Design and tribological performance of graphene nanofluids dispersed by dragging effect of bicomponent gelator.

Nanofluids have excellent lubrication and high thermal conductivity. However, the agglomeration and sedimentation produced by the large surface energy of nanoparticles in base liquid threaten the long-term dispersion stability and impact the wide application of nanofluid. In this work, based on the self-assemble behavior and continuous network structure formed by low molecular weight organic gelator, the uniform clusters were formed through regulating the kinetics behavior in the gelling process. The dragging effect was demonstrated by oleic acid - sodium dodecyl sulfate (OA-SDS) bicomponent gelator and graphene oxide (GO) nanosheets. The results showed that GO nanofluids dispersed by OA-SDS were stable for more than 12 months. The well-dispersed GO nanofluid exhibited better anti-friction and anti-wear properties under both immersion and electrostatic minimum quantity lubrication conditions. Moreover, the lower contact angle, surface tension and droplet size of nanofluids after charging improved the wettability on the frictional interface. The GO adsorption film formed on the friction interface protected the tribochemical reaction film of iron oxide and prevented the occurrence of sintering of base oil.

Association between physical activity and allostatic load among pregnant women.

Allostatic load (AL) in pregnant women is associated with maternal and infant health outcomes. Whether physical activity (PA) is a modifiable factor associated with AL during pregnancy is unknown. In this cross-sectional study, including 725 pregnant women in 3 different trimesters, 8 biomarkers were included, and the high-risk quartile approach based on sample distribution was used to construct AL index (ALI). ALI <2 was defined as a low level and ≥2 as a high level. Student's t-test or Mann-Whitney U test and chi-squared test or Fisher exact test were used to compare differences in AL with different demographic characteristics among pregnant women. The relationship between PA and AL in pregnant women was analyzed using a binary logistic regression model. The results show that the detection rate of high-risk AL during pregnancy was 47.3%. In the adjusted model, sufficient PA was related to a lower AL than insufficient PA (OR = .693, 95%CI:.494,.971; p = .033). Compared with low- and high-intensity PAs, moderate-intensity PA was associated with lower AL (OR = .645, 95%CI:.447,.930; p = .019). The results suggest that PA is a modifiable factor related to AL, and intervention is recommended to be carried out in the first trimester to prevent the increased likelihood of high AL as pregnancy progresses. In addition, health care personnel should encourage pregnant women to participate in PA, especially moderate-intensity PA, in order to obtain lower AL and promote maternal and child health.

Knockout of microglial Hv1 proton channel reduces neurotoxic A1 astrocytes and neuronal damage via the ROS/STAT3 pathway after spinal cord injury.

Spinal cord injury (SCI) causes severe functional deficits and neuronal damage, accompanied by intense glial activation. The voltage-gated proton channel Hv1, selectively expressed on microglia, is associated with SCI progression. However, the effect of Hv1 on the phenotypes and functions of reactive astrocytes after SCI remains unclear. Here, we combined Hv1 knockout (Hv1-/- ) mice and T10 spinal cord contusion to investigate the effects of microglial Hv1 on SCI pathophysiology and the phenotypes and functions of reactive astrocytes. After SCI, astrocytes proliferated and activated in the peri-injury area and exhibited an A1-dominant phenotype. Hv1 knockout reduced neurotoxic A1 astrocytes and shifted the dominant phenotype of reactive astrocytes from A1 to A2, enhancing synaptogenesis promotion, phagocytosis, and neurotrophy of astrocytes. Moreover, synaptic and axonal remodeling as well as motor recovery after SCI benefited from the improved astrocytic functions of Hv1 knockout. Furthermore, exogenous and endogenous reactive oxygen species (ROS) in astrocytes after SCI were reduced by Hv1 knockout. Our in vitro results showed that inhibition of ROS reduced the neurotoxic A1 phenotype in primary astrocytes via the STAT3 pathway. Similar to the effect of Hv1 knockout, the application of the ROS scavenger N-acetylcysteine reduced SCI-induced neurotoxic A1 astrocytes in vivo. Based on the in vivo and vitro results, we elucidated that microglial Hv1 knockout promotes synaptic and axonal remodeling in SCI mice by decreasing neurotoxic A1 astrocytes and increasing neuroprotective A2 astrocytes via the ROS/STAT3 pathway. Therefore, the Hv1 proton channel is a promising target for the treatment of SCI.

