Anti-Quenching NIR-II J-Aggregates of Benzo[c]thiophene Fluorophore for Highly Efficient Bioimaging and Phototheranostics.

Molecular fluorophores with the second near-infrared (NIR-II) emission hold great potential for deep-tissue bioimaging owing to their excellent biocompatibility and high resolution. Recently, J-aggregates are used to construct long-wavelength NIR-II emitters as their optical bands show remarkable red shifts upon forming water-dispersible nano-aggregates. However, their wide applications in the NIR-II fluorescence imaging are impeded by the limited varieties of J-type backbone and serious fluorescence quenching. Herein, we report a bright benzo[c]thiophene (BT) J-aggregate fluorophore (BT6) with anti-quenching effect for highly efficient NIR-II bioimaging and phototheranostics. The BT fluorophores are manipulated to have Stokes shift over 400 nm and aggregation-induced emission (AIE) property for conquering the self-quenching issue of the J-type fluorophores. Upon forming BT6 assemblies in an aqueous environment, the absorption over 800 nm and NIR-II emission over 1000 nm are boosted for more than 41 and 26 folds, respectively. In vivo visualization of the whole-body blood vessel and imaging-guided phototherapy results verify that BT6 NPs are excellent agent for NIR-II fluorescence imaging and cancer phototheranostics. This work develops a strategy to construct bright NIR-II J-aggregates with precisely manipulated anti-quenching properties for highly efficient biomedical applications. This article is protected by copyright. All rights reserved.

Multiple Natural Polymers in Drug and Gene Delivery Systems.

BACKGROUND: Natural polymers are organic compounds produced by living organisms. In nature, they exist in three main forms, including proteins, polysaccharides and nucleic acids. In recent years, with the continuous research on drug and gene delivery systems, scholars have found that natural polymers have promising applications in drug and gene delivery systems due to their excellent properties such as biocompatibility, biodegradability, low immunogenicity and easy modification. However, since the structure, physicochemical properties, pharmacological properties and biological characteristics of biopolymer molecules have not yet been entirely understood, further studies are required before large-scale clinical application. METHODS: This review focuses on recent advances in the representative natural polymers such as proteins (albumin, collagen, elastin), polysaccharides (chitosan, alginate, cellulose) and nucleic acids. RESULTS: We introduce the characteristics of various types of natural polymers, and further outline the characterization methods and delivery forms of these natural polymers. CONCLUSION: Finally, we discuss possible challenges for natural polymers in subsequent experimental studies and clinical applications. It provides an important strategy for the clinical application of natural polymers in drug and gene delivery systems.

Modeling and Prediction of Water-Jet-Guided Laser Cutting Depth for Inconel 718 Material Using Response Surface Methodology.

In this study, the water-jet-guided laser (WJGL) method was used to cut Inconel 718 alloy with high temperature resistance. The effect of critical parameters of the water-jet-guided laser machining method on the cutting depth was studied by a Taguchi orthogonal experiment. Furthermore, the mathematical prediction model of cutting depth was established by the response surface method (RSM). The validation experiments showed that the mathematical model had a high predictive ability for cutting depth. The optimal cutting depth was obtained by model prediction, and the error was 5.5% compared with the experimental results. Compared with the traditional dry laser cutting, the water conducting laser method reduced the thermal damage and improved the cutting quality. This study provides a reference for the precision machining of Inconel 718 with a water-jet-guided laser.

mRNA Vaccine-A New Cancer Treatment Strategy.

The corresponding mRNA vaccines Comirnaty (BNT162b2) and Spikevax (mRNA-1273) have been authorized for emergency use since the COVID-19 outbreak. Most clinical researches have also discovered that the mRNA vaccine is a revolutionary strategy for preventing and treating numerous diseases, including cancers. Unlike viral vectors or DNA vaccines, mRNA vaccines cause the body to directly produce proteins following injection. Delivery vectors and mRNAs that encode tumor antigens or immunomodulatory molecules work together to trigger an anti-tumor response. Before mRNA vaccines may be employed in clinical trials, a number of challenges need to be resolved. These include establishing effective and safe delivery systems, generating successful mRNA vaccines against diverse types of cancers, and proposing improved combination therapy. Therefore, we need to improve vaccine-specific recognition and develop mRNA delivery mechanisms. This review summarizes the complete mRNA vaccines' elemental composition and discusses recent research progress and future direction for mRNA tumor vaccines.

Interaction-integrated linear mixed model reveals 3D-genetic basis underlying Autism.

