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Epigenetic reprogramming resets parental epigenetic memories and differentiates primordial germ cells (PGCs) into mitotic pro-spermatogonia or oogonia. This process ensures sexually dimorphic germ cell development for totipotency1. In vitro reconstitution of epigenetic reprogramming in humans remains a fundamental challenge. Here we establish a strategy for inducing epigenetic reprogramming and differentiation of pluripotent stem-cell-derived human PGC-like cells (hPGCLCs) into mitotic pro-spermatogonia or oogonia, coupled with their extensive amplification (about >1010-fold). Bone morphogenetic protein (BMP) signalling is a key driver of these processes. BMP-driven hPGCLC differentiation involves attenuation of the MAPK (ERK) pathway and both de novo and maintenance DNA methyltransferase activities, which probably promote replication-coupled, passive DNA demethylation. hPGCLCs deficient in TET1, an active DNA demethylase abundant in human germ cells2,3, differentiate into extraembryonic cells, including amnion, with de-repression of key genes that bear bivalent promoters. These cells fail to fully activate genes vital for spermatogenesis and oogenesis, and their promoters remain methylated. Our study provides a framework for epigenetic reprogramming in humans and an important advance in human biology. Through the generation of abundant mitotic pro-spermatogonia and oogonia-like cells, our results also represent a milestone for human in vitro gametogenesis research and its potential translation into reproductive medicine.A new strategy that involves signalling-molecule-driven differentiation can induce epigenetic reprogramming of human pluripotent stem cell-derived primordial germ cell-like cells to pro-spermatogonia and oogonia-like cells with massive propagation and high efficiency. [ABSTRACT FROM AUTHOR]

Although the mRNA SARS-CoV-2 vaccine has improved the mortality rate in the general population, its efficacy against rapidly mutating virus strains, especially in kidney transplant recipients, remains unclear. We examined the anti-SARS-CoV-2 spike protein IgG antibody and neutralizing antibody titers and cellular immunity against B.1.1, BA.1, and BA.5 antigens in 73 uninfected kidney recipients and 16 uninfected healthy controls who received three doses of an mRNA SARS-CoV-2 vaccine. The IgG antibody titers were significantly lower in recipients than in healthy controls. Similarly, neutralizing antibody titers against three viral variants were significantly lower in recipients. When the virus was mutated, the neutralizing antibody titers decreased significantly in both groups. In cellular immunity analysis, the number of spike-specific CD8 + non-naïve T cells against three variants significantly decreased in recipients. Conversely, the frequency of spike-specific Th2 CD4 + T-cells in recipients was higher than that in healthy controls. Nineteen recipients and six healthy controls also received a bivalent omicron-containing booster vaccine, leading to increase IgG and neutralizing antibody titers in both groups. After that, eleven recipients and five healthy controls received XBB.1.5 monovalent vaccines, increasing the neutralizing antibody titers against not only XBB.1.5, but also EG.5.1 and BA.2.86 antigens in kidney recipients. Although kidney recipients did not gain sufficient immunity against Omicron BA.5 with the third dose of vaccine, humoral response against mutant SARS-CoV-2 lineages significantly increased after bivalent Omicron-containing booster vaccine and the XBB.1.5 monovalent vaccine. Therefore, it is important for kidney recipients to continue to administer updated vaccines. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that endothelial cells can be useful therapeutic targets. One of the potential targets is an endothelial cell-specific protein, Roundabout4 (ROBO4). ROBO4 has been shown to ameliorate multiple diseases in mice, including infectious diseases and sepsis. However, its mechanisms are not fully understood. In this study, using RNA-seq analysis, we found that ROBO4 downregulates prostaglandin-endoperoxide synthase 2 (PTGS2), which encodes cyclooxygenase-2. Mechanistic analysis reveals that ROBO4 interacts with IQ motif-containing GTPase-activating protein 1 (IQGAP1) and TNF receptor-associated factor 7 (TRAF7), a ubiquitin E3 ligase. In this complex, ROBO4 enhances IQGAP1 ubiquitination through TRAF7, inhibits prolonged RAC1 activation, and decreases PTGS2 expression in inflammatory endothelial cells. In addition, Robo4-deficiency in mice exacerbates PTGS2-associated inflammatory diseases, including arthritis, edema, and pain. Thus, we reveal the molecular mechanism by which ROBO4 suppresses the inflammatory response and vascular hyperpermeability, highlighting its potential as a promising therapeutic target for inflammatory diseases. ROBO4 suppresses PTGS2/COX-2 expression by inhibiting prolonged RAC1 activation in endothelial cells, ameliorating inflammatory diseases in mice; these endothelial molecules represent potential therapeutic targets for inflammatory diseases. [ABSTRACT FROM AUTHOR]

We recently achieved the first-in-human transfusion of induced pluripotent stem cell-derived platelets (iPSC-PLTs) as an alternative to standard transfusions, which are dependent on donors and therefore variable in supply. However, heterogeneity characterized by thrombopoiesis-biased or immune-biased megakaryocytes (MKs) continues to pose a bottleneck against the standardization of iPSC-PLT manufacturing. To address this problem, here we employ microRNA (miRNA) switch biotechnology to distinguish subpopulations of imMKCLs, the MK cell lines producing iPSC-PLTs. Upon miRNA switch-based screening, we find imMKCLs with lower let-7 activity exhibit an immune-skewed transcriptional signature. Notably, the low activity of let-7a-5p results in the upregulation of RAS like proto-oncogene B (RALB) expression, which is crucial for the lineage determination of immune-biased imMKCL subpopulations and leads to the activation of interferon-dependent signaling. The dysregulation of immune properties/subpopulations, along with the secretion of inflammatory cytokines, contributes to a decline in the quality of the whole imMKCL population. The authors pioneered the iPSC-derived platelet transfusion in human. Here they employ miRNA switches, identifying RALB as a determinant of immune megakaryocytes and a marker for quality control, advancing standardization of iPSC-platelet production. [ABSTRACT FROM AUTHOR]

