Hydroxylation of Substituted Anilides with Metallaphotocatalysis.

We report the combination of organo-photocatalysis with transition metal (TM) catalysis for directed ortho-hydroxylation of substituted anilides for the synthesis of α-aminophenol derivatives under mild conditions. The developed metallaphotocatalysis utilizes N-pivaloyl as a directing group and phenyl iodine(III) bis(trifluoroacetate) (PIFA) in the combination of the 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) photocatalyst and [RuCl2(p-cymene)]2 TM catalyst under visible-light irradiation at room temperature. The hydroxylation reaction works well for a wide range of substrates containing electron-withdrawing substituents and could be applied to late-stage functionalization and ortho-hydroxyl metabolite generation for drug compounds-containing anilides with electron-withdrawing substituents in a single mild reaction.

Aperiodic Bragg Reflectors for Tunable High-Purity Structural Color Based on Phase Change Material.

Tunable thin-film coating-based reflective color displays have versatile applications including image sensors, camouflage devices, spatial light modulators, and intelligent windows. However, generating high-purity colors using such coatings have posed a challenge. Here, we reveal high-purity color generation using an ultralow-loss phase change material (Sb2S3)-based tunable aperiodic distributed Bragg reflector (A-DBR). By strategically adjusting the periodicity of the adjacent layers of A-DBRs, we realize a narrow photonic bandgap with high reflectivity to generate high-purity orange and yellow colors. In particular, we demonstrate an A-DBR with a large photonic bandgap tunability by changing the structural phase of Sb2S3 layers from amorphous to crystalline. Moreover, we experimentally tailor multistate tunable colors through external optical stimuli. Unlike conventional nano thin-film coatings, our proposed approach offers an irradiance-free, narrowband, and highly reflective color band, achieving exceptional color purity by effectively suppressing reflections in off-color bands.

Schrödinger's Red Beyond 65,000 Pixel-Per-Inch by Multipolar Interaction in Freeform Meta-Atom through Efficient Neural Optimizer.

Freeform nanostructures have the potential to support complex resonances and their interactions, which are crucial for achieving desired spectral responses. However, the design optimization of such structures is nontrivial and computationally intensive. Furthermore, the current "black box" design approaches for freeform nanostructures often neglect the underlying physics. Here, a hybrid data-efficient neural optimizer for resonant nanostructures by combining a reinforcement learning algorithm and Powell's local optimization technique is presented. As a case study, silicon nanostructures with a highly-saturated red color are designed and experimentally demonstrated. Specifically, color coordinates of (0.677, 0.304) in the International Commission on Illumination (CIE) chromaticity diagram - close to the ideal Schrödinger's red, with polarization independence, high reflectance (>85%), and a large viewing angle (i.e., up to ± 25°) is achieved. The remarkable performance is attributed to underlying generalized multipolar interferences within each nanostructure rather than the collective array effects. Based on that, pixel size down to ≈400 nm, corresponding to a printing resolution of 65000 pixels per inch is demonstrated. Moreover, the proposed design model requires only ≈300 iterations to effectively search a thirteen-dimensional (13D) design space - an order of magnitude more efficient than the previously reported approaches. The work significantly extends the free-form optical design toolbox for high-performance flat-optical components and metadevices.

Person Re-Identification Method Based on Dual Descriptor Feature Enhancement.

Person re-identification is a technology used to identify individuals across different cameras. Existing methods involve extracting features from an input image and using a single feature for matching. However, these features often provide a biased description of the person. To address this limitation, this paper introduces a new method called the Dual Descriptor Feature Enhancement (DDFE) network, which aims to emulate the multi-perspective observation abilities of humans. The DDFE network uses two independent sub-networks to extract descriptors from the same person image. These descriptors are subsequently combined to create a comprehensive multi-view representation, resulting in a significant improvement in recognition performance. To further enhance the discriminative capability of the DDFE network, a carefully designed training strategy is employed. Firstly, the CurricularFace loss is introduced to enhance the recognition accuracy of each sub-network. Secondly, the DropPath operation is incorporated to introduce randomness during sub-network training, promoting difference between the descriptors. Additionally, an Integration Training Module (ITM) is devised to enhance the discriminability of the integrated features. Extensive experiments are conducted on the Market1501 and MSMT17 datasets. On the Market1501 dataset, the DDFE network achieves an mAP of 91.6% and a Rank1 of 96.1%; on the MSMT17 dataset, the network achieves an mAP of 69.9% and a Rank1 of 87.5%. These outcomes outperform most SOTA methods, highlighting the significant advancement and effectiveness of the DDFE network.

