Ripretinib inhibits HIV-1 transcription through modulation of PI3K-AKT-mTOR.

Despite the effectiveness of antiretroviral therapy (ART) in prolonging the lifespan of individuals infected with HIV-1, it does not offer a cure for acquired immunodeficiency syndrome (AIDS). The "block and lock" approach aims to maintain the provirus in a state of extended transcriptional arrest. By employing the "block and lock" strategy, researchers endeavor to impede disease progression by preventing viral rebound for an extended duration following patient stops receiving ART. The crux of this strategy lies in the utilization of latency-promoting agents (LPAs) that are suitable for impeding HIV-1 provirus transcription. However, previously documented LPAs exhibited limited efficacy in primary cells or samples obtained from patients, underscoring the significance of identifying novel LPAs that yield substantial outcomes. In this study, we performed high-throughput screening of FDA-approved compound library in the J-Lat A2 cell line to discover more efficacious LPAs. We discovered ripretinib being an LPA candidate, which was validated and observed to hinder proviral activation in cell models harboring latent infections, as well as CD4+ T cells derived from infected patients. We demonstrated that ripretinib effectively impeded proviral activation through inhibition of the PI3K-AKT-mTOR signaling pathway in the HIV-1 latent cells, thereby suppressing the opening states of cellular chromatin. The results of this research offer a promising drug candidate for the implementation of the "block and lock" strategy in the pursuit of an HIV-1 cure.

Dopamine Receptor 1 Impedes ILC2-Mediated Antitumor Immunity.

Ever-growing evidence has revealed that group 2 innate lymphoid cells (ILC2s) exhibit pleiotropic effects in antihelminth immunity, allergy, tissue protection, and cancer. Currently, the role of ILC2s in cancer is highly controversial regarding the intricate tumor microenvironment (TME), and the tumor-promoting or antitumor immunological mechanisms of ILC2s remain largely unknown. In this study, we report that dopamine receptor 1 (DRD1) restrains ILC2 activity in the TME. DRD1 deficiency promotes ILC2 activation, which irritates eosinophil recruitment and cytotoxic CD8+ T cell expansion during ongoing malignancy. Consequently, DRD1-deficient mice exhibit delayed tumor growth and reduced tumor progression. Furthermore, fenoldopam, a selective DRD1 agonist, restrains the ILC2 response in the TME and aggravates tumor burden in mice. Taken together, our data elaborate that the DRD1 signal acts as an excitatory rheostat in regulating ILC2-dependent antitumor immunity.

Characteristics of genotype, drug resistance, and molecular transmission network among newly diagnosed HIV-1 infections in Shenzhen, China.

The HIV-1 pandemic has persisted for four decades, and poses a major challenge to global public health. Shenzhen, a city with large number of migrant populations in China, is suffering HIV-1 epidemic. It is necessary to continuously conduct the molecular surveillance among newly diagnosed HIV-1 patients in these migrant population. In this study, plasma samples of newly diagnosed and ART-naive HIV-1 infections were collected from Shenzhen city in China. The partial genes of HIV-1 gag and pol were amplified and sequenced for the analysis of genotype, drug resistance, and molecular transmission network. Ninety-one sequences of pol gene were obtained from newly diagnosed HIV-1 infections in Shenzhen, and seven HIV-1 subtypes were revealed in this investigation. Among them, the circulating recombinant form (CRF) 07_BC was the mostly frequent subtype (53.8%, 49/91), followed by CRF01_AE (20.9%, 19/91), CRF55_01B (9.9%, 9/91), unique recombinant forms (URFs) (8.8%, 8/91), B (3.3%, 3/91), CRF59_01B (2.2%, 2/91), and CRF08_BC (1.1%, 1/91). The overall prevalence of pretreatment drug resistance (PDR) was 23.1% (21/91), and 52.38% (11/21) of the PDR was specific for the nonnucleotide reverse transcriptase inhibitors (NNRTIs). Furthermore, a total of 3091 pol gene sequences were used to generate 19 molecular transmission clusters, and then one growing cluster, a new cluster, and a cluster with growth reactivation were identified. The result revealed that more sexual partner, CRF_07BC subtype, and seven amino acid deletions in gag p6 region might be the influencing factors associated with the high risk of transmission behavior. Compared with CRF01_AE subtype, CRF07_BC subtype strains were more likely to form clusters in molecular transmission network. This suggests that long-term surveillance of the HIV-1 molecular transmission should be a critical measure to achieve a precise intervention for controlling the spread of HIV-1 in China.

