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Summary: MLL‐rearranged (MLL‐r) leukaemia is observed in approximately 10% of acute myeloid leukaemia (AML) and is associated with a relatively poor prognosis, highlighting the need for new treatment regimens. MLL fusion proteins produced by MLL rearrangements recruit KDM4C to mediate epigenetic reprogramming, which is required for the maintenance of MLL‐r leukaemia. In this study, we used a combinatorial drug screen to selectively identify synergistic treatment partners for the KDM4C inhibitor SD70. The results showed that the drug combination of SD70 and MI‐503, a potent menin‐MLL inhibitor, induced synergistically enhanced apoptosis in MLL::AF9 leukaemia cells without affecting normal CD34+ cells. In vivo treatment with SD70 and MI‐503 significantly prolonged survival in AML xenograft models. Differential gene expression analysis by RNA‐seq following combined pharmacological inhibition of SD70 and MI‐503 revealed changes in numerous genes, with MYC target genes being the most significantly downregulated. Taken together, these data provide preclinical evidence that the combination of SD70 and MI‐503 is a potential dual‐targeted therapy for MLL::AF9 AML. [ABSTRACT FROM AUTHOR]

Realizing the rational control of two-dimensional valleytronics is appealing for potential applications in valleytronic devices. Using density functional theory method, we systematically study the magnetoelectronic coupling properties in ferrovalley/ferroelectricity van der Waals (vdW) heterostructure, ScI2/Ga2STe2. Interestingly, an on/off transition of the valley nature is found for this multiferroic ScI2/Ga2STe2 heterostructure. Under the Ga2STe2-P↑ polarization state, the heterostructure shows a ferromagnetic (FM) semiconducting feature with valley polarization, while it turns out to be FM metal when the ferroelectric (FE) polarization is switched to Ga2STe2-P↓; therefore, a switchable valleytronic device can be realized by altering the FE polarization direction. Furthermore, it is found that such switchable valleytronic behaviors of the ScI2/Ga2STe2 heterostructure can be modulated by applying biaxial strains for both FE polarization directions. The research of nonvolatile electrical control of valley splitting in the two-dimensional ScI2/Ga2STe2 multiferroic heterostructure provides a way for designing all-in-one valleytronic devices. [ABSTRACT FROM AUTHOR]

Currently, two-dimensional (2D) materials with intrinsic antiferromagnetism have stimulated research interest due to their insensitivity to external magnetic fields and absence of stray fields. Here, we predict a family of stable transition metal (TM) borides, TMB12 (TM = V, Cr, Mn, Fe) monolayers, by combining TM atoms and B12 icosahedra based on first-principles calculations. Our results show that the four TMB12 monolayers have stable antiferromagnetic (AFM) ground states with large magnetic anisotropic energy. Among them, three TMB12 (TM=V, Cr, Mn) monolayers display an in-plane easy magnetization axis, while the FeB12 monolayer has an out-of-plane easy magnetization axis. Among them, the CrB12 and the FeB12 monolayers are AFM semiconductors with band gaps of 0.13 eV and 0.35 eV, respectively. In particular, the AFM FeB12 monolayer is a spin-polarized AFM material with a Néel temperature of 125 K. Moreover, the electronic and magnetic properties of the CrB12 and the FeB12 monolayers can be modulated by imposing external biaxial strains. Our findings show that the TMB12 monolayers are candidates for designing 2D AFM materials, with potential applications in electronic devices. [ABSTRACT FROM AUTHOR]

Multiferroic van der Waals (vdW) heterostructures (HSs) prepared by combining different ferroic materials offer an exciting platform for next-generation nanoelectronic devices. In this work, we investigate the magnetoelectric coupling properties of multiferroic vdW HSs consisting of a magnetic TMBr2 (TM = V–Ni) monolayer and a ferroelectric Ga2SSe2 monolayer using first-principles theory calculations. It is found that the magnetic orderings in the magnetic TMBr2 layers are robust and the band alignment of these TMBr2/Ga2SSe2 HSs can be altered by reversing the polarization direction of the ferroelectric layer. Among them, VBr2/Ga2SSe2 and FeBr2/Ga2SSe2 HSs can be switched from a type-I to a type-II semiconductor, which allows the generation of spin-polarized and unpolarized photocurrent. Besides, CrBr2/Ga2SSe2, CoBr2/Ga2SSe2 and NiBr2/Ga2SSe2 exhibit a type-II band alignment in reverse ferroelectric polarization states. Moreover, the magnetic configuration and band alignment of these TMBr2/Ga2SSe2 HSs can be further modulated by applying an external strain. Our findings suggest the potential of TMBr2/Ga2SSe2 HSs in 2D multiferroic and spintronic applications. [ABSTRACT FROM AUTHOR]

