Luminescence thermometry driven by a support vector machine: a strategy toward precise thermal sensing.

Luminescence thermometry is a promising non-contact temperature measurement technique, but improving the precision and reliability of this method remains a challenge. Herein, we propose a thermal sensing strategy based on a machine learning. By using Gd3Ga5O12: Er3+-Yb3+ as the sensing medium, a support vector machine (SVM) is preliminarily adopted to establish the relationship between temperature and upconversion emission spectra, and the sensing properties are discussed through the comparison with luminescence intensity ratio (LIR) and multiple linear regression (MLR) methods. Within a wide operating temperature range (303-853 K), the maximum and the mean measurement errors actualized by the SVM are just about 0.38 and 0.12 K, respectively, much better than the other two methods (3.75 and 1.37 K for LIR and 1.82 and 0.43 K for MLR). Besides, the luminescence thermometry driven by the SVM presents a high robustness, although the spectral profiles are distorted by the interferences within the testing environment, where, however, LIR and MLR approaches become ineffective. Results demonstrate that the SVM would be a powerful tool to be applied on the luminescence thermometry for achieving a high sensing performance.

Environmental Influence on Stripe Formation at the Graphite-Water Interface.

Understanding the characteristics of graphite-water interfaces is of scientific significance and practical importance. Ordered stripe structures have been observed at this interface, with their origins debated between condensed gas molecules and airborne hydrocarbons. Atomic force microscopy (AFM) studies have revealed variations in the morphology, formation and growth of these ordered structures. Here, we investigate the graphite-water interface under different environmental conditions using PeakForce Quantitative Nanomechanical (PF-QNM) AFM. Our findings reveal that stripe structures with 4 nm width and 0.5 nm periodicity, form and grow under wet laboratory conditions but not in pure inert gas or cleanroom environments. These stripes appear more readily when the graphite surface is immersed in water, with growth associated with gas nanodomains on the surface. This suggests that atmospheric contaminants migrate to the water-graphite interface, potentially facilitated by gas states. These findings underscore the impact of environmental conditions on graphitic materials, providing new insights into the mechanisms underlying stripe formation and growth.

Substrate access tunnel engineering of a Fe-type nitrile hydratase from Pseudomonas fluorescens ZJUT001 for substrate preference adjustment and catalytic performance enhancement.

Substrate access tunnel engineering is a useful strategy for enzyme modification. In this study, we improved the catalytic performance of Fe-type Nitrile hydratase (Fe-type NHase) from Pseudomonas fluorescens ZJUT001 (PfNHase) by mutating residue Q86 at the entrance of the substrate access tunnel. The catalytic activity of the mutant PfNHase-αQ86W towards benzonitrile, 2-cyanopyridine, 3-cyanopyridine, and 4-hydroxybenzonitrile was enhanced by 9.35-, 3.30-, 6.55-, and 2.71-fold, respectively, compared to that of the wild-type PfNHase (PfNHase-WT). In addition, the mutant PfNHase-αQ86W showed a catalytic efficiency (kcat/Km) towards benzonitrile 17.32-fold higher than the PfNHase-WT. Interestingly, the substrate preference of PfNHase-αQ86W shifted from aliphatic nitriles to aromatic nitrile substrates. Our analysis delved into the structural changes that led to this altered substrate preference, highlighting an expanded entrance tunnel region, theenlarged substrate-binding pocket, and the increased hydrophobic interactions between the substrate and enzyme. Molecular dynamic simulations and dynamic cross-correlation Matrix (DCCM) further supported these findings, providing a comprehensive explanation for the enhanced catalytic activity towards aromatic nitrile substrates.

Discovery of 4-phenyl-1H-indazole derivatives as novel small-molecule inhibitors targeting the PD-1/PD-L1 interaction.

