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Pyroptosis is an inflammatory programmed cell death, showing potentials to be a novel anti-cancer approach. However, the roles of pyroptosis-related (PR) genes (PRGs) in pancreatic adenocarcinoma (PAAD) remain elusive. In the present study, we constructed a novel PR risk signature through the lasso regression analysis. The risk signature was greatly conducive to PAAD prognostic assessment. PR risk score was identified as an independent prognostic factor and could distinguish the prognostic differences of most clinical subgroups. Meanwhile, it could improve the traditional prognostic models based on TNM-staging. Next, its prognostic value was also tested in five validation cohorts. Using CIBERSORT, ESTIMATE, and ssGSEA algorithms, the effects of PR risk signature on tumor immune microenvironment (TIM) were explored. High PR risk suppressed antitumor immune through decreasing the infiltrating levels of CD8 T and NK cells. The genomic information and histological expression of risk PRGs were uncovered by USCA and HPA databases. Somatic mutation, methylation alteration, and homozygous CNV of eight PRGs barely occurred in PAAD samples. As for therapeutic correlation, PR risk score may not predict the efficacy of PD-1/L1 inhibitors and was weakly associated with multiple drug susceptibilities. Finally, the biofunctions of toll like receptor 3 (TLR3) in pancreatic cancer (PC) cells were investigated through qPCR, MTT, colony formation, and Transwell assays. Overexpression of TLR3 could promote the proliferation, migration, and invasion of PC cells. In conclusion, PRGs play crucial roles in prognosis, progression, and immune microenvironment of PAAD. TLR3 is expected to be a promising therapeutic target.

Endothelial-specific m 6 A modulates mouse hematopoietic stem and progenitor cell development via Notch signaling

Lv et al. show that in mice, 5-HT can be synthesized in the aorta-gonad-mesonephros and acts as a novel endogenous regulator of hematopoietic stem and progenitor cell (HSPC) development. The promoting effect of 5-HT on the survival of HSPCs in the intraaortic hematopoietic cluster is mediated through Htr5a-AKT-Foxo1 signaling., The in vitro or ex vivo production of transplantable hematopoietic stem cells (HSCs) holds great promise for the treatment of hematological diseases in the clinic. However, HSCs have not been produced from either embryonic or induced pluripotent stem cells. In this study, we report that 5-hydroxytryptamine (5-HT; also called serotonin) can enhance the generation of hematopoietic stem and progenitor cells (HSPCs) in vitro and is essential for the survival of HSPCs in vivo during embryogenesis. In tryptophan hydroxylase 2–deficient embryos, a decrease in 5-HT synthesized in the aorta-gonad-mesonephros leads to apoptosis of nascent HSPCs. Mechanistically, 5-HT inhibits the AKT-Foxo1 signaling cascade to protect the earliest HSPCs in intraaortic hematopoietic clusters from excessive apoptosis. Collectively, our results reveal an unexpected role of 5-HT in HSPC development and suggest that 5-HT signaling may be a potential therapeutic target for promoting HSPC survival.

The limitation of using mouse embryos for hematopoiesis studies is the added inconvenience in operations, which is largely due to the intrauterine development of the embryo. Although genetic data from knockout (KO) mice are convincing, it is not realistic to generate KO mice for all genes as needed. In addition, performing in vivo rescue experiments to consolidate the data obtained from KO mice is not convenient. To overcome these limitations, the Aorta-Gonad-Mesonephros (AGM) explant culture was developed as an appropriate system to study hematopoietic stem cell (HSC) development. Especially for rescue experiments, it can be used to recover the impaired hematopoiesis in KO mice. By adding the appropriate chemicals into the medium, the impaired signaling can be reactivated or up-regulated pathways can be inhibited. With the use of this method, many experiments can be performed to identify the critical regulators of HSC development, including HSC related gene expression at mRNA and protein levels, colony formation ability, and reconstitution capacity. This series of experiments would be helpful in defining the underlying mechanisms essential for HSC development in mammals.

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.

Serotonin, or 5-hydroxytryptamine (5-HT), is a well-known neurotransmitter that plays vital roles in neural activities and social behaviors. Clinically, deficiency of serotonin is linked with many psychiatric disorders. Interestingly, a large proportion of serotonin is also produced outside the central nervous system (CNS). There is increasing evidence demonstrating important roles of serotonin in the peripheral tissues. Here, we will describe the multiple biological functions of serotonin in hematopoietic system, such as development of hematopoietic stem and progenitor cells (HSPCs), differentiation of hematopoietic cells, maintenance of vascular system, and relationship with hematological diseases. The roles of serotonin in inflammatory responses mediated by hematopoietic cells as well as in liver regeneration are also discussed. Our recent understandings of the impact of serotonin on hematopoietic system, immune responses, and tissue regeneration support utilization of serotonin as a potential therapeutic target for the treatment of hematological diseases and organ repair in clinic.

Summary In mammals, hematopoietic stem and progenitor cells (HSPCs) rapidly expand in the fetal liver (FL), but the underlying mechanism remains unclear. Here, we characterize zebrafish caudal hematopoietic tissue (CHT) and identify an important cellular and molecular mechanism of HSPC expansion. Time-lapse imaging showed that HSPCs localize adjacent to vascular endothelial cells (ECs), and their migration and expansion display caudal vein-specific orientation in the CHT. RNA sequencing and functional analysis identified that an EC-expressed transcription factor, Kruppel-like factor 6a (Klf6a), is essential for the CHT niche. We further demonstrated that Klf6a directly regulates the expression of the chemokine (C-C motif) ligand 25b to modulate HSPC lodgment and proliferation. Ex vivo culture results support the conserved role of Ccl21/Ccr7 signaling in promoting HSPC expansion in mammals. Together, we identify the Klf6a-Ccl25b/Ccr7 axis in controlling the complex HSPC-CHT niche interaction, which may be applicable to in vitro expansion or engraftment of HSPCs after transplantation.

