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Due to its unique structure, articular cartilage has limited self-repair capacity. Microtissues are tiny tissue clusters that can mimic the function of target organs or tissues. Using cells alone for microtissue construction often results in the formation of necrotic cores. However, the extracellular matrix (ECM) of native cartilage can provide structural support and is an ideal source of microcarriers. Autologous adipose-derived mesenchymal stem cells (ADSCs) and bone marrow mesenchymal stem cells (BMSCs) are widely used in cartilage tissue engineering. In this study, we fabricated microcarriers and compared the behavior of two homologous cell types in the microcarrier environment. The microcarrier environment highlighted the advantages of ADSCs and promoted the proliferation and migration of these cells. Then, ADSCs microtissues (ADSCs-MT) and BMSCs microtissues (BMSCs-MT) were fabricated using a three-dimensional dynamic culture system. In vitro and in vivo experiments verified that the cartilage regeneration ability of ADSCs-MT was significantly superior to that of BMSCs-MT. Transcriptomics revealed that ADSCs-MT showed significantly lower expression levels of ECM degradation, osteogenesis, and fibrocartilage markers. Finally, the protective effect of microtissues on inflammatory chondrocytes was validated. Overall, the ADSCs-MT constructed in this study achieved excellent cartilage regeneration and could be promising for the autologous application of cartilage microtissues.

Abstract Background Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson’s disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined. Methods Long culture-induced replicative senescence model and 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature senescence model, and a mouse model of PD were used to investigate the effect of metformin on astrocyte senescence in vivo and in vitro. Immunofluorescence staining and flow cytometric analyses were performed to evaluate the mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA to mouse substantia nigra pars compacta regions to specifically reduce astrocytic cGAS expression to clarify the potential molecular mechanism by which metformin inhibited the astrocyte senescence in PD. Results We showed that metformin inhibited the astrocyte senescence in vitro and in PD mice. Mechanistically, metformin normalized mitochondrial function to reduce mitochondrial DNA release through mitofusin 2 (Mfn2), leading to inactivation of cGAS-STING, which delayed astrocyte senescence and prevented neurodegeneration. Mfn2 overexpression in astrocytes reversed the inhibitory role of metformin in cGAS-STING activation and astrocyte senescence. More importantly, metformin ameliorated dopamine neuron injury and behavioral deficits in mice by reducing the accumulation of senescent astrocytes via inhibition of astrocytic cGAS activation. Deletion of astrocytic cGAS abolished the suppressive effects of metformin on astrocyte senescence and neurodegeneration. Conclusions This work reveals that metformin delays astrocyte senescence via inhibiting astrocytic Mfn2-cGAS activation and suggest that metformin is a promising therapeutic agent for age-associated neurodegenerative diseases.

In this study, Penaeus vannamei was used to analyze the quality of sous-vide combined with high pressure cooked and freeze-dried shrimp (SPF) and boiled and hot air dried shrimp (BH) prepared by traditional thermal processing. The results showed that compared with BH, SPF had lower hardness, fuller color and higher sensory score, which was more popular with consumers. The content of benzaldehyde was significantly higher in SPF than in BH, and SPF had a more prominent seafood-like flavor. The content of polyunsaturated fatty acids was also higher in SPF than in BH. Meanwhile, a dynamic model was established for shelf life prediction. According to the model, SPF had high oxidative stability. Therefore, sous-vide combined with high pressure can improve the quality and flavor of ready-to-eat shrimp. The results from this study provide a theoretical basis for the large-scale production of high-quality, convenience and ready-to-eat shrimp with unique flavor.

