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Background: New-onset permanent pacemaker implantation (PPMI) is still a common complication after transcatheter aortic valve implantation (TAVI) with adverse clinical outcomes., Objective: To investigate whether left bundle branch area pacing (LBBAP) improves long-term clinical results compared to traditional right ventricular pacing (RVP) in patients requiring PPMI following TAVI., Methods: A total of 237 consecutive patients undergoing RVP (N=117) or LBBAP (N=120) following TAVI were retrospectively included. Long-term outcomes including all-cause death, heart failure rehospitalization (HFH) and left ventricular ejection fraction (LVEF) change compared to baseline were obtained until 5 years post-TAVI., Results: The mean age of the overall population was 74 years with a mean surgical risk score as 4.4%. The paced QRS duration was significantly longer in RVP group compared to LBBAP group (151 ± 18 vs. 122 ± 12 ms, P<0.001). There was no difference between two groups in all-cause death (13.7% vs. 13.3%, adjusted HR: 0.76; 95% CI: 0.37 to 1.58; P=0.466) or the composite endpoint of death and HFH (29.9% vs. 19.2%, adjusted HR: 1.22; 95% CI: 0.70 to 2.13; P=0.476), however, the risk of HFH was significantly higher in RVP group at 5 years after TAVI (21.4% vs. 7.5%, adjusted HR: 2.26; 95% CI: 1.01 to 5.08; P=0.048). There was a greater improvement of LVEF over time in LBBAP group (P=0.046 for LVEF changes over time between groups)., Conclusions: LBBAP improved long-term clinical outcomes compared to RVP in patients undergoing PPMI after TAVI in terms of less HFH and better LVEF improvement., (Copyright © 2024. Published by Elsevier Inc.)

In traditional Chinese medicine, Lycium barbarum is of rich medicinal value, and its polysaccharides are particularly interesting due to their significant pharmacological effects and potential health benefits. This study investigated the immunomodulatory effects of Lycium barbarum polysaccharides (LBPs) by examining their interaction with the TLR4/MD-2 complex and the impacts of gastrointestinal digestion on these interactions. We discovered that the affinity binding of LBPs for TLR4/MD-2 and their cytokine induction capability are influenced by molecular weight, with medium-sized LBPs (100-300 kDa) exhibiting stronger binding affinity and induction capability. Conversely, LBPs smaller than 10 kDa showed reduced activity. Additionally, the content of arabinose and galactose within the LBPs fractions was found to correlate positively with both receptor affinity and cytokine secretion. Simulated gastrointestinal digestion resulted in the degradation of LBPs into smaller fragments that are rich in glucose. Although these fragments exhibited decreased binding affinity to the TLR4/MD-2 complex, they maintained their activity to promote cytokine production. Our findings highlight the significance of molecular weight and specific monosaccharide composition in the immunomodulatory function of LBPs and emphasize the influence of gastrointestinal digestion on the effects of LBPs. This research contributes to a better understanding of the mechanisms underlying the immunomodulatory effects of traditional Chinese medicine polysaccharides and their practical application., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Currently, SARS-CoV-2 has not disappeared and continues to prevail worldwide, with the ongoing risk of mutations and the potential for severe COVID-19. The impairment of monocyte mitochondrial function caused by SARS-CoV-2, leading to a metabolic and immune dysregulation, is a crucial factor in the development of severe COVID-19., Purpose: Discover effective phytomedicines based on mitochondrial-related biomarkers in severe SARS-CoV-2 infection., Methods: Firstly, differential gene analysis and gene set enrichment analysis (GSEA) were conducted on monocytes datasets to identify genes and pathways distinguishing severe patients from uninfected individuals. Then, GO and KEGG enrichment analysis on the differentially expressed genes (DEGs) obtained. Take the DEGs and intersect them with the MitoCarta 3.0 gene set to obtain the differentially expressed mitochondrial-related genes (DE-MRGs). Subsequently, machine learning algorithms were employed to screen potential mitochondrial dysfunction biomarkers for severe COVID-19 based on score values. ROC curves were then plotted to assess the distinguish capability of the biomarkers, followed by validation using two additional independent datasets. Next, the effects of the identified biomarkers on metabolic pathways and immune cells were explored through Gene Set Variation Analysis (GSVA) and CIBERSORT. Finally, potential nature products for severe COVID-19 were screened from the expression profile dataset based on dysregulated mitochondrial-related genes, followed by in vitro experimental validation., Results: There are 1812 DEGs and 17 dysregulated mitochondrial processes between severe COVID-19 patients and uninfected individuals. A total of 77 DE-MRGs were identified, and the potential biomarkers were identified as RECQL4, PYCR1, PIF1, POLQ, and GLDC. In both the training and validation sets, the area under the ROC curve (AUC) for these five biomarkers was greater than 0.9. And they did not show significant changes in mild to moderate patients (p > 0.05), indicating their ability to effectively distinguish severe COVID-19. These biomarkers exhibit a highly significant correlation with the dysregulated metabolic processes (p < 0.05) and immune cell imbalance (p < 0.05) in severe patients, as demonstrated by GSVA and CIBERSORT algorithms. Curcumin has the highest score in the predictive model based on transcriptomic data from 496 natural compounds (p = 0.02; ES = 0.90). Pre-treatment with curcumin for 8 h has been shown to alleviate mitochondrial membrane potential damage caused by the SARS-CoV-2 S1 protein (p < 0.05) and reduce elevated levels of reactive oxygen species (ROS) (p < 0.01)., Conclusion: The results of this study indicate a significant correlation between severe SARS-CoV-2 infection and mitochondrial dysfunction. The proposed mitochondrial dysfunction biomarkers identified in this study are associated with the disease progression, metabolic and immune changes in severe SARS-CoV-2 infected patients. Curcumin has a potential role in preventing severe COVID-19 by protecting mitochondrial function. Our findings provide new strategies for predicting the prognosis and enabling early intervention in SARS-CoV-2 infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)

