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Abstract The occurrence of many autoimmune diseases takes root on the disrupted balance among Treg cells, Teff cells, etc. Low-dose interleukin-2 (IL-2) cytokine demonstrates promising clinical efficacy in the expansion of Treg cells and the treatment of autoimmune diseases. However, its clinical application is hindered by the small therapeutic index and short half-life. Previous studies have shown that non-covalent complex of human IL-2 and anti-IL-2 antibody biases cytokine activity towards Treg cells and extends IL-2’s half-life. The clinical translation of such complex is non-trivial. In this study, we discover an anti-human IL-2 antibody and engineer a covalently-linked single-agent fusion of human IL-2 and its antibody that selectively expands Treg cells and exhibits superior disease control activity in animal models of ulcerative colitis and systemic lupus erythematosus, with proper safety profile and good developability. These studies pave the road for its clinical development in diverse autoimmune diseases.

Mutations in CHCHD2 have been reported to be associated with familial Parkinson’s disease (PD). We generated a human induced pluripotent stem cell (hiPSC) line by reprogramming dermal fibroblasts from a PD patient harboring a novel CHCHD2 mutation (c.434G > A, p.R145Q). This line exhibited human embryonic stem cell (hESC)-like clonal morphology, expression of undifferentiated stem cell markers, a normal karyotype and trilineage differentiation capacity and thus the potential to serve as a model for further investigating the underlying molecular mechanisms of CHCHD2 function in PD.

As an important member of innate immunity, macrophages show remarkable plasticity and heterogeneity, and play an important role in immune regulation, tissue development, homeostasis of the internal environment and injury repair. However, the excessive activation of macrophages is closely related to the occurrence and development of many diseases. The prenylated flavonoid structure is one of the characteristic structures isolated from Sophora flavescens, with anti-inflammatory, anti-tumor, anti-allergy and other effects. In this study, the effects of (2R)-3β,7,4′-trihydroxy-5-methoxy-8-prenylflavanone (TMP), a prenylated dihydroflavonol, on the polarization and phagocytosis of macrophages were systematically studied. In LPS-induced M1-type macrophages, TMP dose-dependently inhibited the expression of COX-2, iNOS and the secretion of NO, IL-1β, IL-6 and IL-18, showing an inhibitory effect on M1 polarization. Further experiments revealed that it was related to the inhibition of TLR4-related AKT/mTOR, MAPK and NF-κB signaling pathways; in IL-4-induced M2-type macrophages, TMP down-regulated the expression of M2-related Arg1, IL-10, TGF-β, CD206 and CD163, as well as the phosphorylation levels of AKT1 and STAT6. For macrophages in a physiological state, it was very important for cells to return from a stress state to a phenotypic stability in the M0 state. These results indicated that TMP negatively regulated the M1/M2 polarization of macrophages, and made them tend to M0 homeostasis, which might provide new theoretical and data support for explaining the anti-inflammatory immunoregulatory activity of Sophora flavescens.

Lilium brownii F. E. Brown ex Miellez var. viridulum Baker (Longya lily) is a variety of Lilium brownii F.E. Br. ex Miellez. We used HS-SPME and GC-MS to screened the tissues of L. brownii roots, stems, bulbs, and leaves and obtained 2,4-DTBP as an autotoxic substance for subsequent analysis. 2,4-DTBP was highly autotoxic in some treatment groups. Based on changes in physiological indicators, we carried out transcriptomic analysis to investigate the mechanisms of autotoxicity of substances on L. brownii and obtained 188,505 Unigenes. GO and KEGG enrichment analyses showed that L. brownii responded differently to different concentrations and treatment times of 2,4-DTBP. We observed significant changes in genes associated with ROS, phytohormones, and MAPK signaling cascades. 2,4-DTBP affects chloroplasts, the integrity of the respiratory electron transport chain, and ribosomes, causing L. brownii autotoxicity. Our findings provide a practical genomic resource for future research on L. brownii autotoxicity and evidence for the mechanism of action of autotoxic substances.

