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The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg2+/Mn2+-dependent 1D) is a master negative regulator of the response; gain-of- function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our results demonstrate a role for SOD1 in the survival of PPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy against PPM1D-mutant cancers. [ABSTRACT FROM AUTHOR]

The recent emergence of topological insulators in condensed matter physics has inspired analogous wave phenomena in mechanical systems. However, to date, the design of these mechanical systems has been limited mostly to discrete lattices or perforated structures. Here, we take a ubiquitous design of a bolted elastic plate and demonstrate that it can guide flexural waves crisply around sharp bends. We show that this continuum system eliminates unwanted in-plane plate modes and allows the manipulation of low-frequency flexural modes by exploiting the local resonance of the bolts. We report the existence of a pair of double Dirac cones near the resonant frequency of the bolts, one of which leads to the creation of a topological complete bandgap that forbids all the plate modes. These findings open new possibilities of managing multiple wave modes in elastic solids for applications in energy harvesting, impact mitigation, and structural health monitoring. [ABSTRACT FROM AUTHOR]

Mutations in genes encoding components of chromatin modifying and remodeling complexes are among the most frequently observed somatic events in human cancers. For example, missense and nonsense mutations targeting the mixed lineage leukemia family member 3 (MLL3, encoded by KMT2C) histone methyltransferase occur in a range of solid tumors, and heterozygous deletions encompassing KMT2C occur in a subset of aggressive leukemias. Although MLL3 loss can promote tumorigenesis in mice, the molecular targets and biological processes by which MLL3 suppresses tumorigenesis remain poorly characterized. Here, we combined genetic, epigenomic, and animal modeling approaches to demonstrate that one of the mechanisms by which MLL3 links chromatin remodeling to tumor suppression is by co-activating the Cdkn2a tumor suppressor locus. Disruption of Kmt2c cooperates with Myc overexpression in the development of murine hepatocellular carcinoma (HCC), in which MLL3 binding to the Cdkn2a locus is blunted, resulting in reduced H3K4 methylation and low expression levels of the locus-encoded tumor suppressors p16/Ink4a and p19/Arf. Conversely, elevated KMT2C expression increases its binding to the CDKN2A locus and co-activates gene transcription. Endogenous Kmt2c restoration reverses these chromatin and transcriptional effects and triggers Ink4a/Arf-dependent apoptosis. Underscoring the human relevance of this epistasis, we found that genomic alterations in KMT2C and CDKN2A were associated with similar transcriptional profiles in human HCC samples. These results collectively point to a new mechanism for disrupting CDKN2A activity during cancer development and, in doing so, link MLL3 to an established tumor suppressor network. [ABSTRACT FROM AUTHOR]

DNA Methyltransferase 3 A (DNMT3A) is an important facilitator of differentiation of both embryonic and hematopoietic stem cells. Heterozygous germline mutations in DNMT3A lead to Tatton-Brown-Rahman Syndrome (TBRS), characterized by obesity and excessive height. While DNMT3A is known to impact feeding behavior via the hypothalamus, here we investigated a role in adipocyte progenitors utilizing heterozygous knockout mice that recapitulate cardinal TBRS phenotypes. These mice become morbidly obese due to adipocyte enlargement and tissue expansion. Adipose tissue in these mice exhibited defects in preadipocyte maturation and precocious activation of inflammatory gene networks, including interleukin-6 signaling. Adipocyte progenitor cell lines lacking DNMT3A exhibited aberrant differentiation. Furthermore, mice in which Dnmt3a was specifically ablated in adipocyte progenitors showed enlarged fat depots and increased progenitor numbers, partly recapitulating the TBRS obesity phenotypes. Loss of DNMT3A led to constitutive DNA hypomethylation, such that the DNA methylation landscape of young adipocyte progenitors resemble that of older wild-type mice. Together, our results demonstrate that DNMT3A coordinates both the central and local control of energy storage required to maintain normal weight and prevent inflammatory obesity. [ABSTRACT FROM AUTHOR]

