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Preceding a core-collapse supernova (CCSN), various processes produce an increasing amount of neutrinos of all flavors characterized by mounting energies from the interior of massive stars. Among them, the electron antineutrinos are potentially detectable by terrestrial neutrino experiments such as KamLAND and Super-Kamiokande (SK) via inverse beta decay interactions. Once these pre-supernova (pre-SN) neutrinos are observed, an early warning of the upcoming CCSN can be provided. In light of this, KamLAND and SK, both located in the Kamioka mine in Japan, have been monitoring pre-SN neutrinos since 2015 and 2021, respectively. Recently, we performed a joint study between KamLAND and SK on pre-SN neutrino detection. A pre-SN alert system combining the KamLAND detector and the SK detector was developed and put into operation, which can provide a supernova alert to the astrophysics community. Fully leveraging the complementary properties of these two detectors, the combined alert is expected to resolve a pre-SN neutrino signal from a 15 M ⊙ star within 510 pc of the Earth at a significance level corresponding to a false alarm rate of no more than 1 per century. For a Betelgeuse-like model with optimistic parameters, it can provide early warnings up to 12 hr in advance.

Sterile inflammation after myocardial infarction is classically credited to myeloid cells interacting with dead cell debris in the infarct zone1,2. Here we show that cardiomyocytes are the dominant initiators of a previously undescribed type I interferon response in the infarct borderzone. Using spatial transcriptomics analysis in mice and humans, we find that myocardial infarction induces colonies of interferon-induced cells (IFNICs) expressing interferon-stimulated genes decorating the borderzone, where cardiomyocytes experience mechanical stress, nuclear rupture and escape of chromosomal DNA. Cardiomyocyte-selective deletion of Irf3 abrogated IFNIC colonies, whereas mice lacking Irf3 in fibroblasts, macrophages, neutrophils or endothelial cells, Ccr2-deficient mice or plasmacytoid-dendritic-cell-depleted mice did not. Interferons blunted the protective matricellular programs and contractile function of borderzone fibroblasts, and increased vulnerability to pathological remodelling. In mice that died after myocardial infarction, IFNIC colonies were immediately adjacent to sites of ventricular rupture, while mice lacking IFNICs were protected from rupture and exhibited improved survival3. Together, these results reveal a pathological borderzone niche characterized by a cardiomyocyte-initiated innate immune response. We suggest that selective inhibition of IRF3 activation in non-immune cells could limit ischaemic cardiomyopathy while avoiding broad immunosuppression.

Particle dark matter could belong to a multiplet that includes an electrically charged state. WIMP dark matter (χ0) accompanied by a negatively charged excited state (χ−) with a small mass difference (e.g. < 20 MeV) can form a bound-state with a nucleus such as xenon. This bound-state formation is rare and the released energy is O(1−10) MeV depending on the nucleus, making large liquid scintillator detectors suitable for detection. We searched for bound-state formation events with xenon in two experimental phases of the KamLAND-Zen experiment, a xenon-doped liquid scintillator detector. No statistically significant events were observed. For a benchmark parameter set of WIMP mass mχ0=1 TeV and mass difference Δm=17 MeV, we set the most stringent upper limits on the recombination cross section times velocity 〈σv〉 and the decay-width of χ− to 9.2×10−30 cm3/s and 8.7×10−14 GeV, respectively at 90% confidence level.

Despite the known benefits of data-driven approaches, the lack of approaches for identifying functional neuroimaging patterns that capture both individual variations and inter-subject correspondence limits the clinical utility of rsfMRI and its application to single-subject analyses. Here, using rsfMRI data from over 100k individuals across private and public datasets, we identify replicable multi-spatial-scale canonical intrinsic connectivity network (ICN) templates via the use of multi-model-order independent component analysis (ICA). We also study the feasibility of estimating subject-specific ICNs via spatially constrained ICA. The results show that the subject-level ICN estimations vary as a function of the ICN itself, the data length, and the spatial resolution. In general, large-scale ICNs require less data to achieve specific levels of (within- and between-subject) spatial similarity with their templates. Importantly, increasing data length can reduce an ICN's subject-level specificity, suggesting longer scans may not always be desirable. We also find a positive linear relationship between data length and spatial smoothness (possibly due to averaging over intrinsic dynamics), suggesting studies examining optimized data length should consider spatial smoothness. Finally, consistency in spatial similarity between ICNs estimated using the full data and subsets across different data lengths suggests lower within-subject spatial similarity in shorter data is not wholly defined by lower reliability in ICN estimates, but may be an indication of meaningful brain dynamics which average out as data length increases.