Climate change threatens mental health via increasing exposure to the social and economic disruptions created by extreme weather and large-scale climatic events, as well as through the anxiety associated with recognising the existential threat posed by the climate crisis. Considering the growing levels of climate change awareness across the world, negative emotions like anxiety and worry about climate-related risks are a potentially pervasive conduit for the adverse impacts of climate change on mental health. In this study, we examined how negative climate-related emotions relate to sleep and mental health among a diverse non-representative sample of individuals recruited from 25 countries, as well as a Norwegian nationally-representative sample. Overall, we found that negative climate-related emotions are positively associated with insomnia symptoms and negatively related to self-rated mental health in most countries. Our findings suggest that climate-related psychological stressors are significantly linked with mental health in many countries and draw attention to the need for cross-disciplinary research aimed at achieving rigorous empirical assessments of the unique challenge posed to mental health by negative emotional responses to climate change., Author(s): Charles Adedayo Ogunbode [sup.1] [sup.2] , Ståle Pallesen [sup.3] , Gisela Böhm [sup.3] [sup.4] , Rouven Doran [sup.3] , Navjot Bhullar [sup.5] , Sibele Aquino [sup.6] , Tiago Marot [...]

To expand the single-dose duration over which noninvasive clinical and preclinical cancer imaging can be conducted with high sensitivity, and well-defined spatial and temporal resolutions, a facile strategy to prepare ultrasmall nanoparticulate X-ray contrast media (nano-XRCM) as dual-modality imaging agents for positron emission tomography (PET) and computed tomography (CT) has been established. Synthesized from controlled copolymerization of triiodobenzoyl ethyl acrylate and oligo(ethylene oxide) acrylate monomers, the amphiphilic statistical iodocopolymers (ICPs) could directly dissolve in water to afford thermodynamically stable solutions with high aqueous iodine concentrations (>140 mg iodine/mL water) and comparable viscosities to conventional small molecule XRCM. The formation of ultrasmall iodinated nanoparticles with hydrodynamic diameters of ca. 10 nm in water was confirmed by dynamic and static light scattering techniques. In a breast cancer mouse model, in vivo biodistribution studies revealed that the 64Cu-chelator-functionalized iodinated nano-XRCM exhibited extended blood residency and higher tumor accumulation compared to typical small molecule imaging agents. PET/CT imaging of tumor over 3 days showed good correlation between PET and CT signals, while CT imaging allowed continuous observation of tumor retention even after 10 days post-injection, enabling longitudinal monitoring of tumor retention for imaging or potentially therapeutic effect after a single administration of nano-XRCM.

Abstract Background As a first-line chemotherapeutic agent, 5-fluorouracil (5-FU) exhibits many side effects, weakening its efficacy in cancer treatment. In this study, we hypothesize that Poria cocos polysaccharides (PCP), a traditional Chinese herbal medicine with various bioactivities and prebiotic effects, might improve the therapeutic effect of 5-FU by restoring the homeostasis of the gut microenvironment and the commensal gut microflora. Methods Apc Min/+ mice were employed to evaluate the anti-cancer effect of 5-FU in conjunction with PCP treatment. Body weight and food consumption were monitored weekly. Polyp count was used to assess the anti-cancer effect of PCP and 5-FU. Expressions of mucosal cytokines and gut epithelial junction molecules were measured using qRT-PCR. 16S rRNA gene sequencing of fecal DNAs was used to evaluate the compositional changes of gut microbiota (GM). Transplantation of Lactobacillus johnsonii and Bifidobacterium animalis were performed to verify the prebiotic effects of PCP in improving the efficacy of 5-FU. Results The results showed that PCP treatment alleviated the weight loss caused by 5-FU treatment and reduced the polyp burden in Apc Min/+ mice. Additionally, PCP treatment eased the cytotoxic effects of 5-FU by reducing the expressions of pro-inflammatory cytokines, increasing the anti-inflammatory cytokines; and significantly improving the gut barriers by enhancing the tight junction proteins and associated adhesion molecules. Furthermore, 16S rRNA gene sequencing data showed that PCP alone or with 5-FU could stimulate the growth of probiotic bacteria (Bacteroides acidifaciens, Bacteroides intestinihominis, Butyricicoccus pullicaecorum, and the genera Lactobacillus, Bifidobacterium, Eubacterium). At the same time, it inhibited the growth of potential pathogens (e.g., Alistipes finegoldii, Alistipes massiliensis, Alistipes putredinis., Citrobacter spp., Desulfovibrio spp., and Desulfovibrio desulfuricans). Moreover, the results showed that transplantation of L.johnsonii and B.animalis effectively reduced the polyp burden in Apc Min/+ mice being treated with 5-FU. Conclusion Our study showed that PCP could effectively improve the anti-cancer effect of 5-FU by attenuating its side effects, modulating intestinal inflammation, improving the gut epithelial barrier, and modulating the gut microbiota of ApcMin/+ mice.

