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Octopus sinensis, the species of Cephalopoda, is known as the highest Mollusca and is an economic and new aquaculture species in the coastal waters of southern China. The immune system has been well documented to have a function of resisting the invasion of pathogens in the external environment among mollusca species. As a kind of signaling molecule in the innate immune system, tumor necrosis factor (TNF) receptor-associated factor (TRAF) plays significant roles in TNF receptor (TNFR)/interleukin-1 receptor (IL-1R) /Toll-like receptor (TLR) signaling pathways. Until now, seven TRAF members (TRAF1-7) have been discovered, and they have been reported to participate in regulating signal pathways mediated by pattern recognition receptors and play important roles in the innate immune response of the hosts. In this study, five TRAF genes of O. sinensis (OsTRAF2, OsTRAF3, OsTRAF4, OsTRAF6, and OsTRAF7) were identified, whose full length of the open reading frame is 1473 bp, 1629 bp, 1431 bp, 1353 bp and 2121 bp respectively, encoding 490, 542, 476, 450 and 706 amino acids, respectively. Bioinformatics analysis showed that each OsTRAF has different chromosome locations. In addition to seven consecutive WD40 domains on the C-terminal of OsTRAF7 protein, the C-terminal of OsTRAF proteins all contain a conserved TRAF domain, namely the MATH domain. Phylogenetic analysis showed that OsTRAF proteins were clustered together with TRAF proteins of bivalves. Moreover, TRAF1 and TRAF2, TRAF3 and TRAF5 were clustered together in a large clade, respectively, revealing they have a close genetic relationship. The results of quantitative Real-time PCR showed that OsTRAF genes were highly expressed in the gill, hepatopancreas and white body. After stimulation with PGN, poly I:C and V. parahaemolyticus, the expression levels of OsTRAF genes were up-regulated in the gill, hepatopancreas and white body at different time points. These results indicated that OsTRAF genes play an important role in the antibacterial and antiviral immune response of O. sinensis.

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Toll-like receptors (TLRs) are a class of conserved pattern recognition receptors (PRRs) that are crucial for initiating the innate immune response and aiding in the clearance of pathogenic organisms. Many studies have identified TLR4 as a distinctive member of the TLR family, capable of activating both the Myeloid differentiation factor 88-dependent signaling pathway (MyD88-dependent) and the TIR-domain-containing adaptor inducing IFN-ß dependent signaling pathway (TRIF-dependent). Nevertheless, the role of TLR4 in Cephalopoda is still largely unexplored. To elucidate the immune function of the OsTLR4-1 gene in Octopus sinensis, the OsTLR4-1 gene was first validated and analyzed in this study. The cDNA comprises a 2475 bp ORF region, encoding 824 amino acids. Evolutionary tree analysis indicated a high homology and a close phylogenetic relationship between the Octopus sinensis and other mollusks. RNA interference (RNAi) experiments demonstrated that the expression level of OsTLR4-1 gene and its protein in the lymphocytes of the RNAi group treated with OsTLR4-1 dsRNA was extremely significantly lower than that of the blank control group and negative control group (P <0.01), and the expression of downstream genes of OsTLR4-1, including ligand MyD88, IRAK4, TRAF6, MKK6, Hsp90, COX2, TRAF3, and RIP1, were significantly down-regulated compared to the blank and negative control group (P <0.01). Additionally, OsTLR4-1 expression in lymphocytes was highly significantly up-regulated in the LPS-treated group compared to the blank control group (P <0.01), while its expression was extremely significantly lower in the LPS-treated group after OsTLR4-1 interference than in the blank control group (P <0.01). The expression of its downstream effector genes Big Defensin (Big-Def) and histone H2A.V (H2A.V) was highly significantly up-regulated in lymphocytes in the LPS-treated group compared to the blank control group (P <0.01), while their expression in the LPS-treated group after OsTLR4-1 interference was extremely significantly lower than that in the blank control group (P <0.01). Through comparative transcriptome analysis of the RNAi group and the blank control group, it was found that differentially expressed genes were enriched in the Toll-like receptor signaling pathway, PI3K-AKT signaling pathway, P53 signaling pathway, MAPK signaling pathway, and NF-κB signaling pathway. qRT-PCR results of key genes in these pathways revealed a decrease in all genes except IκB and Jun2 genes. This study enhances our understanding of the immune function of the TLR gene family in O. sinensis and provides a foundation for further research into innate immune signaling pathways in cephalopods.

