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Abstract The SARS-CoV-2 Omicron variant evades most currently approved neutralizing antibodies (nAbs) and caused drastic decrease of plasma neutralizing activity elicited by vaccination or prior infection, urging the need for the development of pan-variant antivirals. Breakthrough infection induces a hybrid immunological response with potentially broad, potent and durable protection against variants, therefore, convalescent plasma from breakthrough infection may provide a broadened repertoire for identifying elite nAbs. We performed single-cell RNA sequencing (scRNA-seq) and BCR sequencing (scBCR-seq) of B cells from BA.1 breakthrough-infected patients who received 2 or 3 previous doses of inactivated vaccine. Elite nAbs, mainly derived from the IGHV2–5 and IGHV3-66/53 germlines, showed potent neutralizing activity across Wuhan-Hu-1, Delta, Omicron sublineages BA.1 and BA.2 at picomolar NT50 values. Cryo-EM analysis revealed diverse modes of spike recognition and guides the design of cocktail therapy. A single injection of paired antibodies cocktail provided potent protection in the K18-hACE2 transgenic female mouse model of SARS-CoV-2 infection.

Abstract Thrombocytopenia is a major complication in a subset of patients with multiple myeloma (MM). However, little is known about its development and significance during MM. Here, we show thrombocytopenia is linked to poor prognosis in MM. In addition, we identify serine, which is released from MM cells into the bone marrow microenvironment, as a key metabolic factor that suppresses megakaryopoiesis and thrombopoiesis. The impact of excessive serine on thrombocytopenia is mainly mediated through the suppression of megakaryocyte (MK) differentiation. Extrinsic serine is transported into MKs through SLC38A1 and downregulates SVIL via SAM-mediated tri-methylation of H3K9, ultimately leading to the impairment of megakaryopoiesis. Inhibition of serine utilization or treatment with TPO enhances megakaryopoiesis and thrombopoiesis and suppresses MM progression. Together, we identify serine as a key metabolic regulator of thrombocytopenia, unveil molecular mechanisms governing MM progression, and provide potential therapeutic strategies for treating MM patients by targeting thrombocytopenia.

Objectives Graft failure (GF) is an intractable complication of transplantation, which can severely affect the efficacy of the graft; however, the characteristics, incidence, and risk factors of primary GF have not been well described. This study aimed to analyze the risk factors and outcomes of primary GF to swiftly identify high-risk patients for GF. Methods We performed a case-control study with a case-control ratio of 1:4 with 869 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) between January 2015 and December 2019 at our center. Results Nineteen (2.19%) patients experienced primary poor graft function (PGF), while eleven (1.27%) patients developed primary graft rejection (GR). Univariate and multivariate logistic analyses identified two independent risk factors for primary PGF: splenomegaly [P = 0.030; odds ratio (OR), 3.486; 95% confidence interval (CI), 1.139 to 13.109], and donor type [non-matched sibling donor (non-MSD)] (P = 0.018; OR, 4.475; 95% CI, 1.289 to 15.537). However, only donor type (non-MSD) was statistically significant (P = 0.020; OR, 19.432; 95% CI, 1.595 to 236.691) for primary GR. The overall survival was significantly lower in the primary PGF (P = 0.001) and GR group (P = 0.000), respectively, compared to the control group. Conclusion GF can significantly affect the overall survival of patients who underwent allo-HSCT, despite its considerably low incidence. A human leukocyte antigen-matched sibling donor should be the first choice for patients undergoing allo-HSCT for the prevention of GF. Moreover, splenomegaly is an independent risk factor for PGF, and caution must be exercised while treating such patients.

Abstract Objective To evaluate the efficacy of autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with favorable-risk acute myeloid leukemia in first remission. Method Twenty patients who received auto-HSCT at our center between January 2014 and January 2021 were retrospectively reviewed. Results Until last follow-up, three patients in the cohort were dead due to relapse. The estimated 1-year and 5-year overall survival were 95.00% ± 4.87% and 83.82% ± 8.58%, respectively. The estimated 5-year RFS and CIR (cumulative incidence of relapse) were 85.00% ± 7.98% and 15.00% ±7.98%, respectively. Conclusion The outcome of auto-HSCT in patients with favorable-risk acute myeloid leukemia in first remission was excellent and auto-HSCT could be an effective treatment for these patients.

Abstract Background Mucosal-associated invariant T (MAIT) cells are innate-like T cells, some studies have reported that the number of circulating MAIT cells reduced in patients with acute graft-versus-host-disease (aGVHD) development. However, the role of donor MAIT cells on aGVHD development and subsequent functional change still remain unclear. Methods The study recruited 86 patients with hematological malignancies who underwent allogeneic hematopoietic cell transplantation (HCT) from May 1, 2018 to June 30, 2019. MAIT cells, their subset, and cytokine levels were measured by flow cytometry. Gray’s test was used to assess the impact of graft MAIT cell proportion and number on aGVHD incidence. The Cox proportional hazard model was used in the multivariate analysis. The comparison for continuous variables was assessed using Mann–Whitney analysis. RNA-sequencing was performed to investigate the possible molecular pathway changes. Results Our study showed that the proportion of MAIT cells in grafts was not different from normal controls, but the CD4/8 subsets were altered. Taking the median of the proportion and number of MAIT cells in the graft as the threshold, the results showed that the incidence of grade B-D aGVHD in patients with MAIT cell proportion ≥ 3.03% was significantly higher than that in patients with MAIT cell proportion

Summary: The role of SET domain containing 7 (SETD7) during human hematopoietic development remains elusive. Here, we found that deletion of SETD7 attenuated the generation of hematopoietic progenitor cells (HPCs) during the induction of hematopoietic differentiation from human embryonic stem cells (hESCs). Further analysis specified that SETD7 was required for lateral plate mesoderm (LPM) specification but dispensable for the generation of endothelial progenitor cells (EPCs) and HPCs. Mechanistically, rather than depending on its histone methyltransferase activity, SETD7 interacted with β-catenin at lysine residue 180 facilitated its degradation. Diminished SETD7 expression led to the accumulation of β-catenin and the consequent activation of the Wnt signaling pathway, which altered LPM patterning and facilitated the production of paraxial mesoderm (PM). Taken together, the findings indicate that SETD7 is related to LPM and PM patterning via posttranslational regulation of the Wnt/β-catenin signaling pathway, providing novel insights into mesoderm specification during hematopoietic differentiation from hESCs.

