Non-IL-2-blocking anti-CD25 antibody inhibits tumor growth by depleting Tregs and has synergistic effects with anti-CTLA-4 therapy.

CD25, also known as the interleukin-2 receptor α chain (IL-2Rα), is highly expressed on regulatory T cells (Tregs), but relatively lower on effector T cells (Teffs). This makes it a potential target for Treg depletion, which can be used in tumor immunotherapy. However, marketed anti-CD25 antibodies (Basiliximab and Daclizumab) were originally developed as immunosuppressive drugs to prevent graft rejection, because these antibodies can block IL-2 binding to CD25 on Teffs, which in turn destroys the function of Teffs. Recent studies have shown that non-IL-2-blocking anti-CD25 antibodies have displayed exciting antitumor effects. Here, we screened out a non-IL-2-blocking anti-CD25 monoclonal antibody (mAb) 7B7 by hybridoma technology, and confirmed its antitumor activity via depleting Tregs in a CD25 humanized mouse model. Subsequently, we verified that the humanized 7B7, named as h7B7-15S, has comparable activities to 7B7, and that its Treg depletion is further increased when combined with anti-CTLA-4, leading to enhanced remodeling of the tumor immune microenvironment. Moreover, our findings reveal that the Fab form of h7B7-15S has the ability to deplete Tregs, independent of the Fc region. Taken together, our studies expand the application of anti-CD25 in tumor immunotherapy and provide insight into the underlying mechanism.

Age-varying associations of parent-adolescent relationship and school connectedness with adolescent self-compassion: Differences by gender.

INTRODUCTION: Parent-adolescent relationships and school connectedness are critical promotive factors for adolescent self-compassion. However, little is known about how the magnitude of the associations between these protective factors and self-compassion changes across continuous age groups and whether gender differences exist in the age-varying associations. This study aims to investigate (1) the age-varying associations of parent-adolescent relationships and school connectedness with self-compassion using time-varying effect modeling and (2) how their age-varying associations may differ by gender. METHODS: A total of 14,776 adolescents aged 10-18 (mean age = 13.53 ± 2.08, 52.3% males) from Shenzhen, China participated in this study. All adolescents completed the online questionnaires in the school computer rooms. RESULTS: The results showed that both parent-adolescent relationships and school connectedness were positively associated with adolescent self-compassion, and the magnitudes fluctuated with age. Specifically, the association between parent-adolescent relationships and self-compassion peaked for adolescents in early adolescence, with the key timing for girls (age group of 10 years old) being slightly earlier than boys (age group of 11 years old). The association between school connectedness and self-compassion was stronger for boys in the early years of adolescence (in the age group of 12.7 years), while stronger for girls during middle adolescence (in the age group of 14.0 years). Overall, girls were more sensitive to connections with parents and schools than boys during most age groups. CONCLUSIONS: The findings demonstrated differential key timing for boys and girls regarding family- and school-based intervention to cultivate self-compassion and highlighted the importance of maintaining strong connections with families and schools for cultivating adolescent self-compassion, particularly for girls.

Palmitoleic acid-rich oleaginous yeast Scheffersomyces segobiensis DSM 27193 exerts anti-obesity effects by ameliorating hepatic steatosis and adipose tissue hypertrophy.

BACKGROUND: Yeast biomass, encompassing fatty acids, terpenoids, vitamins, antioxidants, enzymes, and other bioactive compounds have been extensively utilized in food-related fields. The safety and potential bioactivities of Scheffersomyces segobiensis DSM 27193, an oleaginous yeast strain, are unclear. RESULTS: Scheffersomyces segobiensis DSM 27193 accumulated large palmitoleic acid (POA) levels (43.4 g kg-1 biomass) according to the results of whole-cell components. We annotated the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and predicted the categories and host of the pathogen-host interactions (PHI) genes in S. segobiensis DSM 27193. However, S. segobiensis DSM 27193 did not exert toxic effects in mice. Administration of S. segobiensis DSM 27193 led to substantial weight reduction by diminishing food intake in an obesity mouse model. Additionally, it reversed hepatic steatosis and adipose tissue hypertrophy, and improved abnormalities in serum biochemical profiles such as triglyceride, total cholesterol, low-density lipoprotein cholesterol, lipopolysaccharide, tumor necrosis factor-α, interleukin-1ß, and interleukin-6. CONCLUSION: This study is the first to illustrate the safety and effects of S. segobiensis DSM 27193 against obesity and offers a scientific rationale for its application in functional food supplements. © 2023 Society of Chemical Industry.

