Single-cell transcriptomic analysis identifies an immune-prone population in erythroid precursors during human ontogenesis.

Nonimmune cells can have immunomodulatory roles that contribute to healthy development. However, the molecular and cellular mechanisms underlying the immunomodulatory functions of erythroid cells during human ontogenesis remain elusive. Here, integrated, single-cell transcriptomic studies of erythroid cells from the human yolk sac, fetal liver, preterm umbilical cord blood (UCB), term UCB and adult bone marrow (BM) identified classical and immune subsets of erythroid precursors with divergent differentiation trajectories. Immune-erythroid cells were present from the yolk sac to the adult BM throughout human ontogenesis but failed to be generated in vitro from human embryonic stem cells. Compared with classical-erythroid precursors, these immune-erythroid cells possessed dual erythroid and immune regulatory networks, showed immunomodulatory functions and interacted more frequently with various innate and adaptive immune cells. Our findings provide important insights into the nature of immune-erythroid cells and their roles during development and diseases.

Multi-omics blood atlas reveals unique features of immune and platelet responses to SARS-CoV-2 Omicron breakthrough infection.

Although host responses to the ancestral SARS-CoV-2 strain are well described, those to the new Omicron variants are less resolved. We profiled the clinical phenomes, transcriptomes, proteomes, metabolomes, and immune repertoires of >1,000 blood cell or plasma specimens from SARS-CoV-2 Omicron patients. Using in-depth integrated multi-omics, we dissected the host response dynamics during multiple disease phases to reveal the molecular and cellular landscapes in the blood. Specifically, we detected enhanced interferon-mediated antiviral signatures of platelets in Omicron-infected patients, and platelets preferentially formed widespread aggregates with leukocytes to modulate immune cell functions. In addition, patients who were re-tested positive for viral RNA showed marked reductions in B cell receptor clones, antibody generation, and neutralizing capacity against Omicron. Finally, we developed a machine learning model that accurately predicted the probability of re-positivity in Omicron patients. Our study may inspire a paradigm shift in studying systemic diseases and emerging public health concerns.

Fungal communities are more sensitive to mildew than bacterial communities during tobacco storage processes.

Mildew poses a significant threat to tobacco production; however, there is limited information on the structure of the abundant and rare microbial subcommunities in moldy tobacco leaves. In this study, we employed high-throughput sequencing technology to discern the disparities in the composition, diversity, and co-occurrence patterns of abundant and rare fungal and bacterial subcommunities between moldy and normal tobacco leaves collected from Guizhou, Shanghai, and Jilin provinces, China. Furthermore, we explored the correlation between microorganisms and metabolites by integrating the metabolic profiles of moldy and normal tobacco leaves. The results showed that the fungi are more sensitive to mildew than bacteria, and that the fungal abundant taxa exhibit greater resistance and environmental adaptability than the rare taxa. The loss of rare taxa results in irreversible changes in the diversity, richness, and composition of the fungal community. Moreover, rare fungal taxa and abundant bacterial taxa played crucial roles in maintaining the stability and functionality of the tobacco microecosystem. In moldy tobacco, however, the disappearance of rare taxa as key nodes resulted in reduced connectivity and stability within the fungal network. In addition, metabolomic analysis showed that the contents of indoles, pyridines, polyketones, phenols, and peptides were significantly enriched in the moldy tobacco leaves, while the contents of amino acids, carbohydrates, lipids, and other compounds were significantly reduced in these leaves. Most metabolites showed negative correlations with Dothideomycetes, Alphaproteobacteria, and Gammaproteobacteria, but showed positive correlations with Eurotiales and Bacilli. This study has demonstrated that abundant fungal taxa are the predominant biological agents responsible for tobacco mildew, while bacteria may indirectly contribute to this process through the production and degradation of metabolites. KEY POINTS: • Fungi exhibited greater sensitivity to mildew of tobacco leaf compared to bacteria • Rare fungal taxa underwent significant damage during the mildew process • Mildew may damage the defense system of the tobacco leaf microecosystem.

Concern for mianzi: Relations with adjustment in rural and urban Chinese adolescents.

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, Mage = 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.

Leaders of Peer Groups in Chinese Early Adolescents: The Roles of Social, Academic, and Psychological Characteristics in Group Leadership.

