Search

CD25 is the alpha-chain of the heterotrimer IL-2 receptor. CD25 is expressed on the surface of both immune and non-immune cells with different frequencies. For cancers, CD25 is expressed at high levels in many types of hematological malignancies, but at low levels in most solid tumors. CD25 is also highly expressed in activated circulating immune cells and regulatory T cells (Tregs). Infiltration of Tregs in the tumor microenvironment can lead to an imbalanced ratio of effector T cells (Teffs) and Tregs, which is associated with the progression of cancers. A rescued Teff/Treg cell ratio indicates an efficient anti-tumor response to immunotherapy. CD25 as a potential target for the depletion of Tregs is critical in developing new immunotherapeutic strategies. Few articles have summarized the relationships between CD25 and tumors, or the recent progress of drugs targeting CD25. In this paper, we will discuss the structures of IL-2 and IL-2R, the biological function of CD25 and its important role in tumor therapy. In addition, the latest research on drugs targeting CD25 has been summarized, providing guidance for future drug development.

Background: owing to high heterogeneity and comorbidity, the shared and unique neural mechanisms underlying the development of anxiety and major depressive disorders remain unclear. Using a dimensional model describing shared versus unique symptoms associated with anxiety and depression, this study investigated how longitudinal changes in symptom dimensions relate to threat neurocircuitry. Methods: participants were 18- to 19-year-olds (N = 279, 186 females) who completed self-report measures of anxiety and depression at baseline and at 10, 20, and 30 months. Linear slopes of symptom dimensions of general distress, fear, and anhedonia-apprehension were estimated through a trilevel factorial model. In addition, functional magnetic resonance imaging scans were obtained while participants performed Pavlovian fear conditioning tasks at baseline and 30 months, including three phases of fear acquisition, extinction, and extinction recall. Neural responses in regions of interest related to threat neural circuitry (e.g., amygdala, ventromedial prefrontal cortex, and subgenual anterior cingulate cortex) were extracted. Results: linear mixed models used to estimate relationships between changes of symptom dimensions and neural responses revealed two major findings: 1) greater neural responses to threatening stimuli during fear acquisition at baseline were associated with a greater increase in fear symptoms during the 30-month prospective period; and 2) elevated neural responses to the extinguished stimulus during extinction recall at 30 months were negatively associated with changes in general distress, suggesting that greater increases in general distress are associated with larger deficits in extinction memory. Conclusions: these findings improve our understanding of pathophysiological pathways underlying the development of anxiety and depression, while separating symptom dimensions that are shared versus unique between the two disorders.

There is growing evidence that prevention of metabolic syndrome (MS) by dietary fibers is intricately linked to gut microbiota. In the present work, the mice were fed a high-fat diet (HFD) and orally treated with yeast β-glucan to further examine the effects of β-glucan on MS and gut microbiota and the potential relationship between gut microbiota and its activity. After intervention for 10 weeks, it was found that the treatment of yeast β-glucan could significantly improve the HFD-induced MS. Furthermore, pro-inflammatory cytokines in plasma including IL-6 and IL-1β were decreased. Yeast β-glucan could regulate the diversity and composition of HFD-induced gut microbiota. Moreover, the relative abundances of Lactobacillus and Lactococcus, having significant positive correlation with metabolic changes, were decreased by β-glucan, which might play a critical role in attenuation of MS. Our findings suggest that yeast β-glucan shows promising application as a prebiotic for preventing MS and regulating gut microbiota.

A novel series of hybrid molecules combining pyrrolobenzodiazepine (PBD) and anthracenecarboxyimide pharmacophores were designed, synthesized, and tested for