MiR196a-5p in extracellular vesicles released from human nasopharyngeal carcinoma enhance the phagocytosis and secretion of microglia by targeting ROCK1.

The microenvironment of the brain has become increasingly recognized as an essential regulator in metastatic and primary brain tumors. Recent studies demonstrate that circulating tumor-derived exosomes are critical for the brain tumor microenvironment. Nasopharyngeal carcinoma (NPC), a malignant tumor of the head and neck, often invades the skull base but infrequently extends to brain parenchyma. Neurobiological communication between microglia and tumor-derived extracellular vesicles (EVs) has been extensively studied, but how NPC cells regulate the immune microenvironment in the brain remains unknown. Here, we report that NPC derived EVs lead to increased microglial phagocytosis and proliferation, and heightened levels of IL-6, IL-8, CXCL1 and TGF-ß1. Analysis of microRNAs in EVs reveal that miR196a-5p is the major effector microRNA. Moreover, we demonstrate an enrichment of miR196a-5p in the plasmatic EVs of NPC patients. Further investigation demonstrated that miR196a-5p was transferred to microglia and regulated microglial structure and functions by downregulating the expression of ROCK1. Therefore, these data indicate that NPC-derived EVs are potent modulators of microglial functions in brain microenvironment. Regardless of brain colonization, EVs-mediated functional changes in microglia may be a universal phenomenon that results in the alteration of the tumor host's microenvironment in the brain.

The role of self-esteem and emotion regulation in the associations between childhood trauma and mental health in adulthood: a moderated mediation model.

BACKGROUND: High levels of childhood trauma (CT) have been observed in adults with mental health problems. Herein, we investigated whether self-esteem (SE) and emotion regulation strategies (cognitive reappraisal (CR) and expressive suppression (ES)) affect the association between CT and mental health in adulthood, including depression and anxiety symptoms. METHODS: We performed a cross-sectional study of 6057 individuals (39.99% women, median age = 34 y), recruited across China via the internet, who completed the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Childhood Trauma Questionnaire (CTQ), Self-esteem Scale (SES), and Emotion Regulation Questionnaire (ERQ). Multivariate linear regression analysis and bias-corrected percentile bootstrap methodologies were used to assess the mediating effect of SE, and hierarchical regression analysis and subgroup approach were performed to examine the moderating effects of emotion regulation strategies. RESULTS: After controlling for age and sex, we found that (1) SE mediated the associations between CT and depression symptoms in adulthood (indirect effect = 0.05, 95% confidence interval [CI]: 0.04-0.05, 36.2% mediated), and CT and anxiety symptoms in adulthood (indirect effect = 0.03, 95% CI: 0.03-0.04, 32.0% mediated); (2) CR moderated the association between CT and SE; and (3) ES moderated the association between of CT and mental health in adulthood via SE, and such that both the CT-SE and SE-mental health pathways were stronger when ES is high rather than low, resulting the indirect effect was stronger for high ES than for low ES. CONCLUSIONS: These findings suggested that SE plays a partially mediating role in the association between CT and mental health in adulthood. Furthermore, ES aggravated the negative effect of CT on mental health in adulthood via SE. Interventions such as emotional expression training may help reduce the detrimental effects of CT on mental health. TRIAL REGISTRATION: The study was registered on http://www.chictr.org.cn/index.aspx and the registration number was ChiCTR2200059155.