Biochar amendment and substituting chemical fertilizers with organic manure (organic substitution) have been widely reported to improve intensive vegetable production. However, considering its high potential for reducing carbon and reactive nitrogen (Nr) footprints, very few comprehensive evaluations have been performed on the environmental and economic aspects of biochar amendment or organic substitution. In this study, the comprehensive environmental damage costs from carbon and Nr footprints, measured using the life cycle assessment (LCA) methodology, followed a cradle-to-gate approach, and the carbon storage benefits were incorporated into the newly constructed net ecosystem economic benefit (NEEB) assessment frame in addition to the conventional product income–input cost-benefit methods. One kilogram of harvested vegetables for carbon/Nr footprints and one hectare of cultivated land per crop for cost and benefit were adopted as functional units considering the multi-cropping characteristics for intensive vegetable production. Five fertilization treatments were included: no fertilizer (CK); synthetic fertilizer application (SN); biochar amendment (NB); organic substitution (NM); and a combination of biochar and organic substitution (NMB). These were investigated for five consecutive years of vegetable crop rotations in a typically intensified vegetable production region in China. Adopting the revised NEEB methodology, NB significantly reduced carbon footprint by 73.0% compared to no biochar addition treatment. Meanwhile, NB significantly increased the total benefits by 9.7% and reduced the environmental damages by 52.7% compared to NM, generating the highest NEEB, making it the most effective fertilization strategy among all treatments. It was 4.3% higher compared to NM, which was not significant, but significantly higher than SN and NMB, by 23.0% and 13.6%, respectively. This finding highlights the importance of considering carbon storage benefit for properly assessing NEEB, which is important for developing effective agricultural management strategies and promoting intensive vegetable production with a more sustainable approach.

AIM: To explore the pathogenesis and surgical outcomes of different types of myopic traction maculopathy(MTM)using optical coherence tomography(OCT).METHODS: A total of 193 patients(210 eyes)with MTM were retrospectively included, of which 74 eyes(35.2%)underwent vitrectomy combined with internal limiting membrane(ILM)peeling. The patients were categorized into three groups: foveal detachment(FD), foveoschisis(FS)and lamellar macular hole(LMH). Based on the central foveal thickness(CFT)at baseline(M0), eyes with FD were classified into two subgroups: extensive FD and limited FD. Outcomes included best-corrected visual acuity(BCVA), CFT, posterior staphyloma height(PSH), the presence of epiretinal membrane(ERM)and ILM detachment. Risk factors for BCVA at 6mo after vitrectomy(M6)were analyzed using linear regression.RESULTS: At M0, ERM was highly present in eyes with LMH(rs=0.28, P

Abstract Background Sustained cardiac hypertrophy often develops maladaptive myocardial remodeling, and eventually progresses to heart failure and sudden death. Therefore, maladaptive hypertrophy is considered as a critical therapeutic target for many heart diseases. Mitophagy, a crucial mechanism in mitochondria quality control and cellular homeostasis, has been implicated in diverse cardiac disorders such as myocardial infarction, diabetic cardiomyopathy, cardiac hypertrophy and heart failure. However, what role mitophagy plays in heart diseases remains an enigma. PARKIN functions as an E3 ubiquitin protein ligase and mediates mitophagy cascades. It is still unclear whether PARKIN participates in the regulation of cardiac hypertrophy. Results PARKIN was downregulated in cardiomyocytes and hearts under hypertrophic stress. Enforced expression of PARKIN inhibited Ang II-induced cardiomyocyte hypertrophy. Compared to wide-type mice with Ang II-induced cardiac hypertrophy, Parkin transgenic mice subjected to Ang II administration showed attenuated cardiac hypertrophy and improved cardiac function. In addition, mitophagy machinery was impaired in response to Ang II, which was rescued by overexpression of PARKIN. PARKIN exerted the anti-hypertrophy effect through restoring mitophagy. In further exploring the underlying mechanisms, we found that PARKIN was transcriptionally activated by FOXO3a. FOXO3a promoted mitophagy and suppressed cardiac hypertrophy by targeting Parkin. Conclusions The present study reveals a novel cardiac hypertrophy regulating model composed of FOXO3a, PARKIN and mitophagy program. Modulation of their levels may provide a new approach for preventing cardiac hypertrophy and heart failure. Graphical Abstract

Abstract With the advent of the 5G era, people's demand for information and bandwidth is increasing. The signal source will mainly be high‐frequency radio waves with high bandwidth. However, the coverage of high‐frequency radio waves is very limited, which leads to the emergence of micro base stations. Opportunistic social networks are just suitable for this new transmission method, it is easy for users to simultaneously request content with high popularity in a short time, which will cause a heavy load on the micro base station and a high transmission delay. This paper establishes the community mechanism and proposes a user cache management and cooperative transmission mechanism (CMCT) based on edge community computing by using the predictability of users' requests for popular content. The free user equipment space is used to manage cache distribution through the edge community computing to perform cooperative transmission, thereby reducing the content delivery delay and the load of the micro base station. Simulation experiments show that the CMCT algorithm can reduce end‐to‐end delay and overhead, and improve data transmission efficiency.

