Contrast-enhanced transcranial Doppler for the detection of right-to-left shunt: A new provocation method with a syringe-modified Valsalva maneuver.

BACKGROUND: Contrast-enhanced transcranial Doppler (cTCD) study has been established as one of the most common investigations for detecting right-to-left shunt (RLS). Although the conventional Valsalva maneuver (c-VM) has been used to increase the sensitivity of cTCD for RLS, efforts are still needed to improve the detection rate further. We proposed a new provocation method with a syringe-modified Valsalva maneuver (sm-VM) during cTCD and compared the efficacy of this strategy with cTCD measured at resting and with the provocation of c-VM. METHODS: Consecutive patients with suspicion of RLS who underwent cTCD in our institution between September 27, 2021, and April 1, 2022, were included in this study. Examination of cTCD was performed separately at the resting state and provoked with c-VM and sm-VM. The overall proportion of patients with RLS and their distribution with different RLS grades were compared. RESULTS: A total of 389 patients (mean age: 49.37 years, male: 52.2%) were included in this study. The positive rate for RLS was significantly higher for cTCD detected with sm-VM than those detected at resting state and with c-VM (46.8% vs. 21.6% and 34.2%, all p < .05). Besides, cTCD detected with sm-VM was also associated with a higher proportion of patients with grade III RLS than those detected at resting state and with c-VM (11.3% vs. 1.8% and 0%, all p < .05). CONCLUSIONS: Compared to cTCD detected at resting state and with c-VM, cTCD with sm-VM could further increase the positive detection rate of RLS.

Melatonin Improves Mitochondrial Dysfunction and Attenuates Neuropathic Pain by Regulating SIRT1 in Dorsal Root Ganglions.

Neuropathic pain is a debilitating chronic pain condition and is refractory to the currently available treatments. Emerging evidence suggests that melatonin exerts analgesic effects in rodent models of neuropathic pain. Nevertheless, the exact underlying mechanisms of the analgesic effects of melatonin on neuropathic pain are largely unknown. Here, we observed that spinal nerve ligation (SNL) in rats L5 and L6 induced an obvious decrease in the 50% paw withdrawal threshold (PWT) and paw withdrawal latency (PWL), indicating the induction of mechanical allodynia and the hyperalgesia, and melatonin prevented the genesis and maintenance of mechanical allodynia and the hyperalgesia. Notably, the inhibitory action of melatonin on SNL-induced mechanical allodynia and heat hypersensitivity was inhibited by a SIRT1 inhibitor (EX527). Melatonin treatment increased the expression of neuronal sirtuin1 (SIRT1) in DRGs following nerve injury. Furthermore, melatonin treatment restored the injury-dependent decrease in mitochondrial membrane potential and peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and reduced the injury-dependent increase in hydrogen peroxide and 8-hydroxy-2-deoxyguanosine (8-OHdG), which was inhibited by EX527. In addition, we found that EX527 impeded the inhibitory effects of melatonin on the SNL-induced increased expression of cytokines tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß). In conclusion, the above data demonstrated that melatonin alleviated mechanical allodynia and hyperalgesia induced by peripheral nerve injury via SIRT1 activation. Melatonin resolved mitochondrial dysfunction-oxidative stress-dependent and neuroinflammation mechanisms that were driven by SIRT1 after nerve injury.

Estimation of the global prevalence, incidence, years lived with disability of rheumatoid arthritis in 2019 and forecasted incidence in 2040: results from the Global Burden of Disease Study 2019.

