Circuit-specific gene therapy reverses core symptoms in a primate Parkinson's disease model.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder. Its symptoms are typically treated with levodopa or dopamine receptor agonists, but its action lacks specificity due to the wide distribution of dopamine receptors in the central nervous system and periphery. Here, we report the development of a gene therapy strategy to selectively manipulate PD-affected circuitry. Targeting striatal D1 medium spiny neurons (MSNs), whose activity is chronically suppressed in PD, we engineered a therapeutic strategy comprised of a highly efficient retrograde adeno-associated virus (AAV), promoter elements with strong D1-MSN activity, and a chemogenetic effector to enable precise D1-MSN activation after systemic ligand administration. Application of this therapeutic approach rescues locomotion, tremor, and motor skill defects in both mouse and primate models of PD, supporting the feasibility of targeted circuit modulation tools for the treatment of PD in humans.

Multi-channel optical sensing system with a BP-ANN for heavy metal detection.

A multi-channel optical sensing system for heavy metal concentration detection is presented in this paper. The system utilizes a multi-channel optical path combined with a unique circuit design and BP neural network (BP-ANN) to perform the online analysis of multi-wavelength signals, achieving accurate concentration detection of a heavy metal solution. An array photodiode is used to detect the transmission light intensities at multiple wavelengths through the optical path of the system, which enables the collection of useful spectral information of the solution. The system uses a unique signal acquisition method to effectively improve the efficiency of both signal acquisition and operation. BP-ANN is applied to the online analysis of multi-channel information, which overcomes the influential issue of nonlinear effect on data detection, optimizes the anti-interference ability, and lowers the detection limit of the system. This system eliminates the necessary employment of the expensive and large spectrometers and therefore greatly reduces the instrument cost and occupying space. Additionally, the detection limit of the system is extended lower than that of the conventional spectrophotometer. Compared with the detection limits of heavy metal solution obtained by using a single characteristic light wavelength, the detection limits of Cd2+, Cu2+ and Cr6+ achieved through using multi-channel detection system can be reduced by 42.64%, 38.12%, and 20.62%, respectively, and these detection limits are found as 0.0041mg/L, 0.0091mg/L, and 0.0112mg/L, respectively.

Design, synthesis and biological evaluation of 3,5-dimethylisoxazole and pyridone derivatives as BRD4 inhibitors.

Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extra-terminal (BET) family, has been recognized as an attractive candidate target for the treatment targeting gene transcription in several types of cancers. In this study, two types of novel compounds were designed, synthesized and evaluated as BRD4 inhibitors. Therein, pyridone derivatives were more effective against BRD4 protein and human leukemia cell lines MV4-11. Among them, compounds 11d, 11e and 11f were the most potential ones with IC50 values of 0.55 µM, 0.86 µM and 0.80 µM against BRD4, and exhibited remarkable antiproliferative activities against MV4-11 cells with IC50 values of 0.19 µM, 0.32 µM and 0.12 µM, respectively. Moreover, in western blot assay, compound 11e induced down-regulation of C-Myc, which is a significant downstream gene of BRD4. Cell cycle analysis assay also showed that compound 11e could block MV4-11 cells at G0/G1 phase. Taken together, our results suggested that compound 11e and its derivatives were a class of novel structural potential BRD4 inhibitors and could serve as lead compounds for further exploration.

Discovery and evaluation of novel nitrodihydroimidazooxazoles as promising anti-tuberculosis agents.

New analogues of antitubercular drug Delamanid were prepared, seeking drug candidates with enhanced aqueous solubility and high efficacy. The strategy involved replacement of phenoxy linker proximal to the 2-nitroimidazooxazole of Delamanid by piperidine fused 5 or 6-membered ring heterocycles (ring A). The new compounds were all more hydrophilic than Delamanid, and several class of analogues showed remarkable activities against M. bovis. And among these series, the tetrahydro-naphthyridine-linked nitroimidazoles displayed excellent antimycobacterial activity against both replicating (MABA) and nonreplicating (LORA) M. tb H37Rv and low cytotoxicity. Compared to Delamanid, these new compounds (6, 7, 45) demonstrated dramatically improved physicochemical properties and are suitable for further in vitro and in vivo evaluation.

