The tumor-suppressor protein p53 is tightly controlled in normal cells by its two negative regulators--the E3 ubiquitin ligase MDM2 and its homolog MDMX. Under stressed conditions such as DNA damage, ...p53 escapes MDM2- and MDMX-mediated functional inhibition and degradation, acting to prevent damaged cells from proliferating through induction of cell cycle arrest, DNA repair, senescence or apoptosis. Ample evidence suggests that stress signals induce phosphorylation of MDM2 and MDMX, leading to p53 activation. However, the structural basis of stress-induced p53 activation remains poorly understood because of the paucity of technical means to produce site-specifically phosphorylated MDM2 and MDMX proteins for biochemical and biophysical studies. Herein, we report total chemical synthesis, via native chemical ligation, and functional characterization of (24-108)MDMX and its Tyr99-phosphorylated analog with respect to their ability to interact with a panel of p53-derived peptide ligands and PMI, a p53-mimicking but more potent peptide antagonist of MDMX, using FP and surface plasmon resonance techniques. Phosphorylation of MDMX at Tyr99 weakens peptide binding by approximately two orders of magnitude. Comparative X-ray crystallographic analyses of MDMX and of pTyr99 MDMX in complex with PMI as well as modeling studies reveal that the phosphate group of pTyr99 imposes extensive steric clashes with the C-terminus of PMI or p53 peptide and induces a significant lateral shift of the peptide ligand, contributing to the dramatic decrease in the binding affinity of MDMX for p53. Because DNA damage activates c-Abl tyrosine kinase that phosphorylates MDMX at Tyr99, our findings afford a rare glimpse at the structural level of how stress-induced MDMX phosphorylation dislodges p53 from the inhibitory complex and activates it in response to DNA damage.
A new technique is developed to directly grow Cu nanowire (CuNW) on Si substrate with electro-chemical deposition to produce height-controlled hydrophilic nanowired surfaces for enhancing pool ...boiling performance. For broader heat transfer applications, CuNW and Si nanowires (SiNW) with various nanowire heights were fabricated and examined under pool boiling with water. The heat transfer performance of the samples with NW arrays is enhanced with increasing NW heights regardless of the NW materials. The surface with the tallest NW structure (35 μm-tall SiNW) yielded a heat flux of 134 W/cm
2 at 23 K wall superheat, about 300% higher than a plain Si surface at the same wall superheat.
► A new technique is developed to directly grow copper nanowire on silicon substrate. ► Increasing nanowire height improves boiling performance. ► Optimal results were obtained in pool boiling with 35 nm long nanowires.
Phytases are a group of enzymes capable of releasing phosphates from phytates, one of the major forms of phosphorus (P) in animal feeds of plant origin. These enzymes have been widely used in animal ...feed to improve phosphorus nutrition and to reduce phosphorus pollution in animal waste. This review covers the basic nomenclature and crystal structures of phytases and emphasizes both the protein engineering strategies used for the development of new, effective phytases with improved properties and the potential biotechnological applications of phytases.
By engineering an anti-parity-time (anti-PT ) symmetric cavity magnonics system with precise eigenspace controllability, we observe two different singularities in the same system. One type of ...singularity, the exceptional point (EP), is produced by tuning the magnon damping. Between two EPs, the maximal coherent superposition of photon and magnon states is robustly sustained by the preserved anti-PT symmetry. The other type of singularity, arising from the dissipative coupling of two antiresonances, is an unconventional bound state in the continuum (BIC). At the settings of BICs, the coupled system exhibits infinite discontinuities in the group delay. We find that both singularities coexist at the equator of the Bloch sphere, which reveals a unique hybrid state that simultaneously exhibits the maximal coherent superposition and slow light capability.
Because different patients may respond quite differently to the same drug or treatment, there is an increasing interest in discovering individualized treatment rules. In particular, there is an ...emerging need to find optimal individualized treatment rules, which would lead to the “best” clinical outcome. In this paper, we propose a new class of loss functions and estimators based on robust regression to estimate the optimal individualized treatment rules. Compared to existing estimation methods in the literature, the new estimators are novel and advantageous in the following aspects. First, they are robust against skewed, heterogeneous, heavy‐tailed errors or outliers in data. Second, they are robust against a misspecification of the baseline function. Third, under some general situations, the new estimator coupled with the pinball loss approximately maximizes the outcome's conditional quantile instead of the conditional mean, which leads to a more robust optimal individualized treatment rule than the traditional mean‐based estimators. Consistency and asymptotic normality of the proposed estimators are established. Their empirical performance is demonstrated via extensive simulation studies and an analysis of an AIDS data set.
