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Abstract Targeted protein degradation has emerged as a novel therapeutic modality to treat human diseases by utilizing the cell’s own disposal systems to remove protein target. Significant clinical benefits have been observed for degrading many intracellular proteins. Recently, the degradation of extracellular proteins in the lysosome has been developed. However, there have been limited successes in selectively degrading protein targets in disease-relevant cells or tissues, which would greatly enhance the development of precision medicine. Additionally, most degraders are not readily available due to their complexity. We report a class of easily accessible Folate Receptor TArgeting Chimeras (FRTACs) to recruit the folate receptor, primarily expressed on malignant cells, to degrade extracellular soluble and membrane cancer-related proteins in vitro and in vivo. Our results indicate that FRTAC is a general platform for developing more precise and effective chemical probes and therapeutics for the study and treatment of cancers.

Abstract Background Age > 65 years is a key risk factor for poor outcomes after human influenza infection. Specifically, in addition to respiratory disease, non-neurotropic influenza A virus (IAV) causes neuro-cognitive complications, e.g. new onset depression and increases the risk of dementia after hospitalization. This study aimed to identify potential mechanisms of these effects by determining differences between young and old mice in brain gene expression in a mouse model of non-neurotropic IAV infection. Methods Young (12 weeks) and old (70 weeks) C57Bl/6J mice were inoculated intranasally with 200 PFU H1N1 A/PR/34/8 (PR8) or sterile PBS (mock). Gene expression in lung and brain was measured by qRT-PCR and normalized to β-actin. Findings were confirmed using the nCounter Mouse Neuroinflammation Array (NanoString) and analyzed with nSolver 4.0 and Ingenuity Pathway Analysis (IPA, Qiagen). Results IAV PR8 did not invade the central nervous system. Young and old mice differed significantly in brain gene expression at baseline and during non-neurotropic IAV infection. Expression of brain Ifnl, Irf7, and Tnf mRNAs was upregulated over baseline control at 3 days post-infection (p.i.) only in young mice, but old mice expressed more Ifnl than young mice 7 days p.i. Gene arrays showed down-regulation of the Epigenetic Regulation, Insulin Signaling, and Neurons and Neurotransmission pathways in old mice 3 days p.i. while young mice demonstrated no change or induction of these pathways at the same time point. IPA revealed marked baseline differences between old and young mice. Gene expression related to Cognitive Impairment, Memory Deficits and Learning worsened in old mice relative to young mice during IAV infection. Aged mice demonstrate more severe changes in gene expression related to memory loss and cognitive dysfunction by IPA. Conclusions These data suggest the genes and pathways related to learning and cognitive performance that were worse at baseline in old mice were further worsened by IAV infection, similar to old patients. Early events in the brain triggered by IAV infection portend downstream neurocognitive pathology in old adults.

Background: The mechanism underlying human umbilical cord mesenchymal stem cells (hUC-MSCs) regulating the stability of atherosclerotic plaque was explored by establishing mice models of atherosclerosis induced by a high-fat diet and hUC-MSCs intervention. Methods: The ApoE−/− mice atherosclerosis model was constructed using a high-fat diet, and mice were divided into a normal diet group (ND), high-fat diet group (HFD), hUC-MSCs treatment group (HFDM), while the blank control (BC) consisted of C57BL/6J mice. After successful establishment of the model, the feces, hearts, and aorta of mice were collected. Morphological features were detected using HE, oil red O, and Masson staining. Afterward, 16s rRNA gene sequences was used to detect the species and abundance of the intestinal flora in mice, and an atomic force microscope (AFM) was used to detect the Young's modulus of the fibrous cap of atherosclerotic plaques. Lastly, the expression level of the inflammatory factors NLRP3, IL-1β, and IL-18 were detected via immunohistochemistry and immunofluorescence assays. Results: In terms of morphological characteristics, the expression level of NLRP3, Young's modulus of the fibrous cap, and plaque stability were significantly reduced in HFD, whereas the ratio of Firmicutes to Bacteroidetes (F/B) was significantly increased. Interestingly, hUC-MSCs treatment reversed the above indices, thus enhancing plaque stability. Conclusion: HFD led to dysregulation of intestinal flora homeostasis and induced aberrant expression levels of NLRP3, resulting in a decrease in the Young's modulus of plaques. However, hUC-MSCs treatment improved the biomechanical properties of plaque by modulating the intestinal flora and NLRP3, thereby elevating plaque stability and minimizing the risk of plaque rupture.

Abstract Drilling a series of sinuous wellbore trajectories has emerged as a promising operation, offering significant advantages in enhancing reservoir contact. Based on various development cases (Zili and colleagues), it has been observed that horizontal wells with wavy wellbore trajectories tend to exhibit higher production rates. However, extending the length of these wavy trajectories requires careful consideration in terms of safe drilling practices, as the pressure management associated with these intricate trajectories has been seldom explored. In this study, we establish a modified model for annular pressure to predict and assess the open‐hole extend‐reach limit of horizontal wells with wavy wellbore trajectories. The introduced model incorporates dry friction force and annular geometry influenced by cuttings bed, making it more accurate than traditional models based on experimental observations. The wavy wellbore trajectory comprises three types: the up‐dip wellbore, the down‐dip wellbore, and the complex wellbore. Overall, the horizontal interval limits for the down‐dip wellbore and up‐dip wellbore are smaller than those of the corresponding smooth wellbores under varying factors. Notably, the complex wellbore trajectory offers advantages in navigating formations with narrow pressure windows compared to conventionally horizontal wellbores (smooth wellbores), thanks to its longer extended‐reach limit.