Wogonin inhibits latent HIV-1 reactivation by downregulating histone crotonylation.

BACKGROUND: Wogonin, a flavone isolated from Scutellaria baicalensis Georgi, is a commonly used phytochemical with anti-inflammatory and antitumor properties. However, the antiviral activity of wogonin against human immunodeficiency virus type 1 (HIV-1) has not been reported. PURPOSE: The current study aimed to explore whether wogonin can suppress latent HIV-1 reactivation and the mechanism of wogonin in inhibiting proviral HIV-1 transcription. METHODS: We assessed the effects of wogonin on HIV-1 reactivation using flow cytometry, cytotoxicity assay, quantitative PCR (qPCR), viral quality assurance (VQA), and western blot analysis. RESULTS: Wogonin, a flavone isolated from S. baicalensis, significantly inhibited the reactivation of latent HIV-1 in cellular models and in primary CD4+ T cells from antiretroviral therapy (ART)-suppressed individuals ex vivo. Wogonin exhibited low cytotoxicity and long-lasting inhibition of HIV-1 transcription. Triptolide is a latency-promoting agent (LPA) that inhibits HIV-1 transcription and replication; wogonin had a stronger ability to inhibit HIV-1 latent reactivation than triptolide. Mechanistically, wogonin inhibited the reactivation of latent HIV-1 by inhibiting the expression of p300, a histone acetyltransferase, and decreasing the crotonylation of histone H3/H4 in the HIV-1 promoter region. CONCLUSION: Our study found that wogonin is a novel LPA that can inhibit HIV-1 transcription by HIV-1 epigenetic silencing, which could bear promising significance for future applications of HIV-1 functional cure.

Boosting the photoelectrochemical performance of bismuth vanadate photoanode through homojunction construction.

The photoelectrochemical (PEC) performance of bismuth vanadate (BiVO4) suffers from sluggish charge mobility and substantial charge recombination losses due to its intrinsic defect. To rectify the problem, we developed a novel approach to prepare an n-n+ type II BVOac-BVOal homojunction with staggered band alignment. This architecture involves a built-in electric field that facilitating the electron-hole separation at the BVOac/BVOal interface. As a result, the BVOac-BVOal homojunction shows superior photocurrent density up to 3.6 mA/cm2 at 1.23 V vs. reversible hydrogen electrode (RHE) with 0.1 M sodium sulfite as the hole scavenger, which is 3 times higher than that of the single-layer BiVO4 photoanode. Unlike the previous efforts that modifying the PEC performance of BiVO4 photoanodes through incorporating heteroatoms, the highly-efficient BVOac-BVOal homojunction was achieved without incorporating any heteroatoms in this work. The remarkable PEC activity of the BVOac-BVOal homojunction highlights the tremendous importance of reducing the charge recombination rate at the interface by constructing the homojunction and offers an effective strategy to form the heteroatoms-free BiVO4 thin film as an efficient photoanode material for practical PEC applications.

Ponatinib Represses Latent HIV-1 by Inhibiting AKT-mTOR.

Although antiretroviral therapy (ART) is effective in suppressing viral replication, it does not cure HIV-1 infection due to the presence of the viral latent reservoir. Rather than reactivating the latent viruses, the "block and lock" strategy aims to shift the viral reservoir to a deeper state of transcriptional silencing, thus preventing viral rebound after ART interruption. Although some latency-promoting agents (LPAs) have been reported, none of them have been approved for clinical application due to cytotoxicity and limited efficacy; therefore, it is important to search for novel and effective LPAs. Here, we report an FDA-approved drug, ponatinib, that can broadly repress latent HIV-1 reactivation in different cell models of HIV-1 latency and in primary CD4+ T cells from ART-suppressed individuals ex vivo. Ponatinib does not change the expression of activation or exhaustion markers on primary CD4+ T cells and does not induce severe cytotoxicity and cell dysfunction. Mechanistically, ponatinib suppresses proviral HIV-1 transcription by inhibiting the activation of the AKT-mTOR pathway, which subsequently blocks the interaction between key transcriptional factors and the HIV-1 long terminal repeat (LTR). In summary, we discovered a novel latency-promoting agent, ponatinib, which could have promising significance for future applications of HIV-1 functional cure.

Implantable QR code subcutaneous microchip using photoacoustic and ultrasound microscopy for secure and convenient individual identification and authentication.