Background: Fluoride, a necessary mineral element for our health, is widely presented in drinking water and foods. The intake of excessive fluoride showed potential risk to human health. A strong relation between fluoride exposure and obesity has been reported. However, the knowledge on the potential mechanisms on fluoride-induced obesity is still limited.Results: In this work, we showed here that fluoride alone did not induce obesity in normal diet fed mice, whereas, it could trigger exacerbation of obesity in high-fat diet (HFD) fed mice. Fluoride impaired intestinal barrier and activated Toll-like receptor 4 (TLR4) signaling to induce obesity, which was further verified in TLR4-/- mice. Furthermore, fluoride could deteriorate the gut microbiota in HFD mice. The fecal microbiota transplantation from fluoride-induced mice was sufficient to induce obesity, while the exacerbation of obesity by fluoride was blocked upon gut microbiota depletion. The fluoride-induced bloom of Erysipelatoclostridium ramosum belonged to Erysipelotrichaceae was responsible for exacerbation of obesity. In addition, a potential strategy for prevention of fluoride-induced obesity was proposed by intervention with polysaccharides from Fuzhuan brick tea.Conclusions: Overall, these results provide the first evidence of a comprehensive cross-talk mechanism between fluoride and obesity in HFD fed mice, which is mediated by gut microbiota and intestinal barrier. E. ramosum was identified as a crucial mediator of fluoride induced obesity, which could be explored as potential target for prevention and treatment of obesity with exciting translational value.

The ability to generate and process semantic relations is central to many aspects of human cognition. Theorists have long debated whether such relations are coarsely coded as links in a semantic network or finely coded as distributed patterns over some core set of abstract relations. The form and content of the conceptual and neural representations of semantic relations are yet to be empirically established. Using sequential presentation of verbal analogies, we compared neural activities in making analogy judgments with predictions derived from alternative computational models of relational dissimilarity to adjudicate among rival accounts of how semantic relations are coded and compared in the brain. We found that a frontoparietal network encodes the three relation types included in the design. A computational model based on semantic relations coded as distributed representations over a pool of abstract relations predicted neural activities for individual relations within the left superior parietal cortex and for second-order comparisons of relations within a broader left-lateralized network.

The effects of theasinensin A (TSA) on healthy C57BL/6J mice were investigated. Results showed that long-term administration of 100 mg/kg body weight/day TSA might be non-toxic to healthy mice based on the unaltered basal biochemical indicators related to glucose and lipid metabolism, inflammatory factors and hepatic injury. On the contrary, TSA stimulated the rate of lipid turnover and browning of white adipose tissues, accelerated the adipocytic energy mobilization, and then reduced the white adipocytic size, ultimately enhancing resistance to obesity in healthy mice. Furthermore, TSA not only up-regulated the expression of mucin, tight junction protein, and short-chain fatty acids receptor, but also regulated the intestinal microbiota by enhancing the typical beneficial microbe Akkermansia muciniphila, thereby modulating the colonic microenvironment. These results suggested that TSA had a potential strengthening effect on the resistance of healthy mice to metabolic disorders, which provides a theoretical basis for the utilization of TSA.

Sialylated immunoglobulin G (IgG) is an important immunoglobulin in breast milk, but its effect on adult gut microbiota is not yet clear due to digestion by pepsin. Based on our previous IgG protecting study, effects of sialylated IgG on gut microbiota were investigated by in vitro anaerobic fermentation in the present study. It was found that the addition of sialylated IgG could significantly promote the growth of Bifidobacterium. Meanwhile, three bifidobacterial species B. bifidum CCX 19061, Bembidion breve CCX 19041, and B. longum subsp. infantis CCX 19042 were isolated. Furthermore, B. breve CCX 19041 and B. longum subsp. infantis CCX 19042 showed co-culture growth property with B. bifidum CCX 19061 in a sialylated IgG-based medium, which was also supported by changes of free monosaccharides and N-glycan structure. These findings suggest that the increase of Bifidobacterium in vitro fermentation is attributed to the commensal relationship of the three bifidobacterial species by utilizing sugars released from sialylated IgG.

The modulating effect of 2-O-β-d-glucopyranosyl-l-ascorbic acid (AA-2βG), a natural derivative of ascorbic acid from the fruits of Lycium barbarum, on mice gut microbiota was investigated in the present study. It was found that AA-2βG was able to adjust the structure of mice gut microbiota, elevated the relative abundances of Verrucomicrobia, Porphyromonadaceae, Verrucomicrobiaceae, and Erysipelotrichaceae, and meanwhile reduced the relative abundances of Firmicutes, Lachnospiraceae, Rikenellaceae, Ruminococcaceae, Bdellovibrionaceae, Anaeroplasmataceae, and Peptococcaceae. Through the linear discriminant analysis effect size analysis, the key microbiota that were found to be significantly changed after long-term consumption of AA-2βG were Ruminococcaceae, Porphyromonadaceae, Lachnospiraceae, and Rikenellaceae. In addition, AA-2βG could upregulate pro-inflammatory cytokines, promote tight junctions between intestinal cells, facilitate the generation of short-chain fatty acids (SCFAs), and upregulate the mRNA expression level of SCFAs receptors, indicating that AA-2βG might promote organism health. The results demonstrated that AA-2βG might maintain organism health by modulating gut microbiota.

