Hypocretenolides: collective total syntheses and activities toward metastatic colon cancer.

A concise and collective synthetic route to hypocretenolides was developed for the first time. This route features one-pot addition-alkylation and intramolecular 1,3-dipolar cycloaddition to efficiently assemble the 5/7/6 ring system. Our syntheses enabled multigram preparation of hypocretenolide which facilitated further biological evaluation. Preliminary CCK-8 cytotoxic results of hypocretenolide indicated its IC50 values within 1 µM against 4 colon cancer cell lines. Wound healing and transwell assays suggested the promising inhibitory activities of hypocretenolide toward the migratory capabilities of colon cancer cells in vitro. The animal results confirmed that hypocretenolide can inhibit metastasis of colon cancer cells.

Astrocytic HILPDA promotes lipid droplets generation to drive cognitive dysfunction in mice with sepsis-associated encephalopathy.

AIMS: Sepsis-associated encephalopathy (SAE) is manifested as a spectrum of disturbed cerebral function ranging from mild delirium to coma. However, the pathogenesis of SAE has not been clearly elucidated. Astrocytes play important roles in maintaining the function and metabolism of the brain. Most recently, it has been demonstrated that disorders of lipid metabolism, especially lipid droplets (LDs) dyshomeostasis, are involved in a variety of neurodegenerative diseases. The aim of this study was to investigate whether LDs are involved in the underlying mechanism of SAE. METHODS: The open field test, Y-maze test, and contextual fear conditioning test (CFCT) were used to test cognitive function in SAE mice. Lipidomics was utilized to investigate alterations in hippocampal lipid metabolism in SAE mice. Western blotting and immunofluorescence labeling were applied for the observation of related proteins. RESULTS: In the current study, we found that SAE mice showed severe cognitive dysfunction, including spatial working and contextual memory. Meanwhile, we demonstrated that lipid metabolism was widely dysregulated in the hippocampus by using lipidomic analysis. Furthermore, western blotting and immunofluorescence confirmed that LDs accumulation in hippocampal astrocytes was involved in the pathological process of cognitive dysfunction in SAE mice. We verified that LDs can be inhibited by specifically suppress hypoxia-inducible lipid droplet-associated protein (HILPDA) in astrocytes. Meanwhile, cognitive dysfunction in SAE was ameliorated by reducing A1 astrocyte activation and inhibiting presynaptic membrane transmitter release. CONCLUSION: The accumulation of astrocytic lipid droplets plays a crucial role in the pathological process of SAE. HILPDA is an attractive therapeutic target for lipid metabolism regulation and cognitive improvement in septic patients.

N-C QDs coated with a molecularly imprinted polymer as a fluorescent probe for detection of penicillin.

Many diseases are due to bacterial infections, which are treated by penicillin. Existing methods for penicillin detection have relatively high requirements for sample storage and processing, personnel professionalism, and instruments. Herein, water-soluble N-C quantum dots (QDs) from wheat straw were synthesized in a green way by using an efficient and simple method. The N-C QDs were modified with an imprinted layer by a gel-sol method. Penicillin selectively quenched the fluorescence emission of N-C QDs@MIP, and a linear relationship was obtained in the concentration range of 1.0 × 10-6-15.2 × 10-6 mol L-1. The reliability of the sensor in real sample analysis was satisfactory with results in the range of 93.6%-100%, and the sensor showed good reproducibility and long-term stability. The study provides a simple strategy to fabricate N-C QDs@MIP with a highly selective recognition ability and opens an avenue to develop highly efficient sensing probes for the detection of antibiotics in biological applications.

The cytosolic DNA-sensing cGAS-STING pathway in neurodegenerative diseases.

BACKGROUND: With the widespread prevalence of neurodegenerative diseases (NDs) and high rates of mortality and disability, it is imminent to find accurate targets for intervention. There is growing evidence that neuroimmunity is pivotal in the pathology of NDs and that interventions targeting neuroimmunity hold great promise. Exogenous or dislocated nucleic acids activate the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS), activating the stimulator of interferon genes (STING). The activated STING triggers innate immune responses and then the cGAS-STING signaling pathway links abnormal nucleic acid sensing to the immune response. Recently, numerous studies have shown that neuroinflammation regulated by cGAS-STING signaling plays an essential role in NDs. AIMS: In this review, we summarized the mechanism of cGAS-STING signaling in NDs and focused on inhibitors targeting cGAS-STING. CONCLUSION: The cGAS-STING signaling plays an important role in the pathogenesis of NDs. Inhibiting the cGAS-STING signaling may provide new measures in the treatment of NDs.

