Search

The tumor suppressor TP53 is the most frequently mutated gene in human cancers. Mutant p53 (mutp53) proteins often accumulate to very high levels in human cancers to promote cancer progression through the gain-of-function (GOF) mechanism. Currently, the mechanism underlying mutp53 accumulation and GOF is incompletely understood. Here, we identified TRIM21 as a critical E3 ubiquitin ligase of mutp53 by screening for specific mutp53-interacting proteins. TRIM21 directly interacted with mutp53 but not WT p53, resulting in ubiquitination and degradation of mutp53 to suppress mutp53 GOF in tumorigenesis. TRIM21 deficiency in cancer cells promoted mutp53 accumulation and GOF in tumorigenesis. Compared with p53R172H knockin mice, which displayed mutp53 accumulation specifically in tumors but not normal tissues, TRIM21 deletion in p53R172H knockin mice resulted in mutp53 accumulation in normal tissues, an earlier tumor onset, and a shortened life span of mice. Furthermore, TRIM21 was frequently downregulated in some human cancers, including colorectal and breast cancers, and low TRIM21 expression was associated with poor prognosis in patients with cancers carrying mutp53. Our results revealed a critical mechanism underlying mutp53 accumulation in cancers and also uncovered an important tumor-suppressive function of TRIM21 and its mechanism in cancers carrying mutp53. [ABSTRACT FROM AUTHOR]

Phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme of serine synthesis, is frequently overexpressed in human cancer. PHGDH overexpression activates serine synthesis to promote cancer progression. Currently, PHGDH regulation in normal cells and cancer is not well understood. Parkin, an E3 ubiquitin ligase involved in Parkinson's disease, is a tumor suppressor. Parkin expression is frequently downregulated in many types of cancer, and its tumor-suppressive mechanism is poorly defined. Here, we show that PHGDH is a substrate for Parkin-mediated ubiquitination and degradation. Parkin interacted with PHGDH and ubiquitinated PHGDH at lysine 330, leading to PHGDH degradation to suppress serine synthesis. Parkin deficiency in cancer cells stabilized PHGDH and activated serine synthesis to promote cell proliferation and tumorigenesis, which was largely abolished by targeting PHGDH with RNA interference, CRISPR/Cas9 KO, or small-molecule PHGDH inhibitors. Furthermore, Parkin expression was inversely correlated with PHGDH expression in human breast cancer and lung cancer. Our results revealed PHGDH ubiquitination by Parkin as a crucial mechanism for PHGDH regulation that contributes to the tumor-suppressive function of Parkin and identified Parkin downregulation as a critical mechanism underlying PHGDH overexpression in cancer. [ABSTRACT FROM AUTHOR]

We study the next-to-leading order electroweak corrections to Higgs processes from dimension-six top-quark operators in the Standard Model Effective Field Theory approach. We consider the major production channels, including W H, ZH, and VBF production at the LHC, and ZH, VBF production at future lepton colliders, as well as the major decay channels including H → γγ, γZ, Wlν, Zll, b¯b, μμ, τ τ . The results show that within the current constraints, top-quark operators can shift the signal strength of the loop-induced processes, i.e. H → γγ, γZ, by factors of ∼ O(1)- O(10), and that of the tree-level processes, i.e. all remaining production and decay channels, by ∼ 5 - 10% at the LHC, and up to ∼ 15% at future lepton colliders. This implies that essentially all Higgs channels have started to become sensitive to top-quark couplings, and in particular, Higgs observables at high luminosity LHC as well as future lepton colliders, even below the tt¯ threshold, will improve our knowledge of top-quark couplings. We derive the sensitivities of Higgs measurements to top-quark operators at the high luminosity LHC, using projections for both inclusive and differential measurements. We conclude that treating the dimensionsix top-quark sector and the Higgs/electroweak sector separately may not continue to be a good strategy. A global analysis combining Higgs and top-quark measurements is desirable, and our calculation and implementation provide an automatic and realistic simulation tool for this purpose. [ABSTRACT FROM AUTHOR]