Associations of Socioeconomic Factors and Unhealthy Lifestyles with Allostatic Load: A Meta-analysis.

BACKGROUND: Allostatic load (AL) is a biological tool for objectively assessing chronic stress and has been discussed inconsistently for its correlation with socioeconomic factors and unhealthy lifestyles. Therefore, this meta-analysis was performed to explore the impact of socioeconomic factors and unhealthy lifestyles on AL. METHOD: Different databases, including Web of Science, PubMed, EBSCOhost, Embase, CNKI, VIP, SinoMed, and Wanfang, were searched from inception to June 6, 2023. A total of 25 studies, reporting the correlations of seven socioeconomic factors and three unhealthy lifestyles with AL, were finally included. The pooled odds ratios (OR) and 95% confidence intervals (CIs) were examined using random-effect and fixed-effect models. Literature quality, heterogeneity, and publication bias were evaluated. RESULTS: The meta-analysis showed a significantly increased risk of high AL in the older individuals as compared to the younger ones (OR = 1.05, 95% CI 1.04-1.06), in the individual with low education as compared to those with high education (OR = 1.25, 95% CI 1.05-1.48), and in the individuals with low physical activities as compared to those with high physical activities (OR = 1.44, 95% CI 1.26-1.64). This meta-analysis also showed a significantly decreased risk of high AL in the individuals with high income as compared to those with low income (OR = 0.77, 95% CI 0.71-0.83) and in women as compared to men (OR = 0.80, 95% CI 0.80-0.81). CONCLUSION: This meta-analysis showed older people, men, and people having low physical activity, low income, and low education were more likely to have a high AL. TRIAL REGISTRATION: This meta-analysis was registered on the PROSPERO database with trial registration number CRD42022326105. Instead of providing information at registration, we added an author (Tingyu Mu), who provided critical revisions to the paper in this meta-analysis.

Microglial Hv1 proton channels promote white matter injuries after chronic hypoperfusion in mice.

Microglia are critical in damage/repair processes during ischemic white matter injury (WMI). Voltage-gated proton channel (Hv1) is expressed in microglia and contributes to nicotinamide adenine dinucleotide phosphate oxidase complex-dependent production of reactive oxygen species (ROS). Recent findings have shown that Hv1 is involved in regulating luminal pH of M1-polarized microglial phagosomes and inhibits endocytosis in microglia. We previously reported that Hv1 facilitated production of ROS and pro-inflammatory cytokines in microglia and enhanced damage to oligodendrocyte progenitor cells from oxygen and glucose deprivation. To investigate the role of Hv1 in hypoperfusion-induced WMI, we employed mice that were genetically devoid of Hv1 (Hv1-/- ), as well as a model of subcortical vascular dementia via bilateral common carotid artery stenosis. Integrity of myelin was assessed using immunofluorescent staining and transmission electron microscopy, while cognitive impairment was assessed using an eight-arm radial maze test. Hv1 deficiency was found to attenuate bilateral common carotid artery stenosis-induced disruption of white matter integrity and impairment of working memory. Immunofluorescent staining and western blotting were used to assay changes in oligodendrocytes, OPCs, and microglial polarization. Compared with that in wild-type (WT) mice, Hv1-/- mice exhibited reduced ROS generation, decreased pro-inflammatory cytokines production, and an M2-dominant rather than M1-dominant microglial polarization. Furthermore, Hv1-/- mice exhibited enhanced OPC proliferation and differentiation into oligodendrocytes. Results of mouse-derived microglia-OPC co-cultures suggested that PI3K/Akt signaling was involved in Hv1-deficiency-induced M2-type microglial polarization and concomitant OPC differentiation. These results suggest that microglial Hv1 is a promising therapeutic target for reducing ischemic WMI and cognitive impairment.

Microglial Hv1 exacerbates secondary damage after spinal cord injury in mice.