Impact of ecological presence in virtual reality tourism on enhancing tourists' environmentally responsible behavior.

In an era where environmental conservation is increasingly critical, identifying pathways through which technological innovations like virtual reality tourism (VRT) can promote sustainable behaviors is vital. This study investigates the impact of 'ecological presence', a newly proposed sub-dimension of presence in VRT, on tourists' environmentally responsible behavior (TERB). Through structural equation modeling and fuzzy set qualitative comparative analysis of data from 290 participants, we unveil that ecological presence-defined as the authenticity and immersion of tourists in virtual ecological environments-significantly bolsters biospheric values, environmental self-identity, and personal norms. Additionally, our findings indicate that ecological presence in VRT indirectly promotes TERB, predominantly through the mediation of enhanced biospheric values and environmental self-identity. Notably, ecological presence, biospheric values, and environmental self-identity constitutes a sufficient condition for achieving a high level of TERB. This research highlights the potential of VRT as an innovative tool for tourism administrators to foster environmental stewardship, offering a novel approach to leveraging technology for conservation efforts.

Disparate macrophage responses are linked to infection outcome of Hantan virus in humans or rodents.

Hantaan virus (HTNV) is asymptomatically carried by rodents, yet causes lethal hemorrhagic fever with renal syndrome in humans, the underlying mechanisms of which remain to be elucidated. Here, we show that differential macrophage responses may determine disparate infection outcomes. In mice, late-phase inactivation of inflammatory macrophage prevents cytokine storm syndrome that usually occurs in HTNV-infected patients. This is attained by elaborate crosstalk between Notch and NF-κB pathways. Mechanistically, Notch receptors activated by HTNV enhance NF-κB signaling by recruiting IKKß and p65, promoting inflammatory macrophage polarization in both species. However, in mice rather than humans, Notch-mediated inflammation is timely restrained by a series of murine-specific long noncoding RNAs transcribed by the Notch pathway in a negative feedback manner. Among them, the lnc-ip65 detaches p65 from the Notch receptor and inhibits p65 phosphorylation, rewiring macrophages from the pro-inflammation to the pro-resolution phenotype. Genetic ablation of lnc-ip65 leads to destructive HTNV infection in mice. Thus, our findings reveal an immune-braking function of murine noncoding RNAs, offering a special therapeutic strategy for HTNV infection.

The effect of two facets of physicians' environmental stress on patients' compliance with COVID-19 guidelines: moderating roles of two types of ego network.

Drawing upon the Conservation of Resources Theory, this study seeks to examine the association between two dimensions of environmental stress experienced by physicians and patients' adherence to COVID-19 guidelines, within the context of a social network framework. A third-wave longitudinal study was employed to gather 439 valid data points in China. Social network analysis and structural equation model were used to test the conceptual model. The results reveal the pivotal role of physicians' environmental stress related to their work and family contexts in influencing patients' adherence to COVID-19 guidelines through the mediation of physicians' information sharing. The ego networks of physicians, encompassing both advice-seeking and friendship ties, were observed to negatively moderate the relationship between stress and resource depletion. Broadly, our study shows the importance of understanding physicians' stress caused by the working and family environments, as these factorsnot only impact the psychological well-being of physicians but also significantly affect patients' compliance with COVID-19 guidelines. In addition, the work offers a framework for understanding the impact of the ego advice-seeking network and the ego friend network.

[Mechanism of myeloid differentiation factor 2 on mediating sepsis-associated encephalopathy].