The newly emerging monolayer phosphorene was recently predicted to be a promising thermoelectric material. In this work, we propose to further enhance the thermoelectric performance of phosphorene ...using the strain-induced band convergence. The effect of the uniaxial strain on the thermoelectric properties of phosphorene was investigated by using the first-principles calculations combined with the semiclassical Boltzmann theory. When the zigzag-direction strain is applied, the Seebeck coefficient and electrical conductivity in the zigzag direction can simultaneously be greatly enhanced at the critical strain of 5%, at which the band convergence is achieved. The largest ZT value of 1.65 at 300 K is then conservatively estimated by using the bulk lattice thermal conductivity. When the armchair-direction strain of 8% is applied, the room-temperature ZT value can reach 2.12 in the armchair direction of phosphorene. Our results indicate that strain-induced band convergence could be an effective method to enhance the thermoelectric performance of phosphorene.
The emerging field of cavity spintronics utilizes the cavity magnon polariton (CMP) induced by magnon Rabi oscillations. In contrast to a single-spin quantum system, such a cooperative spin dynamics ...in the linear regime is governed by the classical physics of harmonic oscillators. It makes the magnon Rabi frequency independent of the photon Fock state occupation, and thereby restricts the quantum application of CMP. Here we show that a feedback cavity architecture breaks the harmonic-oscillator restriction. By increasing the feedback photon number, we observe an increase in the Rabi frequency, accompanied with the evolution of CMP to a cavity magnon triplet and a cavity magnon quintuplet. We present a theory that explains these features. Our results reveal the physics of cooperative polariton dynamics in feedback-coupled cavities, and open up new avenues for exploiting the light-matter interactions.
The invasive spotted‐wing drosophila, Drosophila suzukii (Matsumura) (Diptera: Drosophilidae) has caused serious economic losses to the fruit industry. The conventional control methods have many ...limitations and genetic engineering technologies such as CRISPR/Cas9‐mediated gene drive are promising approaches. In the CRISPR/Cas9 system, the transcriptional regulatory elements play an important role in the activities of gRNA. Thus, in order to improve the genome editing efficiency of the CRISPR/Cas9 system in D. suzukii, we cloned and tested four endogenous U6 promoters to drive mutagenesis of the white gene. Our results showed that all the four promoters could be used with variable efficiency. The promoter DsU6‐3 had the highest genome editing efficiency among the four DsU6 promoters. Compared with the DsU6‐3 promoter, the DmU6:3 promoter showed lower efficiency to drive mutagenesis in D. suzukii. These findings expand the range of promoters available to express gRNAs in D. suzukii, facilitating the basic and applied research on this important pest.
Four Drosophila suzukii endogenous U6 promoters were tested to drive mutagenesis of the white gene with the CRISPR/Cas9 system.
The DsU6‐3 promoter showed the highest genome editing efficiency among the four DsU6 promoters.
The Drosophila melanogaster DmU6:3 promoter showed lower efficiency than the corresponding Drosophila suzukii DsU6‐3 promoter.
Abstract The regeneration capacity of the osteoporotic bones is generally lower than that of the normal bones. Current methods of bone defect treatment for osteoporosis are not always satisfactory. ...Recent studies have shown that the silicate based biomaterials can stimulate osteogenesis and angiogenesis due to the silicon (Si) ions released from the materials, and enhance bone regeneration in vivo . Other studies showed that strontium (Sr) plays a distinct role on inhibiting bone resorption. Based on the hypothesis that the combination of Si and Sr may have synergetic effects on osteoporotic bone regeneration, the porous Sr-substituted calcium silicate (SrCS) ceramic scaffolds combining the functions of Sr and Si elements were developed with the goals to promote osteoporotic bone defect repair. The effects of the ionic extract from SrCS on osteogenic differentiation of bone marrow mesenchymal stem cells derived from ovariectomized rats (rBMSCs-OVX), angiogenic differentiation of human umbilical vein endothelial cells (HUVECs) were investigated. The in vitro results showed that Sr and Si ions released from SrCS enhanced cell viability, alkaline phosphatase (ALP) activity, and mRNA expression levels of osteoblast-related genes of rBMSCs-OVX and expression of vascular endothelial growth factor (VEGF) without addition of extra osteogenic and angiogenic reagents. The activation in extracellular signal-related kinases (ERK) and p38 signaling pathways were observed in rBMSCs-OVX cultured in the extract of SrCS, and these effects could be blocked by ERK inhibitor PD98059, and P38 inhibitor SB203580, respectively. Furthermore, the ionic extract of SrCS stimulated HUVECs proliferation, differentiation and angiogenesis process. The in vivo experiments revealed that SrCS dramatically stimulated bone regeneration and angiogenesis in a critical sized OVX calvarial defect model, and the enhanced bone regeneration might be attributed to the modulation of osteogenic differentiation of endogenous mesenchymal stem cells (MSCs) and the inhibition of osteoclastogenesis, accompanying with the promotion of the angiogenic activity of endothelial cells (ECs).
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