The inhibition of the programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway with small molecules is a promising approach for cancer immunotherapy. Herein, novel small molecules compounds bearing various scaffolds including thiophene, thiazole, tetrahydroquinoline, benzimidazole and indazole were designed, synthesized and evaluated for their inhibitory activity against the PD-1/PD-L1 interaction. Among them, compound Z13 exhibited the most potent activity with IC50 of 189.6 nM in the homogeneous time-resolved fluorescence (HTRF) binding assay. Surface plasmon resonance (SPR) assay demonstrated that Z13 bound to PD-L1 with high affinity (KD values of 231 nM and 311 nM for hPD-L1 and mPD-L1, respectively). In the HepG2/Jurkat T co-culture cell model, Z13 decreased the viability rate of HepG2 cells in a concentration-dependent manner. In addition, Z13 showed significant in vivo antitumor efficacy (TGI = 52.6 % at 40 mg/kg) without obvious toxicity in the B16-F10 melanoma model. Furthermore, flow cytometry analysis demonstrated that Z13 inhibited tumor growth in vivo by activating the tumor immune microenvironment. These findings indicate that Z13 is a promising PD-1/PD-L1 inhibitor deserving further investigation.

Discovery of novel resorcinol biphenyl ether-based macrocyclic small molecules as PD-1/PD-L1 inhibitors with favorable pharmacokinetics for cancer immunotherapy.

Programmed death protein 1 (PD-1)/programmed death protein ligand 1 (PD-L1) is one of the most promising immune checkpoints (ICs) in tumor immunology and has been actively pursued as a target for anticancer drug discovery. Based on our previous research in small molecule PD-1/PD-L1 modulators, we designed and synthesized a series of resorcinol biphenyl ether-bearing macrocyclic compounds and evaluated their anti-PD-1/PD-L1 activities. Among them, compound 8d exhibited the highest inhibitory activity against PD-1/PD-L1 interaction with IC50 of 259.7 nM in the homogenous time-resolved fluorescence (HTRF) assay. In addition, 8d displayed in vitro immunomodulatory effects by promoting HepG2 cell death in a HepG2/Jurkat cell co-culture model. Furthermore, 8d effectively inhibited tumor growth (TGI = 74.6% at 40 mg/kg) in a melanoma tumor model in mice without causing obvious toxicity. Moreover, 8d exhibited favorable pharmacokinetics [e.g. high stability, reasonable half-life, and good oral bioavailability (F = 21.5%)]. Finally, molecular modeling studies showed that 8d bound to PD-L1 with high affinity. These results suggest that 8d may serve as a starting point for further development of macrocyclic small molecule-based PD-1/PD-L1 inhibitors for cancer treatment.

Biotechnological production and potential applications of hypocrellins.

Hypocrellins (HYPs), a kind of natural perylenequinones (PQs) with an oxidized pentacyclic core, are important natural compounds initially extracted from the stromata of Hypocrella bambusae and Shiraia bambusicola. They have been widely concerned for their use as anti-microbial, anti-cancers, and anti-viral photodynamic therapy agents in recent years. Considering the restrictions of natural stromal resources, submerged fermentation with Shiraia spp. has been viewed as a promising alternative biotechnology for HYP production, and great efforts have been made to improve HYP production over the past decade. This article reviews recent publications about the mycelium fermentation production of HYPs, and their bioactivities and potential applications, and especially summarizes the progresses toward manipulation of fermentation conditions. Also, their chemical structure and analytic methods are outlined. Herein, it is worth mentioning that the gene arrangement in HYP gene cluster is revised; previous unknown genes in HYP and CTB gene clusters with correct function annotation are deciphered; the homologous sequences of HYP, CTB, and elc are systematically aligned, and especially the biosynthetic pathway of HYPs is full-scale proposed. KEY POINTS: • The mycelial fermentation process and metabolic regulation of hypocrellins are reviewed. • The bioactivities and potential applications of hypocrellins are summarized. • The biosynthesis pathway and regulatory mechanisms of hypocrellins are outlined.

Heat stress enhanced perylenequinones biosynthesis of Shiraia sp. Slf14(w) through nitric oxide formation.