OBJECTIVE: To investigate the role and underlying mechanism of human myeloid differentiation protein 2 (MD2) in the process of neuronal death induced by lipopolysaccharide (LPS) by establishing an in vitro model of sepsis-associated encephalopathy (SAE) by LPS. METHODS: Healthy C57BL/6J mice at 14-18 days of gestation were selected, and brain cortical tissue was taken from fetal mice. Neurons were stimulated with 0 (control), 1, 5 and 10 g/L of LPS for 24 hours. The release of lactate dehydrogenase (LDH) was detected and the death of neurons was observed. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of inflammatory factors interleukins (IL-6, IL-1ß), in order to determine the optimal dose of LPS for establishing an in vitro neuroinflammation model of SAE. The cells were divided into blank control group and LPS group. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling (TUNEL) was used to discover apoptosis. Western blotting was used to detect the expression of the relevant protein markers activated caspase-3, necroptosis-associated protein neuronal receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and phosphorylated RIPK3 (p-RIPK3). Immunofluorescence chemical staining was used to detect the expressions of p-RIPK3 and microtubule-associated protein 2 (MAP2) to evaluate the type of cell death and the degree of neuronal death. Western blotting was used to detect MD2 expression. Immunofluorescence chemical staining was performed to observe the expression and distribution of p-RIPK3 and MD2 in neurons to assess whether MD2 was involved in the inflammatory response promoting neuronal death. In addition, the cells were divided into blank control group, LPS group, and MD2 interfering peptide group (LPS+TC group), and the levels of IL-6, IL-1ß and LDH were detected to evaluate whether interfering with MD2 can alleviate LPS induced neuroinflammation. RESULTS: 10 g/L LPS induced notable neuronal death, and the release of LDH in neurons stimulated with this concentration for 24 hours was significantly higher than that in the blank control group (relative release: 1.45±0.04 vs. 1.00±0.00, P < 0.01), indicating apoptosis and necroptosis occurred in neurons, and the levels of inflammatory factors IL-6 and IL-1ß were remarkable increased [IL-6 (relative level): 1.94±0.04 vs. 1.00±0.00, IL-1ß (relative level): 1.53±0.09 vs. 1.00±0.00, both P < 0.01]. Compared with the blank control group, the apoptosis of cells, cleaved-caspase-3 expression, the p-RIPK3/RIPK3 ratio, and p-RIPK3 expression around neurons in the LPS group were significantly increased [cleaved-caspase-3/GAPDH: 1.55±0.10 vs. 1.00±0.00, P < 0.01; p-RIPK3/RIPK3 ratio (relative value): 1.54±0.06 vs. 1.00±0.00, P < 0.05], which suggested that typical apoptosis and necroptosis apoptosis occurred in neurons in the septic environment. Furthermore, MD2 expression was significantly increased in the LPS group compared with the blank control group (MD2/GAPDH: 1.91±0.07 vs. 1.00±0.00, P < 0.01), and MD2 expression around neurons was increased, indicating that LPS-induced MD2 upregulation may play a key role in neuroinflammation and induction of neuronal death in sepsis. In addition, compared with the LPS group, the MD2-interfering peptide could reduce the expression levels of inflammatory factors IL-6 and IL-1ß [IL-6 (relative level): 1.16±0.08 vs. 1.94±0.04, IL-1ß (relative level): 1.15±0.05 vs. 1.75±0.09, both P < 0.01] and decrease LDH release (relative release: 1.09±0.01 vs. 1.44±0.04, P < 0.05). CONCLUSIONS: LPS induced neuronal inflammatory responses via MD2, which ultimately leads to apoptosis and necroptosis. Interfering with MD2 reduces inflammation and inhibits neuronal death.

Total Syntheses of Brassicicenes A, R, and T.

Here, we report concise and divergent total syntheses of fusicoccane members brassicicenes A, R, and T. The key feature of the synthesis is the rapid construction of the 5/8/5 tricyclic core via four steps: aldol reaction, Stork-Danheiser transposition, and ring-closing metathesis from known compounds followed by concise oxidation state adjustment.

RIPK3 promotes hantaviral replication by restricting JAK-STAT signaling without triggering necroptosis.