OBJECTIVE: We aimed to provide a better understanding of the secular trends in rheumatoid arthritis (RA) burden at the regional and national levels, contributing to identifying the areas with high burden needs and finding the potential areas requiring additional attention, which will facilitate the development of strategies tailored to RA burden. METHOD: Data were obtained from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 study. We presented the secular trends in the prevalence, incidence, and years lived with disability (YLDs) of RA needs by sex, age, sociodemographic index (SDI), region, country, and category between 1990 and 2019 using data from the GBD 2019 study. The age-standardized rates (ASR) and its estimated annual percentage changes (EAPCs) are employed to describe the secular trends in RA. RESULTS: Globally, there were an estimated 18.5 million [95% confidence interval (CI) 31.53 to 41.74)] prevalent cases of RA, with 1.07 million (95% CI 0.95 to 1.18) incident cases per year and almost 2.43 million YLDs (95% CI 1.68 to 3.28) in 2019. The age-standardized prevalence and incidence rates estimated for RA were 224.25 per 100,000 and 12.21 per 100,000 in 2019, with EAPCs of 0.37 (95% CI - 0.32, 0.42) and 0.30 (95% CI 0.25 to 0.34), respectively. The corresponding age-standardized YLDs estimated was 29.35 per 100,000 in 2019, with an EAPC of 0.38 (95% CI: 0.33, 0.43). During the study period, the ASR of RA was consistently higher in females than in males. Moreover, the age-standardized YLD rate of RA was associated with the sociodemographic index (SDI) in 2019 across all 204 countries and territories (R = 0.28). The projections indicate that the age-standardized incidence rates (ASIR) trend will continue to increase from 2019 to 2040, with a projected ASIR of 10.48 and 4.63/100,000 for females and males, respectively. CONCLUSIONS: RA is prevalent and remains a significant global public health challenge. Globally, the burden of RA has increased over the past 30 years and will continue to increase. Prevention and early treatment of RA are pivotal to avoiding disease onset and alleviating the enormous burden. Key Points • The burden of rheumatoid arthritis is increasing globally. • Global estimates indicate that the number of RA incident cases will increase 1.4-fold globally, from approximately 1.07 million at the end of 2019 to approximately 1.5 million by 2040.

Correlation between sedentary activity, physical activity and bone mineral density and fat in America: National Health and Nutrition Examination Survey, 2011-2018.

We compared the relationship between sedentary activity (SA) and physical activity (PA) with bone mineral density (BMD) and body fat percentage in the United States and found a negative association between SA and BMD and a positive association with body fat percentage. A positive association between PA and BMD and a negative association with body fat percentage. SA and PA are associated with changes in skeletal parameters and body fat percentage, and we aimed to investigate and compare the relationship between SA, PA and bone mineral density (BMD) and body fat percentage in men and women. We assessed the relationship between SA, PA and BMD and body fat percentage in 9787 Americans aged 20-59 years (mean age 38.28 ± 11.39 years) from NHANES 2011-2018. BMD and body fat percentage were measured by dual-energy X-ray bone densitometry (DXA). We used multiple linear regression models to examine the relationships between SA, PA and lumbar spine BMD and total body fat percentage, adjusted for a large number of confounding factors. After adjusting for race/ethnicity, age, alcohol and smoking behavior, body mass index (BMI), total protein, blood calcium, blood uric acid, cholesterol, blood phosphorus, vitamin D, and blood urea nitrogen, SA was negatively associated with lumbar spine BMD (ß = - 0.0011 95% CI - 0.0020 to - 0.0002, P = 0.022), and SA was positively associated with total fat percentage (ß = PA was positively associated with lumbar BMD (ß = 0.0046 95% CI 0.0010 to 0.0082, P = 0.012) and there was a negative association between PA and body fat percentage (ß = - 1.177 95% CI - 1.326 to -1.027, P < 0.001). Our results show that physical activity is a key component of maintaining bone health in both men and women and is strongly associated with lower body fat percentages. Sedentary activity is negatively correlated with bone density and is strongly associated with an increase in body fat percentage. Healthcare policy makers should consider reducing sedentary activity and increasing physical activity when preventing osteoporosis and obesity.

3D mapping of intra-articular calcaneal fractures.

To determine the pattern of intra-articular calcaneal fractures (ICFs) by a three-dimensional (3D) mapping and determine whether there were consistent fracture patterns and comminution zones. In this study, 67 patients with ICFS by CT scan were included. The calcaneal fractures fragments in CT were multiplanar reconstructed and virtual reduced. 3D heat mapping was subsequently created by graphically superimposing all fracture lines onto a standard calcaneal template. The cohort included 26 (38.8%) left calcaneal fractures, 27 (40.30%) right calcaneal fractures, and 14 (20.9%) cases with bilateral fractures. Comminuted fractures accounted for 92.5%. Sagittal 3D mapping shows that the fracture line is mainly concentrated at the critical angle of Gissane and extending rear to the posterior of the tuberosity of the lateral wall and the anterior of the medial process of the calcaneus tuberosity but with more significant variation in the medial wall. The average angle of fracture lines concerning the long calcaneal axis (LCA) was 29.1° and 19.2° in the lateral and medial walls. Axial 3D mapping shows that fracture lines were primarily concentrated in the anterior area to the posterior joint facet and extending along the rear joint facet and calcaneus sulcus to the posteriorly of the tuberosity. The mean angle of fracture lines concerning the LAC was 11° in the axial wall. Our data provided elucidated that ICFs have consistent characteristic fracture patterns and comminution zones. This study provides visual guidelines for understanding fracture morphology, which may assist with fracture classification, preoperative planning, development of fixation concepts.

