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Sheep manure and oyster shells as C and Ca sources, respectively, were used to obtain Ca-enriched biochar materials with a high dephosphorization efficiency. This approach is helpful for the utilization of livestock manure and shell solid waste as well as for creating highly adsorbent materials. The results show that as the Ca content in biochar was increased, the material’s phosphate adsorption capacity increased. The maximum adsorption efficiency reached 94%. The highest adsorption capacity (calculated using Langmuir fitting) of the material containing 1:1 biochar/oyster shell weight ratio reached 146.3 mg P/g. With the increase of the pH value of phosphate solution, the adsorption capacity of the sample gradually increased to 89.5–93.3 mg P/g. The adsorption occurred mainly by complexation. The results of this work provide insights into livestock manure and shell solid waste utilization, which yields a material with useful adsorption properties that can be applied for the removal of phosphate and other inorganics from water.

To explore the relationship between childrenapos;s dietary nutrient intakes and hypertension, overweight and obesity.In April 2016, 1033 children aged 9 to 12 from grades 3 to 6 in two primary schools in Hongshan District of Wuhan City were selected by cluster sampling method, with an average age of(10.55±1.10) years, including 545 boys(52.8%) and 488 girls(47.2%), for physical examination and dietary survey. Physical examination included height, weight, blood pressure, etc. Dietary survey was conducted using a 3-day 24 h retrospective method. Principal component factor analysis was used to explore the dietary nutrient patterns of children, and logistic regression was used to analyze the effects of different dietary nutrient patterns on childrenapos;s hypertension, overweight and obesity.In terms of M(P25, P75), compared with normal blood pressure group, hypertensive group had higher energy intake(1761.97(1617.17, 1940.43)kcal vs.1730.95(1556.06, 1905.71)kcal, P=0.011). Compared with normal weight group, overweight and obese group had higher carbohydrate(250.65(226.55, 281.29)g vs.244.41(220.04, 273.01)g, P=0.011), vitamin B_1(0.29(0.22, 0.36)mg vs.0.27(0.22, 0.34)mg, P=0.022), vitamin B_2(0.45(0.33, 0.60)mg vs.0.39(0.32, 0.51)mg, P=0.001), iron(12.64(11.06, 14.48)mg vs.12.39(10.57, 14.21)mg, P=0.033), zinc(5.11(4.00, 6.77)mg vs.4.60(3.87, 5.84)mg, Plt;0.001)intakes, lower calcium intake(185.52(136.92, 264.73)mg vs.207.39(141.25, 300.92)mg, P=0.007). Low cholesterol, low vitamin, high calcium pattern(OR=0.644, 95%CI 0.421-0.985) and Q2 of low protein, low fat and low cholesterol(OR=0.626, 95%CI 0.412-0.951) were protective factors for overweight and obesity.High carbohydrate may be a risk factor for overweight and obesity, while high calcium, low fat and low cholesterol may be protective factors for overweight and obesity.

Use of soil adsorbent is an effective method for the promotion of phosphorus adsorption capacity of soil, though most of the soil adsorbents have weak phosphorus retention ability. Herein, we compared the traditional gypsum (GP) and zeolite (ZP) adsorbents to explore the phosphorus retention ability of lanthanum modified walnut shell biochar (La-BC) in soil. The results showed that with the increase of exogenous phosphorus concentration, the adsorption amount of phosphorus by adsorbents in soil increased at first and then tended to be stable. The maximum adsorption capacity of soil to phosphorus is gypsum, lanthanum-modified biochar > zeolite, and the addition of lanthanum-modified biochar can improve the adsorption capacity of soil to phosphorus, enhance the binding strength of soil and phosphorus, improve the ability of soil to store phosphorus, reducing phosphorus adsorption saturation, and is beneficial to control the leaching of soil phosphorus. FTIR and XRD analysis showed that the adsorption of phosphorus by each adsorbent in soil was mainly chemical precipitation. The response surface analysis showed that the adsorption performance of La-BC+S was the best when the concentration of exogenous phosphorus was 50.0 mg/L, pH was 6.47, and the reaction time was 436.98 min. This study provides a reference for soil adsorbents to hold phosphorus and reduce the risk of phosphorus leaching to avoid groundwater pollution.