Recently, several studies using cultures of human embryos together with single-cell RNA-seq analyses have revealed differences between humans and mice, necessitating the study of human embryos1–8. Despite the importance of human embryology, ethical and legal restrictions have limited post-implantation-stage studies. Thus, recent efforts have focused on developing in vitro self-organizing models using human stem cells9–17. Here, we report genetic and non-genetic approaches to generate authentic hypoblast cells (naive hPSC-derived hypoblast-like cells (nHyCs))—known to give rise to one of the two extraembryonic tissues essential for embryonic development—from naive human pluripotent stem cells (hPSCs). Our nHyCs spontaneously assemble with naive hPSCs to form a three-dimensional bilaminar structure (bilaminoids) with a pro-amniotic-like cavity. In the presence of additional naive hPSC-derived analogues of the second extraembryonic tissue, the trophectoderm, the efficiency of bilaminoid formation increases from 20% to 40%, and the epiblast within the bilaminoids continues to develop in response to trophectoderm-secreted IL-6. Furthermore, we show that bilaminoids robustly recapitulate the patterning of the anterior–posterior axis and the formation of cells reflecting the pregastrula stage, the emergence of which can be shaped by genetically manipulating the DKK1/OTX2 hypoblast-like domain. We have therefore successfully modelled and identified the mechanisms by which the two extraembryonic tissues efficiently guide the stage-specific growth and progression of the epiblast as it establishes the post-implantation landmarks of human embryogenesis.Authentic hypoblast cells created from naive human pluripotent stem cells (hPSCs) spontaneously assemble with naive hPSCs to form a three-dimensional bilaminar structure (bilaminoids) with a pro-amniotic-like cavity. [ABSTRACT FROM AUTHOR]

The maternal liver is challenged by metabolic demands throughout pregnancy. However, hepatocyte dynamics and their physiological significance in pregnancy remain unclear. Here, we show in mice that hepatocyte proliferation is spatiotemporally regulated in each liver lobular zone during pregnancy, with transient proliferation of periportal and pericentral hepatocytes during mid and late gestation, respectively. Using adeno-associated virus (AAV)−8-mediated expression of the cell cycle inhibitor p21 in hepatocytes, we show that inhibition of hepatocyte proliferation during mid, but not late, gestation impairs liver growth. Transcriptionally, genes involved in glucose/glycogen metabolism are downregulated in late pregnancy when midgestational hepatocyte proliferation is attenuated. In addition, hepatic glycogen storage is abolished, with concomitant elevated blood glucose concentrations, glucose intolerance, placental glycogen deposition, and fetal overgrowth. Laser capture microdissection and RNA-seq analysis of each liver lobular zone show zone-specific changes in the transcriptome during pregnancy and identify genes that are periportally expressed at midgestation, including the hyaluronan-mediated motility receptor (Hmmr). Knockdown of Hmmr in hepatocytes by AAV8-shHmmr suppresses periportal hepatocyte proliferation at midgestation and induces impaired hepatic glycogen storage, glucose intolerance, placental glycogen deposition and fetal overgrowth. Our results suggest that periportal hepatocyte proliferation during midgestation is critical for maternal glycogen metabolism and fetal size.Delineation of the zone-specific dynamics of hepatocytes during pregnancy in mice demonstrates that midgestational periportal hepatocyte proliferation is critical for maternal glucose homeostasis during late pregnancy. [ABSTRACT FROM AUTHOR]

Formation of oriented myofibrils is a key event in musculoskeletal development. However, the mechanisms that drive myocyte orientation and fusion to control muscle directionality in adults remain enigmatic. Here, we demonstrate that the developing skeleton instructs the directional outgrowth of skeletal muscle and other soft tissues during limb and facial morphogenesis in zebrafish and mouse. Time-lapse live imaging reveals that during early craniofacial development, myoblasts condense into round clusters corresponding to future muscle groups. These clusters undergo oriented stretch and alignment during embryonic growth. Genetic perturbation of cartilage patterning or size disrupts the directionality and number of myofibrils in vivo. Laser ablation of musculoskeletal attachment points reveals tension imposed by cartilage expansion on the forming myofibers. Application of continuous tension using artificial attachment points, or stretchable membrane substrates, is sufficient to drive polarization of myocyte populations in vitro. Overall, this work outlines a biomechanical guidance mechanism that is potentially useful for engineering functional skeletal muscle. The mechanisms that drive myocyte orientation and fusion to control muscle directionality are not well understood. Here authors show that the developing skeleton produces mechanical tension that instructs the directional outgrowth of skeletal muscles. [ABSTRACT FROM AUTHOR]

Several vaccines have been widely used to counteract the global pandemic caused by SARS-CoV-2. However, due to the rapid emergence of SARS-CoV-2 variants of concern (VOCs), further development of vaccines that confer broad and longer-lasting protection against emerging VOCs are needed. Here, we report the immunological characteristics of a self-amplifying RNA (saRNA) vaccine expressing the SARS-CoV-2 Spike (S) receptor binding domain (RBD), which is membrane-anchored by fusing with an N-terminal signal sequence and a C-terminal transmembrane domain (RBD-TM). Immunization with saRNA RBD-TM delivered in lipid nanoparticles (LNP) efficiently induces T-cell and B-cell responses in non-human primates (NHPs). In addition, immunized hamsters and NHPs are protected against SARS-CoV-2 challenge. Importantly, RBD-specific antibodies against VOCs are maintained for at least 12 months in NHPs. These findings suggest that this saRNA platform expressing RBD-TM will be a useful vaccine candidate inducing durable immunity against emerging SARS-CoV-2 strains. Vaccines with broad and long-lasting protection against variants of concern are still limited. Here, the authors report a self-amplifying RNA (saRNA) vaccine expressing a membrane-anchored SARS-CoV-2 Spike RBD and show that it elicits broad, durable and protective immunity in small animal models and NHPs. [ABSTRACT FROM AUTHOR]

The entrainment mechanism of flux layer into a melt bath during its mechanical stirring was clarified in this study through numerical simulation with an aid of physical model experimentation using silicone oil and water. A three-phase multiphase flow was solved by three-phase Volume of Fluid method combining with Large Eddy Simulation model. The numerical results indicated that the entrainment of oil layer into water proceeds according to the following four steps: 1-flow development due to impeller rotation, 2-formation of low-level zone (LLZ), 3-formation of spiral deflection and 4-entrainment of oil droplet. The spiral deflections are formed due to the shear flow near the water-oil interface, and the entrainment of oil layer occurs at the deflected spots in the LLZ. [ABSTRACT FROM AUTHOR]