Joint Modal Alignment and Feature Enhancement for Visible-Infrared Person Re-Identification.

Visible-infrared person re-identification aims to solve the matching problem between cross-camera and cross-modal person images. Existing methods strive to perform better cross-modal alignment, but often neglect the critical importance of feature enhancement for achieving better performance. Therefore, we proposed an effective method that combines both modal alignment and feature enhancement. Specifically, we introduced Visible-Infrared Modal Data Augmentation (VIMDA) for visible images to improve modal alignment. Margin MMD-ID Loss was also used to further enhance modal alignment and optimize model convergence. Then, we proposed Multi-Grain Feature Extraction (MGFE) Structure for feature enhancement to further improve recognition performance. Extensive experiments have been carried out on SYSY-MM01 and RegDB. The result indicates that our method outperforms the current state-of-the-art method for visible-infrared person re-identification. Ablation experiments verified the effectiveness of the proposed method.

Reflective metalens with an enhanced off-axis focusing performance.

Metalenses are one of the most promising metasurface applications. However, all-dielectric reflective metalenses are rarely studied, especially regarding their off-axis focusing performance. After experimentally studying the material optical properties in this work, we propose reflective metalens based on titanium dioxide (TiO2) and silicon dioxide (SiO2), which operate at a visible wavelength of 0.633 µm. Unlike conventional reflective metalenses based on metallic mirrors, the proposed device was designed based on a modified parabolic phase profile and was integrated onto a dielectric distributed Bragg reflector periodic structure to achieve high reflectivity with five dielectric pairs. The focusing efficiency characteristics of the metalens were experimentally studied for beam angles of incidence between 0∘ and 30∘. The results reveal that the focusing efficiency for the modified metalens design remains higher than 54%, which is higher than 50%, making it promising for photonic miniaturization and integration.

A Microfluidic System of Gene Transfer by Ultrasound.

Ultrasonic gene transfer has advantages beyond other cell transfer techniques because ultrasound does not directly act on cells, but rather pushes the gene fragments around the cells into cells through an acoustic hole effect. Most examples reported were carried out in macro volumes with conventional ultrasonic equipment. In the present study, a MEMS focused ultrasonic transducer based on piezoelectric thin film with flexible substrate was integrated with microchannels to form a microfluidic system of gene transfer. The core part of the system is a bowl-shaped curved piezoelectric film structure that functions to focus ultrasonic waves automatically. Therefore, the low input voltage and power can obtain the sound pressure exceeding the cavitation threshold in the local area of the microchannel in order to reduce the damage to cells. The feasibility of the system is demonstrated by finite element simulation and an integrated system of MEMS ultrasonic devices and microchannels are developed to successfully carry out the ultrasonic gene transfection experiments for HeLa cells. The results show that having more ultrasonic transducers leads a higher transfection rate. The system is of great significance to the development of single-cell biochip platforms for early cancer diagnosis and assessment of cancer treatment.

Nitro-Activated Nucleobase Exchange in the Synthesis of 2'-Fluoro-2'-Deoxyribonucleosides.

Functionalized nucleosides bearing pyrimidine or purine bases can be prepared by activation of accessible pyrimidine nucleosides and subsequent transglycosylation. Nitration of lumicitabine, a 2'-fluoro-2'-deoxycytidine class antiviral agent, and its 2'-fluoro-2'-deoxyuridine precursor produce the same 5-nitro-2'-fluoro-2'-deoxyuridine. Under Vorbrüggen conditions, 5-nitrouracil serves as the leaving nucleobase and enables exchange with pyrimidine and purine nucleobases to anomeric 2'-fluoro-2'-deoxyribonucleosides in favor of ß-anomers generally. The strategy is also applied in the isotopic labeling of 2'-fluoro-2'-deoxyuridines.

Synthesis of deuterium-labeled CCR2 antagonist JNJ-26131300, [4-(1H-indol- 3-yl)-piperidin-1-yl]-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid.