Hollow Co3O4 Nanosphere Surrounded by N-Doped Graphitic Carbon Filled within Multilayer-Sandwiched Graphene Network: A High-Performance Anode for Lithium Storage.

We prepared a multilayer-sandwiched Co3O4/NGC/rGO composite by introducing in situ electrostatic self-assembly method with a subsequent thermal annealing induced Kirkendall effect. In the composite, the hollow Co3O4 nanospheres surrounded by N-doped graphitic carbon (NGC) layer are tightly sandwiched between the reduced graphene oxide (rGO) layers. The layer-by-layer multilayer-sandwiched structure and strong electrostatic interaction bring the space confinement effect and close electrical contact between different components, which greatly strengthen the durability of the electrode structure and electron/ion transport kinetics. Detailed characterization based on electrochemical impedance spectra (EIS) and cyclic voltammograms (CVs) tests confirms that the Co3O4/NGC/rGO electrode possesses accelerated electron/ion-transfer kinetics and enhanced surface-controlled capacitive behaviors. The discharging profile and its differential capacity curve further validate the existence of interfacial storage lithium in the composite, contributing to high reversible capacity. Consequently, benefiting from the synergistic effects of the multilevel controls in component and structure aspects, the Co3O4/NGC/rGO composite displays a superior reversible capacity (930.8 mA h g-1 at 0.5 A g-1), desired rate performance (584 mA h g-1 at 10 A g-1), as well as stable cycling lifetime of over 300 loops with almost no capacity fading even without any additional conductive additives.

Metabolism of SKLB-TB1001, a Potent Antituberculosis Agent, in Animals.

Tuberculosis is a major global health problem, and the emergence of multidrug-resistant and extensively drug-resistant strains has increased the difficulty of treating this disease. Among the novel antituberculosis drugs in the pipeline, decaprenylphosphoryl-beta-d-ribose-2-epimerase (DprE1) inhibitors such as BTZ043 and pBTZ169 exhibited extraordinary antituberculosis potency. Here, the metabolites of the new DprE1 inhibitor SKLB-TB1001 in vivo and its inhibition of cytochrome P450 isoforms and plasma protein binding (PPB) in vitro were studied. The results showed that rapid transformation and high PPB resulted in inadequate exposure in vivo and thus led to the moderate potency of SKLB-TB1001 in vivo This study provided explanations for the discrepant potency of this scaffold in vivo and in vitro Meanwhile, it also provides a rationale for lead optimization of this very promising scaffold of antituberculosis agents to prevent them from being metabolized, thus improving their exposure in vivo.

ControlFace: Feature Disentangling for Controllable Face Swapping.

Face swapping is an intriguing and intricate task in the field of computer vision. Currently, most mainstream face swapping methods employ face recognition models to extract identity features and inject them into the generation process. Nonetheless, such methods often struggle to effectively transfer identity information, which leads to generated results failing to achieve a high identity similarity to the source face. Furthermore, if we can accurately disentangle identity information, we can achieve controllable face swapping, thereby providing more choices to users. In pursuit of this goal, we propose a new face swapping framework (ControlFace) based on the disentanglement of identity information. We disentangle the structure and texture of the source face, encoding and characterizing them in the form of feature embeddings separately. According to the semantic level of each feature representation, we inject them into the corresponding feature mapper and fuse them adequately in the latent space of StyleGAN. Owing to such disentanglement of structure and texture, we are able to controllably transfer parts of the identity features. Extensive experiments and comparisons with state-of-the-art face swapping methods demonstrate the superiority of our face swapping framework in terms of transferring identity information, producing high-quality face images, and controllable face swapping.