The effect of microstructural parameters on channel-type segregations formed during direct chill casting of Al–Mg billets is investigated through numerical simulation by solving the momentum, mass, heat, and species balance equations coupled with phase diagram. The numerical results indicate that the strip-patterned channel-type segregations are formed under conditions when the critical solid fraction is high. The dendrite arm spacing is found to slightly affect the macrosegregation formation. Also, the diameter of floating particles in the slurry zone has a significant effect on the macrosegregation, and the larger the particle diameter is, the greater the extent of macrosegregation. These phenomena are explained in terms of flow conditions. The solutal buoyancy flow in the slurry zone is enhanced with increase of the critical solid volume fraction and floating particle diameter that result in the remarkable formation of channel-type segregations. [ABSTRACT FROM AUTHOR]

Nucleic acid-based adjuvants such as CpG oligonucleotides (CpG ODNs) and poly(I:C) are potential vaccine adjuvants for infectious diseases and cancers. However, the mechanism by which their cell surface receptors promote their uptake into dendritic cells (DCs) and shuttle them to intracellular Toll-like receptors remains to be further investigated. Here, we demonstrated a role for nucleolin, a multifunctional DNA- and RNA-binding protein and a major constituent of the nucleolus, as one of the cell-surface receptors for nucleic acid-based adjuvants. Nucleolin on mouse DC surface bound directly to A-type CpG ODN, B-type CpG ODN, and poly(I:C) and promoted their internalization into cells following DC maturation in vitro. In human DCs, nucleolin also contributed to the binding and internalization of both types of CpG ODNs and subsequent cytokine production. Furthermore, nucleolin played a crucial role in cytokine production and activating antigen-specific antibodies and T cell responses induced by B-type CpG ODN in vivo in mice. Our findings provide valuable information that can help improve the efficacy and safety of these adjuvants. [ABSTRACT FROM AUTHOR]

In rotary gas injection (RGI), which is widely used in aluminum industry, impurities are removed by reaction with halide-containing chemicals injected into the melt. However, the constantly increasing concern on environmental protection obliges aluminum makers to eliminate or significantly reduce their usage. In this study, aiming at enhancing the efficiency of chlorine gas treatment for impurities removal from the melt, we investigated the effect of impeller design on the impurity mass transfer by performing physical model experiments on CO2 absorption, particle image velocimetry (PIV) measurements and numerical simulation. It is shown that a newly designed impeller intensifies the discharged flow as compared to the conventional impeller case that forces the formed bubbles to move to the fragmentation zone near the impeller blade tip. This results in an enhancement of the mass transfer. From the numerical results, it was found that these phenomena could be explained by the trailing vortex structure near the impeller blades. [ABSTRACT FROM AUTHOR]

The development of an in vitro cell model that can be used to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) research is expected. Here we conducted infection experiments in bronchial organoids (BO) and an BO-derived air-liquid interface model (BO-ALI) using 8 SARS-CoV-2 variants. The infection efficiency in BO-ALI was more than 1,000 times higher than that in BO. Among the bronchial epithelial cells, we found that ciliated cells were infected with the virus, but basal cells were not. Ciliated cells died 7 days after the viral infection, but basal cells survived after the viral infection and differentiated into ciliated cells. Fibroblast growth factor 10 signaling was essential for this differentiation. These results indicate that BO and BO-ALI may be used not only to evaluate the cell response to SARS-CoV-2 and coronavirus disease 2019 (COVID-19) therapeutic agents, but also for airway regeneration studies. Bronchial organoids (BO) and BO-derived air-liquid interface models (BO-ALI) are used to model SARS-CoV-2 infection of human bronchial epithelial cells, reporting that ciliated cells were permissive to the virus, unlike basal cells. [ABSTRACT FROM AUTHOR]

Irradiation increases the yield stress and embrittles light water reactor (LWR) pressure vessel steels. In this study, we demonstrate some of the potential benefits and risks of using machine learning models to predict irradiation hardening extrapolated to low flux, high fluence, extended life conditions. The machine learning training data included the Irradiation Variable for lower flux irradiations up to an intermediate fluence, plus the Belgian Reactor 2 and Advanced Test Reactor 1 for very high flux irradiations, up to very high fluence. Notably, the machine learning model predictions for the high fluence, intermediate flux Advanced Test Reactor 2 irradiations are superior to extrapolations of existing hardening models. The successful extrapolations showed that machine learning models are capable of capturing key intermediate flux effects at high fluence. Similar approaches, applied to expanded databases, could be used to predict hardening in LWRs under life-extension conditions. [ABSTRACT FROM AUTHOR]

Naked mole-rats (NMRs) have a very low spontaneous carcinogenesis rate, which has prompted studies on the responsible mechanisms to provide clues for human cancer prevention. However, it remains unknown whether and how NMR tissues respond to experimental carcinogenesis induction. Here, we show that NMRs exhibit extraordinary resistance against potent chemical carcinogenesis induction through a dampened inflammatory response. Although carcinogenic insults damaged skin cells of both NMRs and mice, NMR skin showed markedly lower immune cell infiltration. NMRs harbour loss-of-function mutations in RIPK3 and MLKL genes, which are essential for necroptosis, a type of necrotic cell death that activates strong inflammation. In mice, disruption of Ripk3 reduced immune cell infiltration and delayed carcinogenesis. Therefore, necroptosis deficiency may serve as a cancer resistance mechanism via attenuating the inflammatory response in NMRs. Our study sheds light on the importance of a dampened inflammatory response as a non-cell-autonomous cancer resistance mechanism in NMRs. Naked mole rats are found to be resistant to cancer development through dampened inflammatory response due to genetically determined impaired necroptosis, with essential necroptosis genes RIPK3 and MLKL containing mutations causing premature stop codons. [ABSTRACT FROM AUTHOR]

Channel-type segregation is one of the defects in aluminum casting technology, particularly in the direct chill (DC) process, having a significant influence on the cast quality. Nevertheless, the formation mechanism of three-dimensional (3D) channel-type segregations remains poorly understood. In order to clarify the formation mechanism of defects of this type, we conducted a 3D numerical simulation of the DC casting process of an Al-Mg alloy billet considering the melt flow, heat and mass transfer, solidification, and the motion of the solidified ingot, coupled with the alloy phase diagram. The simulation results showed that the channel-type segregations have strip-patterns and formed easily at high casting speeds, being localized at a distance of a half-radius from the billet centerline. We also compared two-dimensional axisymmetric and 3D simulations, and the results indicated that a two-dimensional axisymmetric simulation is incapable of properly predicting the behavior of channel-type segregations. [ABSTRACT FROM AUTHOR]