Perylenequinones (PQs) are a class of natural polyketides used as photodynamic therapeutics. Heat stress (HS) is an important environmental factor affecting secondary metabolism of fungi. This study investigated the effects of HS treatment on PQs biosynthesis of Shiraia sp. Slf14(w) and the underlying molecular mechanism. After the optimization of HS treatment conditions, the total PQs amount reached 577 ± 34.56 mg/L, which was 20.89-fold improvement over the control. Also, HS treatment stimulated the formation of intracellular nitric oxide (NO). Genome-wide analysis of Shiraia sp. Slf14(w) revealed iNOSL and cNOSL encoding inducible and constitutive NOS-like proteins (iNOSL and cNOSL), respectively. Cloned iNOSL in Escherichia coli BL21 showed higher nitric oxide synthase (NOS) activity than cNOSL, and the expression level of iNOSL under HS treatment was observably higher than that of cNOSL, suggesting that iNOSL is more responsible for NO production in the HS-treated strain Slf14(w) and may play an important role in regulating PQs biosynthesis. Moreover, the putative biosynthetic gene clusters for PQs and genes encoding iNOSL and nitrate reductase (NR) in the HS-treated strain Slf14(w) were obviously upregulated. PQs biosynthesis and efflux stimulated by HS treatment were significantly inhibited upon the addition of NO scavenger, NOS inhibitor, and NR inhibitor, indicating that HS-induced NO, as a signaling molecule, triggered promoted PQs biosynthesis and efflux. Our results provide an effective strategy for PQs production and contribute to the understanding of heat shock signal transduction studies of other fungi.Key points• PQs titer of Shiraia sp. Slf14(w) was significantly enhanced by HS treatment.• HS-induced NO was first reported to participate in PQs biosynthetic regulation.• Novel inducible and constitutive NOS-like proteins (iNOSL and cNOSL) were obtained and their NOS activities were determined.

Rhizoaspergillin A and Rhizoaspergillinol A, including a Unique Orsellinic Acid-Ribose-Pyridazinone-N-Oxide Hybrid, from the Mangrove Endophytic Fungus Aspergillus sp. A1E3.

Two new compounds, named rhizoaspergillin A (1) and rhizoaspergillinol A (2), were isolated from the mangrove endophytic fungus Aspergillus sp. A1E3, associated with the fruit of Rhizophora mucronata, together with averufanin (3). The planar structures and absolute configurations of rhizoaspergillinol A (2) and averufanin (3) were established by extensive NMR investigations and quantum-chemical electronic circular dichroism (ECD) calculations. Most notably, the constitution and absolute configuration of rhizoaspergillin A (1) were unambiguously determined by single-crystal X-ray diffraction analysis of its tri-pivaloyl derivative 4, conducted with Cu Kα radiation, whereas those of averufanin (3) were first clarified by quantum-chemical ECD calculations. Rhizoaspergillin A is the first orsellinic acid-ribose-pyridazinone-N-oxide hybrid containing a unique ß-oxo-2,3-dihydropyridazine 1-oxide moiety, whereas rhizoaspergillinol A (2) and averufanin (3) are sterigmatocystin and anthraquinone derivatives, respectively. From the perspective of biosynthesis, rhizoaspergillin A (1) could be originated from the combined assembly of three building blocks, viz., orsellinic acid, ß-D-ribofuranose, and L-glutamine. It is an unprecedented alkaloid-N-oxide involving biosynthetic pathways of polyketides, pentose, and amino acids. In addition, rhizoaspergillinol A (2) exhibited potent antiproliferative activity against four cancer cell lines. It could dose-dependently induce G2/M phase arrest in HepG2 cells.

Identifying and optimizing ecological spatial patterns based on the bird distribution in the Yellow River Basin, China.

In the Yellow River Basin (YRB), there exists a rich biodiversity of species that has been shaped by its unique geography, climate, and human activities. However, the high speed of economic development has resulted in the fragmentation and loss of habitats that are crucial for the survival of these species. To address this problem, constructing ecological networks has emerged as a promising approach for biodiversity preservation. In the study, we centered on the YRB and employed bird communities as an indicator species to identify ecological sources by combining bioclimatic variables and land use data with the Maximum Entropy (MaxEnt) and Integrated Valuation of Ecosystem Services and Tradeoffs (InVEST) models. We generated a resistance surface using various data such as Digital Elevation Model (DEM), the Normalized Difference Vegetation Index (NDVI), Normalized Difference Water Index (NDWI), nighttime light, road density, railway density, and waterway density. So, we then simulated ecological corridors applying the Minimum Cumulative Resistance (MCR) model and constructed a bird diversity protection network. The results we found suggested that bird hotspots were predominantly clustered upstream and downstream in the YRB. We identified 475 sources covering a total area of 65,088 km2, 681 corridors with a total length of 11,495.05 km. This network served as a critical ecological facility to sustain and protect biodiversity. The bird ecological corridors in the YRB showed that a dense east-west pattern in the central area, with a short length in the west and east and a long length in the central area. Although the central region lacked ecological sources, the east and west were still connected as a tight whole. Two scenarios showed adding ecological stepping stones had a better optimization effect than enhancing ecological connectivity.