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We attained wurtzite ScxAl1-xN (0.16 ≤ x ≤ 0.37) thin films by varying the Sc and Al fluxes at a fixed active nitrogen flux during plasma-assisted molecular beam epitaxy. Atomic fluxes of Sc and Al sources via measured Sc percentage in as-grown ScxAl1-xN thin films were derived as the feedback for precise determination of the ScxAl1-xN growth diagram. We identified an optimal III/N atomic flux ratio of 0.78 for smooth Sc0.18Al0.82N thin films. Further increasing the III/N ratio led to phase separation under N-rich conditions, validated by the observation of high-Sc-content hillocks with energy-dispersive X-ray spectroscopy mapping. At the fixed III/N ratio of 0.78, we found that phase separation with high-Al-content hillocks occurs for x > 0.37, which is substantially lower than the thermodynamically dictated threshold Sc content of ~0.55 in wurtzite ScxAl1-xN. We postulate that these wurtzite-phase purity degradation scenarios are correlated with adatom diffusion and the competitive incorporation process of Sc and Al. Therefore, the ScxAl1-xN growth window is severely restricted by the adatom kinetics. We obtained single crystalline Sc0.37Al0.63N thin films with X-ray diffraction (002)/(102) ω rocking curve full-width at half-maximums of 2156 arcsec and 209 arcsec and surface roughness of 1.70 nm. Piezoelectric force microscopy probing of the Sc0.37Al0.63N epilayer validates unambiguous polarization flipping by 180°.

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BACKGROUND: Atrial fibrillation (AF) is the most common type of arrhythmia. Heart rate variability (HRV) may be associated with AF risk. The aim of this study was to test HRV indices and arrhythmias as predictors of paroxysmal AF based on 24-hour dynamic electrocardiogram recordings of patients. METHODS: A total of 199 patients with paroxysmal AF (AF group) and 204 elderly volunteers over 60 years old (Control group) who underwent a 24-hour dynamic electrocardiogram from August 2022 to March 2023 were included. Time-domain indices, frequency-domain indices, and arrhythmia data of the two groups were classified and measured. Binary logistic regression analysis was performed on variables with significant differences to identify independent risk factors. A nomogram prediction model was established, and the sum of individual scores of each variable was calculated. RESULTS: Gender, age, body mass index and low-density lipoprotein (LDL) did not differ significantly between AF and Control groups (p > 0.05), whereas significant group differences were found for smoking, hypertension, diabetes, and high-density lipoprotein (HDL) (p < 0.05). The standard deviation of all normal to normal (NN) R-R intervals (SDNN), standard deviation of 5-minute average NN intervals (SDANN), root mean square of successive NN interval differences (rMSSD), 50 ms from the preceding interval (pNN50), low-frequency/high-frequency (LF/HF), LF, premature atrial contractions (PACs), atrial tachycardia (AT), T-wave index, and ST-segment index differed significantly between the two groups. Logistic regression analysis identified rMSSD, PACs, and AT as independent predictors of AF. For each unit increase in rMSSD and PACs, the odds of developing AF increased by 1.0357 and 1.0005 times, respectively. For each unit increase in AT, the odds of developing AF decreased by 0.9976 times. The total score of the nomogram prediction model ranged from 0 to 110. CONCLUSION: The autonomic nervous system (ANS) plays a pivotal role in the occurrence and development of AF. The individualized nomogram prediction model of AF occurrence contributes to the early identification of high-risk patients with AF.