Objectives: This network meta-analysis aimed to compare the efficacy and safety of fluoroquinolone (FQ) monotherapy, β-lactam (BL) monotherapy and β-lactam/macrolide (BL-M) combination therapy in hospitalized patients with community-acquired pneumonia (CAP). Methods: Pubmed, Embase and the Cochrane Library were searched for randomized controlled trials (RCTs) comparing FQ monotherapy, BL monotherapy and BL-M combination therapy up to July 2021. The outcomes of interest included all-cause mortality, clinical success, microbiological success and drug-related adverse events. The summary relative risks (RRs) were estimated using pairwise and Bayesian network meta-analysis. Results: A total of 12 RCTs involving 5009 patients were included. In pairwise meta-analysis, no significant differences were found among FQ monotherapy, BL monotherapy and BL-M dual therapy for all-cause mortality, clinical success or microbiological success. FQ monotherapy was associated with fewer adverse events compared with BL-M therapy (RR 0.80, 95% confidence interval [CI] 0.66–0.98). The network meta-analysis showed that there was no significant difference observed among FQ monotherapy, BL monotherapy and BL-M dual therapy regarding all the outcomes. Conclusion: FQ monotherapy, BL monotherapy and BL-M combination therapy demonstrated similar efficacy and safety for hospitalized patients with CAP in this network meta-analysis. Due to the limitations of quality and quantity of the included studies, it is difficult to make a definitive recommendation before more large-scale and high-quality RCTs are conducted.

Abstract In order to improve transmission performance, opportunistic social networks are widely used in 5G mobile network communication for network congestion. However, transferring large amounts of data in an instant will lead to data redundancy problems, which will affect the transmission quality. The authors propose a method called user‐optimized data transmission scheduling based on edge community service in opportunistic social networks (ECSUO). This method constructs the edge community service model by introducing mobile edge computing into the opportunistic social network. Then several scheduling factors are set to coordinate the dynamic priority assessment. The simulation results show that ECSUO performs better than other classical opportunistic complex network algorithms in a variety of transmission quality evaluation indexes, and this method also has good applicability when applied to different transmission models.

IntroductionTo control the COVID-19 pandemic, great efforts have been made to realize herd immunity by vaccination since 2020. Unfortunately, most of the vaccines against COVID-19 were approved in emergency without a full-cycle and comprehensive evaluation process as recommended to the previous vaccines. Metabolome has a close tie with the phenotype and can sensitively reflect the responses to stimuli, rendering metabolomic analysis have the potential to appraise and monitor vaccine effects authentically.MethodsIn this study, a retrospective study was carried out for 330 Chinese volunteers receiving recommended two-dose CoronaVac, a vaccine approved in emergency in 2020. Venous blood was sampled before and after vaccination at 5 separate time points for all the recipients. Routine clinical laboratory analysis, metabolomic and lipidomic analysis data were collected.Results and discussionIt was found that the serum antibody-positive rate of this population was around 81.82%. Most of the laboratory parameters were slightly perturbated within the relevant reference intervals after vaccination. The metabolomic and lipidomic analyses showed that the metabolic shift after inoculation was mainly in the glycolysis, tricarboxylic acid cycle, amino acid metabolism, urea cycle, as well as microbe-related metabolism (bile acid metabolism, tryptophan metabolism and phenylalanine metabolism). Time-course metabolome changes were found in parallel with the progress of immunity establishment and peripheral immune cell counting fluctuation, proving metabolomics analysis was an applicable solution to evaluate immune effects complementary to traditional antibody detection. Taurocholic acid, lysophosphatidylcholine 16:0 sn-1, glutamic acid, and phenylalanine were defined as valuable metabolite markers to indicate the establishment of immunity after vaccination. Integrated with the traditional laboratory analysis, this study provided a feasible metabolomics-based solution to relatively comprehensively evaluate vaccines approved under emergency.