Synthesis of multiple deuterium-labeled CCR2 antagonist JNJ-26131300, that is, [4-(1H-indol-3-yl)-piperidin-1-yl]-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid, is described. First, condensation of indole-D7 with 4-piperidone produced 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-D5 , which subsequently underwent catalytic hydrogenation to give 3-piperidin-4-yl-1H-indole-D5 . Next, bromo-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid was prepared through multiple steps from 3-(3,4,5-trifluoro-phenyl)-acrylic acid and bromo-piperidin-4-yl-acetic acid ethyl ester. Nucleophilic coupling of 3-piperidin-4-yl-1H-indole-D5 with bromo-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid afforded the desired compound [4-(1H-indol-3-yl)-piperidin-1-yl]-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid-D5 .

Low Resistance Asymmetric III-Nitride Tunnel Junctions Designed by Machine Learning.

The tunnel junction (TJ) is a crucial structure for numerous III-nitride devices. A fundamental challenge for TJ design is to minimize the TJ resistance at high current densities. In this work, we propose the asymmetric p-AlGaN/i-InGaN/n-AlGaN TJ structure for the first time. P-AlGaN/i-InGaN/n-AlGaN TJs were simulated with different Al or In compositions and different InGaN layer thicknesses using TCAD (Technology Computer-Aided Design) software. Trained by these data, we constructed a highly efficient model for TJ resistance prediction using machine learning. The model constructs a tool for real-time prediction of the TJ resistance, and the resistances for 22,254 different TJ structures were predicted. Based on our TJ predictions, the asymmetric TJ structure (p-Al0.7Ga0.3N/i-In0.2Ga0.8N/n-Al0.3Ga0.7N) with higher Al composition in p-layer has seven times lower TJ resistance compared to the prevailing symmetric p-Al0.3Ga0.7N/i-In0.2Ga0.8N/n-Al0.3Ga0.7N TJ. This study paves a new way in III-nitride TJ design for optical and electronic devices.

2-Methyl-pentanoyl-carnitine (2-MPC): a urine biomarker for patent Ascaris lumbricoides infection.

Infections with intestinal worms, such as Ascaris lumbricoides, affect hundreds of millions of people in all tropical and subtropical regions of the world. Through large-scale deworming programs, World Health Organization aims to reduce moderate-to-heavy intensity infections below 1%. Current diagnosis and monitoring of these control programs are solely based on the detection of worm eggs in stool. Here we describe how metabolome analysis was used to identify the A. lumbricoides-specific urine biomarker 2-methyl pentanoyl carnitine (2-MPC). This biomarker was found to be 85.7% accurate in determining infection and 90.5% accurate in determining a moderate-to-heavy infection. Our results also demonstrate that there is a correlation between 2-MPC levels in urine and A. lumbricoides DNA detected in stool. Furthermore, the levels of 2-MPC in urine were shown to rapidly and strongly decrease upon administration of a standard treatment (single oral dose of 400 mg albendazole). In an Ascaris suum infection model in pigs, it was found that, although 2-MPC levels were much lower compared to humans, there was a significant association between urinary 2-MPC levels and both worm counts (p = 0.023) and the number of eggs per gram (epg) counts (p < 0.001). This report demonstrates that urinary 2-MPC can be considered an A. lumbricoides-specific biomarker that can be used to monitor infection intensity.

Inverse design of plasmonic metasurfaces by convolutional neural network.

Artificial neural networks have shown effectiveness in the inverse design of nanophotonic structures; however, the numerical accuracy and algorithm efficiency are not analyzed adequately in previous reports. In this Letter, we demonstrate the convolutional neural network as an inverse design tool to achieve high numerical accuracy in plasmonic metasurfaces. A comparison of the convolutional neural networks and the fully connected neural networks show that convolutional neural networks have higher generalization capabilities. We share practical guidelines for optimizing the neural network and analyzed the hierarchy of accuracy in the multi-parameter inverse design of plasmonic metasurfaces. A high inverse design accuracy of $\pm 8\;{\rm nm}$±8nm for the critical geometrical parameters is demonstrated.