Background Inhibitors of the EGFR-RAS-RAF-MEK (MAPK) pathway have been successfully developed to treat cancers. However, many patients do not benefit from these inhibitors due to primary or acquired resistance. In colorectal cancer (CRC), resistance to inhibitors of the MAPK pathway is especially prominent, reflected by low response and short survival. Reactivation of MAPK signaling is a common mechanism of acquired resistance in CRC. WNT pathway is hyperactivated in the majority of CRC patients due to genetic alterations of several genes involved in WNT signaling, e.g., APC, CTNNB1, RSPO and RNF43. Cooperation between RAS-RAF and WNT signaling drives the carcinogenesis of CRC. Concomitant blockade of WNT signaling has been shown to impede the emergence of BRAF inhibitor-resistant clones, thus offering the possibility to overcome acquired resistance. Methods To prove the concept that simultaneous inhibition of the WNT pathway and the MAPK pathway reduces primary or acquired resistance to CRC treatment, we have tested combinations of various inhibitors of both pathways in CRC models, including BRAFV600E ;RSPO3 PDX models, KRASG12C ;RSPO3 cell lines and APC-mutated cell lines with or without KRAS mutations, including KRASG12C ;APC CRC cell lines. We tested MAPK pathway inhibitors, such as cetuximab, selumetinib and cobimetinib (MEK1/2 inhibitors), encorafenib (BRAFV600E inhibitor), and AMG510/sotorasib (KRASG12C inhibitor). Inhibitors of the WNT pathway included a porcupine inhibitor, CGX1321, that blocks the secretion of WNT ligands, currently in clinical development, and a tankyrase inhibitor, CGX11071, that stabilizes AXIN-1/2 and degrades β-catenin. Synergistic effects between inhibitors of the MAPK pathway and the WNT pathway were observed in CRC models in vitro and in vivo. Notably, when CGX1321 was added to encorafenib and cetuximab in CRC PDX models with BRAFV600E and RSPO fusions, a decrease in tumor size (>50%) occurred in two weeks, compared with tumor progression with encorafenib and cetuximab or CGX1321 treatment alone. Notable is the synergy between tankyrase inhibitor CGX11071 and KRASG12C inhibitor AMG510/sotorasib in CRC cell lines with KRASG12C and RSPO fusion (or APC mutations). We launched a phase 1b clinical trial to study the efficacy of CGX1321 in combination with encorafenib and cetuximab in CRC patients with RSPO fusions and BRAFV600E mutations. (NCT02675946). Primary endpoint included safety and RP2D. Secondary endpoints included PK, overall response rate, CR and PR rate, and duration of response by RECIST 1.1 and irRECIST 1.1. The clinical protocol and available data of CGX1321 in combination with encorafenib and cetuximab in CRC patients with RSPO fusions and BRAFV600E mutations will be discussed. Citation Format: Jinjin Cai, Andrew Dorr, Laurie Rosenstein, Jim Labdon, Xiaojuan Li, Hang Zhou, Yanyuan Zhou, Wangjun He, Qiuping He, Xiaoyan Huang, Aparna R. Parikh, Marios Giannakis, Michael An. Synergism between inhibitors of the EGFR-RAS-RAF-MEK pathway and the WNT pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT117.

Metastasis and recurrence account for 95% of deaths from nasopharyngeal carcinoma (NPC). Cancer stem cells (CSCs) are regarded as one of the main reasons for tumor cell resistance to clinical therapy, and cancer metastasis or recurrence, while little is known about CSCs in NPC. The present study uncovers a subpopulation of cells labeled as CD45−EPCAM+PROCR+ in NPC biopsy samples that exhibit stem cell-like characteristics. A relatively low number of these cells initiate xenograft tumors in mice. Functional analysis reveals that protein C receptor (PROCR) not only serves as a stem cell marker in NPC, but also maintains tumor cells’ stemness potential through regulating lipid metabolism and mitochondrial fission. Epistatic studies reveal that cAMP-protein kinase A stimulates Ca2+ release to manipulate lipid metabolism related genes’ expression. Finally, in a cohort of 207 NPC samples, PROCR expression is correlated with tumor metastasis or recurrence, and predicts poor prognosis. These novel findings link PROCR labeled CSCs with lipid metabolism and mitochondrial plasticity, and provides new clinical target against metastatic or recurrent NPC.