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Doping of polycyclic conjugated hydrocarbons (PCHs) with sulfur atoms is becoming more and more important as a means of creating unique functional materials. Recently, thiophene-containing multiple helicenes have garnered enormous attention due to their intriguing electronic and (chir)optical properties compared with carbohelicenes. However, the efficient synthesis of thiopyran-containing multiple helicenes and the underlying sulfur doping mechanisms are rather unexplored. Herein, the synthesis and structural analysis of a thiopyran-containing double [7]helicene 3 are reported. X-ray crystallographic analysis reveals 3 and its dication with C2-symmetric propeller-shape structure and compact p-p interaction in the solid state. 3 exhibits deep-red to near-infrared (NIR) fluorescence emission. Tunable aromaticity of the central benzene ring and thiopyran rings is found by chemical oxidation, which is further confirmed by nucleus-independent chemical shift (NICS), anisotropy of the induced current density (AICD) and harmonic oscillator model of aromaticity (HOMA) analysis. Furthermore, the chiral and photosensitizing characters of 3 are investigated. The excellent deep-red to NIR fluorescence, circularly polarized luminescence (CPL) and photosensitizing activities suggest that 3 can be used as an outstanding photosensitizer in photodynamic therapy (PDT) and bioimaging, especially paving the way for future CPL-PDT and CPL-bio-probe applications.

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Breast cancer is the most common cancer among women worldwide. Postmastectomy radiotherapy (PMRT) is an essential component of combined therapy for early-stage, high-risk breast cancer. Breast reconstruction (BR) is often considered for patients with breast cancer who have undergone mastectomy. There has been a considerable amount of discussion about the optimal approach to combining PMRT with BR in the treatment of breast cancer. PMRT may increase the risk of complications and prevent good aesthetic results after BR, while BR may increase the complexity of PMRT and the radiation dose to surrounding normal tissues. The purpose of this review is to give a broad overview and summary of the current controversies and trends in PMRT and BR in the context of the most recent literature available.

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BACKGROUND: Neuropathic pain (NP) due to nerve injury, disrupts neural plasticity by triggering the release of inflammatory mediators. Alongside the hypothesis that neuro-inflammation contributes to this disruption, Andrographolide (Andro), a traditional bioactive compound derived from Andrographis paniculata, has garnered attention for its potent anti-inflammatory properties. However, whether Andro could ameliorate NP by regulating neuroinflammation remains unknown. PURPOSE: This study aimed to investigate whether and how Andro regulates neuroinflammation and alleviates NP. METHODS: The analgesic effects of Andro on NP were evaluated using both the spinal nerve ligation (SNL) and formalin rat models. A combination of network pharmacology, RNA sequencing, and experimental validation was employed to elucidate the underlying mechanism behind Andro's analgesic effects. Additionally, various techniques such as functional ultrasound, immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR), patch clamp, and electron microscopy were employed to investigate the specific neural cell types, neural functions, and changes in neural plasticity influenced by Andro. RESULTS: Network pharmacology analysis unveiled the crucial roles played by shared targets of Andro and pain in regulating pain-related inflammation, including microglia activation, neuroinflammation, immune modulation, and synaptic transmission. Furthermore, we confirmed Andro's superior efficacy in pain relief compared to the traditional analgesic drug, Gabapentin. In these models, Andro was observed to modulate the haemodynamic response triggered by SNL. Transcriptome analysis and molecular docking studies indicated the involvement of major histocompatibility complex class II (MHCII) genes (Db1, Da, and Bb). Electron microscopy revealed improvements in synaptic ultrastructure, and electrophysiological investigations showed a selective reduction in glutamatergic transmission in neuropathic rats after following Andro treatment. The integration of systems pharmacology analysis and biological validation collectively demonstrated that the mechanism of pain relief involves immune modulation, enhancement of synaptic plasticity, and precise regulation of excitatory neurotransmission. CONCLUSION: In conclusion, this study has demonstrated that Andro, by targeting MHCII genes, may serve as a promising therapeutic candidate for neuropathic pain.

