A FBXO7/EYA2-SCFFBXW7 axis promotes AXL-mediated maintenance of mesenchymal and immune evasion phenotypes of cancer cells.

A mesenchymal tumor phenotype associates with immunotherapy resistance, although the mechanism is unclear. Here, we identified FBXO7 as a maintenance regulator of mesenchymal and immune evasion phenotypes of cancer cells. FBXO7 bound and stabilized SIX1 co-transcriptional regulator EYA2, stimulating mesenchymal gene expression and suppressing IFNα/ß, chemokines CXCL9/10, and antigen presentation machinery, driven by AXL extracellular ligand GAS6. Ubiquitin ligase SCFFBXW7 antagonized this pathway by promoting EYA2 degradation. Targeting EYA2 Tyr phosphatase activity decreased mesenchymal phenotypes and enhanced cancer cell immunogenicity, resulting in attenuated tumor growth and metastasis, increased infiltration of cytotoxic T and NK cells, and enhanced anti-PD-1 therapy response in mouse tumor models. FBXO7 expression correlated with mesenchymal and immune-suppressive signatures in patients with cancer. An FBXO7-immune gene signature predicted immunotherapy responses. Collectively, the FBXO7/EYA2-SCFFBXW7 axis maintains mesenchymal and immune evasion phenotypes of cancer cells, providing rationale to evaluate FBXO7/EYA2 inhibitors in combination with immune-based therapies to enhance onco-immunotherapy responses.

Lysine catabolism reprograms tumour immunity through histone crotonylation.

Cancer cells rewire metabolism to favour the generation of specialized metabolites that support tumour growth and reshape the tumour microenvironment1,2. Lysine functions as a biosynthetic molecule, energy source and antioxidant3-5, but little is known about its pathological role in cancer. Here we show that glioblastoma stem cells (GSCs) reprogram lysine catabolism through the upregulation of lysine transporter SLC7A2 and crotonyl-coenzyme A (crotonyl-CoA)-producing enzyme glutaryl-CoA dehydrogenase (GCDH) with downregulation of the crotonyl-CoA hydratase enoyl-CoA hydratase short chain 1 (ECHS1), leading to accumulation of intracellular crotonyl-CoA and histone H4 lysine crotonylation. A reduction in histone lysine crotonylation by either genetic manipulation or lysine restriction impaired tumour growth. In the nucleus, GCDH interacts with the crotonyltransferase CBP to promote histone lysine crotonylation. Loss of histone lysine crotonylation promotes immunogenic cytosolic double-stranded RNA (dsRNA) and dsDNA generation through enhanced H3K27ac, which stimulates the RNA sensor MDA5 and DNA sensor cyclic GMP-AMP synthase (cGAS) to boost type I interferon signalling, leading to compromised GSC tumorigenic potential and elevated CD8+ T cell infiltration. A lysine-restricted diet synergized with MYC inhibition or anti-PD-1 therapy to slow tumour growth. Collectively, GSCs co-opt lysine uptake and degradation to shunt the production of crotonyl-CoA, remodelling the chromatin landscape to evade interferon-induced intrinsic effects on GSC maintenance and extrinsic effects on immune response.

A universal approach to dual-metal-atom catalytic sites confined in carbon dots for various target reactions.

Here, a molecular-design and carbon dot-confinement coupling strategy through the pyrolysis of bimetallic complex of diethylenetriamine pentaacetic acid under low-temperature is proposed as a universal approach to dual-metal-atom sites in carbon dots (DMASs-CDs). CDs as the "carbon islands" could block the migration of DMASs across "islands" to achieve dynamic stability. More than twenty DMASs-CDs with specific compositions of DMASs (pairwise combinations among Fe, Co, Ni, Mn, Zn, Cu, and Mo) have been synthesized successfully. Thereafter, high intrinsic activity is observed for the probe reaction of urea oxidation on NiMn-CDs. In situ and ex situ spectroscopic characterization and first-principle calculations unveil that the synergistic effect in NiMn-DMASs could stretch the urea molecule and weaken the N-H bond, endowing NiMn-CDs with a low energy barrier for urea dehydrogenation. Moreover, DMASs-CDs for various target electrochemical reactions, including but not limited to urea oxidation, are realized by optimizing the specific DMAS combination in CDs.