Spatio-temporal evolution mechanism and dynamic simulation of nitrogen and phosphorus pollution of the Yangtze River economic Belt in China.

Excess nitrogen and phosphorus inputs are the main causes of aquatic environmental deterioration. Accurately quantifying and dynamically assessing the regional nitrogen and phosphorus pollution emission (NPPE) loads and influencing factors is crucial for local authorities to implement and formulate refined pollution reduction management strategies. In this study, we constructed a methodological framework for evaluating the spatio-temporal evolution mechanism and dynamic simulation of NPPE. We investigated the spatio-temporal evolution mechanism and influencing factors of NPPE in the Yangtze River Economic Belt (YREB) of China through the pollution load accounting model, spatial correlation analysis model, geographical detector model, back propagation neural network model, and trend analysis model. The results show that the NPPE inputs in the YREB exhibit a general trend of first rising and then falling, with uneven development among various cities in each province. Nonpoint sources are the largest source of land-based NPPE. Overall, positive spatial clustering of NPPE is observed in the cities of the YREB, and there is a certain enhancement in clustering. The GDP of the primary industry and cultivated area are important human activity factors affecting the spatial distribution of NPPE, with economic factors exerting the greatest influence on the NPPE. In the future, the change in NPPE in the YREB at the provincial level is slight, while the nitrogen pollution emissions at the municipal level will develop towards a polarization trend. Most cities in the middle and lower reaches of the YREB in 2035 will exhibit medium to high emissions. This study provides a scientific basis for the control of regional NPPE, and it is necessary to strengthen cooperation and coordination among cities in the future, jointly improve the nitrogen and phosphorus pollution tracing and control management system, and achieve regional sustainable development.

Effect of C-type lectin 16 on dengue virus infection in Aedes aegypti salivary glands.

C-type lectins (CTLs) are a family of carbohydrate-binding proteins and an important component of mosquito saliva. Although CTLs play key roles in immune activation and viral pathogenesis, little is known about their role in regulating dengue virus (DENV) infection and transmission. In this study, we established a homozygous CTL16 knockout Aedes aegypti mutant line using CRISPR/Cas9 to study the interaction between CTL16 and viruses in mosquito vectors. Furthermore, mouse experiments were conducted to confirm the transmission of DENV by CTL16-/- A. aegypti mutants. We found that CTL16 was mainly expressed in the medial lobe of the salivary glands (SGs) in female A. aegypti. CTL16 knockout increased DENV replication and accumulation in the SGs of female A. aegypti, suggesting that CTL16 plays an important role in DENV transmission. We also found a reduced expression of immunodeficiency and Janus kinase/signal transducer and activator of transcription pathway components correlated with increased DENV viral titer, infection rate, and transmission efficiency in the CTL16 mutant strain. The findings of this study provide insights not only for guiding future investigations on the influence of CTLs on immune responses in mosquitoes but also for developing novel mutants that can be used as vector control tools.

Study on the mechanism of stir-fried Fructus Tribuli in enhancing the essential hypertension treatment by an integrated "spectrum-effect relationship-network pharmacology-metabolomics" strategy.

Essential hypertension (EH) is a leading cause of cardiovascular morbidity and mortality. Fructus Tribuli (FT), as a traditional medicine, has been frequently used for thousands of years. The crude Fructus Tribuli (CFT), decoction pieces being processed to remove impurities, have been listed as an important medicine for the treatment of hypertension in the elderly. According to the theory of traditional Chinese medicine, the CFT can enhance the EH treatment after being stir-fried into stir-fried Fructus Tribuli (SFT). At present, whether the SFT can enhance the EH treatment and its potential pharmacodynamic substances and mechanism are unknown. In this study, an integrated "spectrum-effect relationship-network pharmacology-metabolomics" strategy was used. Using male spontaneously hypertensive rats as an experimental model, we compared the therapeutic effects of CFT and SFT on EH. Subsequently, to define the pharmacodynamic material basis of SFT in enhancing the EH treatment, the steroidal saponins (main active components of FT) were selected for spectrum-effect relationship analysis. Furthermore, we applied the joint pathway analysis of network pharmacology and metabolomics to explore the underlying mechanism of SFT in enhancing the EH treatment. Results showed that SFT was better than CFT in the EH treatment. The steroidal saponins transformed by stir-frying were the potential pharmacodynamic substances that SFT could enhance the EH treatment. And the mechanism of action might be associated with regulating glycerophospholipid metabolism and arachidonic acid metabolism, especially arachidonic acid metabolism. This study provided a scientific basis for the clinical use of SFT as an important medicine for the EH treatment.

Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a nasty disease with extremely high malignancy and poor prognosis. Annexin A3 (ANXA3) is a potential prognosis biomarker, displaying an excellent correlation of ANXA3 overexpression with patients' poor prognosis. Silencing the expression of ANXA3 effectively inhibits the proliferation and metastasis of TNBC, suggesting that ANXA3 can be a promising therapeutic target to treat TNBC. Herein, we report a first-in-class ANXA3-targeted small molecule (R)-SL18, which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells. (R)-SL18 directly bound to ANXA3 and increased its ubiquitination, thereby inducing ANXA3 degradation with moderate family selectivity. Importantly, (R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model. Furthermore, (R)-SL18 could reduce the ß-catenin level, and accordingly inhibit the Wnt/ß-catenin signaling pathway in TNBC cells. Collectively, our data suggested that targeting degradation of ANXA3 by (R)-SL18 possesses the potential to treat TNBC.

Hydroxysafflor yellow a confers neuroprotection against acute traumatic brain injury by modulating neuronal autophagy to inhibit NLRP3 inflammasomes.

ETHNOPHARMACOLOGICAL RELEVANCE: Hydroxysafflor yellow A (HSYA) is the principal bioactive compound isolated from the plant Carthamus tinctorius L. and has been reported to exert neuroprotective effects against various neurological diseases, including traumatic brain injury (TBI). However, the specific molecular and cellular mechanisms underlying HSYA-mediated neuroprotection against TBI are unclear. AIM OF THE STUDY: This study explored the effects of HSYA on autophagy and the NLRP3 inflammasome in mice with TBI and the related mechanisms. MATERIALS AND METHODS: Mice were subjected to TBI and treated with or without HSYA. Neurological severity scoring, LDH assays and apoptosis detection were first performed to assess the effects of HSYA in mice with TBI. RNA-seq was then conducted to explore the mechanisms that contributed to HSYA-mediated neuroprotection. ELISA, western blotting, and immunofluorescence were performed to further investigate the mechanisms of neuroinflammation and autophagy. Moreover, 3-methyladenine (3-MA), an autophagy inhibitor, was applied to determine the connection between autophagy and the NLRP3 inflammasome. RESULTS: HSYA significantly decreased the neurological severity score, serum LDH levels and apoptosis in mice with TBI. A total of 921 differentially expressed genes were identified in the cortices of HSYA-treated mice with TBI and were significantly enriched in the inflammatory response and autophagy. Furthermore, HSYA treatment markedly reduced inflammatory cytokine levels and astrocyte activation. Importantly, HSYA suppressed neuronal NLRP3 inflammasome activation, as indicated by decreased levels of NLRP3, ASC and cleaved caspase-1 and a reduced NLRP3+ neuron number. It increased autophagy and ameliorated autophagic flux dysfunction, as evidenced by increased LC3 II/LC3 I levels and decreased P62 levels. The effects of HSYA on the NLRP3 inflammasome were abolished by 3-MA. Mechanistically, HSYA may enhance autophagy through AMPK/mTOR signalling. CONCLUSION: HSYA enhanced neuronal autophagy by triggering the AMPK/mTOR signalling pathway, leading to inhibition of the NLRP3 inflammasome to improve neurological recovery after TBI.

Network pharmacology-based approach uncovers the pharmacodynamic components and mechanism of Fructus Tribuli for improving endothelial dysfunction in hypertension.

ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Tribuli (FT), a traditional Chinese medicinal herbal, has been used for the clinical treatment of cardiovascular diseases for many years and affects vascular endothelial dysfunction (ED) in patients with hypertension. AIM OF THE STUDY: This study aimed to demonstrate the pharmacodynamic basis and mechanisms of FT for the treatment of ED. MATERIALS AND METHODS: The present study used ultra-high-performance liquid chromatography coupled with quadruple-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) to analyze and identify the chemical components of FT. The active components in blood were determined after the oral administration of FT by comparative analysis to blank plasma. Then, based on the active components in vivo, network pharmacology was performed to predict the potential targets of FT in treating ED. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were also performed, and component-target-pathway networks were constructed. Interactions between the major active components and main targets were verified by molecular docking. Moreover, spontaneously hypertensive rats (SHRs) were divided into the normal, model, valsartan, low-dose FT, medium-dose FT, and high-dose FT experimental groups. In pharmacodynamic verification studies, treatment effects on blood pressure, serum markers (nitric oxide [NO], endothelin-1 [ET-1,], and angiotensin Ⅱ [Ang Ⅱ)]) of ED, and endothelial morphology of the thoracic aorta were evaluated and compared between groups. Finally, the PI3K/AKT/eNOS pathway was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot of the thoracic aorta of rats in each group to detect the mRNA expression of PI3K, AKT, and eNOS and the protein expression of PI3K, AKT, p-AKT, eNOS, and p-eNOS. RESULTS: A total of 51 chemical components were identified in FT, and 49 active components were identified in rat plasma. Thirteen major active components, 22 main targets, and the PI3K/AKT signaling pathway were screened by network pharmacology. The animal experiment results showed that FT reduced systolic blood pressure and ET-1 and Ang Ⅱ levels and increased NO levels in SHRs to varying degrees. The therapeutic effects were positively correlated with the oral dose of FT. Hematoxylin-eosin (HE) staining confirmed that FT could alleviate the pathological damage of the vascular endothelium. qRT-PCR and Western blot analysis confirmed that up-regulated expression of the PI3K/AKT/eNOS signaling pathway could improve ED. CONCLUSIONS: In this study, the material basis of FT was comprehensively identified, and the protective effect on ED was confirmed. FT had a treatment effect on ED through multi-component, multi-target, and multi-pathways. It also played a role by up-regulating the PI3K/AKT/eNOS signaling pathway.

Discovery of pyrimidine-bridged CA-4 CBSIs for the treatment of cervical cancer in combination with cisplatin with significantly reduced nephrotoxicity.

A series of pyrimidine-bridged CA-4 derivatives (9a-u) targeting colchicine site were designed, synthesized and evaluated. Among them, the most potent compound 9j showed favorable anti-proliferative activities against a panel of cervical cancer cells (IC50 = 0.09-0.15 µM) and tubulin polymerization inhibitory activity (IC50 = 4.6 µM). Meanwhile, compound 9j exhibited superior anti-proliferative activity against cisplatin-resistant HeLa/DDP and SiHa/DDP cells than CA-4 and cisplatin. Particularly, the combination of 30 mg/kg 9j with 3 mg/kg cisplatin resulted in a 73% tumor suppression rate in HeLa xenograft model and reduced the renal dysfunction and injuries caused by high doses of cisplatin. Moreover, 9j was highly selective over the normal human proximal tubular cells (HK-2 cells, IC50 = 188 µM). Mechanism studies revealed that 9j could disrupt tubulin polymerization and vasculature, arrest the cell cycle at the G2/M phase, induce apoptosis, and suppress clonogenesis and migration in HeLa cells. Further druggability characterization in terms of pharmacokinetic profile, acute toxicity, and hERG inhibition confirmed 9j could serve as a promising and safe combination agent for cervical cancer therapy.

JPEG Robust Invertible Grayscale.