Yuxuan Yao,1– 3 Hong Zhao,4 Hua Lu,5 Xiaoli Liu,6 Hui Liu,7 Zhanli Fu,8 Chunyue Li,1 Fude Zhou,1– 3 Wanyin Hou,1– 3 Sufang Shi1– 3 1Department of Nephrology, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, People’s Republic of China; 2Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, People’s Republic of China; 3Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 4Department of Infectious Disease, Center for Liver Disease, Peking University First Hospital, Beijing, People’s Republic of China; 5Department of Nephrology, Xingtai People’s Hospital, Xingtai, Hebei, People’s Republic of China; 6Department of Pathology, Xingtai People’s Hospital, Xingtai, Hebei, People’s Republic of China; 7Department of Pathology, Beijing Youan Hospital, Capital Medical University, Beijing, People’s Republic of China; 8Department of Nuclear Medicine, Peking University First Hospital, Beijing, People’s Republic of ChinaCorrespondence: Wanyin Hou; Hong Zhao, Peking University First Hospital, Xicheng District, Beijing, People’s Republic of China, Tel +86 10-83575685, Email helenwanyin@bjmu.edu.cn; zhaohong_pufh@bjmu.edu.cnAbstract: Q fever, an infectious zoonotic disease caused by Coxiella burnetii, remains prevalent in China. Systemic infections can result in renal or hepatic complications; however, it is rare for both the kidneys and liver to be simultaneously affected. We present a case of a patient who exhibited fever, rapid deterioration in renal function, thrombocytopenia, and severe ascites. Renal biopsy revealed crescentic glomerulonephritis, while liver biopsy demonstrated non-cirrhotic portal hypertension. Metagenomic next-generation sequencing (mNGS) identified the presence of Coxiella burnetii in both venous blood and liver tissue samples. Notably, the patient’s renal insufficiency and ascites showed a positive response to treatment for chronic Q fever. These findings provide valuable insights into the limited understanding of kidney and liver diseases associated with Q fever. Advanced diagnostic technologies, including mNGS and positron emission tomography/computed tomography (PET/CT), have been employed to identify Coxiella burnetii infection.Keywords: Coxiella burnetii, acute kidney injury, non-cirrhotic portal hypertension, biopsies

Zhengzheng Fu,1,&ast; Jingwen Zou,1,&ast; Jing Zhong,1 Jipang Zhan,1 Lian Zhang,1 Xiaoru Xie,1 Lai Zhang,1,2 Wenqiang Li,3 Renliang He1 1Department of Dermatologic Surgery and Dermatologic Oncology, Dermatology Hospital of Southern Medical University, Guangzhou, Guangdong Province, 510000, People’s Republic of China; 2Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, 510006, People’s Republic of China; 3Engineering Technology Research Center for Sports Assistive Devices of Guangdong, Guangzhou Sport University, Guangzhou, Guangdong Province, 510500, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenqiang Li; Renliang He, Department of Dermatologic Surgery and Dermatologic Oncology, Dermatology Hospital of Southern Medical University, Guangdong Provincial Dermatology Hospital, 2 Lujing Road, Yuexiu District, Guangzhou, Guangdong Province, 510000, People’s Republic of China, Email liwq@gzsport.edu.cn; zshrl2006@smu.edu.cnBackground: The skin regulates body processes. When damaged, it is prone to breeding bacteria, causing inflammation and impeding wound healing. There is an urgent need for new dressings that can combat bacteria to aid in infectious wound repair.Methods: In this study, a curcumin-loaded nanocomposite hydrogel dressing (GelMA/AHA-Gel@Cur) with antibacterial properties and strong toughness was synthesized, designed to combine the modified gelatin-based hydrogel (GelMA/AHA) with curcumin-coated gelatin (Gel@Cur) nanoparticles to promote the healing of bacterial infection wounds. Under UV irradiation, methylacrylylated gelatin (GelMA) and aldehyaluronic acid (AHA) formed a composite network hydrogel through radical polymerization and Schiff base reaction. Meanwhile, the residual aldehyde group on the molecular chain of AHA securely locked Gel@Cur nanoparticles in the hydrogel network through Schiff base reaction.Results: The addition of Gel@Cur nanoparticles not only enhanced the hydrogel’s mechanical strength but also facilitated a sustained, gradual release of curcumin, endowing the composite hydrogel with robust antimicrobial capabilities. In an animal model of infected wounds, the composite hydrogel significantly improved wound closure, healing, and vascularization compared to the control group. Hemocompatibility tests confirmed the hydrogel’s safety, with a hemolysis ratio of just 0.45%. Histological evaluation following treatment with the composite hydrogel showed improved tissue architecture, increased collagen deposition, and regeneration of dermal gland structures.Conclusion: The GelMA/AHA-Gel@Cur composite hydrogel exhibits excellent mechanical properties, potent antimicrobial activity, and controlled drug release, along with superior cell and hemocompatibility. These characteristics make it a promising material for infected wound repair and a potential candidate for clinical skin regeneration applications. Keywords: Nanocomposite hydrogel dressings, infected wound repair, antibacterial properties, drug delivery