Increased lipid synthesis is a key characteristic of many cancers that is critical for cancer progression. ATP-citrate lyase (ACLY), a key enzyme for lipid synthesis, is frequently overexpressed or activated in cancer to promote lipid synthesis and tumor progression. Cullin3 (CUL3), a core protein for the CUL3–RING ubiquitin ligase complex, has been reported to be a tumor suppressor and frequently down-regulated in lung cancer. Here, we found that CUL3 interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells. Through negative regulation of ACLY, CUL3 inhibits lipid synthesis, cell proliferation, and xenograft tumor growth of lung cancer cells. Furthermore, ACLY inhibitor SB-204990 greatly abolishes the promoting effect of CUL3 down-regulation on lipid synthesis, cell proliferation, and tumor growth. Importantly, low CUL3 expression is associated with high ACLY expression and poor prognosis in human lung cancer. In summary, our results identify CUL3–KLHL25 ubiquitin ligase as a novel negative regulator for ACLY and lipid synthesis and demonstrate that decreased CUL3 expression is an important mechanism for increased ACLY expression and lipid synthesis in lung cancer. These results also reveal that negative regulation of ACLY and lipid synthesis is a novel and critical mechanism for CUL3 in tumor suppression. [ABSTRACT FROM AUTHOR]

Glutaminase (GLS) isoenzymes GLS1 and GLS2 are key enzymes for glutamine metabolism. Interestingly, GLS1 and GLS2 display contrasting functions in tumorigenesis with elusive mechanism; GLS1 promotes tumorigenesis, whereas GLS2 exhibits a tumor-suppressive function. In this study, we found that GLS2 but not GLS1 binds to small GTPase Rac1 and inhibits its interaction with Rac1 activators guanine-nucleotide exchange factors, which in turn inhibits Rac1 to suppress cancer metastasis. This function of GLS2 is independent of GLS2 glutaminase activity. Furthermore, decreased GLS2 expression is associated with enhanced metastasis in human cancer. As a p53 target, GLS2 mediates p53’s function in metastasis suppression through inhibiting Rac1. In summary, our results reveal that GLS2 is a novel negative regulator of Rac1, and uncover a novel function and mechanism whereby GLS2 suppresses metastasis. Our results also elucidate a novel mechanism that contributes to the contrasting functions of GLS1 and GLS2 in tumorigenesis. [ABSTRACT FROM AUTHOR]

Regulation of energy metabolism is a novel function of p53 in tumor suppression. Parkin (PARK2), a Parkinson disease-associated gene, is a potential tumor suppressor whose expression is frequently diminished in tumors. Here Parkin was identified as a p53 target gene that is an important mediator of p53's function in regulating energy metabolism. The human and mouse Parkin genes contain functional p53 responsive elements, and p53 increases the transcription of Parkin in both humans and mice. Parkin contributes to the function of p53 in glucose metabolism; Parkin deficiency activates glycolysis and reduces mitochondrial respiration, leading to the Warburg effect. Restoration of Parkin expression reverses the Warburg effect in cells. Thus, Parkin deficiency is a novel mechanism for the Warburg effect in tumors. Parkin also contributes to the function of p53 in antioxidant defense. Furthermore, Parkin deficiency sensitizes mice to γ-irradiation-induced tumorigenesis, which provides further direct evidence to support a role of Parkin in tumor suppression. Our results suggest that as a novel component in the p53 pathway, Parkin contributes to the functions of p53 in regulating energy metabolism, especially the Warburg effect, and antioxidant defense, and thus the function of p53 in tumor suppression. [ABSTRACT FROM AUTHOR]

