The AlN lattice-polarity inversion in a high-temperature-annealed c-oriented AlN/sapphire originated from the diffusion of Al and O atoms from sapphire.

AlN films are widely used owing to their superior characteristics, including an ultra-wide bandgap, high breakdown field, and radiation resistance. High-temperature annealing (HTA) makes it easy to obtain high-quality AlN films, with the advantages of a simple process, good repeatability, and low cost. However, it is always found that there is a lattice-polarity inversion from a N-polarity near the sapphire to an Al-polarity in the HTA c-oriented AlN/sapphire. Currently, the formation mechanism is still unclear, which hinders its further wide applications. Therefore, the formation mechanism of the polarity inversion and its impacts on the quality and stress profile of the upper AlN in the HTA c-oriented AlN/sapphire were investigated. The results imply that the inversion originated from the diffusion of the Al and O atoms from the sapphire. Due to the presence of abundant Al vacancies (VAl) in the upper AlN, Al atoms in the sapphire diffuse into the upper AlN during the annealing to fill the VAl, resulting in the O-terminated sapphire, leading to the N-polar AlN. Meanwhile, O atoms in the sapphire also diffuse into the upper AlN during the annealing, forming an AlxOyNz layer and causing the inversion from N- to Al-polarity. The inversion has insignificant impacts on the quality and stress distribution of the upper AlN. Besides, this study predicts the presence of a two-dimensional electron gas at the inversion interface. However, the measured electron concentration is much lower than that predicted, which may be due to the defect compensation, low polarization level, and strong impurity scattering.

Immunomodulatory effect of Liangyi paste on the gut microbiota of mice.

Liangyi paste (LY) is a traditional Chinese medicine made from a mixture of Ginseng and Rehmanniae radix praeparata. The present study aimed to investigate the effects of LY on gut microbiota diversity in immunocompromised mice. The chemical composition of LY extract was analyzed using UPLC-Q-Orbitrap-MS/MS, and the differences in the structure and diversity of the intestinal microbiota of LY extract were examined using 16S rRNA. In this study, identified and analyzed 66 compounds from the LY. These compounds included 11 iridoids, 6 oligosaccharides, 21 protopanaxtriols, 23 protopanaxadiols, 2 OLE, 1 Ionone and 2 phenylethanoside, using advanced UPLC-Q-Orbitrap-MS/MS technology. Through the use of 16S rRNA analysis, the study found that LY significantly increased the relative abundance of the Firmicutes phylum in immunocompromised mice, while decreasing the abundance of the Proteobacteria and Actinobacteria phyla. At the genus level, LY significantly increased the relative abundance of beneficial bacteria such as Clostridium_sensu_stricto_l, Lactobacillus, and Limosilactobacillus in immunocompromised mice. Conversely, the paste extract decreased the relative abundance of harmful bacteria such as Enterococcus and Escherichia Shigella in immunocompromised mice. These findings highlight the potential of LY to serve as a natural dietary supplement for enhancing gut microbiota diversity and promoting gut health. The identification of numerous compounds within the paste extract demonstrates its complexity and potential as a source for further research and development. Additionally, the LY extract exerted a significant influence on both nucleotide and amino acid metabolism. To sum up, the findings suggest that the LY extract has the potential to modulate the structure and diversity of gut microbiota, as well as promote metabolic balance in immunocompromised mice.

Bibliometric Analysis of Global Research on Circular RNA: Current Status and Future Directions.

Circular RNAs (circRNAs) have gained significant attention in recent years. This bibliometric analysis aimed to provide insights into the current state and future trends of global circRNA research. The scientific output on circRNAs from 2010 to 2022 was retrieved from the Web of Science Core Collection with circRNA-related terms as the subjects. Key bibliometric indicators were calculated and evaluated using CiteSpace. A total of 7385 studies on circRNAs were identified. The output and citation number have increased rapidly after 2015. China, the USA, and Germany were top three publishing countries. Currently, circCDR1as, circHIPK3, circPVT1, circSHPRH, and circZNF609 are the most studied circRNAs; and all are related to cancer. The theme of research have shifted from transcript, exon circularization and miRNA sponge topics to the transcriptome, tumor suppressor, and biomarkers, indicating that research interests have evolved from basic to applied research. CircRNAs will continue to be a highly active research area in the near future. From the current understanding of circRNA characterization and regulatory mechanisms as miRNA sponges in cancer, future directions may examine potential diagnostic and therapeutic roles of circRNAs in cancers or the function and mechanism of circRNAs in other diseases.