Objective:. To investigate the risk factors for cytomegalovirus (CMV) infection within 100 days and the relationship between early CMV infection and 1-year relapse for patients with acute leukemia following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods:. Three hundred fifty-nine patients with acute leukemia who received allo-HSCT at our center between January 2015 and January 2020 were retrospectively reviewed. Results:. Of 359 patients, 48.19% (173) patients experienced CMV infection within 100 days posttransplantation. In univariate and multivariate logistic analysis, haploidentical-related donor (HRD) (P < 0.001; odds ratio [OR], 5.542; 95% confidence interval [CI], 3.186–9.639), and ratio of CD3+CD8+ cells in lymphocytes

Abstract Ribosomal protein dysfunction causes diverse human diseases, including Diamond–Blackfan anemia (DBA). Despite the universal need for ribosomes in all cell types, the mechanisms underlying ribosomopathies, which are characterized by tissue-specific defects, are still poorly understood. In the present study, we analyzed the transcriptomes of single purified erythroid progenitors isolated from the bone marrow of DBA patients. These patients were categorized into untreated, glucocorticoid (GC)-responsive and GC-non-responsive groups. We found that erythroid progenitors from untreated DBA patients entered S-phase of the cell cycle under considerable duress, resulting in replication stress and the activation of P53 signaling. In contrast, cell cycle progression was inhibited through induction of the type 1 interferon pathway in treated, GC-responsive patients, but not in GC-non-responsive patients. Notably, a low dose of interferon alpha treatment stimulated the production of erythrocytes derived from DBA patients. By linking the innately shorter cell cycle of erythroid progenitors to DBA pathogenesis, we demonstrated that interferon-mediated cell cycle control underlies the clinical efficacy of glucocorticoids. Our study suggests that interferon administration may constitute a new alternative therapeutic strategy for the treatment of DBA. The trial was registered at www.chictr.org.cn as ChiCTR2000038510.

On the basis of geosynchronous earth orbit multi-beam satellite communication systems, this paper designed the process of user random access to the network and specifi c signaling interaction under the agile beam mechanism, and proposed the scheduling strategy and allocation scheme of the agile signaling beam.This scheme increased the fl exibility of access resource allocation under the premised of ensured that all users could accessed the network, eff ectively improved the utilization rate of satellite network resources.The request of user access to the satellite communication network belongs to the burst type, it is more suitable to use the random competition access, so this paper based on the general random competition access strategy, proposed an adaptive random competition access algorithm based on the heat value, based on the heat value predicted by the network side, the user selects diff erent random access strategies for access.Through the simulation and analysis of the optimization algorithm, it is proved that the algorithm could eff ectively reduced the probability of access collision under various network loads, so as to achieved the purpose of users quickly accessing the network.

Abstract Objective To evaluate the efficacy and safety of P-ALG (porcine anti-lymphocyte globulin) and R-ATG (rabbit anti-thymocyte globulin) in the conditioning regime for patients with acquired aplastic anemia who underwent HLA-haploidentical hematopoietic stem cell transplantation (halpo-HSCT). Methods A total of 91 patients with acquired aplastic anemia who received haplo-HSCT at our center between January 2014 and December 2020 were retrospectively reviewed. Twenty-eight patients were in the P-ALG group while sixty-three patients were in the R-ATG group. Results The median time was 11 versus 13 days (P = 0.294) for myeloid engraftment and 12.5 versus 15 days (P = 0.465) for platelet engraftment in the P-ALG and R-ATG groups, respectively. There were no significant difference in 5-year overall survival (74.83% ± 8.24% vs 72.29% ± 6.26%, P = 0.830), GVHD-free, failure-free survival (71.05% ± 8.65% vs 62.71% ± 6.22%, P = 0.662), failure-free survival (74.83% ± 8.24% vs 66.09% ± 5.84%, P = 0.647) and transplantation-related mortality (25.17% ± 8.24% vs 26.29% ± 6.22%, P = 0.708) between the two groups. The incidence of aGVHD (acute graft versus host disease) (65.39% ± 9.33% vs 62.71% ± 6.30%, P = 0.653), II–IV aGVHD (38.46% ± 9.54% vs 35.64% ± 6.24%, P = 0.695), III–IV aGVHD (19.23% ± 7.73% vs 10.53% ± 4.07%, P = 0.291), cGVHD (chronic graft versus host disease) (22.22% ± 12.25% vs 22.31% ± 6.30%, P = 0.915), and moderate to severe cGVHD (5.56% ± 5.40% vs 9.28% ± 4.46%, P = 0.993) were not significantly different. Similar outcomes were observed between the P-ALG and R-ATG groups for severe bacterial infection (17.9% vs 25.4%, P = 0.431), invasive fungal diseases (3.6% vs 9.5%, P = 0.577) and graft rejection (0% vs 9.5%, P = 0.218). However, the incidence of cytomegalovirus infection and Epstein-Barr virus infection was significantly lower in the P-ALG group (46.4% vs 71.4%, P = 0.022; 3.6% vs 25.4%, P = 0.014). Conclusion The efficacy and safety of P-ALG were similar with R-ATG in the setting of haplo-HSCT for patients with acquired aplastic anemia patients. P-ALG could be an alternative for R-ATG.