Stereo-IA: stereo visual intensity alignment and beyond under radiation variation.

Stereo vision is a hot research topic at present, but due to the radiation changes, there will be a large intensity difference between stereo pairs, which will lead to serious degradation of stereo vision based matching, pose estimation, image segmentation and other tasks. Previous methods are not robust to radiation changes or have a large amount of calculation. Accordingly, this paper proposes a new stereo intensity alignment and image enhancement method based on the latest SuperPoint features. It combines the triangle based bearings-only metric, scale-ANCC and belief propagation model and has strong robustness to radiation changes. The quantitative and qualitative comparison experiments on Middlebury datasets verify the effectiveness of the proposed method, and it has a better image restoration and matching effect under the radiation changes.

Discovery of novel 2-aryl-4-bis-amide imidazoles (ABAI) as anti-inflammatory agents for the treatment of inflammatory bowel diseases (IBD).

A series of 2-Aryl-4-Bis-amide Imidazoles (ABAI-1 to 30) were designed as anti-inflammatory agents. These compounds were synthesized and evaluated for the in vitro anti-inflammatory activities (inhibition of NO production and release of inflammatory cytokines). Several compounds effectively inhibited NO production in lipopolysaccharide (LPS) induced RAW264.7 cells. Among them, ABAI-30 exhibited the highest NO-inhibitory effect (inhibition rate of 87% at 20 µM). The anti-inflammatory mechanism of ABAI-30 was examined and found to be inhibiting the TLR4-pp65 and NLRP3-caspase-1 signaling pathway, thus leading to the downregulation of IL6, IL-1ß and TNFα at both transcriptional and translational levels. Importantly, ABAI-30 demonstrated high in vivo anti-inflammatory efficacy in a dextran sulfate sodium (DSS)-induced colitis mouse model without causing obvious toxicity. Collectively, our study provides a potent anti-inflammatory agent, which deserves further investigation as a novel therapeutic candidate for treating inflammatory bowel diseases.

L-Arginine enhanced perylenequinone production in the endophytic fungus Shiraia sp. Slf14(w) via NO signaling pathway.

Perylenequinones (PQ) are natural polyketides used as anti-microbial, -cancers, and -viral photodynamic therapy agents. Herein, the effects of L-arginine (Arg) on PQ biosynthesis of Shiraia sp. Slf14(w) and the underlying molecular mechanism were investigated. The total content of PQ reached 817.64 ± 72.53 mg/L under optimal conditions of Arg addition, indicating a 30.52-fold improvement over controls. Comparative transcriptome analysis demonstrated that Arg supplement promoted PQ precursors biosynthesis of Slf14(w) by upregulating the expression of critical genes associated with the glycolysis pathway, and acetyl-CoA and malonyl-CoA synthesis. By downregulating the expression of genes related to the glyoxylate cycle pathway and succinate dehydrogenase, more acetyl-CoA flow into the formation of PQ. Arg supplement upregulated the putative biosynthetic gene clusters for PQ and activated the transporter proteins (MFS and ABC) for exudation of PQ. Further studies showed that Arg increased the gene transcription levels of nitric oxide synthase (NOS) and nitrate reductase (NR), and activated NOS and NR, thus promoting the formation of nitric oxide (NO). A supplement of NO donor sodium nitroprusside (SNP) also confirmed that NO triggered promoted biosynthesis and efflux of PQ. PQ production stimulated by Arg or/and SNP can be significantly inhibited upon the addition of NO scavenger carboxy-PTIO, NOS inhibitor Nω-nitro-L-arginine, or soluble guanylate cyclase inhibitor NS-2028. These results showed that Arg-derived NO, as a signaling molecule, is involved in the biosynthesis and regulation of PQ in Slf14(W) through the NO-cGMP-PKG signaling pathway. Our results provide a valuable strategy for large-scale PQ production and contribute to further understanding of NO signaling in the fungal metabolite biosynthesis. KEY POINTS: • PQ production of Shiraia sp. Slf14(w) was significantly improved by L-arginine addition. • Arginine-derived NO was firstly reported to be involved in the biosynthesis and regulation of PQ. • The NO-cGMP-PKG signaling pathway was proposed for the first time to participate in PQ biosynthesis.

