baseline (mean difference (MD) = -1.51, 95% CI -2.42 to -0.60, P = 0.001). The fasting C-peptide level of the MSC-treated group with T1DM was higher than that of the control group (SMD = 0.89, 95% CI 0.36 to 1.42, P = 0.001), and their insulin requirement was significantly lower than it was at baseline (SMD = -1.14, 95% CI -1.52 to -0.77, P < 0.00001). CONCLUSION: Transplantation of mesenchymal stem cells has beneficial effects on diabetes mellitus, especially T1DM, and no obvious adverse reactions.

A novel urine cell-free DNA preservation solution and its application in kidney transplantation.

AIM: Urine cell-free DNA (cfDNA) is a new type of liquid biopsy biomarker used in tumours and allograft injury detection but is highly susceptible to degradation by the high nuclease activity of urine. This study presents a newly developed urine cfDNA preservation solution (AlloU), efficient for examining allograft injury in kidney transplant recipients (KTx). METHODS: We established urine-preserve solution called AlloU based on the response-surface methodology, with two commercial collection reagents (Streck and K2 EDTA preservation solution) included for analysis. A total of 120 urine samples from KTx patients, including morning, nocturnal and random urine from specific storage time were subjected to investigation. The urine total cfDNA concentration was quantified by fluorometry, fragment distribution was analysed by qPCR, and donor-derived cfDNA (ddcfDNA) was detected by next-generation sequencing. RESULTS: Urine total cfDNA concentration and fragment size of samples preserved with AlloU and Streck did not change significantly within 5 days whereas the ddcfDNA also did not change significantly within 7 days. However, compared with EDTA, the total cfDNA concentration increased significantly on the third day. When compare with different urine types, it was found that samples preserved with AlloU showed no significant differences in total cfDNA concentration, fragment size, and ddcfDNA concentration, however, the SD for morning urine was significantly smaller in total cfDNA and ddcfDNA concentration. CONCLUSION: To the best of our knowledge, this is the first report to verify the dynamics of urine cfDNA in KTx, especially in the analysis impact of different urine types on cfDNA detection.

Effects of water improvement and defluoridation on fluorosis-endemic areas in China: A meta-analysis.

This meta-analysis systematically evaluated the effects of water improvement and defluoridation on fluorosis-endemic areas in North and South China. The study used PubMed, Embase, China National Knowledge Infrastructure, and Wanfang to retrieve relevant research studies published between January 2000 and October 2019. The data included water fluoride levels, dental fluorosis prevalence in children 8-15 years of age, urinary fluoride levels in children and adults, and skeletal fluorosis prevalence in adults. Fixed-effects and random-effects models were used in the meta-analysis. A total of 17 research articles met the inclusion criteria and had an average water improvement period of 15.8 years. With water improvement, water fluoride levels decreased from 2.72 mg/L to 0.54 mg/L (95% confidence intervals: -2.75, -1.58), which was below the standard for drinking water (1.5 mg/L). Additionally, after water improvement, the prevalence of dental fluorosis decreased from 54.5% to 36.2% (95% confidence intervals: 0.12, 0.31) in children, and the prevalence of skeletal fluorosis decreased from 13.7% to 4.2% (95% confidence intervals: 0.16, 0.40) in adults. Urinary fluoride levels decreased from 3.06 mg/L to 1.70 mg/L (OR = -2.03, 95% confidence intervals: -2.77, -1.30) in children and from 2.29 mg/L to 1.72 mg/L (OR = -0.57, 95% confidence intervals: 0.65, -0.49) in adults. The results showed that the prevalence of dental fluorosis and skeletal fluorosis and urinary fluoride levels were significantly reduced by water improvement. This study findings revealed that the effects of water improvement and defluoridation were greater in South China than in North China, and it is obviously related to the time of water improvement and reducing fluoride.

Fabrication of multilayered electrospun poly(lactic-co-glycolic acid)/polyvinyl pyrrolidone + poly(ethylene oxide) scaffolds and biocompatibility evaluation.

Poly(lactic-co-glycolic acid)/polyvinyl pyrrolidone + poly(ethylene oxide) [PLGA/(PVP + PEO)] scaffolds with different polymer concentrations were fabricated using multilayered electrospinning, and their physicochemical properties and biocompatibility were examined to screen for scaffolds with excellent performance in tissue engineering (TE). PLGA solution (15% w/v) was used as the bottom solution, and a mixed solution of 12% w/v PVP + PEO was applied as the surface layer solution. The mass ratios of PVP vs. PEO in each 10 ml surface layer mixed solution were 1.08 g: 0.12 g; 0.96 g: 0.24 g; and 0.84 g: 0.36 g. Compared to the conventional electrospinning method used to fabricate the pure PVP + PEO (0.96 g: 0.24 g, Group A) scaffold and pure PLGA (Group E) scaffold, the multilayer electrospinning technique of alternating sprays of the bottom layer solution and the surface layer solution was adopted to fabricate multilayer nanofiber scaffolds, including PLGA/(PVP + PEO) (1.08 g: 0.12 g, Group B), PLGA/(PVP + PEO) (0.96 g: 0.24 g, Group C), and PLGA/(PVP + PEO) (0.84 g: 0.36 g, Group D). The morphology and characteristics of the five scaffolds were analyzed, and the biocompatibilities of the cell-scaffold composites were assessed through methods including Cell Counting Kit-8 (CCK8) analysis, 4',6-diamidino-2-phenylindole (DAPI) staining, and scanning electron microscopy. Therefore, with a PVP-to-PEO mass ratio of 0.96 g: 0.24 g, an optimal multilayer nanofiber scaffold was fabricated by the multilayer electrospinning technique. The excellent biocompatibility and mechanical properties of the scaffold were confirmed by in vitro experiments, which demonstrated the scaffold's promising application potential in the field of TE.