Individual identification and authentication techniques are merged into many aspects of human life with various applications, including access control, payment or banking transfer, and healthcare. Yet conventional identification and authentication methods such as passwords, biometrics, tokens, and smart cards suffer from inconvenience and/or insecurity. Here, inspired by quick response (QR) code and implantable microdevices, implantable and minimally-invasive QR code subcutaneous microchips (QRC-SMs) are proposed to be an effective approach to carry useful and private information, thus enabling individual identification and authentication. Two types of QRC-SMs, QRC-SMs with "hole" and "flat" elements and QRC-SMs with "titanium-coated" and "non-coated" elements, are designed and fabricated to store personal information. Corresponding ultrasound microscopy and photoacoustic microscopy are used for imaging the QR code pattern underneath skin, and open-source artificial intelligence algorithm is applied for QR code detection and recognition. Ex vivo experiments under tissue and in vivo experiments with QRC-SMs implanted in live mice have been performed, demonstrating successful information retrieval from implanted QRC-SMs. QRC-SMs are hidden subcutaneously and invisible to the eyes. They cannot be forgotten, misplaced or lost, and can always be ready for timely medical identification, access control, and payment or banking transfer. Hence, QRC-SMs provide promising routes towards private, secure, and convenient individual identification and authentication.

DFT Study on the Oxidation Mechanism of Common Cyclic Carbonates in the Presence of BF4- Anions.

Oxidative decomposition reactions of common cyclic carbonates in the presence of BF4- anions were investigated using density functional theory. A polarized continuum model was utilized to model solvent effects in the oxidation of ethylene carbonate (EC) and propylene carbonate (PC) clusters. We have found that the presence of BF4- significantly reduces EC and PC oxidation stability, from 7.11 to 6.17 and from 7.10 to 6.06 V (vs Li+/Li), respectively. The sequence of EC and PC oxidative decomposition paths and the oxidative products were affected by the BF4- anion. The decomposition products of the oxidized EC-BF4- contained CO2, vinyl alcohol, and acetaldehyde, while the decomposition products of the oxidized PC-BF4- contained CO2, acetone, and propanal, in agreement with the previous experimental studies. The oxidative decomposition reactions for PC-BF4- are compared with those for the isolated PC, PC2, PC-ClO4-, and PC-PF6-.

Miniature Probe for Optomechanical Focus-Adjustable Optical-Resolution Photoacoustic Endoscopy.

Photoacoustic microscopy (PAM) is a promising imaging modality because it is able to reveal optical absorption contrast in high resolution on the order of a micrometer. It can be applied in an endoscopic approach by implementing PAM into a miniature probe, termed photoacoustic endoscopy (PAE). Here we develop a miniature focus-adjustable PAE (FA-PAE) probe characterized by both high resolution (in micrometers) and large depth of focus (DOF) via a novel optomechanical design for focus adjustment. To realize high resolution and large DOF in a miniature probe, a 2-mm plano-convex lens is specially adopted, and the mechanical translation of a single-mode fiber is meticulously designed to allow the use of multi-focus image fusion (MIF) for extended DOF. Compared with existing PAE probes, our FA-PAE probe achieves high resolution of [Formula: see text] within unprecedentedly large DOF of 3.2 mm, more than 27 times the DOF of the probe without performing focus adjustment for MIF. The superior performance is first demonstrated by imaging both phantoms and animals including mice and zebrafish in vivo by linear scanning. Further, in vivo endoscopic imaging of a rat's rectum by rotary scanning of the probe is conducted to showcase the capability of adjustable focus. Our work opens new perspectives for PAE biomedical applications.

De-Noising of Photoacoustic Microscopy Images by Attentive Generative Adversarial Network.

As a hybrid imaging technology, photoacoustic microscopy (PAM) imaging suffers from noise due to the maximum permissible exposure of laser intensity, attenuation of ultrasound in the tissue, and the inherent noise of the transducer. De-noising is an image processing method to reduce noise, and PAM image quality can be recovered. However, previous de-noising techniques usually heavily rely on manually selected parameters, resulting in unsatisfactory and slow de-noising performance for different noisy images, which greatly hinders practical and clinical applications. In this work, we propose a deep learning-based method to remove noise from PAM images without manual selection of settings for different noisy images. An attention enhanced generative adversarial network is used to extract image features and adaptively remove various levels of Gaussian, Poisson, and Rayleigh noise. The proposed method is demonstrated on both synthetic and real datasets, including phantom (leaf veins) and in vivo (mouse ear blood vessels and zebrafish pigment) experiments. In the in vivo experiments using synthetic datasets, our method achieves the improvement of 6.53 dB and 0.26 in peak signal-to-noise ratio and structural similarity metrics, respectively. The results show that compared with previous PAM de-noising methods, our method exhibits good performance in recovering images qualitatively and quantitatively. In addition, the de-noising processing speed of 0.016 s is achieved for an image with 256×256 pixels, which has the potential for real-time applications. Our approach is effective and practical for the de-noising of PAM images.