Tumor suppressor p53 is crucial for embryonic implantation through transcriptional up-regulation of uterine leukemia inhibitory factor (LIF). This article reports that p53 and estrogen receptor α were activated in endometrial tissues during implantation to coordinately regulate LIF production. By using human p53 knockin (Hupki) mice carrying a single nucleotide polymorphism (SNP) at codon 72 (arginine/proline), the arginine allele was demonstrated to produce higher uterine LIF levels during implantation than the proline allele. In humans, the diversity of haplotypes of the p53 gene has decreased during evolution, because the arginine allele, existing in only a subset of haplotypes, is under positive selection. This observation is consistent with previous results showing that the proline allele is enriched in patients undergoing in vitro fertilization (IVF). Studies with p63- and p73-knockout mice have demonstrated the involvement of p63 and p73 in female reproduction and their roles in egg formation and apoptosis (p63) and spindle checkpoint (p73) in female mice. Here, the role of p63 and p73 in human reproduction was investigated. Selected alleles of SNPs in p63 and p73 genes were enriched in IVF patients. These ?ndings demonstrate that the p53 family members are involved in several steps to regulate female reproduction in mice and humans. [ABSTRACT FROM AUTHOR]

Whereas cell cycle arrest, apoptosis. and senescence are traditionally thought of as the major functions of the tumor suppressor p53. recent studies revealed two unique functions for this protein: p53 regulates cellular energy metabolism and antioxidant defense mechanisms. Here, we identify glutaminase 2 (GLS2) as a previously uncharacterized p53 target gene to mediate these two functions of the p53 protein. GLS2 encodes a mitochondrial glutaminase catalyzing the hydrolysis of glutamine to glutamate. p53 increases the GLS2 expression under both nonstressed and stressed conditions. GLS2 regulates cellular energy metabolism by increasing production of glutamate and α-ketoglutarate, which in turn results in enhanced mitochondrial respiration and ATP generation. Further- more, GLS2 regulates antioxidant defense function in cells by increasing reduced glutathione (GSH) levels and decreasing ROS levels, which in turn protects cells from oxidative stress (e.g., H2O2)-induced apoptosis. Consistent with these functions of GLS2, the activation of p53 increases the levels of glutamate and α-ketoglutarate, mitochondrial respiration rate, and GSH levels and decreases reactive oxygen species (ROS) levels in cells. Furthermore, GLS2 expression is lost or greatly decreased in hepatocellular carcinomas and the overexpression of GLS2 greatly reduced tumor cell colony formation. These results demonstrated that as a unique p53 target gene, GLS2 is a mediator of p53's role in energy metabolism and antioxidant defense, which can contribute to its role in tumor suppression. [ABSTRACT FROM AUTHOR]

The article presents case study of a 11-month-old girl who had been delivered at full term and had showed normal growth and development features in the first five months, and mentions that later when the patient showed symptoms such as vomiting, cough and fever, achalasia was diagnosed. [ABSTRACT FROM AUTHOR]

We present a convex geometry perspective to the effective field theory (EFT) parameter space. We show that the second s derivatives of the forward EFT amplitudes form a convex cone, whose extremal rays are closely connected with states in the UV theory. For tree-level UV completions, these rays are simply theories with all UV particles living in at most one irreducible representation of the symmetries of the theory. In addition, all the extremal rays are determined by the symmetries and can be systematically identified via group theoretical considerations. The implications are twofold. First, geometric information encoded in the EFT space can help reconstruct the UV completion. In particular, we will show that the dim-8 operators are important in reverse engineering the UV physics from the standard model EFT and, thus, deserve more theoretical and experimental investigations. Second, theoretical bounds on the Wilson coefficients can be obtained by identifying the boundaries of the cone and are, in general, stronger than the current positivity bounds. We show explicit examples of these new bounds and demonstrate that they originate from the scattering amplitudes corresponding to entangled states. [ABSTRACT FROM AUTHOR]

The article discusses submucosal fibrosis in achalasia patients followed by the causes and impact on peroral endoscopic myotomy (POEM).