Genetic interactions play critical roles in genotype-phenotype associations. We developed a novel interaction-integrated linear mixed model (ILMM) that integrates a priori knowledge into linear mixed models. ILMM enables statistical integration of genetic interactions upfront and overcomes the problems of searching for combinations. To demonstrate its utility, with 3D genomic interactions (assessed by Hi-C experiments) as a priori, we applied ILMM to whole-genome sequencing data for Autism Spectrum Disorders (ASD) and brain transcriptome data, revealing the 3D-genetic basis of ASD and 3D-expression quantitative loci (3D-eQTLs) for brain tissues. Notably, we reported a potential mechanism involving distal regulation between FOXP2 and DNMT3A, conferring the risk of ASD.

Intramolecular Cyclization: A Convenient Strategy to Realize Efficient BT.2020 Blue Multi-Resonance Emitter for Organic Light-Emitting Diodes.

Rationally tuning the emission position and narrowing the full width at half-maximum (FWHM) of an emitter is of great importance for many applications. By synergistically improving rigidity, strengthening the resonant strength, inhibiting molecular bending and rocking, and destabilizing the HOMO energy level, a deep-blue emitter (CZ2CO) with a peak wavelength of 440 nm and an ultranarrow spectral FWHM of 16 nm (0.10 eV) was developed via intramolecular cyclization in a carbonyl/N resonant core (QAO). The dominant υ0-0 transition character of CZ2CO gives a Commission Internationale de I'Éclairage coordinates (CIE) of (0.144, 0.042), nicely complying with the BT.2020 standard. Moreover, a hyper-fluorescent device based on CZ2CO shows a high maximum external quantum efficiency (EQEmax ) of 25.6 % and maintains an EQE of 22.4 % at a practical brightness of 1000 cd m-2 .

Dual-prodrug cascade activation for chemo/chemodynamic mutually beneficial combination cancer therapy.

The combination of chemodynamic therapy (CDT) and chemotherapy has shown promise for achieving improved cancer treatment outcomes. However, due to the lack of synergy rationale, a simple one-plus-one combination therapy remains suboptimal in overcoming the obstacles of each treatment approach. Herein, we report a nanoplatform consisting of a pH-sensitive ferrocene- and cinnamaldehyde-based polyprodrug and a hydrogen peroxide-responsive doxorubicin (DOX) prodrug. Under an acidic tumor environment, the cinnamaldehyde polyprodrug will be activated to release free cinnamaldehyde, which can increase the intracellular hydrogen peroxide level and enhance the Fenton reaction. Subsequently, due to the collapse of nanoparticle structures, the DOX prodrug will be released and activated under a hydrogen peroxide stimulus. Meanwhile, the quinone methide produced during DOX prodrug activation can consume glutathione, an important antioxidant, and thus in turn enhance the efficacy of CDT. This design of a nanoplatform with dual-prodrug cascade activation provides a promising mutually beneficial cooperation mode between chemotherapy and CDT for enhancing antitumor efficacy.

Integrating transcription factor occupancy with transcriptome-wide association analysis identifies susceptibility genes in human cancers.

Transcriptome-wide association studies (TWAS) have successfully discovered many putative disease susceptibility genes. However, TWAS may suffer from inaccuracy of gene expression predictions due to inclusion of non-regulatory variants. By integrating prior knowledge of susceptible transcription factor occupied elements, we develop sTF-TWAS and demonstrate that it outperforms existing TWAS approaches in both simulation and real data analyses. Under the sTF-TWAS framework, we build genetic models to predict alternative splicing and gene expression in normal breast, prostate and lung tissues from the Genotype-Tissue Expression project and apply these models to data from large genome-wide association studies (GWAS) conducted among European-ancestry populations. At Bonferroni-corrected P < 0.05, we identify 354 putative susceptibility genes for these cancers, including 189 previously unreported in GWAS loci and 45 in loci unreported by GWAS. These findings provide additional insight into the genetic susceptibility of human cancers. Additionally, we show the generalizability of the sTF-TWAS on non-cancer diseases.

Identifying magnetosome-associated genes in the extended CtrA regulon in Magnetospirillum magneticum AMB-1 using a combinational approach.