Aims/Background Peripheral nerve injury affects some people with multiple myeloma; this condition can be brought on by the disease itself or by the treatments they receive. Such a complication increases patients' financial burden, causes treatment to be interrupted or delayed, and reduces treatment efficacy. However, opinions regarding the risk factors for peripheral neuropathy are currently divided. Consequently, the primary goals of this study were to determine the prevalence of peripheral neuropathy and related risk factors in newly diagnosed and untreated patients of multiple myeloma. Methods Sixty-one patients with newly diagnosed and untreated multiple myeloma were retrospectively analyzed. Peripheral neuropathy (PN) in all patients was assessed via electromyography. The patients were divided into two groups according to the presence of PN. The differences in body mass index, haemoglobin, monoclonal M protein (M protein) and other related indicators between the two groups were analyzed using independent sample t-tests and Mann-Whitney U tests. Results Of the 61 patients, 72% had PN. Neuroelectrophysiological studies revealed that PN patients have abnormalities in both their motor and sensory fibres. We discovered that PN was strongly correlated with age, haemoglobin, and levels of creatinine (p = 0.039, p = 0.045, and p = 0.030, respectively). Conclusion Age, haemoglobin and creatinine levels are associated with the occurrence of PN. Investigation of the incidence and risk factors of multiple myeloma-associated PN can provide a better theoretical basis for the selection of treatment options and the enhancement of patient well-being and satisfaction. [ABSTRACT FROM AUTHOR]

Face recognition is widely used in daily life such as shopping,security check,travel,payment and work attendance.Face recognition systems need strong computing power and large storage space,so face images that need to be recognized are usually transmitted to the cloud platform through the network.Due to the problems of network coverage,congestion and delay,face re-cognition systems are difficult to meet the needs of actual application,and the user experience is poor.Aiming at the problems in face recognition,a face recognition method based on edge-cloud collaboration is proposed.This method combines the processing ability of cloud computing and the real-time performance of edge computing,so that face recognition systems are not constrained by the network status,and its application is more extensive and the user experience is better.In the cloud,the LResNet feature extraction method is proposed to improve the ResNet34 network structure,and the ArcFace face loss function is used to supervise the training process,so that the network can learn more face angle features.At the edge,due to the limited computing resources and storage resources,a SResNet feature extraction method is proposed.Deep separable convolution is used to lighten the LResNet network structure,and it has greatly reduced network parameters and computation.The face recognition experiment on edge-cloud collaboration shows that the system can recognize faces in real time with a high accuracy rate under any network status.

IntroductionRetinoic acid-induced 2 (RAI2) was initially related to cell differentiation and induced by retinoic acid. RAI2 has been identified as an emerging tumor suppressor in breast cancer and colorectal cancer.MethodsIn this study, we performed systematic analyses of RAI2 in breast cancer. Meta-analysis and Kaplan-Meier survival curves were applied to identify the survival prediction potential of RAI2. Moreover, the association between RAI2 expression and the abundance of six tumor-infiltrating immune cells was investigated by TIMER, including B cells, CD8+ T cells, CD4+ T cells, B cells, dendritic cells, neutrophils, and macrophages. The expression profiles of high and low RAI2 mRNA levels in GSE7390 were compared to identify differentially expressed genes (DEGs) and the biological function of these DEGs was analyzed by R software, which was further proved in GSE7390.ResultsOur results showed that the normal tissues had more RAI2 expression than breast cancer tissues. Patients with high RAI2 expression were related to a favorable prognosis and more immune infiltrates. A total of 209 DEGs and 182 DEGs were identified between the expression profiles of high and low RAI2 mRNA levels in the GSE7390 and GSE21653 databases, respectively. Furthermore, Gene Ontology (GO) enrichment indicated that these DEGs from two datasets were both mainly distributed in “biological processes” (BP), including “organelle fission” and “nuclear division”. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis demonstrated that these DEGs from two datasets were both significantly enriched in the “cell cycle”. Common hub genes between the DEGs in GSE7390 and GSE21653 were negatively associated with RAI2 expression, including CCNA2, MAD2L1, MELK, CDC20, and CCNB2.DiscussionsThese results above suggested that RAI2 might play a pivotal role in preventing the initiation and progression of breast cancer. The present study may contribute to understanding the molecular mechanisms of RAI2 and enriching biomarkers to predict patient prognosis in breast cancer.