Harnessing the Lysosomal Sorting Signals of the Cation-Independent Mannose-6-Phosphate Receptor for Targeted Degradation of Membrane Proteins.

Membrane proteins are a crucial class of therapeutic targets that remain challenging to modulate using traditional occupancy-driven inhibition strategies or current proteolysis-targeting degradation approaches. Here, we report that the inherent endolysosomal sorting machinery can be harnessed for the targeted degradation of membrane proteins. A new degradation technique, termed signal-mediated lysosome-targeting chimeras (SignalTACs), was developed by genetically fusing the signaling motif from the cation-independent mannose-6-phosphate receptor (CI-M6PR) to a membrane protein binder. Antibody-based SignalTACs were constructed with the CI-M6PR signal peptides fused to the C-terminus of both heavy and light chains of IgG. We demonstrated the scope of this platform technology by degrading five pathogenesis-related membrane proteins, including HER2, EGFR, PD-L1, CD20, and CD71. Furthermore, two simplified constructs of SignalTACs, nanobody-based and peptide-based SignalTACs, were created and shown to promote the lysosomal degradation of target membrane proteins. Compared to the parent antibodies, SignalTACs exhibited significantly higher efficiency in inhibiting tumor cell growth both in vitro and in vivo. This work provides a simple, general, and robust strategy for degrading membrane proteins with molecular precision and may represent a powerful platform with broad research and therapeutic applications.

Peripherin: A proposed biomarker of traumatic axonal injury triggered by mechanical force.

Traumatic axonal injury (TAI) is one of the most common pathological features of severe traumatic brain injury (TBI). Our previous study using proteomics suggested that peripherin (PRPH) should be a potential candidate as a biomarker for TAI diagnosis. This study is to further elucidate the role and association of PRPH with TAI. In the animal study, we performed immunohistochemistry, ELISA and morphological analysis to evaluate PRPH level and distribution following a severe impact. PRPH-positive regions were widely distributed in the axonal tract throughout the whole brain. Axonal injuries with PRPH inclusion were observed post-TBI. Besides, PRPH was significantly increased in both cerebral spinal fluid and plasma at the early phase post-TBI. Colocalization analysis based on microscopy revealed that PRPH represents an immunohistological biomarker in the neuropathological diagnosis of TAI. Brain samples from patients with TBI were included to further test whether PRPH is feasible in the real practice of neuropathology. Immunohistochemistry of PRPH, NFH, APP and NFL on human brain tissues further confirmed PRPH as an immunohistological biomarker that could be applied in practice. Collectively, we conclude that PRPH mirrors the cytoskeleton injury of axons and could represent a neuropathological biomarker for TAI.

Application of Adaptive Laboratory Evolution in Lipid and Terpenoid Production in Yeast and Microalgae.

Due to the complexity of metabolic and regulatory networks in microorganisms, it is difficult to obtain robust phenotypes through artificial rational design and genetic perturbation. Adaptive laboratory evolution (ALE) engineering plays an important role in the construction of stable microbial cell factories by simulating the natural evolution process and rapidly obtaining strains with stable traits through screening. This review summarizes the application of ALE technology in microbial breeding, describes the commonly used methods for ALE, and highlights the important applications of ALE technology in the production of lipids and terpenoids in yeast and microalgae. Overall, ALE technology provides a powerful tool for the construction of microbial cell factories, and it has been widely used in improving the level of target product synthesis, expanding the range of substrate utilization, and enhancing the tolerance of chassis cells. In addition, in order to improve the production of target compounds, ALE also employs environmental or nutritional stress strategies corresponding to the characteristics of different terpenoids, lipids, and strains.

Inhalable vaccine of bacterial culture supernatant extract mediates protection against fatal pulmonary anthrax.