Leadership in peer groups is an important issue in adolescent socioemotional development, yet it has received limited attention in research. This one-year longitudinal study examined peer group leadership and the roles of social, academic, and psychological characteristics in the dynamics of group leadership. Participants included 1061 Chinese students (initial mean age =11.17 years; SD = 6.98 months; 49.4% female). Data were collected from peer assessments, teacher ratings, and self-reports. The longitudinal social network analysis (SIENA) indicated that peer group leadership was fluid with leadership status evolving over time across groups in a hierarchical manner. Adolescents displaying higher social competence and aggression and lower shyness were more likely to become group leaders. Academic performance and loneliness were not significantly associated with the dynamics of peer group leadership. The results help understand peer group leadership and contributions of social behaviors to the attainment of leadership status in peer groups in early adolescence.

A splicing factor switch controls hematopoietic lineage specification of pluripotent stem cells.

Alternative splicing (AS) leads to transcriptome diversity in eukaryotic cells and is one of the key regulators driving cellular differentiation. Although AS is of crucial importance for normal hematopoiesis and hematopoietic malignancies, its role in early hematopoietic development is still largely unknown. Here, by using high-throughput transcriptomic analyses, we show that pervasive and dynamic AS takes place during hematopoietic development of human pluripotent stem cells (hPSCs). We identify a splicing factor switch that occurs during the differentiation of mesodermal cells to endothelial progenitor cells (EPCs). Perturbation of this switch selectively impairs the emergence of EPCs and hemogenic endothelial progenitor cells (HEPs). Mechanistically, an EPC-induced alternative spliced isoform of NUMB dictates EPC specification by controlling NOTCH signaling. Furthermore, we demonstrate that the splicing factor SRSF2 regulates splicing of the EPC-induced NUMB isoform, and the SRSF2-NUMB-NOTCH splicing axis regulates EPC generation. The identification of this splicing factor switch provides a new molecular mechanism to control cell fate and lineage specification.

Academic performance and depression in Chinese children: Same-domain and cross-domain effects in friendships.

This 1-year longitudinal study examined the effects of academic performance and depression in friendships among elementary school children in China. Participants included 1122 children (44% boys) within 561 stable friendship dyads initially in fourth and fifth grades (initial Mage  = 11 years). Data on academic performance, depression, and friendship were collected from multiple sources in the period of 2012 to 2014. Dyadic analysis using the actor-partner interdependence model showed that friends' academic performance significantly and positively predicted children's later academic performance, indicating same-domain effects, and significantly and negatively predicted children's later depression, indicating cross-domain effects, with a medium effect size (ε3  = .70) for the effects of academic performance. The results help understand the role of friendship in children's development in the Chinese context.

Enjoyment of Chinese and mathematics and school performance in Chinese children and adolescents.

This 2-year longitudinal study examined relations between enjoyment of learning in Chinese and mathematics, two major subjects in Chinese schools, and indexes of school performance. The participants included 1041 students (501 boys) initially in third, fifth, and seventh grades (mean age = 10.49 years) in China. Data on enjoyment of Chinese and mathematics were collected from students' self-reports and data on school performance were collected from multiple sources in 2017 and 2019. The results showed that enjoyment of mathematics positively predicted later academic achievement, self-perceptions of academic competence, teacher-rated school competence, and peer-assessed leadership-social competence. Enjoyment of Chinese negatively predicted later mathematics achievement and self-perceptions of academic competence and nonsignificantly predicted other school performance variables. The results were discussed in Chinese context.

Comparison of porcine ALG and rabbit ATG on outcomes of HLA-haploidentical hematopoietic stem cell transplantation for patients with acquired aplastic anemia.

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.

Mucosal-associated invariant T cells predict increased acute graft-versus-host-disease incidence in patients receiving allogeneic hematopoietic stem cell transplantation.

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 < 3.03% (56.3%, 95% CI 37.1-71.2 versus 23.1%, 95% CI 13.8-46.2; P = 0.038).The number of MAIT cells in the graft was not associated with aGVHD development (P = 0.173), however, when the graft contained more CD4 positive, CD8 positive, and CD4/CD8 double-positive MAIT cells, the incidence of aGVHD was significantly increased (P = 0.019, P = 0.035 and P = 0.027, respectively). Besides, reduced frequencies and counts of circulating MAIT cells were observed in patients with aGVHD when compared to patients without aGVHD, accompanied by enhanced production of Tumor necrosis factor-α, Interferon-γ and upregulated programmed death-1, CXC Chemokine Receptor-6 (CXCR6) and CD38 expression. Gene set enrichment analysis of MAIT cell RNA-seq data showed interferon-α response pathway upregulated in aGVHD patients when compared with patients without aGVHD and healthy controls. CONCLUSIONS: Our study shows that MAIT cells in grafts and peripheral blood are both closely related to the aGVHD development post allogeneic HCT. Interferon-α response pathway perhaps is a critical regulation mechanism for the MAIT cell involvement in aGVHD development.