Although channel-type macro-segregations are a well-known defect formed in Direct Chill (DC) casting of aluminum alloys, their formation mechanism remains unclear up to now. To investigate the possible mechanisms, we carried out numerical simulation considering thermo-solutal flow and solidification coupled with phase diagram. The main emphasis is placed on the effect of shrinkage flow and slurry flow on the macro-segregation characteristics. The shrinkage flow causes negative segregations to form along the center axis of billet especially at high casting speeds, while channel-type segregations are not formed under these conditions. On the other hand, the slurry flow in mushy zone results in formation of the channel-type segregations in large billets at low casting speeds. In addition, formation of three types of channel-type segregations is predicted in the following locations (1) flow separation zone, (2) flow stagnant zone, (3) mushy zone where the upward solutal buoyant flow is generated. The formation condition of channel-type segregation is considered using solutal Rayleigh number for binary alloys. [ABSTRACT FROM AUTHOR]

The use of an adjuvant in vaccination is thought to be effective for enhancing immune responses to various pathogens. We genetically constructed a live attenuated simian human immunodeficiency virus (SHIV) to express the adjuvant molecule Ag85B (SHIV-Ag85B). SHIV-Ag85B could not be detected 4 weeks after injection in cynomolgus macaques, and strong SHIV-specific T cell responses were induced in these macaques. When the macaques in which SHIV-Ag85B had become undetectable were challenged with pathogenic SHIV89.6P at 37 weeks after SHIV-Ag85B had become undetectable, SHIV89.6P was not detected after the challenge. Eradication of SHIV89.6P was confirmed by adoptive transfer experiments and CD8-depletion studies. The SHIV-Ag85B-inoculated macaques showed enhancement of Gag-specific monofunctional and polyfunctional CD8+ T cells in the acute phase of the pathogenic SHIV challenge. The results suggest that SHIV-Ag85B elicited strong sterile immune responses against pathogenic SHIV and that it may lead to the development of a vaccine for AIDS virus infection. [ABSTRACT FROM AUTHOR]

The structure of written texts is analyzed by focusing on word sequences. As a method, word sequences in texts are transformed into rank sequences of the occurrence frequency of each word and return maps are drawn. The features of word sequences are extracted by comparing with the surrogate data, i.e., a sequence in which all the words are randomly rearranged. A total of 140 written texts consisting of ten languages are selected for analysis. To characterize the distribution in the return map quantitatively, two characteristic quantities are defined, the distance between the original distribution and surrogate distribution, and the correlation coefficient of the adjacent word ranks. The results show that there is a negative correlation in the rank of adjacent words in almost all languages, and features of return maps of the same language texts are similar. A clustering structure which implies the relation to language (sub)family is observed. A mathematical model is proposed for reproducing features of the return map for multiple languages. The numerical simulations achieve results similar to those of the real data quantitatively. [ABSTRACT FROM AUTHOR]

In vivo reprogramming provokes a wide range of cell fate conversion. Here, we discover that in vivo induction of higher levels of OSKM in mouse somatic cells leads to increased expression of primordial germ cell (PGC)-related genes and provokes genome-wide erasure of genomic imprinting, which takes place exclusively in PGCs. Moreover, the in vivo OSKM reprogramming results in development of cancer that resembles human germ cell tumors. Like a subgroup of germ cell tumors, propagated tumor cells can differentiate into trophoblasts. Moreover, these tumor cells give rise to induced pluripotent stem cells (iPSCs) with expanded differentiation potential into trophoblasts. Remarkably, the tumor-derived iPSCs are able to contribute to non-neoplastic somatic cells in adult mice. Mechanistically, DMRT1, which is expressed in PGCs, drives the reprogramming and propagation of the tumor cells in vivo. Furthermore, the DMRT1-related epigenetic landscape is associated with trophoblast competence of the reprogrammed cells and provides a therapeutic target for germ cell tumors. These results reveal an unappreciated route for somatic cell reprogramming and underscore the impact of reprogramming in development of germ cell tumors. The mechanisms by which in vivo expression of the Yamanaka transcription factors (OSKM) renders somatic cells permissive for differentiation remain unclear. Here, the authors show that in vivo reprogramming using OSKM generates germ cell tumors and drives acquisition of totipotency-like features in somatic cells through DMRT1. [ABSTRACT FROM AUTHOR]

Interleukin-27 (IL-27) is a cytokine that suppresses human immunodeficiency virus (HIV)-1 infection in macrophages and is considered as an immunotherapeutic reagent for infectious diseases. It is reported that IL-27 suppresses autophagy in Mycobacterium tuberculosis-infected macrophages; however, a role for IL-27 on autophagy induction has been less studied. In this study, we investigated the impact of IL-27 in both autophagy induction and HIV-1 infection in macrophages. Primary human monocytes were differentiated into macrophages using human AB serum (huAB) alone, macrophage-colony stimulating factor (M-CSF) alone, or a combination of IL-27 with huAB or M-CSF. Electron microscopy and immunofluorescence staining demonstrated that a 20-fold increase in autophagosome formation was only detected in IL-27 + huAB-induced macrophages. Western blot analysis indicated that the autophagosome induction was not linked to either dephosphorylation of the mammalian target of rapamycin (mTOR) or lipidation of microtubule-associated protein 1A/1B-light chain 3 (LC3), an autophagosomal marker, implying that IL-27 can induce autophagy through a novel non-canonical pathway. Here we show for the first time that IL-27 induces autophagy during monocyte-to-macrophage differentiation in a subtype-dependent manner. [ABSTRACT FROM AUTHOR]

InxGa1−xSe mixed crystals have been successfully grown from an indium flux by the traveling heater method at three growth temperatures. The thickness of the grown InxGa1−xSe mixed crystal perpendicular to (001) was more than 3 mm. The lattice constant, and optical and electrical properties of the InxGa1−xSe mixed crystals and undoped GaSe crystals were investigated and compared. The indium content of the InxGa1−xSe mixed crystals was observed to increase with decreasing growth temperature, while the lattice constant along the c-axis was observed to follow Vegard's law. It was confirmed that a bandgap of In0.020Ga0.980Se is narrower than that of undoped GaSe according to the photoluminescence (PL) spectra. Compared with undoped GaSe crystal, the carrier concentration p was decreased by the incorporation of indium (In0.020Ga0.980Se, p = 6.4 × 1014 cm−3 at 257 K; In0.037Ga0.963Se, p = 2.6 × 1014 cm−3 at 257 K). In addition, it was suggested that the dominant carrier scattering mechanism of high-indium-content crystals at low temperature is ionized impurity scattering. [ABSTRACT FROM AUTHOR]

