Solid tumours respond poorly to immune checkpoint inhibitor (ICI) therapies. One major therapeutic obstacle is the immunosuppressive tumour microenvironment (TME). Cancer-associated fibroblasts ...(CAFs) are a key component of the TME and negatively regulate antitumour T-cell response. Here, we aimed to uncover the mechanism underlying CAFs-mediated tumour immune evasion and to develop novel therapeutic strategies targeting CAFs for enhancing ICI efficacy in oesophageal squamous cell carcinoma (OSCC) and colorectal cancer (CRC).
Anti-WNT2 monoclonal antibody (mAb) was used to treat immunocompetent C57BL/6 mice bearing subcutaneously grafted mEC25 or CMT93 alone or combined with anti-programmed cell death protein 1 (PD-1), and the antitumour efficiency and immune response were assessed. CAFs-induced suppression of dendritic cell (DC)-differentiation and DC-mediated antitumour immunity were analysed by interfering with CAFs-derived WNT2, either by anti-WNT2 mAb or with short hairpin RNA-mediated knockdown. The molecular mechanism underlying CAFs-induced DC suppression was further explored by RNA-sequencing and western blot analyses.
A negative correlation between WNT2
CAFs and active CD8
T cells was detected in primary OSCC tumours. Anti-WNT2 mAb significantly restored antitumour T-cell responses within tumours and enhanced the efficacy of anti-PD-1 by increasing active DC in both mouse OSCC and CRC syngeneic tumour models. Directly interfering with CAFs-derived WNT2 restored DC differentiation and DC-mediated antitumour T-cell responses. Mechanistic analyses further demonstrated that CAFs-secreted WNT2 suppresses the DC-mediated antitumour T-cell response via the SOCS3/p-JAK2/p-STAT3 signalling cascades.
CAFs could suppress antitumour immunity through WNT2 secretion. Targeting WNT2 might enhance the ICI efficacy and represent a new anticancer immunotherapy.
A deep ensemble convolutional neural network (CNN) model to inspect printed circuit board (PCB) board dual in-line package (DIP) soldering defects with Hybrid-YOLOv2 (YOLOv2 as a foreground detector ...and ResNet-101 as a classifier) and Faster RCNN with ResNet-101 and Feature Pyramid Network (FPN) (FRRF) achieved a detection rate of 97.45% and a false alarm rate (FAR) of 20%-30% in the previous study <xref ref-type="bibr" rid="ref34">34 . However, applying the method to other production lines, environmental variations, such as lighting, orientations of the sample feeds, and mechanical deviations, led to the degradation in detection performance. This article proposes an effective self-adaption method that collects "exception data" like the samples with which the Artificial Intelligent (AI) model made mistakes from the automated optical inspection inference edge to the training server, retraining with exceptions on the server and deploying back to the edge. The proposed defect detection system has been verified with real tests that achieved a detection rate of 99.99% with an FAR 20%-30% and less than 15 s of inspection time on a resolution <inline-formula> <tex-math notation="LaTeX">7296 \times 6000 </tex-math></inline-formula> PCB image. The proposed system has proven capable of shortening inspection and repair time for online operators, where a 33% efficiency boost from the three production lines of the collaborated factory has been reported <xref ref-type="bibr" rid="ref6">6 . The contribution of the proposed retraining mechanism is threefold: 1) because the retraining process directly learns from the exceptions, the model can quickly adapt to the characteristic of each production line, leading to a fast and reliable mass deployment; 2) the proposed retraining mechanism is a necessary self-service for conventional users as it incrementally improves the detection performance without professional guidance or fine-tuning; and 3) the semiautomatic exception data collection method helps to reduce the time-consuming manual labeling during the retraining process.
Dysbiosis of gut microbiota are commonly reported in autism spectrum disorder (ASD) and may contribute to behavioral impairment. Vitamin A (VA) plays a role in regulation of gut microbiota. This ...study was performed to investigate the role of VA in the changes of gut microbiota and changes of autism functions in children with ASD.
Sixty four, aged 1 to 8 years old children with ASD completed a 6-month follow-up study with VA intervention. High-performance liquid chromatography was used to assess plasma retinol levels. The Autism Behaviour Checklist (ABC), Childhood Autism Rating Scale (CARS) and Social Responsiveness Scale (SRS) were used to assess autism symptoms. CD38 and acid-related orphan receptor alpha (RORA) mRNA levels were used to assess autism-related biochemical indicators' changes. Evaluations of plasma retinol, ABC, CARS, SRS, CD38 and RORA mRNA levels were performed before and after 6 months of intervention in the 64 children. Illumina MiSeq for 16S rRNA genes was used to compare the differences in gut microbiota before and after 6 months of treatment in the subset 20 of the 64 children. After 6 months of intervention, plasma retinol, CD38 and RORA mRNA levels significantly increased (all P < 0.05); the scores of ABC, CARS and SRS scales showed no significant differences (all P > 0.05) in the 64 children. Meanwhile, the proportion of Bacteroidetes/Bacteroidales significantly increased and the proportion of Bifidobacterium significantly decreased in the subgroup of 20 (all false discovery rate (FDR) q < 0.05).