Magnetotactic bacteria (MTB) are worth studying because of magnetosome biomineralization. Magnetosome biogenesis in MTB is controlled by multiple genes known as magnetosome-associated genes. Recent advances in bioinformatics provide a unique opportunity for studying functions of magnetosome-associated genes and networks that they are involved in. Furthermore, various types of bioinformatics analyses can also help identify genes associated with magnetosome biogenesis. To predict novel magnetosome-associated genes in the extended CtrA regulon, we analyzed expression data of Magnetospirillum magneticum AMB-1 in the GSE35625 dataset in NCBI GEO. We identified 10 potential magnetosome-associated genes using a combinational approach of differential expression analysis, Gene ontology and Kyoto encyclopedia of genes and genomes pathway enrichment analysis, protein-protein interaction network analysis and weighted gene co-expression network analysis. Meanwhile, we also discovered and compared two co-expression modules that most known magnetosome-associated genes belong to. Our comparison indicated the importance of energy on regulating co-expression module structures for magnetosome biogenesis. At the last stage of our research, we predicted at least four real magnetosome-associated genes out of 10 potential genes, based on a comparison of evolutionary trees between known and potential magnetosome-associated genes. Because of the discovery of common subtrees that the stressed species are enriched in, we proposed a hypothesis that multiple types of environmental stress can trigger magnetosome evolution in different waters, and therefore its evolution can recur at different times in various locations on earth. Overall, our research provides useful information for identifying new MTB species and understanding magnetosome biogenesis.

The Role of Balancing Carrier Transport in Realizing an Efficient Orange-Red Thermally Activated Delayed-Fluorescence Organic Light-Emitting Diode.

Simultaneously realizing improved carrier mobility and good photoluminescence (PL) efficiency in red thermally activated delayed-fluorescence (TADF) emitters remains challenging but important. Herein, two isomeric orange-red TADF emitters, oPDM and pPDM, with the same basic donor-acceptor backbone but a pyrimidine (Pm) attachment at different positions are designed and synthesized. The two emitters show similarly good PL properties, including narrow singlet-triplet energy offsets (0.11 and 0.15 eV) and high photoluminescence quantum yields (ca. 100 and 88%) in doped films. An orange-red organic light-emitting diode (OLED) employing oPDM as an emitter achieves an almost twice as high maximum external quantum efficiency (28.2%) compared with that of a pPDM-based OLED. More balanced carrier-transporting properties are responsible for their contrasting device performances, and the position effect of the Pm substituent leads to significantly distinct molecular packing behaviors in the aggregate states and different carrier mobilities.

Macrophage Sprouty4 deficiency diminishes sepsis-induced acute lung injury in mice.

OBJECTIVE: Inflammation and oxidative stress play critical roles in sepsis-induced acute lung injury (ALI). Sprout4 (Spry4) is involved in regulating inflammation and tissue injury; however, its role and mechanism in sepsis-induced ALI remain elusive. METHODS: Macrophage-specific Spry4 knockout (Spry4MKO), transgenic (Spry4MTG) mice and matched control littermates were generated and exposed to cecum ligation and puncture (CLP) surgery to establish bacterial sepsis-induced ALI. Bone marrow-derived macrophages (BMDMs) from Spry4MKO or Spry4MTG mice were isolated and subjected to lipopolysaccharide (LPS) stimulation to further validate the role of Spry4 in vitro. To verify the necessity of AMP-activated protein kinase (AMPK), Spry4 and AMPK double knockout mice and compound C were used in vivo and in vitro. BMDMs were treated with STO-609 to inhibit calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2). RESULTS: We found that macrophage Spry4 was increased in CLP mice and positively correlated with sepsis-induced ALI. Macrophage Spry4 deficiency prevented, while macrophage Spry4 overexpression exacerbated sepsis-induced inflammation, oxidative stress and ALI in mice and BMDMs. Mechanistic studies revealed that macrophage Spry4 deficiency alleviated sepsis-induced ALI through activating CaMKK2/AMPK pathway. CONCLUSION: Our study identify macrophage Spry4 as a promising predictive and therapeutic target of sepsis-induced ALI.

A novel method for drug-target interaction prediction based on graph transformers model.

BACKGROUND: Drug-target interactions (DTIs) prediction becomes more and more important for accelerating drug research and drug repositioning. Drug-target interaction network is a typical model for DTIs prediction. As many different types of relationships exist between drug and target, drug-target interaction network can be used for modeling drug-target interaction relationship. Recent works on drug-target interaction network are mostly concentrate on drug node or target node and neglecting the relationships between drug-target. RESULTS: We propose a novel prediction method for modeling the relationship between drug and target independently. Firstly, we use different level relationships of drugs and targets to construct feature of drug-target interaction. Then, we use line graph to model drug-target interaction. After that, we introduce graph transformer network to predict drug-target interaction. CONCLUSIONS: This method introduces a line graph to model the relationship between drug and target. After transforming drug-target interactions from links to nodes, a graph transformer network is used to accomplish the task of predicting drug-target interactions.