Discovery of KRas G12C-IN-3 and Pomalidomide-based PROTACs as degraders of endogenous KRAS G12C with potent anticancer activity.

A series of KRAS G12C-targeting PROTACs (PROteolysis TArgeting Chimeras) were designed and synthesized based on KRas G12C-IN-3 (a KRAS G12C inhibitor) and pomalidomide as degraders of KRAS G12C with a molecular weight of < 900. Among them, compound KP-14 (m.w. = 852.16; tPSA = 174.53) showed the highest KRAS G12C-degrading capability in NCI-H358 cancer cells (DC50≈1.25 µM). KP-14 bound to KRAS G12C through the acrylamide warhead and recruited the E3 ligase CRBN, causing rapid and sustained KRAS G12C degradation which led to suppression of MAPK signaling pathway in NCI-H358 cells. In addition, KP-14 selectively induced the degradation of KRAS G12C but not other KRAS isoforms such as G13D via PROTAC mechanism. Furthermore, KP-14 exhibited potent antiproliferative activity against NCI-H358 cancer cells and was able to suppress the formation of NCI-H358 tumor colonies. Collectively, this work suggests that KP-14 may serve as a tool compound for exploring the degradation of KRAS G12C by PROTAC strategy and deserve further investigation as a potential anticancer agent.

Performance of Polydopamine Complex and Mechanisms in Wound Healing.

Polydopamine (PDA) has been gradually applied in wound healing of various types in the last three years. Due to its rich phenol groups and unique structure, it can be combined with a variety of materials to form wound dressings that can be used for chronic infection, tissue repair in vivo and serious wound healing. PDA complex has excellent mechanical properties and self-healing properties, and it is a stable material that can be used for a long period of time. Unlike other dressings, PDA complexes can achieve both photothermal therapy and electro activity. In this paper, wound healing is divided into four stages: antibacterial, anti-inflammatory, cell adhesion and proliferation, and re-epithelialization. Photothermal therapy can improve the bacteriostatic rate and remove reactive oxygen species to inhibit inflammation. Electrical signals can stimulate cell proliferation and directional migration. With low reactive oxygen species (ROS) levels, inflammatory factors are down-regulated and growth factors are up-regulated, forming regular collagen fibers and accelerating wound healing. Finally, five potential development directions are proposed, including increasing drug loading capacity, optimization of drug delivery platforms, improvement of photothermal conversion efficiency, intelligent electroactive materials and combined 3D printing.

Metal-Air Transistors: Semiconductor-Free Field-Emission Air-Channel Nanoelectronics.

Scattering-free transport in vacuum tubes has always been superior to solid-state transistors. It is the advanced fabrication with mass production capability at low cost which drove solid-state nanoelectronics. Here, we combine the best of vacuum tubes with advanced nanofabrication technology. We present nanoscale, metal-based, field emission air channel transistors. Comparative analysis of tungsten-, gold-, and platinum-based devices is presented. Devices are fabricated with electron beam lithography, achieving channel lengths less than 35 nm. With this small channel length, vacuum-like carrier transport is possible in air under room temperature and pressure. Source and drain electrodes have planar, symmetric, and sharp geometry. Because of this, devices operate in bidirection with voltages <2 V and current values in few tens of nanoamperes range. The experimental data shows that influential operation mechanism is Fowler-Nordheim tunnelling in tungsten and gold devices, while Schottky emission in platinum device. The presented work enables a technology where metal-based switchable nanoelectronics can be created on any dielectric surface with low energy requirements.

Collective interactions in the nucleation and growth of surface droplets.

