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Caixing Shi,1 Yueyao Li,2 Zhidong You,3 Yiran Tian,4 Xiaoyu Zhu,4 Hao Xu,4 Menghan Yang,4 Yutong Zhang,4 Rui Dong,4 Huirong Quan,4 Yongyi Shang,4 Xiaojin Li1 1School of Basic Medicine, Jining Medical University, Jining, 272067, People’s Republic of China; 2College of Integrated Chinese and Western Medicine, Jining Medical University, Jining, 272067, People’s Republic of China; 3School of Nursing, Jining Medical University, Jining, 272067, People’s Republic of China; 4School of Clinical Medicine, Jining Medical University, Jining, 272067, People’s Republic of ChinaCorrespondence: Xiaojin Li, School of Basic Medicine, Jining Medical University, No. 133 hehua Road, Taibai Lake New District, Jining, 272067, People’s Republic of China, Tel +8615265775150, Email jinli10221@163.comPurpose: Acute liver injury (ALI) is characterized by inflammation and oxidative stress (OS). Although mangiferin (MGF) has antioxidant and anti-inflammatory effects, its role in ALI remains unclear. Accordingly, we investigated the MGF molecular mechanism in carbon tetrachloride (CCl4)-induced ALI in vivo and in vitro.Materials and Methods: The CCl4 was utilized to induce ALI in mice. In vivo, the therapeutic effects of MGF on CCl4-induced liver injury were evaluated through biochemical assays and histomorphological analysis. Additionally, immunohistochemistry, immunofluorescence, ELISA and Western blotting were further applied to explore the mechanism. In vitro, The CCK-8 assay and flow cytometry were employed to investigate the protective effects of MGF against CCl4-induced toxicity in HepG2 cells, while mitochondrial reactive oxygen species levels and Western blotting were used to explore the biological effects and molecular mechanisms.Results: MGF treatment resulted in a reduction in serum levels of AST and ALT, diminished concentrations of TNF-α, IL-6, and IL-1β in liver tissue, and concurrently decreased cellular apoptosis. Furthermore, MGF pretreatment enhanced the activity of SOD and GSH while concurrently diminishing the MDA production. This study further demonstrated the upregulation of Nrf2, NQO1, and HO-1 protein expression levels, as well as the downregulation of p-p65 protein expression levels. In vitro investigations revealed that the mitigation of CCl4-induced inflammation and OS by MGF was mediated via the Nrf2- antioxidant response element (ARE) pathway, which was disrupted by ML385 in HepG2 cells.Conclusion: CCl4 can induce liver injury, while treatment with MGF mitigates ALI by inhibiting oxidative stress, inflammation, and apoptosis. The protective mechanism of MGF is mediated by the Nrf2-ARE pathway activation.Keywords: mangiferin, liver injury, oxidative stress, inflammation, Nrf2

