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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.

In the process of missile penetration, the prediction of interceptor interception point and interception time can provide strong support for successful penetration. Therefore, aiming at the attack and defense scenario of interceptor intercepting cruise missile, a neural network model based on LSTM is proposed for the prediction of interception time and interception point. The interceptor trajectory data is obtained through attack and defense simulation as the training set to train the network. The model takes the position of interceptor as the input, uses the neural network to estimate the interceptor trajectory type, and obtains the interception point and interception time. The experimental results show that the proposed network can effectively predict the interception point and interception time with small prediction error, and can provide an effective reference for missile penetration strategy.