The crumbs (crb) apical polarity genes are essential for the development and functions of epithelia. Adult zebrafish retinal neuroepithelium expresses three crb genes {crbl, crb2a, and crb2b); however, it is unknown whether and how Crbl differs from other Crb proteins in expression, localization, and functions. Here, we show that, unlike zebrafish Crb2a and Crb2b as well as mammalian Crbl and Crb2, zebrafish Crbl does not localize to the subapical regions of photoreceptors and Muller glial cells; rather, it localizes to a small region of cone outer segments: the cell membranes surrounding the axonemes. Moreover, zebrafish Crbl is not required for retinal morphogenesis and photoreceptor patterning. Interestingly, Crbl promotes rod survival under strong white light irradiation in a previously unreported non-cell-autonomous fashion; in addition, Crbl delays UV and blue cones' chromatin condensation caused by UV light irradiation. Finally, Crbl plays a role in cones' responsiveness to light through an arrestin-translocation-independent mechanism. The localization of Crbl and its functions do not differ between male and female fish. We conclude that zebrafish Crbl has diverged from other vertebrate Crb proteins, representing a neofunctionalization in Crb biology during evolution. [ABSTRACT FROM AUTHOR]

Single top production processes at hadron colliders provide information on the relation between the top quark and the electroweak sector of the standard model. We compute the next-to-leading order QCD corrections to the three main production channels: t-channel, s-channel, and tW associated production, in the standard model including operators up to dimension six. The calculation can be matched to parton shower programs and can therefore be directly used in experimental analyses. The QCD corrections are found to significantly impact the extraction of the current limits on the operators, because both of an improved accuracy and a better precision of the theoretical predictions. In addition, the distributions of some of the key discriminating observables are modified in a nontrivial way, which could change the interpretation of measurements in terms of UV complete models. [ABSTRACT FROM AUTHOR]

Background and aims Peroral endoscopic myotomy (POEM) is now an established treatment for esophageal achalasia. The standard protocol ensures a smooth operation in most patients, but technical challenges and failures exist and little is known about the incidence, causes, and impact of aborted procedures. Here, using a large patient cohort, we attempted to answer these questions. Methods All patients admitted for planned POEM between August 2010 and July 2015 underwent chart review. Aborted POEM was defined as the inability to finish the procedure after submucosal injection. The cause of the failure, clinical course, management, and follow-up data were analyzed. Results Thirteen of the 1693 POEMs (0.77 %) were aborted. Out of the 13 failures, 12 (92.3 %) were due to severe submucosal fibrosis, which precluded tunneling, and one (7.7 %) was due to atrial fibrillation related to the electric current of the endoscopic knife. Submucosal fibrosis, prior Heller myotomy, and age ( ≥ 60 years) were related to technical failure, while a disease duration of ≥ 6 years, sigmoid esophagus, mucosal edema, and prior interventions were risk factors for the presence of fibrotic changes. In turn, fibrosis was correlated with a prolonged operation, longer hospital stay, more mucosal injuries, and more major perioperative adverse events. Finally, the yearly frequency of aborted POEMs decreased after the second year as operators became more experienced. Conclusions Aborted POEM is a rare event and is largely due to the presence of submucosal fibrosis, which not only causes increased procedural difficulties, but also gives rise to major adverse events. [ABSTRACT FROM AUTHOR]