Bacteroidetes/Bacteroidales were the key taxa related to VA. Moreover, VA played a role in the changes in autism biomarkers. It remains unclear whether the VA concentration is associated with autism symptoms.
The study protocol was peer reviewed and approved by the institutional review board of Children's Hospital, Chongqing Medical University in 2013 and retrospectively registered in Chinese Clinical Trial Registry (ChiCTR) on November 6, 2014 (TRN: ChiCTR-ROC-14005442 ).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The advantageous characteristics of invasive pests, particularly their ability to reproduce and adapt to the environment, have been observed. However, it remains unclear what specific inherent ...superiority enables fruit pests to successfully invade and dominate in interactions with other species. In this study, we report that Cydia pomonella (Linnaeus), a notorious invasive pest of pome fruits and walnuts globally, employs unique reproductive strategies in response to quercetin, a plant compound in host fruits. By monitoring adult dynamics and fruit infestation rates, we observed a competitive relationship between C. pomonella and the native species Grapholita molesta (Busck). C. pomonella was able to occupy vacant niches to ensure its population growth. We also found that quercetin had different effects on the reproductive capacity and population growth of C. pomonella and G. molesta. While quercetin stimulated the fecundity and population growth of G. molesta, it inhibited C. pomonella. However, C. pomonella was able to rapidly increase its population after exposure to quercetin by adopting an ‘accelerated burst’ of oviposition strategy, with each individual making a greater reproductive contribution compared to the control. We further demonstrated that the effect of quercetin on oviposition is regulated by the juvenile hormone (JH) signaling pathway in C. pomonella, allowing it to prioritize survival. The enhanced reproductive fitness of G. molesta in response to quercetin is attributed to the regulation of JH titers and key genes such as Met and Kr-h1, which in turn up-regulate reproduction-related genes Vg and VgR. In contrast, C. pomonella is inhibited. These findings shed light on the mechanisms interspecific competition and help to improve our understanding of the global spread of C. pomonella, which can be attributed to its inherent superiority in terms of reproductive strategy.
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•A competitive relationship between Cydia pomonella and Grapholita molesta was recorded.•C. pomonella occupies vacant niches to ensure its population development.•Quercetin stimulates fecundity of G. molesta, inhibits C. pomonella.•C. pomonella employs an accelerated burst oviposition strategy regulated by JH pathway.•Inherent superiority of reproductive strategy facilitates C. pomonella global spread.
Global warming has increased the frequency and duration of high temperature (HT) stress. Photosynthesis determines yield in maize and is extremely HT sensitive. The effects of HT on photosynthesis in ...maize leaves have been strongly examined under controlled conditions. Here, to explore the mechanism and primary inhibitory sites of HT to photosynthesis, the HT sensitivity of photosynthesis in XY335 and ZD958 maize hybrids was systematically studied in field by multiple methods. HT decreased leaf area and photosynthetic rate of unit leaf area and hence limited growth. HT disrupted chloroplast and mitochondrial membrane structure, possibly delaying photosynthetic recovery after HT. These changes were greater in XY335 than ZD958. Stomatal conductance decreased significantly under HT, and this did not restrict CO2 fixation but may weaken the heat dissipation through transpiration. HT caused photoinhibition of PSII but not PSI. HT damaged both the oxygen‐evolving complex, located at donor side of PSII, and electron transfer from QA to QB, located at acceptor side of PSII. Interference of electron transfer from QA to QB caused by degradation of QB‐binding (D1) protein was the primary site of PSII inhibition by HT in maize leaves. The different stomatal behaviour and photoinhibition sites under HT between maize and wheat were discussed.