Outcome of autologous stem cell transplantation in patients with favorable-risk acute myeloid leukemia in first remission.

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.

FDA approval summary: Crizotinib for pediatric and young adult patients with relapsed or refractory systemic anaplastic large cell lymphoma.

In January 2021, the U.S. Food and Drug Administration (FDA) approved crizotinib for pediatric patients 1 year and older and young adults with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). This is the first approval for pediatric sALCL. Approval was based on a single-arm trial of crizotinib monotherapy that included 26 patients, aged 1-20 years, with previously treated sALCL. Efficacy was based on centrally assessed objective response rate (88%) and duration of response. Herein, we highlight unique aspects of the regulatory review, including extension of the indication to young adults, postmarketing safety, and dose optimization strategies.

Characteristics of fungal communities and the sources of mold contamination in mildewed tobacco leaves stored under different climatic conditions.

Tobacco mildew is a common postharvest problem caused by fungal growth. It can directly decrease product quality and cause serious economic loss in the tobacco industry. However, the fungal community characteristics of mildewed tobacco leaves and the related influencing factors remain unknown. Here, next-generation sequencing was used to characterize the fungal communities present in mildewed and healthy tobacco leaves stored under three different climatic conditions. Mildewed leaves showed a higher pH and total nitrogen content as well as a lower carbon nitrogen ratio than healthy leaves. Fungal diversity and richness were significantly lower in the mildewed tobacco leaves than in healthy tobacco leaves, with saprophytic fungi such as Xeromyces, Aspergillus, and Wallemia being the dominant molds. Network analysis showed that the complexity, connectivity, and stability of the fungal network were significantly poorer in heavy mildew tobacco leaves than in healthy leaves. NMDS and PERMANOVA analysis showed that the distribution of fungal communities in warehoused tobacco leaves differed significantly across different regions, and temperature and humidity were the key factors affecting these differences. Mildew-causing fungi were significantly enriched in tobacco leaf samples collected in the period between the completion of flue-curing and the start of pre-re-curing. This study demonstrated that mildew is an irreversible process that destroys the balance of the tobacco ecosystem, and that environmental factors play important roles in shaping fungal communities in tobacco leaves.Key points• The diversity and composition of the fungal communities in mildewed tobacco leaves were significantly different from those in healthy tobacco leaves.• Climatic factors may play an important role in shaping fungal communities in tobacco leaves.• Tobacco leaves were most vulnerable to mold contamination between the post-flue-curing and pre-re-curing period.

Heat shock transcription factor 1 regulates the fetal γ-globin expression in a stress-dependent and independent manner during erythroid differentiation.

Heat shock transcription factor 1 (HSF1) is a highly versatile transcription factor that, in addition to protecting cells against proteotoxic stress, is also critical during diverse developmental processes. Although the functions of HSF1 have received considerable attention, its potential role in ß-globin gene regulation during erythropoiesis has not been fully elucidated. Here, after comparing the transcriptomes of erythrocytes differentiated from cord blood or adult peripheral blood hematopoietic progenitor CD34+ cells in vitro, we constructed the molecular regulatory network associated with ß-globin genes and identified novel and putative globin gene regulators by combining the weighted gene coexpression network analysis (WGCNA) and context likelihood of relatedness (CLR) algorithms. Further investigation revealed that one of the identified regulators, HSF1, acts as a key activator of the γ-globin gene in human primary erythroid cells in both erythroid developmental stages. While during stress, HSF1 is required for heat-induced globin gene activation, and HSF1 downregulation markedly decreases globin gene induction in K562 cells. Mechanistically, HSF1 occupies DNase I hypersensitive site 3 of the locus control region upstream of ß-globin genes via its canonical binding motif. Hence, HSF1 executes stress-dependent and -independent roles in fetal γ-globin regulation during erythroid differentiation.

Inflammation-Associated Cytokines IGFBP1 and RANTES Impair the Megakaryocytic Potential of HSCs in PT Patients after Allo-HSCT.