Hu Li,1,2,&ast; Cong Cong Yang,3,&ast; Tianyu Bai,1 Jian Sun,4,5 Zhonghua Fu,4,6 Jia Mi,3 Li-Wei Chou7– 9 1Department of Acupuncture-Moxibustion and Tuina, Shandong Provincial Third Hospital, Shandong University, Jinan, 250031, People’s Republic of China; 2School of Acupuncture and Tuina, Shandong University of Traditional Chinese Medicine, Jinan, 250355, People’s Republic of China; 3Department of Ultrasound, Shandong Provincial Third Hospital, Shandong University, Jinan, 250031, People’s Republic of China; 4Clinical Medical College of Acupuncture & Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, 510405, People’s Republic of China; 5Second Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, 510006, People’s Republic of China; 6Institute of Fu’s Subcutaneous Needling, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 7Department of Physical Medicine and Rehabilitation, China Medical University Hospital, China Medical University, Taichung, 404332, Taiwan; 8Department of Physical Therapy and Graduate Institute of Rehabilitation Science, China Medical University, Taichung, 406040, Taiwan; 9Department of Physical Medicine and Rehabilitation, Asia University Hospital, Asia University, Taichung, 413505, Taiwan&ast;These authors contributed equally to this workCorrespondence: Li-Wei Chou, Department of Physical Medicine and Rehabilitation, China Medical University Hospital, China Medical University, No. 2 Yuh-Der Road, Taichung, 404332, Taiwan, Email chouliwe@gmail.comBackground: Knee osteoarthritis (OA) is a leading cause of disability worldwide, with clinicians often observing increased muscle stiffness associated with joint pain and dysfunction. This study examines the impact of Fu’s Subcutaneous Needling (FSN), a non-pharmacological technique, on muscle stiffness in the lower limbs of individuals with knee OA.Materials and Methods: This study protocol is a pilot, single-center, randomized controlled trial. Sixty knee OA patients will be allocated equally for FSN or electroacupuncture (EA) treatments. Interventions will be applied thrice weekly for the first two weeks and twice weekly for the subsequent two weeks for a total of ten sessions. Assessments will be conducted at baseline, post-initial session, after four weeks of intervention, and at the end of a four-week follow-up. The primary outcome will be the muscle stiffness in the lower extremities, as measured by shear wave elastography (SWE). Secondary outcomes include response rate, a reduction in the mean pain intensity on the Numerical Rating Scale (NRS) by at least two points and on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function subscale by six points at week four compared with baseline. Weekly monitoring of the NRS and WOMAC scores will determine the rapidity of pain alleviation and functional improvement, along with 12-item short-form (SF-12) score changes from baseline to week four.Results: This is the first standardized protocol examining the effects of FSN on lower limb muscle stiffness in patients with knee OA by SWE. We hypothesize that FSN could outperform EA in alleviating lower limb stiffness associated with knee OA. Findings will contribute to the body of knowledge regarding the efficacy of acupuncture-derived interventions in managing muscle stiffness and may guide future research directions.Study Registration: The trial has been registered on the Chinese Clinical Trial Registry (Registered number: ChiCTR2300073615). Registered 17 July 2023.Keywords: Fu’s subcutaneous needling, electroacupuncture, muscle stiffness, knee osteoarthritis, shear wave elastography

Xiang Li,1,2 Jun Zhang,3 Zhongxue Fu1 1Department of General Surgery, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Department of General Surgery, Chongqing University FuLing Hospital, Chongqing, People’s Republic of China; 3Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Zhongxue Fu, Department of General Surgery, The Third Affiliated Hospital of Chongqing Medical University, No. 1 Shuanghu Branch Road, Huixing Street, Yubei District, Chongqing, People’s Republic of China, Email fzx19990521@126.comPurpose: This study aims to investigate the correlation between a novel integrated inflammatory marker: The inflammation-combined prognostic index (ICPI), combining NLR, PLR, and MLR, with the clinicopathological characteristics and overall survival (OS) of gastric cancer (GC).Patients and Methods: Data from 876 patients with GC were retrospectively analyzed from January 1, 2017, to April 30, 2023. PSM was employed to mitigate confounding factors between groups. Receiver operating characteristic (ROC) curves were utilized to determine the optimal cutoff value. Univariate, LASSO, and multivariate regression analyses were executed. Subsequently, a nomogram for predicting OS was developed and validated.Results: The cohort with a poor prognosis exhibited significantly elevated levels of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and ICPI (P< 0.001). Similarly, higher levels of NLR, PLR, MLR, and ICPI were associated with a poorer prognosis (P< 0.001). Following regression analysis, ICPI, T-stage, lymph node ratio (LNR), and primary site were identified as independent risk factors affecting OS. A nomogram was constructed based on these factors to predict 1-, 3-, and 5-year OS, yielding C-indexes of 0.8 and 0.743 for the training and validation sets, respectively. The calibration curves demonstrated close alignment between predicted and actual results, indicating high predictive accuracy. Moreover, the decision curve underscored the practical utility of the model.Conclusion: The new inflammatory parameter ICPI integrates NLR, PLR and MLR. The ICPI-based nomogram and web calculator accurately predict OS in patients with GC.Keywords: gastric cancer, ICPI, PSM, nomogram, OS

BACKGROUND: Recent advances in resting-state fMRI allow us to study spatial dynamics, the phenomenon of brain networks spatially evolving over time. However, most dynamic studies still use subject-specific, spatially-static nodes. As recent studies have demonstrated, incorporating time-resolved spatial properties is crucial for precise functional connectivity estimation and gaining unique insights into brain function. Nevertheless, estimating time-resolved networks poses challenges due to the low signal-to-noise ratio, limited information in short time segments, and uncertain identification of corresponding networks within and between subjects. METHODS: We adapt a reference-informed network estimation technique to capture time-resolved spatial networks and their dynamic spatial integration and segregation. We focus on time-resolved spatial functional network connectivity (spFNC), an estimate of network spatial coupling, to study sex-specific alterations in schizophrenia and their links to multi-factorial genomic data. RESULTS: Our findings are consistent with the dysconnectivity and neurodevelopment hypotheses and align with the cerebello-thalamo-cortical, triple-network, and frontoparietal dysconnectivity models, helping to unify them. The potential unification offers a new understanding of the underlying mechanisms. Notably, the posterior default mode/salience spFNC exhibits sex-specific schizophrenia alteration during the state with the highest global network integration and correlates with genetic risk for schizophrenia. This dysfunction is also reflected in high-dimensional (voxel-level) space in regions with weak functional connectivity to corresponding networks. CONCLUSIONS: Our method can effectively capture spatially dynamic networks, detect nuanced SZ effects, and reveal the intricate relationship of dynamic information to genomic data. The results also underscore the potential of dynamic spatial dependence and weak connectivity in the clinical landscape.

Cosmic-ray muons produce various radioisotopes when passing through material. These spallation products can be backgrounds for rare event searches such as in solar neutrino, double-β decay, and dark matter search experiments. The KamLAND-Zen experiment searches for neutrinoless double-β decay in 745 kg of xenon dissolved in liquid scintillator. The experiment includes dead-time-free electronics with a high efficiency for detecting muon-induced neutrons. The production yields of different radioisotopes are measured with a combination of delayed coincidence techniques, newly developed muon reconstruction, and xenon spallation identification methods. The observed xenon spallation products are consistent with results from the fluka and geant4 simulation codes.