In a harsh geological environment, different geo-disasters might co-occur or be in a chain sequence. Currently, existing research in related fields documents numerous instances of disaster chains and responses, which provided this study with important materials for determining disaster chains probability and summarized the disaster prevention and mitigation (DPM) mode. In this study, through the depth of the geo-disaster chains cases and the DPM cases, enabled a mitigation mode analysis summary. We take the case of geo-disaster chains as an example for this study, and represent 20 typical geo-disaster chains by data fusion and structuring of 139 geo-disaster chains cases.The probability assessment of geo-disaster chains is crucial for risk management and regional resilience. We introduced a Bayesian network (BN) model to describe the process of geo-disaster chains formation to map the structure and assess the joint probability of geo-disaster chains. The BN results showed that the longer the disaster chains length, the smaller the probability of the chains occurring. Among these, the probability of “Collapses-landslides-debris flows–barrier lakes–flash floods” is the lowest (0.069). Through sensitivity analysis, it is found that precipitation is the most sensitive factor in the development of geo-disaster. Interpretive structural modeling (ISM) is employed to examine the DPM index system across three key aspects: disaster emergency preparation, disaster response, and disaster recovery, and the conceptualized interaction among these components. ISM results showed that government policy intervention and scientific DPM measures can effectively reduce the losses caused by the development of geo-disaster chains. This research combined the occurrence process of the disaster chains with the disaster response process, and determined the entire chains of characterization from disaster understanding to disaster response, and helped reduce the vulnerabilities caused by disasters.

Abstract The most common site of metastasis in breast cancer is the bone, where the balance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation is disrupted. This imbalance causes osteolytic bone metastasis in breast cancer, which leads to bone pain, pathological fractures, spinal cord compression, and other skeletal-related events (SREs). These complications reduce patients' quality of life significantly and have a profound impact on prognosis. In this review, we begin by providing a brief overview of the epidemiology of bone metastasis in breast cancer, including current diagnostic tools, treatment approaches, and existing challenges. Then, we will introduce the pathophysiology of breast cancer bone metastasis (BCBM) and the animal models involved in the study of BCBM. We then come to the focus of this paper: a discussion of several biomarkers that have the potential to provide predictive and prognostic value in the context of BCBM—some of which may be particularly compatible with more comprehensive liquid biopsies. Beyond that, we briefly explore the potential of new technologies such as single-cell sequencing and organoid models, which will improve our understanding of tumor heterogeneity and aid in the development of improved biomarkers. The emerging biomarkers discussed hold promise for future clinical application, aiding in the prevention of BCBM, improving the prognosis of patients, and guiding the implementation of personalized medicine.

Abstract Purpose To summarize our single-center experience with percutaneous ultrasound (US)-guided radiofrequency ablation (RFA) for pediatric recurrent hepatocellular carcinoma (RHCC). Methods From September 2007 to September 2021, patients under 18 who underwent percutaneous US-guided RFA for RHCC were retrospectively enrolled in this study. Local effectiveness, complications, local tumor progression (LTP), progression free survival (PFS), and overall survival (OS) were evaluated. Results A total of 10 patients (9 male and 1 female; mean age, 11.7 ± 4 years ; age range, 6–17 years) with 15 intrahepatic RHCC lesions were enrolled in this study. Complete ablation (CA) was achieved in 14 out of 15 lesions (93.3%) after the first RFA. During the follow-up (mean, 63.1 ± 18 months; range, 5.3-123.3 months), LTP did not occur. Five patients died including three with tumor progression and one with liver failure. The accumulative one- and three-year PFS rates were 30% and 10%, respectively. The accumulative one- and three-year OS rates were 77.8% and 44.4%, respectively. Conclusions Our single-center experience suggests the safety and feasibility of percutaneous US-guided RFA for pediatric RHCC.

Based on the theories of symbiosis and configurational analysis, this study constructs a theoretical framework for exploring the sustainable development of tea agricultural heritage systems, with an empirical investigation of 40 typical cases in China. Utilizing fuzzy-set qualitative comparative analysis (fsQCA) and integrating multi-source data, this study delves into the intricate mechanisms underlying its sustainable development. The findings indicate that the sustainable development of tea agricultural heritage systems is not determined by a single factor but results from the interplay of multiple conditions. Specifically, ecological protection performance and regional driving capacity serve as necessary conditions, while research resource allocation, industrial comprehensive strength, and heritage site development level act as sufficient conditions. Furthermore, the sustainable development pathways can be categorized into two types, namely “dual-cycle drive” and “total-factor drive”, encompassing four configurations. The “dual-cycle drive” emphasizes the mutually beneficial symbiosis between ecological and socio-economic sustainability, involving ecological protection, research resources, regional driving capacity, and industrial strength. The “total-factor drive”, on the other hand, reflects the synergistic symbiosis of ecology, socio-economy, and culture, incorporating various combinations of factors such as ecological protection, regional driving capacity, tea culture inheritance, and heritage site development. Lastly, the driving combinations leading to non-sustainable development exhibit asymmetry, suggesting that the formation of non-sustainability is not merely the reverse outcome of sustainable conditions. The absence of key conditions, such as ecological protection or regional driving capacity, results in the emergence of non-sustainable configurations. In conclusion, this study unveils the complexity and multidimensionality of the sustainable development of tea agricultural heritage systems, providing a scientific basis and practical pathways for formulating effective protection and sustainable development strategies.