Experimental Research and Optimization of Ti-6Al-4V Alloy Microgroove Machining Based on Waterjet-Guided High-Power Laser.

In order to improve the tribological properties of Ti-6Al-4V alloy and further broaden the application scope of titanium alloy materials in the industrial field, a preparation method of a waterjet-guided high-power laser processing surface microgroove was studied. In this paper, a multifocus coupling lens was innovatively designed to replace the spherical lens in the traditional waterjet-guided laser coupling device, which avoids the gas explosion phenomenon in the coupling of the high-power laser and waterjet, and realizes the high-quality coupling of the high-power laser and water beam fiber. Then, with the microgroove morphology as the response target, the single-factor test and response surface test of the water-guided laser processing microgroove were carried out. Based on the experimental results, an approximate mathematical model of the response surface between the process parameters and the microgroove topography target was constructed, and the quantitative relationship between the waterjet-guided laser processing parameters and the target response was studied. At the same time, the optimal combination of process parameters was obtained by multiobjective optimization, so as to effectively improve the microgroove morphology. This technology provides method guidance and a decision-making reference for subsequent waterjet-guided laser processing of titanium alloy surface functional microstructures.

Independently evolved viral effectors convergently suppress DELLA protein SLR1-mediated broad-spectrum antiviral immunity in rice.

Plant viruses adopt diverse virulence strategies to inhibit host antiviral defense. However, general antiviral defense directly targeted by different types of plant viruses have rarely been studied. Here, we show that the single rice DELLA protein, SLENDER RICE 1 (SLR1), a master negative regulator in Gibberellin (GA) signaling pathway, is targeted by several different viral effectors for facilitating viral infection. Viral proteins encoded by different types of rice viruses all directly trigger the rapid degradation of SLR1 by promoting association with the GA receptor OsGID1. SLR1-mediated broad-spectrum resistance was subverted by these independently evolved viral proteins, which all interrupted the functional crosstalk between SLR1 and jasmonic acid (JA) signaling. This decline of JA antiviral further created the advantage of viral infection. Our study reveals a common viral counter-defense strategy in which different types of viruses convergently target SLR1-mediated broad-spectrum resistance to benefit viral infection in the monocotyledonous crop rice.

Photo-controllable Luminescence from Radicals Leading to Ratiometric Emission Switching via Dynamic Intermolecular Coupling.

The development of photoinduced luminescent radicals with dynamic emission color is still challenging. Herein we report a novel molecular radical system (TBIQ) that shows photo-controllable luminescence, leading to a wide range of ratiometric color changes via light excitation. The conjugated skeleton of TBIQ is decorated with steric-demanding tertiary butyl groups that enable appropriate intermolecular interaction to make dynamic intermolecular coupling possible for controllable behaviors. We reveal that the helicenic pseudo-planar conformation of TBIQ experiences a planarization process after light excitation, leading to more compactly stacked supermolecules and thus generating radicals via intermolecular charge transfer. The photo-controllable luminescent radical system is employed for a high-level information encryption application. This study may offer unique insight into molecular dynamic motion for optical manufacturing and broaden the scope of smart-responsive materials for advanced applications.

Cutaneous metastasis of carcinomatous component of ovarian carcinosarcoma: A case report and review of the literature.

Skin metastasis of ovarian cancer is extremely rare. We report an unusual case of ovarian carcinosarcoma with cutaneous metastasis of carcinomatous component that displayed distinct clinical manifestation. A 48-year-old woman presented to the dermatologist complaining of a new onset of erythematous, plaque-like skin rash with multiple small nodules on the left inner thigh, the area measuring 8 × 5cm. While the patient had no history of dermatologic conditions, she underwent a total hysterectomy and bilateral salpingo-oophorectomy, omentectomy, and lymph node dissection 16 months ago with a pathology confirmed stage IIIC ovarian carcinosarcoma. Of note, the carcinomatous component, mainly adenocarcinoma with hybrid features of seromucinous, endometrioid and minor high-grade serous carcinoma, involved bilateral fallopian tubes, omentum, and parametrium with extensive lymph node metastases. A skin biopsy specimen revealed an adenocarcinoma involving epidermis, dermis, and subcutaneous tissue with nodular contours, consistent with metastatic carcinomatous component of carcinosarcoma. Both carcinomatous component of primary ovarian carcinosarcoma and metastatic adenocarcinoma in the skin demonstrated Pax8, WT-1, and ER positivity and a mutation pattern of p53. The patient passed away 15 months after identification of skin metastasis. This case represents a unique example of cutaneous metastasis of ovarian carcinosarcoma with distinct clinical manifestation and detailed histopathological description. Alertness to the possibility of cutaneous metastasis, in combination with clinical history, morphological and immunohistochemical findings, is critical for a definitive classification.