PtPd Atomic Layer Shelled PdCu Hollow Nanoparticles on Partially Unzipped Carbon Nanotubes for Breaking the Activity-Stability Trade-Off toward the Hydrogen Oxidation Reaction in Alkaline Media.

Developing highly active yet stable catalysts for the hydrogen oxidation reaction (HOR) in alkaline media remains a significant challenge. Herein, we designed a novel catalyst of atomic PtPd-layer shelled ultrasmall PdCu hollow nanoparticles (HPdCu NPs) on partially unzipped carbon nanotubes (PtPd@HPdCu/W-CNTs), which can achieve a high mass activity, 5 times that of the benchmark Pt/C, and show exceptional stability with negligible decay after 20,000 cycles of accelerated degradation test. The atomically thin PtPd shell serves as the primary active site for the HOR and a protective layer that prevents Cu leaching. Additionally, the HPdCu substrate not only tunes the adsorption properties of the PtPd layer but also prevents corrosive Pt from reaching the interface between NPs and the carbon support, thereby mitigating carbon corrosion. This work introduces a new strategy that leverages the distinct advantages of multiple components to address the challenges associated with slow kinetics and poor durability toward the HOR.

Advanced Nanocarbons Toward two-Electron Oxygen Electrode Reactions for H2O2 Production and Integrated Energy Conversion.

Hydrogen peroxide (H2O2) plays a pivotal role in advancing sustainable technologies due to its eco-friendly oxidizing capability. The electrochemical two-electron (2e-) oxygen reduction reaction and water oxidation reaction present an environmentally green method for H2O2 production. Over the past three years, significant progress is made in the field of carbon-based metal-free electrochemical catalysts (C-MFECs) for low-cost and efficient production of H2O2 (H2O2EP). This article offers a focused and comprehensive review of designing C-MFECs for H2O2EP, exploring the construction of dual-doping configurations, heteroatom-defect coupling sites, and strategic dopant positioning to enhance H2O2EP efficiency; innovative structural tuning that improves interfacial reactant concentration and promote the timely release of H2O2; modulation of electrolyte and electrode interfaces to support the 2e- pathways; and the application of C-MFECs in reactors and integrated energy systems. Finally, the current challenges and future directions in this burgeoning field are discussed.

Efficient and Selective Adsorption of cis-Diols via the Suzuki-Miyaura Cross-Coupling-Modified Phenylboronic-Acid Functionalized Covalent Organic Framework.

In this work, a functional group (boronic acid) was modified onto a covalent organic framework (COF) using the Suzuki-Miyaura cross-coupling reaction to obtain a phenylboronic acid-functionalized covalent organic framework (BrCOF-PBA). This product was used as a selective adsorbent and largely as an efficient solid-phase extractant of flavonoids containing cis-diol structures like quercetin (QUE). Five or six-membered cyclic esters generated from the COF were characterized, and some physicochemical studies were performed, resulting in excellent chemical stability and crystallinity, high specific surface area, stable pore structure, and regular pore size. Unique selectivity of BrCOF-PBA was observed toward QUE and exhibited a huge adsorption capacity (213.96 mg g-1) in a relatively short time (90 min). In contrast, the adsorption properties of morin (MOR) and kaempferol (KAE) with a certain degree of chemical similarity to QUE were only 27.62 and 21.76 mg g-1, respectively. BrCOF-PBA also demonstrated good reusability and robustness, making it an attractive composite material for further analytical applicability.

Orchestrating Cellular Balance: ncRNAs and RNA Interactions at the Dominant of Autophagy Regulation in Cancer.