We report a measurement of the strange axial coupling constant gAs using atmospheric neutrino data at KamLAND. This constant is a component of the axial form factor of the neutral-current quasielastic (NCQE) interaction. The value of gAs significantly changes the ratio of proton and neutron NCQE cross sections. KamLAND is suitable for measuring NCQE interactions as it can detect nucleon recoils with low-energy thresholds and measure neutron multiplicity with high efficiency. KamLAND data, including the information on neutron multiplicity associated with the NCQE interactions, makes it possible to measure gAs with a suppressed dependence on the axial mass MA, which has not yet been determined. For a comprehensive prediction of the neutron emission associated with neutrino interactions, we establish a simulation of particle emission via nuclear deexcitation of C12, a process not considered in existing neutrino Monte Carlo event generators. Energy spectrum fitting for each neutron multiplicity gives gAs=-0.14-0.26+0.25, which is the most stringent limit obtained using NCQE interactions without MA constraints. The two-body current contribution considered in this analysis relies on a theoretically effective model and electron scattering experiments and requires future verification by direct measurements and future model improvement.

Xinyao Shui,1,&ast; Jingsong Chen,2– 4,&ast; Ziyue Fu,1 Haoyue Zhu,1 Hualin Tao,2– 4 Zhaoyinqian Li2– 4 1Clinical Medical College, Southwest Medical University, Luzhou, People’s Republic of China; 2Department of Laboratory Medicine, the Affiliated Hospital of Southwest Medical University, Luzhou, People’s Republic of China; 3Sichuan Province Engineering Technology Research Center of Molecular Diagnosis of Clinical Diseases, Luzhou, People’s Republic of China; 4Molecular Diagnosis of Clinical Diseases Key Laboratory of Luzhou, Luzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhaoyinqian Li, Department of Laboratory Medicine, the Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Jiangyang District, Luzhou, Sichuan, 646000, People’s Republic of China, Email lizhaoyinqian@swmu.edu.cnAbstract: Ischemic stroke is the most common type of stroke, which is the main cause of death and disability on a global scale. As the primary immune cells in the brain that are crucial for preserving homeostasis of the central nervous system microenvironment, microglia have been found to exhibit dual or even multiple effects at different stages of ischemic stroke. The anti-inflammatory polarization of microglia and release of neurotrophic factors may provide benefits by promoting neurological recovery at the lesion in the early phase after ischemic stroke. However, the pro-inflammatory polarization of microglia and secretion of inflammatory factors in the later phase of injury may exacerbate the ischemic lesion, suggesting the therapeutic potential of modulating the balance of microglial polarization to predispose them to anti-inflammatory transformation in ischemic stroke. Microglia-mediated signaling crosstalk with other cells may also be key to improving functional outcomes following ischemic stroke. Thus, this review provides an overview of microglial functions and responses under physiological and ischemic stroke conditions, including microglial activation, polarization, and interactions with other cells. We focus on approaches that promote anti-inflammatory polarization of microglia, inhibit microglial activation, and enhance beneficial cell-to-cell interactions. These targets may hold promise for the creation of innovative therapeutic strategies.Keywords: microglia, ischemic stroke, phagocytosis, polarization, crosstalk, anti-inflammatory, therapeutic targets

Nan Jiang,1,&ast; Wei Jin,2,&ast; Zhenghui Fu,3,&ast; He Cao,1 Hong Zheng,3 Quqing Wang,1 Qiongting Zhang,3 Kang Ju,3 Jiwei Wang1 1Key Laboratory of Health Technology Assessment of Ministry of Health, School of Public Health, Fudan University, Shanghai, People’s Republic of China; 2Department of Patriotic Public Health and Health Promotion instruction, Shanghai Municipal Center for Health Promotion, Shanghai, People’s Republic of China; 3Shanghai Changning Mental Health Center (Affiliated to East China Normal University), Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiwei Wang, Key Laboratory of Health Technology Assessment of Ministry of Health, School of Public Health, Fudan University, Shanghai, People’s Republic of China, Email jiweiwang@fudan.edu.cn Kang Ju, Shanghai Changning Mental Health Center (Affiliated to East China Normal University), Shanghai, People’s Republic of China, Email jukang2009@163.comPurpose: This study aims to explore the serial mediating effect of stigma and depression on the association between social support and medication adherence.Patients and Methods: A cross-sectional survey was undertaken in the Changning District of Shanghai using a five-part questionnaire from August to December 2023. A convenient sampling method was employed, and 35 patients with schizophrenia were invited from each of the 9 streets in Changning District to participate in the survey, resulting in a total of 305 valid questionnaires collected. The questionnaire measured social support, stigma, depression, medication adherence, and demographic characteristics. Data analysis involved descriptive statistics, independent samples t-tests, ANOVA, Pearson correlation analysis, and the bootstrap method.Results: There was a direct and significantly positive association between social support and medication adherence (β = 0.69, p < 0.001). Moreover, increased levels of stigma (β = - 0.45, p = 0.013) and depression (β = - 0.09, p = 0.017) were both associated with a decline in medication adherence. Bootstrapping analysis revealed that the association between social support and medication adherence operated indirectly through stigma (β = 0.11, 95% CI: 0.03, 0.18). Additionally, social support was indirectly associated with medication adherence through depression (β = 0.15, 95% CI: 0.04, 0.30). Further analysis indicated that social support had an indirect association with medication adherence through both stigma and depression (β = 0.04, 95% CI: 0.01, 0.07).Conclusion: Stigma and depression serially mediate the association between social support and medication adherence among patients with schizophrenia. This serial multiple mediation model underscores the importance of integrating social support interventions with psychological interventions aimed at reducing stigma and depression, thereby effectively enhancing medication adherence in patients with schizophrenia.Keywords: social support, stigma, depression, medication adherence, schizophrenia