ObjectiveThis study aimed to investigate the diagnostic performance of volume mismatch sign on discriminating paramedial bithalamic tumors from non-tumors.MethodsIn this study, we recruited patients with tumors or non-tumors of the paramedial bithalamus. We confirmed the diagnosis by pathology, laboratory tests documented in medical records, medical imaging at the baseline, or through at least 1 year of follow-up. Cases with paramedial thalamic lesions on only one side or purely midbrain illnesses were excluded. Additionally, any case without involvement of the medial thalami (i.e., those with one or both-sided anterior, lateral, or posterior thalamic lesions) was excluded. Two neuroradiologists were trained independently to evaluate volume mismatch sign on magnetic resonance T2-weighted images or T2 fluid-attenuated inversion recovery images. A positive volume mismatch sign means that the ratio of the larger-sided lesion volume to the smaller-sided lesion volume is >150%. The volume of each lesion was calculated by multiplying the anteroposterior diameter by the left-right diameter and by the height of the lesion and then dividing by 2. The kappa value was calculated to show the consistency between the two observers. The chi-square test was used to evaluate differences in volume mismatch sign between the bilthalamic midline tumor and non-tumor groups. The positive (PPV) and negative (NPV) predictive values, sensitivity, and specificity were calculated to evaluate the ability of volume mismatch sign to differentiate paramedial bilateral thalamus tumors from non-tumors. A two-tailed P ≤ 0.05 was considered to be statistically significant. The analyses were performed using the statistical software SPSS version 26.ResultsA total of 96 patients were enrolled in this study between March 2012 and October 2022. A high agreement between the two observers on the volume mismatch sign of bilateral paramedian thalamic diseases was found, and the Kappa value was 0.828. A statistically significant difference was observed for the volume mismatch sign between the paramedial bithalamic tumor and the non-tumorous groups (χ2 = 35.465, P < 0.001). The presence of volume mismatch sign in paramedial bithalamic illnesses predicted the presence of tumors with a sensitivity and specificity of 69.2% and 90.9%, respectively, and PPV and NPV were 90.0% and 71.4%.ConclusionVolume mismatch sign may indicate tumors in paramedian bithalamic diseases.

Emerging technologies have been widely used in applications designed to increase potential for learning enhancement. This study develops a mobile application to integrate augmented reality (AR) functionality into physical puzzle-type games. In the application, learners see visualizations of three-dimensional (3D) dinosaurs and interact with relevant multimedia learning content. To evaluate the effectiveness of the proposed platform, experiments were conducted to evaluate impact on learner achievement and motivation. Experimental (AR-based) and control (paper-based) groups included a total of 53 fifth-grade students. Pre- and post-activity questionnaires (adapted from the Attention, Relevance, Confidence, Satisfaction (ARCS) Model of Motivational Design), and pre- and post-learning quizzes were used for assessment. Results showed that the AR-based group scored significantly higher (p < 0.05) than the Paper-based group, raising implications for a new approach to teaching natural science at the elementary school level. However, the AR-based group also showed a relative drop in confidence, suggesting that further investigation is needed to understand the impact of AR technology on learner motivation. This study provides a case for the integration of AR technology into typical physical games. The results raise important concerns for further research in technology enhancement in education. Future research should include a wider range of content topics and target groups.

Background Sepsis-induced acute kidney injury (S-AKI) is a common complication in critically ill patients. Therefore, reliable biomarkers for predicting S-AKI outcomes are necessary. Serum cell-free DNA (cfDNA) is a circulating extracellular DNA fragment used as a noninvasive screening tool for many diseases, including sepsis. This study aimed to investigate the prognostic value of cfDNA in S-AKI patients and its relationship with some other parameters.Methods A total of 89 S-AKI patients admitted to the intensive care unit (ICU) from June 2021 to December 2021 were enrolled in this study. The patients were categorized into the low cfDNA group (< 855 ng/ml) and high cfDNA group (≥ 855 ng/ml) and were followed up for three months. CfDNA was extracted from serum and quantified using Quant-iT PicoGreen dsDNA Reagent.Results Overall survival was significantly lower in the high cfDNA group than in the low cfDNA group (Log-Rank p = 0.012). Univariate Cox proportional hazard model showed that cfDNA was significantly associated with all-cause mortality (HR [hazard ratio] 2.505, 95% CI [95% confidence interval] 1.184–5.298, p = 0.016). Also, serum cfDNA was a significant risk factor for all-cause mortality after adjusting for covariates (HR 2.191, 95% CI 1.017–4.721, p = 0.045). Moreover, cfDNA was positively correlated with several baseline parameters, including serum creatine, aspartate aminotransferase, alanine aminotransferase, prothrombin time, and International Normalized Ratio.Conclusion High serum cfDNA level is associated with higher mortality among the S-AKI population, indicating that cfDNA is a valuable biomarker for S-AKI prognosis. [ABSTRACT FROM AUTHOR]