Autophagy, a complex and highly regulated cellular process, is critical for the maintenance of cellular homeostasis by lysosomal degradation of cellular debris, intracellular pathogens, and dysfunctional organelles. It has become an interesting and attractive topic in cancer because of its dual role as a tumor suppressor and cell survival mechanism. As a highly conserved pathway, autophagy is strictly regulated by diverse non-coding RNAs (ncRNAs), ranging from short and flexible miRNAs to lncRNAs and even circRNAs, which largely contribute to autophagy regulatory networks via complex RNA interactions. The potential roles of RNA interactions during autophagy, especially in cancer procession and further anticancer treatment, will aid our understanding of related RNAs in autophagy in tumorigenesis and cancer treatment. Herein, we mainly summarized autophagy-related mRNAs and ncRNAs, also providing RNA-RNA interactions and their potential roles in cancer prognosis, which may deepen our understanding of the relationships between various RNAs during autophagy and provide new insights into autophagy-related therapeutic strategies in personalized medicine.

Evolution of the point defects involved under the action of mechanical forces on mechanically machined fused silica surfaces.

Point defects with different species are concentrated on most mechanically machined fused silica optical surfaces with surface defects, which would sharply decrease the laser damage resistance under intense laser irradiation. Various point defects have distinct roles in affecting the laser damage resistance. Especially, the proportions of various point defects have not been identified, posing the challenge in relating the intrinsic quantitative relationship among various point defects. To fully reveal the comprehensive effect of various point defects, it is necessary to systematically explore the origins, evolution laws and especially the quantitative relationship among point defects. Herein, seven types of point defects are determined. The unbonded electrons in point defects are found to tend to be ionized to induce laser damage and there is a definite quantitative relationship between the proportions of oxygen-deficient point defects and that of peroxide point defects. The conclusions are further verified based on the photoluminescence (PL) emission spectra and the properties (e.g., reaction rule and structural feature) of the point defects. On basis of the fitted Gaussian components and electronic-transition theory, the quantitative relationship between PL and the proportions of various point defects is constructed for the first time. E'-Center accounts for the highest proportion among them. This work is beneficial for fully revealing the comprehensive action mechanisms of various point defects and providing new insights in elucidating the defect-induced laser damage mechanisms of optical components under intense laser irradiation from the atomic scale.

Evolution of intrinsic defects and ring structures on the surface of fused silica optics after CO2 laser conditioning.

Recently and interestingly, experiments show that the CO2 laser conditioning can significantly increase the laser-induced damage threshold (LIDT) of fused silica optics, but its underlying mechanism has not been clearly revealed. This Letter reports the experimental studies on the evolution of the intrinsic point defects and intrinsic ring structures on the surface of fused silica optics under the CO2 laser irradiation. The laser conditioning can effectively reduce the intrinsic defect contents in the surface layer of mechanically processed fused silica. However, the suppression effect of defects can be affected by the initial surface state. If there are micro-cracks on the component surface, the effect of the laser conditioning would be limited. The evolution of the intrinsic ring structures indicate that most of the intrinsic defects tend to recombine as short (Si-O)n ring structures during the laser healing of the micro-fractures. The observed recombination behavior and suppression of the intrinsic defects can help find out the reason for the increase of the LIDT of the fused silica optics.

Nuclear Receptors in Cancer Inflammation and Immunity.

Members of the nuclear receptor (NR) superfamily orchestrate cellular processes that can impact on numerous cancer hallmarks. NR activity plays important roles in the tumor microenvironment by controlling inflammation and immune responses. We summarize recent insights into the diverse mechanisms by which NR activity can control tumor inflammation, the roles of different NRs in modulating tumor immunity, and the biological features of immune cells that express specific NRs in the context of cancer. NR-dependent alterations in tumor inflammation and immunity may be amenable to pharmacological manipulation and offer new clues regarding the development of novel cancer therapeutic regimens.