In the process of solvent exchange, oil droplets nucleate and grow on a solid substrate in response to the oversaturation generated through the displacement of a good oil solvent by a poor one. The mean size of the droplets depends on flow rate, flow geometry and solution conditions. In this work, we investigate the surface coverage of the droplets and the correlation between the base area of the droplets and of the bare zone surrounding the droplets for various flow and solution conditions during the solvent exchange. The surface coverage increases with the increase in the flow rate, channel height and the oil concentration, and reaches a plateau between 35% and 50%. The spatial correlation is analysed with the help of the radial distribution function g(r) and a Voronoi tessellation. When the surface coverage reaches ∼25-30%, the number density of the droplets starts to drop, reflecting the mutual interaction and merging of the droplets. With further decrease in the droplet spacing and increase in surface coverage, the Voronoi analysis shows that the base area of the droplets increases linearly with the area size of the depleted zone. The collective interaction in the growth of surface nanodroplets is universal, independent of the specific conditions that control the droplet growth.

19 F DOSY diffusion-NMR spectroscopy of fluoropolymers.

A new pulse sequence for obtaining 19 F detected DOSY (diffusion ordered spectroscopy) spectra of fluorinated molecules is presented and used to study fluoropolymers based on vinylidene fluoride and chlorotrifluoroethylene. The performance of 19 F DOSY NMR experiments (and in general any type of NMR experiment) on fluoropolymers creates some unique complications that very often prevent detection of important signals. Factors that create these complications include: (1) the presence of many scalar couplings among 1 H, 19 F and 13 C; (2) the large magnitudes of many 19 F homonuclear couplings (especially 2 JFF ); (3) the large 19 F chemical shift range; and (4) the low solubility of these materials (which requires that experiments be performed at high temperatures). A systematic study of the various methods for collecting DOSY NMR data, and the adaptation of these methods to obtain 19 F detected DOSY data, has been performed using a mixture of low molecular weight, fluorinated model compounds. The best pulse sequences and optimal experimental conditions have been determined for obtaining 19 F DOSY spectra. The optimum pulse sequences for acquiring 19 F DOSY NMR data have been determined for various circumstances taking into account the spectral dispersion, number and magnitude of couplings present, and experimental temperature. Pulse sequences and experimental parameters for optimizing these experiments for the study of fluoropolymers have been studied. Copyright © 2016 John Wiley & Sons, Ltd.

Effects of the Molecular Structure of a Self-Assembled Monolayer on the Formation and Morphology of Surface Nanodroplets.

The formation and morphology of microscopic droplets on a chemically modified surface are important for many droplet-related applications. In this study, we examined the formation and morphological characteristics of nanodroplets produced in the same process of solvent exchange on a gold surface coated with a methyl-terminated alkanethiol monolayer. From atomic force microscopy images, we obtained the contact angles of polymerized nanodroplets in 12 combinations of the length of a straight alkyl chain and the type of droplet liquid. Our results show a significant decrease in the number density of the droplets as the number of methyl groups extends from 8 to 12 or 14. The contact angle of the droplets on octanethiol is significantly larger than that on dodecanethiol or tetradecanethiol, possibly because of the screening effect from the monolayer. Our results demonstrate that under the same solution conditions the morphology of surface nanodroplets is sensitive to the detailed molecular structures of the monolayer on the substrate. This finding has important implications for understanding static wetting on the microscopic scale and the origin of three-phase contact line pinning.

Synthesis of Discrete Alkyl-Silica Hybrid Nanowires and Their Assembly into Nanostructured Superhydrophobic Membranes.

We report the synthesis of highly flexible and mechanically robust hybrid silica nanowires (NWs) which can be used as novel building blocks to construct superhydrophobic functional materials with three-dimensional macroporous networks. The hybrid silica NWs, with an average diameter of 80 nm and tunable length of up to 12 µm, are prepared by anisotropic deposition of the hydrolyzed tetraethylorthosilicate in water/n-pentanol emulsions. A mechanistic investigation reveals that the trimethoxy(octadecyl)silane introduced to the water-oil interface in the synthesis plays key roles in stabilizing the water droplets to sub-100 nm and also growing a layer of octadecyl groups on the NW surface. This work opens a solution-based route for the one-pot preparation of monodisperse, hydrophobic silica NWs and represents an important step toward the bottom-up construction of 3D superhydrophobic materials and macroporous membranes.