Invertible grayscale is a special kind of grayscale from which the original color can be recovered. Given an input color image, this seminal work tries to hide the color information into its grayscale counterpart while making it hard to recognize any anomalies. This powerful functionality is enabled by training a hiding sub-network and restoring sub-network in an end-to-end way. Despite its expressive results, two key limitations exist: 1) The restored color image often suffers from some noticeable visual artifacts in the smooth regions. 2) It is very sensitive to JPEG compression, i.e., the original color information cannot be well recovered once the intermediate grayscale image is compressed by JPEG. To overcome these two limitations, this article introduces adversarial training and JPEG simulator respectively. Specifically, two auxiliary adversarial networks are incorporated to make the intermediate grayscale images and final restored color images indistinguishable from normal grayscale and color images. And the JPEG simulator is utilized to simulate real JPEG compression during the online training so that the hiding and restoring sub-networks can automatically learn to be JPEG robust. Extensive experiments demonstrate that the proposed method is superior to the original invertible grayscale work both qualitatively and quantitatively while ensuring the JPEG robustness. We further show that the proposed framework can be applied under different types of grayscale constraints and achieve excellent results.

Terrestrosin D, a spirostanol saponin from Tribulus terrestris L. with potential hepatorenal toxicity.

ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Tribuli (FT) has been commonly used as a traditional medicine for thousands of years. With the diverse uses of FT, more attention has been paid to its hepatorenal toxicity. However, the compounds causing the hepatorenal toxicity of FT remain undetermined. Terrestrosin D (TED), a major spirostanol saponin isolated from FT, may exert hepatorenal toxicity. AIM OF THE STUDY: This study aimed to evaluate the potential hepatorenal toxicity of TED, and preliminarily explore the possible mechanism of TED-induced hepatorenal toxicity. MATERIALS AND METHODS: Cytotoxicity assays, a repeated-dose 28-day in-vivo study, a toxicokinetic study, and a tissue distribution study were used to evaluate the potential hepatorenal toxicity of TED. Furthermore, network pharmacology was applied to preliminarily explore the possible mechanism of TED-induced hepatorenal toxicity. RESULTS: Both the in vitro and in vivo studies showed that the spirostanol saponin TED had potential hepatorenal toxicity. Nonetheless, hepatorenal toxicity induced by oral treatment with TED at a dosage range of 5 - 15 mg/kg daily for 28 consecutive days to Sprague-Dawley (SD) rats was reversible after 14 days of TED withdrawal. The toxicokinetic study demonstrated that the systematic exposure of SD rats to TED had an accumulation phenomenon and a dose-dependent trend after a 28-day repeated-dose oral administration. The tissue distribution study revealed that TED had a targeted distribution in the liver and kidneys accompanied by a phenomenon of accumulation in SD rats. Network pharmacology combined with molecular docking methods was used to screen for the key targets (HSP90AA1, CNR1, and DRD2) and the key pathways of TED-induced hepatorenal toxicity. CONCLUSIONS: The spirostanol saponin TED, a major spirostanol saponin isolated from FT, had potential hepatorenal toxicity.

Discovery of quinolone derivatives as antimycobacterial agents.

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis), is an important public health issue. Current first-line drugs administered to TB patients have been in use for over 40 years, whereas second-line drugs display strong side effects and poor compliance. Additionally, designing effective regimens to treat patients infected with multi- and extremely-drug-resistant (MDR and XDR) strains of TB is challenging. In this report, we screened our compound library and identified compound 1 with antituberculosis activity and a minimal inhibitory concentration (MIC) against M. tuberculosis of 20 µg mL-1. Structure optimization and the structure-activity relationship of 1 as the lead compound enabled the design and synthesis of a series of quinolone derivatives, 6a1-6a2, 6b1-6b36, 6c1, 6d1-6d14, 7a1-7a2, 7b1-7b2, 7c1, 8a1-8a5, 9a1-9a4 and 10a1-10a6. These compounds were evaluated in vitro for anti-tubercular activity against the M. tuberculosis H37Rv strain. Among them, compounds 6b6, 6b12 and 6b21 exhibited MIC values in the range of 1.2-3 µg mL-1 and showed excellent activity against the tested MDR-TB strain (MIC: 3, 2.9 and 0.9 µg mL-1, respectively). All three compounds were non-toxic toward A549 and Vero cells (>100 and >50 µg mL-1, respectively). In addition, an antibacterial spectrum test carried out using compound 6b21 showed that this compound specifically inhibits M. tuberculosis. These can serve as a new starting point for the development of anti-TB agents with therapeutic potential.