Pulmonary anthrax is the most fatal clinical form of anthrax and currently available injectable vaccines do not provide adequate protection against it. Hence, next-generation vaccines that effectively induce immunity against pulmonary anthrax are urgently needed. In the present study, we prepared an attenuated and low protease activity Bacillus anthracis strain A16R-5.1 by deleting five of its extracellular protease activity-associated genes and its lef gene through the CRISPR-Cas9 genome editing system. This mutant strain was then used to formulate a lethal toxin (LeTx)-free culture supernatant extract (CSE) anthrax vaccine, of which half was protective antigen (PA). We generated liquid, powder, and powder reconstituted formulations that could be delivered by aerosolized intratracheal inoculation. All of them induced strong humoral, cellular, and mucosal immune responses. The vaccines also produced LeTx neutralizing antibodies and conferred full protection against the lethal aerosol challenges of B. anthracis Pasteur II spores in mice. Compared to the recombinant PA vaccine, the CSE anthrax vaccine with equal PA content provided superior immunoprotection against pulmonary anthrax. The preceding results suggest that the CSE anthrax vaccine developed herein is suitable and scalable for use in inhalational immunization against pulmonary anthrax.

Function of the Polyketide Synthase Domains of Schizochytrium sp. on Fatty Acid Synthesis in Yarrowia lipolytica.

It is well known that polyunsaturated fatty acids (PUFAs) in Schizochytrium sp. are mainly synthesized via the polyketide synthase (PKS) pathway. However, the specific mechanism of PKS in fatty acid synthesis is still unclear. In this work, the functions of ORFA, ORFB, ORFC, and their individual functional domain genes on fatty acid synthesis were investigated through heterologous expression in Yarrowia lipolytica. The results showed that the expression of ORFA, ORFB, ORFC, and their individual functional domains all led to the increase of the very long-chain PUFA content (mainly eicosapentaenoic acid). Furthermore, the transcriptomic analysis showed that except for the 3-ketoacyl-ACP synthase (KS) domain of ORFB, the expression of an individual functional domain, including malonyl-CoA: ACP acyltransferase, 3-hydroxyacyl-ACP dehydratase (DH), 3-ketoacyl-ACP reductase, and KS domains of ORFA, acyltransferase domains of ORFB, and two DH domains of ORFC resulted in upregulation of the tricarboxylic acid cycle and pentose phosphate pathway, downregulation of the triacylglycerol biosynthesis, fatty acid synthesis pathway, and ß-oxidation in Yarrowia lipolytica. These results provide a theoretical basis for revealing the function of PKS in fatty acid synthesis in Y. lipolytica and elucidate the possible mechanism for PUFA biosynthesis.

Long-term outcomes of definitive radiotherapy-based comprehensive treatment for inoperable stage I-III non-metastatic pancreatic cancer / 中华放射肿瘤学杂志

Objective:To analyze long-term outcomes of inoperable non-metastatic pancreatic cancer patients treated with definitive radiotherapy-based comprehensive treatment.Methods:Clinical data of 168 patients with medically unfit, refusal to surgery or inoperable non-metastatic pancreatic cancer treated with radiotherapy-based comprehensive treatment in PLA General Hospital between January 2016 and December 2020 were retrospectively analyzed. Survival outcomes,prognostic factors and patterns of treatment failure were analyzed in the radiotherapy ( n=95) and combined chemoradiotherapy ( n=73) groups. The survival analysis was conducted by Kaplan-Meier method. The survival curve was compared by log-rank test. Independent prognostic factors were identified by Cox proportional harzard model. Results:With a median follow-up of 20.2 months in the entire group, the median overall survival (OS) and median progression-free survival (PFS) were 18.0 and 12.3 months. The corresponding median OS and median PFS after receiving radiotherapy were 14.3 and 7.7 months. The 1-, 2-and 3-year OS rates were 72.1%, 36.6% and 21.5%, and the 1- and 2-year local control rates were 82.6% and 64.3%, respectively. The median OS for stage Ⅰ, stage Ⅱ and stage III were 27.1, 18.0 and 17.0 months, respectively. There was no significant difference in the median OS of patients with localized disease (stage Ⅰ-Ⅱ) between the radiotherapy and combined chemoradiotherapy groups (21.1 vs. 20.4 months, P=0.470). In patients with locally advanced disease (stage Ⅲ), combined chemoradiotherapy group showed better median OS compared with radiotherapy group (19.2 vs. 13.8 months, P=0.004). Clinical stage, CA19-9 before radiotherapy, comprehensive treatment and biological effective dose (BED 10) were identified as the independent prognostic factors for OS ( P=0.032, 0.011, 0.003 and 0.014). The cumulative 1- and 2-year actuarial rates of treatment failure, local-regional recurrence and distant metastasis were 48% and 74.4%, 15.0% and 27.4%, 23.6% and 33.1%, respectively. Liver metastasis (16.1%, 27/168) and local recurrence (11.9%, 20/168) were the primary patterns of treatment failure. Conclusions:Definitive radiotherapy-based comprehensive treatment effectively prolongs long-term survival in patients with inoperable non-metastatic pancreatic cancer. Definitive radiotherapy can be an alternative treatment option with curative intent for patients with localized pancreatic cancer who are medically unfit or refuse to undergo surgery. The combination of radiotherapy and chemotherapy remains an effective treatment choice for locally advanced unresectable pancreatic cancer.