Correction: Conjugated polymer-based luminescent probes for ratiometric detection of biomolecules.

Correction for 'Conjugated polymer-based luminescent probes for ratiometric detection of biomolecules' by Lingfeng Zhao et al., J. Mater. Chem. B, 2022, https://doi.org/10.1039/d2tb00937d.

Conjugated polymer-based luminescent probes for ratiometric detection of biomolecules.

Accurate monitoring of the biomolecular changes in biological and physiological environments is of great significance for the pathogenesis, development, diagnosis and treatment of diseases. Compared with traditional luminescent probes on the basis of an intensity-dependent single-channel readout, ratiometric fluorescence detection is a more reliable sensing or imaging method which can monitor different emission signals in two or more channels with a built-in self-calibration functionality, attracting growing attention in biomolecule detection. As a kind of luminescent material with many prospects, conjugated polymers with an easily functionalized organic molecular structure, high brightness, superior stability, tunable emission, and superior biocompatibility have been widely adopted as ratiometric fluorescent probes in biosensing and bioimaging. This review first summarizes the design principles of luminescent conjugated polymers that have been developed as methods for the ratiometric measurement of biomolecules. Additionally, their potential in accurate biodetection of living biosystems was investigated. This paper aims to provide a comprehensive review of the existing challenges and latest advancements in ratiometric detection of various biomolecules with high selectivity and sensitivity. We sincerely expect that the information presented in this review could inspire broader interests across various disciplines and stimulate more exciting achievements in biodetection for the benefit of biomedical research.

Angiogenesis and Functional Vessel Formation Induced by Interstitial Flow and Vascular Endothelial Growth Factor Using a Microfluidic Chip.

Angiogenesis occurs during both physiological and pathological processes. In this study, a microfluidic chip for the development of angiogenesis was utilized to assess angiogenic sprouting and functional vessel formation. We also found that vascular endothelial growth factor (VEGF) was a determinant of the initiation of vascular sprouts, while the direction of these sprouts was greatly influenced by interstitial flow. Isoforms of VEGF such as VEGF121, VEGF165, and VEGF189 displayed different angiogenic properties on the chip as assessed by sprout length and number, vessel perfusion, and connectivity. VEGF165 had the highest capacity to induce vascular sprouting among the three isoforms assessed and furthermore, also induced functional vessel formation. This chip could be used to analyze the effect of different angiogenic factors and drugs, as well as to explore the mechanism of angiogenesis induced by such factors.

Phonon Thermal Transport in Silicene/Graphene Heterobilayer Nanostructures: Effect of Interlayer Interactions.

Heterostructuring, as a promising route to optimize the physical properties of 2D materials, has attracted great attention from the academic community. In this paper, we investigated the room-temperature in-plane and cross-plane phonon thermal transport in silicene/graphene van der Waals (vdW) heterostructures using molecular dynamics simulations. Our simulation results demonstrated that heat current along the graphene layer is remarkably larger than that along the silicene layer, which suggests that graphene dominates the thermal transport in silicene/graphene heterostructures. The in-plane phonon thermal conductivity of the silicene/graphene heterostructures could be a compromise between monolayer graphene and monolayer silicene. Heterostructuring can remarkably reduce the in-plane thermal conductivity of the graphene layer but increase the in-plane thermal conductivity of the silicene layer in heterobilayers compared with the freestanding monolayer counterparts because of their different structures. We also simulated the interlayer interaction strength effect on the in-plane phonon thermal conductivity and cross-plane interfacial thermal resistance of silicene/graphene heterostructures. Total in-plane phonon thermal conductivity and interfacial thermal resistance both decrease with the increase in the interlayer interaction strength in the silicene/graphene heterobilayers. In addition, the calculated interfacial thermal resistance shows the effect of the thermal transport direction across the interface. This study provides a useful reference for the thermal management regulation of 2D vdW heterostructures.

Investigation of nonlinear photoacoustic microscopy using a low-cost infrared lamp.