With the global spread of COVID-19 posing ongoing challenges to public health systems, there is an ever-increasing demand for effective therapeutics that can mitigate both viral transmission and disease severity. This review surveys the landscape of polysaccharides derived from traditional Chinese medicine, acclaimed for their medicinal properties and potential to contribute to the COVID-19 response. We specifically focus on the capability of these polysaccharides to thwart SARS-CoV-2 entry into host cells, a pivotal step in the viral life cycle that informs transmission and pathogenicity. Moreover, we delve into the concept of trained immunity, an innate immune system feature that polysaccharides may potentiate, offering an avenue for a more moderated yet efficacious immune response against various pathogens, including SARS-CoV-2. Our comprehensive overview aims to bolster understanding of the possible integration of these substances within anti-COVID-19 measures, emphasizing the need for rigorous investigation into their potential applications and underlying mechanisms. The insights provided here strongly support ongoing investigations into the adjunctive use of polysaccharides in the management of COVID-19, with the anticipation that such findings could lead to a deeper appreciation and clearer elucidation of the antiviral potentials inherent in complex Chinese herbal remedies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The vascular disrupting agent (VDA) 5,6-dimethylxanthenone-4-acetic acid (DMXAA) induces apoptosis in vascular endothelial cells and leads to tumor hemorrhagic necrosis. While DMXAA has been proven to be a potent agonist of murine stimulator of interferon genes (mSTING), it has little effect on human-STING (hSTING). This species selectivity of DMXAA may explain its effectiveness against solid tumors in mice and its failure in clinical trials. However, DMXAA did reduce tumor volume in some patients during clinical trials. These paradoxical results have prompted us to investigate the anti-tumor mechanism of DMXAA beyond STING in the destruction of tumor vasculature in humans. In this study, we demonstrated that DMXAA binds to both human and mouse macrophage capping protein (CapG), with a KD of 5.839 μM for hCapG and a KD of 2.867 μM for mCapG, as determined by surface plasmon resonance (SPR) analysis. Homology modeling and molecular docking analysis of hCapG indicated that the critical residues involved in the hydrogen bond interaction of DMXAA with hCapG were Arg153, Thr151, and GLN141, Asn234. In addition, electrostatic pi-cation interaction occurred between DMXAA and hCapG. Further functional studies revealed that CapG protein plays a crucial role in the effects of DMXAA on human umbilical endothelial vein cell (HUEVC) angiogenesis and migration, as well as the expression of cytoskeletal proteins actin and tubulin, and the invasion of A549 lung adenocarcinoma cells. Our study has originally uncovered a novel cross-species pathway underlying the antitumor vascular disruption of DMXAA extends beyond STING activation. This finding deepens our understanding of the multifaceted actions of flavonoid VDAs in animal models and in clinical settings, and may provide insights for the precise therapy of DMXAA based on the biomarker CapG protein., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Viral respiratory infections are major human health concerns. The most striking epidemic disease, COVID-19 is still on going with the emergence of fast mutations and drug resistance of pathogens. A few polysaccharide macromolecules from traditional Chinese medicine (TCM) have been found to have direct anti-SARS-CoV-2 activity but the mechanism remains unclear. In this study, we evaluated the entry inhibition effect of Lycium barbarum polysaccharides (LBP) in vitro and in vivo. We found LBP effectively suppressed multiple SARS-CoV-2 variants entry and protected K18-hACE2 mice from invasion with Omicron pseudovirus (PsV). Moreover, we found LBP interfered with early entry events during infection in time-of-addition (TOA) assay and SEM observation. Further surface plasmon resonance (SPR) study revealed the dual binding of LBP with Spike protein and ACE2, which resulted in the disruption of Spike-ACE2 interaction and subsequently triggered membrane fusion. Therefore, LBP may act as broad-spectrum inhibitors of virus entry and nasal mucosal protective agent against newly emerging respiratory viruses, especially SARS-CoV-2., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2024. Published by Elsevier B.V.)

Cellular transitions hold great promise in translational medicine research. However, therapeutic applications are limited by the low efficiency and safety concerns of using transcription factors. Small molecules provide a temporal and highly tunable approach to overcome these issues. Here, we present PC3T, a computational framework to enrich molecules that induce desired cellular transitions, and PC3T was able to consistently enrich small molecules that had been experimentally validated in both bulk and single-cell datasets. We then predicted small molecule reprogramming of fibroblasts into hepatic progenitor-like cells (HPLCs). The converted cells exhibited epithelial cell-like morphology and HPLC-like gene expression pattern. Hepatic functions were also observed, such as glycogen storage and lipid accumulation. Finally, we collected and manually curated a cell state transition resource containing 224 time-course gene expression datasets and 153 cell types. Our framework, together with the data resource, is freely available at http://pc3t.idrug.net.cn/ . We believe that PC3T is a powerful tool to promote chemical-induced cell state transitions., (© 2023. Springer Nature Limited.)

The activation of the microglia plays an important role in the neuroinflammation induced by different stimulations associated with Alzheimer's disease (AD). Different stimulations, such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) and cytokines, trigger a consequence of activation in the microglia with diverse changes of the microglial cell type response in AD. The activation of the microglia is often accompanied by metabolic changes in response to PAMPs, DAMPs and cytokines in AD. Actually, we do not know the distinct differences on the energetic metabolism of microglia when subject to these stimuli. This research assessed the changes of the cell type response and energetic metabolism in mouse-derived immortalized cells (BV-2 cells) induced by a PAMP (LPS), DAMPs (Aβ and ATP) and a cytokine (IL-4) in mouse-derived immortalized cells (BV-2 cells) and whether the microglial cell type response was improved by targeting the metabolism. We uncovered that LPS, a proinflammatory stimulation of PAMPs, modified the morphology from irregular to fusiform, with stronger cell viability, fusion rates and phagocytosis in the microglia accompanied by a metabolic shift to the promotion of glycolysis and the inhibition of oxidative phosphorylation (OXPHOS). Aβ and ATP, which are two known kinds of DAMPs that trigger microglial sterile activation, induced the morphology from irregular to amoebic, and significantly decreased others in the microglia, accompanied by boosting or reducing both glycolysis and OXPHOS. Monotonous pathological changes and energetic metabolism of microglia were observed under IL-4 exposure. Further, the inhibition of glycolysis transformed the LPS-induced proinflammatory morphology and decreased the enhancement of LPS-induced cell viability, the fusion rate and phagocytosis. However, the promotion of glycolysis exerted a minimal effect on the changes of morphology, the fusion rate, cell viability and phagocytosis induced by ATP. Our study reveals that microglia induced diverse pathological changes accompanied by various changes in the energetic metabolism in response to PAMPs, DAMPs and cytokines, and it may be a potential application of targeting the cellular metabolism to interfere with the microglia-mediated pathological changes in AD.

The novel coronavirus disease, COVID-19, has rapidly spread worldwide. Developing methods to identify the therapeutic activity of drugs based on phenotypic data can improve the efficiency of drug development. Here, a state-of-the-art machine-learning method was used to identify drug mechanism of actions (MoAs) based on the cell image features of 1105 drugs in the  LINCS database. As the multi-dimensional features of cell images are affected by non-experimental factors, the characteristics of similar drugs vary considerably, and it is difficult to effectively identify the MoA of drugs as there is substantial noise. By applying the supervised information theoretic metric-learning (ITML) algorithm, a linear transformation made drugs with the same MoA aggregate. By clustering drugs to communities and performing enrichment analysis, we found that transferred image features were more conducive to the recognition of drug MoAs. Image features analysis showed that different features play important roles in identifying different drug functions. Drugs that significantly affect cell survival or proliferation, such as cyclin-dependent kinase inhibitors, were more likely to be enriched in communities, whereas other drugs might be decentralized. Chloroquine and clomiphene, which block the entry of virus, were clustered into the same community, indicating that similar MoA could be reflected by the cell image. Overall, the findings of the present study laid the foundation for the discovery of MoAs of new drugs, based on image data. In addition, it provided a new method of drug repurposing for COVID-19., Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-021-09727-5., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© The Author(s), under exclusive licence to Springer Nature B.V. 2021.)