CD25: A potential tumor therapeutic target.

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.

A critical review of Fuzhuan brick tea: processing, chemical constituents, health benefits and potential risk.

Fuzhuan brick tea (FBT) is a traditional popular beverage in the border regions of China. Nowadays, FBT has been attracted great attention due to its uniquely flavor and various health-promoting functions. An increasing number of efforts have been devoted to the studies on health benefits and chemistry of FBT over the last decades. However, FBT was still received much less attention than green tea, oolong tea and black tea. Therefore, it is necessary to review the current encouraging findings about processing, microorganisms, chemical constituents, health benefits and potential risk of FBT. The fungus fermentation is the key stage for processing of FBT, which is involved in a complex and unique microbial fermentation process. The fungal community in FBT is mainly dominated by "golden flower" fungi, which is identified as Aspergillus cristatus. A great diversity of novel compounds is formed and identified after a series of biochemical reactions during the fermentation process of FBT. FBT shows various biological activities, such as antioxidant, anti-inflammatory, anti-obesity, anti-bacterial, and anti-tumor activities. Furthermore, the potential risk of FBT was also discussed. It is expected that this review could be useful for stimulating further research of FBT.

Distributed Code for Semantic Relations Predicts Neural Similarity during Analogical Reasoning.

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.

A unified psychological space for human perception of physical and social events.

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.

Infant perception of sex differences in biological motion displays.

We examined mechanisms underlying infants' ability to categorize human biological motion stimuli from sex-typed walk motions, focusing on how visual attention to dynamic information in point-light displays (PLDs) contributes to infants' social category formation. We tested for categorization of PLDs produced by women and men by habituating infants to a series of female or male walk motions and then recording posthabituation preferences for new PLDs from the familiar or novel category (Experiment 1). We also tested for intrinsic preferences for female or male walk motions (Experiment 2). We found that infant boys were better able to categorize PLDs than were girls and that male PLDs were preferred overall. Neither of these effects was found to change with development across the observed age range (∼4-18 months). We conclude that infants' categorization of walk motions in PLDs is constrained by intrinsic preferences for higher motion speeds and higher spans of motion and, relatedly, by differences in walk motions produced by men and women.

Causal Action: A Fundamental Constraint on Perception and Inference About Body Movements.

The human body navigates the environment via locomotory movements that leverage gravity and limb biomechanics to propel the body in a particular direction. This process creates a causal link between limb movements and whole-body translation. However, it is unknown whether humans use this causal relation as a constraint in perception and inference with body movements. In the present study, participants rated actions of other individuals as more natural when limb movements (as a cause) occurred before body displacements (as an effect) than when limb movements temporally lagged behind body displacements. This causal expectation for human body movements not only affected perceptual impressions regarding the naturalness of observed actions but also guided the interpretation of motion cues within a more generalized causal context. We interpret these results within a framework of causality as evidence that the constraint of causal action plays an important role in perception and inference with body movements.

Spatial summation revealed in the earliest visual evoked component C1 and the effect of attention on its linearity.

In natural scenes, multiple objects are usually presented simultaneously. How do specific areas of the brain respond to multiple objects based on their responses to each individual object? Previous functional magnetic resonance imaging (fMRI) studies have shown that the activity induced by a multiobject stimulus in the primary visual cortex (V1) can be predicted by the linear or nonlinear sum of the activities induced by its component objects. However, there has been little evidence from electroencephelogram (EEG) studies so far. Here we explored how V1 responded to multiple objects by comparing the EEG signals evoked by a three-grating stimulus with those evoked by its two components (the central grating and 2 flanking gratings). We focused on the earliest visual component C1 (onset latency of ∼50 ms) because it has been shown to reflect the feedforward responses of neurons in V1. We found that when the stimulus was unattended, the amplitude of the C1 evoked by the three-grating stimulus roughly equaled the sum of the amplitudes of the C1s evoked by its two components, regardless of the distances between these gratings. When the stimulus was attended, this linear spatial summation existed only when the three gratings were far apart from each other. When the three gratings were close to each other, the spatial summation became compressed. These results suggest that the earliest visual responses in V1 follow a linear summation rule when attention is not involved and that attention can affect the earliest interactions between multiple objects.