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APS is a cheap and eco-friendly oxidant which enables one-step extraction of nanochitin (NCh) from fishery wastes. However, it is challenging to improve the preparation efficiency and NCh quality simultaneously, owing to the uneven or uncontrollable oxidation. Herein, we propose a simple and controllable way to isolate chitin nanofibers (ChNFs) from squid pen by gradient heating activated (GHA)- ammonium persulfate (APS) oxidation. Compared to the isothermal activated (ITA)-APS oxidation, our strategy reduced the mass ratio of squid pen to APS from 1:45 to 1:6 and reaction time from 15 h to 8 h. Meanwhile, the as-prepared ChNFs exhibited high yield (91.5 %), light transmittance (98 % at 500 nm), crystallinity index (96.9 %), and carboxyl content (1.53 mmol/g). GHA-APS oxidation involved multiple continuous heating and isothermal stages. The former stimulates a moderate activation of APS and enhances the oxidation rate, while the latter provides a duration for surface chemistry. This non-isothermal heating facilitates the continuous decomposition of APS at a relatively high and consistent rate, thereby enhances its oxidation efficiency. Furthermore, green assessments indicate this method is simple, time-saving, eco-friendly and cost-effective. Overall, this work introduces a novel perspective for the industrial extraction of high-efficiency and high-quality nanomaterials.

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Yogurt is popular as a natural and healthy food, but its flavor greatly affects acceptability by consumers. Flavor compounds of yogurt is generally produced by the metabolism of lactose, protein and fat, and the resulting flavors include carbonyls, acids, esters and alcohols, etc. Each flavor compounds could individually provide the corresponding flavor, or it can be combined with other compounds to form a new flavor. The flavor network was formed among the metabolites of milk components, and acetaldehyde, as the central compounds, played a role in connecting the whole network. The flavor compounds can be affected by many factors, such as the use of different raw milks, ways of homogenization, sterilization, fermentation, post ripening, storage condition and packaging materials, etc., which can affect the overall flavor of yogurt. This paper provides an overview of the volatile flavor compounds in yogurt, the pathways of production of the main flavor compounds during yogurt fermentation, and the factors that influence the flavor of yogurt including type of raw milk, processing, and storage. It also tries to provide theoretical guidance for the product of yogurt in ideal flavor, but further research is needed to provide a more comprehensive description of the flavor system of yogurt.

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Crafting an inorganic semiconductor heterojunction with defect engineering and morphology modulation is a strategic approach to produce clean energy by the highly efficient light-driven splitting of water. In this paper, a novel Z-scheme sulfur-vacancy containing Zn3In2S6 (Vs-Zn3In2S6) nanosheets/In2O3 hollow hexagonal prisms heterostructrue (Vs-ZIS6INO) was firstly constructed by an oil bath method, in which Vs-Zn3In2S6 nanosheets grew on the surfaces of In2O3 hollow hexagonal prisms to form a hollow core-shell structure. The obtained Vs-ZIS6INO heterostructrue exhibited much enhanced activity of the production of H2 and H2O2 by the light-driven water splitting. In particular, under visible light irradiation (λ > 420 nm), the rate of generation of H2 of Vs-ZIS6INO sample containing 30 wt% Vs-Zn3In2S6 (30Vs-ZIS6INO) could reach 3721 µmol g-1h-1, which was 87 and 6 times higher than those of Zn3In2S6 (43 µmol g-1h-1) and Vs-Zn3In2S6 (586 µmol g-1h-1), respectively. Meanwhile, 30Vs-ZIS6INO could exhibit the rate of H2O2 production of 483 µmol g-1h-1 through the dual pathways of indirect 2e- oxygen reduction (ORR) and water oxidation (WOR) without adding any sacrifice agents, far exceeding In2O3 (7 µmol g-1h-1) and Vs-Zn3In2S6 (58 µmol g-1h-1). The excellent photocatalytic activities of H2 and H2O2 generations of Vs-ZIS6INO sample might result from the synergistic effect of the sulfur vacancy, hollow core-shell structure, and Z-scheme heterostructure, which accelerated the electron delocalization, enhanced the absorption and conversion of solar energy, reduced the carrier diffusion distance, and ensured high REDOX ability. In addition, the possible photocatalytic mechanisms for the production of H2 and H2O2 were discussed in detail. This study provided a new idea and reference for constructing the novel and efficient inorganic semiconductor heterostructures by coordinating vacancy defect and morphology design to adequately utilize water splitting for the production of clean energy.