Thanks to the rapid development of naked-eye 3D and wireless communication technology, 3D video related applications on mobile devices have attracted a lot of attention. Nevertheless, the time-varying characteristics of the wireless channel is very challenging for conventional source-channel coding based transmission strategy. Also, the high complexity of source-channel coding based transmission scheme is undesired for low power mobile terminals. An advanced transmission scheme named Softcast was proposed to achieve efficient transmission performance for 2D image/video. Unfortunately, it cannot be directly applied to wireless 3D video transmission with high efficiency. This paper proposes a more efficient soft transmission scheme for 3D video with a graceful quality adaptation within a wide range of channel Signal-to-Noise Ratio (SNR). The proposed method first extends the linear transform to 4 dimensions with additional view dimension to eliminate the view redundancy, and then metadata optimization and chunk interleaving are designed to further improve the transmission performance. Meanwhile, a synthesis distortion based chunk discard strategy is developed to improve the overall 3D video quality under the condition of limited bandwidth. The experimental results demonstrate that the proposed method significantly improves the 3D video transmission performance over the wireless channel for low power and low complexity scenarios.

Abstract Background Yungui Plateau in Southwest China is characterized by multi-language and multi-ethnic communities and is one of the regions with the wealthiest ethnolinguistic, cultural and genetic diversity in East Asia. There are numerous Tai-Kadai (TK)-speaking populations, but their detailed evolutionary history and biological adaptations are still unclear. Results Here, we genotyped genome-wide SNP data of 77 unrelated TK-speaking Zhuang and Dong individuals from the Yungui Plateau and explored their detailed admixture history and adaptive features using clustering patterns, allele frequency differentiation and sharing haplotype patterns. TK-speaking Zhuang and Dong people in Guizhou are closely related to geographically close TK and Hmong-Mien (HM)-speaking populations. Besides, we identified that Guizhou TK-speaking people have a close genetic relationship with Austronesian (AN)-speaking Atayal and Paiwan people, which is supported by the common origin of the ancient Baiyue tribe. We additionally found subtle genetic differences among the newly studied TK people and previously reported Dais via the fine-scale genetic substructure analysis based on the shared haplotype chunks. Finally, we identified specific selection candidate signatures associated with several essential human immune systems and neurological disorders, which could provide evolutionary evidence for the allele frequency distribution pattern of genetic risk loci. Conclusions Our comprehensive genetic characterization of TK people suggested the strong genetic affinity within TK groups and extensive gene flow with geographically close HM and Han people. We also provided genetic evidence that supported the common origin hypothesis of TK and AN people. The best-fitted admixture models further suggested that ancestral sources from northern millet farmers and southern inland and coastal people contributed to the formation of the gene pool of the Zhuang and Dong people.

Objective: Explore and establish the best process of Taxilli Herba tea fermented by Aspergillus cristatus, and dig the potential mechanism of Taxilli Herba tea fermented by A. cristatus on the prevention and treatment effect of non-alcoholic fatty liver disease (NAFLD). Methods: In order to optimize the process of Taxilli Herba tea fermented by A. cristatus, analytic hierarchy process (AHP) was applied, main chemical components and organoleptic evaluation were taken as evaluation indexes, single factor experiments were taken, and orthogonal experiment was used. Moreover, to dig and evaluate the prevention and treatment effect of NAFLD, the model in Zebrafish larval induced by 0.1% egg yolk powder and 5 mmol·mL−1 thioacetamide was used. Finally, technologies of UPLC-Q-TOF-MS/MS and network pharmacology were applied to select key compounds and core targets, and accomplish molecular docking. Results: The optimal fermentation process was as follows: The content of water was 35%, the time of pile-fermentation was 3 h, the concentration of A. cristatus was 1×106 CFU·mL−1, and fermentation time was 7 d. Taxilli Herba tea fermented by A. cristatus showed significant prevention and treatment effects in NAFLD (P

Objective: To explore the effect of different processing technology on the quality and functional activity of Taxilli Herba tea. Methods: A total of eight different samples of Taxilli Herba tea were prepared by different procedures combined with 3 processing technologies including natural fermentation, fixation, and Aspergillus cristatus fermentation. After processing, determinations were done on the main chemical components, antioxidant activity, influence on α-amylase activity, and organoleptic evaluation. Results: The content of 5 chemical compounds, including water extract, free amino acid, tea polyphenol, total flavonoid, and soluble sugar in Taxilli Herba tea, were increased (P < 0.05) after fixation while the antioxidant activity was improved too. The delightful odour of Taxilli Herba tea processed by natural fermentation was enhanced. The α-amylase activity of Taxilli Herba tea fermented by A. cristatus was significantly improved (P

Ecosystem services (ESs) are closely related to human well-being (HWB). Recently, urbanization has increased worldwide, which has had a significant impact on the ecosystem service supply–demand (ESSD) and HWB. However, previous studies have primarily focused on the spatiotemporal pattern of ESSD and HWB, while ignoring their evolutionary pathways, especially in karst areas. We aimed to quantify the optimal trade-offs of ESSD under the constraints of urbanization and the nonlinear relationship between ESSD and HWB, further constructing a tree-like framework to explore the evolutionary pathways of urbanization, ESSD, and HWB from a landscape evolution perspective. We used the production possibility frontier (PPF) to quantify the optimal trade-offs of three ESSDs, the generalized additive model (GAM) to fit the nonlinear relationship between ESSD and HWB, and the geographic evolution tree model (Geotree) to construct the tree-like structure of urbanization levels, comprehensive ecosystem service supply–demand (CESD), and HWB. There is a trade-off between the deficit of carbon storage services (CS) and water yield services (WY), but a synergy between the deficit of WY and the surplus of FS. Further, there is a synergy between the deficit of CSs and the surplus of food supply services (FS). The response of HWB to the ESSD of CS is not obvious, but the response to the ESSD of WY and FS is obvious. Based on the Geotree model, the urbanization, CESD, and HWB present strong coupling relationships, which show the characteristics of clustering, stratified heterogeneity, and evolution.