Attention-dependent early cortical suppression contributes to crowding.

Crowding, the identification difficulty for a target in the presence of nearby flankers, is ubiquitous in spatial vision and is considered a bottleneck of object recognition and visual awareness. Despite its significance, the neural mechanisms of crowding are still unclear. Here, we performed event-related potential and fMRI experiments to measure the cortical interaction between the target and flankers in human subjects. We found that the magnitude of the crowding effect was closely associated with an early suppressive cortical interaction. The cortical suppression was reflected in the earliest event-related potential component (C1), which originated in V1, and in the BOLD signal in V1, but not other higher cortical areas. Intriguingly, spatial attention played a critical role in the manifestation of the suppression. These findings provide direct and converging evidence that attention-dependent V1 suppression contributes to crowding at a very early stage of visual processing.

Psychodynamic profiles of major depressive disorder and generalized anxiety disorder in China.

Traditional clinical diagnoses relying on symptoms may overlook latent factors that illuminate mechanisms and potentially guide treatment. The Operationalized Psychodynamic Diagnosis (OPD) system may compensate for symptom-based diagnosis by measuring psychodynamic profiles underlying mental disorders through conflicts and structure axes. However, OPD has not been widely adopted in China, and it remains unclear whether OPD can be used as an effective approach to distinguish between depression and anxiety. The current study aims to adopt the OPD system to investigate the psychodynamic profiles of major depressive disorder (MDD) and generalized anxiety disorder (GAD) in China, targeting patients with "pure" symptoms without comorbidity. We recruited 42 MDD patients, 32 GAD patients, and 31 healthy controls (HC), and assessed their self-report depression and anxiety symptoms, along with their underlying psychodynamic profiles through OPD interviews. Overall, both MDD and GAD patients showed more prominent conflict issues and lower levels of structure than HC. The MDD and GAD groups yielded different conflict profiles and conflict processing modes when processing their second conflicts. Importantly, the multi-dimensional psychodynamic profiles achieved machine learning classification of clinical groups with an accuracy of 0.84, supporting successful distinction of MDD and GAD patients. In conclusion, the OPD demonstrated sensitivity in revealing distinct psychodynamic profiles underlying "pure" depression and anxiety clinical populations in China. This work calls for future incorporation of OPD as a tool to investigate psychodynamic formulations underlying mental disorders, compensating for traditional symptom-based diagnostic approaches to guide precise individualized interventions.

RNAi silencing CHS1 gene shortens the mortality time of Plutella xylostella feeding Bt-transgenic Brassica napus.

BACKGROUND: Insect-resistance genetically modified (GM) plants derived from Bacillus thuringiensis (Bt) have been cultivated to control pests, but continuous cultivation of Bt-transgenic plants at large-scale regions leads to the resistance evolution of target insects to transgenic plants. RNA interference (RNAi) technology is considered an effective strategy in delaying the resistance evolution of target insects. RESULTS: We here developed a single transgenic oilseed rape (Brassica napus) line with hairpin RNA of the chitin-synthase 1 gene (CHS1) of Plutella xylostella (hpPxCHS1) and a pyramid transgenic B. napus line harboring hpPxCHS1 and Bt gene (Cry1Ac). Escherichia coli HT115 delivered hpPxCHS1 showed negative effects on the growth of P. xylostella. The single transgenic and pyramid transgenic B. napus significantly reduced the larval weight and length of P. xylostella and increased its lethality rate, with down-regulation expression of the PxCHS1 gene in insects. CONCLUSION: Compared to Bt-transgenic B. napus, pyramid-transgenic B. napus shorted the mortality time of P. xylostella, indicating that RNAi technology synergistic with Bt protein improves the effectiveness of controlling target insects. Our results proved that RNAi can delay the resistance evolution of target insects to Bt-transgenic plants. © 2024 Society of Chemical Industry.