Synthesis of carboxy-polyethylene glycol-amine (CA (PEG)n ) and [1-14 C]-CA (PEG)n via oxa-Michael addition of amino-polyethylene glycols to propiolates vs to acrylates.

Synthesis of carboxy-polyethylene glycol-amine (CA (PEG)n ) via oxa-Michael addition of amino-polyethylene glycols to either acrylates or propiolates was investigated. Compared with the oxa-Michael addition to acrylates, the corresponding addition to propiolates was found to proceed under mild reaction conditions and afford the adducts in high yields from a broad scope of substrates. A two-step efficient and convenient synthesis of benzyl [1-14 C]-propiolate from 14 CO2 was therefore developed and utilized as a common synthon to afford practical and high yielding access to [1-14 C]-CA (PEG)n .

MicroRNA­539 inhibits cell proliferation, colony formation and invasion in pancreatic ductal adenocarcinoma by directly targeting IGF­1R.

MicroRNAs (miRNAs) possess oncogenic and tumour­suppressive roles in the carcinogenesis and progression of pancreatic ductal adenocarcinoma (PDAC) by regulating the expression of numerous cancer­related genes. Thus, the investigation on the expression and roles of miRNAs in PDAC may facilitate the identification of novel and effective targets for the clinical diagnosis and treatment of patients with PDAC. miRNA­539 (miR­539) has been studied in multiple types of human cancer. However, its expression and potential biological function in PDAC remain unclear. In the current study, the expression level, clinical significance, roles and underlying molecular mechanism of miR­539 in PDAC. The present results demonstrated that miR­539 expression was downregulated in PDAC tissues and cell lines. A low miR­539 level was associated with TNM stage and lymph node metastasis of patients with PDAC. miR­539 overexpression induced a significant reduction in the proliferation, colony formation and invasion of PDAC cells. Insulin­like growth factor 1 receptor (IGF­1R) was confirmed as a direct target gene of miR­539 in PDAC. Further analysis indicated that IGF­1R was overexpressed in PDAC tissues. Notably, the mRNA expression of IGF­1R was negatively correlated with miR­539 levels in PDAC tissues. In addition, the recovered IGF­1R expression also partially counteracted the suppressive roles of miR­539 overexpression in PDAC cells. Overall, miR­539 may inhibit the aggressive behaviour of PDAC by directly targeting IGF­1R and may serve as a novel therapeutic target for patients with this disease.

Using Mosaicity to Tune Thermal Transport in Polycrystalline Aluminum Nitride Thin Films.

The effect of controlling the c-axis alignment (mosaicity) to the cross-plane thermal transport in textured polycrystalline aluminum nitride (AlN) thin films is experimentally and theoretically investigated. We show that by controlling the sputtering conditions we are able to deposit AlN thin films with varying c-axis grain tilt (mosaicity) from 10° to 0°. Microstructural characterization shows that the films are nearly identical in thickness and grain size, and the difference in mosaicity alters the grain interface quality. This has a significant effect to thermal transport where a thermal conductivity of 4.22 vs 8.09 W/mK are measured for samples with tilt angles of 10° versus 0° respectively. The modified Callaway model was used to fit the theoretical curves to the experimental results using various phonon scattering mechanisms at the grain interface. It was found that using a non-gray model gives an overview of the phonon scattering at the grain boundaries, whereas treating the grain boundary as an array of dislocation lines with varying angle relative to the heat flow, best describes the mechanism of the thermal transport. Lastly, our results show that controlling the quality of the grain interface provides a tuning knob to control thermal transport in polycrystalline materials.

Syntheses of isotope-labeled SGLT2 inhibitor canagliflozin (JNJ-28431754).

Canagliflozin (Invokana, JNJ-28431754) is an orally bioavailable and selective SGLT2 (subtype 2 sodium-glucose transport protein) inhibitor approved for the treatment of type 2 diabetes. Herein, we report the synthesis of 13 C and 14 C-labeled canagliflozin. Stable isotope-labeled [13 C6 ]canagliflozin was synthesized in 4 steps starting from [13 C6 ]-labeled glucose. The [14 C]-Labeled canagliflozin was synthesized by incorporation of [14 C] into the benzylic position between the thiophene and benzene rings of the compound. Detailed synthesis of the isotope-labeled compounds is reported.

Metabolism and excretion of canagliflozin in mice, rats, dogs, and humans.