Prolonged isolated thrombocytopenia (PT) is a severe complication in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Whether the megakaryoctic potential of hematopoietic stem cells (HSCs) in bone marrow is intact and what factors drive the pathological process of PT remain elusive. A retrospective study in patients (n = 285) receiving HSCT revealed that the occurrence of PT was approximately 8% and the number of platelets and megakaryocytes in PT patients is much lower compared with control subjects. To test whether the deficiency of thrombopoiesis was caused by the activities of HSCs, the megakaryocytic differentiation potential of HSCs before or after transplantation was assessed. Interestingly, a substantial decrease of megakaryocytic differentiation was observed 2 weeks after transplantation of HSCs in all of the allo-HSCT recipients. However, 4 weeks after transplantation, the ability of HSCs to generate CD41+CD42b+ megakaryocytes in successful platelet engraftment patients recovered to the same level as those of HSCs before implantation. In contrast, HSCs derived from PT patients throughout the postimplantation period exhibited poor survival and failed to differentiate properly. A protein array analysis demonstrated that multiple inflammation-associated cytokines were elevated in allo-HSCT recipients with PT. Among them, insulin-like growth factor-binding protein 1 and regulated on activation, normal T cell expressed and secreted were found to significantly suppress the proliferation and megakaryocytic differentiation of HSCs in vitro. Our results suggested that the occurrence of PT may be attributed, at least partially, to the damage to HSC function caused by inflammation-associated cytokines after HSCT. These findings shed light on the mechanism underlying HSC megakaryocytic differentiation in PT patients and may provide potential new strategies for treating PT patients after HSCT.

Cigarette smoke (CS) and nicotine delay neutrophil spontaneous death via suppressing production of diphosphoinositol pentakisphosphate.

Diphosphoinositol pentakisphosphate (InsP7), a higher inositol phosphate containing energetic pyrophosphate bonds, is beginning to emerge as a key cellular signaling molecule. However, the various physiological and pathological processes that involve InsP7 are not completely understood. Here we report that cigarette smoke (CS) extract and nicotine reduce InsP7 levels in aging neutrophils. This subsequently leads to suppression of Akt deactivation, a causal mediator of neutrophil spontaneous death, and delayed neutrophil death. The effect of CS extract and nicotine on neutrophil death can be suppressed by either directly inhibiting the PtdIns(3,4,5)P3/Akt pathway, or increasing InsP7 levels via overexpression of InsP6K1, an inositol hexakisphosphate (InsP6) kinase responsible for InsP7 production in neutrophils. Delayed neutrophil death contributes to the pathogenesis of CS-induced chronic obstructive pulmonary disease. Therefore, disruption of InsP6K1 augments CS-induced neutrophil accumulation and lung damage. Taken together, these results suggest that CS and nicotine delay neutrophil spontaneous death by suppressing InsP7 production and consequently blocking Akt deactivation in aging neutrophils. Modifying neutrophil death via this pathway provides a strategy and therapeutic target for the treatment of tobacco-induced chronic obstructive pulmonary disease.

A novel small-molecule tumor necrosis factor α inhibitor attenuates inflammation in a hepatitis mouse model.

Overexpression of tumor necrosis factor α (TNFα) is a hallmark of many inflammatory diseases, including rheumatoid arthritis, inflammatory bowel disease, and septic shock and hepatitis, making it a potential therapeutic target for clinical interventions. To explore chemical inhibitors against TNFα activity, we applied computer-aided drug design combined with in vitro and cell-based assays and identified a lead chemical compound, (E)-4-(2-(4-chloro-3-nitrophenyl) (named as C87 thereafter), which directly binds to TNFα, potently inhibits TNFα-induced cytotoxicity (IC50 = 8.73 µM) and effectively blocks TNFα-triggered signaling activities. Furthermore, by using a murine acute hepatitis model, we showed that C87 attenuates TNFα-induced inflammation, thereby markedly reducing injuries to the liver and improving animal survival. Thus, our results lead to a novel and highly specific small-molecule TNFα inhibitor, which can be potentially used to treat TNFα-mediated inflammatory diseases.

Identification of key regulatory pathways of myeloid differentiation using an mESC-based karyotypically normal cell model.

Understanding the process of myeloid differentiation offers important insights into both normal and abnormal developmental processes but is limited by the dearth of experimental models. Here we show that myeloid progenitors can be derived from embryonic stem cells, immortalized, and applied to the study of the mechanisms underlying myeloid differentiation. The embryonic stem cell-derived myeloid progenitors, when immortalized with estrogen-regulated Hoxb8 protein, demonstrate normal karyotyping, are genetically tractable, and can be differentiated into functional neutrophils. Using this model, we identified mammalian target of rapamycin complex 1 as a critical regulator of myeloid differentiation. Together, our studies led to a convenient, karyotypically normal, and genetically manipulatable cellular system, which can be used to shed new light on the mechanisms for myeloid differentiation.

Affinity for solitude in Chinese children and adolescents: Relations with social, school, and psychological adjustment.

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 (Mages = 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. (PsycInfo Database Record (c) 2024 APA, all rights reserved).