Hantaan virus (HTNV) is a rodent-borne virus that causes hemorrhagic fever with renal syndrome (HFRS), resulting in a high mortality rate of 15%. Interferons (IFNs) play a critical role in the anti-hantaviral immune response, and IFN pretreatment efficiently restricts HTNV infection by triggering the expression of a series of IFN-stimulated genes (ISGs) through the Janus kinase-signal transducer and activator of transcription 1 (JAK-STAT) pathway. However, the tremendous amount of IFNs produced during late infection could not restrain HTNV replication, and the mechanism remains unclear. Here, we demonstrated that receptor-interacting protein kinase 3 (RIPK3), a crucial molecule that mediates necroptosis, was activated by HTNV and contributed to hantavirus evasion of IFN responses by inhibiting STAT1 phosphorylation. RNA-seq analysis revealed the upregulation of multiple cell death-related genes after HTNV infection, with RIPK3 identified as a key modulator of viral replication. RIPK3 ablation significantly enhanced ISGs expression and restrained HTNV replication, without affecting the expression of pattern recognition receptors (PRRs) or the production of type I IFNs. Conversely, exogenously expressed RIPK3 compromised the host's antiviral response and facilitated HTNV replication. RIPK3-/- mice also maintained a robust ability to clear HTNV with enhanced innate immune responses. Mechanistically, we found that RIPK3 could bind STAT1 and inhibit STAT1 phosphorylation dependent on the protein kinase domain (PKD) of RIPK3 but not its kinase activity. Overall, these observations demonstrated a noncanonical function of RIPK3 during viral infection and have elucidated a novel host innate immunity evasion strategy utilized by HTNV.

Autophagy Suppresses Ferroptosis by Degrading TFR1 to Alleviate Cognitive Dysfunction in Mice with SAE.

Sepsis-associated encephalopathy (SAE) is a serious complication of sepsis that is characterized by long-term cognitive impairment, which imposes a heavy burden on families and society. However, its pathological mechanism has not been elucidated. Ferroptosis is a novel form of programmed cell death that is involved in multiple neurodegenerative diseases. In the current study, we found that ferroptosis also participated in the pathological process of cognitive dysfunction in SAE, while Liproxstatin-1 (Lip-1) effectively inhibited ferroptosis and alleviated cognitive impairment. Additionally, since an increasing number of studies have suggested the crosstalk between autophagy and ferroptosis, we further proved the essential role of autophagy in this process and demonstrated the key molecular mechanism of the autophagy-ferroptosis interaction. Currently, we showed that autophagy in the hippocampus was downregulated within 3 days of lipopolysaccharide injection into the lateral ventricle. Moreover, enhancing autophagy ameliorated cognitive dysfunction. Importantly, we found that autophagy suppressed ferroptosis by downregulating transferrin receptor 1 (TFR1) in the hippocampus, thereby alleviating cognitive impairment in mice with SAE. In conclusion, our findings indicated that hippocampal neuronal ferroptosis is associated with cognitive impairment. In addition, enhancing autophagy can inhibit ferroptosis via degradation of TFR1 to ameliorate cognitive impairment in SAE, which shed new light on the prevention and therapy for SAE.

STING strengthens host anti-hantaviral immunity through an interferon-independent pathway.

Hantaan virus (HTNV), the prototype virus of hantavirus, could escape innate immunity by restraining type I interferon (IFN) responses. It is largely unknown whether there existed other efficient anti-hantaviral tactics in host cells. Here, we demonstrate that the stimulator of interferon genes (STING) strengthens the host IFN-independent anti-hantaviral immunity. HTNV infection activates RIG-I through IRE1-XBP 1-mediated ER stress, which further facilitates the subcellular translocation and activation of STING. During this process, STING triggers cellular autophagy by interacting with Rab7A, thus restricting viral replication. To note, the anti-hantaviral effects of STING are independent of canonical IFN signaling. Additionally, neither application of the pharmacological antagonist nor the agonist targeting STING could improve the outcomes of nude mice post HTNV challenge in vivo. However, the administration of plasmids exogenously expressing the mutant C-terminal tail (ΔCTT) STING, which would not trigger the type I IFN responses, protected the nude mice from lethal HTNV infection. In summary, our research revealed a novel antiviral pathway through the RIG-I-STING-autophagy pathway, which offered novel therapeutic strategies against hantavirus infection.

Effect of an Herbal-Based Injection on 28-Day Mortality in Patients With Sepsis: The EXIT-SEP Randomized Clinical Trial.