Background: Fluoride, a necessary mineral element for our health, is widely presented in drinking water and foods. The intake of excessive fluoride showed potential risk to human health. A strong relation between fluoride exposure and obesity has been reported. However, the knowledge on the potential mechanisms on fluoride-induced obesity is still limited.Results: In this work, we showed here that fluoride alone did not induce obesity in normal diet fed mice, whereas, it could trigger exacerbation of obesity in high-fat diet (HFD) fed mice. Fluoride impaired intestinal barrier and activated Toll-like receptor 4 (TLR4) signaling to induce obesity, which was further verified in TLR4-/- mice. Furthermore, fluoride could deteriorate the gut microbiota in HFD mice. The fecal microbiota transplantation from fluoride-induced mice was sufficient to induce obesity, while the exacerbation of obesity by fluoride was blocked upon gut microbiota depletion. The fluoride-induced bloom of Erysipelatoclostridium ramosum belonged to Erysipelotrichaceae was responsible for the exacerbation of obesity. In addition, a potential strategy for prevention of fluoride-induced obesity was proposed by intervention with polysaccharides from Fuzhuan brick tea.Conclusions: Overall, these results provide the first evidence of a comprehensive cross-talk mechanism between fluoride and obesity in HFD fed mice, which is mediated by gut microbiota and intestinal barrier. E. ramosum was identified as a crucial mediator of fluoride-induced obesity, which could be explored as potential target for prevention and treatment of obesity with exciting translational value.

When viewing the actions of others, we not only see patterns of body movements, but we also “see” the intentions and social relations of people, enabling us to understand the surrounding social environment. Previous research has shown that experienced forensic examiners—Closed Circuit Television (CCTV) operators—convey superior performance in identifying and predicting hostile intentions from surveillance footages than novices. However, it remains largely unknown what visual content CCTV operators actively attend to when viewing surveillance footage, and whether CCTV operators develop different strategies for active information seeking from what novices do. In this study, we conducted computational analysis for the gaze-centered stimuli captured by experienced CCTV operators and novices’ eye movements when they viewed the same surveillance footage. These analyses examined how low-level visual features and object-level semantic features contribute to attentive gaze patterns associated with the two groups of participants. Low-level image features were extracted by a visual saliency model, whereas object-level semantic features were extracted by a deep convolutional neural network (DCNN), AlexNet, from gaze-centered regions. We found that visual regions attended by CCTV operators versus by novices can be reliably classified by patterns of saliency features and DCNN features. Additionally, CCTV operators showed greater inter-subject correlation in attending to saliency features and DCNN features than did novices. These results suggest that the looking behavior of CCTV operators differs from novices by actively attending to different patterns of saliency and semantic features in both low-level and high-level visual processing. Expertise in selectively attending to informative features at different levels of visual hierarchy may play an important role in facilitating the efficient detection of social relationships between agents and the prediction of harmful intentions.Author SummaryImagine seeing a person walking toward another person menacingly on the street, we may instantly feel that some physical confrontation will happen in the next second. However, it remains unclear how we efficiently infer social intentions and outcomes from the observed dynamic visual input. To answer this question, CCTV experts, who have years of experience on observing social scenes and making online predictions of the action outcomes, provide a unique perspective. Here, we collected experts’ and novices’ eye movements when observing different action sequences and compared the attended visual information between groups. A saliency model was used to compare low-level visual features such as luminance and color, and a deep convolutional neural network was used to extract object-level semantic visual features. Our findings showed that experts obtained different patterns of low-level and semantic-level features in visual processing compared to novices. Thus, the expertise in selectively attending to informative features at different levels of visual hierarchy may play an important role in facilitating the efficient detection of social relationships between agents and the prediction of harmful intentions.