Excessive stress leads to disruptions of the central nervous system. Individuals' responses to stress and trauma differ from person to person. Some may develop various neuropsychiatric disorders, such as post-traumatic stress disorder, major depression, and anxiety disorders, while others may successfully adapt to the same stressful events. These two neural phenotypes are called susceptibility and resilience. Previous studies have suggested resilience/susceptibility as a complex, non-specific systemic response involving central and peripheral systems. Emerging research of mechanisms underlying resilience is mostly focussing on the physiological adaptation of specific brain circuits, neurovascular impairment of the blood-brain barrier, the role of innate and adaptive factors of the immune system, and the dysbiosis of gut microbiota. In accordance with the microbiota-gut-brain axis hypothesis, the gut microbiome directly influences the interface between the brain and the periphery to affect neuronal function. This review explored several up-to-date studies on the role of gut microbiota implicated in stressful events-related resilience/susceptibility. We mainly focus on the changes in behavior and neuroimaging characteristics, involved brain regions and circuits, the blood-brain barrier, the immune system, and epigenetic modifications, which contribute to stress-induced resilience and susceptibility. The perspective of the gut-brain axis could help to understand the mechanisms underlying resilience and the discovery of biomarkers may lead to new research directions and therapeutic interventions for stress-induced neuropsychiatric disorders., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

A substantial body of evidence has indicated that intracerebral O-linked N-acetyl-β-D-glucosamine (O-GlcNAc), a generalized post-translational modification, was emerging as an effective regulator of stress-induced emotional and cognitive impairments. Our previous studies showed that the Liuwei Dihuang formula (LW) significantly improved the emotional and cognitive dysfunctions in various types of stress mouse models. In the current study, we sought to determine the effects of LW on intracerebral O-GlcNAc levels in chronic unpredictable mild stress (CUMS) mice. The dynamic behavioral tests showed that anxiety- and depression-like behaviors and object recognition memory of CUMS mice were improved in a dose-dependent manner after LW treatment. Moreover, linear discriminate analysis (LEfSe) of genera abundance revealed a significant difference in microbiome among the study groups. LW showed a great impact on the relative abundance of these gut microbiota in CUMS mice and reinstated them to control mouse levels. We found that LW potentially altered the Uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis process, and the abundance of O-GlcNAcase (OGA) and O-GlcNAc transferase (OGT) in CUMS mice, which was inferred using PICRUSt analysis. We further verified advantageous changes in hippocampal O-GlcNAc modification of CUMS mice following LW administration, as well as changes in the levels of OGA and OGT. In summary, LW intervention increased the levels of hippocampal O-GlcNAc modification and ameliorated the emotional and cognitive impairments induced by chronic stress in CUMS mice. LW therefore could be considered a potential prophylactic and therapeutic agent for chronic stress., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huang, Wang, Liu, Wang, Xiao and Zhou.)

Adult neurogenesis plays a crucial role in cognitive function and mood regulation, while aberrant adult neurogenesis contributes to various neurological and psychiatric diseases. With a better understanding of the significance of adult neurogenesis, the demand for improving adult neurogenesis is increasing. More and more research has shown that traditional Chinese medicine (TCM), including TCM prescriptions (TCMPs), Chinese herbal medicine, and bioactive components, has unique advantages in treating neurological and psychiatric diseases by regulating adult neurogenesis at various stages, including proliferation, differentiation, and maturation. In this review, we summarize the progress of TCM in improving adult neurogenesis and the key possible mechanisms by which TCM may benefit it. Finally, we suggest the possible strategies of TCM to improve adult neurogenesis in the treatment of neuropsychiatric disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shen, Jiang and Zhou.)

The chemical warfare agent sulfur mustard (SM) causes severe cutaneous lesions characterized by epidermal cell death, apoptosis, and inflammation. At present, the molecular mechanisms underlying SM-induced injury are not well understood, and there is no standard treatment protocol for SM-exposed patients. Here, we conducted a high-content screening of the Food and Drug Administration (FDA)-approved drug library of 1018 compounds against SM injury on an immortal human keratinocyte HaCaT cell line, focusing on cell survival. We found that the B-Raf inhibitor vemurafenib had an apparent therapeutic effect on HaCaT cells and resisted SM toxicity. Other tested B-Raf inhibitors, both type-I (dabrafenib and encorafenib) and type-II (RAF265 and AZ628), also exhibited potent therapeutic effects on SM-exposed HaCaT cells. Both SM and vemurafenib triggered extracellular signal-related kinase (ERK) activation. The therapeutic effect of vemurafenib in HaCaT cells during SM injury was ERK-dependent, indicating a specific role of ERK in keratinocyte regulatory mechanisms. Furthermore, vemurafenib partially improved cutaneous damage in a mouse ear vesicant model. Collectively, our results provide evidence that the B-Raf inhibitor vemurafenib is a potential therapeutic agent against SM injury, and oncogenic B-Raf might be an exciting new therapeutic target following exposure to mustard vesicating agents.

Stress can affect people's judgment and make them take risky decisions. Abnormal decision-making behavior is a core symptom of psychiatric disorders, such as anxiety, depression, and substance abuse. However, the neuronal mechanisms underlying such impairments are largely unknown. The anterior insular cortex (AIC) is a crucial structure to integrate sensory information with emotional and motivational states. These properties suggest that AIC can influence a subjective prediction in decision-making. In this study, we demonstrated that stressed mice prefer to take more risky choices than control mice using a gambling test. Manipulating the neural activity of AIC or selectively inhibiting the AIC-BLA pathway with chemogenetic intervention resulted in alterations in risk decision-making in mice. Different sexes may have different decision-making strategies in risky situations. Endogenous estrogen levels affect emotional cognition by modulating the stress system function in women. We observed decision-making behavior in mice of different sexes with or without stress experience. The result showed that female mice did not change their choice strategy with increasing risk/reward probability and performed a lower risk preference than male mice after stress. Using the pharmacological method, we bilaterally injected an estrogen receptor (ER) antagonist that resulted in more risky behavior and decreased synaptic plasticity in the AIC of female mice. Our study suggested that the AIC is a crucial region involved in stress-induced alteration of decision-making, and estrogen in the AIC may regulate decision-making behavior by regulating synaptic plasticity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shi, Feng, Zhou, Li, Fu and Zhou.)

Sulfur mustard (SM), an extremely reactive alkylating toxicant, which poses a continuing threat to both military and civilian populations. SM targets three major organs including skin, eyes and lungs. In recent years, more and more clinical findings have shown that cognitive and emotional disorders in veterans intoxicated with SM, such as anxiety, depression, apathy, cognitive decline and so on, which indicated the long time toxic effects on mental and neurological health of SM. The experimental studies in animal and cell models have also found neurotoxicity which are similar to clinical results. However, these neuropsychological problems are not studied well in victims of SM and the mental and neurological complications are often not subjected to treatment or undertreated. Until now, the exact mechanism of the action of SM toxicity has not been elucidated and no specific therapy for its poisoning exists. Therefore, the studies on neurotoxicity of SM should be strengthened. This review summarizes the main progress of clinical and experimental researches on neurotoxicity of SM for the past few years., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Background: Renal and liver dysfunctions are risk factors for mortality in patients with severe aortic stenosis (AS). Transcatheter aortic valve implantation (TAVI) has the potential to break the vicious cycle between AS and hepatorenal dysfunction by relieving aortic valve obstruction., Hypothesis: A part of patients can derive hepatorenal function improvement from TAVI, and this noncardiac benefit improves the intermediate-term outcomes., Methods: We developed this retrospective cohort study in 439 consecutive patients undergoing TAVI and described the dynamic hepatorenal function assessed by model for end-stage liver disease model for end-stage liver disease (MELD)-XI score in subgroups. The endpoint was 2-year all-cause mortality., Results: Receiver-operating characteristic analysis showed that the baseline MELD-XI score of 10.71 was the cutoff point. A high MELD-XI score (>10.71) at baseline was an independent predictor of the 2-year mortality hazard ratio (HR: 2.65 [1.29-5.47], p = .008). After TAVI, patients with irreversible high MELD-XI scores had a higher risk of 2-year mortality than patients who improved from high to low MELD-XI scores (HR: 2.50 [1.06-5.91], p = .03). Factors associated with reversible MELD-XI scores improvement were low baseline MELD-XI scores (≤12.00, odds ratio [OR]: 2.02 [1.04-3.94], p = .04), high aortic valve peak velocity (≥5 m/s, OR: 2.17 [1.11-4.24], p = .02), and low body mass index (≤25 kg/m 2 , OR: 2.73 [1.25-5.98], p = .01)., Conclusion: High MELD-XI score at baseline is an independent predictor for 2-year mortality. Patients with hepatorenal function improvement after TAVI have better outcomes. For patients with irreversible hepatorenal dysfunction after TAVI, further optimization of the subsequent treatment after TAVI is needed to improve the outcomes., (© 2022 The Authors. Clinical Cardiology published by Wiley Periodicals, LLC.)