Background:Older adults represent the segment of population most exposed to the risk of suicide nearly everywhere in the world. Previous studies showed that hopelessness was an important risk factor for suicide.Aims:This study aimed to evaluate the reliability and validity of the four-item Beck Hopelessness Scale (BHS-4) in psychological autopsy study among Chinese rural elderly.Method:Two-stage stratified cluster sampling method was used to select research sites. Using case-control psychological autopsy study, face-to-face interviews were conducted to collected information.Results:A total of 242 elderly suicide deaths and 242 matched living comparisons were investigated, including 135 males and 107 females for each group. Intraclass Correlation Coefficients (ICC) of the controls were 0.682-0.713. The median score of BHS-4 among suicides was significantly higher than that among controls. The corrected correlation coefficient between items and total score were 0.184-0.723. Cronbach’s Alphas coefficient was 0.834. Only one common factor was precipitated by exploratory factor analysis and the cumulative variance contribution rates were 59.558% for suicides and 52.722% for living controls. The correlation coefficient between hopelessness and depression were 0.481 among suicide death and 0.617 among living controls.Conclusion:The information provided by the informants through psychological autopsy method had high reliability to reflect the actual situation of suicides and controls. BHS-4 has good reliability and validity among Chinese rural elderly suicides. It is suitable for psychological autopsy study among Chinese rural elderly.

Aim The present study aimed to evaluate the validity of proxy informants' reports on Life Event Scale for the Elderly (LESE) by using psychological autopsy method among rural older adults in China. Methods A multistage stratified cluster sampling method was used to select research sites. Using a case-control psychological autopsy study, face-to-face interviews were carried out to collect information from 242 suicide cases and 242 living controls. We compared the intensity and number of life events to assess the validity and reliability of LESE with proxy data reported by different informants. Data from proxy respondents of the living controls were compared with data reported by the targets (gold standards). Intraclass correlation coefficients were computed to evaluate the consistency of informants. Spearman's correlation analysis was used to analyze the convergent validity and discriminate validity of the LESE. Results The number of life events between different informants showed higher intraclass correlation coefficients values than the intensity of life events, but the results of correlation analysis was similar. The LESE was positively correlated with depression, loneliness and hopelessness, and negatively correlated with quality of life, family function and social support both in suicide cases and living controls. Conclusions The LESE has good convergent validity and discriminant validity. LESE is a valid instrument for measuring life events in psychological autopsy studies. We suggest using the number of life events to assess the validity and reliability with proxy data in a psychological autopsy study, which is more reliable than using the intensity of life events. Geriatr Gerontol Int 2019; 19: 547-551.

Nasopharyngeal carcinoma (NPC) progression is regulated by genetic, epigenetic, and epitranscript modulation. As one of the epitranscript modifications, the role of N6-Methyladenosine (m6A) has not been elucidated in NPC. In the present study, we found that the poorly methylated gene ZNF750 (encoding zinc finger protein 750) was downregulated in NPC tumor tissues and cell lines. Ectopic expression of ZNF750 blocked NPC growth in vitro and in vivo. Further studies revealed that m6A modifications maintained the low expression level of ZNF750 in NPC. Chromatin immunoprecipitation sequencing identified that ZNF750 directly regulated FGF14 (encoding fibroblast growth factor 14), ablation of which reversed ZNF750’s tumor repressor effect. Moreover, the ZNF750-FGF14 signaling axis inhibited NPC growth by promoting cell apoptosis. These findings uncovered the critical role of m6A in NPC, and stressed the regulatory function of the ZNF750-FGF14 signaling axis in modulating NPC progression, which provides theoretical guidance for the clinical treatment of NPC.

Background: Caregiver perceptions of child diet status can influence the effect of health intervention, but research focused on the correctness of caregiver's perception is limited. This study aimed to figure out the correctness of caregiver's perception of their child's diet status and find out the factors which may influence their judgement.Methods: 815 children from grade 3rd to 6th and their caregivers were recruited from two primary schools by cluster sampling. 3-day 24-hour recall was used to record children’s diet, caregiver’s perceptions was obtained through questionnaires. Multivariate logistic regression models were used to explore the influencing factors of the correctness of caregiver’s perception.Results: Among the 597 children with “balanced” diet, 62.1% were correctly perceived as having a “healthy” diet by their caregivers; but for the 218 children with “imbalanced” diet, just 16.1% were correctly identified. Those who were correctly identified as having an unhealthy diet consumed less fruits and more snacks than those unidentified (pOR=0.305, p=0.016). Caregivers with high educational level were more likely to correctly perceive children’s healthy diet status (OR=3.628, p=0.038).Conclusions: Caregivers were generally lack of the ability to identify children's unhealthy diet. Obesity, significantly low consumption of fruits or high consumption of snacks can raise caregivers’ awareness. Extensive health education targeting caregivers is in emergency.