Hyaluronan (HA) is a mucopolysaccharide that naturally exists in all living organisms as the main component of the extracellular matrix. Over the last 30 years, HA has been used as the main ingredient in cosmetic products, eye drops, and medicinal products. It is also taken orally as a health supplement. However, the physiological effect of the ingested HA is not clear. In the current study, the interaction between HA and gut microbiota, and the potential prebiotic effects were investigated. HA was used to treat the C57BL/6 mice for 15 consecutive days, then fecal genomic DNA was extracted from fecal samples for 16S rRNA amplicon sequencing. The results showed that HA could significantly change the composition of gut microbiota (GM), e.g., increased the relative abundance of beneficial bacteria, including short-chain fatty acids (SCFAs)-producing bacteria and xylan/cellulose-degrading bacteria, whereas decreased the relative abundance of potential pathogens including sulfate-reducing bacteria (SRB), inflammation and cancer-related bacteria. The rotarod test was used to evaluate the anti-fatigue effects of HA in C57BL/6 mice. The results showed that HA could lengthen the mice's retention time on the accelerating rotarod. HA increased the concentration of glycogen and superoxide dismutase (SOD) in mice's muscle and liver, whereas decreased the serum concentration of malondialdehyde (MDA). Moreover, the metabolic products of Desulfovibrio vulgaris (MPDV), the model SRB bacteria, showed cytotoxic effects on H9c2 cardiomyocytes in a dosage-dependent manner. MPDV also caused mitochondrial damage by inducing mitochondrial fragmentation, depolarization, and powerless ATP production. Taken together, we show that HA possesses significant prebiotic and anti-fatigue effects in C57BL/6 mice.

This study combines the Nash–Cournot competition model and the stochastic optimization model to examine the impact of electric vehicle (EV) quantity fluctuations on microgrid operations, aiming to optimize energy usage in a competitive electricity market. Integrating distributed energy resources and bidirectional charging, microgrids offer a novel approach for energy optimization, aiding in renewable energy generation, peak demand management, and emission reduction. Empirical evidence highlights benefits in Taiwan's electricity market and net-zero emissions target by 2050, with a case study demonstrating enhanced local renewable energy generation due to EVs and microgrid integration. As the number of EVs increases, electricity sales from microgrids decline, but electricity purchases remain stable. The degree of electricity liberalization also influences the supply and demand dynamics of the electricity market. Microgrids selling electricity only to the main grid increases total power consumption by 65.55 million MWh, reducing the market share of the state-owned utility (Taipower). Conversely, allowing retailers to purchase from microgrids increases total consumption by 30.87 million MWh with a slight market share decrease for Taipower. This study contributes to providing an adaptable and flexible general model for future studies to modify and expand based on different scenarios and variables to shape energy and environmental policies. [ABSTRACT FROM AUTHOR]

TMP269 is a selective class IIA histone deacetylase inhibitor that has a protective effect on the central nervous system, whose specific mechanism of action is unclear. We aimed to reveal the optimal concentration of TMP269 for protecting against cerebral ischemia/reperfusion injury and its neuroprotective mechanism. Male Sprague-Dawley rats were randomly divided into sham, ischemia/reperfusion, and 1, 4, 10 and 16 mg/kg TMP269 groups. Cerebral ischemia/reperfusion injury was induced by middle cerebral artery occlusion. TMP269 was intraperitoneally administered at different doses 0.5 hours before ischemia induction. Western blot assay and immunohistochemistry were used to detect effects of TMP269 on histone 2 acetylation. The results showed that the level of histone 2 acetylation was increased 24 hours after TMP269 injection. 2,3,5-Triphenyltetrazolium chloride staining was utilized to examine effect of TMP269 on infarct volume. The results found that different doses of TMP269 could reduce the infarct volume. Western blot assay, immunohistochemistry and Evans blue staining were employed to measure the effect of TMP269 on blood-brain barrier. The results showed that TMP269 counteracted the abnormal endothelial cell permeability changes caused by cerebral ischemia/reperfusion. Western blot assay and immunohistochemistry were used to determine the effect of TMP269 on tissue kallikrein. The results found that TMP269 up-regulated the expression of tissue kallikrein. Western blot assay further determined the optimal concentration to be 4 mg/kg. In conclusion, TMP269 plays a neuroprotective role by up-regulating the level of histone 2 acetylation, alleviating endothelial cell injury after cerebral ischemia/reperfusion, and up-regulating the expression of tissue kallikrein. The experimental protocol was approved in 2014 by the Department of Laboratory Animal Science, Fudan University, China (approval No. 20140143C001).