With excessive nitrogen (N) input, high nitrous oxide (N2O) emissions are frequently observed in greenhouse vegetable fields. We hypothesized that the underlying production mechanisms can be derived across a wide selection of vegetable fields in the middle and lower reaches of the Yangtze River. Thus, we investigated the emission characteristics and relative contributions of ammonia-oxidizing archaea (AOA) and bacteria (AOB) and other microbial processes to the N2O production from five long-term greenhouse vegetable fields through an incubation experiment with combined inhibition methods. The results showed that the ammonia oxidation process is the dominant contributor to N2O production at all five sites, accounting for 88–97% of the total N2O emissions. Regardless of acidic, neutral, or alkaline soil, AOA-driven N2O emission rates were consistently higher than AOB-driven N2O emission rates. Both AOA-driven and AOB-driven N2O emissions exhibited positive correlations with soil pH, with significant increases in soil N2O production associated with high pH levels. Therefore, general production mechanisms were derived, such that more attention should be paid to AOA-driven N2O emissions and to vegetable soils with a relatively high pH in the middle and lower reaches of the Yangtze River.

Abstract Background SMARCAs, belonged to SWI/SNF2 subfamilies, are critical to cellular processes due to their modulation of chromatin remodeling processes. Although SMARCAs are implicated in the tumor progression of various cancer types, our understanding of how those members affect pancreatic carcinogenesis is quite limited and improving this requires bioinformatics analysis and biology approaches. Methods To address this issue, we investigated the transcriptional and survival data of SMARCAs in patients with pancreatic cancer using ONCOMINE, GEPIA, Human Protein Atlas, and Kaplan–Meier plotter. We further verified the effect of significant biomarker on pancreatic cancer in vitro through functional experiment. Results The Kaplan–Meier curve and log-rank test analyses showed a positive correlation between SMARCA1/2/3/SMARCAD1 and patients’ overall survival (OS). On the other hand, mRNA expression of SMARCA6 (also known as HELLS) showed a negative correlation with OS. Meanwhile, no significant correlation was found between SMARCA4/5/SMARCAL1 and tumor stages and OS. The knockdown of HELLS impaired the colony formation ability, and inhibited pancreatic cancer cell proliferation by arresting cells at S phase. Conclusions Data mining analysis and cell function research demonstrated that HELLS played oncogenic roles in the development and progression of pancreatic cancer, and serve as a poor prognostic biomarker for pancreatic cancer. Our work laid a foundation for further clinical applications of HELLS in pancreatic cancer.

Bio-based aerogels, which are poised as compelling thermal insulators, demand intricate synthesis procedures and have limited durability under harsh conditions. The integration of smart stimuli–response transitions in biomass aerogels holds promise as a solution, yet remains a challenge. Here, we introduce a pioneering strategy that employs reversible-gel-assisted ambient-pressure drying without organic solvents to craft multifunctional bio-based aerogels. By exploiting the thermally reversible gelling propensity of select biomasses, we anchor emulsified bubbles within cross-linked hydrogels, circumventing surface tension issues during mild drying. The resultant aerogels feature a robust porous matrix that is imbued with stable bubbles, yielding low thermal conductivity, high flame retardancy and robust resistance to diverse rigors. This innovative approach facilitates a paradigm shift in intelligent fire protection in which aerogels transition from robust to flexible in response to water stimuli, effectively shielding against thermal hazards and external forces. This work opens up a facile, eco-friendly and mild way to fabricate advanced biomass aerogels with stimuli-responsive transformation. [ABSTRACT FROM AUTHOR]