The pathological process of spinal cord injury (SCI) is complex, particularly during secondary damage that triggers a multiphasic glial reaction consisting of both detrimental and beneficial effects. Deletion of a novel voltage-gated proton channel (Hv1) functionally expressed in microglia has been shown to confer neuroprotection during ischemic stroke. Here, we hypothesized that microglial Hv1 may also participate in the process of SCI through modulating glial responses. To test this hypothesis, we employed an SCI model in Hv1-knockout (Hv1-/-) and wild type (WT) mice and assessed resulting microglial polarization, accumulation of pro-inflammatory cytokines, astrocytic activation, oligodendrocytic apoptosis, lesion sizes, and demyelinated areas. Compared with post-SCI results in WT mice, post-SCI Hv1-/- mice exhibited an M2-dominant microglial polarization, decreased accumulation of microglia, and reduced production of pro-inflammatory factors such as tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1ß). Additionally, Hv1-/- mice had significantly attenuated reactive astrogliosis and reduced expression of chondroitin sulphate proteoglycans (CSPGs) after SCI. Furthermore, Hv1 deficiency reduced SCI-induced oligodendrocytic apoptosis, demyelinated areas, and cavity formation. Collectively, our results provide the first evidence suggesting that microglial Hv1 may be a multi-mechanism therapeutic target for the treatment of SCI.

Deficiency of the microglial Hv1 proton channel attenuates neuronal pyroptosis and inhibits inflammatory reaction after spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) causes neurological dysfunction with devastating consequences. SCI pathogenesis is accompanied by inflammasome activation and neuronal damage. But the spatial pattern and the time course of neuronal pyroptosis and apoptosis after SCI should be further elucidated. The microglial voltage-gated proton channel (Hv1) is implicated in reactive oxygen species (ROS)-induced neuronal damage following ischemic stroke. However, there is a lack of quantification on the neuronal pyroptosis and apoptosis associated with microglial Hv1 after SCI. METHODS: We analyzed spatial and temporal characteristics of neuronal pyroptosis and apoptosis following SCI and investigated the effects of Hv1 deficiency on neuronal pyroptosis and the nod-like receptor 3 (NLRP3) inflammasome pathway by using a mouse model of SCI. We tested the effects of Hv1-deficient microglia on ROS production in vivo and examined the relationship between ROS and neuronal pyroptosis in vitro. RESULTS: We observed that apoptosis was detected closer to the injury core than pyroptosis. The incidence of neuronal apoptosis peaked on day 1 after SCI and occurred before pyroptosis. Hv1 deficiency reduced neuronal apoptosis and NLRP3-inflammasome-mediated pyroptosis, improved axonal regeneration, and reduced motor deficits. SCI led to elevated ROS levels, whereas Hv1 deficiency downregulated microglial ROS generation. In vitro, ROS upregulated neuronal pyroptosis and activated the NLRP3 inflammasome pathway, both of which were reversed by addition of a ROS scavenger. Our results suggested that microglial Hv1 regulated neuronal apoptosis and NLRP3-induced neuronal pyroptosis after SCI by mediating ROS production. CONCLUSION: Following SCI, neuronal pyroptosis lasted longer and occurred farther away from the injury core compared with that of neuronal apoptosis. Microglial Hv1 deficiency downregulated microglial ROS generation and reduced apoptosis and NLRP3-induced neuronal pyroptosis. Our findings may provide novel insights into Hv1-associated mechanisms underlying neuronal damage after SCI.

Polyunsaturated fatty acid supplement alleviates depression-incident cognitive dysfunction by protecting the cerebrovascular and glymphatic systems.