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Gamma-aminobutyric acid (GABA) produced by lactic acid bacteria (LAB) is safe and has several health benefits. Levilactobacillus brevis YSJ3 was selected from 110 LAB. It exhibited the highest in vitro GABA production level of 970.10 µg/mL. Whole-genome analysis revealed that L. brevis YSJ3 contained gadR, gadC, gadB and gadA. Furthermore, the Luedeking-Piret model was fitted, which indicated that GABA production was divided into three stages. The gadR 0079, gadC 0080, and gadB 0081 were confirmed to promote GABA synthesis. Moreover, 55 metabolites, particularly those involved in arginine metabolism, were significantly different at 6 and 20 h of cultivation. Notably, L. brevis YSJ3 significantly improved sleep in mice and increased GABA levels in the mice's gut compared with the control group. This suggests that the oral administration of L. brevis YSJ3 improves sleep quality, probably by increasing intestinal GABA levels. Overall, L. brevis YSJ3 was confirmed as a GABA-producing strain in vitro and in vivo, making it a promising probiotic candidate for its application in food and medicine.

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Aims/Background Blended learning has been a commonly adopted teaching mode in the medical education community in recent years. Many studies have shown that the blended learning mode is superior to the traditional teaching mode. Nonetheless, pinpointing the specific advantages provided by blended teaching methods is challenging, since multiple elements influence their effectiveness. This study aimed to investigate the reliability of the conclusions of published randomised controlled trials (RCTs) on blended learning in medical education by assessing their quality, and to provide suggestions for future related studies. Methods Two investigators searched PUBMED and EMBASE, and assessed RCTs related to medical blended learning published from January 1, 2010 to December 31, 2021. The analysis of the overall quality of each report was based on the 2010 consolidated standard of reporting trials (CONSORT) Statement applying a 28-point overall quality score. We also conducted a multivariate assessment including year of publication, region of the trial, journal, impact factor, sample size, and the primary outcome. Results A total of 22 RCTs closely relevant to medical blended learning were eventually selected for study. The results demonstrated that half of the studies failed to explicitly describe at least 34% of the items in the 2010 CONSORT Statement. Medical blended learning is an emerging new teaching mode, with 95.45% of RCTs published since 2010. However, many issues that we consider crucial were not satisfactorily addressed in the selected RCTs. Conclusion Although the 2010 CONSORT Statement was published more than a decade ago, the quality of RCTs remains unsatisfactory. Some important items were inadequately reported in many RCTs such as sample size, blinding, and concealment. We encourage researchers who focus on the effects of blended learning in medical education to incorporate the guidelines in the 2010 CONSORT Statement when designing and conducting relevant research. Researchers, reviewers, and editors also need to work together to improve the quality of relevant RCTs in accordance with the requirements of the 2010 CONSORT Statement.

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White tea stored for various times have different flavors. However, the mechanism of flavor conversion remains elusive. Flavonoids and amino acids are two typical flavor components in tea. Herein, the contents of 46 flavonoids and 40 amino acids were measured in white tea (Shoumei) stored for 1, 3, 5 and 7 years, respectively. L-tryptophan, L-ornithine and L-theanine contribute to the refreshing taste of Shoumei 1 and 3. Quercetin, rutin and hesperidin contribute to aging charm and grain aroma of Shoumei 5 and 7. 306 bacterial OTUs and 268 fungal OTUs core microbiota existed in all samples. Interestingly, white teas contained higher richness of fungi than bacteria. The correlation analysis showed that the cooperation with bacteria and fungi may result in the flavonoids and amino acids composition changes in white teas during storage. Overall, this study provides new insights into flavor conversion of white tea during storage.