Mechanosensitive Ion Channel TMEM63A Gangs Up with Local Macrophages to Modulate Chronic Post-amputation Pain / 神经科学通报·英文版

Post-amputation pain causes great suffering to amputees, but still no effective drugs are available due to its elusive mechanisms. Our previous clinical studies found that surgical removal or radiofrequency treatment of the neuroma at the axotomized nerve stump effectively relieves the phantom pain afflicting patients after amputation. This indicated an essential role of the residual nerve stump in the formation of chronic post-amputation pain (CPAP). However, the molecular mechanism by which the residual nerve stump or neuroma is involved and regulates CPAP is still a mystery. In this study, we found that nociceptors expressed the mechanosensitive ion channel TMEM63A and macrophages infiltrated into the dorsal root ganglion (DRG) neurons worked synergistically to promote CPAP. Histology and qRT-PCR showed that TMEM63A was mainly expressed in mechanical pain-producing non-peptidergic nociceptors in the DRG, and the expression of TMEM63A increased significantly both in the neuroma from amputated patients and the DRG in a mouse model of tibial nerve transfer (TNT). Behavioral tests showed that the mechanical, heat, and cold sensitivity were not affected in the Tmem63a-/- mice in the naïve state, suggesting the basal pain was not affected. In the inflammatory and post-amputation state, the mechanical allodynia but not the heat hyperalgesia or cold allodynia was significantly decreased in Tmem63a-/- mice. Further study showed that there was severe neuronal injury and macrophage infiltration in the DRG, tibial nerve, residual stump, and the neuroma-like structure of the TNT mouse model, Consistent with this, expression of the pro-inflammatory cytokines TNF-α, IL-6, and IL-1β all increased dramatically in the DRG. Interestingly, the deletion of Tmem63a significantly reduced the macrophage infiltration in the DRG but not in the tibial nerve stump. Furthermore, the ablation of macrophages significantly reduced both the expression of Tmem63a and the mechanical allodynia in the TNT mouse model, indicating an interaction between nociceptors and macrophages, and that these two factors gang up together to regulate the formation of CPAP. This provides a new insight into the mechanisms underlying CPAP and potential drug targets its treatment.

Stratification of malignant renal neoplasms from cystic renal lesions using deep learning and radiomics features based on a stacking ensemble CT machine learning algorithm.

Using nephrographic phase CT images combined with pathology diagnosis, we aim to develop and validate a fusion feature-based stacking ensemble machine learning model to distinguish malignant renal neoplasms from cystic renal lesions (CRLs). This retrospective research includes 166 individuals with CRLs for model training and 47 individuals with CRLs in another institution for model testing. Histopathology results are adopted as diagnosis criterion. Nephrographic phase CT scans are selected to build the fusion feature-based machine learning algorithms. The pretrained 3D-ResNet50 CNN model and radiomics methods are selected to extract deep features and radiomics features, respectively. Fivefold cross-validated least absolute shrinkage and selection operator (LASSO) regression methods are adopted to identify the most discriminative candidate features in the development cohort. Intraclass correlation coefficients and interclass correlation coefficients are employed to evaluate feature's reproducibility. Pearson correlation coefficients for normal distribution features and Spearman's rank correlation coefficients for non-normal distribution features are used to eliminate redundant features. After that, stacking ensemble machine learning models are developed in the training cohort. The area under the receiver operator characteristic curve (ROC), calibration curve, and decision curve analysis (DCA) are adopted in the testing cohort to evaluate the performance of each model. The stacking ensemble machine learning algorithm reached excellent diagnostic performance in the testing dataset. The calibration plot shows good stability when using the stacking ensemble model. Net benefits presented by DCA are higher than the Bosniak 2019 version classification when employing any machine learning algorithm. The fusion feature-based machine learning algorithm accurately distinguishes malignant renal neoplasms from CRLs, which outperformed the Bosniak 2019 version classification, and proves to be more applicable for clinical decision-making.