Erythropoietin (EPO) is a crucial hormone for erythropoiesis and produced by adult kidneys. Insufficient EPO production in chronic kidney disease (CKD) can cause renal anemia. Although hypoxia-inducible factors (HIFs) are known as a main regulator, the mechanisms of EPO production have not been fully elucidated. In this study, we aimed to examine the roles of retinoic acid (RA) in EPO production using EPO-producing cells derived from human induced pluripotent stem cells (hiPSC-EPO cells) that we previously established. RA augmented EPO production by hiPSC-EPO cells under hypoxia or by treatment with prolyl hydroxylase domain-containing protein (PHD) inhibitors that upregulate HIF signals. Combination treatment with RA and a PHD inhibitor improved renal anemia in vitamin A-depleted CKD model mice. Our findings using hiPSC-EPO cells and CKD model mice may contribute to clarifying the EPO production mechanism and developing efficient therapies for renal anemia. [ABSTRACT FROM AUTHOR]

The RV144 HIV-1 vaccine trial has been the only clinical trial to date that has shown any degree of efficacy and associated with the presence of vaccine-elicited HIV-1 envelope-specific binding antibody and CD4+ T-cell responses. This trial also showed that a vector-prime protein boost combined vaccine strategy was better than when used alone. Here we have studied three different priming vectors—plasmid DNA, recombinant MVA, and recombinant VSV, all encoding clade C transmitted/founder Env 1086 C gp140, for priming three groups of six non-human primates each, followed by a protein boost with adjuvanted 1086 C gp120 protein. Our data showed that MVA-priming favors the development of higher antibody binding titers and neutralizing activity compared with other vectors. Analyses of the draining lymph nodes revealed that MVA-prime induced increased germinal center reactivity characterized by higher frequencies of germinal center (PNAhi) B cells, higher frequencies of antigen-specific B-cell responses as well as an increased frequency of the highly differentiated (ICOShiCD150lo) Tfh-cell subset. [ABSTRACT FROM AUTHOR]

The squamous–columnar junction (SCJ) is a boundary consisting of precisely positioned transitional epithelium between the squamous and columnar epithelium. Transitional epithelium is a hotspot for precancerous lesions, and is therefore clinically important; however, the origins and physiological properties of transitional epithelium have not been fully elucidated. Here, by using mouse genetics, lineage tracing, and organoid culture, we examine the development of the SCJ in the mouse stomach, and thus define the unique features of transitional epithelium. We find that two transcription factors, encoded by Sox2 and Gata4, specify primitive transitional epithelium into squamous and columnar epithelium. The proximal–distal segregation of Sox2 and Gata4 expression establishes the boundary of the unspecified transitional epithelium between committed squamous and columnar epithelium. Mechanistically, Gata4-mediated expression of the morphogen Fgf10 in the distal stomach and Sox2-mediated Fgfr2 expression in the proximal stomach induce the intermediate regional activation of MAPK/ERK, which prevents the differentiation of transitional epithelial cells within the SCJ boundary. Our results have implications for tissue regeneration and tumorigenesis, which are related to the SCJ. How boundary regions form in the epithelia of tissues, for example, the squamous–columnar junction is unclear. Here, the authors identify the transcription factors Sox2 and Gata4 as specifying the transitional epithelium in the murine squamous–columnar junction region in the stomach epithelia. [ABSTRACT FROM AUTHOR]

The development of precise folding techniques for synthetic polymer chains that replicate the unique structures and functions of biopolymers has long been a key challenge. In particular, spiro-type (i.e., 8-, trefoil-, and quatrefoil-shaped) polymer topologies remain challenging due to their inherent structural complexity. Herein, we establish a folding strategy to produce spiro-type multicyclic polymers via intramolecular ring-opening metathesis oligomerization of the norbornenyl groups attached at predetermined positions along a synthetic polymer precursor. This strategy provides easy access to the desired spiro-type topological polymers with a controllable number of ring units and molecular weight while retaining narrow dispersity (Ɖ < 1.1). This effective strategy marks an advancement in the development of functionalized materials composed of specific three-dimensional nanostructures. Intramolecular ring-opening metathesis oligomerisation is a useful method for constructing multicyclic polymer cages. Here, it is applied to the synthesis of spirocyclic polymers with figure-8, trefoil, and quatrefoil structures with low polydispersity. [ABSTRACT FROM AUTHOR]

The present study proposed, for the first time, an evaluation method to predict the generation rate of aluminum dross in melting or holding furnaces during mechanical stirring of molten aluminum through water model experiments and numerical simulation. In the experiments, a gas–liquid interface reaction between CO2 gas and NaOH solution was exploited as a model reaction between the aluminum melt and air moisture, and perlite particles were used to model dross layer on the free surface of liquid aluminum. The results reveal that the reaction rate is increased with the impeller rotation speed. Besides, the reaction rate depends on the impeller rotation direction, but this dependence is different for the cases of presence and absence of particles on the liquid surface. In the first case, the reaction rate at the counter-clock rotation was higher than that at the clock-wise rotation. On the other hand, in the second case, the clock-wise impeller rotation yielded a higher reaction rate compared to the counter-clock rotation case. These phenomena can be explained by the mass transfer across the gas–liquid interface at the particle-free area. [ABSTRACT FROM AUTHOR]

De novo establishment of DNA methylation is accomplished by DNMT3A and DNMT3B. Here, we analyze de novo DNA methylation in mouse embryonic fibroblasts (2i-MEFs) derived from DNA-hypomethylated 2i/L ES cells with genetic ablation of Dnmt3a or Dnmt3b. We identify 355 and 333 uniquely unmethylated genes in Dnmt3a and Dnmt3b knockout (KO) 2i-MEFs, respectively. We find that Dnmt3a is exclusively required for de novo methylation at both TSS regions and gene bodies of Polycomb group (PcG) target developmental genes, while Dnmt3b has a dominant role on the X chromosome. Consistent with this, tissue-specific DNA methylation at PcG target genes is substantially reduced in Dnmt3a KO embryos. Finally, we find that human patients with DNMT3 mutations exhibit reduced DNA methylation at regions that are hypomethylated in Dnmt3 KO 2i-MEFs. In conclusion, here we report a set of unique de novo DNA methylation target sites for both DNMT3 enzymes during mammalian development that overlap with hypomethylated sites in human patients. De novo DNA methylation is carried out by DNMT3A and DNMT3B, but the distinct functions of these two enzymes is poorly understood. Here the authors present a comprehensive, genome-wide identification of target sites for de novo DNA methylation by the DNMT3A and DNMT3B in mouse ES cells and embryos, identifying unique de novo DNA methylation target sites for both DNMT3 enzymes. [ABSTRACT FROM AUTHOR]