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.

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Porcine reproductive and respiratory syndrome (PRRS) caused by the PRRS virus (PRRSV) is an important swine disease worldwide. PRRSV has a limited tropism for certain cells, which may at least in part be attributed to the expression of the necessary cellular molecules serving as the virus receptors or factors on host cells for virus binding or entry. However, these molecules conferring PRRSV infection have not been fully characterized. Here we show the identification of non-muscle myosin heavy chain 9 (MYH9) as an essential factor for PRRSV infection using the anti-idiotypic antibody specific to the PRRSV glycoprotein GP5. MYH9 physically interacts with the PRRSV GP5 protein via its C-terminal domain and confers susceptibility of cells to PRRSV infection. These findings indicate that MYH9 is an essential factor for PRRSV infection and provide new insights into PRRSV-host interactions and viral entry, potentially facilitating development of control strategies for this important swine disease.

An oxalate precursor route was used to synthesize (Bi,Na) 0,83- Ba 0.17 TiO 3 nanopowders. Perovskite phases developed at 750 °C, and the particles were uniform and well dispersed with a diameter smaller than 100 nm. Using such powders, a dense ceramics with a particular subgrain microstructure was sintered at the low temperature of ))20"C. This ceramics exhibits excellent electrical properties: the electromechanical coupling factor k p is 18.3%, the dielectric loss tanδ is 2.23%, the depolarization temperature T d is 235 °C, and the temperature corresponding to the maximum value of the dielectric constant T m is 249°C. Furthermore, the temperature range of the antiferroelectric state decreased.

Avian hepatitis E virus (HEV) is related genetically and antigenically to human and swine HEVs and capsid protein of avian HEV shares approximately 48-49% amino acid sequence identities with those of human and swine HEVs. Six monoclonal antibodies (MAbs) were produced and used to locate different epitopes in the ORF2 region of aa 339-570 of avian HEV Chinese isolate. The results showed that five epitopes were located in the aa 339-414 region and one in the aa 510-515 region. Two epitopes located in aa 339-355 and aa 384-414 regions are the immunodominant epitopes on the surface of the avian HEV particles as demonstrated by immune capture of viral particles and immunohistochemical detection of the ORF2 antigens with two MAbs.

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.

Large size and high-quality YCa 4 O(BO 3 ) 3 (YCOB) crystal can be grown using the conventional Czochralski pulling method. The theoretical calculations of the effective coefficient (d eff ) and the walk-off angles at 530 nm of YCOB along various phase-matching (PM) directions are reported. The PM direction along (0 = 64.5°, φ = 144.5°) for YCOB crystal has the largest d eff- Second-harmonic generation (SHG) experiments were performed on YCOB crystal along various PM directions. The results show that in 6 mm long YCOB crystal, the SHG conversion efficiency is 39% along the PM direction (θ = 64.5°, φ = 144.5°) at 80 MW/cm 2 input power density, which is larger than that along (0 = 64.5°, φ = 35.5°) and the PM direction in the XZ main plane. The experimental result is in good agreement with the theoretical calculations.

Using (Bi0.5Na0.5)0.83Ba0.17TiO3 nanopowders synthesized by an oxalate precursor route, 0.2-wt %-CuO-doped ceramics can be sintered at a low temperature of 880 °C. The shrinkage rate is 16.5%, the relative density D r is 98%, the relative dielectric constant εT 33/ε0 (1 kHz) is 705, the loss tan δ (1 kHz) is 2.50%, the electromechanical coupling factor k p is 13.6%, and the piezoelectric charge coefficient d 33 is 105 pC/N.

(Bi0.5Na0.5)0.83Ba0.17TiO3–x wt % CuO ceramics were prepared by a conventional ceramics fabrication method. The effects of CuO doping on densification, microstructure, and electrical properties are presented. The 0.2 wt % CuO-doped sample sintered at 1060 °C for 2 h exhibits good properties: a shrinkage rate of 16.5%, a relative density of 97%, a relative dielectric constant ε 33 T /ε 0 of 555 and a dielectric loss of 2.10% at 1 kHz, an electromechanical coupling factor k p of 18.0%, a piezoelectric charge coefficient d 33 of 148 pC/N, a frequency constant N p of 3096 Hz·m, a mechanical quality factor Q m of 52, a depolarization temperature T d of 218 °C, and a temperature corresponding to the maximum dielectric constant T m of 249 °C.

The nonlinear optical coefficients of YCa4O(BO3)3 (YCOB) have been calculated for the first time to the authors’ knowledge by use of the revised Gaussian 92 program on the basis of the anionic group theory. The d11,d12,d32, and d33 coefficients of the crystal were determined by the Maker fringes method at λ=1064 nm, and d13, and d31 were also evaluated by measurement of the Maker fringes. The coefficients determined by the Maker fringes are in agreement with the theoretical values. On the basis of the dij coefficients and the Sellmeier equations, the effective second-harmonic generation (SHG) coefficient deff of YCOB as a function of phase-matching angles θ and Φ was determined. It is interesting that the maximum effective SHG coefficient deff of YCOB is not in the principal plane but is located out of the X–Z plane in the positions θ=65.9°,Φ=36.5° and θ=66.3°,Φ=143.5°. It is also worth noting that the largest deff of YCOB in the region of 0°