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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.

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.

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.

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.

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.

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.

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.

As breast cancer is the leading cause of cancer-related deaths in women population worldwide, ongoing endeavor has been made for alternative regimens with improved efficacy but fewer adverse effects. Recently, active components from the spores of Ganoderma lucidum have attracted much attention for their versatile biological activities owing to the advance in sporoderm-breaking technology. Here, anticancer potential of an extract derived from the sporoderm-breaking spores of G. lucidum (ESG) was explored in a 4T1-breast cancer xenograft mice model. Results showed that ESG was able to suppress 4T1 tumor growth in vivo rather than in vitro. Flowcytometry analysis revealed that ESG could significantly increase both cytotoxic T cell (Tc) population and the ratio of Tc to helper T cell (Th) in peripheral blood of the tumor-bearing mouse; similar promotion on Tc was also found in tumor-infiltrating lymphocyte. Moreover, ESG evidently downregulated the two immune checkpoints, programmed cell death protein-1 (PD-1, in the spleen) and cytotoxic T lymphocyte antigen-4 (CTLA-4, in the tumor), suggesting that ESG could effectively restore the T cell paradigm by recovering the exhaustion status via suppressing the co-inhibitory checkpoints. By 16S rRNA gene sequence analysis on the fecal microbiota, it was found that ESG would remodeling the overall structure of the samples from tumor-bearing mice toward that of the normal counterparts, including 18 genera in 5 phyla, together with regulations on several genes that are responsible for signaling pathways involved in metabolism, cellular processes, and environmental information processing. Collectively, this study demonstrated that ESG would serve as a natural anticancer adjuvant via a restoration on the exhausted Tc, highlighting important clinical implications for the treatment of breast cancer.

The electro-peroxone (E-peroxone) process is an emerging electrocatalytic ozonation process that is enabled by in situ producing hydrogen peroxide (H2O2) from cathodic oxygen reduction during ozonation. The in situ-generated H2O2 can then promote ozone (O3) transformation to hydroxyl radicals (•OH), and thus enhance the abatement of ozone-refractory pollutants compared to conventional ozonation. In this study, a chemical kinetic model was employed to simulate micropollutant abatement during the E-peroxone treatment of various water matrices (surface water, secondary wastewater effluent, and groundwater). Results show that by following the O3 and •OH exposures during the E-peroxone process, the abatement kinetics of a variety of model micropollutants could be well predicted using the model. In addition, the effect of specific ozone doses on micropollutant abatement efficiencies could be quantitatively evaluated using the model. Therefore, the chemical kinetic model can be used to reveal important information for the design and optimization of the treatment time and ozone doses of the E-peroxone process for cost-effective micropollutant abatement in water and wastewater treatment.

Searching novel hypouricemic agents of high efficacy and safety has attracted a great attention. Previously, we reported the hypouricemic effect of Ganoderma applanatum, but its bioactives, was not referred. Herein, we report the hypouricemic effect of 2,5-dihydroxyacetophenone (DHAP), a compound screened from Ganoderma applanatum computationally. Serum parameters, such as uric acid (SUA), xanthine oxidase (XOD) activity, blood urea nitrogen (BUN), and creatinine were recorded. Real-time reverse transcription PCR (RT-PCR) and Western blot were exploited to assay RNA and protein expressions of organic anion transporter 1 (OAT1), glucose transporter 9 (GLUT9), uric acid transporter 1 (URAT1), and gastrointestinal concentrative nucleoside transporter 2 (CNT2). DHAP at 20, 40, and 80 mg/kg exerted excellent hypouricemic action on hyperuricemic mice, reducing SUA from hyperuricemic control (407 ± 31 μmol/L, p < 0.01) to 180 ± 29, 144 ± 13, and 139 ± 31 μmol/L, respectively. In contrast to the renal toxic allopurinol, DHAP showed some kidney-protective effects. Moreover, its suppression on XOD activity, in vivo and in vitro, suggested that XOD inhibition may be a mechanism for its hypouricemic effect. Given this, its binding mode to XOD was explored by molecular docking and revealed that three hydrogen bonds may play key roles in its binding and orientation. It upregulated OAT1 and downregulated GLUT9, URAT1, and CNT2 too. In summary, its hypouricemic effect may be mediated by regulation of XOD, OAT1, GLUT9, URAT1, and CNT2.

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 [...]

Abstract Background The primer and amplicon length have been found to affect PCR based estimates of microbial diversity by pyrosequencing, while other PCR conditions have not been addressed using any deep sequencing method. The present study determined the effects of polymerase, template dilution and PCR cycle number using the Solexa platform. Results The PfuUltra II Fusion HS DNA Polymerase (Stratagene) with higher fidelity showed lower amount of PCR artifacts and determined lower taxa richness than the Ex Taq (Takara). More importantly, the two polymerases showed different efficiencies for amplifying some of very abundant sequences, and determined significantly different community structures. As expected, the dilution of the DNA template resulted in a reduced estimation of taxa richness, particularly at the 200 fold dilution level, but the community structures were similar for all dilution levels. The 30 cycle group increased the PCR artifacts while comparing to the 25 cycle group, but the determined taxa richness was lower than that of the 25 cycle group. The PCR cycle number did not changed the microbial community structure significantly. Conclusions These results highlight the PCR conditions, particularly the polymerase, have significant effect on the analysis of microbial diversity with next generation sequencing methods.