Generating mutant Aedes aegypti mosquitoes using the CRISPR/Cas9 system.

Implementation of CRISPR/Cas9 methodologies for mosquito gene editing has not yet become widespread. This protocol details the procedure for Aedes aegypti mosquito gene editing using homology-directed repair and fluorescent marker insertion, which facilitates the generation and screening of mutant mosquito lines for gene function testing. We describe optimized methods for single guide RNA plasmid preparation, homologous recombination donor plasmid construction, embryo microinjection, and precise gene knock-in confirmation. We also provide general guidance for establishing mutant mosquito lines. For details on the practical use and execution of this protocol, please refer to Li et al. (2020).

Transgenic Expression of Human C-Type Lectin Protein CLEC18A Reduces Dengue Virus Type 2 Infectivity in Aedes aegypti.

The C-type lectins, one family of lectins featuring carbohydrate binding domains which participate in a variety of bioprocesses in both humans and mosquitoes, including immune response, are known to target DENV. A human C-type lectin protein CLEC18A in particular shows extensive glycan binding abilities and correlates with type-I interferon expression, making CLEC18A a potential player in innate immune responses to DENV infection; this potential may provide additional regulatory point in improving mosquito immunity. Here, we established for the first time a transgenic Aedes aegypti line that expresses human CLEC18A. This expression enhanced the Toll immune pathway responses to DENV infection. Furthermore, viral genome and virus titers were reduced by 70% in the midgut of transgenic mosquitoes. We found significant changes in the composition of the midgut microbiome in CLEC18A expressing mosquitoes, which may result from the Toll pathway enhancement and contribute to DENV inhibition. Transgenic mosquito lines offer a compelling option for studying DENV pathogenesis, and our analyses indicate that modifying the mosquito immune system via expression of a human immune gene can significantly reduce DENV infection.

Abundant Defects-Induced Interfaces Enabling Effective Anchoring for Polysulfides and Enhanced Kinetics in Lean Electrolyte Lithium-Sulfur Batteries.

In response to the concept of "compact energy storage", research on electrolyte dosage dwindling is definitely efficient owing to present electrolyte usage up to 70 wt % in a cell. While less electrolyte usage leads to slow reaction kinetics. Herein, a heterojunction, MoP/MoS2 core with much defects and vacancies coated by porous carbon shell, is synthesized. Besides, the small particle size of MoP/MoS2@C facilitates a close packing to form a dense and porous modified layer on PP-based (F-PP) separator. The heterojunction with defects exposes abundant interfaces and assures an adequate local electrolyte availability and an improved electrolyte affinity that are beneficial for Li+ transfer. When using F-PP separator, Li-S cell performs well in the lean electrolyte. Apart from a high discharging capacity of 517.1 mAh g-1 at 5 C in E/S = 10 (only half benchmark dosage), the cell realizes a favorable stability at C/2 over 500 cycles even in E/S = 7 (0.065% decay per cycle), demonstrating an effective polysulfides (PS) shuttling relief and reversibility of PS-relating chemical conversion. All these enhanced electrochemical behaviors in lean electrolyte result from a three-in-one strategy realized by defects-included MoP/MoS2@C heterojunction, including incorporating the lithiuphilic and sulfophilic sites for PS confinement and electrocatalysis triggered by abundant S vacancies and Lewis and Brønsted acid sites.