Hematopoietic stem cell (HSC) utilizes its quiescence feature to combat exhaustion for lifetime blood cell supply. To date, how certain chromatin architecture and subsequent transcription profile permit HSC quiescence remains unclear. Here, we show an essential role of chromatin remodeler zinc finger HIT-type containing 1 (Znhit1) in maintaining HSC quiescence. We find that loss of Znhit1 leads to exhaustion of stem cell pool and impairment of hematopoietic function. Mechanically, Znhit1 determines the chromatin accessibility at distal enhancers of HSC quiescence genes, including Pten, Fstl1, and Klf4, for sustained transcription and consequent PI3K–Akt signaling inhibition. Moreover, Znhit1–Pten–PI3K–Akt axis also participates in controlling myeloid expansion and B-lymphoid specification. Our findings therefore identify a dominant role of Znhit1-mediated chromatin remodeling in preserving HSC function for hematopoietic homeostasis.

Background The main strategy against nasopharyngeal carcinoma (NPC) is radiotherapy. However, radioresistance mediated recurrence is a leading clinical bottleneck in NPC. Revealing the mechanism of NPC radioresistance will help improve the therapeutic effect. Methods In this study, the role of TRIM21 (tripartite motif–containing 21) in NPC receiving ionizing radiation was firstly examined both in vivo and in vitro. Mass spectrometry analysis was performed to identify the downstream targets of TRIM21. NPC cells with TRIM21 or SERPINB5 (serpin family B member 5) overexpression or knockout were used to determine the epistatic relationship among SERPINB5, GMPS (guanine monophosphate synthase) and TRIM21. Flow cytometry, co-immunoprecipitation, western blot and immunofluorescence were employed to strengthen the results. Finally, immunohistochemistry using 4 radiosensitive and 8 radioresistent NPC patient samples was perform to examine the association between SERPINB5 or GMPS expression and patient radio-sensitivity. Results As an E3 ligase, TRIM21 was highly expressed in NPC. After ionizing radiation, TRIM21 repressed TP53 expression by mediating GMPS ubiquitination and degradation. Overexpression of TRIM21 protected NPC cells from radiation mediated cell apoptosis in vitro and in vivo. Further analysis revealed that TRIM21 mediated GMPS repression was dependent on SERPINB5, and SERPINB5 served as an adaptor which prevented GMPS from entering into the nucleus and introduced TRIM21 for GMPS ubiquitination. Moreover, the in vitro and in vivo results validated the finding that SERPINB5 promoted NPC cell radioresistance, and the radioresistant patients had higher SERPINB5 expression. Conclusions Overall, our data showed that TRIM21–SERPINB5-mediated GMPS degradation facilitated TP53 repression, which promoted the radioresistance of NPC cells. This novel working model related to TP53 suppression provided new insight into NPC radioresistence clinically.

The correct presentation of Figure 9 has been redrawn and submitted because of the partial text deviation caused by the problem in Figure 9 itself.

In this study, the ionic cross-linking method was used to synchronize the granulation and magnetization of biochar powder. A precursor of Ca/Mg modified, tobacco stalk biochar combined with sodium alginate as the functional monomer, CaCl2 solution as the cross-linking agent, and a Fe3O4 magnetic fluid dopant were used to prepare magnetic biochar particles (EMCSB3), which were easy to separate and recover. The adsorption performance of phosphate by these EMCSB3 was explored. The Langmuir model fitted adsorption capacity of phosphate on the EMCSB3 was 8.93 mgP g−1, which was comparable to other materials at the same concentration. The process of phosphate adsorption by magnetic particles followed a pseudo-second-order model, and the adsorption mechanism was chemisorption. EMCSB3 was suitable for use in environments with pH ≤ 8, the best dosage was 6.67 g l−1, and its removal rate was maintained at about 85%. Phosphate adsorption was greatly affected by coexisting CO3 2−. This study provides a technical approach for the granulation and magnetization of powdered biochar and improves its feasibility of use.