Simulated gastrointestinal digestion of two different sources of biodegradable microplastics and the influence on gut microbiota.

Biodegradable plastics, were considered environmentally friendly, may produce more microplastic particles (MPs) within the same period and exert more pronounced adverse effects on human health than traditional non-biodegradable plastics. Thus, this study investigated the changes of two kinds of biodegradable MPs from different sources in the digestive tract by using simulated digestion and fermentation models in vitro, with particle size, scanning electron microscopy (SEM) and gel permeation chromatography (GPC) analysis, and their implications on the gut microbiota were detected by full-length bacterial 16S rRNA gene amplicon sequencing. Poly(ε-caprolactone) (PCL) MPs exhibited stability in the upper gastrointestinal tract, while poly(lactic acid) (PLA) MPs were degraded beginning in the small intestine digestion phase. Both PCL and PLA MPs were degraded and oligomerized during colonic fermentation. Furthermore, this study highlighted the disturbance of the gut microbiota induced by MPs and their oligomers. PCL and PLA MPs significantly changed the composition and reduced the α-diversity of the gut microbiota. PCL and PLA MPs exhibited the same inhibitory effects on key probiotics such as Bifidobacterium, Lactobacillus, Faecalibacterium, Limosilactobacillus, Blautia, Romboutsia, and Ruminococcus, which highlighted the potential hazards of these materials for human health. In conclusion, this study illuminated the potential biodegradation of MPs through gastrointestinal digestion and the complex interplay between MPs and the gut microbiota. The degradable characteristic of biodegradable plastics may cause more MPs and greater harm to human health.

Patterns of saliency and semantic features distinguish gaze of expert and novice viewers of surveillance footage.

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. Experienced forensic examiners - Closed Circuit Television (CCTV) operators - have been shown to convey superior performance in identifying and predicting hostile intentions from surveillance footage than novices. However, it remains largely unknown what visual content CCTV operators actively attend to, and whether CCTV operators develop different strategies for active information seeking from what novices do. Here, we conducted computational analysis for the gaze-centered stimuli captured by experienced CCTV operators and novices' eye movements when viewing the same surveillance footage. 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 the looking behavior of CCTV operators differs from novices by actively attending to visual contents with different patterns of saliency and semantic features. Expertise in selectively utilizing 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.

Exploring the Biogenic Transformation Mechanism of Polyphenols by Lactobacillus plantarum NCU137 Fermentation and Its Enhancement of Antioxidant Properties in Wolfberry Juice.

This study investigated the transformation of polyphenols, including free and bound polyphenols during the fermentation of wolfberry juice by Lactobacillus plantarum NCU137. Results indicated that fermentation significantly increased the free polyphenols content and released bound polyphenols, enhancing the antioxidant activity. Analysis showed that there were 19 free polyphenols, mainly scopoletin, pyrogallol, and dihydroferulic acid, and 16 bound polyphenols, especially p-coumaric acid, feruloyl hexoside, and caffeic acid. A significant correlation was observed between the generation and degradation of polyphenols, and specific bound polyphenols peaked during the 24-48 h fermentation. Furthermore, reduced surface roughness and galacturonic acid content in wolfberry residue, along with increased pectinase activity, suggested substantial pectin degradation in the cell wall, which may be associated with the release of polyphenols, due to pectin serving as carriers for bound polyphenols. The fermentation also increased polyphenol oxidase and peroxidase activity, contributing to polyphenol breakdown. These findings provide insights for improving wolfberry juice production.

Anthocyanins from Lycium ruthenicum Murray Ameliorated High-Fructose Diet-Induced Neuroinflammation through the Promotion of the Integrity of the Intestinal Barrier and the Proliferation of Lactobacillus.