Organic–inorganic hybrid two-dimensional (2D) perovskites have recently attracted great attention in optical and optoelectronic applications due to their inherent natural quantum-well structure. We report the growth of high-quality millimeter-sized single crystals belonging to homologous two-dimensional (2D) hybrid organic–inorganic Ruddelsden–Popper perovskites (RPPs) of (BA)2(MA)n−1PbnI3n+1 (n = 1, 2, and 3) by a slow evaporation at a constant-temperature (SECT) solution-growth strategy. The as-grown 2D hybrid perovskite single crystals exhibit excellent crystallinity, phase purity, and spectral uniformity. Low-threshold lasing behaviors with different emission wavelengths at room temperature have been observed from the homologous 2D hybrid RPP single crystals. Our result demonstrates that solution-growth homologous organic–inorganic hybrid 2D perovskite single crystals open up a new window as a promising candidate for optical gain media. [ABSTRACT FROM AUTHOR]

Large-area graphene is commonly prepared through chemical vapor deposition (CVD); in situ and nondestructive methods for its characterization are desirable. In this paper, we demonstrate a practical method--exploiting magnetic dipole resonance and coupling effects--with which the Raman signals of graphene on copper (Cu) foil can be directly, faithfully, and greatly enhanced. The magnetic dipole resonance of a silicon nanoparticle (SiNP) can effectively couple its electromagnetic field with the Cu foil to induce an enormous electric field located solely at the position of the SiNP on the graphene. The coupled electromagnetic field can lead to hot spots of high electric field intensity (E²/E0² = 123.2) within the graphene. Even when we positioned only a few SiNPs upon the graphene/Cu foil, we obtained a Raman signal enhancement (ca. 206 times) much greater than that of graphene transferred onto a 300 nm oxide film (ca. 12 times). From a series of experiments comparing the Raman signals of graphene before and after removing the SiNPs on the graphene/Cu foil, we found that the coated SiNPs had almost no effect on the quality of the as-grown graphene. Furthermore, we have used the SiNP-enhanced Raman signals to distinguish the local quality of as-grown graphene at different areas and, therefore, the quality of the underlying Cu foil. Thus, this approach based on magnetic dipole resonance and coupling appears to be very useful for in situ and nondestructive characterization of as-grown graphene on Cu foil, without the need for transfer processes or harmful processing conditions. [ABSTRACT FROM AUTHOR]

Self-renewal is a hallmark of both hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs); therefore, the identification of mechanisms that are required for LSC, but not HSC, function could provide therapeutic opportunities that are more effective and less toxic than current treatments. Here, we employed an in vivo shRNA screen and identified jumonji domain-containing protein JMJD1C as an important driver of MLL-AF9 leukemia. Using a conditional mouse model, we showed that loss of JMJD1C substantially decreased LSC frequency and caused differentiation of MLL-AF9- and homeobox A9-driven (HOXA9-driven) leukemias. We determined that JMJD1C directly interacts with HOXA9 and modulates a HOXA9-controlled gene-expression program. In contrast, loss of JMJD1C led to only minor defects in blood homeostasis and modest effects on HSC self-renewal. Together, these data establish JMJD1C as an important mediator of MLL-AF9- and HOXA9-driven LSC function that is largely dispensable for HSC function. [ABSTRACT FROM AUTHOR]

NS1 is the only nonstructural protein that enters the lumen of the endoplasmic reticulum (ER), where NS1 is glycosylated, forms a dimer, and is subsequently secreted during flavivirus replication as dimers or hexamers, which appear to be highly immunogenic to the infected host, as protective immunity can be elicited against homologous flavivirus infections. Here, by using a trans-complementation assay, we identified the C-terminal end of NS1 derived from Japanese encephalitis virus (JEV), which was more flexible than other regions in terms of housing foreign epitopes without a significant impact on virus replication. This mapped flexible region is located in the conserved tip of the core β-ladder domain of the multimeric NS1 structure and is also known to contain certain linear epitopes, readily triggering specific antibody responses from the host. Despite becoming attenuated, recombinant JEV with insertion of a neutralizing epitope derived from enterovirus 71 (EV71) into the C-terminal end of NS1 not only could be normally released from infected cells, but also induced dual protective immunity for the host to counteract lethal challenge with either JEV or EV71 in neonatal mice. These results indicated that the secreted multimeric NS1 of flaviviruses may serve as a natural protein carrier to render epitopes of interest more immunogenic in the C terminus of the core β-ladder domain. [ABSTRACT FROM AUTHOR]

