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  • 1
    Publication Date: 2018-10-16
    Description: A comprehensive study of the electronic structure, thermodynamic and electrical transport properties reveals the existence of inhomogeneous superconductivity due to structural disorder in Ca 3 Rh 4 Sn 13 doped with La (Ca 3− x La x Rh 4 Sn 13 ) or Ce (Ca 3− x Ce x Rh 4 Sn 13 ) with superconducting critical temperatures ##IMG## [http://ej.iop.org/images/1367-2630/20/10/103020/njpaae4a8ieqn1.gif] {${T}_{c}^{\star }$} higher than those ( T c ) observed in the parent compounds. The T − x diagrams and the entropy S ( x ) T isotherms document well the relation between the degree of atomic disorder and separation of the high-temperature ##IMG## [http://ej.iop.org/images/1367-2630/20/10/103020/njpaae4a8ieqn2.gif] {${T}_{c}^{\star }$} and
    Electronic ISSN: 1367-2630
    Topics: Physics
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  • 2
    Publication Date: 2018-07-27
    Description: Ras mutations are commonly observed in juvenile myelomonocytic leukemia (JMML) and chronic myelomonocytic leukemia (CMML). JMML and CMML transform into acute myeloid leukemia (AML) in about 10% and 50% of patients, respectively. However, how additional events cooperate with Ras to promote this transformation are largely unknown. We show that absence of the ubiquitin-specific peptidase 22 (USP22), a component of the Spt-Ada-GCN5-acetyltransferase chromatin-remodeling complex that is linked to cancer progression, unexpectedly promotes AML transformation in mice expressing oncogenic Kras G12D/+ . USP22 deficiency in Kras G12D/+ mice resulted in shorter survival compared with control mice. This was due to a block in myeloid cell differentiation leading to the generation of AML. This effect was cell autonomous because mice transplanted with USP22-deficient Kras G12D/+ cells developed an aggressive disease and died rapidly. The transcriptome profile of USP22-deficient Kras G12D/+ progenitors resembled leukemic stem cells and was highly correlated with genes associated with poor prognosis in AML. We show that USP22 functions as a PU.1 deubiquitylase by positively regulating its protein stability and promoting the expression of PU.1 target genes. Reconstitution of PU.1 overexpression in USP22-deficient Kras G12D/+ progenitors rescued their differentiation. Our findings uncovered an unexpected role for USP22 in Ras-induced leukemogenesis and provide further insights into the function of USP22 in carcinogenesis.
    Keywords: Myeloid Neoplasia, Phagocytes, Granulocytes, and Myelopoiesis
    Print ISSN: 0006-4971
    Electronic ISSN: 1528-0020
    Topics: Biology , Medicine
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  • 3
    Publication Date: 2018-05-08
    Description: GATA-binding protein 3 (GATA3) acts as the master transcription factor for type 2 T helper (Th2) cell differentiation and function. However, it is still elusive how GATA3 function is precisely regulated in Th2 cells. Here, we show that the transcription factor B cell lymphoma 11b (Bcl11b), a previously unknown component of GATA3 transcriptional complex, is involved in GATA3-mediated gene regulation. Bcl11b binds to GATA3 through protein–protein interaction, and they colocalize at many important cis-regulatory elements in Th2 cells. The expression of type 2 cytokines, including IL-4, IL-5, and IL-13, is up-regulated in Bcl11b -deficient Th2 cells both in vitro and in vivo; such up-regulation is completely GATA3 dependent. Genome-wide analyses of Bcl11b- and GATA3-regulated genes (from RNA sequencing), cobinding patterns (from chromatin immunoprecipitation sequencing), and Bcl11b-modulated epigenetic modification and gene accessibility suggest that GATA3/Bcl11b complex is involved in limiting Th2 gene expression, as well as in inhibiting non-Th2 gene expression. Thus, Bcl11b controls both GATA3-mediated gene activation and repression in Th2 cells.