INTRODUCTION: Depression, the most prevalent mood disorder, has high comorbidity with cerebrovascular disease and cognitive decline. However, there is little understanding of the cellular mechanisms involved in depression and its comorbid cerebrovascular damage and cognition impairment. Here, we tested the prediction that the chronic unpredictable mild stress (CUMS) mouse model would manifest in disturbed glymphatic function and that dietary supplementation with polyunsaturated fatty acids (PUFA) could ameliorate these deficits while alleviating the depression-associated cognitive decline. METHODS: To test the treatment effects of PUFA or Es on behaviours, we applied the tail suspension, open field, and sucrose preference tests to assess depressive symptoms, and applied the Morris water maze test to assess cognition in groups of control, chronic unpredictable mild stress (CUMS), PUFA, and escitalopram (Es) treatment. We measured the extracellular concentrations of dopamine (DA), 5-hydroxytryptamine (5-HT) and noradrenaline (NA) in microdialysates from prefrontal cortex (PFC) by liquid chromatography mass spectrometry. Glia cells and inflammatory factors were analysed with fluorescent immunochemistry and western blot, respectively. We tested brain vasomotor function with two-photon and laser speckle imaging in vivo, and measured glymphatic system function by two-photon imaging in vivo and fluorescence tracer imaging ex vivo, using awake and anesthetized mice. Besides, we monitored cortical spreading depression by laser speckle imaging system. AQP4 depolarization is analysed by fluorescent immunochemistry and western blot. RESULTS: We confirmed that CUMS elicited depression-like and amnestic symptoms, accompanied by decreased monoamines neurotransmitter concentration in PFC and upregulated neuroinflammation markers. Moreover, CUMS mice showed reduced arterial pulsation and compliance in brain, and exhibited depolarized expression of AQP4, thus indicating glymphatic dysfunction both in awake and anesthetized states. PUFA supplementation rescued depression-like behaviours of CUMS mice, reduced neuroinflammation and cerebrovascular dysfunction, ultimately improved cognitive performance, all of which accompanied by restoring glymphatic system function. In contrast, Es treatment alleviated only the depression-like behavioural symptoms, while showing no effects on glymphatic function and depression-incident cognitive deficits. CONCLUSIONS: The CUMS depression model entails suppression of the glymphatic system. PUFA supplementation rescued most behavioural signs of depression and the associated cognitive dysfunction by restoring the underlying glymphatic system disruption and protecting cerebral vascular function.

Molecular and clinical relationship between live-attenuated Japanese encephalitis vaccination and childhood onset myasthenia gravis.

OBJECTIVE: The incidence of childhood onset myasthenia gravis (CMG) in China is higher than that in other countries; however, the reasons for this are unclear. METHODS: We investigated the clinical and immunological profiles of CMG, and assessed the potential precipitating factors. For the mouse studies, the possible implication of vaccination in the pathogenesis was explored. RESULTS: In our retrospective study, 51.22% of the 4,219 cases of myasthenia gravis (MG) were of the childhood onset type. The cohort study uncovered that the pathophysiology of CMG was mediated by immune deviation, rather than through gene mutations or virus infections. The administration of the live-attenuated Japanese encephalitis vaccine (LA-JEV), but not the inactivated vaccine or other vaccines, in mice induced serum acetylcholine receptor (AChR) antibody production, reduced the AChR density at the endplates, and decreased both muscle strength and response to repetitive nerve stimulation. We found a peptide (containing 7 amino acids) of LA-JEV similar to the AChR-α subunit, and immunization with a synthesized protein containing this peptide reproduced the MG-like phenotype in mice. INTERPRETATION: Our results describe the immunological profile of CMG. Immunization with LA-JEV induced an autoimmune reaction against the AChR through molecular mimicry. These findings might explain the higher occurrence rate of CMG in China, where children are routinely vaccinated with LA-JEV, compared with that in countries, where this vaccination is not as common. Efforts should be made to optimize immunization strategies and reduce the risk for developing autoimmune disorders among children. Ann Neurol 2018;84:386-400.

Focal Solute Trapping and Global Glymphatic Pathway Impairment in a Murine Model of Multiple Microinfarcts.