Huanhuan Wang,1,* Dan Xiao,2,* Hua Zhou,3,* Shu Chen,4 Guangjun Xiao,4 Juan Hu,4 Hui Quan,2 Miao Luo,5 Shaocheng Zhang2,6 1School of Laboratory Medicine, Chengdu Medical College, Chengdu, Sichuan, People’s Republic of China; 2Department of Laboratory Medicine, the Second Affiliated Hospital of Chengdu Medical College (Nuclear Industry 416 Hospital), Chengdu, Sichuan, People’s Republic of China; 3Department of Laboratory Medicine, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 4Department of Laboratory Medicine, Suining Central Hospital, Suining, Sichuan, People’s Republic of China; 5Department of Laboratory Medicine, the People’s Hospital of Yubei District of Chongqing, Chongqing, People’s Republic of China; 6School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shaocheng Zhang; Miao Luo, Email 102024001@cmc.edu.cn; 536513878@qq.comPurpose: Visceral adiposity is a significant risk factor for severe COVID-19. However, the impact of the Chinese visceral adiposity index (CVAI) on the efficacy of SARS-CoV-2 vaccines remains poorly understood. This study aims to explore the impact of CVAI on the production of neutralizing antibodies (NAb) in inactivated SARS-CoV-2 vaccines and the potential mechanism, thereby optimizing vaccination guidance.Methods: In this cross-sectional study, 206 health workers (completed two SARS-CoV-2 vaccination on February 8th and March 10th, 2021, respectively) were recruited. All baseline anthropometric parameters of the participants were collected, and venous blood samples were obtained 6 weeks later to measure peripheral innate immune cells, inflammatory cytokines, and NAb titers against SARS-CoV-2. CVAI were calculated according to the formula and divided participants into two groups depending on CVAI median.Results: The median NAb titer among healthcare workers was 12.94 AU/mL, with an efficacy of 87.86% for the SARS-CoV-2 vaccine. NAb titers were lower in the CVAI dysfunction group than in the CVAI reference group (median: 11.40 AU/mL vs 15.57 AU/mL), the hsCRP levels (median: 0.50 mg/L vs 0.30 mg/L) and peripheral monocyte count (mean: 0.47 × 109/L vs 0.42 × 109/L) in the CVAI dysfunction group were higher than in the CVAI reference group. Additionally, CVAI showed positive correlations with hsCRP, monocytes, lymphocytes, and B-lymphocytes, and a negative correlation with NAb titers.Conclusion: CVAI may inhibit SARS-CoV-2 neutralizing antibody expression through inducing immune dysfunction and chronic inflammation. Thus, more attention should be paid to the vaccination for high CVAI population to improve the effectiveness of vaccination, which could provide more robust support for COVID-19 epidemic prevention and control.Keywords: Chinese visceral adiposity index, immune function, chronic inflammation, SARS-CoV-2 vaccine, neutralizing antibody

Abstract Next-generation humanised mouse models and single-cell RNA sequencing (scRNAseq) approaches enable in-depth studies into human immune cell biology. Here we used NSG-SGM3 mice engrafted with human umbilical cord haematopoietic stem cells to investigate how human immune cells respond to and/or are changed by traumatic spinal cord injury (SCI). We hypothesised that the use of such mice could help advance our understanding of spinal cord injury-induced immune depression syndrome (SCI-IDS), and also how human leukocytes change as they migrate from the circulation into the lesion site. Our scRNAseq experiments, supplemented by flow cytometry, demonstrate the existence of up to 11 human immune cell (sub-) types and/or states across the blood and injured spinal cord (7 days post-SCI) of humanised NSG-SGM3 mice. Further comparisons of human immune cell transcriptomes between naïve, sham-operated and SCI mice identified a total of 579 differentially expressed genes, 190 of which were ‘SCI-specific’ (that is, genes regulated only in response to SCI but not sham surgery). Gene ontology analysis showed a prominent downregulation of immune cell function under SCI conditions, including for T cell receptor signalling and antigen presentation, confirming the presence of SCI-IDS and the transcriptional signature of human leukocytes in association with this phenomenon. We also highlight the activating influence of the local spinal cord lesion microenvironment by comparing the transcriptomes of circulating versus infiltrated human immune cells; those isolated from the lesion site were enriched for genes relating to both immune cell activity and function (e.g., oxidative phosphorylation, T cell proliferation and antigen presentation). We lastly applied an integrated bioinformatics approach to determine where immune responses in humanised NSG-SGM3 mice appear congruent to the native responses of human SCI patients, and where they diverge. Collectively, our study provides a valuable resource and methodological framework for the use of these mice in translational research.

Abstract Spatial transcriptomics (ST) technologies generate multiple data types from biological samples, namely gene expression, physical distance between data points, and/or tissue morphology. Here we developed three computational-statistical algorithms that integrate all three data types to advance understanding of cellular processes. First, we present a spatial graph-based method, pseudo-time-space (PSTS), to model and uncover relationships between transcriptional states of cells across tissues undergoing dynamic change (e.g. neurodevelopment, brain injury and/or microglia activation, and cancer progression). We further developed a spatially-constrained two-level permutation (SCTP) test to study cell-cell interaction, finding highly interactive tissue regions across thousands of ligand-receptor pairs with markedly reduced false discovery rates. Finally, we present a spatial graph-based imputation method with neural network (stSME), to correct for technical noise/dropout and increase ST data coverage. Together, the algorithms that we developed, implemented in the comprehensive and fast stLearn software, allow for robust interrogation of biological processes within healthy and diseased tissues.