Traditional model-based control methods typically require accurate system dynamics. However, when controlling a complex non-linear system such as a quadrotor unmanned aerial vehicle (QUAV), the dynamics are unknown and it is challenging to tune the control parameters manually. This paper proposes a novel model-free learning method that combines the advantages of a model-based method, i.e., sliding mode control (SMC), with the iterative learning control (ILC) method. Specifically, we selected a designed sliding surface to obtain the expected tracking error trajectory as the learning objective, and the system tracking errors of the angles of the QUAV constitute the state space. Then, the policy of converging to the sliding surface is learned by an ILC algorithm. We have provided theoretical proof of the convergence, and validated the proposed method with real-world experiments where the sine wave signals of roll and pitch angles were tracked. The results have demonstrated the effectiveness of the method with less tracking errors as well as faster learning speed compared with a baseline PID controller and a sliding mode controller.

Abstract Platelets, the chief effector of hemostasis, are small anucleate blood cells generated from megakaryocytes (MKs), and the defects in platelet production or function lead to a variety of bleeding complications. Emerging evidence indicates that MKs and platelets are much more diverse than previously appreciated and involved in many physiological and pathological processes besides hemostasis, such as innate and adaptive immune responses, angiogenesis, and tumor metastasis, while the ontogenic variations in MK and platelet function have also become a focus in the field. However, whether MKs and platelets fulfill these distinct functions by utilizing distinct subpopulations remains poorly understood. New studies aimed at deciphering the MK transcriptome at the single‐cell level have provided some key insights into the functional heterogeneity of MKs. In this review, we will discuss some of the recent discoveries of functional and developmental heterogeneity of MKs and its potential link to the heterogeneity of platelets. We will also discuss the implications of these findings while focusing on the ex vivo generation of platelets from human pluripotent stem cells. The improved understanding of the heterogeneity underlying human MK development and platelet production should open new avenues for future platelet regeneration and clinical treatment of related diseases.

Abstract Over the past 13 years, there have been advances in characterizing the patient experience in oncology trials, primarily using patient-reported outcomes (PROs). This review aims to provide details on the PRO measures and analyses used in multiple myeloma (MM) registrational trials. We identified registrational trials supporting MM indications from 2007 to 2020 from FDA databases. Trial protocols, statistical analysis plans, and clinical study reports were reviewed for PRO measures used, collection methods, statistical analyses, baseline and instrument completion definitions, and thresholds for clinical meaningfulness. Twenty-five trials supporting 20 MM indications were identified; 17 (68%) contained submitted PRO data. Of the 17 trials, 14 were randomized controlled trials and the remainder were single-arm trials. All but one trial were open label trials. Seven trials collected data electronically and five in paper format. The majority of trials evaluated at least two PRO measures (82%) with two trials (12%) utilizing four measures. Nine unique PRO measures were used, most commonly the EORTC QLQ-30 (87%), EQ-5D (65%), and QLQ-MY20 (47%). All 17 (100%) trials provided descriptive summaries, 10 (59%) carried out longitudinal mixed model analysis, 9 (53%) conducted responder analysis, and 2 (12%) did a basic inferential test. We noted substantial heterogeneity in terms of PRO collection methods, measures, definitions, and analyses, which may hinder the ability to effectively capture and interpret patient experience in future MM clinical trials. Further research is needed to determine the most appropriate approaches for statistical and analytical methodologies for PRO data in MM trials.

Abstract The ISTH London 2022 Congress is the first held (mostly) face‐to‐face again since the COVID‐19 pandemic took the world by surprise in 2020. For 2 years we met virtually, but this year’s in‐person format will allow the ever‐so‐important and quintessential creativity and networking to flow again. What a pleasure and joy to be able to see everyone! Importantly, all conference proceedings are also streamed (and available recorded) online for those unable to travel on this occasion. This ensures no one misses out. The 2022 scientific program highlights new developments in hemophilia and its treatment, acquired and other inherited bleeding disorders, thromboinflammation, platelets and coagulation, clot structure and composition, fibrinolysis, vascular biology, venous thromboembolism, women’s health, arterial thrombosis, pediatrics, COVID‐related thrombosis, vaccine‐induced thrombocytopenia with thrombosis, and omics and diagnostics. These areas are elegantly reviewed in this Illustrated Review article. The Illustrated Review is a highlight of the ISTH Congress. The format lends itself very well to explaining the science, and the collection of beautiful graphical summaries of recent developments in the field are stunning and self‐explanatory. This clever and effective way to communicate research is revolutionary and different from traditional formats. We hope you enjoy this article and will be inspired by its content to generate new research ideas.

Abstract. Ten-eleven translocation 2 (TET2) functions as a methylcytosine dioxygenase that catalyzes the iterative oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine. TET2 has been shown to be crucial for the maintenance and differentiation of hematopoietic stem cells, and its deletion and/or mutations results in the expansion of HSPCs, and leads to hematological malignancies. TET2 mutations were found in a variety of hematological disorders such as CMML (60%), MDS (30%), MPN (13%) and AML (20%). Interestingly, it was shown that CMML patients with TET2 mutation exhibited fewer platelets than CMML patients without TET2 mutation. However, the role and function of TET2 in platelet hemostasis and thrombogenesis is not well defined. Here in this study, using a genetically engineered Tet2 deletion mouse model, we found that the absence of Tet2 caused a decrease in the proportion of MEP cells and hyperploid megakaryocytes. Additionally, Tet2-deficient mice displayed impaired platelet activation and aggregation under stimulation of ADP and low concentrations of thrombin, although the modestly compromised platelet function and MEP differentiation in Tet2-deficient mice could be compensated without affecting blood coagulation function. Our study indicate that Tet2 deficiency leads to mild impairment of platelet function and thrombopoiesis in mice.