Scientific knowledge is an underlying basis for technological innovation in the pharmaceutical industry. Collaboration is the main way to participate in the creation of scientific knowledge for pharmaceutical firms. Will network positions in scientific collaboration affect their technological innovation performance? Moreover, what factors moderate the firms' scientific collaboration network positions and technological innovation link? Using a dataset based on 194 Chinese publicly traded pharmaceutical companies, this paper constructs the dynamic scientific collaboration networks among 1,826 organizations by analyzing 4,092 papers included in CNKI and Web of Science databases. Then we probe the impact and boundaries of positions in the scientific collaboration network of pharmaceutical firms on their technological innovation performance through the negative binomial modeling approach. Our study confirms that degree centrality has an inverted U-shaped impact on pharmaceutical firms' technological innovation performance, while structural holes benefit it. Moreover, this article identifies that the strength of scientific collaboration positively moderates the U-shaped relationship between degree centrality and technological innovation of pharmaceutical firms, the matching of high patent stock and high structural holes can promote their technological innovation performance. The results deepen the present understanding of scientific collaboration in the pharmaceutical industry and offer new insights into the formulation of pharmaceutical firms' scientific collaboration strategies.

Breast cancer has overtaken lung cancer as the most frequently diagnosed cancer type and is the leading cause of death for women worldwide. It has been demonstrated in published studies that long non-coding RNAs (lncRNAs) involved in genomic stability are closely associated with the progression of breast cancer, and remarkably, genomic stability has been shown to predict the response to immune checkpoint inhibitors (ICIs) in cancer therapy, especially colorectal cancer. Therefore, it is of interest to explore somatic mutator-derived lncRNAs in predicting the prognosis and ICI efficacy in breast cancer patients. In this study, the lncRNA expression data and somatic mutation data of breast cancer patients from The Cancer Genome Atlas (TCGA) were downloaded and analyzed thoroughly. Univariate and multivariate Cox proportional hazards analyses were used to generate the genomic instability-related lncRNAs in a training set, which was subsequently used to analyze a testing set and combination of the two sets. The qRT-PCR was conducted in both normal mammary and breast cancer cell lines. Furthermore, the Kaplan–Meier and receiver operating characteristic (ROC) curves were applied to validate the predictive effect in the three sets. Finally, the Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to evaluate the association between genomic instability-related lncRNAs and immune checkpoints. As a result, a six-genomic instability-related lncRNA signature (U62317.4, MAPT-AS1, AC115837.2, EGOT, SEMA3B-AS1, and HOTAIR) was identified as the independent prognostic risk model for breast cancer patients. Compared with the normal mammary cells, the qRT-PCR showed that HOTAIR was upregulated while MAPT-AS1, EGOT, and SEMA3B-AS1 were downregulated in breast cancer cells. The areas under the ROC curves at 3 and 5 years were 0.711 and 0.723, respectively. Moreover, the patients classified in the high-risk group by the prognostic model had abundant negative immune checkpoint molecules. In summary, this study suggested that the prognostic model comprising six genomic instability-related lncRNAs may provide survival prediction. It is necessary to identify patients who are suitable for ICIs to avoid severe immune-related adverse effects, especially autoimmune diseases. This model may predict the ICI efficacy, facilitating the identification of patients who may benefit from ICIs.

Abstract Background Therapeutic antibodies targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis induce potent and durable anti-tumor responses in multiple types of cancers. However, only a subset of patients benefits from anti-PD-1/PD-L1 therapies. As a negative regulator of anti-tumor immunity, TGF-β impairs the efficacy of anti-PD-1/PD-L1 and induces drug resistance. Developing a novel treatment strategy to simultaneously block PD-1/PD-L1 and TGF-β would be valuable to enhance the effect of anti-PD-1/PD-L1 and relieve drug resistance. Methods Based on the Check-BODY™ technology platform, we developed an anti-TGF-β/PD-L1 bispecific antibody YM101. The bioactivity of the anti-TGF-β moiety was determined by Smad-luciferase reporter assay, transwell assay, western blotting, CCK-8, and flow cytometry. The bioactivity of the anti-PD-L1 moiety was measured by T cell activation assays. EMT-6, CT26, and 3LL tumor models were used to investigate the anti-tumor activity of YM101 in vivo. RNA-seq, immunohistochemical staining, and flow cytometry were utilized to analyze the effect of YM101 on the tumor microenvironment. Results YM101 could bind to TGF-β and PD-L1 specifically. In vitro experiments showed that YM101 effectively counteracted the biological effects of TGF-β and PD-1/PD-L1 pathway, including activating Smad signaling, inducing epithelial-mesenchymal transition, and immunosuppression. Besides, in vivo experiments indicated the anti-tumor activity of YM101 was superior to anti-TGF-β and anti-PD-L1 monotherapies. Mechanistically, YM101 promoted the formation of ‘hot tumor’: increasing the numbers of tumor infiltrating lymphocytes and dendritic cells, elevating the ratio of M1/M2, and enhancing cytokine production in T cells. This normalized tumor immune microenvironment and enhanced anti-tumor immune response might contribute to the robust anti-tumor effect of YM101. Conclusion Our results demonstrated that YM101 could simultaneously block TGF-β and PD-L1 pathways and had a superior anti-tumor effect compared to the monotherapies.