Importance: Previous research has suggested that Xuebijing injection (XBJ), an herbal-based intravenous preparation, may reduce mortality among patients with sepsis. Objective: To determine the effect of XBJ vs placebo on 28-day mortality among patients with sepsis. Design, Setting, and Participants: The Efficacy of Xuebijing Injection in Patients With Sepsis (EXIT-SEP) trial was a multicenter, randomized double-blind, placebo-controlled trial conducted in intensive care units at 45 sites and included 1817 randomized patients with sepsis (sepsis 3.0) present for less than 48 hours. Patients aged 18 to 75 years with a Sequential Organ Failure Assessment score of 2 to 13 were enrolled. The study was conducted from October 2017 to June 2019. The final date of follow-up was July 26, 2019. Data analysis was performed from January 2020 to August 2022. Interventions: The patients were randomized to receive either intravenous infusion of XBJ (100 mL, n = 911) or volume-matched saline placebo (n = 906) every 12 hours for 5 days. Main Outcomes and Measures: The primary outcome was 28-day mortality. Results: Among the 1817 patients who were randomized (mean [SD] age, 56.5 [13.5] years; 1199 [66.0%] men), 1760 (96.9%) completed the trial. In these patients, the 28-day mortality rate was significantly different between the placebo group and the XBJ group (230 of 882 patients [26.1%] vs 165 of 878 patients [18.8%], respectively; P < .001). The absolute risk difference was 7.3 (95% CI, 3.4-11.2) percentage points. The incidence of adverse events was 222 of 878 patients (25.3%) in the placebo group and 200 of 872 patients (22.9%) in the XBJ group. Conclusions and Relevance: In this randomized clinical trial among patients with sepsis, the administration of XBJ reduced 28-day mortality compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03238742.

What drives the adoption of online health communities? An empirical study from patient-centric perspective.

BACKGROUND: Online health communities (OHCs) provide platforms for patients to seek advice from physicians and receive professional suggestions online. It can improve the efficiency of patients' diagnosis of simple diseases and alleviate hospital congestion. However, few empirical studies have comprehensively explored the factors influencing patients' intention to use OHCs through objective data. This study aims to fill this gap by identifying key factors that influence patients' acceptance of OHCs and proposing effective ways to promote the applications of OHCs in China. METHODS: Based on the Unified Theory of Acceptance and Usage of Technology (UTAUT), extended with additional constructs identified with patients' information demands in OHCs, this study developed a research model and proposed nine hypotheses. An online survey involving 783 valid responses was conducted in China to collect data to validate the proposed model. Confirmatory factor analysis and partial least squares (PLS) path model were conducted for instrument validation and hypothesis testing. RESULTS: Price value, eHealth literacy, and performance expectancy are the most prominent constructs in the study context. Interestingly, relation quality was also found to have a significant positive relationship with behavioral intention. CONCLUSIONS: Based on these findings, OHC operators need to create a user-friendly platform, improve information quality, set reasonable prices, and establish consummate security systems. Physicians and related organizations can raise awareness and assist patients in developing the skills to appropriately comprehend and utilize information in OHCs. This study contributes to both technology adoption theory and practice.

Chaperone-mediated autophagy (CMA) alleviates cognitive impairment by reducing neuronal death in sepsis-associated encephalopathy (SAE).

Sepsis-associated encephalopathy (SAE) is a common and severe complication of sepsis, which causes long-term neurological deficits, such as cognitive impairment. Despite extensive research, there is still lack of specific treatments for SAE. Chaperone-mediated autophagy (CMA), a selective type of autophagy, has been reported to be related to cognitive dysfunctions in many neurodegenerative diseases. The aim of this study was to investigate the alteration of CMA activity in the hippocampus of SAE mice and explore the neuroprotective effect of enhanced CMA. Cecal ligation and puncture (CLP) was conducted to induce SAE. In the contextual fear conditioning test, the ratio of freezing time of CLP mice significantly decreased compared with that of the mice in the Sham group, indicating cognitive impairment in SAE mice. The expression of lysosome-associated membrane protein type 2A (Lamp2a) and chaperone heat shock cognate 71 kDa protein (Hsc70), positive markers for CMA activity, decreased in hippocampal neurons of SAE mice. Although overexpression of Lamp2a in neurons via adeno-associated virus injection in the hippocampus had little effect on the mortality of septic mice, this intervention significantly alleviated the memory impairments in contextual fear conditioning test, Y-maze test and novel objective recognition test, and attenuated the neural death observed in SAE mice. We further demonstrated that the overexpression of Lamp2a in the hippocampus increased the expression of phosphorylated cyclic-AMP response element binding protein (p-CREB), brain-derived neurotrophic factor (BDNF) and B-cell lymphoma-2 (Bcl-2), and suppressed the expression of cleaved caspase-3. Taken together, our study results suggested that the upregulation of CMA activity ameliorated cognitive impairments and neuron loss in SAE mice partially through the p-CREB-BDNF/Bcl-2 signaling pathways, providing a potential therapeutic target for SAE.