Engineering the xylose metabolism in Schizochytrium sp. to improve the utilization of lignocellulose.

BACKGROUND: Schizochytrium sp. is a heterotrophic, oil-producing microorganism that can efficiently produce lipids. However, the industrial production of bulk chemicals using Schizochytrium sp. is still not economically viable due to high-cost culture medium. Replacing glucose with cheap and renewable lignocellulose is a highly promising approach to reduce production costs, but Schizochytrium sp. cannot efficiently metabolize xylose, a major pentose in lignocellulosic biomass. RESULTS: In order to improve the utilization of lignocellulose by Schizochytrium sp., we cloned and functionally characterized the genes encoding enzymes involved in the xylose metabolism. The results showed that the endogenous xylose reductase and xylulose kinase genes possess corresponding functional activities. Additionally, attempts were made to construct a strain of Schizochytrium sp. that can effectively use xylose by using genetic engineering techniques to introduce exogenous xylitol dehydrogenase/xylose isomerase; however, the introduction of heterologous xylitol dehydrogenase did not produce a xylose-utilizing engineered strain, whereas the introduction of xylose isomerase did. The results showed that the engineered strain 308-XI with an exogenous xylose isomerase could consume 8.2 g/L xylose over 60 h of cultivation. Xylose consumption was further elevated to 11.1 g/L when heterologous xylose isomerase and xylulose kinase were overexpressed simultaneously. Furthermore, cultivation of 308-XI-XK(S) using lignocellulosic hydrolysates, which contained glucose and xylose, yielded a 22.4 g/L of dry cell weight and 5.3 g/L of total lipid titer, respectively, representing 42.7 and 30.4% increases compared to the wild type. CONCLUSION: This study shows that engineering of Schizochytrium sp. to efficiently utilize xylose is conducive to improve its utilization of lignocellulose, which can reduce the costs of industrial lipid production.

Developing a dynamic equilibrium system in Escherichia coli to improve the production of recombinant proteins.

The combination of Escherichia coli BL21 (DE3) and the pET expression system is used extensively for the expression of various recombinant proteins (RPs). However, RP overexpression often introduces a growth burden for the host, especially in the case of toxic proteins. The key to solving this problem is to reduce the host burden associated with protein overproduction, which is often achieved by regulating the expression or activity of T7 RNAP or growth-decoupled systems. However, these strategies mainly relieve or interrupt the robbing of host resources, and do not eliminate other types of host burdens in the production process. In this study, we constructed a production system based on a dynamic equilibrium to precisely relieve the host burden and increase the RP production. The system is composed of three modules, including the overexpression of basic growth-related genes (rRNA, RNAP core enzyme, sigma factors), prediction and overexpression of key proteins using the enzyme-constrained model ec_iECBD_1354, and dynamic regulation of growth-related and key protein expression intensity based on a burden-driven promoter. Using this system, the production of many high-burden proteins, including autolysis protein and E. coli membrane proteins, was increased to varying degrees. Among them, the cytosine transporter protein (CodB) was most significantly improved, with a 4.02-fold higher production compared to the wild strain. This system can effectively reduce the optimizing costs, and is suitable for developing various types of RP expression hosts rapidly. KEY POINTS: • The basic growth-related resources can relieve the host burden from recombinant protein. • The enzyme-constrained model can accurately predict key genes to improve yield. • The expression intensity can be dynamically adjusted with changes in burden.

Strategies for efficient production of recombinant proteins in Escherichia coli: alleviating the host burden and enhancing protein activity.