Intra-Articular Platelet-Rich Plasma Combined With Hyaluronic Acid Injection for Knee Osteoarthritis Is Superior to Platelet-Rich Plasma or Hyaluronic Acid Alone in Inhibiting Inflammation and Improving Pain and Function.

PURPOSE: To evaluate the effectiveness and explore the therapeutic mechanisms of platelet-rich plasma (PRP) combined with hyaluronic acid (HA) as a treatment for knee osteoarthritis (KOA). METHODS: In total, 122 knees were randomly divided into HA (34 knees), PRP (40 knees), and PRP+HA (48 knees) groups. Platelet densities in whole blood and PRP were examined using Wright-Giemsa staining. Visual analogue scale, Lequesne, Western Ontario and McMaster Universities Osteoarthritis Index, Lysholm scores, and postoperative complications were evaluated. High-frequency color Doppler imaging was used to observe the synovium and cartilage. Enzyme-linked immunosorbent assays were used to quantify interleukin-1ß, tumor necrosis factor-α, matrix metalloproteinase-3, and tissue inhibitor of metalloproteinase-1 levels in synovial fluid. RESULTS: The platelet density in PRP was 5.13-times that in whole blood (P = .002). At 24 months, pain and function scores in the PRP+HA group were better than those in the HA-alone and PRP-alone groups (Ppain = .000; Pfunction = .000). At 6 and 12 months, synovial hyperplasia in the PRP and PRP+HA groups was improved (P < .05). After 6 and 12 months, the synovial peak systolic velocity, synovial end-diastolic velocity, systolic/diastolic ratio, and resistance index were improved in the PRP+HA group (P < .05). Complications were greatest in the PRP group (P = .008). After 6 and 12 months, interleukin-1ß, tumor necrosis factor-α, matrix metalloproteinase-3, and tissue inhibitor of metalloproteinase-1 in the PRP and PRP+HA groups decreased (P < .05), with more apparent inhibition in the PRP+HA group (P < .05). CONCLUSIONS: PRP combined with HA is more effective than PRP or HA alone at inhibiting synovial inflammation and can effectively improve pain and function and reduce adverse reactions. Its mechanism involves changes in the synovium and cytokine content. LEVEL OF EVIDENCE: Level II, Prospective cohort study.

SNHG17 promotes the proliferation and migration of colorectal adenocarcinoma cells by modulating CXCL12-mediated angiogenesis.

BACKGROUND: Colorectal adenocarcinoma (CRA) is one of the leading causes of cancer-related deaths in the world. Long non-coding RNAs (lncRNAs) have been implicated to be effective regulators in the disease course of human cancers, including CRA. Small nucleolar RNA host gene 17 (SNHG17) belongs to lncRNAs, and it has been reported in breast cancer and gastric cancer. However, the function of SNHG17 and its mechanism in CRA progression remain largely unknown. In this study, we attended to shedding some light on the role of SNHG17 in CRA. METHODS: RT-qPCR was used to assess SNHG17 expression in CRA cells. CCK-8 assay, colony formation and transwell assay were carried out to detect the regulatory effect of SNHG17 silencing on CRA cell proliferation and migration. The angiogenesis of SNHG7-downregulated CRA cells was analyzed by tube formation assay. Mechanism experiments were conducted to identify the interaction between miR-23a-3p and SNHG17 or C-X-C motif chemokine ligand 12 (CXCL12). RESULTS: SNHG17 possessed with high expression in CRA cells. Knockdown of SNHG17 caused the inhibition on CRA cell proliferation and migration. SNHG17 promoted CRA cell proliferation and migration by sponging miR-23a-3p to upregulate CXCL12. CONCLUSION: SNHG17 promotes the proliferation and migration of CRA cells by inhibiting miR-23a-3p to modulate CXCL12-mediated angiogenesis.

Osteoblastic differentiation of stem cells induced by graphene oxide-hydroxyapatite-alginate hydrogel composites and construction of tissue-engineered bone.