In the present study, we found that anthocyanins from Lycium ruthenicum Murray (ACN) potently ameliorated a high-fructose diet (HFrD)-induced neuroinflammation in mice. ACN improved the integrity of the intestinal barrier and suppressed the toll-like receptor 4 (TLR4) signaling pathway to ameliorate the neuroinflammation, which was verified by Tlr4-/- mice. Furthermore, ACN could modulate the HFrD-induced dysbiosis of gut microbiota. The fecal microbiota transplantation from ACN-induced mice was sufficient to attenuate the neuroinflammation, while the amelioration of neuroinflammation by ACN was blocked upon gut microbiota depletion. In addition, ACN-induced increment of the relative abundance of Lactobacillus might be responsible for the alleviation of the neuroinflammation, which was further confirmed in the promoting effect of ACN on the growth of Lactobacillus in vitro. Overall, these results provided the evidence of a comprehensive cross-talk mechanism between ACN and neuroinflammation in HFrD-fed mice, which was mediated by reducing gut microbiota dysbiosis and maintaining the intestinal barrier integrity.

Broadening the scope: Multiple functional connectivity networks underlying threat and safety signaling.

Introduction: Threat learning and extinction processes are thought to be foundational to anxiety and fear-related disorders. However, the study of these processes in the human brain has largely focused on a priori regions of interest, owing partly to the ease of translating between these regions in human and non-human animals. Moving beyond analyzing focal regions of interest to whole-brain dynamics during threat learning is essential for understanding the neuropathology of fear-related disorders in humans. Methods: 223 participants completed a 2-day Pavlovian threat conditioning paradigm while undergoing fMRI. Participants completed threat acquisition and extinction. Extinction recall was assessed 48 hours later. Using a data-driven group independent component analysis (ICA), we examined large-scale functional connectivity networks during each phase of threat conditioning. Connectivity networks were tested to see how they responded to conditional stimuli during early and late phases of threat acquisition and extinction and during early trials of extinction recall. Results: A network overlapping with the default mode network involving hippocampus, vmPFC, and posterior cingulate was implicated in threat acquisition and extinction. Another network overlapping with the salience network involving dACC, mPFC, and inferior frontal gyrus was implicated in threat acquisition and extinction recall. Other networks overlapping with parts of the salience, somatomotor, visual, and fronto-parietal networks were involved in the acquisition or extinction of learned threat responses. Conclusions: These findings help confirm previous investigations of specific brain regions in a model-free fashion and introduce new findings of spatially independent networks during threat and safety learning. Rather than being a single process in a core network of regions, threat learning involves multiple brain networks operating in parallel coordinating different functions at different timescales. Understanding the nature and interplay of these dynamics will be critical for comprehensive understanding of the multiple processes that may be at play in the neuropathology of anxiety and fear-related disorders.

Effects of long-term administration of theasinensin A on healthy C57BL/6J mice: Enhancing the function of epididymal white adipose tissue and regulating the colonic microenvironment.

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.

Intracellular Polysaccharides of Aspergillus cristatus from Fuzhuan Brick Tea Leverage the Gut Microbiota and Repair the Intestinal Barrier to Ameliorate DSS-Induced Colitis in Mice.

The intracellular polysaccharides of Aspergillus cristatus (IPSs) from Fuzhuan brick tea have been demonstrated to improve immune function linked to modulating the gut microbiota. Herein, to further investigate the efficacy of IPSs to maintain gut homeostasis, the protection of the purified fraction of IPSs (IPSs-2) on the mice with colitis induced by dextran sulfate sodium (DSS) and the underlying mechanisms were explored in this study. The results revealed that IPSs-2 alleviated the typical symptoms of colitis and suppressed the excessive inflammatory mediators, regulating the genes related to inflammatory responses in the colon at the mRNA level. Meanwhile, IPSs-2 treatment reinforced the intestinal barrier function by ameliorating the DSS-induced histological injury, facilitating the differentiation of goblet cells to enhance Mucin-2 generation, and enhancing the expression of tight junction proteins to alleviate colitis. In addition, IPSs protected against colitis by promoting the production of short-chain fatty acids (SCFAs), the activation of SCFAs receptors, and the leverage of the gut microbiota via the enrichment of Bacteroides, Parabacteroides, Faecalibacterium, Flavonifractor_plautii, and Butyricicoccus, linking with reducing inflammation and repairing intestinal barrier function. Overall, our research revealed the therapeutic potential of IPSs-2 as a prebiotic for attenuating inflammatory bowel disease and provided a rationale for future investigation.