A 3D/3D hetero-interpenetrated MOF with a novel (3,9)-c net and 6-c lcy net for the fluorescence detection of carbaryl.

An exceptional Zn-based MOF material with two-fold hetero-interpenetrated nets consisting of a 3D lcy network and a novel 3D (3,9)-coordinated framework has been constructed. The Zn-based MOF exhibits a rare yellow-green fluorescence and can be used as a fluorescence sensor to detect carbaryl with a detection limit of 4.5 µM.

Rabies Virus Neutralizing Activity, Safety, and Immunogenicity of Recombinant Human Rabies Antibody Compared with Human Rabies Immunoglobulin in Healthy Adults.

Objective: Preliminary assessment of rabies virus neutralizing activity, safety and immunogenicity of a recombinant human rabies antibody (NM57) compared with human rabies immunoglobulin (HRIG) in Chinese healthy adults. Methods: Subjects were randomly (1:1:1) allocated to Groups A (20 IU/kg NM57), B (40 IU/kg NM57), or C (20 IU/kg HRIG). One injection was given on the day of enrollment. Blood samples were collected on days -7 to 0 (pre-injection), 3, 7, 14, 28, and 42. Adverse events (AEs) and serious AEs (SAEs) were recorded over a period of 42 days after injection. Results: All 60 subjects developed detectable rabies virus neutralizing antibodies (RVNAs) (> 0.05 IU/mL) on days 3, 7, 14, 28, and 42. The RVNA levels peaked on day 3 in all three groups, with a geometric mean concentration (GMC) of 0.2139 IU/mL in Group A, 0.3660 IU/mL in Group B, and 0.1994 IU/mL in Group C. At each follow-up point, the GMC in Group B was significantly higher than that in Groups A and C. The areas under the antibody concentration curve over 0-14 days and 0-42 days in Group B were significantly larger than those in Groups A and C. Fifteen AEs were reported. Except for one grade 2 myalgia in Group C, the other 14 were all grade 1. No SAEs were observed. Conclusion: The rabies virus neutralizing activity of 40 IU/kg NM57 was superior to that of 20 IU/kg NM57 and 20 IU/kg HRIG, and the rabies virus neutralizing activity of 20 IU/kg NM57 and 20 IU/kg HRIG were similar. Safety was comparable between NM57 and HRIG.

High-repetition-rate, quarter acoustic wave oscillation period pulse compression using transient stimulated Brillouin scattering.

In this work we demonstrate the compression of laser pulses at a high repetition rate, using transient stimulated Brillouin scattering (SBS). Output pulses with pulse durations close to the quarter-acoustic wave oscillation period (τf) was obtained. We find that the primary factors which limit the compression of pulses under high repetition-rate, transient conditions are the inherently low gain in the transient regime, thermal accumulation within the SBS medium and optical breakdown. We show that short phonon lifetimes can suppress the trailing edge amplification of the output pulse, while also reducing the threshold and improve energy efficiency. In this work, we demonstrate the generation of output laser pulses with a repetition-rate of 200 Hz and an average pulse duration of 1.08τf using the electronic-fluorinated liquid FC-43. Due to the fast decay of the acoustic field, compressed pulses with duration <τf were also observed. We also demonstrate efficient output of pulses with repetition-rate of 200 Hz and energy efficiency of up to 40% using the heat transfer fluid HT-230.

Elucidating tumor heterogeneity from spatially resolved transcriptomics data by multi-view graph collaborative learning.

Spatially resolved transcriptomics (SRT) technology enables us to gain novel insights into tissue architecture and cell development, especially in tumors. However, lacking computational exploitation of biological contexts and multi-view features severely hinders the elucidation of tissue heterogeneity. Here, we propose stMVC, a multi-view graph collaborative-learning model that integrates histology, gene expression, spatial location, and biological contexts in analyzing SRT data by attention. Specifically, stMVC adopting semi-supervised graph attention autoencoder separately learns view-specific representations of histological-similarity-graph or spatial-location-graph, and then simultaneously integrates two-view graphs for robust representations through attention under semi-supervision of biological contexts. stMVC outperforms other tools in detecting tissue structure, inferring trajectory relationships, and denoising on benchmark slices of human cortex. Particularly, stMVC identifies disease-related cell-states and their transition cell-states in breast cancer study, which are further validated by the functional and survival analysis of independent clinical data. Those results demonstrate clinical and prognostic applications from SRT data.