The purified fraction 3 of polysaccharides from Fuzhuan brick tea (FBTPS-3) could attenuate the colitis and modulate the gut microbiota. However, the relationship between anti-inflammatory effect of FBTPS-3 and the gut microbiota is still unknown. Thus, the anaerobic fermentation in vitro was used to investigate the potential mechanism. FBTPS-3 could be utilized and degraded by gut microbiota from inflammatory bowel disease (IBD) subjects. Furthermore, FBTPS-3 could modulate the composition and structure of IBD gut microbiota toward to that of healthy group. FBTPS-3 showed a superior modulated effect on IBD gut microbiota by increasing Bacteroides and decreasing Escherichia/Shigella. Furthermore, the fermentation solution rather than FBTPS-3 itself showed anti-inflammatory effects on lipopolysaccharide-treated RAW264.7 macrophages, which might be due to the metabolites such as short-chain fatty acids (SCFAs). Thus, FBTPS-3 can be expected as novel prebiotics for treatment of IBD via modulating gut microbiota, and promoting the production of SCFAs.

There is growing evidence that prevention of metabolic syndrome (MS) by dietary fibers is intricately linked to gut microbiota. In the present work, the mice were fed a high-fat diet (HFD) and orally treated with yeast β-glucan to further examine the effects of β-glucan on MS and gut microbiota and the potential relationship between gut microbiota and its activity. After intervention for 10 weeks, it was found that the treatment of yeast β-glucan could significantly improve the HFD-induced MS. Furthermore, pro-inflammatory cytokines in plasma including IL-6 and IL-1β were decreased. Yeast β-glucan could regulate the diversity and composition of HFD-induced gut microbiota. Moreover, the relative abundances of

Immune checkpoint inhibitors have achieved unprecedented success in cancer immunotherapy. However, the overall response rate to immune checkpoint inhibitor therapy for many cancers is only between 20 and 40%, and even less for colorectal cancer (CRC) patients. Thus, there is an urgent need to develop an efficient immunotherapeutic strategy for CRC. Here, we developed a novel CRC combination therapy consisting of a multiple receptor tyrosine kinase inhibitor (Foretinib) and anti-PD-1 antibody. The combination therapy significantly inhibited tumor growth in mice, led to improved tumor regression without relapse (83% for CT26 tumors and 50% for MC38 tumors) and prolonged overall survival. Mechanistically, Foretinib caused increased levels of PD-L1 via activating the JAK2-STAT1 pathway, which could improve the effectiveness of the immune checkpoint inhibitor. Moreover, the combination therapy remodeled the tumor microenvironment and enhanced anti-tumor immunity by further increasing the infiltration and improving the function of T cells, decreasing the percentage of tumor-associated macrophages (TAMs) and inhibiting their polarization toward the M2 phenotype. Furthermore, the combination therapy inhibited the metastasis of CT26-Luc tumors to the lung in BALB/c mouse by reducing proportions of regulatory T-cells, TAMs and M2 phenotype TAMs in their lungs. This study suggests that a novel combination therapy utilizing both Foretinib and anti-PD-1 antibody could be an effective combination strategy for CRC immunotherapy.

One of the great feats of human perception is the generation of quick impressions of both physical and social events based on sparse displays of motion trajectories. Here we aim to provide a unified theory that captures the interconnections between perception of physical and social events. A simulation-based approach is used to generate a variety of animations depicting rich behavioral patterns. Human experiments used these animations to reveal that perception of dynamic stimuli undergoes a gradual transition from physical to social events. A learning-based computational framework is proposed to account for human judgments. The model learns to identify latent forces by inferring a family of potential functions capturing physical laws, and value functions describing the goals of agents. The model projects new animations into a sociophysical space with two psychological dimensions: an intuitive sense of whether physical laws are violated, and an impression of whether an agent possesses intentions to perform goal-directed actions. This derived sociophysical space predicts a meaningful partition between physical and social events, as well as a gradual transition from physical to social perception. The space also predicts human judgments of whether individual objects are lifeless objects in motion, or human agents performing goal-directed actions. These results demonstrate that a theoretical unification based on physical potential functions and goal-related values can account for the human ability to form an immediate impression of physical and social events. This ability provides an important pathway from perception to higher cognition.