Abstract Background Strategies of generating functional blood cells from human pluripotent stem cells (hPSCs) remain largely unsuccessful due to the lack of a comprehensive understanding of hematopoietic development. Endothelial-to-hematopoietic transition (EHT) serves as the pivotal mechanism for the onset of hematopoiesis and is negatively regulated by TGF-β signaling. However, little is known about the underlying details of TGF-β signaling during EHT. Methods In this study, by applying genome-wide gene profiling, we identified muscle segment homeobox2 (MSX2) as a potential mediator of TGF-β signaling during EHT. We generated MSX2-deleted human embryonic stem cell (hESC) lines using the CRISPR/Cas9 technology and induced them to undergo hematopoietic differentiation. The role of MSX2 in hematopoiesis and functional regulation of TGFβ signaling in EHT was studied. Results We identified MSX2 as a novel regulator of human hematopoiesis. MSX2 deletion promotes the production of hematopoietic cells from hESCs. Functional and bioinformatics studies further demonstrated that MSX2 deletion augments hematopoietic differentiation of hESCs by facilitating EHT. Mechanistically, MSX2 acts as a downstream target of TGFβ signaling to mediate its function during EHT. Conclusions Our results not only improve the understanding of EHT, but may also provide novel insight into the efficient production of functional blood cells from hPSCs for regenerative medicine.

Abstract It has been previously shown that (never in mitosis gene A)‐related kinase 2 (NEK2) is upregulated in multiple myeloma (MM) and contributes to drug resistance. However, the mechanisms behind this upregulation remain poorly understood. In this study, it is found that amplification of NEK2 and hypermethylation of distal CpG islands in its promoter correlate strongly with increased NEK2 expression. Patients with NEK2 amplification have a poor rate of survival and often exhibit TP53 deletion, which is an independent prognostic factor in MM. This combination of TP53 knockout and NEK2 overexpression induces asymmetric mitosis, proliferation, drug resistance, and tumorigenic behaviors in MM in vitro and in vivo. In contrast, delivery of wild type p53 and suppression of NEK2 in TP53−/− MM cell lines inhibit tumor formation and enhance the effect of Bortezomib against MM. It is also discovered that inactivating p53 elevates NEK2 expression genetically by inducing NEK2 amplification, transcriptionally by increased activity of cell cycle‐related genes like E2F8 and epigenetically by upregulating DNA methyltransferases. Dual defects of TP53 and NEK2 may define patients with the poorest outcomes in MM with p53 inactivation, and NEK2 may serve as a novel therapeutic target in aggressive MM with p53 abnormalities.

Background Cordyceps militaris is a fungus that parasitizes insects. Compounds from C. militaris are valuable in medicine and functional food. There are many kinds of bacteria in the natural sclerotia of C. militaris. However, the community structure of microorganisms in samples from different places may be different, and their corresponding ecological functions require experimental verification. Methods We used high-throughput sequencing technology to analyze bacterial 16S rRNA gene sequences in sclerotia of three samples of C. militaris from Liaoning Province, China. We isolated, identified and verified the function of culturable bacterial strains from the sclerotia. Results Pseudomonas, Pedobacter, Sphingobacterium, and Serratia were the dominant bacterial genera in the sclerotia. And function prediction showed that Pseudomonas and Pedobacter could be heterotrophic, Sphingobacterium could decompose urea, and Serratia could reduce nitrate. Two strains of bacteria isolated from the sclerotia of C. militaris, N-2 and N-26, were identified as Stenotrophomonas maltophilia and Pseudomonas baetica, respectively, based on culture and biochemical characteristics. When these isolated strains were co-cultured with C. militaris, the mycelium biomass and mycelium pellet diameter decreased, and the content of extracellular polysaccharide increased. Strain N-26 decreased the cordycepin content in C. militaris. Conclusions Bacteria in sclerotia have an important effect on the growth of C. militaris and the production of its metabolites.

Abstract Megakaryocytes (MKs) and their progeny platelets function in a variety of biological processes including coagulation, hemostasis, inflammation, angiogenesis, and innate immunity. However, the divergent developmental and cellular landscape of adult MKs remains mysterious. Here, by deriving the single‐cell transcriptomic profiling of MKs from human adult bone marrow (BM), cellular heterogeneity within MKs is unveiled and an MK subpopulation with high enrichment of immune‐associated genes is identified. By performing the dynamic single‐cell transcriptomic landscape of human megakaryopoiesis in vitro, it is found that the immune signatures of MKs can be traced back to the progenitor stage. Furthermore, two surface markers, CD148 and CD48, are identified for mature MKs with immune characteristics. At the functional level, these CD148+CD48+ MKs can respond rapidly to immune stimuli both in vitro and in vivo, exhibit high‐level expression of immune receptors and mediators, and may function as immune‐surveillance cells. The findings uncover the cellular heterogeneity and a novel immune subset of human adult MKs and should greatly facilitate the understanding of the divergent functions of MKs under physiological and pathological conditions.

An amendment to this paper has been published and can be accessed via the original article.