The heterogeneity of tumor immune microenvironment (TIME) plays important roles in the development and immunotherapy response of hepatocellular carcinoma (HCC). Using machine learning algorithms, we introduced the immune index (IMI), a prognostic model based on the HCC immune landscape. We found that IMI low HCCs were enriched in stem cell and proliferating signatures, and yielded more TP53 mutation and 17p loss compared with IMI high HCCs. More importantly, patients with high IMI exhibited better immune-checkpoint blockade (ICB) response. To facilitate clinical application, we employed machine learning algorithms to develop a gene model of the IMI (IMI G ), which contained 10 genes. According to our HCC cohort examination and single-cell level analysis, we found that IMI G high HCCs exhibited favorable survival outcomes and high levels of NK and CD8 + T cells infiltration. Finally, after coculture with autologous tumor infiltrating lymphocytes, IMI G high tumor cells exhibited a better response to nivolumab treatment. Collectively, the IMI and IMI G may serve as powerful tools for the prognosis, classification and ICB treatment response prediction of HCC., Competing Interests: Declarations of interest None., (Copyright © 2022. Published by Elsevier Ltd.)

Memory accuracy involves two major processes: pattern separation and pattern completion. Pattern separation refers to the ability to reduce overlap among similar inputs to avoid interference, and pattern completion refers to the ability to retrieve the whole information from partial or degraded cues. Impairments in pattern separation/pattern completion contribute to cognitive deficits in several diseases of the nervous system. Therefore, it is better to evaluate both pattern separation and pattern completion in one apparatus. However, few tools are available to assess pattern separation and pattern completion within the same apparatus for rodents. In this study, we designed a series of images with varying degrees of similarity to the correct image to evaluate pattern separation and pattern completion. First, mice were trained to discriminate between two totally different images, and once the correct percentage reached above 77% for two consecutive days, the images with different degrees of similarity were used to measure pattern separation and pattern completion. The results showed the mice performed progressively worse from S0 to S4 (increasing similarity) when discriminating similar images in pattern separation, and the mice performed progressively worse from C0 to C4 (decreasing cues information) when recalling the correct image according to partial cues in pattern completion, implying a good image similarity-dependent manner for memory accuracy evaluation. In sum, we designed a convenient, effective paradigm to evaluate pattern separation and pattern completion based on a touchscreen pairwise discrimination task, which may provide a new method for the studies of the effects and mechanisms of memory accuracy enhancing drugs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Sun, Wang, Han, Zhang, Huang and Zhou.)

Background: Indirectly experiencing traumatic events either by witnessing or learning of a loved one's suffering is associated with the highest prevalence rates of epidemiological features of PTSD. Social species can develop fear by observing conspecifics in distress. Observational fear learning (OFL) is one of the most widely used paradigms for studying fear contagion in mice. However, the impact of empathic fear behavior and social hierarchy on fear transfer in mice is not well understood., Methods: Fear emotions are best characterized in mice by using complementary tests, rather than only freezing behavior, and simultaneously avoiding behavioral variability in different tests across time. In this study, we modified the OFL model by implementing freezing (FZ), open field (OF), and social interaction (SI) tests in a newly designed experimental facility and applied Z-normalization to assess emotionality changes across different behaviors., Results: The integrated emotionality scores revealed a robustly increased emotionality of observer mice and, more importantly, contributed to distinguishing susceptible individuals. Interestingly, fos-positive neurons were mainly found in the interoceptive network, and mice of a lower social rank showed more empathy-like behaviors., Conclusion: Our findings highlight that combining this experimental model with the Z -scoring method yields robust emotionality measures of individual mice, thus making it easier to screen and differentiate between empathic fear-susceptible mice and resilient mice, and refining the translational applicability of these models., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shi, Feng, Shi, Fu and Zhou.)

Cancer cells respond to various stressful conditions through the dynamic regulation of RNA m6A modification. Doxorubicin is a widely used chemotherapeutic drug that induces DNA damage. It is interesting to know whether cancer cells regulate the DNA damage response and doxorubicin sensitivity through RNA m6A modification. Here, we found that doxorubicin treatment significantly induced RNA m6A methylation in breast cancer cells in both a dose- and a time-dependent manner. However, protein arginine methyltransferase 5 (PRMT5) inhibited RNA m6A modification under doxorubicin treatment by enhancing the nuclear translocation of the RNA demethylase AlkB homolog 5 (ALKBH5), which was previously believed to be exclusively localized in the nucleus. Then, ALKBH5 removed the m6A methylation of BRCA1 for mRNA stabilization and further enhanced DNA repair competency to decrease doxorubicin efficacy in breast cancer cells. Importantly, we identified the approved drug tadalafil as a novel PRMT5 inhibitor that could decrease RNA m6A methylation and increase doxorubicin sensitivity in breast cancer. The strategy of targeting PRMT5 with tadalafil is a promising approach to promote breast cancer sensitivity to doxorubicin through RNA methylation regulation., (Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Analysis of drug-induced expression profiles facilitated comprehensive understanding of drug properties. However, many compounds exhibit weak transcription responses though they mostly possess definite pharmacological effects. Actually, as a representative example, over 66.4% of 312,438 molecular signatures in the Library of Integrated Cellular Signatures (LINCS) database exhibit low-transcriptional activities (i.e. TAS-low signatures). When computing the association between TAS-low signatures with shared mechanism of actions (MOAs), commonly used algorithms showed inadequate performance with an average area under receiver operating characteristic curve (AUROC) of 0.55, but the computation accuracy of the same task can be improved by our developed tool Genetic profile activity relationship (GPAR) with an average AUROC of 0.68. Up to 36 out of 74 TAS-low MOAs were well trained with AUROC ≥ 0.7 by GPAR, higher than those by other approaches. Further studies showed that GPAR benefited from the size of training samples more significantly than other approaches. Lastly, in biological validation of the MOA prediction for a TAS-low drug Tropisetron, we found an unreported mechanism that Tropisetron can bind to the glucocorticoid receptor. This study indicated that GPAR can serve as an effective approach for the accurate identification of low-transcriptional activity drugs and their MOAs, thus providing a good tool for drug repurposing with both TAS-low and TAS-high signatures., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: To determine survival rates and the underlying mechanism of genes in the TRIM family in Kidney Clear Cell Carcinoma (KIRC)., Methods: Transcriptional and survival data of TRIM genes in KIRC patients were retrieved from the UCSC Xena, and GEPIA databases. The function of TRIM genes in KIRC was investigated, focusing on potential ubiquitination, miRNAs regulation, and enrichment analysis. Next, TRIM gene survival values were determined, followed by the development of a survival-related signature., Results: Only TRIM26 was down expressed in the carcinoma tissue and had a survival value in KIRC relative to control tissues, which was supplied by vitro experiment. The patients with lower expression of TRIM26 would have the chance to live a shorter time. SNRPB, which also plays a role in ubiquitination, directly interacted with TRIM26. Moreover, two miRNAs (hsa-let-7i-5p, and hsa-miR-1228-5p) that regulated levels of TRIM26 expression were also identified. Next, we constructed a signature (TRIM4/7/27/58/65/72) and found that high-risk scores of the signature were associated with poor survival rates in KIRC patients. while its resultant risk scores were correlated with immune cell components and markers., Conclusions: TRIM26 was differentially expressed between KIRC and normal tissues and had a survival value in the KIRC. hsa-let-7i-5p/hsa-miR-1228-5p-TRIM26-SNRPB was a potential mechanism axis that may play a role on the KIRC cells. A survival signature (TRIM4/7/27/58/65/72) was successfully established to predict the survival of KIRC patients.