The Role of Ferroptosis in Nervous System Disorders.

Ferroptosis is distinct from other apoptotic forms of programmed cell death and is characterized by the accumulation of iron and lipid peroxidation. Iron plays a crucial role in the oxidation of lipids via the Fenton reaction with oxygen. Hence, iron accumulation causes phospholipid peroxidation which induces ferroptosis. Moreover, detoxification by glutathione is disrupted during ferroptosis. A growing number of studies have implicated ferroptosis in nervous system disorders such as depression, neurodegenerative disease, stroke, traumatic brain injury, and sepsis-associated encephalopathy. This review summarizes the pathogenesis of ferroptosis and its relationship with various nervous system disorders.

Selective activation of cholinergic neurotransmission from the medial septal nucleus to hippocampal pyramidal neurones improves sepsis-induced cognitive deficits in mice.

BACKGROUND: Sepsis-associated encephalopathy is characterised by cognitive dysfunction, and might be mediated by deficits in neurotransmission. Reduced cholinergic neurotransmission in the hippocampus impairs memory function. We assessed real-time alterations of acetylcholine neurotransmission from the medial septal nucleus to the hippocampus, and explored whether sepsis-induced cognitive deficits can be relieved by activating upstream cholinergic projections. METHOD: Lipopolysaccharide (LPS) injection or caecal ligation and puncture (CLP) was used to induce sepsis and associated neuroinflammation in wild-type and mutant mice. Adeno-associated viruses for calcium and acetylcholine imaging, and for optogenetic and chemogenetic modulation of cholinergic neurones were injected into the hippocampus or medial septum, and a 200-µm-diameter optical fibre was implanted to collect acetylcholine and calcium signals. Cholinergic activity of the medial septum was manipulated and combined with cognitive assessment after LPS injection or CLP. RESULTS: Intracerebroventricular LPS injection reduced postsynaptic acetylcholine (from 0.146 [0.001] to 0.0047 [0.0005]; p=0.004) and calcium (from 0.0236 [0.0075] to 0.0054 [0.0026]; p=0.0388) signals in hippocampal Vglut2-positive glutamatergic neurones, whereas optogenetic activation of cholinergic neurones in the medial septum reversed LPS-induced reductions in these two signals. Intraperitoneal LPS injection decreased acetylcholine concentration in the hippocampus (476 [20] pg ml-1 to 382 [14] pg ml-1; p=0.0001). Reduction in long-term potentiation (238 [23] % to 150 [12] %; p=0.0082) and enhancement of hippocampal pyramidal neurone action potential frequency (5.8 [1.5] Hz to 8.2 [1.8] Hz; p=0.0343) were relieved, and neurocognitive performance was improved by chemogenetic activation of cholinergic innervation of the hippocampus 3 days after LPS injection in septic mice. CONCLUSIONS: Systemic or local LPS reduced cholinergic neurotransmission from the medial septum to hippocampal pyramidal neurones, and their selective activation alleviated defects in hippocampal neuronal function and synaptic plasticity and ameliorated memory deficits in sepsis model mice through enhanced cholinergic neurotransmission. This provides a basis for targeting cholinergic signalling to the hippocampus in sepsis-induced encephalopathy.

PINK1 protects against dendritic cell dysfunction during sepsis through the regulation of mitochondrial quality control.