The spontaneously hypertensive rat (SHR) is a selectively bred animal strain that is frequently used to model attention‐deficit hyperactivity disorder (ADHD) because of certain genetically determined ...behavioural characteristics. To test the hypothesis that the characteristically altered response to positive reinforcement in SHRs may be due to altered phasic dopamine response to reward, we measured phasic dopamine signals in the SHRs and Sprague Dawley (SD) rats using in vivo fast‐scan cyclic voltammetry. The effects of the dopamine reuptake inhibitor, methylphenidate, on these signals were also studied. Phasic dopamine signals during the pairing of a sensory cue with electrical stimulation of midbrain dopamine neurons were significantly smaller in the SHRs than in the SD rats. Over repeated pairings, the dopamine response to the sensory cue increased, whereas the response to the electrical stimulation of dopamine neurons decreased, similarly in both strains. However, the final amplitude of the response to the sensory cue after pairing was significantly smaller in SHRs than in the SD rats. Methylphenidate increased responses to sensory cues to a significantly greater extent in the SHRs than in the SD rats, due largely to differences in the low dose effect. At a higher dose, methylphenidate increased responses to sensory cues and electrical stimulation similarly in SHRs and SD rats. The smaller dopamine responses may explain the reduced salience of reward‐predicting cues previously reported in the SHR, whereas the action of methylphenidate on the cue response suggests a potential mechanism for the therapeutic effects of low‐dose methylphenidate in ADHD.
The rapid development of the aviation industry has brought about the deterioration of the climate, which makes airline efficiency become a hot issue of social concern. As an important nonparametric ...method, Data Envelopment Analysis (DEA), has been widely applied in efficiency evaluation. This paper examines 130 papers published in the period of 1993–2020 to summarize the literature involving the special application of DEA models in airline efficiency. The paper begins with an overall review of the existing literature, and then the radial DEA, nonradial DEA, network DEA, dynamic DEA, and DEA models with undesirable outputs applied in airline efficiency are introduced. The main advantages and disadvantages of the above models are summarized, and the drivers of airline efficiency are analyzed. Finally, the literature review ends up with future research directions and conclusions.
By mimicking natural photosynthesis, generating hydrogen through visible-light-driven splitting of water would be an almost ideal process for converting abundant solar energy into a usable fuel in an ...environmentally friendly and high-energy-density manner. In a search for efficient photocatalysts that mimic such a function, here we describe a series of cycloplatinated polymer dots (Pdots), in which the platinum complex unit is presynthesized as a comonomer and then covalently linked to a conjugated polymer backbone through Suzuki–Miyaura cross-coupling polymerization. On the basis of our design strategy, the hydrogen evolution rate (HER) of the cycloplatinated Pdots can be enhanced by 12 times in comparison to that of pristine Pdots under otherwise identical conditions. In comparison to the Pt-complex-blended counterpart Pdots, the HER of cycloplatinated Pdots is over 2 times higher than that of physically blended Pdots. Furthermore, enhancement of the photocatalytic reaction time with high eventual hydrogen production and low efficiency rolloff are observed by utilizing the cycloplatinated Pdots as photocatalysts. On the basis of their performance, our cyclometallic Pdot systems appear to be alternative types of promising photocatalysts for visible-light-driven hydrogen evolution.
Coxsackieviruses A10 (CV-A10) and A6 (CV-A6) have been associated with increasingly occurred sporadic hand-foot-mouth disease (HFMD) cases and outbreak events globally. However, our understanding of ...epidemiological and genetic characteristics of these new agents remains far from complete. This study was to explore the circulation of CV-A10 and CV-A6 in HFMD and their genetic characteristics in China. A hospital based surveillance was performed in three heavily inflicted regions with HFMD from March 2009 to August 2011. Feces samples were collected from children with clinical diagnosis of HFMD. The detection and genotyping of enteroviruses was performed by real-time PCR and sequencing of 5'UTR/VP1 regions. Phylogenetic analysis and selection pressure were performed based on the VP1 sequences. Logistic regression model was used to identify the effect of predominant enterovirus serotypes in causing severe HFMD. The results showed 92.0% of 1748 feces samples were detected positive for enterovirus, with the most frequently presented serotypes as EV-71 (944, 54.0%) and CV-A16 (451, 25.8%). CV-A10 and CV-A6 were detected as a sole pathogen in 82 (4.7%) and 44 (2.5%) cases, respectively. Infection with CV-A10 and EV-71 were independently associated with high risk of severe HFMD (OR = 2.66, 95% CI: 1.40-5.06; OR = 4.81, 95% CI: 3.07-7.53), when adjusted for age and sex. Phylogenetic analysis revealed that distinct geographic and temporal origins correlated with the gene clusters based on VP1 sequences. An overall ω value of the VP1 was 0.046 for CV-A10 and 0.047 for CV-A6, and no positively selected site was detected in VP1 of both CV-A10 and CV-A6, indicating that purifying selection shaped the evolution of CV-A10 and CV-A6. Our study demonstrates variety of enterovirus genotypes as viral pathogens in causing HFMD in China. CV-A10 and CV-A6 were co-circulating together with EV-71 and CV-A16 in recent years. CV-A10 infection might also be independently associated with severe HFMD.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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