Summary: GATA2 is essential for the endothelial-to-hematopoietic transition (EHT) and generation of hematopoietic stem cells (HSCs). It is poorly understood how GATA2 controls the development of human pluripotent stem cell (hPSC)-derived HS-like cells. Here, using human embryonic stem cells (hESCs) in which GATA2 overexpression was induced by doxycycline (Dox), we elucidated the dual functions of GATA2 in definitive hematopoiesis before and after the emergence of CD34+CD45+CD90+CD38– HS-like cells. Specifically, GATA2 promoted expansion of hemogenic precursors via the EHT and then helped to maintain HS-like cells in a quiescent state by regulating cell cycle. RNA sequencing showed that hPSC-derived HS-like cells were very similar to human fetal liver-derived HSCs. Our findings will help to elucidate the mechanism that controls the early stages of human definitive hematopoiesis and may help to develop a strategy to generate hPSC-derived HSCs. : In this article, Professor Ma and his colleagues at IBT of CAMS & PUMC show that overexpression of GATA2 promoted expansion of hemogenic precursors through EHT, and thereafter enhanced the maintenance of HS-like cells in dormancy by cell-cycle arrest. hESC-derived HS-like cells were highly similar to human fetal liver (FL) HSCs. Keywords: GATA2, hESCs, hematopoietic stem cells, definitive hematopoiesis, cell cycle

Abstract Background Human pluripotent stem cells (hPSCs) provide supplies of potential functional blood cells to suffice the clinical needs. However, the underlying mechanism of generating genuine hematopoietic stem cells (HSCs) and functional blood cells from hPSCs remains largely elusive. Method In this study, we supplied R-spondin2 exogenously during hematopoietic differentiation of hPSCs under various culture conditions and analyzed the production of hematopoietic progenitor cells (HPCs). We further added R-spondin2 at different temporal window to pin down the stage at which R-spondin2 conferred its effects. RNA-SEQ-based gene profiling was applied to analyze genes with significantly altered expression and altered signaling pathways. Finally, megakaryocytic differentiation and platelet generation were determined using HPCs with R-spondin2 treatment. Results We found that R-spondin2 generated by hematopoiesis-supporting stromal cells significantly enhances hematopoietic differentiation of hPSCs. Supply of R-spondin2 exogenously at the early stage of mesoderm differentiation elevates the generation of APLNR+ cells. Furthermore, early treatment of cells with R-spondin2 enables us to increase the output of hPSC-derived platelet-like particles (PLPs) with intact function. At the mechanistic level, R-spondin2 activates TGF-β signaling to promote the hematopoietic differentiation. Conclusions Our results demonstrate that a transient supply of R-spondin2 can efficiently promote hematopoietic development by activating both WNT and TGF-β signaling. R-spondin2 can be therefore used as a powerful tool for large-scale generation of functional hematopoietic progenitors and platelets for translational medicine.

Erythropoietin (EPO) drives erythropoiesis and is secreted mainly by the kidney upon hypoxic or anemic stress. The paucity of EPO production in renal EPO-producing cells (REPs) causes renal anemia, one of the most common complications of chronic nephropathies. Although mitochondrial dysfunction is commonly observed in several renal and hematopoietic disorders, the mechanism by which mitochondrial quality control impacts renal anemia remains elusive. In this study, we showed that FUNDC1, a mitophagy receptor, plays a critical role in EPO-driven erythropoiesis induced by stresses. Mechanistically, EPO production is impaired in REPs in Fundc1-/- mice upon stresses, and the impairment is caused by the accumulation of damaged mitochondria, which consequently leads to the elevation of the reactive oxygen species (ROS) level and triggers inflammatory responses by up-regulating proinflammatory cytokines. These inflammatory factors promote the myofibroblastic transformation of REPs, resulting in the reduction of EPO production. We therefore provide a link between aberrant mitophagy and deficient EPO generation in renal anemia. Our results also suggest that the mitochondrial quality control safeguards REPs under stresses, which may serve as a potential therapeutic strategy for the treatment of renal anemia.

The vibrations generated by a three-phase power transformer reduce the comfort of residents and the service life of surrounding equipment. To resolve this tough issue, a quasi-zero-stiffness (QZS) isolator for the transformer is proposed. This paper is devoted to developing a QZS isolator in a simple way for engineering practices. The vertical springs are used to support the heavy weight of the transformer, while the oblique springs are employed to fulfill negative stiffness to neutralize the positive stiffness of the vertical spring. Hence, a combination of the vertical and oblique spring can yield high static but low dynamic stiffness, and the vibration isolation efficiency can be improved substantially. The dynamic analysis for the QZS vibration isolation system is conducted by the harmonic balance method, and the vibration isolation performance is estimated. Finally, the prototype of the QZS isolator is manufactured, and then the vibration isolation performance is tested comparing with the linear isolator under real power loading conditions. The experimental results show that the QZS isolator prominently outperforms the existing linear isolator. This is the first time to devise a QZS isolator for three-phase power transformers with heavy payloads in engineering practices.