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Objective: The study analyzed the impact of urbanization on epidemiological characteristics of respiratory infectious disease in Tongzhou District, Beijing during 2014-2022 to provide reference for prevention and control priorities of respiratory infectious diseases during the innovative urbanization process in China. Methods: The incidence data of notifiable respiratory infectious diseases (NRIDs) in Tongzhou Beijing during 2014-2022 were summarized. The trend of incidence rate was analyzed by Joinpoint regression model, and entropy method was performed to construct the comprehensive index of urbanization (CIU) and generalized linear model was used to analyze the influence of CIU on the incidence rate of respiratory infectious diseases. Results: Totally 72616 NRIDs cases were reported in Tongzhou District during 2014-2022, and the incidence rate of NRIDs was higher during 2017-2019 (153/100 000) than during 2014-2016 (930/100 000) and during 2020-2022 (371/100 000), respectively (both P < 0.001). The CIU constantly increased with slight fluctuation in 2016 and 2018, respectively. The incidence rate of NRIDs showed an increase along with the CIU during 2014-2019 (r = 0.95, P = 0.004), while the incidence rate's tendency was interrupted by COVID-19 during 2020 with slight decrease in 2020-2021 and rebounded in 2022. For the patients aged <15 years, the incidence rate of NRIDs revealed a very sharp rise at the urbanization period without COVID-19 pandemic compared with that under pre-urbanization period (RR = 7.93, 95 % CI 7.63-8.24), and dropped off to the similar level as of pre-urbanization period when COVID-19 pandemic spread. Conclusions: Urbanization process may increase the incidence of NRIDs but constrained by COVID-19. Certain measures should be taken to prevent and control the effects by urbanization process, such as good natural environment with less population density, ecological environment with good air quality, promoted hand hygiene, mask wearing, keeping interpersonal distance, vaccination, media publicity for NRIDs' prevention and control.

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SAR imagery plays a crucial role in geological and environmental monitoring, particularly in highland mountainous regions. However, inherent geometric distortions in SAR images often undermine the precision of remote sensing analyses. Accurately identifying and classifying these distortions is key to analyzing their origins and enhancing the quality and accuracy of monitoring efforts. While the layover and shadow map (LSM) approach is commonly utilized to identify distortions, it falls short in classifying subtle ones. This study introduces a novel LSM ground-range slope (LG) method, tailored for the refined identification of minor distortions to augment the LSM approach. We implemented the LG method on Sentinel-1 SAR imagery from the tri-junction area where the Xiaojiang, Pudu, and Jinsha rivers converge at the Yunnan-Sichuan border. By comparing effective monitoring-point densities, we evaluated and validated traditional methods-LSM, R-Index, and P-NG-against the LG method. The LG method demonstrates superior performance in discriminating subtle distortions within complex terrains through its secondary classification process, which allows for precise and comprehensive recognition of geometric distortions. Furthermore, our research examines the impact of varying slope parameters during the classification process on the accuracy of distortion identification. This study addresses significant gaps in recognizing geometric distortions and lays a foundation for more precise SAR imagery analysis in complex geographic settings.

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Nanomaterials, with unique physical, chemical, and biocompatible properties, have attracted significant attention as an emerging active platform in cancer diagnosis and treatment. Amongst them, metal-organic framework (MOF) nanostructures are particularly promising as a nanomedicine due to their exceptional surface functionalities, adsorption properties, and organo-inorganic hybrid characteristics. Furthermore, when bioactive substances are integrated into the structure of MOFs, these materials can be used as anti-tumor agents with superior performance compared to traditional nanomaterials. In this review, we highlight the most recent advances in MOFs-based materials for tumor therapy, including their application in cancer treatment and the underlying mechanisms.

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Confined evaporation-induced self-assembly (C-EISA) is a powerful technique to guide disordered nanoparticles into long-range organized structures. Herein, we investigate the C-EISA behavior of 1-butyl-3-vinylimidazolium cation ([VBIm]+) grafted cellulose nanocrystals (CNC-C) in a parallel-plates confined geometry. Interestingly, CNC-C can spontaneously assemble into maze-like patterns with branch dimensions on the micrometer scale and uniformly distributed throughout the confined space, which is completely different from the lamellar self-assembly patterns of unmodified CNCs. Combining in situ observations and microscopic characterization, we speculate that the formation of maze-like patterns originates from the reduction of colloidal stability induced by the grafted imidazolium cations. The electrostatic attraction between CNC-C aggregated bundles and glass substrates acts as anchor points, thereby leading to the unstable motion of the liquid-air menisci during the inward intrusion of air. Due to the physicochemical properties and unique C-EISA behavior, the CNC-C based adhesive can maintain adhesion at temperatures of ca. 200 °C, while rapidly debonding when immersed in water, demonstrating the potential to be used as stimuli-responsive temporary or removable adhesives. Furthermore, the strategy proposed in this work for achieving CNCs patterning is also promising to be extended to other anisotropic rod-shaped nanoparticles.