Microinfarcts occur commonly in the aging brain as a consequence of diffuse embolic events and are associated with the development of vascular dementia and Alzheimer's disease. However, the manner in which disperse microscopic lesions reduce global cognitive function and increase the risk for Alzheimer's disease is unclear. The glymphatic system, which is a brain-wide perivascular network that supports the recirculation of CSF through the brain parenchyma, facilitates the clearance of interstitial solutes including amyloid ß and tau. We investigated whether glymphatic pathway function is impaired in a murine model of multiple microinfarcts induced by intraarterial injection of cholesterol crystals. The analysis showed that multiple microinfarcts markedly impaired global influx of CSF along the glymphatic pathway. Although suppression of global glymphatic function was transient, resolving within 2 weeks of injury, CSF tracers also accumulated within tissue associated with microinfarcts. The effect of diffuse microinfarcts on global glymphatic pathway function was exacerbated in the mice aged 12 months compared with the 2- to 3-month-old mice. These findings indicate that glymphatic function is focally disrupted around microinfarcts and that the aging brain is more vulnerable to this disruption than the young brain. These observations suggest that microlesions may trap proteins and other interstitial solutes within the brain parenchyma, increasing the risk of amyloid plaque formation.SIGNIFICANCE STATEMENT Microinfarcts, small (<1 mm) ischemic lesions, are strongly associated with age-related dementia. However, how these microscopic lesions affect global cognitive function and predispose to Alzheimer's disease is unclear. The glymphatic system is a brain-wide network of channels surrounding brain blood vessels that allows CSF to exchange with interstitial fluid, clearing away cellular wastes such as amyloid ß. We observed that, in mice, microinfarcts impaired global glymphatic function and solutes from the CSF became trapped in tissue associated with microinfarcts. These data suggest that small, disperse ischemic lesions can impair glymphatic function across the brain and trapping of solutes in these lesions may promote protein aggregation and neuroinflammation and eventually lead to neurodegeneration, especially in the aging brain.

Kruppel-like factor 4 inhibits non-small cell lung cancer cell growth and aggressiveness by stimulating transforming growth factor-ß1-meidated ERK/JNK/NF-κB signaling pathways.

Non-small cell lung cancer is one of the most common epithelial tumors that cause the most common cancer-related mortality due to invasive ability. Research has found that Kruppel-like factor 4, a zinc-finger transcription factor, plays a critical role in the tumor evolution and progression. However, the molecular signal pathways mediated by Kruppel-like factor 4 in the progression of non-small cell lung cancer cells have not been well understood yet. In this study, we investigated the possible role and potential mechanism of Kruppel-like factor 4 in growth and aggressiveness of non-small cell lung cancer cells. Results showed that Kruppel-like factor 4 is downregulated in non-small cell lung cancer cells. Here, we found that Kruppel-like factor 4 knockdown promoted growth and aggressiveness of non-small cell lung cancer cells, as well as enhanced apoptotic resistance induced by tunicamycin. We also found that Kruppel-like factor 4 overexpression significantly suppressed growth and aggressiveness of non-small cell lung cancer cells. Apoptosis rate of non-small cell lung cancer cells induced by tunicamycin was promoted by Kruppel-like factor 4 overexpression. Kruppel-like factor 4 overexpression inhibited transforming growth factor-ß1, extracellular signal-regulated protein kinase, C-jun N-terminal kinase, and nuclear factor-κB expression levels in non-small cell lung cancer cells. Mechanistically, Kruppel-like factor 4-mediated tumorigenesis involved suppression of a transforming growth factor-ß1-meidated extracellular signal-regulated protein kinase/C-jun N-terminal kinase/nuclear factor-κB transcriptional program in non-small cell lung cancer cells. Our results revealed that Kruppel-like factor 4 overexpression non-small cell lung cancer cell reduces tumor growth in experimental mice. Overall, these data indicate the inhibitory role of Kruppel-like factor 4 in non-small cell lung cancer cells and elaborate a potential molecular signal pathway involving in growth and aggressiveness. Findings identify Kruppel-like factor 4 can be regarded as a possible new molecular agent for designing novel therapeutic protein drug for lung cancer treatment to control non-small cell lung cancer growth.

