Photo-thermal synergistic excitation: Feasible strategy to detect ethanol for wide bandgap ZIF-8 at low work temperature.

Zeolitic Imidazolate Framework-8 (ZIF-8) material was prepared by chemical precipitation method. The microstructure and physical properties of the as-prepared samples were characterized by XRD, BET, FESEM and UV spectrophotometer. The self-made four-channel measurement device was used to test the gas sensitivity of ZIF-8 material toward ethanol gas under photo-thermal synergistic excitation. The results showed that the sample was typical ZIF-8 (Eg = 4.96 eV) with a regular dodecahedron shape and the specific surface is up to 1793 m2/g. The as-prepared ZIF-8 has a gas response value of 55.04 to 100 ppm ethanol at 75°C and it shows good gas sensing selectivity and repeated stability. The excellent gas sensitivity can be attributed to the increase of free electron concentration in the ZIF-8 conduction band by photo-thermal synergistic excitation, and the large specific surface area of ZIF-8 material provides more active sites for gas-solid surface reaction. The reaction mechanism of ZIF-8 material under multi-field excitation was also discussed.

A Novel Class of Ribosome Modulating Agents Exploits Cancer Ribosome Heterogeneity to Selectively Target the CMS2 Subtype of Colorectal Cancer.

Ribosomes in cancer cells accumulate numerous patient-specific structural and functional modifications that facilitate tumor progression by modifying protein translation. We have taken a unique synthetic chemistry approach to generate novel macrolides, Ribosome modulating agents (RMA), that are proposed to act distal to catalytic sites and exploit cancer ribosome heterogeneity. The RMA ZKN-157 shows two levels of selectivity: (i) selective translation inhibition of a subset of proteins enriched for components of the ribosome and protein translation machinery that are upregulated by MYC; and (ii) selective inhibition of proliferation of a subset of colorectal cancer cell lines. Mechanistically, the selective ribosome targeting in sensitive cells triggered cell-cycle arrest and apoptosis. Consequently, in colorectal cancer, sensitivity to ZKN-157 in cell lines and patient-derived organoids was restricted to the consensus molecular subtype 2 (CMS2) subtype that is distinguished by high MYC and WNT pathway activity. ZKN-157 showed efficacy as single agent and, the potency and efficacy of ZKN-157 synergized with clinically approved DNA-intercalating agents which have previously been shown to inhibit ribogenesis as well. ZKN-157 thus represents a new class of ribosome modulators that display cancer selectivity through specific ribosome inhibition in the CMS2 subtype of colorectal cancer potentially targeting MYC-driven addiction to high protein translation. Significance: This study demonstrates that ribosome heterogeneity in cancer can be exploited to develop selective ribogenesis inhibitors. The colorectal cancer CMS2 subtype, with a high unmet need for therapeutics, shows vulnerability to our novel selective ribosome modulator. The mechanism suggests that other cancer subtypes with high MYC activation could also be targeted.

Blocking xCT and PI3K/Akt pathway synergized with DNA damage of Riluzole-Pt(IV) prodrugs for cancer treatment.

Cancer treatment requires the participation of multiple targets/pathways, and single approach is hard to effectively curb the proliferation and metastasis of carcinoma cells. In this work, we conjugated FDA-approved riluzole and platinum(II) drugs into a series of unreported riluzole-Pt(IV) compounds, which were designed to simultaneously target DNA, the solute carrier family 7 member 11 (SLC7A11, xCT), and the human ether a go-go related gene 1 (hERG1), to exert synergistic anticancer effect. Among them, c,c,t-[PtCl2(NH3)2(OH)(glutarylriluzole)] (compound 2) displayed excellent antiproliferative activity with IC50 value of 300-times lower than that of cisplatin in HCT-116, and optimal selectivity index between carcinoma and human normal liver cells (LO2). Mechanism studies indicated that compound 2 released riluzole and active Pt(II) species after entering cells to exhibit a prodrug behavior against cancer, which obviously increased DNA-damage and cell apoptosis, as well as suppressed metastasis in HCT-116. Compound 2 persisted in the xCT-target of riluzole and blocked the biosynthesis of glutathione (GSH) to trigger oxidative stress, which could boost the killing to cancer cells and reduce Pt-drug resistance. Meanwhile, compound 2 significantly inhibited invasion and metastasis of HCT-116 cells by targeting hERG1 to interrupt the phosphorylation of phosphatidylinositide 3-kinases/proteinserine-threonine kinase (PI3K/Akt), and reverse epithelial-mesenchymal transformation (EMT). Based on our results, the riluzole-Pt(IV) prodrugs studied in this work could be regarded as a new class of very promising candidates for cancer treatment compared to traditional platinum drugs.