Pluripotent stem cells are increasingly used to model different aspects of embryogenesis and organ formation1. Despite recent advances in in vitro induction of major mesodermal lineages and cell types2,3, experimental model systems that can recapitulate more complex features of human mesoderm development and patterning are largely missing. Here we used induced pluripotent stem cells for the stepwise in vitro induction of presomitic mesoderm and its derivatives to model distinct aspects of human somitogenesis. We focused initially on modelling the human segmentation clock, a major biological concept believed to underlie the rhythmic and controlled emergence of somites, which give rise to the segmental pattern of the vertebrate axial skeleton. We observed oscillatory expression of core segmentation clock genes, including HES7 and DKK1, determined the period of the human segmentation clock to be around five hours, and demonstrated the presence of dynamic travelling-wave-like gene expression in in vitro-induced human presomitic mesoderm. Furthermore, we identified and compared oscillatory genes in human and mouse presomitic mesoderm derived from pluripotent stem cells, which revealed species-specific and shared molecular components and pathways associated with the putative mouse and human segmentation clocks. Using CRISPR–Cas9-based genome editing technology, we then targeted genes for which mutations in patients with segmentation defects of the vertebrae, such as spondylocostal dysostosis, have been reported (HES7, LFNG, DLL3 and MESP2). Subsequent analysis of patient-like and patient-derived induced pluripotent stem cells revealed gene-specific alterations in oscillation, synchronization or differentiation properties. Our findings provide insights into the human segmentation clock as well as diseases associated with human axial skeletogenesis. A system involving in vitro induction of presomitic mesoderm recapitulates oscillatory expression of core segmentation clock genes and travelling-wave-like gene expression, suggesting that this system can be used to study the human segmentation clock and provide insights into diseases associated with human axial skeletogenesis. [ABSTRACT FROM AUTHOR]

The present study investigated the mechanism of surface vortex formation in an aluminum melt vessel stirred by an axial-flow impeller mechanically. The oxide film is formed at the aluminum melt/air interface, and the movement of the interface entrains the oxide film and inclusions. Hence, the transient movement of melt–air interface is significant. The present study conducted a water model experiment and numerical simulation focusing on the movement of gas–liquid interface. The present study found that the oxide film can be entrained by two phenomena: (1) local surface vortex and (2) sloshing near the vessel wall. The local surface vortex is formed due to the pressure distribution around the impeller, and the sloshing is caused by macroinstabilities, which is generated by the discharged flow of axial-flow impeller. Besides, the shape of gas–liquid interface is dependent on the impeller shape. The axial-flow impeller gives rise to steeply curved shape of gas–liquid interface near the impeller shaft. [ABSTRACT FROM AUTHOR]

In order to determine the optimum heating rate for the planned microgravity experiments on the International Space Station (ISS), axisymmetric 2D numerical simulations were performed under the zero-gravity condition to investigate the effect of heating rate on the dissolution process of the seed and feed crystals in a sandwich system of InGaSb. The simulation results showed that the dissolution lengths of the seed and feed crystals are strongly affected by heating rate. A higher heating rate leads to larger feed and seed dissolutions. Simulation results suggest that the microgravity experiments on the ISS should not adopt a heating rate higher than 3.6 K/h in order to avoid a complete dissolution of the feed and/or seed crystals in this sandwich system. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to identify and compare risk factors for surgical site infection (SSI) and non-surgical site infections (non-SSIs), particularly urinary tract infection (UTI), after spine surgery.Methods: We retrospectively reviewed 825 patients (median age 59.0 years (range 33-70 years); 442 males) who underwent spine surgery at Kagoshima University Hospital from January 2009 to December 2014. Patient parameters were compared using the Mann-Whitney U and Fisher's exact tests. Risk factors associated with SSI and UTI were analyzed via the multiple logistic regression analysis. P < 0.05 was considered statistically significant.Results: SSI occurred in 14 of 825 cases (1.7 %), and non-SSI occurred in 23 of 825 cases (2.8 %). Most non-SSIs were UTIs (20 of 23 cases, 87.0 %). In the 14 patients with SSI, UTI occurred before SSI onset in one patient, and after SSI onset in two patients. UTI onset before SSI was not a risk factor for SSI. Multiple logistic regression analysis indicated that common risk factors for SSI and UTI were operation time (P = 0.0019 and 0.0162, respectively) and ASA classification 3 (P = 0.0132 and 0.0356, respectively). The 1 week post-operative C-reactive protein (CRP) level was a risk factor for UTI (P = 0.0299), but not for SSI (P = 0.4996).Conclusions: There was no relationship between SSI and symptomatic UTI after spine surgery. Risk factors for post-operative SSI and UTI were operative time and ASA classification 3; 1 week post-operative CRP was a risk factor for UTI only. [ABSTRACT FROM AUTHOR]

Allograft bone is a widely used as a convenient tool for reconstructing massive bone defects in orthopedic surgery. However, allografts are associated with the risk of viral disease transmission. One of the viruses transmitted in this manner is human T-lymphotropic virus type 1 (HTLV-1), which is found worldwide but is unevenly distributed. The southwestern parts of Japan are a highly endemic for HTLV-1. We investigated the HTLV-1 seroprevalence in candidate allograft donors at the regional bone bank in Kagoshima, Japan during its first 5 years of service. Between 2008 and 2012, we collected 282 femoral heads at the Kagoshima regional bone bank from living donors with osteoarthritis of the hip joint. Among the 282 candidate donors, 32 donors (11.3 %) were seropositive for anti-HTLV-1 antibody; notably, this prevalence is higher than that reported for blood donors in this area. Additionally, to determine if HTLV-1 genes are detectable after processing, we examined the bone marrow of the femoral heads from seropositive donors by conducting PCR assays. Our results confirm the existence of viral genes following the heat treatment processing of the femoral heads. Therefore, it is important to inactivate a virus completely by heat-treatment. Together, our findings highlight the importance of HTLV-1 screening at bone banks, particularly in HTLV-1-endemic areas such as southwest Japan. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus-1 (HIV-1) has infected more than 60 million people and caused nearly 30 million deaths worldwide, ultimately the consequence of cytolytic infection of CD4+ T cells. In humans and in macaque models, most of these cells contain viral DNA and are rapidly eliminated at the peak of viraemia, yet the mechanism by which HIV-1 induces helper T-cell death has not been defined. Here we show that virus-induced cell killing is triggered by viral integration. Infection by wild-type HIV-1, but not an integrase-deficient mutant, induced the death of activated primary CD4 lymphocytes. Similarly, raltegravir, a pharmacologic integrase inhibitor, abolished HIV-1-induced cell killing both in cell culture and in CD4+ T cells from acutely infected subjects. The mechanism of killing during viral integration involved the activation of DNA-dependent protein kinase (DNA-PK), a central integrator of the DNA damage response, which caused phosphorylation of p53 and histone H2AX. Pharmacological inhibition of DNA-PK abolished cell death during HIV-1 infection in vitro, suggesting that processes which reduce DNA-PK activation in CD4 cells could facilitate the formation of latently infected cells that give rise to reservoirs in vivo. We propose that activation of DNA-PK during viral integration has a central role in CD4+ T-cell depletion, raising the possibility that integrase inhibitors and interventions directed towards DNA-PK may improve T-cell survival and immune function in infected individuals. [ABSTRACT FROM AUTHOR]