Prediction of Nanoscale Water Meniscus Shape between Deliquescent KDP Crystal Optics and AFM Probe for Water-Dissolution Repairing.

KDP (KH2PO4) crystal optics are the key elements for megajoule laser facilities. Nanoscale surface defects would cause laser-induced damage when the optics are irradiated by a high-fluence laser (over 10 J/cm2). Dip-pen nanolithography (DPN) could be used to repair the nanoscale surface defects in the KDP optics by the water meniscus. The high humidity required for high-efficiency and soft KDP surfaces penetrated by the AFM probe brings challenges for accurately predicting the water meniscus shape to evaluate the effectiveness of the DPN water-dissolution repairing. The multisolutions of the Young-Laplace and Kelvin equations also lead to the wrong water meniscus shape. A theoretical model that takes the high humidity and the penetration of the AFM probes into account is developed. The parametrization Young-Laplace equations are adopted for the zero contact angle of the water films, and the AFM probe is treated as the combination of the cone and sphere for the water meniscus whose size is larger than the AFM tip radius under high humidity. The penetration of the AFM probe is modeled by Hertz theory. Both the water films (3.3 nm thickness at 99% relative humidity) and indentations (1.46 nm depth at 300 nN contact force) are non-negligible for the nanoscale water meniscus between the KDP surface and the AFM probe. Moreover, the rough-fine two-step method is proposed to lock the correct solution of the Young-Laplace and Kelvin equations. The effectiveness of the proposed model is verified by comparison with reported ESEM images and pull-off forces. In addition, the overgrowth dots on the KDP surface are compared with the water meniscus. The linear growth of the water meniscus would cause the linear growth of the overgrowth dot, which proves the proposed model could be used to guide the DPN water-dissolution repairing for the nanoscale surface defects in the KDP optics.

Carbon-Based Electrocatalysts for Acidic Oxygen Reduction Reaction.

Oxygen reduction reaction (ORR) is vital for clean and renewable energy technologies, which require no fossil fuel but catalysts. Platinum (Pt) is the best-known catalyst for ORR. However, its high cost and scarcity have severely hindered renewable energy devices (e.g., fuel cells) for large-scale applications. Recent breakthroughs in carbon-based metal-free electrochemical catalysts (C-MFECs) show great potential for earth-abundant carbon materials as low-cost metal-free electrocatalysts towards ORR in acidic media. This article provides a focused, but critical review on C-MFECs for ORR in acidic media with an emphasis on advances in the structure design and synthesis, fundamental understanding of the structure-property relationship and electrocatalytic mechanisms, and their applications in proton exchange membrane fuel cells. Current challenges and future perspectives in this emerging field are also discussed.

Formation mechanism of bubbles in the crack healing process of fused silica using a CO2 laser.

The machining-induced cracks and other defects on the surface of fused silica would incur damage when irradiated by intense lasers, which greatly shortens the service life of the fused silica optical components. The high absorption coefficient of fused silica for far-infrared lasers makes it possible to use low-energy CO2 lasers to melt and heal micro defects on the surface, and hence improve its damage threshold under the service conditions of extremely intense laser. However, the air in the cracks may evolve into bubbles during the laser healing process, but the law of crack morphology evolution and the bubble formation mechanism have not been clearly revealed. In this work, a simulation model of the healing process of fused silica surface cracks under the effect of low-energy CO2 laser is established. Three bubble formation mechanisms (i.e., the uneven fluidity caused by temperature gradient, the collapse effect caused by inclined cracks, and the internal cracks) are identified based on the simulation results of cracks with various original morphologies and characteristic structural parameters. The simulated fused silica morphology is consistent with the results of the laser healing experiment. This work can provide theoretical guidance for the optimization of optical manufacturing parameters of fused silica, as well as the CO2 laser healing and polishing strategies.