Abstract Background Gestational trophoblastic neoplasia (GTN) is rare, and it is even rarer for GTN to merge with primary malignant tumors in other organs. Herein is described a rare clinical case of GTN combined with primary lung cancer and mesenchymal tumor of the sigmoid colon, followed with literature review. Case presentation The patient was hospitalized due to diagnosis of GTN with primary lung cancer. Firstly, two cycles of chemotherapy including 5-fluorouracil (5-FU) and actinomycin-D(Act-D) was given. Laparoscopic total hysterectomy and right salpingo-oophorectomy was performed during the third chemotherapy. During the operation, a 3*2 cm nodule was removed which was protruded from the serous surface of the sigmoid colon, and the nodule was confirmed mesenchymal tumor pathologically, in accord with gastrointestinal stromal tumor. During the treatment of GTN, Icotinib tablets were taken orally to control the progression of lung cancer. After 2 cycles of consolidation chemotherapy of GTN, she received thoracoscopic lower lobe of right lung lobectomy and the mediastinum lymph nodes removal. She undertook gastroscopy and colonoscopy and the tubular adenoma of the descending colon was removed. At present, the regular follow-up is taken and she remains free of tumors. Conclusions GTN combined with primary malignant tumors in other organs are extremely rare in clinical practice. When imaging examination reveals a mass in other organs, clinicians should be aware of the possibility of a second primary tumor. It will increase the difficulty of GTN staging and treatment. We emphasis the importance of the collaboration of multidisciplinary teams. Clinicians should choose a reasonable treatment plan according to the priorities of different tumors.

Abstract Background Fine-scale genetic structure of ethnolinguistically diverse Chinese populations can fill the gap in the missing diversity and evolutionary landscape of East Asians, particularly for anthropologically informed Chinese minorities. Hmong–Mien (HM) people were one of the most significant indigenous populations in South China and Southeast Asia, which were suggested to be the descendants of the ancient Yangtze rice farmers based on linguistic and archeological evidence. However, their deep population history and biological adaptative features remained to be fully characterized. Objectives To explore the evolutionary and adaptive characteristics of the Miao people, we genotyped genome-wide SNP data in Guizhou HM-speaking populations and merged it with modern and ancient reference populations via a comprehensive population genetic analysis and evolutionary admixture modeling. Results The overall genetic admixture landscape of Guizhou Miao showed genetic differentiation between them and other linguistically diverse Guizhou populations. Admixture models further confirmed that Miao people derived their primary ancestry from geographically close Guangxi Gaohuahua people. The estimated identity by descent and effective population size confirmed a plausible population bottleneck, contributing to their unique genetic diversity and population structure patterns. We finally identified several natural selection candidate genes associated with several biological pathways. Conclusions Guizhou Miao possessed a specific genetic structure and harbored a close genetic relationship with geographically close southern Chinese indigenous populations and Guangxi historical people. Miao people derived their major ancestry from geographically close Guangxi Gaohuahua people and experienced a plausible population bottleneck which contributed to the unique pattern of their genetic diversity and structure. Future ancient DNA from Shijiahe and Qujialing will provide new insights into the origin of the Miao people.

Abstract Background The lack of a satisfactory strategy for postoperative pain management significantly impairs the quality of life for many patients. However, existing nanoplatforms cannot provide a longer duration of nerve blockage with intensity-adjustable characteristics under imaging guidance for clinical applications. Results To overcome this challenge, we proposed a biocompatible nanoplatform that enables high-definition ultrasound imaging-guided, intensity-adjustable, and long-lasting analgesia in a postoperative pain management model in awake mice. The nanoplatform was constructed by incorporating perfluoropentane and levobupivacaine with red blood cell membranes decorated liposomes. The fabricated nanoplatform can achieve gas-producing and can finely escape from immune surveillance in vivo to maximize the anesthetic effect. The analgesia effect was assessed from both motor reactions and pain-related histological markers. The findings demonstrated that the duration of intensity-adjustable analgesia in our platform is more than 20 times longer than free levobupivacaine injection with pain relief for around 3 days straight. Moreover, the pain relief was strengthened by repeatable ultrasound irradiation to effectively manage postoperative pain in an intensity-adjustable manner. No apparent systemic and local tissue injury was detected under different treatments. Conclusion Our results suggest that nanoplatform can provide an effective strategy for ultrasound imaging-guided intensity-adjustable pain management with prolonged analgesia duration and show considerable transformation prospects.