Abstract Epithelial‐mesenchymal transition (EMT) or its reverse process mesenchymal‐epithelial transition (MET) occurs in multiple physiological and pathological processes. However, whether an entire EMT–MET process exists and the potential function during human hematopoiesis remain largely elusive. Utilizing human pluripotent stem cell (hPSC)‐based systems, it is discovered that while EMT occurs at the onset of human hematopoietic differentiation, MET is not detected subsequently during differentiation. Instead, a biphasic activation of mesenchymal genes during hematopoietic differentiation of hPSCs is observed. The expression of mesenchymal genes is upregulated during the fate switch from pluripotency to the mesoderm, sustained at the hemogenic endothelium (HE) stage, and attenuated during hemogenic endothelial cell (HEP) differentiation to hematopoietic progenitor cells (HPCs). A similar expression pattern of mesenchymal genes is also observed during human and murine hematopoietic development in vivo. Wnt signaling and its downstream gene SNAI1 mediate the up‐regulation of mesenchymal genes and initiation of mesoderm induction from pluripotency. Inhibition of transforming growth factor‐β (TGF‐β) signaling and downregulation of HAND1, a downstream gene of TGF‐β, are required for the downregulation of mesenchymal genes and the capacity of HEPs to generate HPCs. These results suggest that the biphasic regulation of mesenchymal genes is an essential mechanism during human hematopoiesis.

Poor graft function (PGF) following allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is a life-threatening complication and is characterized by bilineage or trilineage blood cell deficiency and hypoplastic marrow with full chimerism. With the rapid development of allo-HSCT, especially haploidentical-HSCT, PGF has become a growing concern. The most common risk factors illustrated by recent studies include low dose of infused CD34 + cells, donor-specific antibody, cytomegalovirus infection, graft versus host disease (GVHD), iron overload and splenomegaly, among others. Because of the poor prognosis of PGF, it is crucial to uncover the underlying mechanism, which remains elusive. Recent studies have suggested that the bone marrow microenvironment may play an important role in the pathogenesis of PGF. Deficiency and dysfunction of endothelial cells and mesenchymal stem cells, elevated reactive oxygen species (ROS) levels, and immune abnormalities are believed to contribute to PGF. In this review, we also discuss recent clinical trials that evaluate the safety and efficacy of new strategies in patients with PGF. CD34 + -selected stem-cell boost (SCB) is effective with an acceptable incidence of GVHD, despite the need for a second donation. Alternative strategies including the applications of mesenchymal stem cells, N-acetyl- l -cysteine (NAC), and eltrombopag have shown favorable outcomes, but further large-scale studies are needed due to the small sample sizes of the recent clinical trials.

Summary: Attempts to generate functional blood cells from human pluripotent stem cells (hPSCs) remain largely unsuccessful, mainly due to the lack of understanding of the regulatory network of human hematopoiesis. In this study, we identified leucine-rich-repeat-containing G-protein-coupled receptor 4 (LGR4) as an essential regulator of early hematopoietic differentiation of hPSCs. The deletion of LGR4 severely impairs mesoderm development, thereby limiting hematopoietic differentiation both in vitro and in vivo. In contrast, LGR5 is dispensable for hPSC hematopoiesis. The four R-spondin proteins show differential activities and dependencies on LGR4 in hematopoietic differentiation. The deletion of LGR4 almost entirely abolishes the enhancement induced by R-spondin1 and R-spondin3, but not R-spondin2. In addition, ZNRF3 is required for the response of R-spondin1–R-spondin3. At the mechanistic level, LGR4 regulates transforming growth factor beta (TGF-beta) signaling to control hematopoietic differentiation. Together, our results reveal vital roles of LGR4 in hematopoietic development and uncover distinct functions and underlying mechanisms for R-spondins.

Abstract Microbiome plays an important role during the tobacco aging process which was an indispensable link in the production and processing of cigarettes. However, the structure and functions of microbiome have not been clarified during the tobacco aging process. In this study, 16S rDNA and ITS amplicon sequencing techniques were used to analyze the core microbiome of 15 tobacco samples from five different aging stages. The whole bacterial microbiome was classified into 29 microbial phyla and 132 orders. Enterobacteriales (63%), Pseudomonadales (16%), Sphingomonadales (8%), Xanthomonadales (4%), Burkholderiales (4%), Rhizobiales (3%), and Bacillales (2%) comprised the core bacterial microbiome. The whole fungal microbiome was classified into five microbial phyla and 52 orders. Incertae_sedis_Eurotiomycetes (27%), Wallemiales (25%), Sporidiobolales (17%), Capnodiales (5%), Eurotiales (2%), an unclassified Ascomycota (12%), and an unidentified Eurotiomycetes (4%) comprised the core fungal microbiome. FAPROTAX function prediction suggested that the core microbiome has a substantial potential for the carbon cycle, nitrate metabolism, aromatic compound degradation, chitinolysis, cellulolysis, and xylanolysis, but simultaneously, the core microbiome is also a source of human pathogens. The dynamics of the bacterial community were primarily determined by the total nitrogen in tobacco leaves during the aging process, while those of the fungal microbiome were primarily determined by total organic carbon. This study indicated that the core microbiome activities may play an important role in regulating the loss of carbon organic compounds and enhancing the secondary metabolites during tobacco leaves aging process.

Hydrothermal alteration minerals are an effective prospecting indicator. Advanced spaceborne thermal emission and reflection radiometer (ASTER) satellite data are some of the most commonly adopted multispectral data for the mapping of hydrothermal alteration minerals. Compared to multispectral data, hyperspectral data have stronger ground object recognition ability. Chinese Gaofen-5 (GF-5) is the first hyperspectral satellite independently developed by China that has the advantages of both wide-width and high-spectral-resolution technology. However, the mapping ability of GF5 data for hydrothermal alteration minerals requires further study. In this study, ASTER and GF-5 satellite data were implemented to map hydrothermal alteration minerals in the Longtoushan Pb-Zn deposit, SW China. Selective principal component analysis (SPCA) technology was employed to map iron oxide/hydroxides, argillic, quartz, and carbonate minerals at the pixel level using ASTER data, and the mixture tuned matched filtering (MTMF) method was implemented for the extracted hematite, kaolinite, calcite, and dolomite at the sub-pixel level using GF-5 data. When mapping the hydrothermal alteration minerals, the distribution features of the hydrothermal alteration minerals from the Longtoushan Pb-Zn deposit were systematically revealed. A comprehensive field investigation and petrographic study were conducted to verify the extraction accuracy of the hydrothermal alteration minerals. The results showed that the overall accuracies for the ASTER and GF-5 data were 82.6 and 92.9 and that the kappa coefficients were 0.78 and 0.90, respectively. This indicates that the GF-5 data are able to map hydrothermal alteration minerals well and that they can be promoted as a hyperspectral data source for mapping systematic hydrothermal alteration minerals in the future.