Abstract Background Sleep is a complex and dynamic biological process characterized by different sleep patterns. Comprehensive sleep monitoring and analysis using multivariate polysomnography (PSG) records has achieved significant efforts to prevent sleep-related disorders. To alleviate the time consumption caused by manual visual inspection of PSG, automatic multivariate sleep stage classification has become an important research topic in medical and bioinformatics. Results We present a unified hybrid self-attention deep learning framework, namely HybridAtt, to automatically classify sleep stages by capturing channel and temporal correlations from multivariate PSG records. We construct a new multi-view convolutional representation module to learn channel-specific and global view features from the heterogeneous PSG inputs. The hybrid attention mechanism is designed to further fuse the multi-view features by inferring their dependencies without any additional supervision. The learned attentional representation is subsequently fed through a softmax layer to train an end-to-end deep learning model. Conclusions We empirically evaluate our proposed HybridAtt model on a benchmark PSG dataset in two feature domains, referred to as the time and frequency domains. Experimental results show that HybridAtt consistently outperforms ten baseline methods in both feature spaces, demonstrating the effectiveness of HybridAtt in the task of sleep stage classification.

Side effects of chemotherapy are burning questions for physicians and patients involved in cancers. Ganoderma lucidum is a widely consumed traditional Chinese medicine and edible mushroom with multiple functional properties. The present study aims to investigate the potential of polysaccharides from spore of G. lucidum (SGP) on small intestinal barrier function recovery against paclitaxel (PTX) challenge in a breast cancer mice model and IEC-6 cell line. The 4T1 tumor-bearing mice were treated with PTX together with four-week daily oral administration of SGP. Results indicated that combination of PTX and SGP reversed body weight lost and remolded the histology of small intestine, accompanied with promoted proliferation but suppressed apoptosis in intestinal cells. Intestinal barrier function was enhanced by the combination as indicated by reduced endotoxemia and the up-regulation of tight junction proteins, including Zonula occludens-1 (ZO-1), E-cadherin, β-catenin and Occludin. The protection of SGP was further confirmed in IEC-6 cells affected by PTX in vitro. The combination treatment prevented PTX-induced apoptosis in IEC-6 by inhibiting microtubule polymerization, and the aforementioned tight junction proteins were also upregulated. These findings suggest a promising protective effect of SGP against small intestinal barrier injury caused by PTX, highlighting its clinical implication against the chemotherapy side effects.

Increasing evidence highlights the cardinal role of gut microbiota in tumorigenesis and chemotherapy outcomes. Paclitaxel (PTX), although as a first-line chemotherapy reagent for breast cancer, still requires for improvement on its efficacy and safety due to drug resistance and adverse effects. The present work explored the enhancement of a polysaccharide derived from spore of Ganoderma lucidum (SGP) with PTX in a murine 4T1-breast cancer model. Results showed that the combination of PTX and SGP displayed an improved tumor control, in which mRNA expression of several Warburg effect-related proteins, i.e., glucose transporter 3 (Glut3), lactate dehydrogenase A (Ldha), and pyruvate dehydrogenase kinase (Pdk), and the metabolite profile of tumor was evidently altered. Flowcytometry analysis revealed that the combination treatment recovered the exhausted tumor infiltration lymphocytes (TILs) via inhibiting the expressions of immune checkpoints (PD-1 and Tim-3), while PTX alone evidently increased that of CTLA-4. 16S rRNA sequencing revealed a restoration by the combination treatment on gut microbiota dysbiosis induced by PTX, especially that Bacteroides, Ruminococcus, and other 5 genera were significantly enriched while the cancer-risk genera, Desulfovibrio and Odoribacter, were decreased. Moreover, spearman correlation analysis showed that abundance of Ruminococcus was significantly negative-associated with the amount of frucotose-6-phosphate within the tumor. Collectively, the present study suggests the clinical implication of SGP as an adjuvant candidate for PTX against breast cancer, which possibly relies on the regulation of tumor metabolism and gut microbiota.