Post-traumatic stress disorder (PTSD) can be triggered not only in people who have personally experienced traumatic events but also in those who witness them. Physiological and psychological stress can have different effects on neural activity, but little is known about the underlying mechanisms. There is ample evidence that the insular cortex, especially the anterior insular cortex (aIC), is critical to both the sensory and emotional experience of pain. It is therefore worthwhile to explore the effects of direct and indirect stress on the synaptic plasticity of the aIC. Here, we used a mouse model of observational fear to mimic direct suffering (Demonstrator, DM) and witnessing (Observer, OB) of traumatic events. After observational fear training, using a 64-channel recording system, we showed that both DM and OB mice exhibited a decreased ratio of paired-pulse with intervals of 50 ms in the superficial layers of the aIC but not in the deep layers. We found that theta-burst stimulation (TBS)-induced long-term potentiation (LTP) in OB mice was significantly higher than in DM mice, and the recruitment of synaptic responses occurred only in OB mice. Compared with naive mice, OB mice showed stronger recruitment and higher amplitude in the superficial layers of the aIC. We also used low-frequency stimulation (LFS) to induce long-term depression (LTD). OB mice showed greater LTD in both the superficial and deep layers of the aIC than naive mice, but no significant difference was found between OB and DM mice. These results provide insights into the changes in synaptic plasticity in the aIC after physiological and psychological stress, and suggest that different types of stress may have different mechanisms. Furthermore, identification of the possible causes of the differences in stress could help treat stress-related disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shi, Fu, Shi and Zhou.)

Lycium barbarum is widely used as a functional food and medicinal herb to promote health and longevity in China and in some other Asian countries. In modern pharmacological and chemical studies, the most valuable and well-researched component of L. barbarum is a group of unique water-soluble glycoconjugates that are collectively termed Lycium barbarum polysaccharides (LBPs). Numerous modern pharmacological studies have revealed that LBPs possess antiaging, antidiabetic, antifibrotic, neuroprotective, and immunomodulation properties, while the immunomodulatory effect is primary and is involved in other activities. However, due to their structural heterogeneity and lack of chromophores, it has long been unclear how LBPs work on the immune system. A few studies have recently provided some insights into the proposed mode of action of LBPs, such as structure-activity relationships, receptor recognition, and gut microbiota modulation of LBPs. This review provides a comprehensive overview of the immunoregulating properties of LBPs and their related mechanisms of action., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Environmental quality strongly depends on human behavior patterns. Many environmental challenges are rooted in human actions, and thus, it is believed that these problems can be reduced through the promotion of pro-environmental behaviors (PB). Owing to this reality, the current study aims to reduce the environmental footprint of a hospital by promoting its employees' environment-specific behavior via corporate social responsibility (CSR) and ethical leadership (EL). More importantly, the study also considered the role of female leaders in the proposed relationship. The current study collected the data from the respondents employed in different hospitals of a developing economy through a questionnaire (paper-pencil method). A total of 489 valid responses were collected, which were analyzed by employing the structural equation modeling (SEM) technique. As per the current study's findings, there is a positive relationship between CSR, while EL mediates between CSR and PB. Likewise, the moderating role of female leaders in the proposed relationship was more significant than that of male leaders. More specifically, the study's findings have considerable theoretical and practical implications, as it opens paths for researchers to further investigate the applicability of different dimensions of CSR and the role of gender in environmental sustainability. It provides insight to policymakers on how to restructure their CSR preferences, priorities on the environment, and gender differences.

Neuroinflammation is often accompanied by central nervous system (CNS) injury seen in various CNS diseases, with no specific treatment. Drug repurposing is a strategy of finding new uses for approved or investigational drugs, and can be enabled by the Library of Integrated Network-based Cellular Signatures (LINCS), a large drug perturbation database. In this study, the signatures of Lipopolysaccharide (LPS) were compared with the signatures of compounds contained in the LINCS dataset. To the top 100 compounds obtained, the Quantitative Structure-Activity Relationship (QSAR)-based tool admetSAR was used to identify the top 10 candidate compounds with relatively high blood-brain barrier (BBB) penetration. Furthermore, the seventh-ranked compound, dutasteride, a 5-α-reductase inhibitor, was selected for in vitro and in vivo validation of its anti-neuroinflammation activity. The results showed that dutasteride significantly reduced the levels of IL-6 and TNF-α in the supernatants of LPS-stimulated BV2 cells, and decreased the levels of IL-6 in the hippocampus and plasma, and the number of activated microglia in the brain of LPS administration mice. Furthermore, dutasteride also attenuated the cognitive impairment caused by LPS stimulation in mice. Taken together, this study demonstrates that the LINCS dataset-based drug repurposing strategy is an effective approach, and the predicted candidate, dutasteride, has the potential to ameliorate LPS-induced neuroinflammation and cognitive impairment.