Escherichia coli, one of the most efficient expression hosts for recombinant proteins (RPs), is widely used in chemical, medical, food and other industries. However, conventional expression strains are unable to effectively express proteins with complex structures or toxicity. The key to solving this problem is to alleviate the host burden associated with protein overproduction and to enhance the ability to accurately fold and modify RPs at high expression levels. Here, we summarize the recently developed optimization strategies for the high-level production of RPs from the two aspects of host burden and protein activity. The aim is to maximize the ability of researchers to quickly select an appropriate optimization strategy for improving the production of RPs.

Color image encryption scheme based on alternate quantum walk and controlled Rubik's Cube.

Aiming at solving the trouble that digital image information is easily intercepted and tampered during transmission, we proposed a color image encryption scheme based on alternate quantum random walk and controlled Rubik's Cube transformation. At the first, the color image is separated into three channels: channel R, channel G and channel B. Besides, a random sequence is generated by alternate quantum walk. Then the six faces of the Rubik's Cube are decomposed and arranged in a specific order on a two-dimensional plane, and each pixel of the image is randomly mapped to the Rubik's Cube. The whirling of the Rubik's Cube is controlled by a random sequence to realize image scrambling and encryption. The scrambled image acquired by Rubik's Cube whirling and the random sequence received by alternate quantum walk are bitwise-XORed to obtain a single-channel encrypted image. Finally the three-channel image is merged to acquire the final encrypted image. The decryption procedure is the reverse procedure of the encryption procedure. The key space of this scheme is theoretically infinite. After simulation experiments, the information entropy after encryption reaches 7.999, the NPCR is 99.5978%, and the UACI is 33.4317%. The encryption scheme with high robustness and security has a excellent encryption effect which is effective to resist statistical attacks, force attacks, and other differential attacks.

Low Molecular Weight Sericin Enhances the In Vitro of Immunological Modulation and Cell Migration.

Sericin, a waste product of the silk textile industry, has favorable physicochemical and biological properties. In this study, we extracted a low molecular weight (MW) sericin (LMW-sericin; below 10 kDa) by a performing high-temperature and high-pressure method and confirmed the MW using matrix-assisted laser desorption ionization-time of flight and liquid chromatography-mass spectrometry. Furthermore, we determined its biological effects on macrophages and human adipose stem cells (hASCs) as cell models to investigate the biocompatibility, immunomodulation behavior, and potential signaling pathway-related wound healing via analyses of gene expression of focal adhesion and human cytokines and chemokines using quantitative real-time polymerase chain reaction and cytokine assay. LMW-sericin showed good biocompatibility both in macrophages and hASCs. Macrophages cultured with 0.1 mg/ml LMW-sericin displayed an improved inflammatory response shown by the upregulation of CXCL9, IL12A, BMP7, and IL10, which developed Th1 and Th2 balance. LMW-sericin also improved the differentiation of macrophages toward the M2 phenotype by significantly enhancing the expression of Arg-1, which is conducive to the repair of the inflammatory environment. Moreover, the gene expression of hASCs showed that LMW-sericin promoted the secretion of beneficial adhesion molecules that potentially activate the gene transcription of differentiation and migration in hASCs, as well as significantly enhanced the levels of PKCß1, RhoA, and RasGFR1 as fruitful molecules in wound healing. These findings provide insights into LMW-sericin application as a potential biomaterial for wound management.

Treatment of Obese Zebrafish with Saringosterol Acetate through AMP Activated Protein Kinase Pathway.

OBJECT: Edible Brown Seaweed Sargassum fusiforme (Harvey) Setchell, 1931 abbreviated as Sargassum fusiforme was used for folk medical therapy in East Asia countries over five hundred years. Saringosterol acetate (SA) was isolated from S. fusiforme in our previous study and indicated various effects. However, anti-obesity activity of SA and its mechanism still unknown. METHOD: The inhibitory effect of SA, isolated from S. fusiforme, on adipogenesis in 3T3-L1 adipocytes was investigated in vitro and in zebrafish model. Cell toxicity, differentiation, signaling pathway, and lipid accumulation of SA treated 3T3-L1 adipocytes were determined. The body weight and triglyceride content of diet-induced obese (DIO) adult male zebrafish were measured from 12 to 17 weeks after fertilization. RESULT: SA attenuated the differentiation of cells and reduced lipid accumulation, and triglyceride content in the 3T3-L1 adipocytes. During the differentiation of adipocytes, SA suppressed fat accumulation and decreased the expression of signal factors responsible for adipogenesis. In SA-treated adipocytes, while fatty acid synthetase was downregulated, AMP-activated protein kinase (AMPK) was upregulated. Furthermore, SA suppressed body weight and triglyceride content in DIO zebrafish. CONCLUSION: SA is a potential therapeutic agent in the management of metabolic disorders, such as obesity.