In this study, a calcium-modified biochar with a high dephosphorization efficiency was obtained using sheep manure as a carbon source and oyster shells as a calcium(Ca) source. However, it was found that the calcium-modified biochar had a low-pH inadaptability. Based on this, lanthanum(La) was doped in place of Ca to prepare biochar with a strong phosphate adsorption ability in a wide range of pH. The results showed that with the increase of Ca content, the phosphorus adsorption capacity of the material with a mass ratio of biochar to oyster shells of 1:1 (BC-Ca5) increased gradually, and the maximum adsorption capacity that was fitted by the Langmuir equation reached 78.11 mg P/g. Also, the adsorption capacity was 48.70 mg P/g when the pH > 7, and lower than 6 mg P/g when pH ≤ 7. The maximum adsorption capacity fitted to the Langmuir equation of the material with a mass ratio of biochar, oyster shells, and La of 1:1(BC-La4) reached 88.34 mg P/g, and the adsorption capacity reached 50 mg P/g under all pH conditions except pH = 7. Ca was mostly found on the surface of the biochar, and La was mainly present in the internal pore structure. The FTIR, XRD, and XPS results showed that the main adsorption mechanism was complexation. This study provides a reference for the resource utilization of livestock and poultry manure and shell solid wastes, as well as metal sources for metal modified biochar, and improving the adsorption performance of calcium-modified biochar.

A La(OH)3 nanorod/walnut shell biochar composite (LN-WB) was successfully prepared by a parallel flow co-precipitating method and used to reclaim phosphate. LN-WB effectively adsorbed phosphate over a wide pH range (from 3 to 11) and when the initial phosphorus concentration was 10 mg P/L, the removal efficiency was close to 100 %. According to the Langmuir model, the adsorption capacity of LN-WB for phosphate was 75.08 mg P/g, corresponding to a molar ratio of P/La as high as 1.27. The adsorption process fit pseudo-second-order kinetics well and was mainly controlled by chemisorption. The loading efficiency of La on WB was up to 73.89 %. In initial solutions of pH = 3 and pH = 11, most of the La was retained on the biochar after phosphate adsorption. Characterization results indicated that the adsorption mechanism of phosphate on LN-WB was mainly electrostatic attraction, surface precipitation, and ligand exchange.

Preparing biochar from tobacco stalks modified with Mg is a feasible way to utilize tobacco stalks as a resource. However, the capacity of phosphate removal of Mg-biochar is affected greatly with increasing pH. In the present work, biochar produced from the tobacco stalks was modified via Mg addition and eggshells during the preparation for improving the phosphate adsorption performance at higher pH. The results revealed that the theoretical maximum adsorption capacity of phosphate for the biochar increased from 110.62 to 272.37 mg P/g when the mass ratio of Mg to tobacco stalk increased from 0.12:1 to 0.48:1 (M-C). The adsorption capacity of the biochar with a mass ratio of 0.3:1 (M-C2) was more than 200 mg P/g in the pH range of 3 to 7 but with further increase of pH from 7 to 12 the capacity decreased from 205 to 135.2 mg P g−1. Addition of eggshells with the magnesium solution during the dipping process can effectively improve the capacity of the modified biochar for phosphate in the alkaline condition. When the mass ratio of eggshell to tobacco stalk was ≥0.25:1, the phosphate adsorption capacities of the biochar can reach above 200 mg P/g within a wide pH range of 3 to 12, and the maximum adsorption capacity can reach more than 270 mg P g−1 for the mass ratio of 1:1 (EM-C24). The characterization results demonstrated that Ca and Mg were loaded on the biochar. The high adsorption performance provides reference values for the utilization of tobacco stalks and eggshells.

Inflammatory signaling under pathological conditions like infection and inflammation has been extensively studied. Whether inflammatory signaling plays a role in physiology and development remains elusive. The review summarizes recent advances in inflammatory signaling with particular focus on how distinct inflammatory signaling regulates hematopoietic stem cell (HSC) development. Understanding the underlying mechanism of inflammatory signaling on HSC development may help to generate and/or expand a large number of functional HSCs for clinical application.Like the hematopoietic progenitors, HSCs can be the first responders to infection. An unexpected observation is that genes involved in innate immunity and inflammatory signaling are enriched in emerging HSCs and their niche during embryogenesis. Thus, inflammatory signaling may also play a role in HSC development in the absence of infection and inflammation.Inflammatory signaling is not only an important regulator of HSCs in response to infection, but also plays a previously unrecognized role in HSC development in the absence of infection and inflammation. The baseline inflammatory signaling can be activated to promote HSC development in cell autonomous and noncell autonomous manners. However, direct response of HSCs to inflammatory stimuli is not always advantageous and excessive chronic signaling can have negative effects on HSC regulation and function.