Abstract Background Despite considerable progress in the development of methods for hematopoietic differentiation, efficient generation of transplantable hematopoietic stem cells (HSCs) and other genuine functional blood cells from human embryonic stem cells (hESCs) is still unsuccessful. Therefore, a better understanding of the molecular mechanism underlying hematopoietic differentiation of hESCs is highly demanded. Methods In this study, by using whole-genome gene profiling, we identified Myeloid Ectopic Viral Integration Site 2 homolog (MEIS2) as a potential regulator of hESC early hematopoietic differentiation. We deleted MEIS2 gene in hESCs using the CRISPR/CAS9 technology and induced them to hematopoietic differentiation, megakaryocytic differentiation. Results In this study, we found that MEIS2 deletion impairs early hematopoietic differentiation from hESCs. Furthermore, MEIS2 deletion suppresses hemogenic endothelial specification and endothelial to hematopoietic transition (EHT), leading to the impairment of hematopoietic differentiation. Mechanistically, TAL1 acts as a downstream gene mediating the function of MEIS2 during early hematopoiesis. Interestingly, unlike MEIS1, MEIS2 deletion exerts minimal effects on megakaryocytic differentiation and platelet generation from hESCs. Conclusions Our findings advance the understanding of human hematopoietic development and may provide new insights for large-scale generation of functional blood cells for clinical applications.

Tamoxifen resistance is a major problem in the treatment of ERa positive breast cancer. Here, the authors show that LEM4 confers tamoxifen resistance by activating the cyclin D-CDK4/6-Rb axis and ERa signaling in endocrine-resistant breast cancer.

LncRNAs modulate diverse physiological cellular processes, however, their involvement in heme-dependent processes are not yet clear. Here the authors reveal the role of lncRNA UCA1 in erythroid cell development.

Summary: The gap in knowledge of the molecular mechanisms underlying differentiation of human pluripotent stem cells (hPSCs) into the mesenchymal cell lineages hinders the application of hPSCs for cell-based therapy. In this study, we identified a critical role of muscle segment homeobox 2 (MSX2) in initiating and accelerating the molecular program that leads to mesenchymal stem/stromal cell (MSC) differentiation from hPSCs. Genetic deletion of MSX2 impairs hPSC differentiation into MSCs. When aided with a cocktail of soluble molecules, MSX2 ectopic expression induces hPSCs to form nearly homogeneous and fully functional MSCs. Mechanistically, MSX2 induces hPSCs to form neural crest cells, an intermediate cell stage preceding MSCs, and further differentiation by regulating TWIST1 and PRAME. Furthermore, we found that MSX2 is also required for hPSC differentiation into MSCs through mesendoderm and trophoblast. Our findings provide novel mechanistic insights into lineage specification of hPSCs to MSCs and effective strategies for applications of stem cells for regenerative medicine. : In this article, Zhou and colleagues show that MSX2 rapidly initiates and accelerates MSC specification of hPSCs by regulating TWIST1 and PRAME. The study provides novel mechanistic insights into lineage specification of hPSCs to MSCs and effective strategies for applications of stem cells for regenerative medicine. Keywords: human pluripotent stem cells, mesenchymal stem/stromal cells, MSX2, TWIST1

Abstract Background Refinement of therapeutic-scale platelet production in vitro will provide a new source for transfusion in patients undergoing chemotherapy or radiotherapy. However, procedures for cost-effective and scalable platelet generation remain to be established. Methods In this study, we established human embryonic stem cell (hESC) lines containing knock-in of thrombopoietin (TPO) via CRISPR/Cas9-mediated genome editing. The expression and secretion of TPO was detected by western blotting and enzyme-linked immunosorbent assay. Then, we tested the potency for hematopoietic differentiation by coculturing the cells with mAGM-S3 cells and measured the generation of CD43+ and CD45+ hematopoietic progenitor cells (HPCs). The potency for megakaryocytic differentiation and platelet generation of TPO knock-in hESCs were further detected by measuring the expression of CD41a and CD42b. The morphology and function of platelets were analyzed with electronic microscopy and aggregation assay. Results The TPO gene was successfully inserted into the AAVS1 locus of the hESC genome and two cell lines with stable TPO expression and secretion were established. TPO knock-in exerts minimal effects on pluripotency but enhances early hematopoiesis and generation of more HPCs. More importantly, upon its knock-in, TPO augments megakaryocytic differentiation and platelet generation. In addition, the platelets derived from hESCs in vitro are functionally and morphologically comparable to those found in peripheral blood. Furthermore, TPO knock-in can partially replace the large quantities of extrinsic TPO necessary for megakaryocytic differentiation and platelet generation. Conclusions Our results demonstrate that autonomous production of cytokines in hESCs may become a powerful approach for cost-effective and large-scale platelet generation in translational medicine.