Abstract Background Increasing evidence shows that endothelial apoptosis contributes to cigarette smoke (CS)-induced disease progression, such as chronic obstructive pulmonary disease (COPD). Our previous studies have validated Notch1 as an anti-apoptotic signaling in CS-induced endothelial apoptosis. Resveratrol (RESV) is a naturally occurring polyphenol that exhibits an anti-apoptotic activity in endothelial cells that exposed to many kinds of destructive stimulus. However, the effects of resveratrol on Notch1 signaling in CS-induced endothelial apoptosis have not yet been fully elucidated. Therefore, the aim of this study was to examine whether RESV can protect endothelial cells from CS-induced apoptosis via regulating Notch1 signaling. Methods Human umbilical vein endothelial cells (HUVECs) were pretreated with RESV for 2 h, followed by cotreatment with 2.5%CSE for 24 h to explore the role of RESV in CSE induced endothelial apoptosis. 3-methyladenine (3-MA) or rapamycin was used to alter autophagic levels. Lentivirus Notch1 intracellular domain (LV-N1ICD), γ-secretase inhibitor (DAPT) and Notch1 siRNA were used to change Notch1 expression. The expression of Notch1, autophagic and apoptotic markers were examined by Western blot and the apoptosis rate was detected by Flow cytometry analysis. Results Our results showed that activating autophagy reduced CSE-induced endothelial apoptosis, while blocking autophagy promoted cell apoptosis in HUVECs. RESV pretreatment attenuated the CSE-induced endothelial apoptosis and activated Notch1 signaling. RESV pretreatment also increased LC3b-II and Beclin1 production, decreased p62 and mTOR expression. 3-MA treatment inhibited autophagy and aggravated CSE induced apoptosis, while rapamycin promoted autophagy, led to a decrease in cell apoptosis. LV-N1ICD transfection upregulated autophagy and reduced apoptosis. However, this protective effect was abolished by 3-MA treatment. In cells treated with DAPT or Notch1 siRNA, autophagy was decreased, while apoptosis was increased. RESV partly rescued the DAPT or Notch1 siRNA induced apoptosis by activating Notch1 signaling. Conclusion In HUVECs, RESV attenuates CSE induced endothelial apoptosis by inducing autophagy in a Notch1-dependent manner.

Abstract During malignant transformation, accumulated somatic mutations endow cancer cells with increased invasiveness and immunogenicity. Under selective pressure, these highly immunogenic cancer cells develop multiple strategies to evade immune attack. It has been well established that cancer cells could downregulate the expression of major histocompatibility complex, acquire alterations in interferon pathway, and upregulate the activities of immune checkpoint pathways. Besides, cancer cells secret numerous cytokines, exosomes, and microvesicles to regulate the functions and abundances of components in the tumor microenvironment including immune effector cells and professional antigen presentation cells. As the vital determinant of post-transcriptional regulation, microRNAs (miRNAs) not only participate in cancer initiation and progression but also regulate anti-cancer immune response. For instance, some miRNAs affect cancer immune surveillance and immune escape by interfering the expression of immune attack-associated molecules. A growing body of evidence indicated that cancer-derived immune modulatory miRNAs might be promising targets to counteract cancer immune escape. In this review, we summarized the role of some miRNAs in cancer immune escape and discussed their potential clinical application as treatment targets.