RationaleA family of short synthetic, triphosphorylated stem-loop RNAs (SLRs) have been designed to activate the retinoic-acid-inducible gene I (RIG-I) pathway and induce a potent interferon (IFN) response, which may have therapeutic potential. We investigated immune response modulation by SLR10. We addressed whether RIG-I pathway activation with SLR10 leads to protection of nonsmoking (NS) and cigarette smoke (CS)-exposed mice after influenza A virus (IAV) infection.MethodsMice were given 25 µg of SLR10 1 day before IAV infection. We compared the survival rates and host immune responses of NS and CS-exposed mice following challenge with IAV.ResultsSLR10 significantly decreased weight loss and increased survival rates in both NS and CS-exposed mice during IAV infection. SLR10 administration repaired the impaired proinflammatory response in CS-exposed mice without causing more lung injury in NS mice as assessed by physiologic measurements. Although histopathologic study revealed that SLR10 administration was likely to result in higher pathological scores than untreated groups in both NS and CS mice, this change was not enough to increase lung injury evaluated by lung-to-body weight ratio. Both qRT-PCR on lung tissues and multiplex immunoassay on bronchoalveolar lavage fluids (BALFs) showed that most IFNs and proinflammatory cytokines were expressed at lower levels in SLR10-treated NS mice than control-treaded NS mice at day 5 post infection (p.i.). Remarkably, proinflammatory cytokines IL-6, IL-12, and GM-CSF were increased in CS-exposed mice by SLR10 at day 5 p.i. Significantly, SLR10 elevated the ratio of the two chemokines (CXCL9 and CCL17) in BALFs, suggesting macrophages were polarized to classically activated (M1) status. In vitro testing also found that SLR10 not only stimulated human alveolar macrophage polarization to an M1 phenotype, but also reversed cigarette smoke extract (CSE)-induced M2 to M1 polarization.ConclusionsOur data show that SLR10 administration in mice is protective for both NS and CS-exposed IAV-infected mice. Mechanistically, SLR10 treatment promoted M1 macrophage polarization in the lung during influenza infection. The protective effects by SLR10 may be a promising intervention for therapy for infections with viruses, particularly those with CS-enhanced susceptibility to adverse outcomes.

In this work, the heterojunctions of CuInS2 embedded in the g-C3N4 materials (xCuInS2/g-C3N4, abbreviated as xCIS/GCN) was successfully prepared for peroxymonosulfate (PMS) activation under visible light. The catalysts are characterized by different techniques, such as XRD, FTIR, SEM, TEM, and UV-vis. The unique heterojunction composites can suppress the recombination of photogenerated pairs. The catalytic results showed that the 3CIS/GCN exhibited excellent catalytic levofloxacin (LVF) degradation efficiency, while more than 98.9% of LVF was removed in 60 min over a wide pH range. SO4•−, O2•−, OH•, and 1O2 were verified as the main reactive species for LVF degradation via the quenching experiments and electron paramagnetic resonance technology (EPR). The synergetic effect of xCIS/GCN, PMS, and visible light irradiation was discussed. The possible LVF degradation pathway was proposed through byproducts analysis (LC-MS). Moreover, the 3CIS/GCN/vis-PMS system has very low metal leaching. Owing to xCIS/GCN having good properties for PMS activation, it has potential applications for LVF or other hazardous pollutants degradation.

Residual lesions and undetectable metastasis after insufficient radiofrequency ablation (iRFA) are associated with earlier new metastases and poor survival in cancer patients, for induced aggressive tumor phenotype and immunosuppression. Programmed cell death protein 1(PD-1) blockade has been reported to enhance the radiofrequency ablation-elicited antitumor immunity, but its ability to eliminate incompletely ablated residual lesions has been questioned. Here, we report a combined treatment modality post iRFA based on integrating an oxygen self-enriching nanodrug PFH-Ce6 liposome@O2 nanodroplets (PCL@O2)-augmented noninvasive sonodynamic therapy (SDT) with PD-1 blockade. PCL@O2 containing Ce6 as the sonosensitizer and PFH as O2 reservoir, was synthesized as an augmented SDT nanoplatform and showed increased ROS generation to raise effective apoptosis of tumor cells, which also exposed more calreticulin to induce stronger immunogenic cell death (ICD). Combining with PD-1 blockade post iRFA, this optimized SDT induced a better anti-tumor response in MC38 tumor bearing mouse model, which not only arrested residual primary tumor progression, but also inhibited the growth of distant tumor, therefore prolonging the survival. Profiling of immune populations within the tumor draining lymph nodes and tumors further revealed that combination therapy effectively induced ICD, and promoted the maturation of dendritic cells, tumor infiltration of T cells, as well as activation of cytotoxic T lymphocytes. While iRFA alone could result in an increase of regulatory T cells (Tregs) in the residual tumors, SDT plus PD-1 blockade post iRFA reduced the number of Tregs in both primary and distant tumors. Moreover, the combined treatment could significantly initiate long-term immune memory, manifesting as elevated levels of CD8+ and CD4+ central memory cells. Therefore, this study establishes the preclinical proof of concept to apply oxygen self-enriching SDT to augment cancer immunotherapy after iRFA.

Abstract During influenza A virus (IAV) infection, it is unclear whether type I interferons (IFNs) have defensive antiviral effects or contribute to immunopathology in smokers. We treated nonsmoking (NS) and cigarette smoke (CS)-exposed mice intranasally with early (prophylactic) or late (therapeutic) IFN-β. We compared the mortality and innate immune responses of the treated mice following challenge with IAV. In NS mice, both early and late IFN-β administration decreased the survival rate in mice infected with IAV, with late IFN-β administration having the greatest effect on survival. In contrast, in CS-exposed mice, early IFN-β administration significantly increased survival during IAV infection while late IFN-β administration did not alter mortality. With regards to inflammation, in NS mice, IFN-β administration, especially late administration, significantly increased IAV-induced inflammation and lung injury. Early IFN-β administration to CS-exposed mice did not increase IAV-induced inflammation and lung injury as occurred in NS mice. Our results demonstrate, although IFN-β administration worsens the susceptibility of NS mice to influenza infection with increased immunopathology, early IFN-β administration to CS-exposed mice, which have suppression of the intrinsic IFN response, improved outcomes during influenza infection.