Indole-Based Long-Wavelength Fluorescent Probes for Bioimaging of S-Nitrosylation in Mitochondria.

S-Nitrosylation has been found to play an important role in regulating mitochondrial function. However, probes for detection of protein S-nitrosylation in mitochondria remain unexplored. Herein, a novel 4-(pyridin-4-yl)vinyl-substituted indole was designed, exhibiting a long-wavelength emission and a high fluorescent quantum yield. Functionalization of the 7-position of the indole ring with an arylphosphine ester resulted with probes with efficient mitochondria-targeting ability. Furthermore, the indole-arylphosphine displayed a significant fluorescence enhancement upon exposure to S-nitrosoglutathione (GSNO) at low micromolar concentrations in A431 cells. Taken together, this study provides a new indole-based fluorescent probe with a unique long-wavelength emission for direct detection of S-nitrosylation in mitochondria, which may represent a powerful tool for understanding the critical roles of S-nitrosylation within mitochondria of living organisms.

Comparison of Dechlorane Plus Concentrations in Sequential Blood Samples of Pregnant Women in Taizhou, China.

To develop an appropriate sampling strategy to assess the intrauterine exposure to dechlorane plus (DP), we investigated DP levels in sequential maternal blood samples collected in three trimesters of pregnancy, respectively, from women living in Taizhou. The median concentration of DPs (sum of syn-DP and anti-DP) in all samples was 30.5 pg g−1 wet-weight and 5.01 ng g−1 lipid-adjusted weight, respectively. The trimester-related DP concentrations were consistently strongly correlated (p < 0.01), indicating that a single measurement of DP levels could represent intrauterine exposure without sampling from the same female repeatedly; however, the wet-weight levels significantly increased across trimesters (p < 0.05), while the lipid-adjusted levels did not significantly vary. Notably, whether lipid-adjusted weight or wet-weight levels, the variation extent of DP across trimesters was found to be less than 41%, and those for other persistent organic pollutants (POPs) reported in the literature were also limited to 100%. The limitation in variation extents indicated that, regardless of the time of blood collection during pregnancy and how the levels were expressed, a single measurement could be extended to screen for exposure risk if necessary. Our study provides different strategies for sampling the maternal blood to serve the requirement for assessment of in utero exposure to DP.

Antibody-Drug Conjugates Targeting the Human Epidermal Growth Factor Receptor Family in Cancers.

Members of the human epidermal growth factor receptor (HER) family, which includes HER1 (also known as EGFR), HER2, HER3 and HER4, have played a central role in regulating cell proliferation, survival, differentiation and migration. The overexpression of the HER family has been recognized as one of the most common cellular dysregulation associated with a wide variety of tumor types. Antibody-drug conjugates (ADCs) represent a new and promising class of anticancer therapeutics that combine the cancer specificity of antibodies with cytotoxicity of chemotherapeutic drugs. Two HER2-directed ADCs, trastuzumane-emtansine (T-DM1) and trastuzumab-deruxtecan (DS-8201a), have been approved for HER2-positive metastatic breast cancer by the U.S. Food and Drug Administration (FDA) in 2013 and 2019, respectively. A third HER2-directed ADC, disitamab vedotin (RC48), has been approved for locally advanced or metastatic gastric or gastroesophageal junction cancer by the NMPA (National Medical Products Administration) of China in 2021. A total of 11 ADCs that target HER family receptors (EGFR, HER2 or HER3) are currently under clinical trials. In this review article, we summarize the three approved ADCs (T-DM1, DS-8201a and RC48), together with the investigational EGFR-directed ADCs (ABT-414, MRG003 and M1231), HER2-directed ADCs (SYD985, ARX-788, A166, MRG002, ALT-P7, GQ1001 and SBT6050) and HER3-directed ADC (U3-1402). Lastly, we discuss the major challenges associated with the development of ADCs, and highlight the possible future directions to tackle these challenges.