Palladium-catalyzed oxidative homocoupling of terminal acetylenes, in air, occurred in the presence of 1-(2-pyridylethynyl)-2-(2-thienylethynyl)benzene as ligand, affording the corresponding conjugated diynes. [ABSTRACT FROM AUTHOR]

We propose an analog-digital circuit for detecting the movement of an object. The proposed unit circuit is a simple structure since the digital part of the circuit is constructed with only one NOT circuit and one NOR circuit. The measured results on a constructed test circuit showed that the proposed circuit can output the pulsed voltage (motion signal) when an object moves on the circuit. We proposed and constructed the system in this study in order to track target. Since the array in the proposed circuits was introduced at the first stage of the system, the circuit for tracking the target became a simple structure. It was clear from the measured results of the test system that it can track and capture a target in the center of the input section. [ABSTRACT FROM AUTHOR]

Dietary restriction is the most effective and reproducible intervention to extend lifespan in divergent species. In mammals, two regimens of dietary restriction, intermittent fasting (IF) and chronic caloric restriction, have proven to extend lifespan and reduce the incidence of age-related disorders. An important characteristic of IF is that it can increase lifespan even when there is little or no overall decrease in calorie intake. The molecular mechanisms underlying IF-induced longevity, however, remain largely unknown. Here we establish an IF regimen that effectively extends the lifespan of Caenorhabditis elegans, and show that the low molecular weight GTPase RHEB-1 has a dual role in lifespan regulation; RHEB-1 is required for the IF-induced longevity, whereas inhibition of RHEB-1 mimics the caloric-restriction effects. RHEB-1 exerts its effects in part by the insulin/insulin growth factor (IGF)-like signalling effector DAF-16 in IF. Our analyses demonstrate that most fasting-induced upregulated genes require RHEB-1 function for their induction, and that RHEB-1 and TOR signalling are required for the fasting-induced downregulation of an insulin-like peptide, INS-7. These findings identify the essential role of signalling by RHEB-1 in IF-induced longevity and gene expression changes, and suggest a molecular link between the IF-induced longevity and the insulin/IGF-like signalling pathway. [ABSTRACT FROM AUTHOR]

This review article describes recent studies on the self-assembly and co-assembly of Π-conjugated molecules into nanotubes and nanocoils. Such Π-conjugated molecules include phenylenes, phenylene vinylenes, phenylene ethynylenes, porphyrins, phthalocyanines, and polycyclic aromatic hydrocarbons, which are properly modified with hydrophilic and/or hydrophobic side chains for cooperative interactions. Not only nanocoils but also most reported nanotubes possess a helical chirality. These assembling events possibly show chiral amplification, where one-handedness can be realized even from stereochemically impure components (majority rule). Combination of components leading to non-tubular assemblies with properly chosen chiral components may give rise to nanotubes or nanocoils with one-handed helical chirality (sergeants-and-soldiers effect). Covalent modification of assembled components can enhance physical robustness against heating and solvolysis. [ABSTRACT FROM AUTHOR]

Transcriptional initiation of each gene is assumed to be independently controlled in mammals. On the other hand, recent large-scale transcriptome analyses have shown that the genome is pervasively transcribed, such that the most of its DNA gives rise to RNAs. This raises the question of whether it is possible to pinpoint and activate a particular locus without perturbing numerous neighbouring transcripts. Here we show that intensive transcription at one locus frequently spills over into its physical neighbouring loci. Rapid induction of immediate-early genes (IEGs) in response to growth factor stimulation is accompanied by co-upregulation of their neighbouring genes. Profiling the primary transcripts in the nucleus with whole-genome tiling arrays delineated simultaneous activation of transcription centred on IEGs. Even in surrounding intergenic regions, transcriptional activation took place at the same time. Acetylation levels of histone H3 and H4 are elevated along with the IEG induction and neighbouring co-upregulation. Inhibition of the mitogen-activated protein kinase (MAPK) pathway or the transcription factor SRF suppresses all transcriptional upregulation. These results suggest that transcriptional activation has a ripple effect, which may be advantageous for coordinated expression. [ABSTRACT FROM AUTHOR]

Accumulating evidence shows that tight junctions (TJs) in the granular layer contribute to the epidermal barrier, suggesting that the regulation of TJ assembly in keratinocytes may provide a clue to understanding the role of barrier formation in epidermis. In this study, we investigated the behavior of TJ-related molecules in cultured human keratinocytes during keratinization induced by transfer to high-calcium medium, and the effect of RNA interference of TJ-related molecules on intercellular permeability and morphological features. The expression of TJ-related molecules and transepithelial electrical resistance were increased by transfer to high-calcium medium. In cells under the same conditions, we observed by freeze-fracture electron microscopy that TJ strands developed on the apposing cell membranes. In contrast, the transepithelial electrical resistance was clearly suppressed when the expression of claudin-1 or occludin was blocked by RNA interference. The morphological features of these knock-down cells were the same as those of MOCK cells, except for a marked decrease in the number of TJ strands. Furthermore, claudin-1 suppression inhibited occludin localization at the cell membrane, whereas suppression of occludin did not influence the localization of claudin-1. These results suggest that claudin-1 plays a crucial role in recruiting occludin to TJs, and that occludin is involved in intercellular barrier function. [ABSTRACT FROM AUTHOR]