Antarctic krill oil (KO) prepared using supercritical carbon dioxide extraction and characterized using gas chromatography-mass spectrometry was used to investigate its preventive effect on ethanol-induced gastric tissue damage in a rat model in vivo. KO characterization showed that 74.96% of the unsaturated fatty acids consist of oleic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Rats pre-treated with KO (100, 200, and 500 mg/kg) showed mitigated oxidative stress through enhanced antioxidant enzyme superoxide dismutase (SOD) and reducing enzymes malondialdehyde (MDA) and myeloperoxidase (MPO) in gastric mucosal injury induced by ethanol. Additionally, the secretion of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), the expression of the IκBα/NF-κB signaling pathway, and nitric oxide (NO) production was suppressed. The results also demonstrated a significant decrease in histological injury and hemorrhage scores in a dose-dependent manner in the KO range. Therefore, KO has potential as a food supplement to alleviate ethanol-induced acute gastric mucosal injury.

Abstract Background Hospital anxiety caused by strabismus surgery has an unpleasant and disturbing feeling for both children and their parents. This study aimed to determine the effect of viewing a self-produced audio-visual animation introduction on preoperative anxiety and emergence agitation of pediatric patients undergoing strabismus surgery. Methods In this prospective randomized study, 1 hundred children scheduled for strabismus surgery with aged 3 ~ 6 years. The children were randomly divided into 2 groups (n = 50 for each), Group A: using a self-produced audio-visual animation introduction; Group C: controlled group without audio-visual animation introduction. Children’s preoperative anxiety was determined by the modified Yale Preoperative Anxiety Scale (mYPAS) at different time points: the night before surgery(T1), at pre-anesthetic holding room(T2), and just before anesthesia induction(T3). The Spielberger State-Trait Anxiety Inventory (STAI) was used to record the anxiety of parents at T1,T2 and T3. The incidence and the degree of emergence agitation were recorded. Results The mYPAS scores at T2 and T3 were higher than T1(p

Abstract Background Influenza is a highly contagious, acute, febrile respiratory infection caused by a negative-sense, single-stranded RNA virus, which belongs in the Orthomyxoviridae family. Cigarette smoke (CS) exposure worsens influenza infection in terms of frequency and severity in both human and animal models. Methods C57BL/6 mice with or without CS exposure for 6 weeks were inoculated intranasally with a single, non-lethal dose of the influenza A virus (IAV) A/Puerto Rico/8/1934 (PR8) strain. At 7 and 10 days after infection, lung and mediastinal lymph nodes (MLN) cells were collected to determine the numbers of total CD4 + and CD8 + T cells, and IAV-specific CD4 + and CD8 + T cells, using flow cytometry. Bronchoalveolar lavage fluid (BALF) was also collected to determine IFN-γ levels and total protein concentration. Results Although long-term CS exposure suppressed early pulmonary IAV-antigen specific CD8 + and CD4 + T cell numbers and IFN-γ production in response to IAV infection on day 7 post-infection, CS enhanced numbers of these cells and IFN-γ production on day 10. The changes of total protein concentration in BALF are consistent with the changes in the IFN-γ amounts between day 7 and 10, which suggested that excessive IFN-γ impaired barrier function and caused lung injury at the later stage of infection. Conclusions Our results demonstrated that prior CS exposure caused a biphasic T cell and IFN-γ response to subsequent infection with influenza in the lung. Specifically, the number of IAV antigen-specific T cells on day 10 was greatly increased by CS exposure even though CS decreased the number of the same group of cells on day 7. The result suggested that CS affected the kinetics of the T cell response to IAV, which was suppressed at an early stage and exaggerated at a later stage. This study is the first to describe the different effect of long-term CS on T cell responses to IAV at early and late stages of infection in vivo.

Purpose: to evaluate and monitor the timely thermal ablation changes of rabbit liver by using two elastographic methods—real-time elastography (RTE) and shear wave elastography (SWE)—as compared to contrast-enhanced ultrasound (CEUS) and physical specimens. Materials and Methods: 20 ablation zones were created in the livers of 20 rabbits using radiofrequency ablation (RFA). After the ablation, RTE and SWE were used to measure the elastic properties of the twenty ablation zones. The consistency of efficacy evaluation for RTE and SWE measurements was analyzed using the Bland–Altman test. The areas of the thermal ablation zones were also measured and compared according to the images provided by RTE, SWE, CEUS, and gross physical specimen measurement. Results: RTE and SWE could clearly display the shape of RFA ablation zones within one hour after the ablation. The average elasticity ratio for the ablation zone measured by RTE was 3.41 ± 0.67 (2.23–4.76); the average elasticity value measured by SWE was 50.7 ± 11.3 kPa (33.2–70.4 kPa). The mean areas of the ablation zones measured with RTE, SWE, gross specimen, and CEUS were 1.089 ± 0.199 cm2, 1.059 ± 0.201 cm2, 1.081 ± 0.201 cm2, and 3.091 ± 0.591 cm2, respectively. The Bland–Altman test showed that RTE and SWE have great consistency. Area measurements by CEUS were significantly larger than those of the other three methods (p < 0.05). Conclusion: RTE and SWE are both able to accurately confirm the range of ablation zones shortly after the ablation for rabbit livers.

The important role of interferons (IFNs) in antiviral innate immune defense is well established. Although recombinant IFN-α was approved for cancer and chronic viral infection treatment by regulatory agencies in many countries starting in 1986, no IFNs are approved for treatment of influenza A virus (IAV) infection. This is partially due to the complex effects of IFNs in acute influenza infection. IAV attacks the human respiratory system and causes significant morbidity and mortality globally. During influenza infection, depending on the strain of IAV and the individual host, type I IFNs can have protective antiviral effects or can contribute to immunopathology. In the context of virus infection, the immune system has complicated mechanisms regulating the expression and effects of type I IFN to maximize the antiviral response by both activating and enhancing beneficial innate cell function, while limiting immunopathological responses that lead to exaggerated tissue damage. In this review, we summarize the complicated, but important, role of type I IFNs in influenza infections. This includes both protective and harmful effects of these important cytokines during infection.