Pharmacological activation of estrogen receptor beta augments innate immunity to suppress cancer metastasis.

Metastases constitute the greatest causes of deaths from cancer. However, no effective therapeutic options currently exist for cancer patients with metastasis. Estrogen receptor ß (ERß), as a member of the nuclear receptor superfamily, shows potent tumor-suppressive activities in many cancers. To investigate whether modulation of ERß could serve as a therapeutic strategy for cancer metastasis, we examined whether the selective ERß agonist LY500307 could suppress lung metastasis of triple-negative breast cancer (TNBC) and melanoma. Mechanistically, while we observed that LY500307 potently induced cell death of cancer cells metastasized to lung in vivo, it does not mediate apoptosis of cancer cells in vitro, indicating that the cell death-inducing effects of LY500307 might be mediated by the tumor microenvironment. Pathological examination combined with flow cytometry assays indicated that LY500307 treatment induced significant infiltration of neutrophils in the metastatic niche. Functional experiments demonstrated that LY500307-treated cancer cells show chemotactic effects for neutrophils and that in vivo neutrophil depletion by Ly6G antibody administration could reverse the effects of LY500307-mediated metastasis suppression. RNA sequencing analysis showed that LY500307 could induce up-regulation of IL-1ß in TNBC and melanoma cells, which further triggered antitumor neutrophil chemotaxis. However, the therapeutic effects of LY500307 treatment for suppression of lung metastasis was attenuated in IL1B-/- murine models, due to failure to induce antitumor neutrophil infiltration in the metastatic niche. Collectively, our study demonstrated that pharmacological activation of ERß could augment innate immunity to suppress cancer metastatic colonization to lung, thus providing alternative therapeutic options for cancer patients with metastasis.

Secondary peak of downstream light field modulation caused by Gaussian mitigation pits on the rear KDP surface.

Micro-milling has been proved to be the most effective method to mitigate the growth of laser-induced surface damage on potassium dihydrogen phosphate (KDP) crystals used in high power laser systems. However, the secondary peak of downstream light field modulation caused by Gaussian mitigation pits on the rear KDP surface would cause potential risk to damage downstream optics. In order to explore the effect of the mitigation pits on the secondary peak, we numerically calculated the downstream light field modulations caused by Gaussian mitigation pits on the rear KDP surface based on the angular spectrum diffraction theory. The results suggest that the secondary peaks are dependent on the parameters of the width, depth, depth error and title error. Among them, the tilt error and depth have greater influence on the mitigation effect. To reduce the laser damage risk caused by the secondary peak, the depth of the pre-designed mitigated contour should be optimized according to the actual operating conditions. The tilt error and depth error are proposed to be controlled within 1' and 2 µm, respectively, during the micro-milling. Also, the experiments verified the calculation results of downstream modulations and the effects of these parameters on the secondary peak. This work can not only provide available models for evaluating the laser damage risk of secondary peak caused by mitigation pits on the KDP surface but also contribute to the development of optimal micro-milling parameters for laser damage mitigation as well as the installation strategy of optical components employed in the high power laser systems.

Epigenetics in ovarian cancer: premise, properties, and perspectives.

Malignant ovarian tumors bear the highest mortality rate among all gynecological cancers. Both late tumor diagnosis and tolerance to available chemical therapy increase patient mortality. Therefore, it is both urgent and important to identify biomarkers facilitating early identification and novel agents preventing recurrence. Accumulating evidence demonstrates that epigenetic aberrations (particularly histone modifications) are crucial in tumor initiation and development. Histone acetylation and methylation are respectively regulated by acetyltransferases-deacetylases and methyltransferases-demethylases, both of which are implicated in ovarian cancer pathogenesis. In this review, we summarize the most recent discoveries pertaining to ovarian cancer development arising from the imbalance of histone acetylation and methylation, and provide insight into novel therapeutic interventions for the treatment of ovarian carcinoma.