This study aimed to investigate the effect of graphene oxide (GO)-hydroxyapatite (HA)-sodium alginate (SA) composite application in the field of bone tissue engineering. Four scaffold groups were established (SA-HA, SA-HA-0.8%GO, SA-HA-1.0%GO and SA-HA-1.2%GO) and mixed with bone marrow mesenchymal stem cells (BMSCs). Hydrogel viscosity was measured at room temperature, and after freeze-drying and Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) to detect substance crystallinity, the printability of each hydrogel type was measured with a printing grid. Scanning electron microscopy (SEM) was used to observe the internal microstructure of the scaffolds and to evaluate the growth and proliferation of cells on the scaffold. A hollow cylinder was printed to compare the forming effect of the hydrogel bioinks, and cell-hydrogel composites were implanted under the skin of nude mice to observe the effect of the hydrogels on osteogenesis in vivo. Increased GO concentrations led to reduced scaffold degradation rates, increased viscosity, increased printability, increased mechanical properties, increased scaffold porosity and increased cell proliferation rates. In vivo experiments showed that hematoxylin and eosin (HE) staining, Alizarin red staining, alkaline phosphatase staining and collagen type I immunohistochemical staining increased as the implantation time increased. These results demonstrate that GO composites have high printability as bioinks and can be used for bioprinting of bone by altering the ratio of the different components.

Macrophage-Derived IL-1ß Regulates Emergency Myelopoiesis via the NF-κB and C/ebpß in Zebrafish.

Myeloid phagocytes, neutrophils in particular, are easily consumed when they fight against a large number of invading microbes. Hence, they require efficient and constant replenishment from their progenitors via the well-orchestrated emergency myelopoiesis in the hematopoietic organs. The cellular and molecular details of the danger-sensing and warning processes to activate the emergency myelopoiesis are still under debate. In this study, we set up a systemic infection model in zebrafish (Danio rerio) larvae via circulative administration of LPS. We focused on the cross-talk of macrophages with myeloid progenitors in the caudal hematopoietic tissue. We revealed that macrophages first detected LPS and sent out the emergency message via il1ß The myeloid progenitors, rather than hematopoietic stem and progenitor cells, responded and fulfilled the demand to adapt myeloid expansion through the synergistic cooperation of NF-κB and C/ebpß. Our study unveiled a critical role of macrophages as the early "whistle blowers" to initiate emergency myelopoiesis.

Prognostic value of the donor-derived cell-free DNA assay in acute renal rejection therapy: A prospective cohort study.

Donor-derived cell-free DNA (dd-cfDNA) is a promising biomarker for monitoring allograft status. However, whether dd-cfDNA can reflect real-time anti-rejection treatment effects remains unclear. We prospectively recruited 28 patients with acute renal rejection, including 5 with ABMR, 12 with type IA or type IB rejection, and 11 with type IIA or IIB rejection. dd-cfDNA levels in peripheral blood were measured using human single nucleotide polymorphism (SNP) locus capture hybridization. The percentage of dd-cfDNA (dd-cfDNA%) declined significantly from 2.566 ± 0.549% to 0.773 ± 0.116% (P < .001) after anti-rejection therapy. The dd-cfDNA% decreased steadily over the course of 3 days with daily methylprednisolone injections, but no significant difference in the dd-cfDNA% was observed between the end of anti-rejection therapy and 2 weeks later. Changes in the dd-cfDNA% (∆dd-cfDNA%) demonstrated a positive correlation with estimated glomerular filtration rates at 1 month (ρ = 2.570, P = .022), 3 months (ρ = 3.210, P = .027), and 6 months (ρ = 2.860, P = .019) after therapy. Thus, the dd-cfDNA assay shows prognostic capabilities in therapy outcome and allograft recovery; however, its ability is inhibited by methylprednisolone regardless of the types of rejection. Additionally, a reassessment of frequency intervals for testing is required.

Biofabrication of valentine-shaped heart with a composite hydrogel and sacrificial material.

3D bioprinting represents a potential solution for organs regeneration, however, the production of complex tissues and organs that are in large size, randomly shaped, hollow, and contain integrated pre-vascularization still faces multiple challenges. This study aimed to test the feasibility of our 3D printing scheme for the manufacturing of micro-fluid channel networks complex three-dimensional tissue structures. The reverse engineering software was used to design the CAD model and polyvinyl alcohol (PVA) was used as the sacrificial material to print the sacrificial stent use the bioprinter nozzle 1. Hydrogel composite H9c2 and human umbilical vein endothelial cells (HUVECs) were mixed with sodium alginate, agarose solution and platelet-rich plasma (PRP) as cellular bioink, which was extruded through nozzle 2 to deposit the internal pores of the sacrificial scaffold. The scaffold dissolved, change to a flexible, hollow and micro-fluid channel networks complex structure. The 3D-bioprinting technology can construct a micro-fluid channel networks valentine heart with a self-defined height and hollow in suitable mechanical properties. The cells proliferate and maintain their biological properties within the printed constructs. This study demonstrates that valentine heart-like constructs can be fabricated with 3D bioprinting using sacrificial and hydrogel materials.