Epithelial integrity in metazoan organs is maintained through the regulated proliferation and differentiation of organ-specific stem and progenitor cells. Although the epithelia of organs such as the intestine regenerate constantly and thus remain continuously proliferative (1), other organs, such as the mammalian urinary bladder, shift from near-quiescence to a highly proliferative state in response to epithelial injury (2-4). The cellular and molecular mechanisms underlying this injury-induced mode of regenerative response are poorly defined. Here we show in mice that the proliferative response to bacterial infection or chemical injury within the bladder is regulated by signal feedback between basal cells of the urothelium and the stromal cells that underlie them. We demonstrate that these basal cells include stem cells capable of regenerating all cell types within the urothelium, and are marked by expression of the secreted protein signal Sonic hedgehog (Shh). On injury, Shh expression in these basal cells increases and elicits increased stromal expression of Wnt protein signals, which in turn stimulate the proliferation of both urothelial and stromal cells. The heightened activity of this signal feedback circuit and the associated increase in cell proliferation appear to be required for restoration of urothelial function and, in the case of bacterial injury, may help clear and prevent further spread of infection. Our findings provide a conceptual framework for injury-induced epithelial regeneration in endodermal organs, and may provide a basis for understanding the roles of signalling pathways in cancer growth and metastasis., The multi-layered bladder epithelium consists of a lumenal layer of fully differentiated, usually binucleate umbrella cells (5), which overlie intermediate cells with limited proliferative potential, and long-term label-retaining basal cells [...]

Research was conducted to examine the cleavage of the purified LeuRS into two peptides of 64 and 33 kDa, the location of cleavage site within the large connecting polypeptide (CP1) and the effect of cleavage on function. Results demonstrate that the cleavage of the E2O2-A293 peptide bond in the CP1 domain of LeuRS does not disturb the structure of its active center for the ATP~PP(sub i) exchange reaction, the cleaved enzyme still catalyzing leucine activation.

The aim of this study was to evaluate the impact of genetic polymorphisms in the pharmacokinetics of metabolism and transportation of lenvatinib in the Chinese population. Sixty-three healthy Chinese individuals were recruited and administered with a single dose of 4 mg lenvatinib. Allelic discriminations for 10 SNPs of CYP3A4 (20230 G>A(*1G)), CYP3A5 (6986 A>G(*3)), ABCB1 (1236 C>T, 2677 G>T/A, 3435 C>T), ABCG2 (421 C>A, 34 G>A), ABCC2 (-24 C>T, 1249 G>A, 3972 C>T) were performed. The concentrations of lenvatinib in the plasma were determined by UPLC-MS/MS. Under the fasting condition, individuals carrying of ABCB1 3435 C>T genotype presented lower Cmax (p < 0.01) and λz (p < 0.05), but higher t1/2 (p < 0.05) than those carrying C/C and T/T genotypes. For ABCB1 2677 G>T/A variant, individuals with the G/T and A/G genotype showed higher AUC (p < 0.05) and t1/2 (p < 0.01), but lower λz (p < 0.05) than those carrying G/G genotypes. Individuals with the A/T, A/A and T/T genotype had higher AUC, but no significant differences (p > 0.05) were observed. They also had higher t1/2 (p < 0.01) and lower λz (p < 0.01) than those carrying G/G genotypes. Under the fed condition, no difference in any pharmacokinetic parameters were observed with any polymorphisms in the 10 fragments. Data in this paper had demonstrated that polymorphisms ABCB1 3435 C>T and ABCB1 2677 G>T/A were associated with the pharmacokinetic variability of lenvatinib. [ABSTRACT FROM AUTHOR]

In the mouse, Frizzled3 (Fz3) and Frizzled6 (Fz6) have been shown previously to control axonal growth and guidance in the CNS and hair patterning in the skin, respectively. Here, we report that Fz3 and Fz6 redundantly control neural tube closure and the planar orientation of hair bundles on a subset of auditory and vestibular sensory cells. In the inner ear, Fz3 and Fz6 proteins are localized to the lateral faces of sensory and supporting cells in all sensory epithelia in a pattern that correlates with the axis of planar polarity. Interestingly, the polarity of Fz6 localization with respect to the asymmetric position of the kinocilium is reversed between vestibular hair cells in the cristae of the semicircular canals and auditory hair cells in the organ of Corti. Vangl2, one of two mammalian homologs of the Drosophila planar cell polarity (PCP) gene van Gogh/Strabismus, is also required for correct hair bundle orientation on a subset of auditory sensory cells and on all vestibular sensory cells. In the inner ear of a Vangl2 mutant (Looptail; Lp), Fz3 and Fz6 proteins accumulate to normal levels but do not localize correctly at the cell surface. These results support the view that vertebrates and invertebrates use similar molecular mechanisms to control a wide variety of PCP-dependent developmental processes. This study also establishes the vestibular sensory epithelium as a tractable tissue for analyzing PCP, and it introduces the use of genetic mosaics for determining the absolute orientation of PCP proteins in mammals. [ABSTRACT FROM AUTHOR]

Leukemia stem cells (LSC) are a rare population capable of limitless self-renewal and are responsible for the initiation, maintenance, and relapse of leukemia. Elucidation of the mechanisms underlying the regulation of LSC function could provide novel treatment strategies. Here, we show that TWIST1 is extremely highly expressed in the LSC of MLL-AF9+ acute myeloid leukemia (AML), and its upregulation is positively regulated by KDM4C in a H3K9me3 demethylation-dependent manner. We further demonstrate that TWIST1 is essential for the viability, dormancy, and self-renewal capacities of LSC, and that it promotes the initiation and maintenance of MLL-AF9-mediated AML. In addition, TWIST1 directly interacts and collaborates with HOXA9 in inducing AML in mice. Mechanistically, TWIST1 exerts its oncogenic function by activating the WNT5a/RAC1 axis. Collectively, our study uncovers a critical role of TWIST1 in LSC function and provides new mechanistic insights into the pathogenesis of MLL-AF9+ AML.