Han Tang,1,* Ji Chen,2,* Lu He Qi,3 Meng Lyu,4 Hong Quan,1 Zhi Jie Tan1 1Key Laboratory of Artificial Micro- and Nano-Structures of Ministry of Education, School of Physics and Technology, Wuhan University, Wuhan, People’s Republic of China; 2Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 3School of Resource and Environmental Sciences, Wuhan University, Wuhan, People’s Republic of China; 4Department of Gastrointestinal Surgery, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong Quan; Zhi Jie Tan, School of Physics and Technology, Wuhan University, Wuhan, Hubei Province, 430072, People’s Republic of China, Email 00007962@whu.edu.cn; zjtan@whu.edu.cnBackground: Photothermal therapy (PTT) has gained considerable interest as an emerging modality for cancer treatment in recent years. Radiation therapy (RT) has been widely used in the clinic as a traditional treatment method. However, RT and PTT treatments are limited by side effects and penetration depth, respectively. In addition, hypoxia within the tumor can lead to increased resistance to treatment.Methods: We synthesized multiple sizes of AuPt by modulating the reaction conditions. The smallest size of AuPt was selected and modified with folic acid (FA) for PTT and RT synergy therapy. Various methods including transmission electron microscope (TEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FITR) are used to determine the structure and composition of AuPt-FA (AF). In addition, we researched the photothermal properties of AF with IR cameras and infrared lasers. Flow cytometry, colony formation assays, CCK8, and fluorescent staining for probing the treatment effect in vitro. Also, we explored the targeting of AF by TEM and In Vivo Imaging Systems (IVIS). In vivo experiments, we record changes in tumor volume and weight as well as staining of tumor sections (ROS, Ki67, and hematoxylin and eosin).Results: The AuPt with particle size of 16 nm endows it with remarkably high photothermal conversion efficiency (46.84%) and catalase activity compared to other sizes of AuPt (30 nm and 100 nm). AF alleviates hypoxia in the tumor microenvironment, leading to the production of more reactive oxygen species (ROS) during the treatment. In addition, the therapeutic effect was significantly enhanced by combining RT and PTT, with an apoptosis rate of 81.1% in vitro and an in vivo tumor volume reduction rate of 94.0% in vivo.Conclusion: These results demonstrate that AF potentiates the synergistic effect of PTT and RT and has the potential for clinical translation. Keywords: photothermal, radiotherapy, hypoxia relief, catalase activity, microscale, synergistic effect

BackgroundGastric cancer (GC) is the fifth most common type of cancer and the fourth most common cause of cancer-related mortality. Although the risk of GC and peptic ulcer disease (PUD) is known to be increased by H. pylori infection, evidence regarding the direct relationship between PUD and GC across ethnicities is inconclusive. Therefore, we investigated the association between PUD and GC in the Stomach cancer Pooling (StoP) consortium.MethodsHistory of peptic ulcer disease was collected using a structured questionnaire in 11 studies in the StoP consortium, including 4106 GC cases and 6922 controls. The two-stage individual-participant data meta-analysis approach was adopted to generate a priori. Unconditional logistic regression and Firth's penalized maximum likelihood estimator were used to calculate study-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between gastric ulcer (GU)/duodenal ulcer (DU) and risk of GC.ResultsHistory of GU and DU was thoroughly reported and used in association analysis, respectively, by 487 cases (12.5%) and 276 controls (4.1%), and 253 cases (7.8%) and 318 controls (6.0%). We found that GU was associated with an increased risk of GC (OR = 3.04, 95% CI: 2.07-4.49). No association between DU and GC risk was observed (OR = 1.03, 95% CI: 0.77-1.39).ConclusionsIn the pooled analysis of 11 case-control studies in a large consortium (i.e., the Stomach cancer Pooling (StoP) consortium), we found a positive association between GU and risk of GC and no association between DU and GC risk.