Novel read through agent: ZKN-0013 demonstrates efficacy in APCmin model of familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is a precancerous, colorectal disease characterized by hundreds to thousands of adenomatous polyps caused by mutations in the tumor suppressor gene adenomatous polyposis coli (APC). Approximately 30% of these mutations are premature termination codons (PTC), resulting in the production of a truncated, dysfunctional APC protein. Consequently, the ß-catenin degradation complex fails to form in the cytoplasm, leading to elevated nuclear levels of ß-catenin and unregulated ß-catenin/wnt-pathway signaling. We present in vitro and in vivo data demonstrating that the novel macrolide, ZKN-0013, promotes read through of premature stop codons, leading to functional restoration of full-length APC protein. Human colorectal carcinoma SW403 and SW1417 cells harboring PTC mutations in the APC gene showed reduced levels of nuclear ß-catenin and c-myc upon treatment with ZKN-0013, indicating that the macrolide-mediated read through of premature stop codons produced bioactive APC protein and inhibited the ß-catenin/wnt-pathway. In a mouse model of adenomatous polyposis coli, treatment of APCmin mice with ZKN-0013 caused a significant decrease in intestinal polyps, adenomas, and associated anemia, resulting in increased survival. Immunohistochemistry revealed decreased nuclear ß-catenin staining in the epithelial cells of the polyps in ZKN-0013-treated APCmin mice, confirming the impact on the ß-catenin/wnt-pathway. These results indicate that ZKN-0013 may have therapeutic potential for the treatment of FAP caused by nonsense mutations in the APC gene. KEY MESSAGES: • ZKN-0013 inhibited the growth of human colon carcinoma cells with APC nonsense mutations. • ZKN-0013 promoted read through of premature stop codons in the APC gene. • In APCmin mice, ZKN-0013 treatment reduced intestinal polyps and their progression to adenomas. • ZKN-0013 treatment in APCmin mice resulted in reduced anemia and increased survival.

Boosting-GNN: Boosting Algorithm for Graph Networks on Imbalanced Node Classification.

The graph neural network (GNN) has been widely used for graph data representation. However, the existing researches only consider the ideal balanced dataset, and the imbalanced dataset is rarely considered. Traditional methods such as resampling, reweighting, and synthetic samples that deal with imbalanced datasets are no longer applicable in GNN. This study proposes an ensemble model called Boosting-GNN, which uses GNNs as the base classifiers during boosting. In Boosting-GNN, higher weights are set for the training samples that are not correctly classified by the previous classifiers, thus achieving higher classification accuracy and better reliability. Besides, transfer learning is used to reduce computational cost and increase fitting ability. Experimental results indicate that the proposed Boosting-GNN model achieves better performance than graph convolutional network (GCN), GraphSAGE, graph attention network (GAT), simplifying graph convolutional networks (SGC), multi-scale graph convolution networks (N-GCN), and most advanced reweighting and resampling methods on synthetic imbalanced datasets, with an average performance improvement of 4.5%.

Improving the Transferability of Adversarial Examples With a Noise Data Enhancement Framework and Random Erasing.

Deep neural networks (DNNs) are proven vulnerable to attack against adversarial examples. Black-box transfer attacks pose a massive threat to AI applications without accessing target models. At present, the most effective black-box attack methods mainly adopt data enhancement methods, such as input transformation. Previous data enhancement frameworks only work on input transformations that satisfy accuracy or loss invariance. However, it does not work for other transformations that do not meet the above conditions, such as the transformation which will lose information. To solve this problem, we propose a new noise data enhancement framework (NDEF), which only transforms adversarial perturbation to avoid the above issues effectively. In addition, we introduce random erasing under this framework to prevent the over-fitting of adversarial examples. Experimental results show that the black-box attack success rate of our method Random Erasing Iterative Fast Gradient Sign Method (REI-FGSM) is 4.2% higher than DI-FGSM in six models on average and 6.6% higher than DI-FGSM in three defense models. REI-FGSM can combine with other methods to achieve excellent performance. The attack performance of SI-FGSM can be improved by 22.9% on average when combined with REI-FGSM. Besides, our combined version with DI-TI-MI-FGSM, i.e., DI-TI-MI-REI-FGSM can achieve an average attack success rate of 97.0% against three ensemble adversarial training models, which is greater than the current gradient iterative attack method. We also introduce Gaussian blur to prove the compatibility of our framework.

ShapeEditor: A StyleGAN Encoder for Stable and High Fidelity Face Swapping.

With the continuous development of deep-learning technology, ever more advanced face-swapping methods are being proposed. Recently, face-swapping methods based on generative adversarial networks (GANs) have realized many-to-many face exchanges with few samples, which advances the development of this field. However, the images generated by previous GAN-based methods often show instability. The fundamental reason is that the GAN in these frameworks is difficult to converge to the distribution of face space in training completely. To solve this problem, we propose a novel face-swapping method based on pretrained StyleGAN generator with a stronger ability of high-quality face image generation. The critical issue is how to control StyleGAN to generate swapped images accurately. We design the control strategy of the generator based on the idea of encoding and decoding and propose an encoder called ShapeEditor to complete this task. ShapeEditor is a two-step encoder used to generate a set of coding vectors that integrate the identity and attribute of the input faces. In the first step, we extract the identity vector of the source image and the attribute vector of the target image; in the second step, we map the concatenation of the identity vector and attribute vector onto the potential internal space of StyleGAN. Extensive experiments on the test dataset show that the results of the proposed method are not only superior in clarity and authenticity than other state-of-the-art methods but also sufficiently integrate identity and attribute.