In epithelia, tight junctions (TJs) create a primary barrier to the diffusion of solutes through the paracellular pathway. Although TJ-related molecules are present in the epidermis, the precise mechanisms underlying TJ functions in this tissue remain unclear. In this study, we use an ultraviolet (UV) B-irradiated murine skin model, in which the epidermal barrier function has been perturbed, to demonstrate a correlation between the expression patterns of TJ-related molecules and the epidermal permeability of TJs. Occludin remained localized in the upper epidermis, regardless of UVB irradiation (0.15 J per cm2). ZO-1 was localized in the upper portion of normal epidermis, and within 3–4 days of UVB irradiation, it was expressed throughout the upper epidermis and their expression coincided with epidermal thickening. Protein expression of claudin-1 and occludin did not alter until 3 and 4 days after UVB irradiation, respectively and thereafter expression remained elevated above pre-irradiation levels. An in vivo epidermal permeability assay revealed that tight junction-barrier function was perturbed by UVB irradiation, whereby biotinylated markers clearly permeated the stratum granulosum 3–5 days after irradiation. These results suggest that TJ-related molecules play important roles in epidermal barrier function in murine skin and show that changes in their expression patterns are associated with epidermal barrier perturbation after UVB irradiation. Specifically, it appears that epidermal barrier recovery is accelerated by the increased production and dense localization of occludin in the cell–cell contact region of the stratum granulosum. [ABSTRACT FROM AUTHOR]

Nano-sized metal particles are attracting much interest in industrial and biomedical applications due to the recent progress and development of nanotechnology, and the surface-modifications by appropriate polymers are key techniques to stably express their characteristics. Herein, we applied cyclic poly(ethylene glycol) (c-PEG), having no chemical inhomogeneity, to provide a polymer topology-dependent stabilization for the surface-modification of gold nanoparticles (AuNPs) through physisorption. By simply mixing c-PEG, but not linear counterparts, enables AuNPs to maintain dispersibility through freezing, lyophilization, or heating. Surprisingly, c-PEG endowed AuNPs with even better dispersion stability than thiolated PEG (HS–PEG–OMe). The stronger affinity of c-PEG was confirmed by DLS, ζ-potential, and FT-IR. Furthermore, the c-PEG system exhibited prolonged blood circulation and enhanced tumor accumulation in mice. Our data suggests that c-PEG induces physisorption on AuNPs, supplying sufficient stability toward bio-medical applications, and would be an alternative approach to the gold–sulfur chemisorption. Many nanoparticles are stabilised by chemical functionalisation with poly(ethylene glycol) (PEG). Here, the authors report on the functionalisation of gold nanoparticles by the physical absorption of cyclic PEG and demonstrate superior stabilisation against heating, freezing and lyophilisation. [ABSTRACT FROM AUTHOR]

Discrete block co-oligomers (BCOs) are gaining considerable attention due to their potential to form highly ordered ultrasmall nanostructures suitable for lithographic templates. However, laborious synthetic routes present a major hurdle to the practical application. Herein, we report a readily available discrete BCO system that is capable of forming various self-assembled nanostructures with ultrasmall periodicity. Click coupling of propargyl-functionalized sugars (containing 1–7 glucose units) and azido-functionalized terpenoids (containing 3, 4, and 9 isoprene units) afforded the discrete and monodisperse BCOs with a desired total degree of polymerization and block ratio. These BCOs microphase separated into lamellar, gyroid, and cylindrical morphologies with the domain spacing (d) of 4.2–7.5 nm. Considering easy synthesis and rich phase behavior, presented BCO systems could be highly promising for application to diverse ~4-nm nanofabrications. Ordered nanostructures generated by block copolymer microphase separation are promising templates for nanopatterning technologies, but achieving ultrasmall microphase-separated structures is highly challenging. Here the authors report a discrete block co-oligomer system capable of forming self-assembled nanostructures with ultrasmall periodicity. [ABSTRACT FROM AUTHOR]

Background: Intrahepatic cholangiocarcinoma (ICC) is the second most common malignancy of primary liver cancer. Among the several pathological types of ICC, only five cases of the clear cell type have been reported, including the one presented below. Here we report a unique case of clear cell type ICC following laparoscopic hepatectomy. Case presentation: A 67-year-old woman had a history of hepatitis B virus. Computed tomography revealed a ring-like enhanced mass 35 mm in diameter at segment 7 in the early phase. The enhancement was prolonged to the late phase through the portal phase, while the shape was irregular. Ethoxybenzy magnetic resonance imaging revealed that the tumor had a low signal intensity on T1-weighted imaging and a high signal intensity on T2-weighted imaging. Diffusion-weighted images identified that the tumor had remarkably high signal intensity. Tumor enhancement was not detected throughout the tumor in the hepatocyte phase. Upon ICC diagnosis, a laparoscopic S7 subsegmentectomy was performed. The patient's postoperative course was uneventful. An immunohistochemical examination revealed that the cells tested positive for cytokeratin 7 (CK7), CK19, and CD56 and negative for CK20, CD10, α-fetoprotein, thyroid transcription factor-1. At 2 years after surgery, the patient remains alive without recurrence. Conclusions: Here we presented a case of clear cell ICC that was treated by laparoscopic hepatectomy. Immunological analysis, especially by CD56 and several CK markers, is helpful for diagnosing this disease. [ABSTRACT FROM AUTHOR]

Clear cell sarcoma (CCS) is a rare soft tissue sarcoma caused by the EWS/ATF1 fusion gene. Here, we established induced pluripotent stem cells (iPSCs) from EWS/ATF1-controllable murine CCS cells harboring sarcoma-associated genetic abnormalities. Sarcoma-iPSC mice develop secondary sarcomas immediately after EWS/ATF1 induction, but only in soft tissue. EWS/ATF1 expression induces oncogene-induced senescence in most cell types in sarcoma-iPSC mice but prevents it in sarcoma cells. We identify Tppp3-expressing cells in peripheral nerves as a cell-of-origin for these sarcomas. We show cell type-specific recruitment of EWS/ATF1 to enhancer regions in CCS cells. Finally, epigenetic silencing at these enhancers induces senescence and inhibits CCS cell growth through altered EWS/ATF1 binding. Together, we propose that distinct responses to premature senescence are the basis for the cell type-specificity of cancer development. The EWS-ATF1 fusion gene causes clear cell sarcoma (CCS). Here, the authors show that the downstream effects of EWS-ATF1 expression are strictly context dependent, and reveal the cell of origin for CCS to be Tppp3-expressing cells in peripheral nerves. [ABSTRACT FROM AUTHOR]