Zhen-Zhen Wang,1– 3,&ast; Hang Li,4,&ast; Anish R Maskey,2,&ast; Kamal Srivastava,2,5,&ast; Changda Liu,6,&ast; Nan Yang,2,5 Taoyun Xie,7 Ziyi Fu,8 Junxiong Li,9 Xiaohong Liu,10 Hugh A Sampson,6 Xiu-Min Li2,11 1Academy of Chinese Medical Science, Henan University of Chinese Medicine, Zhengzhou, Henan, People’s Republic of China; 2Department of Pathology, Microbiology & Immunology, New York Medical College, Valhalla, NY, USA; 3Collaborative Innovation Center of Research and Development on the Whole Industry Chain of Yu-Yao, Zhengzhou, Henan, People’s Republic of China; 4Central Lab, Shenzhen Bao’an Chinese Medicine Hospital, Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, People’s Republic of China; 5General Nutraceutical Technology, Elmsford, NY, USA; 6Department of Pediatrics, Division of Allergy and Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 7The Affiliated TCM Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of China; 8The First Clinical College, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 9Guangdong Province Hospital of Integrated Chinese and Western Medicine, Foshan, Guangdong, People’s Republic of China; 10Department of Respiratory Medicine, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People’s Republic of China; 11Department of Otolaryngology, Westchester Medical Center New York Medical College, Valhalla, NY, USA&ast;These authors contributed equally to this workCorrespondence: Xiu-Min Li, Tel +1 914-594-4197, Email XiuMin_Li@NYMC.eduIntroduction: Neutrophil predominant airway inflammation is associated with severe and steroid-resistant asthma clusters. Previously, we reported efficacy of ASHMI, a three-herb TCM asthma formula in a steroid-resistant neutrophil-dominant murine asthma model and further identified Ganoderic Acid C1 (GAC1) as a key ASHMI active compound in vitro. The objective of this study is to investigate GAC1 effect on neutrophil-dominant, steroid-resistant asthma in a murine model.Methods: In this study, Balb/c mice were systematically sensitized with ragweed (RW) and alum and intranasally challenged with ragweed. Unsensitized/PBS challenged mice served as normal controls. Post sensitization, mice were given 4 weeks of oral treatment with GAC1 or acute dexamethasone (Dex) treatment at 48 hours prior to challenge. Pulmonary cytokines were measured by ELISA, and lung sections were processed for histology by H&E staining. Furthermore, GAC1 effect on MUC5AC expression and on reactive oxygen species (ROS) production in human lung epithelial cell line (NCI-H292) was determined by qRT-PCR and ROS assay kit, respectively. Computational analysis was applied to select potential targets of GAC1 in steroid-resistant neutrophil-dominant asthma. Molecular docking was performed to predict binding modes between GAC1 and Dex with TNF-α.Results: The result of the study showed that chronic GAC1 treatment, significantly reduced pulmonary inflammation (P < 0.01– 0.001 vs Sham) and airway neutrophilia (P < 0.01 vs Sham), inhibited TNF-α, IL-4 and IL-5 levels (P < 0.05– 0.001 vs Sham). Acute Dex treatment reduced eosinophilic inflammation and IL-4, IL-5 levels, but had no effect on neutrophilia and TNF-α production. GAC1 treated H292 cells showed decreased MUC5AC gene expression and production of ROS (P < 0.001 vs stimulated/untreated cells). Molecular docking results showed binding energy of complex GAC1-TNF was − 10.8 kcal/mol.Discussion: GAC1 may be a promising anti-asthma botanical drug for treatment of steroid-resistant asthma.Keywords: asthma, mouse model, neutrophilic inflammation, Ganoderma, ganoderic acid

The KamLAND-Zen experiment has provided stringent constraints on the neutrinoless double-beta (0νββ) decay half-life in ^{136}Xe using a xenon-loaded liquid scintillator. We report an improved search using an upgraded detector with almost double the amount of xenon and an ultralow radioactivity container, corresponding to an exposure of 970 kg yr of ^{136}Xe. These new data provide valuable insight into backgrounds, especially from cosmic muon spallation of xenon, and have required the use of novel background rejection techniques. We obtain a lower limit for the 0νββ decay half-life of T_{1/2}^{0ν}>2.3×10^{26}  yr at 90% C.L., corresponding to upper limits on the effective Majorana neutrino mass of 36-156 meV using commonly adopted nuclear matrix element calculations.

We report the results of a search for MeV-scale astrophysical neutrinos in KamLAND presented as an excess in the number of coincident neutrino interactions associated with the publicly available high-energy neutrino datasets from the IceCube Neutrino Observatory. We find no statistically significant excess in the number of observed low-energy electron antineutrinos in KamLAND, given a coincidence time window of ±500 s, ±1,000 s, ±3,600 s, and ±10,000 s around each of the IceCube neutrinos. We use this observation to present limits from 1.8 MeV to 100 MeV on the electron antineutrino fluence, assuming a mono-energetic flux. We then compare the results to several astrophysical measurements performed by IceCube and place a limit at the 90% confidence level on the electron antineutrino isotropic thermal luminosity from the TXS 0506+056 blazar.