In this study, the chemical structure of asphalt aging was analyzed and identified based on 1H-NMR quantitative technology and chemometrics analysis. The characteristic full component information of 30 samples before and after aging from 5 different oil sources was measured by 1H-NMR, and the results were converted into a data matrix. This study used PCA, HAC, OPLS-DA, and Fisher discriminant analysis to evaluate the change rules of the chemical composition of asphalt from different oil sources after aging. The results showed that the 1H-NMR spectra of 30 asphalt samples were very similar, and hydrogen could be divided into 4 categories according to the chemical shift: HA, Hα, Hβ, and Hγ. The shapes of 1H-NMR of asphalt samples from different oil sources showed slight differences, while the shapes of the 1H-NMR spectra of asphalt samples with different aging degrees from the same oil source was basically the same. The results of PCA and HAC analysis showed that the samples of the same asphalt and asphalt with similar oil sources before and after aging were still in the same category, and the spatial distance was very close, while the spatial distance of asphalts from different oil sources was very different. The Fisher discriminant function established by PCA and HAC can be used to distinguish asphalt samples from different oil sources with an accuracy of up to 100%.

Cigarette smoke (CS) is a significant public health problem and a leading risk factor for the development of chronic obstructive pulmonary disease (COPD) in the developed world. Respiratory viral infections, such as the influenza A virus (IAV), are associated with acute exacerbations of COPD and are more severe in cigarette smokers. To fight against viral infection, the host has developed an innate immune system, which has complicated mechanisms regulating the expression and activation of cytokines and chemokines to maximize the innate and adaptive antiviral response, as well as limiting the immunopathology that leads to exaggerated lung damage. In the case of IAV, responders include airway and alveolar epithelia, lung macrophages and dendritic cells. To achieve a successful infection, IAV must overcome these defenses. In this review, we summarize the detrimental role of CS in influenza infections. This includes both immunosuppressive and proinflammatory effects on innate immune responses during IAV infection. Some of the results, with respect to CS effects in mouse models, appear to have discordant results, which could be at least partially addressed by standardization of animal viral infection models to evaluate the effect of CS exposure in this context.

Abstract Background Retinoic acid-inducible gene I (RIG-I) is an important regulator of virus-induced antiviral interferons (IFNs) and proinflammatory cytokines which participate in clearing viral infections. Cigarette smoke (CS) exposure increases the frequency and severity of respiratory tract infections. Methods We generated a RIG-I transgenic (TG) mouse strain that expresses the RIG-I gene product under the control of the human lung specific surfactant protein C promoter. We compared the mortality and host immune responses of RIG-I TG mice and their litter-matched wild type (WT) mice following challenge with influenza A virus (IAV). Results RIG-I overexpression increased survival of IAV-infected mice. CS exposure increased mortality in WT mice infected with IAV. Remarkably, the effect of RIG-I overexpression on survival during IAV infection was enhanced in CS-exposed animals. CS-exposed IAV-infected WT mice had a suppressed innate response profile in the lung compared to sham-exposed IAV-infected WT mice in terms of the protein concentration, total cell count and inflammatory cell composition in the bronchoalveolar lavage fluid. RIG-I overexpression restored the innate immune response in CS-exposed mice to that seen in sham-exposed WT mice during IAV infection, and is likely responsible for enhanced survival in RIG-I TG mice as restoration preceded death of the animals. Conclusions Our results demonstrate that RIG-I overexpression in mice is protective for CS enhanced susceptibility of smokers to influenza infection, and that CS mediated RIG-I suppression may be partially responsible for the increased morbidity and mortality of the mice exposed to IAV. Thus, optimizing the RIG-I response may be an important treatment strategy for CS-enhanced lung infections, particularly those due to IAV.

Fluorescence properties of a molecule can be used to study the structural and functional nature of biological processes. Physical properties, including fluorescence lifetime, emission spectrum, emission polarization, and others, help researchers probe a molecule, produce desired effects, and infer causes and consequences. Correlative imaging techniques such as hyperdimensional imaging microscopy (HDIM) combine the physical properties and biochemical states of a fluorophore. Here we present a fiber-based imaging system that can generate hyper-dimensional contrast by combining multiple fluorescence properties into a single fluorescence lifetime decay curve. Fluorescence lifetime imaging microscopy (FLIM) with controlled excitation polarization and temporally dispersed emission can generate a spectrally coded, polarization-filtered lifetime distribution for a pixel. This HDIM scheme generates a better contrast between different molecules than that from individual techniques. This setup uses only a single detector and is simpler to implement, modular, cost-efficient, and adaptable to any existing FLIM microscope. We present higher contrast data from Arabidopsis thaliana epidermal cells based on intrinsic anthocyanin emission properties under multiphoton excitation. This work lays the foundation for an alternative hyperdimensional imaging system and demonstrates that contrast-based imaging is useful to study cellular heterogeneity in biological samples.