Nonlinear photoacoustic microscopy (PAM) is a novel approach to enhance contrast and resolution. In this study, a low-cost infrared (IR) lamp as a simple approach for nonlinear PAM is demonstrated. Numerical simulations are first performed to verify the nonlinear photoacoustic effect under steady heating for two cases: (a) Differentiation of absorbers with different Grüneisen coefficients; (b) enhancement of photoacoustic amplitude. Then, sets of experiments are conducted to experimentally demonstrate our proposed approach: (a) Longitudinal monitoring of photoacoustic A-line signals from two samples, porcine tissue ex vivo and hemoglobin and indocyanine green (ICG) solutions in tubes in vitro for demonstrating the above-mentioned two cases; (b) PAM imaging of hemoglobin and ICG solutions in tubes before and after IR lamp heating. Different signal change and amplitude enhancement are observed in different demonstrations, showing the efficacy of the proposed approach. By virtue of cost-effectiveness and decent performance, our work facilitates nonlinear PAM studies.

Cerebrovascular imaging in vivo by non-contact photoacoustic microscopy based on photoacoustic remote sensing with a laser diode for interrogation.

Photoacoustic microscopy (PAM) is a unique tool for biomedical applications because it can visualize optical absorption contrast in vivo. Recently, non-contact PAM based on non-interferometric photoacoustic remote sensing (PARS), termed PARS microscopy, has shown promise for selected imaging applications. A variety of superluminescent diodes (SLDs) have been employed in the PARS microscopy system as the interrogation light source. Here, we investigate the use of a low-cost laser diode (LD) as the interrogation light source in PARS microscopy, termed PARS-LD. A side-by-side comparison of PARS-LD and a PARS microscopy system using an SLD was conducted that showed comparable performance in terms of resolution and signal-to-noise ratio. More importantly, for the first time to our knowledge, in vivo PAM imaging of mouse brain vessels was conducted in a non-contact manner, and the results show that PARS-LD provides great performance.

Miniature non-contact photoacoustic probe based on fiber-optic photoacoustic remote sensing microscopy.

Photoacoustic (PA) remote sensing (PARS) microscopy, featured by non-contact operation, has shown great potential for PA microscopy (PAM) imaging applications. However, current PARS microscopy systems are mainly based on free-space light, making the imaging head bulky and inconvenient to use. These issues hinder selected applications such as PA endoscopy and handheld PAM. Here, we report a miniature probe capable of non-contact PAM based on PARS microscopy. By utilizing fiber-optic components including a wavelength division multiplexer and an optical circulator, the imaging head can be highly miniaturized with a diameter of ∼3.0mm. Also, since all light is transmitted via fibers, the fiber-optic PARS microscopy system is relatively easy to build and facilitates scanning of the probe. In vivo imaging of a zebrafish larva and imaging of lithium metal batteries are conducted using the probe, showing its good imaging capability.

Photoacoustic-fluorescence microendoscopy in vivo.

A miniature endoscope capable of imaging multiple tissue contrasts in high resolution is highly attractive, because it can provide complementary and detailed tissue information of internal organs. Here we present a photoacoustic (PA)-fluorescence (FL) endoscope for optical-resolution PA microscopy (PAM) and FL microscopy (FLM). The endoscope with a diameter of 2.8 mm achieves high lateral resolutions of 5.5 and 6.3 µm for PAM and FLM modes, respectively. In vivo imaging of zebrafish larvae and a mouse ear is conducted, and high-quality images are obtained. Additionally, in vivo endoscopic imaging of a rat rectum is demonstrated, showing the endoscopic imaging capability of our endoscope. By providing dual contrasts with high resolution, the endoscope may open up new opportunities for clinical endoscopic imaging applications.

Photoacoustic microscopy with sparse data by convolutional neural networks.

The point-by-point scanning mechanism of photoacoustic microscopy (PAM) results in low-speed imaging, limiting the application of PAM. In this work, we propose a method to improve the quality of sparse PAM images using convolutional neural networks (CNNs), thereby speeding up image acquisition while maintaining good image quality. The CNN model utilizes attention modules, residual blocks, and perceptual losses to reconstruct the sparse PAM image, which is a mapping from a 1/4 or 1/16 low-sampling sparse PAM image to a latent fully-sampled one. The model is trained and validated mainly on PAM images of leaf veins, showing effective improvements quantitatively and qualitatively. Our model is also tested using in vivo PAM images of blood vessels of mouse ears and eyes. The results suggest that the model can enhance the quality of the sparse PAM image of blood vessels in several aspects, which facilitates fast PAM and its clinical applications.