The decay of the primordial isotopes 238U, 235U, 232Th, and 40K has contributed to the terrestrial heat budget throughout the Earth's history. Hence, the individual abundance of those isotopes are key parameters in reconstructing contemporary Earth models. The geoneutrinos produced by the radioactive decays of uranium and thorium have been observed with the Kamioka Liquid-Scintillator Antineutrino Detector (KamLAND). Those measurements have been improved with more than 18-year observation time, and improvement in detector background levels mainly with an 8-year nearly reactor-free period, which now permit spectroscopy with geoneutrinos. Our results yield the first constraint on both uranium and thorium heat contributions. The KamLAND result is consistent with geochemical estimations based on elemental abundances of chondritic meteorites and mantle peridotites. The High-Q model is disfavored at 99.76% C.L. and a fully radiogenic model is excluded at 5.2σ assuming a homogeneous heat producing element distribution in the mantle.

We present the results of a search for core-collapse supernova neutrinos, using long-term KamLAND data from 2002 March 9 to 2020 April 25. We focus on the electron antineutrinos emitted from supernovae in the energy range of 1.8-111 MeV. Supernovae will make a neutrino event cluster with the duration of ∼10 s in the KamLAND data. We find no neutrino clusters and give the upper limit on the supernova rate to be 0.15 yr−1 with a 90% confidence level. The detectable range, which corresponds to a >95% detection probability, is 40-59 kpc and 65-81 kpc for core-collapse supernovae and failed core-collapse supernovae, respectively. This paper proposes to convert the supernova rate obtained by the neutrino observation to the Galactic star formation rate. Assuming a modified Salpeter-type initial mass function, the upper limit on the Galactic star formation rate is

Resting-state functional magnetic resonance imaging is currently the mainstay of functional neuroimaging and has allowed researchers to identify intrinsic connectivity networks (aka functional networks) at different spatial scales. However, little is known about the temporal profiles of these networks and whether it is best to model them as continuous phenomena in both space and time or, rather, as a set of temporally discrete events. Both categories have been supported by series of studies with promising findings. However, a critical question is whether focusing only on time points presumed to contain isolated neural events and disregarding the rest of the data is missing important information, potentially leading to misleading conclusions. In this work, we argue that brain networks identified within the spontaneous blood oxygenation level-dependent (BOLD) signal are not limited to temporally sparse burst moments and that these event present time points (EPTs) contain valuable but incomplete information about the underlying functional patterns. We focus on the default mode and show evidence that is consistent with its continuous presence in the BOLD signal, including during the event absent time points (EATs), i.e., time points that exhibit minimum activity and are the least likely to contain an event. Moreover, our findings suggest that EPTs may not contain all the available information about their corresponding networks. We observe distinct default mode connectivity patterns obtained from all time points (AllTPs), EPTs, and EATs. We show evidence of robust relationships with schizophrenia symptoms that are both common and unique to each of the sets of time points (AllTPs, EPTs, EATs), likely related to transient patterns of connectivity. Together, these findings indicate the importance of leveraging the full temporal data in functional studies, including those using event-detection approaches.

We present two results of a search for MeV-scale neutrino and anti-neutrino events correlated with gravitational wave events/candidates and large solar flares with KamLAND. The KamLAND detector is a large-volume neutrino detector using liquid scintillator, which is located at 1 km underground under the top of Mt. Ikenoyama in Kamioka, Japan. KamLAND has multiple reaction channels to detect neutrinos. Electron antineutrino can be detected via inverse-beta decay with 1.8 MeV neutrino energy threshold. All flavors of neutrinos can be detected via neutrino-electron scattering without neutrino energy threshold. KamLAND has continued the neutrino observation since 2002 March. We use the data set of 60 gravitational waves provided by the LIGO/Virgo collaboration during their second and third observing runs and search for coincident electron antineutrino events in KamLAND. We find no significant coincident signals within a ±500 s timing window from each gravitational wave and present 90% C.L. upper limits on the electron antineutrino fluence between 108–1013 cm−2 for neutrino energies of 1.8–111 MeV. For a solar-flare neutrino search at KamLAND, we determine the timing window using the solar X-ray data set provided by the GOES satellite series from 2002 to 2019 and search for the excess of coincident event rate on the all-flavor neutrinos. We find no significant event rate excess in the flare time windows and get 90% C.L. upper limits on the fluence of neutrinos of all flavors (electron anti-neutrinos) between 1010–1013 cm−2 (108–1013 cm−2) for neutrino energies in the energy range of 0.4–35 MeV.

We present the results of a time-coincident event search for low-energy electron antineutrinos in the KamLAND detector with gamma-ray bursts (GRBs) from the Gamma-ray Coordinates Network and Fermi Gamma-ray Burst Monitor. Using a variable coincidence time window of ±500 s plus the duration of each GRB, no statistically significant excess above the background is observed. We place the world's most stringent 90% confidence level upper limit on the electron antineutrino fluence below 17.5 MeV. Assuming a Fermi-Dirac neutrino energy spectrum from the GRB source, we use the available redshift data to constrain the electron antineutrino luminosity and effective temperature.