Elevated Homocysteine Level Related to Poor Outcome After Thrombolysis in Acute Ischemic Stroke.

BACKGROUND Hyperhomocysteinemia (HHcy) is a well-known risk factor for ischemic stroke. However, whether HHcy can influence the treatment outcome of acute ischemic stroke (AIS) patients has yet to be fully determined. In this study, we investigated the relationship between serum homocysteine (Hcy) level and prognosis in AIS patients who received tissue plasminogen activator (tPA) treatment. MATERIAL AND METHODS Patients were recruited according to the research criteria and grouped by their serum Hcy levels. Neurological outcome was evaluated by National Institute of Health Stroke Scale (NIHSS) score system before and 1 week after treatment, and functional outcome was evaluated by modified Rankin Scale (MRS) score system after 3 months. All patients took CT/MRI examination to detect cerebral hemorrhage in 24 hours after tPA treatment. Receiver operating characteristic curve (ROC) was employed to assess if serum homocysteine level can be used as an index to predict the outcome after tPA treatment. RESULTS The mean (±SD) serum Hcy level of 194 patients was 22.62±21.23 µmol/L. After 1-week tPA treatment, the NIHSS scores of high Hcy level group were significantly higher than those of low level group (p<0.05), meantime the high Hcy group showed obvious symptomatic intracerebral hemorrhage risk after 24 hours (p<0.05). Poor outcome was presented in mRS score results after 3 months in high Hcy level group, which compared with low Hcy level group (p<0.01). The ROC showed that Hcy level was a moderately sensitive and specific index to predict the prognosis with an optimal cut-off value at 19.95 µmol/L (sensitivity [58.2%], specificity [80.3%]). CONCLUSIONS High serum homocysteine level could potentially predict poor prognosis in acute ischemic stroke patients after tPA treatment.

Impairment of paravascular clearance pathways in the aging brain.

OBJECTIVE: In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid (ISF). Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. The objective of this study was to evaluate whether the efficiency of CSF-ISF exchange and interstitial solute clearance is impaired in the aging brain. METHODS: CSF-ISF exchange was evaluated by in vivo and ex vivo fluorescence microscopy and interstitial solute clearance was evaluated by radiotracer clearance assays in young (2-3 months), middle-aged (10-12 months), and old (18-20 months) wild-type mice. The relationship between age-related changes in the expression of the astrocytic water channel aquaporin-4 (AQP4) and changes in glymphatic pathway function was evaluated by immunofluorescence. RESULTS: Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparenchymally injected amyloid-ß was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF-ISF exchange. INTERPRETATION: We propose that impaired glymphatic clearance contributes to cognitive decline among the elderly and may represent a novel therapeutic target for the treatment of neurodegenerative diseases associated with accumulation of misfolded protein aggregates.

Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain.

CSF from the subarachnoid space moves rapidly into the brain along paravascular routes surrounding penetrating cerebral arteries, exchanging with brain interstitial fluid (ISF) and facilitating the clearance of interstitial solutes, such as amyloid ß, in a pathway that we have termed the "glymphatic" system. Prior reports have suggested that paravascular bulk flow of CSF or ISF may be driven by arterial pulsation. However, cerebral arterial pulsation could not be directly assessed. In the present study, we use in vivo two-photon microscopy in mice to visualize vascular wall pulsatility in penetrating intracortical arteries. We observed that unilateral ligation of the internal carotid artery significantly reduced arterial pulsatility by ~50%, while systemic administration of the adrenergic agonist dobutamine increased pulsatility of penetrating arteries by ~60%. When paravascular CSF-ISF exchange was evaluated in real time using in vivo two-photon and ex vivo fluorescence imaging, we observed that internal carotid artery ligation slowed the rate of paravascular CSF-ISF exchange, while dobutamine increased the rate of paravascular CSF-ISF exchange. These findings demonstrate that cerebral arterial pulsatility is a key driver of paravascular CSF influx into and through the brain parenchyma, and suggest that changes in arterial pulsatility may contribute to accumulation and deposition of toxic solutes, including amyloid ß, in the aging brain.