A mass spectrometric insight into the origins of benign gynecological disorders.

Applications of mass spectrometry (MS) are rapidly expanding and encompass molecular and cellular biology. MS aids in the analysis of in vivo global molecular alterations, identifying potential biomarkers which may improve diagnosis and treatment of various pathologies. MS has added new dimensionality to medical research. Pioneering gynecologists now study molecular mechanisms underlying female reproductive pathology with MS-based tools. Although benign gynecologic disorders including endometriosis, adenomyosis, leiomyoma, and polycystic ovarian syndrome (PCOS) carry low mortality rates, they cause significant physical, mental, and social detriments. Additionally, some benign disorders are unfortunately associated with malignancies. MS-based technology can detect malignant changes in formerly benign proteomes and metabolomes with distinct advantages of speed, sensitivity, and specificity. We present the use of MS in proteomics and metabolomics, and summarize the current understanding of the molecular pathways concerning female reproductive anatomy. Highlight discoveries of novel protein and metabolite biomarkers via MS-based technology, we underscore the clinical application of these techniques in the diagnosis and management of benign gynecological disorders. © 2015 Wiley Periodicals, Inc. Mass Spec Rev 36:450-470, 2017.

Mutation-induced protein interaction kinetics changes affect apoptotic network dynamic properties and facilitate oncogenesis.

It has been a consensus in cancer research that cancer is a disease caused primarily by genomic alterations, especially somatic mutations. However, the mechanism of mutation-induced oncogenesis is not fully understood. Here, we used the mitochondrial apoptotic pathway as a case study and performed a systematic analysis of integrating pathway dynamics with protein interaction kinetics to quantitatively investigate the causal molecular mechanism of mutation-induced oncogenesis. A mathematical model of the regulatory network was constructed to establish the functional role of dynamic bifurcation in the apoptotic process. The oncogenic mutation enrichment of each of the protein functional domains involved was found strongly correlated with the parameter sensitivity of the bifurcation point. We further dissected the causal mechanism underlying this correlation by evaluating the mutational influence on protein interaction kinetics using molecular dynamics simulation. We analyzed 29 matched mutant-wild-type and 16 matched SNP--wild-type protein systems. We found that the binding kinetics changes reflected by the changes of free energy changes induced by protein interaction mutations, which induce variations in the sensitive parameters of the bifurcation point, were a major cause of apoptosis pathway dysfunction, and mutations involved in sensitive interaction domains show high oncogenic potential. Our analysis provided a molecular basis for connecting protein mutations, protein interaction kinetics, network dynamics properties, and physiological function of a regulatory network. These insights provide a framework for coupling mutation genotype to tumorigenesis phenotype and help elucidate the logic of cancer initiation.

A simple method based on Sanger sequencing and MS Word wildcard searching to identify Cas9-induced frameshift mutations.

Recent advances in targeted genome editing have enabled sequence-specific modifications in eukaryotic genomes. As it can be easily reprogrammed, the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 nuclease system has been studied extensively and is now a widely used genome editing tool. Generally, Cas9 nucleases are designed to target the coding regions in exons of protein-coding genes, which are expected to cause frameshift indel mutations and interrupt protein expression. In such cases, it is often necessary to separate single clones that harbor double frameshift mutant alleles from clones that harbor the wild-type allele or an in-frame mutant allele. We developed a simple and efficient method to identify frameshift mutations in diploid genomes based on Sanger sequencing and MS Word wildcard searching (SWS). As indel mutations induced by Cas9 are varied, Sanger sequencing of PCR products from a single mutant genome will generate double peaks that begin at the indel sites. By positioning the putative sequences deduced from the double peak regions in the sequencing graph onto the wild-type sequence by MS Word wildcard searching, it is possible to predict exactly how many nucleotides were deleted or inserted in each allele of the genome. The SWS strategy greatly facilitates the process of identifying single clones with biallelic frameshift mutations from pooled cells or model organisms.