Qingsong Liu,1,2,&ast; Lunyu Li,2,&ast; Dan Zheng,1 Songlin Jin,2 Xiaotian Guan,2 Zeting Fu,2 Zhigang Xiong,1 Haili Ding3 1Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 2School of Sports Medicine and Health, Chengdu Sport University, Chengdu, People’s Republic of China; 3Insititute of Sports Medicine and Health, Chengdu Sport University, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Haili Ding, No. 2, Gymnasium Road, Chengdu, Sichuan, People’s Republic of China, Tel +86 13688467479, Email dingdingtang111@163.comPurpose: This study examined the underlying mechanisms of SJD’s anti-inflammatory and analgesic effects on acute GA flares.Methods: This study used pharmacology network and molecular docking methods. The active ingredients of ShuiJingDan (SJD) were obtained from the Traditional Chinese Medicine Systems Pharmacology Analysis Platform (TCMSP), and the relevant targets of GA were obtained from the Online Mendelian Inheritance in Man (OMIM) database and Therapeutic Target Database (TTD). The core drug group–target–disease Venn diagram was formed by crossing the active ingredients of SJD and the relevant targets. Gene Ontology (GO) analysis was conducted for functional annotation, DAVID was used for Kyoto Encyclopedia of Genes, and Genomes pathway enrichment analysis, and R was used to find the core targets. The accuracy of SJD network pharmacology analysis in GA treatment was verified by molecular docking simulations. Finally, a rat GA model was used to further verify the anti-inflammatory mechanism of SJD in the treatment of GA.Results: SJD mainly acted on target genes including IL1B, PTGS2, CXCL8, EGF, and JUN, as well as signal pathways including NF-κB, Toll-like receptor (TLR), IL-17, and MAPK. The rat experiments showed that SJD could significantly relieve ankle swelling, reduce the local skin temperature, and increased the paw withdrawal threshold. SJD could also reduce synovial inflammation, reduced the concentrations of interleukin-1β (IL-1β), IL-8, and COX-2 in the synovial fluid, and suppressed the expression of IL1B, CXCL8, and PTGS2 mRNA in the synovial tissue.Conclusion: SJD has a good anti-inflammatory effect to treat GA attacks, by acting on target genes such as IL-1β, PTGS2, and CXCL8.Keywords: ShuiJingDan, gouty arthritis, network pharmacology, molecular docking, IL-1β, COX-2

Yicheng Guo,1 Huiqun Gan,1 Shigui Xu,1 Guosheng Zeng,2 Lili Xiao,2 Zhijun Ding,2 Jie Zhu,3 Xinglong Xiong,3 Zhiyuan Fu1 1Department of Pharmacy, Dermatology Hospital of Jiangxi Province, Nanchang, People’s Republic of China; 2Jiangxi Provincial Clinical Research Center for Skin Diseases, Nanchang, People’s Republic of China; 3Candidate Branch of National Clinical Research Center for Skin Diseases, Nanchang, People’s Republic of ChinaCorrespondence: Zhiyuan Fu, Department of Pharmacy, Dermatology Hospital of Jiangxi Province, 388, Yinbing Road, Nanchang, Jiangxi, People’s Republic of China, Tel +86 13970827820, Email fuzhiyuan0774@yeah.netPurpose: This study aims to confirm the efficacy of Xijiao Dihuang decoction (XJDHT), a classic prescription, in treating psoriasis and to explore the potential therapeutic mechanism.Methods: For pharmacodynamic analysis, a mouse model of imiquimod cream (IMQ)-induced psoriasis was constructed. Active ingredients and genes of XJDHT, as well as psoriasis-related targets, were obtained from public databases. Intersecting genes (IGEs) of XJDHT and psoriasis were collected by Venn Diagram. A protein–protein interaction (PPI) network of IGEs is constructed through the STRING database. The Molecular Complex Detection (MCODE) and Cytohubba plug-ins of Cytoscape software were used to identified hub genes. In addition, we conducted enrichment analysis of IGEs using the R package clusterProfiler. Hub genes were validated via external GEO databases. The influence of XJDHT on Hub gene expression was examined by qPCR and ELISA, and molecular docking was used to evaluate the binding efficacy between active ingredients and hub genes.Results: The results revealed that XJDHT possesses 92 potential genes for psoriasis, and 8 Hub genes were screened. Enrichment analysis suggested that XJDHT ameliorate psoriasis through multiple pathways, including AGE-RAGE, HIF-1, IL-17 and TNF signaling pathway. Validation data confirmed the differential expression of IL6, VEGFA, TNF, MMP9, STAT3, and TLR4. Molecular docking revealed a strong affinity between active ingredients and Hub genes. The efficacy of XJDHT in improving psoriatic lesions in model mice was demonstrated by PASI score and HE staining, potentially attributed to the down-regulation of VEGFA, MMP9, STAT3, TNF, and IL-17A, as evidenced by ELISA and qPCR.Conclusion: This study employed network pharmacology and in vitro experiments to identify the potential mechanisms underlying the therapeutic effects of XJDHT on psoriasis, providing a new theoretical basis for its clinical application in the treatment of psoriasis.Keywords: psoriasis, Xijiao Dihuang decoction, network pharmacology, molecular docking, angiogenesis

We report on a search for electron antineutrinos ( ) from astrophysical sources in the neutrino energy range 8.3-30.8 MeV with the KamLAND detector. In an exposure of 6.72 kton-year of the liquid scintillator, we observe 18 candidate events via the inverse beta decay reaction. Although there is a large background uncertainty from neutral current atmospheric neutrino interactions, we find no significant excess over background model predictions. Assuming several supernova relic neutrino spectra, we give upper flux limits of 60-110 cm-2 s-1 (90% confidence level, CL) in the analysis range and present a model-independent flux. We also set limits on the annihilation rates for light dark matter pairs to neutrino pairs. These data improve on the upper probability limit of 8B solar neutrinos converting into , (90% CL) assuming an undistorted shape. This corresponds to a solar flux of 60 cm-2 s-1 (90% CL) in the analysis energy range.