AdipoRon Engages Microglia to Antinociception through the AdipoR1/AMPK Pathway in SNI Mice.

Background: Microglia-associated neuroinflammation plays a crucial role in the initiation and development of neuropathic pain (NeuP). AdipoRon is an analog of adiponectin that exerts an anti-inflammatory effect in various diseases through the adiponectin receptor 1 (AdipoR1) signaling mechanism. Adenosine monophosphate-activated protein kinase (AMPK) is a downstream target of AdipoR1, and the AdipoR1/AMPK pathway is involved in the regulation of inflammation. This study is aimed at investigating whether AdipoRon could alleviate NeuP by inhibiting the expression of microglia-derived tumor necrosis factor-alpha (TNF-α) through the AdipoR1/AMPK pathway. Methods: In vivo, the NeuP model was established in mice through the spared nerve injury. The von Frey test was used to detect the effect of AdipoRon on the mechanical paw withdrawal threshold. Western Blot was performed to detect the effects of AdipoRon on the expression of TNF-α, AdipoR1, AMPK, and p-AMPK. Immunofluorescence was performed to observe the effects of AdipoRon on spinal microglia. In vitro, lipopolysaccharide (LPS) was used to induce inflammatory responses in BV2 cells. The effect of AdipoRon on cell proliferation was detected by CCK-8. qPCR was used to examine the effects of AdipoRon on the expression of TNF-α and polarization markers. And the effect of AdipoRon on the AdipoR1/AMPK pathway was confirmed by Western Blot. Results: Intraperitoneal injection of AdipoRon alleviated mechanical nociception in SNI mice, and the application of AdipoRon reduced the expression of TNF-α and the number of microglia in the ipsilateral spinal cord. Additionally, AdipoRon decreased the protein level of AdipoR1 and increased the protein level of p-AMPK in the ipsilateral spinal cord. In vitro, AdipoRon inhibited BV2 cell proliferation and reversed LPS-induced TNF-α expression and polarization imbalance. Furthermore, AdipoRon reversed the LPS-induced increase in AdipoR1 expression and decrease in p-AMPK expression in BV2 cells. Conclusions: AdipoRon may alleviate NeuP by reducing microglia-derived TNF-α through the AdipoR1/AMPK pathway.

Characteristics of submental muscles function and hyoid bone movement in patients with dysphagia after stroke.

BACKGROUND: Dysphagia is one of the common complications after stroke. Dysphagia significantly increases the probability of serious adverse consequences. The purpose of this study was to compare the characteristics of submental muscles electromyography and hyoid motion parameters between patients with dysphagia after stroke and healthy controls, and whether there is a synergistic effect between the function of the submental muscles and the movement of the hyoid. METHODS: Fifteen patients with post-stroke dysphagia and fifteen healthy adults simultaneously underwent the videofluoroscopic and surface electromyography of the submental muscles while swallowing 5 ml of concentrated liquid barium sulphate. The electromyographic signal of the submental muscles was analysed along with parameters of hyoid movement. FINDINGS: Stage transition duration and duration of surface electromyographic activity were extended significantly in post-stroke dysphagia patients(P < 0.05). Surface electromyography amplitude and hyoid movement were significantly reduced in patients (P < 0.05). There was a significant correlation between the maximum hyoid movement distance and the peak sEMG amplitude in healthy controls (r = 0.660, P = 0.014), but not in patients with dysphagia after stroke (r = 0.425, P = 0.148). INTERPRETATION: Submental muscles electromyographic signal changes in patients may be the result of uncoordinated muscle contractions and decreased muscle strength. Furthermore, the reduced hyoid movement distance may be due to impaired function of the submental muscles. In addition, the submental muscles and hyoid movement or other swallowing structures functions were impaired to varying degrees, resulting in the disappearance of the correlation between the maximum movement distance of the hyoid and the peak amplitude.

Comorbid depressive symptoms can aggravate the functional changes of the pain matrix in patients with chronic back pain: A resting-state fMRI study.