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Structure-guided image completion aims to inpaint a local region of an image according to an input guidance map from users. While such a task enables many practical applications for interactive editing, existing methods often struggle to hallucinate realistic object instances in complex natural scenes. Such a limitation is partially due to the lack of semantic-level constraints inside the hole region as well as the lack of a mechanism to enforce realistic object generation. In this work, we propose a learning paradigm that consists of semantic discriminators and object-level discriminators for improving the generation of complex semantics and objects. Specifically, the semantic discriminators leverage pretrained visual features to improve the realism of the generated visual concepts. Moreover, the object-level discriminators take aligned instances as inputs to enforce the realism of individual objects. Our proposed scheme significantly improves the generation quality and achieves state-of-the-art results on various tasks, including segmentation-guided completion, edge-guided manipulation and panoptically-guided manipulation on Places2 datasets. Furthermore, our trained model is flexible and can support multiple editing use cases, such as object insertion, replacement, removal and standard inpainting. In particular, our trained model combined with a novel automatic image completion pipeline achieves state-of-the-art results on the standard inpainting task.

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Toll-like receptors (TLRs) are one of the extensively studied pattern recognition receptors (PRRs) and play crucial roles in the immune responses of vertebrates and invertebrates. In this study, 14 TLR genes were identified from the genome-wide data of Octopus sinensis. Protein structural domain analysis showed that most TLR proteins had three main structural domains: extracellular leucine-rich repeats (LRR), transmembrane structural domains, and intracellular Toll/IL-1 receptor domain (TIR). The results of subcellular localization prediction showed that the TLRs of O. sinensis were mainly located on the plasma membrane. The results of quantitative real-time PCR (qPCR) showed that the detected TLR genes were differentially expressed in the hemolymph, white bodies, hepatopancreas, gills, gill heart, intestine, kidney, and salivary gland of O. sinensis. Furthermore, the present study investigated the expression changes of O. sinensis TLR genes in hemolymph, white bodies, gills, and hepatopancreas in different phases (6 h, 12 h, 24 h, 48 h) after stimulation with PGN, poly(I: C) and Vibrio parahaemolyticus. The expression of most of the TLR genes was upregulated at different time points after infection with pathogens or stimulation with PAMPs, a few genes were unchanged or even down-regulated, and many of the TLR genes were much higher after V. parahaemolyticus infection than after PGN and poly(I:C) stimulation. The results of this study contribute to a better understanding of the molecular immune mechanisms of O. sinensis TLRs genes in resistance to pathogen stimulation.

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We aimed to identify the druggable cell-intrinsic vulnerabilities and target-based drug therapies for PitNETs using the high-throughput drug screening (HTS) and genomic sequencing methods. We examined 9 patient-derived PitNET primary cells in HTS. Based on the screening results, the potential target genes were analyzed with genomic sequencing from a total of 180 PitNETs. We identified and verified one of the most potentially effective drugs, which targeted the Histone deacetylases (HDACs) both in in vitro and in vivo PitNET models. Further RNA sequencing revealed underlying molecular mechanisms following treatment with the representative HDACs inhibitor, Panobinostat. The HTS generated a total of 20,736 single-agent dose responses which were enriched among multiple inhibitors for various oncogenic targets, including HDACs, PI3K, mTOR, and proteasome. Among these drugs, HDAC inhibitors (HDACIs) were, on average, the most potent drug class. Further studies using in vitro, in vivo, and isolated PitNET primary cell models validated HDACIs, especially Panobinostat, as a promising therapeutic agent. Transcriptional surveys revealed substantial alterations to the Nrf2 signaling following Panobinostat treatment. Moreover, Nrf2 is highly expressed in PitNETs. The combination of Panobinostat and Nrf2 inhibitor ML385 had a synergistic effect on PitNET suppression. The current study revealed a class of effective anti-PitNET drugs, HDACIs, based on the HTS and genomic sequencing. One of the representative compounds, Panobinostat, may be a potential drug for PitNET treatment via Nrf2-mediated redox modulation. Combination of Panobinostat and ML385 further enhance the effectiveness for PitNET treatment.

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