Competing Interests: Funding Support and Author Disclosures The work was supported by National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University (Z20192010). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Cranial radiotherapy is clinically used in the treatment of brain tumours; however, the consequent cognitive and emotional dysfunctions seriously impair the life quality of patients. LW-AFC, an active fraction combination extracted from classical traditional Chinese medicine prescription Liuwei Dihuang decoction, can improve cognitive and emotional dysfunctions in many animal models; however, the protective effect of LW-AFC on cranial irradiation-induced cognitive and emotional dysfunctions has not been reported. Recent studies indicate that impairment of adult hippocampal neurogenesis (AHN) and alterations of the neurogenic microenvironment in the hippocampus constitute critical factors in cognitive and emotional dysfunctions following cranial irradiation. Here, our research further investigated the potential protective effects and mechanisms of LW-AFC on cranial irradiation-induced cognitive and emotional dysfunctions in mice. Methods: LW-AFC (1.6 g/kg) was intragastrically administered to mice for 14 days before cranial irradiation (7 Gy γ-ray). AHN was examined by quantifying the number of proliferative neural stem cells and immature neurons in the dorsal and ventral hippocampus. The contextual fear conditioning test, open field test, and tail suspension test were used to assess cognitive and emotional functions in mice. To detect the change of the neurogenic microenvironment, colorimetry and multiplex bead analysis were performed to measure the level of oxidative stress, neurotrophic and growth factors, and inflammation in the hippocampus. Results: LW-AFC exerted beneficial effects on the contextual fear memory, anxiety behaviour, and depression behaviour in irradiated mice. Moreover, LW-AFC increased the number of proliferative neural stem cells and immature neurons in the dorsal hippocampus, displaying a regional specificity of neurogenic response. For the neurogenic microenvironment, LW-AFC significantly increased the contents of superoxide dismutase, glutathione peroxidase, glutathione, and catalase and decreased the content of malondialdehyde in the hippocampus of irradiated mice, accompanied by the increase in brain-derived neurotrophic factor, insulin-like growth factor-1, and interleukin-4 content. Together, LW-AFC improved cognitive and emotional dysfunctions, promoted AHN preferentially in the dorsal hippocampus, and ameliorated disturbance in the neurogenic microenvironment in irradiated mice. Conclusion: LW-AFC ameliorates cranial irradiation-induced cognitive and emotional dysfunctions, and the underlying mechanisms are mediated by promoting AHN in the dorsal hippocampus and improving the neurogenic microenvironment. LW-AFC might be a promising therapeutic agent to treat cognitive and emotional dysfunctions in patients receiving cranial radiotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wei, Feng, Zhang, Wang, Chu, Shi, Zhou and Zhang.)

It is pivotal and remains challenge for cancer precision treatment to identify the survival outcome interactions between genes, cells and drugs. Here, we present siGCD, a web-based tool for analysis and visualization of the survival interaction of Genes, Cells and Drugs in human cancers. siGCD utilizes the cancer heterogeneity to simulate the manipulated gene expression, cell infiltration and drug treatment, which overcomes the data and experimental limitations. To illustrate the performance of siGCD, we identified the survival interaction partners of EGFR (gene level), T cells (cell level) and sorafenib (drug level), and our prediction was consistent with previous reports. Moreover, we validate the synergistic effect of regorafenib and glyburide, and found that glyburide could significantly improve the regorafenib response. These results demonstrate that siGCD could benefit cancer precision medicine in a wide range of advantageous application scenarios including gene regulatory network construction, immune cell regulatory gene identification, drug (especially multiple target drugs) response biomarker screening and combination therapeutic design., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Researchers have emphasized the positive and negative influences of ambivalent leader-follower relationships, but it is not clear when the ambivalent relationship is associated with good or bad influences. To answer this question, we reviewed the definition and identified 10 different types of ambivalent leader-follower relationships. Further, we demonstrate that the negative outcomes (more inflexibility, disengagement, and worse performance) can be explained by the workplace stressor perspective, and that the positive outcomes (more flexibility, engagement, and better performance) can be explained by paradox view. Finally, drawing from conservation of resources (COR) theory, we integrate workplace stressor framework and the paradox view to address when the ambivalent leader-follower relationship is beneficial or detrimental for followers. We proposed that the degree of ambivalence, support from the third party, and integrative complexity of follower will influence the possible positive or negative influences. Limitations and future directions were also discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhao and Zhou.)

Here, we described the generation of human induced pluripotent stem cells (iPSC) from peripheral blood mononuclear cells (PBMCs) of a 87-year-old female patient with sporadic Alzheimer's disease (sAD) having APOE3 (ε3/ε3) genotype. iPSC line were generated from PBMCs with four factors of OCT4, SOX2, c-MYC and KLF4 using episomal system. The pluripotency of the iPSC line was assessed by embryoid body (EB) formation. Flow cytometry analyses revealed >97% cells positive for the pluripotency markers NANOG, OCT4 and SSEA4. Furthermore, the iPSC line displayed a normal karyotype (46, XX). The iPSC line may provide valuable tools for the study of sAD pathogenesis., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Based on the polarization property of fluorescent dipoles, fluorescence super-resolution microscopy recently has been proposed by modulating the polarization of the excitation light. In this technique, the super-resolution image is reconstructed by processing the polarization-modulated fluorescence image stack with an iteration algorithm. However, the mechanism of resolution improvement by polarization modulation has been questioned. In this paper, the mechanism of resolution enhancement by polarization modulation is analyzed in reciprocal space. The mathematical model and the reconstruction algorithm of fluorescence super-resolution microscopy via polarization modulation are proposed in reciprocal space. The corresponding simulation results and analysis show that polarization modulation can enlarge the highest detected spatial frequency of fluorescence microscopy to achieve super resolution, which verifies the role of polarization modulation in resolution improvement and provides a useful reference to study fluorescence super-resolution microscopy via polarization modulation in reciprocal space.

Background: Querying drug-induced gene expression profiles with machine learning method is an effective way for revealing drug mechanism of actions (MOAs), which is strongly supported by the growth of large scale and high-throughput gene expression databases. However, due to the lack of code-free and user friendly applications, it is not easy for biologists and pharmacologists to model MOAs with state-of-art deep learning approach., Results: In this work, a newly developed online collaborative tool, Genetic profile-activity relationship (GPAR) was built to help modeling and predicting MOAs easily via deep learning. The users can use GPAR to customize their training sets to train self-defined MOA prediction models, to evaluate the model performances and to make further predictions automatically. Cross-validation tests show GPAR outperforms Gene set enrichment analysis in predicting MOAs., Conclusion: GPAR can serve as a better approach in MOAs prediction, which may facilitate researchers to generate more reliable MOA hypothesis.

The cell-type-specific response of neural cells to oxidative stress, a crucial mechanism for accelerating aging and cognitive dysfunction in Alzheimer's disease (AD), is still far from understood. Here, we employed human-induced pluripotent stem cells (hiPSCs)-derived neural stem cells (hiPSC-NSCs), neurons (hiPSC-Neurons), and microglia-like cells (hiPSC-MGLs) from sporadic AD (sAD) patients, age-matched cognitive normal controls (CNCs), and young subjects to observe human neural cell-type response to H 2 O 2 stimulation. Without H 2 O 2 exposure, reactive oxygen species (ROS) cannot be detected in hiPSC-NSCs from all three groups, but the viability of hiPSC-NSCs from AD patients was significantly lower than those of CNCs and young subjects. There were no significant differences in ROS, viabilities, neurite length, and neurite branch points in hiPSC-Neurons among three groups. No significant differences in viabilities, phagocytosis, and secretion of cytokines were observed in hiPSC-MGLs among three groups, but higher ROS levels in sAD hiPSC-MGLs. Under H 2 O 2 exposure, the viability, neurite length, and neurite branch points of hiPSC-Neurons from AD patients reduced more significantly accompanied by more ROS release. H 2 O 2 exposure caused hiPSC-MGLs from AD patients to release more ROS, cytokines, and stronger phagocytosis. Nevertheless, H 2 O 2 exposure had no effect on viability of hiPSC-NSCs. Our results showed hiPSC-Neurons and hiPSC-MGLs were more sensitive to H 2 O 2 than hiPSC-NSCs, which indicated the different response styles of hiPSC-NSCs, hiPSC-Neurons, and hiPSC-MGLs to oxidative stress. HiPSC-derived neural cells from AD patients suffered more severe injury from H 2 O 2 than those of CNCs and young subjects, indicating that the vulnerability to oxidative stress of AD patients can be recapitulated in hiPSCs.