Oral reference dose (RfD) is a key parameter for deriving the human health ambient water quality criteria (AWQC) for non-carcinogenic substances. In this study, a non-experimental approach was used to calculate the RfD values, which explore the potential correlation between toxicity and physicochemical characteristics and the chemical structure of pesticides. The molecular descriptors of contaminants were calculated using T.E.S.T software from EPA, and a prediction model was developed using a stepwise multiple linear regression (MLR) approaches. Approximately 95% and 85% of the data points differ by less than 10-fold and 5-fold between predicted values and true values, respectively, which improves the efficiency of RfD calculation. The model prediction values have certain reference values in the absence of experimental data, which is beneficial to the advancement of contaminant health risk assessment. In addition, using the prediction model constructed in this manuscript, the RfD values of two pesticide substances in the list of priority pollutants are calculated to derive human health water quality criteria. Furthermore, an initial assessment of the health risk was performed by the quotient value method based on the human health water quality criteria calculated by the prediction model.

AimsThe renin-angiotensin system (RAS) is over-activated and the serum angiotensin II (Ang II) level increased in obese patients, while their correlations were incompletely understood. This study aims to explore the role of Ang II in diet-induced obesity by focusing on adipose lipid anabolism and catabolism.MethodsRat model of AT1aR gene knockout were established to investigate the special role of Ang II on adipose lipid metabolism. Wild-type (WT) and AT1aR gene knockout (AT1aR-/-) SD rats were fed with normal diet or high-fat diet for 12 weeks. Adipose morphology and adipose lipid synthesis and lipolysis were examined.ResultsAT1aR deficiency activated lipolysis-related enzymes and increased the levels of NEFAs and glycerol released from adipose tissue in high-fat diet rats, while did not affect triglycerides synthesis. Besides, AT1aR knockout promoted energy expenditure and fatty acids oxidation in adipose tissue. cAMP levels and PKA phosphorylation in the adipose tissue were significantly increased in AT1aR-/- rats fed with high-fat. Activated PKA could promote adipose lipolysis and thus improved adipose histomorphology and insulin sensitivity in high-fat diet rats.ConclusionsAT1aR deficiency alleviated adipocyte hypertrophy in high-fat diet rats by promoting adipose lipolysis probably via cAMP/PKA pathway, and thereby delayed the onset of obesity and related metabolic diseases.

Objective. To detect EGFR/KRAS genes in pleural effusion cell-free DNA in patients with advanced non-small-cell lung cancer (NSCLC) and to explore the clinical significance of EGFR/KRAS mutation status in pleural effusion. Methods. A retrospective collection was performed on the specimens of pleural effusion and matched tissues from 50 patients with advanced NSCLC admitted to the hospital between January 2019 and January 2021. DNA mutation status of EGFR/KRAS in different specimens was detected and compared by pyrosequencing. The clinicopathological data and follow-up data of survival were collected. The relationship between DNA mutation and clinicopathological characteristics and prognosis was analyzed. Results. In the 50 pleural effusion specimens, there were 22 cases (44.00%) with EGFR mutations (19/21 exon mutations), including 12 cases with EGFR19 deletion mutation and 10 cases with EGFR21 exon L858R mutation. There were 6 cases (12.00%) with KRAS mutations (single-base substitution mutations), including 4 cases with 12-codon mutation and 2 cases with 13-codon mutation. In the 50 tissue specimens, there were 24 cases (48.00%) with EGFR mutations and 4 cases (8.00%) with KRAS mutations. There was no significant difference between pleural effusion specimens and tissue specimens, with good consistency (kappa = 0.920–0.779, P>0.05). EGFR mutation in pleural effusion was related to smoking history, types of pathological tissues, and lymph node metastasis (P

C10H6Cl3NO, monoclinic, P21/n (no. 14), a = 9.7097(10) Å, b = 10.6037(11) Å, c = 10.1735(10) Å, β = 96.580(4)°, V = 1040.55(18) Å3, Z = 4, Rgt(F) = 0.0214, wRref(F2) = 0.0574, T = 101 K.

Air pollution has become a major health risk in China. Here Zhang et al. report that maternal and neonatal exposure to particulate matter increases the risk of neonatal jaundice based on the study of 25,782 newborns born in China between 2014 and 2017.