High penetration of intermittent generation increases uncertainty and variability in balancing reserve needs. New tools are needed to help the balancing authority system operator plan for intraday and intra-hour balance between generation and load. The Grid Reserve and Flexibility Planning tool (GRAF-Plan) helps plan for adequate balancing reserves for future years or seasons for expected wind and solar generation. It also assesses the flexibility of the scheduled generation fleet to meet such requirements. The estimations are based on utilities’ operational practices (e.g., forecasting and time frame of reserve deployment), and it incorporates detailed data from renewable generation and load. Application of the tool in estimating reserve requirements in Central America under different levels of renewable generation (high and low) and for the Western Electricity Coordinating Council (WECC) 2030 Anchor Data Set scenario is discussed.

Weikang Shi,&ast; Huiyi He,&ast; Jicong Jiang, Yu Gao, Hehe Quan Department of Dermatology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hehe Quan Email 13587748556@qq.comPurpose: Infantile hemangioma (IH) is the most common benign tumor in infancy, and superficial IH is the most common type. IH can reportedly resolve spontaneously, but this is associated with complications, such as scars, atrophy, hypopigmentation, telangiectasia, and skin sagging, in 70% of cases. This study explores the safety and feasibility of therapeutic intervention with the 595-nm pulsed-dye laser (PDL) combined with 0.5% timolol maleate solution in superficial IH and compares the difference in efficacy between the early group and the late group.Patients and Methods: This retrospective study examined 167 patients with superficial IH who underwent combination therapy at the Dermatology Clinic of the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University between July 2019 and July 2020. The early and late groups were composed of children aged ≤ 2 and > 2 months, respectively. Treatment was administered for 6 months, and patients were followed up for another 6 months. Two independent, double-blinded physicians reviewed photographs of the skin lesions before and after treatment to evaluate efficacy.Results: The early group demonstrated higher treatment efficacy than the late group. The early (n = 45) and late (n = 122) groups had treatment efficacy rates of 95.5% and 86.1%, respectively; the difference was statistically significant (P< 0.05). The early and late groups underwent 3.51 ± 0.50 and 4.73 ± 0.68 months of treatment, respectively; the difference was statistically significant (P< 0.05). Seventeen (44.4%) patients in the early group had immediate adverse reactions but no permanent sequelae, whereas 25 (20.49%) and 13 (10.7%) patients in the late group had immediate and permanent sequelae, respectively. The difference was statistically significant (P< 0.05).Conclusion: This retrospective study demonstrated that 595-nm PDL combined with 0.5% timolol maleate solution was a safe and effective local treatment for superficial IH. Early treatment required fewer treatments, had better curative effects, and a lower probability of permanent sequelae.Keywords: infantile hemangiomas, pulsed-dye laser, timolol maleate solution, timing and efficacy