Normal human embryonic stem cells (hESCs) can develop neoplastic cancer stem cell (CSC) properties after coculture with transformed hESCs in vitro. In the present study, the influence of the tumor microenvironment on malignant transformation of bone marrow stromal cells (BMSCs) was studied after allografting a mixture of enhanced green fluorescent protein (EGFP)-labeled BMSCs and C6 glioma cells into the rat brain to understand the influence of the cellular environment, especially the tumor environment, on the transformation of grafted BMSCs in the rat brain. We performed intracerebral transplantation in the rat brain using EGFP-labeled BMSCs coinjected with C6 tumor cells. After transplantation, the EGFP-labeled cells were isolated from the tumor using fluorescence-activated cell sorting, and the characteristics of the recovered cells were investigated. Glioma-specific biomarkers of the sorted cells and the biological characteristics of the tumors were analyzed. The BMSCs isolated from the cografts were transformed into glioma CSCs, as indicated by the marked expression of the glioma marker GFAP in glioma cells, and of Nestin and CD133 in neural stem cells and CSCs, as well as rapid cell growth, decreased level of the tumor suppressor gene p53, increased level of the oncogene murine double minute gene 2 (MDM2), and recapitulation of glioma tissues in the brain. These data suggest that BMSCs can be transformed into CSCs, which can be further directed toward glioma formation under certain conditions, supporting the notion that the tumor microenvironment is involved in transforming normal BMSCs into glial CSCs.

Based on the GB 15086-2013, the strength of the sliding door retention components is analyzed and optimized on a vehicle by LS-DYNA software, and the results are used for instructing experiment. The simulation accuracy is affected by five key and important factors. It indicated that the result of the simulation is consistent with experimental results. The distinction between the experiment result and the simulation result is within 10%, which satisfies with the national regulations.

The purpose of this chapter is to present a framework for examining meaning-making in the science classroom through a range of resources. Based on the notion of social semiotics from systemic functional linguistics, we propose a framework that examines the affordances of meaning in one mode, such as language, or gesture, or animation, and the multiplying of meaning across these modes. We argue that knowing what meaning can be afforded by a mode and the ways to communicate meaning across modes can enhance learning opportunities in the science classroom. We focus on three modes used in the science classroom, namely language, gesture, and animation, and propose a framework that helps unpack the meanings made. We draw on data collected from a 66-minute video recording of a Grade 9 class studying the process of digestion. We investigate the organization of meaning in the identified modes and the multiplying of meaning across modes in constructing explanations. While gestures and animation are found to make meaning through the logics of time and space, language plays a significant role in mediating the technicality of scientific knowledge. The findings also identified two ways of multiplying meaning across modes, namely, creating multimodal links and reiterating organizing structures. The complex mediation of meaning within each mode and across modes highlights the need for explicit instruction by the teacher to support and highlight how meaning is made in science and other teaching and learning contexts. We suggest that the findings are relevant for apprenticing learners into the world of science, and also apprenticing scientists into the world of teaching.

In vertebrates, embryonic hematopoietic stem and progenitor cells (HSPCs) are derived from a subset of endothelial cells, the hemogenic endothelium (HE), through the endothelial-to-hematopoietic transition (EHT). Notch signaling is essential for HSPC development during embryogenesis across vertebrates. However, whether and how it regulates EHT remains unclear. Here, we show that G protein-coupled receptor 183 (Gpr183) signaling serves as an indispensable switch for HSPC emergence by repressing Notch signaling before the onset of EHT. Inhibition of Gpr183 significantly upregulates Notch signaling and abolishes HSPC emergence. Upon activation by its ligand 7α-25-OHC, Gpr183 recruits β-arrestin1 and the E3 ligase Nedd4 to degrade Notch1 in specified HE cells and then facilitates the subsequent EHT. Importantly, 7α-25-OHC stimulation promotes HSPC emergence in vivo and in vitro, providing an attractive strategy for enhancing the in vitro generation of functional HSPCs.