Acyl guanidine inhibitors of ß-secretase (BACE-1): optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis.

This report describes the discovery and optimization of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-π interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma Aß levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain Aß levels were not obtained.

Small molecule receptor protein tyrosine phosphatase γ (RPTPγ) ligands that inhibit phosphatase activity via perturbation of the tryptophan-proline-aspartate (WPD) loop.

Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of tyrosine residues, a process that involves a conserved tryptophan-proline-aspartate (WPD) loop in catalysis. In previously determined structures of PTPs, the WPD-loop has been observed in either an "open" conformation or a "closed" conformation. In the current work, X-ray structures of the catalytic domain of receptor-like protein tyrosine phosphatase γ (RPTPγ) revealed a ligand-induced "superopen" conformation not previously reported for PTPs. In the superopen conformation, the ligand acts as an apparent competitive inhibitor and binds in a small hydrophobic pocket adjacent to, but distinct from, the active site. In the open and closed WPD-loop conformations of RPTPγ, the side chain of Trp1026 partially occupies this pocket. In the superopen conformation, Trp1026 is displaced allowing a 3,4-dichlorobenzyl substituent to occupy this site. The bound ligand prevents closure of the WPD-loop over the active site and disrupts the catalytic cycle of the enzyme.

Inhibition of influenza virus replication via small molecules that induce the formation of higher-order nucleoprotein oligomers.

Influenza nucleoprotein (NP) plays multiple roles in the virus life cycle, including an essential function in viral replication as an integral component of the ribonucleoprotein complex, associating with viral RNA and polymerase within the viral core. The multifunctional nature of NP makes it an attractive target for antiviral intervention, and inhibitors targeting this protein have recently been reported. In a parallel effort, we discovered a structurally similar series of influenza replication inhibitors and show that they interfere with NP-dependent processes via formation of higher-order NP oligomers. Support for this unique mechanism is provided by site-directed mutagenesis studies, biophysical characterization of the oligomeric ligand:NP complex, and an X-ray cocrystal structure of an NP dimer of trimers (or hexamer) comprising three NP_A:NP_B dimeric subunits. Each NP_A:NP_B dimeric subunit contains two ligands that bridge two composite, protein-spanning binding sites in an antiparallel orientation to form a stable quaternary complex. Optimization of the initial screening hit produced an analog that protects mice from influenza-induced weight loss and mortality by reducing viral titers to undetectable levels throughout the course of treatment.

Solid-phase synthesis of a library based on biphenyl-containing trypsin-like serine protease inhibitors.

The solid-phase synthesis of a library based on an unusual biphenyl-containing trypsin-like serine protease inhibitor is described. Key to this effort was the synthesis of a highly functionalized aryl boronic acid reagent which required the development of a novel and efficient method to convert a triflate to a pinacolboronate in large scale.

Discovery and optimization of (R)-prolinol-derived agonists of the Growth Hormone Secretagogue receptor (GHSR).

The discovery and optimization of a novel series of prolinol-derived GHSR agonists is described. This series emerged from a 11,520-member solid-phase library targeting the GPCR protein superfamily, and the rapid optimization of low micromolar hits into single-digit nanomolar leads can be attributed to the solid-phase synthesis of matrix libraries, which revealed multiple non-additive structure-activity relationships. In addition, the separation of potent diastereomers highlighted the influence of the alpha-methyl stereochemistry of the phenoxyacetamide sidechain on GHSR activity.

Solid-phase synthesis and anti-infective activity of a combinatorial library based on the natural product anisomycin.

The solid-phase synthesis of a library based on the natural product anisomycin is described. The resulting library was tested against a panel of bacterial and fungal targets, and active compounds were identified in a Staphylococcus aureus whole-cell assay and an efflux-deficient fungal whole-cell assay.

Solid-phase synthesis of alkyl aryl ethers via the Ullmann condensation.

Alkyl aryl ether formation is a frequently employed reaction in organic synthesis. Ullmann condensation is an alternative method to the widely used Mitsunobu reaction and is very useful in situations where application of the Mitsunobu reaction is limited. By application of this reaction to solid-phase synthesis of a series of alkyl aryl ethers, reaction conditions (catalyst, solvent, temperature, time, etc.) for a sterically hindered class of alcohols were investigated and optimized. A range of aryl halides was used to explore the scope of the reaction in solid phase.