The preparation of a novel Au 6 cluster bearing a bidentate mixed carbene-thiolate ligand is presented. The length of linker between the central benzimidazole and thiolate has a strong effect on the formation of cluster products, with a C 2 chain giving an Au 6 cluster, while a C 3 chain results in no evidence of cluster formation. Density functional theory analysis predicts a non-metallic cluster with a large HOMO-LUMO (3.2-3.6 eV) and optical gap.

Two healthy elderly donated their peripheral blood mononuclear cells (PBMCs). The induced pluripotent stem cell lines (IPTi005-A and IPTi007-A) were reprogrammed by episomal vector system with Yamanaka factors OCT4, SOX2, C-MYC and KLF4. Both the two iPSC lines can differentiate into three germ layers determined by embryoid bodies (EBs) differentiation. Flow cytometry analysis showed that more than 90% cells expressed NANOG, OCT4 and SSEA4. Besides, the iPSC lines of IPTi005-A and IPTi007-A were confirmed to exhibit a normal karyotype. In the studies of age-related disease, the iPSC lines can be used as controls., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Aging is a natural biological process associated with cognitive decline and neuroendocrine-immune system changes; the neuroendocrine-immune system plays crucial role in brain aging and neurodegeneration, and it is essential to discern beneficial attempts to delay the aging progress based on immunological aging. In this study, we have investigated the effects of Traditional Chinese Medicine (TCM)-Liuwei Dihuang decoction (LW)-and donepezil, memantine, and melatonin on cognitive decline in aging mice. The aged SAMR1 mice received oral administration of donepezil (1mg/kg), memantine (10 mg/kg), melatonin (10 mg/kg), and LW (10 g/kg) for 3 months. A shuttle box, Morris water maze, and elevated-zero maze were performed to assess cognitive function, and flowcytometry, Luminex, and radioimmunoassay were performed to measure the lymphocyte subsets, inflammatory factors, and hormones. We observed that survival days of mice was increased with melatonin and LW, the anxiety behavior was significantly improved by memantine, melatonin, and LW treatment, active avoidance responses significantly improved by LW, donepezil, and memantine, the spatial learning ability was significantly improved by donepezil, and LW and melatonin were beneficial to the spatial memory of old mice. For immune function, LW increased CD4 + and CD4 + CD28 + cells and reduced TNF-α, IL-1β, and G-CSF in plasma, and it also promoted the secretion of anti-inflammatory factors IL-4, IL-5, and IL-10 by regulating the active of Th2 cells in spleen. Donepezil and memantine exerted protective effects against CD4 + CD28 + cell decrease caused by aging and reduced the pro-inflammatory factors TNF-α, IL-1β, and G-CSF in plasma. Melatonin could reverse CD8 + CD28 + cell imbalances and increased B cells. For endocrine factors, LW increased TSH levels in the pituitary, and melatonin increased the GH level in blood. Our findings indicated that LW improved the cognitive decline in aging mice, and this might be associated with modulation of the active T cells and HPG axis hormones as well as increasing anti-inflammatory factors. Meanwhile, donepezil and memantine have advantages in regulating adaptive immunity, melatonin has advantages in the regulation of B cells and pituitary hormones, and LW exhibits a better effect on neuroendocrine immune function compared with the others from a holistic point of view. LW might be a potential therapeutic strategy for anti-aging-related syndromes, and it can also provide a value on medication guidance about drug combinations or treatment in clinic., (Copyright © 2020 Zeng, Zhang, Wang, Cheng, Zhang and Zhou.)

Drawing on the goal-setting theory and social cognitive career theory (SCCT), this study empirically proposes an operational definition of career success criteria clarity (CSCC) and further explores its impact on career satisfaction, person-job fit, and subjective well-being through the mediating role of career decision-making self-efficacy (CDSE). A pilot study of 231 samples showed that the CSCC scale had good reliability and validity. To further test the effects of CSCC on crucial employment outcomes, as well as the mediating role of CDSE, 240 employees were included in an additional survey. Structural equation modeling path analysis supported all the expected hypotheses. Results indicated that: (1) CSCC was positively correlated to career satisfaction; (2) CSCC was positively correlated to person-job fit; (3) CSCC was positively correlated to subjective well-being; (4) CSCC was positively correlated to CDSE; (5) CDSE fully mediated the relationship between CSCC and career satisfaction; (6) CDSE fully mediated the relationship between CSCC and person-job fit; and (7) CDSE partly mediated the relationship between CSCC and subjective well-being. The results contributed to social cognitive career theory model and provided suggestions for both the career educators and consultants., (Copyright © 2020 Xin, Zhou, Li and Tang.)

Conventional fluorescence polarization microscopy has been largely used to monitor the orientation and the structural information of biomolecules labeled with fluorescence dipoles but suffers from the optical diffraction limit. Here, we put forward a novel algorithm to simultaneously acquire the super-resolution image and the effective orientation distribution information of dipole clusters at corresponding super-resolution. In this paper, the orientation distribution of dipole clusters is statistically modeled by its mean orientation and orientation deviation, which are, respectively, represented by the middle direction and the opening angle of a sector shape. According to this model and microscopy imaging theory, the joint reconstruction algorithm is deduced mathematically in detail based on the conjugate gradient least-squares method. By applying this algorithm to different samples, the reconstructed results prove more than twice the resolution of wide-field images and the orientation distribution information at corresponding spatial resolution. Furthermore, the high accuracy of this algorithm in reconstructing super-resolution orientation distribution information is verified by Monte Carlo simulations.

The insular cortex, anatomically close to amygdala, is also an integrative hub for sensory, emotional and cognitive function. Growing body of evidences suggest that alterations in insular structure and function have also been implicated in anxiety disorders. However, the reciprocal connections and precise subdivision of insular cortex involved in anxiety activities remains mechanistically unclear. In the present study, using anterograde and retrograde tracing methods, we verified that the anterior (AIa) but not posterior (AIp) agranular insular cortex is a major source of projections to the amygdala. Consistently, excitotoxic lesions only in AIa induced the anxiolytic behaviors and impaired fear memory. Using optogenetics methods, we found that selectively photoactivation of AIa GABAergic neurons remarkably promoted cued fear extinction and relieved anxiety in PSTD mice model. Finally, the participation of AIa in the storage of learned fear is also supported by the abolished LTP after fear conditioning and decreased the cued freezing using protein synthesis inhibitor immediately following training. Our results underscore the importance of AIa in fear and anxiety behavior and suggest that the AIa might share functions and interaction with amygdala in in anxiety related disorders., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This study seeks to examine how and when job crafting trickles down from leaders to followers in a team context. Drawing on social learning theory, we hypothesize that team leaders' job resources mediate the relationship between team leaders' job crafting and team members' job crafting. Empowering leadership is proposed to strengthen the mediation effect, such that under a stronger (higher) empowering leadership style the relationship between team leaders' job resources and team members' job crafting is further strengthened, thereby positively influencing the overall mediated relationship. We tested our multilevel moderated mediation model with leader-subordinate paired data from 64 work teams in seven Chinese enterprises over two time periods. The results support our hypothesized mediated relationship; however, contrary to our prediction, we find that empowering leadership negatively moderates the relationship between team leaders' job resources and team members' job crafting, and weakens the mediation effect of team leaders' job resources. Theoretical and practical implications are discussed.