Inflammatory signaling has been shown to be essential for stress hematopoiesis in adult bone marrow, either through increasing proliferation or by directing differentiation of hematopoietic stem and progenitor cells (HSPCs) toward myeloid or lymphoid lineages. However, its role in embryonic normal hematopoiesis has been unknown. Here, we demonstrate that in both zebrafish and mouse embryos, inflammatory signaling is necessary and sufficient for HSPC emergence, in the absence of infection or pathological inflammation. Mechanistically, inflammatory signaling regulates hemogenic endothelium-derived HSPC development through a conserved Toll-like receptor 4 (TLR4)-nuclear factor κ-light-chain enhancer of activated B core (NF-κB) signaling, which then promotes Notch activity, a well-known signal required for HSPC specification in vertebrates. Our findings establish a previously unrecognized link between inflammatory signaling and HSPC emergence, and provide new insights into regenerative medicine and novel therapies to treat innate immune-related diseases.

During development, hematopoietic stem cells (HSCs) undergo a rapid expansion in the fetal liver (FL) after their emergence in the aorta–gonad–mesonephros (AGM) region. We recently reported that the endolysosomal trafficking factor BLOS2, encoded by the Bloc1s2 gene, regulates HSC/hematopoietic progenitor cell emergence in the AGM region; however, whether it plays a role in the FL remains unknown. Here, we show that BLOS2 plays an essential role in the regulation of HSC proliferation and differentiation in the FL. Bloc1s2 depletion leads to elevated Notch signaling, with an increased frequency but weakened self-renewal ability of FL HSCs. Functional assays show that Bloc1s2 −/− FL HSCs harbor impaired lymphoid and myeloid differentiation abilities. These findings reveal that balanced control of Notch signaling by BLOS2 is required for HSC homeostasis during FL hematopoiesis.

SummaryT lymphoid-primed progenitors are hematopoietic progenitors destined to enter the thymus. The in vivo characterization of these embryonic progenitors is challenging, however, due to the intrauterine development of mouse embryos. Thus, how the fate of these cells is determined has not been fully defined in mammals. Here we use zebrafish embryos to show that the homing of T lymphoid-primed progenitors to the thymus is impaired, concomitant with a decrease in ccr9a expression, in the absence of irf4a. Strikingly, fate mapping assays at the single-cell level showed a fate change of irf4a-deficient T lymphoid-primed progenitors to myeloid cells, accompanied by an increase in Pu.1 expression. These data indicate that in addition to regulating ccr9a expression, Irf4a is essential in T lymphoid-primed progenitors for repressing Pu.1 expression to prevent an alternate fate. Our findings provide insight into the fate determination mechanism of T lymphoid-primed progenitors.

The earliest HSCs are derived from haemogenic endothelium via endothelial-to-haematopoietic transition during vertebrate embryogenesis; however, the underlying mechanism is largely unclear. Here we show that interplay of Smad1/5 and ERK signalling is essential for haemogenic endothelium-based HSC emergence. Smad1/5 directly inhibits erk expression through recruiting HDAC1 to and inducing de-acetylation of the erk promoter in endothelial cells. Over-activated ERK signalling conferred by inhibition of Smad1/5 promotes the arterial endothelial cell fate and constitutively strengthens the tight junction between endothelial cells, thereby repressing the specification of haemogenic endothelium and the following endothelial-to-haematopoietic transition process. These findings provide new insights into the in vitro generation of transplantable HSCs for potential clinical applications. Vertebrate haematopoietic stem cells are produced from the haemogenic endothelium by an endothelial-to-haematopoietic transition. Here, the authors show that, in zebrafish and mice, this transition depends on interplay of Smad transcription factors and the ERK signalling pathway.

Previous studies on developmental hematopoiesis have mainly focused on signaling and transcription factors, while the appreciation of epigenetic regulation including that of microRNAs is recent. Here, we show that in zebrafish and mouse, miR-142-3p is specifically expressed in hematopoietic stem cells (HSCs). Knockdown of miR-142a-3p in zebrafish led to a reduced population of HSCs in the aorta-gonad-mesonephros (AGM) region as well as T-cell defects in the thymus. Mechanistically, miR-142a-3p regulates HSC formation and differentiation through the repression of interferon regulatory factor 7 (irf7)-mediated inflammation signaling. Finally, we show that miR-142-3p is also involved in the development of HSCs in mouse AGM, suggesting that it has a highly conserved role in vertebrates. Together, these findings unveil the pivotal roles that miR-142a-3p plays in the formation and differentiation of HSCs by repressing irf7 signaling.