The title compounds are a class of structurally simple analogues of quaternary benzo[c]phenanthridine alkaloids (QBAs). In order to develop novel QBA-like antifungal drugs, in this study, 24 of the title compounds with various substituents on the N-phenyl ring were evaluated for bioactivity against seven phytopathogenic fungi using the mycelial growth rate method and their SAR discussed. Almost all the compounds showed definite activities in vitro against each of the test fungi at 50 μg/mL and a broad antifungal spectrum. In most cases, the mono-halogenated compounds 2-12 exhibited excellent activities superior to the QBAs sanguinarine and chelerythrine. Compound 8 possessed the strongest activities on each of the fungi with EC50 values of 8.88-19.88 μg/mL and a significant concentration-dependent relationship. The SAR is as follows: the N-phenyl group is a high sensitive structural moiety for the activity and the characteristics and position of substituents intensively influence the activity. Generally, electron-withdrawing substituents remarkably enhance the activity while electron-donating substituents cause a decrease of the activity. In most cases, ortha- and para-halogenated isomers were more active than the corresponding m-halogenated isomers. Thus, the title compounds emerged as promising lead compounds for the development of novel biomimetic antifungal agrochemicals. Compounds 8 and 2 should have great potential as new broad spectrum antifungal agents for plant protection. [ABSTRACT FROM AUTHOR]

Epidemiological studies strongly suggest that chronic psychological stress promotes tumorigenesis. However, its direct link in vivo and the underlying mechanisms that cause thi5 remain unclear. This study provides direct evidence that chronic stress promotes tumorigenesis in vivo; chronic restraint, a well-established mouse model to induce chronic stress, greatly promotes ionizing radiation (IR)-induced tumorigenesis in pS3+/- mice. The tumor suppressor protein p53 plays a central role in tumor prevention. Loss or attenuation of p53 function contriubutes greatly to tumorigenesis. We found that chronic restraint decreases the levels and function of p53 in mice, and furthermore, promotes the growth of human xenograft tumors in a largely p53-dependent manner. Our results show that glucocorticoids elevated during chronic restraint mediate the effect of chronic restraint on p53 through the induction of serumand glucocorticoid-induced protein kinase (SOK1), which in turn increases MDM2 activity and decreases p53 function. Taken together, this study demonstrates that chronic stress promotes tumorigenesis in mice, and the attenuation of p53 function is an important part of the underlying mechanism, which can be mediated by glucocortcoids elevated during chronic restraint . [ABSTRACT FROM AUTHOR]

Abstract: A new volume coordinate method for developing 3D hexahedral elements, called hexahedral volume coordinate method (HVCM), is systematically established in this paper: (i) several characteristic parameters of a hexahedron are defined and the degeneration conditions under which a hexahedron degenerates into other special polyhedrons are given; (ii) the volume coordinates of any point within a convex hexahedron are defined; (iii) transformation relations between the volume coordinates and the Cartesian or isoparametric coordinates are presented; (iv) the differential formulas for volume coordinates in hexahedral elements are given. This new coordinate system can keep not only the advantages of local natural coordinate system, but also a linear relation with the Cartesian coordinate system. Then, for checking the validity of the new HVCM, it is used to formulate three new incompatible eight-node hexahedral elements, HVCC8, HVCC8-ES and HVCC8-EM, by a similar procedure of famous Wilson’s incompatible mode. Numerical results show that the present elements exhibit much better performance than that of conventional isoparametric elements in most distorted mesh cases, especially for MacNeal’s thin beam problem. It demonstrates that the new HVCM is a powerful tool for constructing high-performance hexahedral finite element models. [Copyright &y& Elsevier]

Based on the lower bound theorem of limit analysis, a solution procedure for limit analysis of three-dimensional elastoplastic structures was established using conventional boundary element method (BEM). The elastic stress field for lower bound limit analysis was computed directly by three-dimensional boundary element method (3-D BEM). The self-equilibrium stress field was constructed by the linear combination of several self-equilibrium “basis vectors” which can be computed by elastic-plastic incremental iteration of 3-D BEM analysis. The lower bound limit analysis problem was finally reduced to a series of nonlinear programming sub-problems with relatively few optimal variables. The complex method was used to solve the nonlinear programming sub-problems. The numerical results show that the present solution procedure has good accuracy and high efficiency. [ABSTRACT FROM AUTHOR]