Canagliflozin is an oral antihyperglycemic agent used for the treatment of type 2 diabetes mellitus. It blocks the reabsorption of glucose in the proximal renal tubule by inhibiting the sodium-glucose cotransporter 2. This article describes the in vivo biotransformation and disposition of canagliflozin after a single oral dose of [(14)C]canagliflozin to intact and bile duct-cannulated (BDC) mice and rats and to intact dogs and humans. Fecal excretion was the primary route of elimination of drug-derived radioactivity in both animals and humans. In BDC mice and rats, most radioactivity was excreted in bile. The extent of radioactivity excreted in urine as a percentage of the administered [(14)C]canagliflozin dose was 1.2%-7.6% in animals and approximately 33% in humans. The primary pathways contributing to the metabolic clearance of canagliflozin were oxidation in animals and direct glucuronidation of canagliflozin in humans. Unchanged canagliflozin was the major component in systemic circulation in all species. In human plasma, two pharmacologically inactive O-glucuronide conjugates of canagliflozin, M5 and M7, represented 19% and 14% of total drug-related exposure and were considered major human metabolites. Plasma concentrations of M5 and M7 in mice and rats from repeated dose safety studies were lower than those in humans given canagliflozin at the maximum recommended dose of 300 mg. However, biliary metabolite profiling in rodents indicated that mouse and rat livers had significant exposure to M5 and M7. Pharmacologic inactivity and high water solubility of M5 and M7 support glucuronidation of canagliflozin as a safe detoxification pathway.

Expeditious syntheses of stable and radioactive isotope-labeled anticonvulsant agent, JNJ-26990990, and its metabolites.

Syntheses of stable and radioactive isotope-labeled anticonvulsant agent, JNJ-26990990, that is, N-(benzo[b]thien-3-ylmethyl)-sulfamide and its metabolites are described. [(13)C(15)N]Benzo[b]thiophene-3-carbonitrile was first prepared by coupling of 3-bromo-benzo[b]thiophene with [(13)C(15)N]-copper cyanide. The resultant [(13)C(15)N]benzo[b]thiophene-3-carbonitrile was reduced with lithium aluminum deuteride to give [(13)CD2(15)N]benzo[b]thiophen-3-yl-methylamine; which was then coupled with sulfamide to afford [(13)CD2(15)N]-N-(benzo[b]thien-3-ylmethyl)-sulfamide, the stable isotope-labeled compound with four stable isotope atoms. Direct oxidation of [(13)CD2(15)N]-N-(benzo[b]thien-3-ylmethyl)-sulfamide with hydrogen peroxide and peracetic acid gave the stable isotope-labeled sulfoxide and sulfone metabolites. On the other hand, radioactive (14)C-labeled N-(benzo[b]thien-3-ylmethyl)-sulfamide was prepared conveniently by sequential coupling of 3-bromo-benzo[b]thiophene with [(14)C]-copper cyanide, reduction of the carbonitrile to carboxaldehyde, and reductive amination with sulfamide.

Synthesis and evaluation of 2,7-diamino-thiazolo[4,5-d] pyrimidine analogues as anti-tumor epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors.

2,7-Diamino-thiazolo[4,5-d]pyrimidine analogues were synthesized as novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Representative compounds showed potent and selective EGFR inhibitory activities and inhibited in vitro cellular proliferation in EGFR-overexpressing human tumor cells. The synthesis and preliminary biological, physical, and pharmacokinetic evaluation of these thiazolopyrimidine compounds are reported.

Design, synthesis, and evaluation of 3,4-disubstituted pyrazole analogues as anti-tumor CDK inhibitors.

Two series of 3,4-disubstituted pyrazole analogues, 3-(benzimidazol-2-yl)-4-[2-(pyridin-3-yl)-vinyl]-pyrazoles (2) and 3-(imidazol-2-yl)-4-[2-(pyridin-3-yl)-vinyl]-pyrazoles (3), were synthesized as novel cyclin-dependent kinase (CDK) inhibitors. Representative compounds showed potent and selective CDK inhibitory activities and inhibited in vitro cellular proliferation in various human tumor cells. The design, synthesis, and preliminary biological evaluation of these pyrazole compounds are reported.