[Retracted] Total flavonoids suppress lung cancer growth via the COX­2­mediated Wnt/ß­catenin signaling pathway.

[This retracts the article DOI: 10.3892/ol.2020.11271.].

Characterizing cerebrospinal fluid mobility using heavily T2-weighted 3D fast spin echo (FSE) imaging with improved multi-directional diffusion-sensitized driven-equilibrium (iMDDSDE) preparation.

Cerebrospinal fluid (CSF) flow patterns and their relationship with arterial pulsation can depict the function of glymphatic system (GS). We propose an improved multi-directional diffusion-sensitized driven-equilibrium (iMDDSDE) prepared heavily T2-weighted 3D FSE (iMDDSDE-HT2) magnetic resonance imaging (MRI) method to noninvasively assess the mobility (MO) of CSF distributed in the ventricles and perivascular spaces (PVS). This method could obtain 3D high resolution (1 mm isotropic) imaging of CSF MO with full brain coverage within five min and distinguish the CSF MO across different pulse phases using a peripheral pulse unit (PPU). The MO curves had the largest amplitude value in the PVS of middle cerebral artery (11.11 × 10-9 m2/s) and the largest amplitude growth rate in the posterior cerebral artery (189%). The average coefficient of variations (CVs) in non-pulse trigger and pulse phase 1 and 3 were 0.11, 0.10 and 0.09 respectively. The MO in older healthy participants was lower compared to the young participants, and the MO in cerebral major artery stenosis patients with acute ischemia stroke (AIS) were lower compared to those without AIS in several ventriclar ROIs (P < 0.05). This sequence is a clinically feasible method to effectively evaluate CSF flow patterns in human brain.

Associations between sleep duration trajectories and risk of cardio-metabolic disease among middle-aged and older Chinese adults.

BACKGROUND: The association of a single time-point measure of sleep duration with cardio-metabolic disease has been extensively studied, but few studies have focused on the impact of sleep duration trajectory. This study aims to model the sleep duration trajectory as predictors for the subsequent development of cardio-metabolic disease. METHODS: This study recruited a notably large population (n = 9883) of subjects aged at least 45 years from the China Health and Retirement Longitudinal Study (CHARLS), who participated in sequential surveys conducted in 2011, 2013, 2015, and 2018. Sleep duration trajectories were plotted using data of night sleep duration recorded at intervals from 2011 to 2015 by latent class trajectory model. The onset of cardio-metabolic diseases from 2015 to 2018 were confirmed and then the risk of different sleep duration trajectories on incident cardio-metabolic disease was examined using cox proportional hazards regression model. RESULTS: We identified four sleep duration trajectories. Compared to the normal-stable trajectory, the short-stable trajectory was significantly associated with higher risk of incident stroke (hazard ratio [HR], 1.32; 95 % confidence interval [CI], 1.02 to 1.70), dyslipidemia (HR, 1.22; 95%CI, 1.01 to 1.49), and diabetes (HR, 1.42; 95%CI, 1.13 to 1.78) within three years of follow-up, and the short-increasing trajectory predicted a higher risk of incident stroke (HR, 2.38; 95%CI, 1.25 to 4.55). CONCLUSIONS: Short sleep trajectory could increase the risk of incident stroke, dyslipidemia, and diabetes, and an increasing sleep trajectory was associated with increased risk of incident stroke among middle-aged and older Chinese adults.