Summary: Human pluripotent stem cells (hPSCs) provide an unlimited source for generating various kinds of functional blood cells. However, efficient strategies for generating large-scale functional blood cells from hPSCs are still lacking, and the mechanism underlying human hematopoiesis remains largely unknown. In this study, we identified myeloid ectopic viral integration site 1 homolog (MEIS1) as a crucial regulator of hPSC early hematopoietic differentiation. MEIS1 is vital for specification of APLNR+ mesoderm progenitors to functional hemogenic endothelial progenitors (HEPs), thereby controlling formation of hematopoietic progenitor cells (HPCs). TAL1 mediates the function of MEIS1 in HEP specification. In addition, MEIS1 is vital for megakaryopoiesis and thrombopoiesis from hPSCs. Mechanistically, FLI1 acts as a downstream gene necessary for the function of MEIS1 during megakaryopoiesis. Thus, MEIS1 controls human hematopoiesis in a stage-specific manner and can be potentially manipulated for large-scale generation of HPCs or platelets from hPSCs for therapeutic applications in regenerative medicine. : H. Wang et al. identify MEIS1 as an essential regulator of early hematopoiesis and megakaryopoiesis from hPSCs in a stage-specific manner. This can be potentially manipulated for large-scale generation of HPCs or platelets from hPSCs for therapeutic applications in regenerative medicine. Keywords: MEIS1, hPSCs, hematopoiesis, megakaryopoiesis, TAL1, FLI1, hemogenic endothelial, thrombopoiesis

This study examined relations of affinity for solitude with social-behavioral, academic, and psychological adjustment in Chinese children and adolescents. The participants included 3,417 students (1,714 boys) in fourth, sixth, and eighth grades (M[subscript ages] = 10, 12, and 14 years, respectively) in China. Data on affinity for solitude were collected from students' self-reports and data on adjustment were collected from multiple sources. The results showed that whereas affinity for solitude was negatively associated with social competence and academic achievement and positively associated with behavioral problems in Grade 4, the associations were weaker or nonsignificant in Grade 6. Moreover, affinity for solitude was positively associated with academic achievement and negatively associated with behavioral problems in Grade 8. Affinity for solitude was negatively associated with psychological adjustment in general, but the associations were weaker in higher grades. The results indicate that the functional meaning of affinity for solitude may differ across developmental periods. Parents, teachers, and professionals should be aware of the different implications of affinity for solitude in childhood and adolescence and use different strategies to support children and adolescents who display affinity for solitude.

An amendment to this paper has been published and can be accessed via the original article.

The Pulang porphyry copper deposit (PCD), one of the main potential areas for copper resource exploration in China, exhibits typical porphyry alteration zoning. However, further investigation of the indicative significance of alteration minerals, additional insight into metallogenic characteristics, and prospecting guidelines continue to be challenging. In this study, ASTER and WorldView-3 data were used to map hydrothermal alteration minerals by employing band ratios, principal component analysis, and spectrum-area techniques; and subsequently, the indication significance of alteration minerals was studied in-depth. The following new insights into the metallogenic structure and spatial distribution of alteration zoning in Pulang PCD were obtained and verified. (1) A new NE trending normal fault, passing through the northeast of Pulang PCD, was discovered. (2) Two mineralization alteration centers, exhibiting alteration zoning characteristics of potassic-silicified, phyllic, and propylitic zones from the inside to the outside, were observed on both sides of the fault. (3) At the junction of the redivided potassic-silicification and phyllic zones, favorable prospecting potential areas were delineated. This study shows that the spectral/multi-sensor satellite data are valuable and cost-effective tools for the preliminary stages of porphyry copper exploration in inaccessible and remote areas around the world.

The development of human erythroid cells has been mostly examined in models of adult hematopoiesis, while their early derivation during embryonic and fetal stages is largely unknown. We observed the development and maturation of erythroblasts derived from human pluripotent stem cells (hPSCs) by an efficient co-culture system. These hPSC-derived early erythroblasts initially showed definitive characteristics with a glycophorin A+ (GPA+) CD34lowCD36− phenotype and were distinct from adult CD34+ cell-derived ones. After losing CD34 expression, early GPA+CD36− erythroblasts matured into GPA+CD36low/+ stage as the latter expressed higher levels of β-globin along with a gradual loss of mesodermal and endothelial properties, and terminally suppressed CD36. We establish a unique in vitro model to trace the early development of hPSC-derived erythroblasts by serial expression of CD34, GPA, and CD36. Our findings may provide insight into the understanding of human early erythropoiesis and, ultimately, therapeutic potential.

The present study examined relations between concern for mianzi, or the social perception of one's prestige and standing in the group, and adjustment in Chinese adolescents. Participants were seventh- and ninth-grade students in rural and urban regions of China (n = 794, M[subscript age] = 14 years). Data were obtained from multiple sources including peer assessments, teacher ratings, self-reports, and school records. The results showed that concern for mianzi was associated with social competence, leadership, academic achievement, as well as aggression and mixed peer relationships in rural adolescents. In contrast, concern for mianzi was associated with comprehensive social, school, and psychological adjustment problems in urban adolescents. The results indicate the role of context in shaping the relations between adolescents' concern for mianzi and adjustment.

In human pathological conditions, the acidification of local environment is a frequent feature, such as tumor and inflammation. As the pH of microenvironment alters, the functions of immune cells are about to change. It makes the extracellular acidification a key modulator of innate immunity. Here we detected the impact of extracellular acidification on neutrophil apoptosis and functions, including cell death, respiratory burst, migration and phagocytosis. As a result, we found that under the acid environment, neutrophil apoptosis delayed, respiratory burst inhibited, polarization augmented, chemotaxis differed, endocytosis enhanced and bacteria killing suppressed. These findings suggested that extracellular acidification acts as a key regulator of neutrophil apoptosis and functions.