We report the result of a search for neutrinos in coincidence with solar flares from the GOES flare database. The search was performed on a 10.8 kton-year exposure of KamLAND collected from 2002 to 2019. This large exposure allows us to explore previously unconstrained parameter space for solar flare neutrinos. We found no statistical excess of neutrinos and established 90% confidence level upper limits of 8.4 × 107 cm-2 (3.0 × 109 cm-2) on the electron antineutrino (electron neutrino) fluence at 20 MeV normalized to the X12 flare, assuming that the neutrino fluence is proportional to the X-ray intensity.

Bo Liu,1,2 Yan Li,2,3 Jinying Xiang,2,3 Yuehan Li,2,3 Mi Zhou,2,3 Yinying Ren,2,3 Zhou Fu,2,3 Fengxia Ding2,3 1Department of Cardiothoracic Surgery, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2Chongqing Key Laboratory of Pediatrics, Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Respiratory Medicine, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Fengxia Ding, Department of Respiratory Medicine, Ministry of Education Key Laboratory of Child Development and Disorder, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Children’s Hospital of Chongqing Medical University, No. 136, Zhongshan 2nd Road, Yuzhong Dis, Chongqing, 400014, People’s Republic of China, Tel +86-15178712548, Email 482613@hospital.cqmu.edu.cnObjective: This study aimed to investigate the role of pyroptosis in alveolar macrophages regarding the immune microenvironment of acute respiratory distress syndrome (ARDS) and its prognosis.Methods: ARDS Microarray data were downloaded from Gene Expression Omnibus (GEO). Support vector machine (SVM) and random forest (RF) models were applied to identify hub pyroptosis-related genes (PRGs) with prognostic significance in ARDS. RT-PCR was used to detect the relative expression of PRGs mRNA in alveolar macrophages of ARDS mice. Consensus clustering analysis was conducted based on the expression of the PRGs to identify pyroptosis modification patterns. Bioinformatic algorithms were used to study the immune traits and biological functions of the pyroptosis patterns. Finally, protein-protein interaction (PPI) networks were established to identify hub regulatory proteins with implications for the pyroptosis patterns.Results: In our study, a total of 12 PRGs with differential expression were obtained. Four hub PRGs, including GPX4, IL6, IL18 and NLRP3, were identified and proven to be predictive of ventilator-free days (VFDS) in ARDS patients. The AUC values of the 4 PRGs were 0.911 (GPX4), 0.879 (IL18), 0.851 (IL6) and 0.841 (NLRP3), respectively. In ARDS mice, GPX4 mRNA decreased significantly, while IL6, IL18, and NLRP3 mRNA increased. Functional analysis revealed that IL6 had the strongest positive correlation with the CCR pathway, while GPX4 exhibited the strongest negative correlation with the T co-inhibition pathway. Based on the expression of the 4 PRGs, three pyroptosis modification patterns representing different immune states were obtained, and pattern C might represent immune storm.Conclusion: The results showed that pyroptosis plays an important regulatory role in the immune microenvironment of ARDS. This finding provides new insights into the pathogenesis, diagnosis, and treatment of ARDS.Keywords: ARDS, macrophage, pyroptosis, immune, prognosis

Chenrui Zhang,1 Jinping Li,2 Rong Lu,2 Song Wang,2 Zheng Fu,2 Zhi Yao1 1Department of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Educational Ministry of China, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People’s Republic of China; 2Kangzhe Pharmaceutical Technology Development Company, Ltd., Tianjin, People’s Republic of ChinaCorrespondence: Zhi Yao, Tianjin Medical University, Tianjin, 300070, People’s Republic of China, Tel/Fax +8622-83336817, Email yaozhi@tmu.edu.cn Zheng Fu, Kangzhe Pharmaceutical Technology Development Company, Tianjin, 300110, People’s Republic of China, Tel/Fax +86 13821232027, Email fuzhengcn@vip.sina.comBackground: The number of incidences of antimicrobial resistance is rising continually, necessitating new and effective antibacterial drugs. The present study aimed to assess the in vitro and in vivo activity of XF-73 against antibiotic-resistant Staphylococcus aureus (S. aureus) isolates and to investigate the potential mechanism of action of XF-73.Methods: The in vitro antibacterial activity of XF-73 and comparator antibacterial drugs, (mupirocin, fusidine, retapamulin, vancomycin, erythromycin, linezolid and daptomycin), against S. aureus (both antibiotic sensitive and resistant strains) was assessed using a broth microdilution method. Two different superficial Staphylococcal skin infection murine models were established to study the in vivo efficacy of XF-73 against antibiotic-resistant strains. The effect of XF-73 on the ultrastructure and cellular morphology of S. aureus was studied using transmission electron microscopy (TEM) and scanning electron microscopy (SEM).Results: The MICs (minimum inhibitory concentration) determined by the broth microdilution method for XF-73 demonstrated that the compound had a high potency against S. aureus isolates with varying susceptibility to the study drugs. Also, the antibacterial activity of XF-73 was superior or similar to most of the tested antibacterial drugs. We also found that the XF-73 dermal formulation significantly inhibited S. aureus survival in both the murine skin tape-stripping and suture superficial skin infection models, maintained a consistently high inhibitory capacity against the antibiotic-resistant strains tested and was significantly more effective than mupirocin ointment, a commonly used antibiotic for the treatment of skin infections. The morphological studies using TEM suggest that XF-73 had a rapid (2 minute) bacterial cell wall disruption activity, with longer incubation (10 minute) subsequently causing membrane damage. SEM analysis demonstrated that this cell wall and cell membrane disruption did not lead to disintegration of the plasma membrane, and did not cause bacterial cell lysis.Conclusion: Therefore, XF-73 may be an effective drug alternative to combat multi-drug-resistant skin infections in the clinical setting.Keywords: antibiotic resistance, mupirocin-resistant strains, skin infections, bacterial cell membrane, in vivo, S. aureus