We report distinctive magnetotransport properties of a graphene p-n-p junction prepared by controlled diffusion of metallic contacts. In most cases, materials deposited on a graphene surface introduce substantial carrier scattering, which greatly reduces the high mobility of intrinsic graphene. However, we show that an oxide layer only weakly perturbs the carrier transport, which enables fabrication of a high-quality graphene p-n-p junction through a one-step and resist-free method. The measured conductance-gate voltage (G-VG) curves can be well described by a metal contact model, which confirms the charge-density depinning due to the oxide layer. The graphene p-n-p junction samples exhibit a pronounced quantum Hall (QH) effect, a well-defined transition point of the zeroth Landau level (LL), and scaling behavior. The scaling exponent obtained from the evolution of the zeroth LL width as a function of temperature exhibits a relatively low value of κ = 0.21 ± 0.01. Moreover, we calculate the energy level for the LLs based on the distribution of plateau-plateau transition points, further validating the assignment of the LL index of the QH plateau-plateau transition. [ABSTRACT FROM AUTHOR]

The digestive function of the stomach depends on acidification of the gastric lumen. Acid secretion into the lumen is triggered by activation of the PKA cascade, which ultimately results in the insertion of gastric H,K-ATPases into the apical plasma membranes of parietal cells. A coupling protein is ezrin, whose phosphorylation at Ser-66 by PKA is required for parietal cell activation. However, little is known regarding the molecular mechanism(s) by which this signaling pathway operates in gastric acid secretion. Here we show that PKA cooperates with MST4 to orchestrate histamine-elicited acid secretion by phosphorylating ezrin at Ser-66 and Thr-567. Histamine stimulation activates PKA, which phosphorylates MST4 at Thr-178 and then promotes MST4 kinase activity. Interestingly, activated MST4 then phosphorylates ezrin prephosphorylated by PKA. Importantly, MST4 is important for acid secretion in parietal cells because either suppression of MST4 or overexpression of non-phosphorylatable MST4 prevents the apical membrane reorganization and proton pump translocation elicited by histamine stimulation. In addition, overexpressing MST4 phosphorylation-deficient ezrin results in an inhibition of gastric acid secretion. Taken together, these results define a novel molecular mechanism linking the PKA-MST4-ezrin signaling cascade to polarized epithelial secretion in gastric parietal cells. [ABSTRACT FROM AUTHOR]

This work presents polymer photovoltaic devices based on poly(3-hexylthiophene) (P3HT) and TiO2 nanorod hybrid bulk heterojunctions. Interface, modification of a TiO2 nanorod surface is conducted to yield a very promising device performance of 2.20% with a short circuit current density (Jsc) of 4.33 mA/cm², an open circuit voltage (V∞) of 0.78 V, and a fill factor (FF) of 0.65 under simulated A.M. 1.5 illumination (100 mW/cm²). The suppression of recombination at P3HT/TiO2 nanorod interfaces by the attachment of effective ligand molecules substantially improves device performance. The correlation between surface photovoltage and hybrid morphology is revealed by scanning Kelvin probe microscopy. The proposed method provides a new route for fabricating low-cost, environmentally friendly polymer/inorganic hybrid bulk heterojunction photovoltaic devices. [ABSTRACT FROM AUTHOR]

Combinations of different aromatic polymers and organic solvents have been studied as dispersing agents for preparing single-walled carbon nanotubes solutions, using optical absorbance, photoluminescence-excitation mapping, computer modeling, and electron microscopic imaging to characterize the solutions. Both the polymer structure and solvent used strongly influence the dispersion of the nanotubes, leading in some cases to very high selectivity in terms of diameter and chiral angle. The highest selectivities are observed using toluene with the rigid polymers PFO-BT and PFO to suspend isolated nanotubes. The specific nanotube species selected are also dependent on the solvent used and can be adjusted by the use of THF or xylene. Where the structure has more flexible conformations, the polymers are shown to be less selective but show an enhanced overall solubilization of nanotube material. When chloroform is used as the solvent, there is a large increase in the overall solubilization, but the nanotubes are suspended as bundles rather than as isolated tubes which leads to a quenching of their photoluminescence. [ABSTRACT FROM AUTHOR]