Summary: Background: Nanocovax is a recombinant severe acute respiratory syndrome coronavirus 2 subunit vaccine composed of full-length prefusion stabilized recombinant SARS-CoV-2 spike glycoproteins (S-2P) and aluminium hydroxide adjuvant. Methods: We conducted a dose-escalation, open label trial (phase 1) and a randomized, double-blind, placebo-controlled trial (phase 2) to evaluate the safety and immunogenicity of the Nanocovax vaccine (in 25 mcg, 50 mcg, and 75 mcg doses, aluminium hydroxide adjuvanted (0·5 mg/dose) in 2-dose regime, 28 days apart (ClinicalTrials.gov number, NCT04683484). In phase 1, 60 participants received two intramuscular injection of the vaccine following dose-escalation procedure. The primary outcomes were reactogenicity and laboratory tests to evaluate the vaccine safety. In phase 2, 560 healthy adults received either vaccine doses similar in phase 1 (25 or 50 or 75 mcg S antigen in 0·5 mg aluminium per dose) or adjuvant (0·5 mg aluminium) in a ratio of 2:2:2:1. One primary outcome was the vaccine safety, including solicited adverse events for 7 day and unsolicited adverse events for 28 days after each injection as well as serious adverse event or adverse events of special interest throughout the study period. Another primary outcome was anti-S IgG antibody response (Index unit/ml). Secondary outcomes were surrogate virus neutralisation (inhibition percentage), wild-type SARS-CoV-2 neutralisation (dilution fold), and T-cell responses by intracellular staining for interferon gamma (IFNg). Anti-S IgG and neutralising antibody levels were compared with convalescent serum samples from symptomatic Covid-19 patients. Findings: For phase 1 study, no serious adverse events were observed for all 60 participants. Most adverse events were grade 1 and disappeared shortly after injection. For phase 2 study, after randomisation, 480 participants were assigned to receive the vaccine with adjuvant, and 80 participants were assigned to receive the placebo (adjuvant only). Reactogenicity was absent or mild in the majority of participants and of short duration (mean ≤3 days). Unsolicited adverse events were mild in most participants. There were no serious adverse events related to Nanocovax. Regarding the immunogenicity, Nanocovax induced robust anti-S antibody responses. In general, there humoral responses were similar among vaccine groups which reached their peaks at day 42 and declined afterward. At day 42, IgG levels of vaccine groups were 60·48 [CI95%: 51·12–71·55], 49·11 [41·26–58·46], 57·18 [48·4-67·5] compared to 7·10 [6·32-13·92] of convalescent samples. IgG levels reported here can be converted to WHO international standard binding antibody unit (BAU/ml) by multiplying them to a conversion factor of 21·8. Neutralising antibody titre of vaccine groups at day 42 were 89·2 [52·2–152·3], 80·0 [50·8–125.9] and 95·1 [63·1–143·6], compared to 55·1 [33·4-91·0] of the convalescent group. Interpretation: Up to day 90, Nanocovax was found to be safe, well tolerated, and induced robust immune responses. Funding: This work was funded by the Coalition for Epidemic Preparedness Innovations (CEPI), the Ministry of Science and Technology of Vietnam, and Nanogen Pharmaceutical Biotechnology JSC.

Summary: Langerhans cells (LC) are skin-resident antigen-presenting cells that regulate immune responses to epithelial microorganisms. Human papillomavirus (HPV) infection can promote malignant epithelial transformation. As LCs are considered important for controlling HPV infection, we compared the transcriptome of murine LCs from skin transformed by K14E7 oncoprotein and from healthy skin. We identified transcriptome heterogeneity at the single cell level amongst LCs in normal skin, associated with ontogeny, cell cycle, and maturation. We identified a balanced co-existence of immune-stimulatory and immune-inhibitory LC cell states in normal skin that was significantly disturbed in HPV16 E7-transformed skin. Hyperplastic skin was depleted of immune-stimulatory LCs and enriched for LCs with an immune-inhibitory gene signature, and LC-keratinocyte crosstalk was dysregulated. We identified reduced expression of interleukin (IL)-34, a critical molecule for LC homeostasis. Enrichment of an immune-inhibitory LC gene signature and reduced levels of epithelial IL-34 were also found in human HPV-associated cervical epithelial cancers.

How and where patients with advanced cancer facing limited survival spend their time is critical. Healthcare contact days (days with healthcare contact outside the home) offer a patient-centered and practical measure of how much of a person's life is consumed by healthcare. We retrospectively analyzed contact days among decedent veterans with stage IV gastrointestinal cancer at the Minneapolis Veterans Affairs Healthcare System from 2010 to 2021. Among 468 decedents, the median overall survival was 4 months. Patients spent 1 in 3 days with healthcare contact. Over the course of illness, the percentage of contact days followed a "U-shaped" pattern, with an initial post-diagnosis peak, a lower middle trough, and an eventual rise as patients neared the end-of-life. Contact days varied by clinical factors and by sociodemographics. These data have important implications for improving care delivery, such as through care coordination and communicating expected burdens to and supporting patients and care partners. [ABSTRACT FROM AUTHOR]