Multiferroic van der Waals (vdW) heterostructures (HSs) prepared by combining different ferroic materials offer an exciting platform for next-generation nanoelectronic devices. In this work, we investigate the magnetoelectric coupling properties of multiferroic vdW HSs consisting of a magnetic TMBr 2 (TM = V-Ni) monolayer and a ferroelectric Ga 2 SSe 2 monolayer using first-principles theory calculations. It is found that the magnetic orderings in the magnetic TMBr 2 layers are robust and the band alignment of these TMBr 2 /Ga 2 SSe 2 HSs can be altered by reversing the polarization direction of the ferroelectric layer. Among them, VBr 2 /Ga 2 SSe 2 and FeBr 2 /Ga 2 SSe 2 HSs can be switched from a type-I to a type-II semiconductor, which allows the generation of spin-polarized and unpolarized photocurrent. Besides, CrBr 2 /Ga 2 SSe 2 , CoBr 2 /Ga 2 SSe 2 and NiBr 2 /Ga 2 SSe 2 exhibit a type-II band alignment in reverse ferroelectric polarization states. Moreover, the magnetic configuration and band alignment of these TMBr 2 /Ga 2 SSe 2 HSs can be further modulated by applying an external strain. Our findings suggest the potential of TMBr 2 /Ga 2 SSe 2 HSs in 2D multiferroic and spintronic applications.

Telomerase is essential for telomere length maintenance. Mutations in either of the two core components of telomerase, telomerase RNA (TR) or the catalytic protein component telomerase reverse transcriptase (TERT), cause the genetic disorders dyskeratosis congenita, pulmonary fibrosis, and other degenerative diseases. Overexpression of the TERT protein has been reported to have telomere length-independent roles, including regulation of the Wnt signaling pathway. To examine the phenotypes of TERT haploinsufficiency and determine whether loss of function of TERT has effects other than those associated with telomere shortening, we characterized both mTERT⁺/⁻ and mTERT⁻/⁻ mice on the CAST/EiJ genetic background. Phenotypic analysis showed a loss of tissue renewal capacity with progressive breeding of heterozygous mice that was indistinguishable from that of mTR-deficient mice. mTERT⁻/⁻ mice, from heterozygous mTERT⁺/⁻ mouse crosses, were born at the expected Mendelian ratio (26.5%; n = 1,080 pups), indicating no embryonic lethality of this genotype. We looked for, and failed to find, hallmarks of Wnt deficiency in various adult and embryonic tissues, including those of the lungs, kidneys, brain, and skeleton. Finally, mTERT⁻/⁻ cells showed wild-type levels of Wnt signaling in vitro. Thus, while TERT overexpression in some settings may activate the Wnt pathway, loss of function in a physiological setting has no apparent effects on Wnt signaling. Our results indicate that both TERT and TR are haploinsufficient and that their deficiency leads to telomere shortening, which limits tissue renewal. Our studies imply that hypomorphic loss-of-function alleles of hTERT and hTR should cause a similar disease spectrum in humans.

In the mouse, Frizzled3 (Fz3) and Frizzled6 (Fz6) have been shown previously to control axonal growth and guidance in the CNS and hair patterning in the skin, respectively. Here, we report that Fz3 and Fz6 redundantly control neural tube closure and the planar orientation of hair bundles on a subset of auditory and vestibular sensory cells. In the inner ear, Fz3 and Fz6 proteins are localized to the lateral faces of sensory and supporting cells in all sensory epithelia in a pattern that correlates with the axis of planar polarity. Interestingly, the polarity of Fz6 localization with respect to the asymmetric position of the kinocilium is reversed between vestibular hair cells in the cristae of the semicircular canals and auditory hair cells in the organ of Corti. Vangl2, one of two mammalian homologs of the Drosophila planar cell polarity (PCP) gene van Gogh/Strabismus, is also required for correct hair bundle orientation on a subset of auditory sensory cells and on all vestibular sensory cells. In the inner ear of a Vangl2 mutant (Looptail; Lp), Fz3 and Fz6 proteins accumulate to normal levels but do not localize correctly at the cell surface. These results support the view that vertebrates and invertebrates use similar molecular mechanisms to control a wide variety of PCP-dependent developmental processes. This study also establishes the vestibular sensory epithelium as a tractable tissue for analyzing PCP, and it introduces the use of genetic mosaics for determining the absolute orientation of PCP proteins in mammals.