    Print ISSN: 0022-1007
    Electronic ISSN: 1540-9538
    Topics: Medicine
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  • 4
    Publication Date: 2018-01-20
    Description: Initiation of eukaryotic chromosome replication follows a spatiotemporal program. The current model suggests that replication origins compete for a limited pool of initiation factors. However, it remains to be answered how these limiting factors are preferentially recruited to early origins. Here, we report that Dbf4 is enriched at early origins through its interaction with forkhead transcription factors Fkh1 and Fkh2. This interaction is mediated by the Dbf4 C terminus and was successfully reconstituted in vitro. An interaction-defective mutant, dbf4C , phenocopies fkh alleles in terms of origin firing. Remarkably, genome-wide replication profiles reveal that the direct fusion of the DNA-binding domain (DBD) of Fkh1 to Dbf4 restores the Fkh-dependent origin firing but interferes specifically with the pericentromeric origin activation. Furthermore, Dbf4 interacts directly with Sld3 and promotes the recruitment of downstream limiting factors. These data suggest that Fkh1 targets Dbf4 to a subset of noncentromeric origins to promote early replication in a manner that is reminiscent of the recruitment of Dbf4 to pericentromeric origins by Ctf19.
    Print ISSN: 0890-9369
    Topics: Biology
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  • 5
    Publication Date: 2018-11-20
    Description: Although a number of studies have recently explored the contribution of the adaptive immunity in IL-33–mediated antitumor effects, innate immune involvement has been poorly characterized. Utilizing Rag1 –/– mice (lacking T and B lymphocytes), we show in this study that either systemic administration of recombinant IL-33 or ectopic expression of IL-33 in melanoma cells is sufficient to inhibit tumor growth independent of adaptive antitumor immunity. We have demonstrated that IL-33–mediated antitumor effects depend on expansion and activation of NK cells. Interestingly, IL-33 also promoted the expansion of active type 2 innate lymphoid cells (ILC2s) via its receptor, ST2, which in turn inhibited NK activation and cytotoxicity. This IL-33–induced ILC2 activity coincided with greater expression of the immunosuppressive ectoenzyme CD73. Removal of CD73 from ILC2s in culture with NK cells resulted in markedly increased activation levels in NK cells, offering a potential mechanism by which ILC2s might suppress NK cell–mediated tumor killing. Thus, our data reveal an important contribution of IL-33–induced ILC2 to tumor growth by weakening NK cell activation and tumor killing, regardless of adaptive immunity.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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  • 6
    Publication Date: 2018-06-09
    Description: Soft adaptable materials that change their shapes, volumes, and properties in response to changes under ambient conditions have important applications in tissue engineering, soft robotics, biosensing, and flexible displays. Upon water absorption, most existing soft materials, such as hydrogels, show a positive volume change, corresponding to a positive swelling. By contrast, the negative swelling represents a relatively unusual phenomenon that does not exist in most natural materials. The development of material systems capable of large or anisotropic negative swelling remains a challenge. We combine analytic modeling, finite element analyses, and experiments to design a type of soft mechanical metamaterials that can achieve large effective negative swelling ratios and tunable stress-strain curves, with desired isotropic/anisotropic features. This material system exploits horseshoe-shaped composite microstructures of hydrogel and passive materials as the building blocks, which extend into a periodic network, following the lattice constructions. The building block structure leverages a sandwiched configuration to convert the hydraulic swelling deformations of hydrogel into bending deformations, thereby resulting in an effective shrinkage (up to around –47% linear strain) of the entire network. By introducing spatially heterogeneous designs, we demonstrated a range of unusual, anisotropic swelling responses, including those with expansion in one direction and, simultaneously, shrinkage along the perpendicular direction. The design approach, as validated by experiments, allows the determination of tailored microstructure geometries to yield desired length/area changes. These design concepts expand the capabilities of existing soft materials and hold promising potential for applications in a diverse range of areas.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 7
    Publication Date: 2018-11-06
    Description: T follicular helper (Tfh) cells express transcription factor BCL-6 and cytokine IL-21. Mature Tfh cells are also capable of producing IFN- without expressing the Th1 transcription factor T-bet. Whether this IFN-–producing Tfh population represents a unique Tfh subset with a distinct differentiation pathway is poorly understood. By using T-bet fate–mapping mouse strains, we discovered that almost all the IFN-–producing Tfh cells have previously expressed T-bet and express high levels of NKG2D. DNase I hypersensitivity analysis indicated that the Ifng gene locus is partially accessible in this "ex–T-bet" population with a history of T-bet expression. Furthermore, multicolor tissue imaging revealed that the ex–T-bet Tfh cells found in germinal centers express IFN- in situ. Finally, we found that IFN-–expressing Tfh cells are absent in T-bet–deficient mice, but fully present in mice with T-bet deletion at late stages of T cell differentiation. Together, our findings demonstrate that transient expression of T-bet epigenetically imprints the Ifng locus for cytokine production in this Th1-like Tfh cell subset.
    Print ISSN: 0022-1007
    Electronic ISSN: 1540-9538
    Topics: Medicine
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