BACKGROUND: Dendritic cell (DC) dysfunction plays a central role in sepsis-induced immunosuppression. Recent research has indicated that collective mitochondrial fragmentation contributes to the dysfunction of immune cells observed during sepsis. PTEN-induced putative kinase 1 (PINK1) has been characterized as a guide for impaired mitochondria that can keep mitochondrial homeostasis. However, its role in the function of DCs during sepsis and the related mechanisms remain obscure. In our study, we elucidated the effect of PINK1 on DC function during sepsis and its underlying mechanism of action. METHODS: Cecal ligation and puncture (CLP) surgery and lipopolysaccharide (LPS) treatment were used as in vivo and in vitro sepsis models, respectively. RESULTS: We found that changes in mitochondrial PINK1 expression of DCs paralleled changes in DC function during sepsis. The ratio of DCs expressing MHC-II, CD86, and CD80, the mRNAs level of dendritic cells expressing TNF-α and IL-12, and the level of DC-mediated T-cell proliferation were all decreased, both in vivo and in vitro during sepsis, when PINK1 was knocked out. This suggested that PINK1 knockout prevented the function of DCs during sepsis. Furthermore, PINK1 knockout inhibited Parkin RBR E3 ubiquitin protein (Parkin)-dependent mitophagy and enhanced dynamin-related protein 1 (Drp1)-related mitochondrial fission, and the negative effects of PINK1 knockout on DC function following LPS treatment were reversed by Parkin activation and Drp1 inhibitor. Knockout of PINK1 also increased apoptosis of DCs and the mortality of CLP mice. CONCLUSION: Our results indicated that PINK1 protected against DC dysfunction during sepsis through the regulation of mitochondrial quality control.

[Rapamycin alleviates cognitive impairment in mice with sepses-associated encephalopathy by promoting autophagy].

Objective To investigate the role of rapamycin in alleviating cognitive dysfunction by promoting autophagy in mice with sepsis-associated encephalopathy (SAE). Methods The model of SAE mice was established by caecal ligation and perforation (CLP). Murine sepsis score (MSS) was used to evaluate the severity of sepsis in SAE mice. And the cognitive function was tested by the contextual fear conditioning test. The expression levels of microtubule-associated protein 1 light chain 3 (LC3) and P62 in the hippocampus of the SAE mice were detected by Western blot analysis. Furthermore, the expression and distribution of LC3 in the hippocampal neurons were observed by immunofluorescence. Results The mortality of CLP-induced mice reached 41.7% with 14 days after the procedure, and significant cognitive dysfunction was detected in the surviving mice. Meanwhile, autophagy in the hippocampal tissue was impaired 14 days after CLP. The cognitive dysfunction of SAE mice was alleviated by promoting autophagy via rapamycin. Conclusion Rapamycin alleviated the cognitive dysfunction of SAE mice by promoting autophagy in the hippocampal neurons.

Factors influencing patients' opt-in intention of exchanging health information.

Introduction: Health information exchange (HIE) exhibits tremendous benefits in improving the quality of healthcare and reducing healthcare costs. However, it also poses challenges related to data security, data privacy, patient engagement, etc. Objective: This study aimed to explore the factors affecting patients' opt-in intention to HIE by using an empirical study based on the theory of planned behavior. Methods: A Web-based survey was conducted involving 501 valid participants in China (69% validity rate). Results: Information sensitivity and perceived HIE transparency affected the patients' opt-in intention to HIE through the mediation of perceived behavior control and trust in HIE. Information sensitivity negatively influenced perceived behavior control (-0.551, P < 0.001) and trust in HIE (-0.489, P < 0.001). Perceived transparency of HIE positively influenced perceived behavior control (0.396, P < 0.001) and trust in HIE (0.471, P < 0.001). Moreover, patients' opt-in intention to HIE can be positively affected by perceived HIE transparency (0.195, P < 0.001) and trust in HIE (0.294, P < 0.001). In addition, the moderating effect of health status was positive and significant between trust in HIE and opt-in intention to HIE but not between the perceived behavior control and opt-in intention to HIE. Conclusion: This study contributes to the theory of planned behavior and enriches the literature on HIE efforts. HIE administrators should design personalized health services on the basis of these different health statuses to successfully achieve patients' opt-in intention to HIE.