In this study, the effects of 2-O-β-d-glucopyranosyl-l-ascorbic acid (AA-2βG), a natural ascorbic acid derivative from the fruits of Lycium barbarum, on treating the dextran sulfate sodium (DSS)-induced colitis in mice were investigated. The results revealed that AA-2βG had palliating effects on DSS-induced inflammatory bowel disease (IBD) in terms of slowing down the trends of body weight and solid fecal mass loss, reducing colitis disease activity index, improving serum physiological and biochemical indicators, increasing colon length, blocking proinflammatory cytokines, and increasing tight junction proteins. Additionally, AA-2βG treatment could promote the production of short-chain fatty acids and modulate the composition of the gut microbiota. The key bacteria related to IBD were found to be Porphyromonadaceae, Prevotellaceae, Rikenellaceae, Parasutterella, Parabacteroides, and Clostridium. The results indicated that AA-2βG might treat IBD through the regulation of gut microbiota, suggesting that AA-2βG has the potential to be used as a dietary supplement in the treatment of IBD.

DDR1 has been identified as a cancer-associated receptor tyrosine kinase that is highly expressed in several malignancies relative to normal tissues. Clinically approved multi-kinase inhibitors, such as nilotinib, inhibit DDR1-mediated tumor growth in xenograft models, suggesting DDR1 might be a potential target for cancer treatments. Here, we employed an antibody-based strategy with a novel anti-DDR1 antibody-drug conjugate (ADC) for colon carcinoma treatment. We developed T4 H11 -DM4, an ADC targeting DDR1 which carries the tubulin inhibitor payload DM4. Immunohistochemical analysis of a tissue microarray containing 100 colon cancer specimens revealed that DDR1 was highly expressed in 81% of tumor tissues. Meanwhile, high expression of DDR1 was associated with poor survival in patients. In vitro, T4 H11 -DM4 exhibited potent anti-proliferative activity with half maximal inhibitory concentration (IC50 ) values in the nanomolar range in a panel of colon cancer cell lines. In vivo, the antitumor efficacy of T4 H11 -DM4 was evaluated in three colon cancer cell lines expressing different levels of DDR1. T4 H11 -DM4 achieved complete tumor regression at doses of 5 and 10 mg·kg-1 in HT-29 and HCT116 tumor models. Moreover, a correlation between in vivo efficacy of T4 H11 -DM4 and the levels of DDR1 expression on the cell surface was observed. Tumor cell proliferation was caused by the induction of mitotic arrest, indicating that the antitumor effect in vivo was mediated by DM4. In addition, T4 H11 -DM4 was efficacious in oxaliplatin-resistant colon cancer models. In exploratory safety studies, T4 H11 -DM4 exhibited no overt toxicities when multi-doses were administered at 10 mg·kg-1 into BALB/c nude mice or when a single dose up to 50 mg·kg-1 was administered into BALB/c mice. Overall, our findings highlight the potential of DDR1-targeted ADC and may facilitate the development of a new effective therapeutic strategy for colon cancer.

Crude polysaccharides from Coralline pilulifera (CPPS) were purified by DEAE Sepharose Fast Flow to afford four purified fractions of CPPS-1, CPPS-2, CPPS-3 and CPPS-4. The physicochemical property and digestion under simulated saliva, gastric, small intestinal conditions and fermentation of CPPS-3 were investigated in vitro. CPPS-3 was composed of glucose and galactose, its molecular weight was 716 kDa, the contents of carbohydrate, protein, uronic acid and sulfuric radical were 67.84%, 1.00%, 0.38% and 9.07%, respectively. There was no significant difference on the molecular weight and content of reducing sugars, and no monosaccharides were released after saliva, gastric and small intestine digestion, indicating that CPPS-3 could not be digested under the simulated digestion conditions. After fermentation for 24 h in vitro, the carbohydrate content was decreased to 30.76%, suggesting that CPPS-3 could be broken down and utilized by gut microbiota. Some health-promoting gut microbiota such as Bacteroides, Megamonas and Veillonella were significantly enhanced, suggesting that CPPS-3 could regulate the composition of gut microbiota. What's more, CPPS-3 could promote the productions of short-chain fatty acids (22.17 and 16.17 mmol/L at 24 h for CPPS-3 and control, respectively), which could contribute to host health. Therefore, CPPS-3 is expected to be developed as functional foods.