Influenza A virus (IAV) infection is a major cause of morbidity and mortality. Retinoic acid-inducible protein I (RIG-I) plays an important role in the recognition of IAV in most cell types, and leads to the activation of interferon (IFN). We investigated mechanisms of RIG-I and IFN induction by IAV in the BCi-NS1.1 immortalized human airway basal cell line and in the A549 human alveolar epithelial cell line. We found that the basal expression levels of RIG-I and regulatory transcription factor (IRF) 7 were very low in BCi-NS1.1 cells. IAV infection induced robust RIG-I and IRF7, not IRF3, expression. siRNA against IRF7 and mitochondrial antiviral-signaling protein (MAVS), but not IRF3, significantly inhibited RIG-I mRNA expression and IFN induction by IAV infection. Most importantly, even without virus infection, IFN-β alone induced RIG-I, and siRNA against IRF7 did not inhibit RIG-I induction by IFN-β. Similar results were found in the alveolar basal epithelial A549 cell line. RIG-I and IRF7 expression in humans is highly inducible and greatly amplified by IFN produced from virus infected cells. IFN induction can be separated into two phases, that initially induced by the virus with basal RIG-I (the first phase), and that induced by the subsequent virus with amplified RIG-I from the first phase IFN (the second phase). The de novo synthesis of IRF7 is required for the second phase IFN induction during influenza virus infection in human lung bronchial and alveolar epithelial cells.

Using echo-top height and hourly rainfall datasets, a new reflectivity-rainfall (Z-R) relationship is established in the present study for the radar-based quantitative precipitation estimation (RQPE), taking into account both the temporal evolution (dynamical) and the types of echoes (i.e., based on echo-top height classification). The new Z-R relationship is then applied to derive the RQPE over the middle and lower reaches of Yangtze River for two short-time intense rainfall cases in summer (2200 UTC 1 June 2016 and 2200 UTC 18 June 2016) and one stratiform rainfall case in winter (0000 UTC 15 December 2017), and then the comparative analyses between the RQPE and the RQPEs derived by the other two methods (the fixed Z-R relationship and the dynamical Z-R relationship based on radar reflectivity classification) are accomplished. The results show that the RQPE from the new Z-R relationship is much closer to the observation than those from the other two methods because the new method simultaneously considers the echo intensity (reflecting the size and concentration of hydrometers to a certain extent) and the echo-top height (reflecting the updraft to a certain extent). Two statistics of 720 rainfall events in summer (April to June 2017) and 50 rainfall events in winter (December 2017) over the same region show that the correlation coefficient (root-mean-squared error and relative error) between RQPE derived by the new Z-R relationship and observation is significantly increased (decreased) compared to the other two Z-R relationships. Besides, the new Z-R relationship is also good at estimating rainfall with different intensities as compared to the other two methods, especially for the intense rainfall.

Retinoic acid-inducible gene I (RIG-I) is an important regulator of virus-induced antiviral interferons (IFNs) and proinflammatory cytokines. It requires interaction with an adaptor molecule, mitochondrial antiviral-signaling protein (MAVS), to activate downstream signaling pathways. To elucidate the mechanism(s) by which RIG-I-dependent recognition of IAV infection in vivo triggers innate immune responses, we infected mutant mice lacking RIG-I or MAVS with influenza A virus (IAV) and measured their innate immune responses. As has previously been demonstrated with isolated deletion of the virus recognition receptors TLR3, TLR7, and NOD2, RIG-I or MAVS knockout (KO) did not result in higher mortality and did not reduce IAV-induced cytokine responses in mice. Infected RIG-I KO animals displayed similar lung inflammation profiles as did WT mice, in terms of the protein concentration, total cell count, and inflammatory cell composition in the bronchoalveolar lavage fluid. RNA-Seq results demonstrated that all types of mice exhibited equivalent antiviral and inflammatory gene responses following IAV infection. Together, the results indicated that although RIG-I is important in innate cytokine responses in vitro, individual deletion of the genes encoding RIG-I or MAVS did not change survival or innate responses in vivo after IAV infection in mice.

Influenza infection is a major cause of morbidity and mortality. Retinoic acid-inducible gene I (RIG-I) is believed to play an important role in the recognition of, and response to, influenza virus and other RNA viruses. Our study focuses on the hypothesis that pandemic H1N1/09 influenza virus alters the influenza-induced proinflammatory response and suppresses host antiviral activity. We first compared the innate response to a clinical isolate of influenza A(H1N1)pdm09 virus, OK/09, a clinical isolate of seasonal H3N2 virus, OK/06, and to a laboratory adapted seasonal H1N1 virus, PR8, using a unique human lung organ culture model. Exposure of human lung tissue to either pandemic or seasonal influenza virus resulted in infection and replication in alveolar epithelial cells. Pandemic virus induces a diminished RIG-I mRNA and antiviral cytokine response than seasonal virus in human lung. The suppression of antiviral response and RIG-I mRNA expression was confirmed at the protein level by ELISA and western blot. We performed a time course of RIG-I and interferon-β (IFN-β) mRNA induction by the two viruses. RIG-I and IFN-β induction by OK/09 was of lower amplitude and shorter duration than that caused by PR8. In contrast, the pandemic virus OK/09 caused similar induction of proinflammatory cytokines, IL-8 and IL-6, at both the transcriptional and translational level as PR8 in human lung. Differential antiviral responses did not appear to be due to a difference in cellular infectivity as immunohistochemistry showed that both viruses infected alveolar macrophages and epithelial cells. These findings show that influenza A(H1N1)pdm09 virus suppresses anti-viral immune responses in infected human lung through inhibition of viral-mediated induction of the pattern recognition receptor, RIG-I, though proinflammatory cytokine induction was unaltered. This immunosuppression of the host antiviral response by pandemic virus may have contributed to the more serious lung infections that occurred in the H1N1 pandemic of 2009.