All-inorganic CsPbBr 3 perovskite nanocrystals with mean size of ∼300 nm were synthesized via a facile two-step solution synthesis route. High-resolution transmission electron microscopy and X-ray diffraction characterizations confirm the as-prepared CsPbBr 3 nanoparticles are single-crystals with good crystallinity, although a CsPb 2 Br 5 impure phase also exists in the final product. Power-/temperature-dependent and time-resolved photoluminescence measurements reveal the notable and stable excitonic emission feature of these CsPbBr 3 nanocrystals. As a proof-of-concept demonstration, a LED with p-GaN/n-ZnO heterojunction as blue-violet excitation chip and CsPbBr 3 nanocrystals as green phosphors, was fabricated and a white electroluminescence was achieved from this perovskite nanocrystals decorated LED. [ABSTRACT FROM AUTHOR]

The present study was designed to investigate the effects of high-mobility group box 1 (HMGB1) knockdown on the proliferation, migration and invasion of the HONE-1 human nasopharyngeal carcinoma cell line and explore the possible underlying mechanisms. HMGB1-knockdown HONE-1 cells were generated by lentiviral transfection, and HMGB1 expression was demonstrated to be obviously decreased in these cells. A Cell Counting kit-8 assay was used to determine cell proliferation, while flow cytometric analysis was employed to determine the apoptotic rate. In addition, in vitro wound healing, cell adhesion and invasion assays were performed to evaluate the metastatic potential of the cells. Western blot analysis was used to determine the protein expression of apoptosis signaling proteins caspase-3, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein, receptor for advanced glycation end products (RAGE) as well as phosphorylated and total extracellular signal-regulated kinase 1/2 in HONE-1 cells. The results of the present study demonstrated that HMGB1 knockdown suppressed the proliferation, migration and invasion of HONE-1 cells, the mechanisms of which may be associated with the induction of mitochondria-mediated apoptosis and inhibition of HMGB1/RAGE pathways. [ABSTRACT FROM AUTHOR]

The article discusses a study which reveals the ability of BAG2, a protein of Bcl-2 associated athanogene (BAG) family to promote the accumulation of mutant p53 (mutp53) proteins and gain-of-function (GOF) in tumors.

Transition metal dichalcogenides (TMDs) with a typical layered structure are highly sensitive to their layer number in optical and electronic properties. Seeking a simple and effective method for layer number identification is very important to low-dimensional TMD samples. Herein, a rapid and accurate layer number identification of few-layer WS2 and WSe2 is proposed via locking their photoluminescence (PL) peak-positions. As the layer number of WS2/WSe2 increases, it is found that indirect transition emission is more thickness-sensitive than direct transition emission, and the PL peak-position differences between the indirect and direct transitions can be regarded as fingerprints to identify their layer number. Theoretical calculation confirms that the notable thickness-sensitivity of indirect transition derives from the variations of electron density of states of W atom d-orbitals and chalcogen atom p-orbitals. Besides, the PL peak-position differences between the indirect and direct transitions are almost independent of different insulating substrates. This work not only proposes a new method for layer number identification via PL studies, but also provides a valuable insight into the thickness-dependent optical and electronic properties of W-based TMDs. [ABSTRACT FROM AUTHOR]

We present a method for designing an open acoustic cloak that can conceal a perturbation on flat ground and simultaneously meet the requirement of communication and matter interchange between the inside and the outside of the cloak. This cloak can be constructed with a multilayered structure and each layer is an isotropic and homogeneous medium. The design scheme consists of two steps: firstly, we apply a conformal coordinate transformation to obtain a quasi-perfect cloak with heterogeneous isotropic material; then, according to the profile of the material distribution, we degenerate this cloak into a multilayered-homogeneous isotropic cloak, which has two open windows with negligible disturbance on its invisibility performance. This may greatly facilitate the fabrication and enhance the applicability of such a carpet-type cloak. [ABSTRACT FROM AUTHOR]