Multi-shelled hollow structures have attracted extensive attention due to their promising performance in many areas. To date, however, the synthesis of non-spherical hollow multilayer porous structures remains a huge challenge. In this work, we present a straightforward synthesis route for the preparation of double-shelled SnO2 cubes without any additional templates. The sensor based on as-obtained double-shelled SnO2 hollow cubes shows high sensitivity and a fast response time (1 s) to isopropanol at a low operating temperature of 180 °C. The excellent gas sensing performance of the sensor to isopropanol can be attributed to the particular construction with multilayer hollow and mesoporous shells. Significantly, the extraction strategy also provides a new way for preparing non-spherical SnO2 hollow multilayer porous structures.

Both the movements of people and inanimate objects are intimately bound up with physical causality. Furthermore, in contrast to object movements, causal relationships between limb movements controlled by humans and their body displacements uniquely reflect agency and goal-directed actions in support of social causality. To investigate the development of sensitivity to causal movements, we examined the looking behavior of infants between 9 and 18 months of age when viewing movements of humans and objects. We also investigated whether individual differences in gender and gross motor functions may impact the development of the visual preferences for causal movements. In Experiment 1, infants were presented with walking stimuli showing either normal body translation or a “moonwalk” that reversed the horizontal motion of body translations. In Experiment 2, infants were presented with unperformable actions beyond infants’ gross motor functions (i.e., long jump) either with or without ecologically valid body displacement. In Experiment 3, infants were presented with rolling movements of inanimate objects that either complied with or violated physical causality. We found that female infants showed longer looking times to normal walking stimuli than to moonwalk stimuli, but did not differ in their looking time to movements of inanimate objects and unperformable actions. In contrast, male infants did not show sensitivity to causal movement for either category. Additionally, female infants looked longer at social stimuli of human actions than male infants. Under the tested circumstances, our findings indicate that female infants have developed a sensitivity to causal consistency between limb movements and body translations of biological motion, only for actions with previous visual and motor exposures, and demonstrate a preference toward social information.

Fuzhuan brick tea (FBT), one of the unique dark teas, has various health-promoting functions. In the present study, one polysaccharide fraction, namely FBTPS-2-1, was extracted and purified from FBT, and its structure and potential immunostimulatory activity were investigated. The results showed that FBTPS-2-1,one of typical heteropolysaccharides, was mainly composed of Gal, Ara, and Glc with little molar content of Man, Rha, GalA, and GlcA in molar ratio of 46.59:22.13:13.57:8.20:6.02:2.12:1.38 and molecular weight of 748 kDa. The backbone of FBTPS-2-1 contained →4)-β-d-Galp-(1→4)-β-d-Galp-(1→, →4)-β-d-Galp-(1→4)-α-d-Glcp-(1→, →4)-α-d-Glcp-(1→4)-α-d-Glcp-(1→, →4)-α-d-Glcp-(1→4)-β-d-Galp-(1→, →3)-β-d-Galp-(1→4)-β-d-Galp-(1→, →3,6)-β-d-Galp-(1→3)-β-d-Galp-(1→ and →3,6)-β-d-Galp-(1→3,6)-β-d-Galp-(1→. The linkages of branches in FBTPS-2-1 were mainly composed of α-l-Araf-(1→3,6)-β-d-Galp-(1→, →5)-α-l-Araf-(1→3,6)-β-d-Galp-(1→, →6)-β-d-Galp-(1→3,6)-β-d-Galp-(1→, α-l-Araf-(1→3,5)-α-l-Araf-(1→, →3,5)-α-l-Araf-(1→5)-α-l-Araf-(1→, α-d-Galp-(1→3,5)-α-l-Araf-(1→ and →5)-α-l-Araf-(1→6)-β-d-Galp-(1→. Furthermore, FBTPS-2-1 could increase the phagocytosis of macrophages and promote the secretion of NO and a variety of inflammatory cytokines, including TNF-α, IL-1β, and IL-6, indicating noticeable immune enhancement activity. Thus, FBTPS-2-1 could serve as a potentially functional food to improve human health by modulating the host immunoreaction.