Fungal bioactive polysaccharides are well known and have been widely used in Asia as a part of the traditional diet and medicine. In fact, some biopolymers (mainly β-glucans or glycoconjugate) have already made their way to the market as antitumor or immunostimulating drugs. In the last decades, the relationship between structure and activity of polysaccharides and their detailed mode of action have been the core of intense research to understand and utilize their medicinal properties. Most of the antitumor polysaccharides belong to conserved β-glucans, with a linear β-(1→3)-glucan backbone and attached β-(1→6) branch. Structurally different β-glucans appear to have different affinities toward their receptors and thus generate markedly different host responses. However, their antitumor activities are mainly influenced by molecular mass, degree of branching, conformation, and structure modification of the polysaccharides. β-Glucans act on several immune receptors including Dectin-1, complement receptor (CR3) and TLR-2/6, then trigger both innate and adaptive response and enhance opsonic and nonopsonic phagocytosis. Various receptor interactions explain the possible mode of actions of polysaccharides., Competing Interests: Conflict of interest No conflict of interest., (© 2020 Elsevier Inc. All rights reserved.)

LW-AFC is a new formula derived from the Liuwei Dihuang decoction, a classical traditional Chinese medicine prescription. Based on our research, LW-AFC is a promising drug for Alzheimer's disease (AD). The studies were conducted primarily in two typical AD mouse models: SAMP8 and APP/PS1 mice. The results showed that LW-AFC could improve many cognitive behaviors, such as spatial learning and memory ability, passive and active avoidance response, and object recognition memory capability. In addition, LW-AFC could also alleviate the AD-like pathology in animal models, such as neuron loss and Aβ deposition. Subsequent studies found that LW-AFC could rebalance hypothalamic-pituitary-adrenal (HPA) axis and hypothalamic-pituitary-gonadal (HPG) axis, and modulate the disturbance of immune system and gut flora. These data suggested that the anti-AD effects of LW-AFC might be mainly via modulating the neuroendocrine immunomodulation (NIM) network. As inhibiting the immune function by immunosuppressant could abolish the protective effects of LW-AFC against long-term potentiation (LTP) impairment model, it is likely that LW-AFC balancing the NIM network is initiated by modulating the immune system., Competing Interests: Conflict of interest The authors confirm that they have no conflicts of interest., (© 2020 Elsevier Inc. All rights reserved.)

A 62-year old sporadic Alzheimer's disease (sAD) male patient with APOE3 (ε3/ε3) genotype donated his peripheral blood mononuclear cells (PBMCs). The induced pluripotent stem cell (iPSC) line was established by episomal vector system with the four factors OCT4, SOX2, C-MYC and KLF4. EB differentiation in vitro showed that iPSC line had a potential to differentiate into three germ layers. More than 90% cells expressed NANOG, OCT4 and SSEA4 detected by flow cytometry. In addition, the iPSC line was karyotypically normal. The iPSC line may provide new valuable tools for studying pathogenesis of sAD and screening candidate drugs for the disease., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Neuroinflammation is known as a typical feature associated with many neurodegenerative diseases including Alzheimer's disease (AD) and impairs the synaptic plasticity of the hippocampus. LW-AFC is an active fraction combination being extracted from Liuwei Dihuang decoction, a classic traditional Chinese medicine prescription. This study aimed to investigate the effects of LW-AFC on synaptic plasticity in mice with lipopolysaccharide (LPS) treatment. The results showed that the administration of LPS caused fever and long-term potentiation (LTP) impairment in mice. The pretreatment with LW-AFC had an antipyretic effect on fever and improved the impaired LTP induced by LPS, alleviated the microglia and astrocytes activation in the hippocampus, regulated the abnormal T-lymphocyte subpopulation in the spleen and blood caused by LPS, and reduced the aberrant secretion of cytokines in the brain and plasma. The compounds paeoniflorin, morroniside, and loganic acid in LW-AFC regulated the TNF- α secretion in non-LPS- and LPS-stimulated BV-2 cells. These data suggest that LW-AFC improves the LPS-induced impairment of LTP and alleviates the activation of glial cells in the hippocampus, which might be associated with modulating immune responses., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper., (Copyright © 2019 Ju Zeng et al.)

Mounting evidence points to alterations in the gut microbiota-neuroendocrine immunomodulation (NIM) network that might drive Alzheimer's Disease (AD) pathology. In previous studies, we found that Liuwei Dihuang decoction (LW) had beneficial effects on the cognitive impairments and gastrointestinal microbiota dysbiosis in an AD mouse model. In particular, CA-30 is an oligosaccharide fraction derived from LW. We sought to determine the effects of CA-30 on the composition and function of the intestinal microbiome in the senescence-accelerated mouse prone 8 (SAMP8) mouse strain, an AD mouse model. Treatment with CA-30 delayed aging processes, ameliorated cognition in SAMP8 mice. Moreover, CA-30 ameliorated abnormal NIM network in SAMP8 mice. In addition, we found that CA-30 mainly altered the abundance of four genera and 10 newborn genera. Advantageous changes in carbohydrate-active enzymes of SAMP8 mice following CA-30 treatment, especially GH85, were also noted. We further found that seven genera were significantly correlated with the NIM network and cognitive performance. CA-30 influenced the relative abundance of these intestinal microbiomes in SAMP8 mice and restored them to SAMR1 mouse levels. CA-30 ameliorated the intestinal microbiome, rebalanced the NIM network, improved the AD-like cognitive impairments in SAMP8 mice, and can thus be a potential therapeutic agent for AD.

Mounting evidence has shown that inflammation might drive Alzheimer's disease (AD) pathology and contribute to its exacerbation. Previous studies have indicated that indomethacin or atorvastatin are beneficial in treating AD; however, no significant clinical effects have been shown. Furthermore, no study has investigated the efficacy of combining these agents for treating AD. This study sought to determine the effect of a combination of indomethacin and atorvastatin in the PrP-hAβPPswe/PS1 ΔE9 (APP/PS1) transgenic AD mouse model. Treatment with indomethacin and atorvastatin ameliorated impairments in spatial learning and memory, and the active avoidance response in APP/PS1 mice. Moreover, we found a suppression of Aβ plaques and decreased concentration of Aβ 1-42 in the hippocampus of APP/PS1 mice following treatment. In addition, indomethacin and atorvastatin ameliorated abnormal cytokine secretion, lymphocyte subset disorder, and hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axis imbalances in APP/PS1 mice. The combination of indomethacin and atorvastatin restored immune and neuroendocrine processes, attenuated pathologic changes and cognitive impairments in APP/PS1 transgenic mice, and could thus be a potential therapeutic agent for AD., (Copyright © 2019. Published by Elsevier B.V.)