Objective: The purposes of this study are to explore (1) whether comorbid depressive symptoms in patients with chronic back pain (CBP) affect the pain matrix. And (2) whether the interaction of depression and CBP exacerbates impaired brain function. Methods: Thirty-two patients with CBP without comorbid depressive symptoms and thirty patients with CBP with comorbid depressive symptoms were recruited. All subjects underwent functional magnetic resonance imaging (fMRI) scans. The graph theory analysis, mediation analysis, and functional connectivity (FC) analysis were included in this study. All subjects received the detection of clinical depressive symptoms and pain-related manifestations. Result: Compared with the CBP group, subjects in the CBP with comorbid depressive symptoms (CBP-D) group had significantly increased FC in the left medial prefrontal cortex and several parietal cortical regions. The results of the graph theory analyses showed that the area under the curve of small-world property (t = -2.175, p = 0.034), gamma (t = -2.332, p = 0.023), and local efficiency (t = -2.461, p = 0.017) in the CBP-D group were significantly lower. The nodal efficiency in the ventral posterior insula (VPI) (t = -3.581, p = 0.0007), and the network efficiency values (t = -2.758, p = 0.008) in the pain matrix were significantly lower in the CBP-D group. Both the topological properties and the FC values of these brain regions were significantly correlated with self-rating depression scale (SDS) scores (all FDR corrected) but not with pain intensity. Further mediation analyses demonstrated that pain intensity had a mediating effect on the relationship between SDS scores and Pain Disability Index scores. Likewise, the SDS scores mediated the relationship between pain intensity and PDI scores. Conclusion: Our study found that comorbid depressive symptoms can aggravate the impairment of pain matrix function of CBP, but this impairment cannot directly lead to the increase of pain intensity, which may be because some brain regions of the pain matrix are the common neural basis of depression and CBP.

NRBF2 regulates the chemoresistance of small cell lung cancer by interacting with the P62 protein in the autophagy process.

Reversing chemotherapy resistance in small cell lung cancer (SCLC) is crucial to improve patient prognosis. The present study aims to investigate the underlying mechanisms in SCLC chemoresistance. We see that nuclear receptor binding factor 2 (NRBF2) is a poor prognostic factor in SCLC. The effects of NRBF2 on chemoresistance were determined in SCLC. The underlying molecular mechanisms of NRBF2 in the autophagy process in SCLC were examined. NRBF2 positively regulated autophagy, leading to drug resistance in SCLC. The MIT domain of NRBF2 directly interacted with the PB1 domain of P62. This interaction increased autophagic P62 body formation, revealing the regulatory role of NRBF2 in autophagy. Notably, NRBF2 was directly modulated by the transcription factor XRCC6. The MIT domain of NRBF2 interacts with the PB1 domain of P62 to regulate the autophagy process, resulting in SCLC chemoresistance. NRBF2 is likely a useful chemotherapy response marker and therapeutic target in SCLC.

LANCL1 as the Key Immune Marker in Neuropathic Pain.

Objective: This study is to explore key immune markers and changes of immune microenvironment in neuropathic pain (NeuP). Method: The data sets of GSE145199 and GSE145226 in Gene Expression Omnibus (GEO) database was used to analyze, and the key immune markers were verified by GSE70006 and GSE91396, and the infiltration degree of immune cells in different samples were analyzed by CIBERSORT analysis package. Results: In this study, we found a key immune marker, namely, LANCL1. Regulatory axis closely related to LANCL1 has also been found, namely, miR-6325/LANCL1 axis. In the immune infiltration analysis, we also found that the LANCL1 is positively correlated with T cells CD4 naïve (r = 0.880, p < 0.05). Conclusion: In this study, we found that LANCL1 may be a protective factor for NeuP, and the miR-6325/LANCL1 axis may be involved in the occurrence and development of NeuP. Cascade reactions including mast cells, macrophages, and T cells may be an important reason for the aggravation of nerve damage.

Lonicerin attenuates house dust mite-induced eosinophilic asthma through targeting Src/EGFR signaling.

Eosinophilic asthma is the predominant phenotype of asthma, and although these patients are sensitive to glucocorticoid therapy, they also experience many side effects. Lonicerin is a kind of bioflavonoid isolated from the Chinese herb Lonicera japonica Thunb, which has anti-inflammatory and immunomodulatory effects. The aim of this study was to elucidate the effects of lonicerin on eosinophilic asthma and its potential mechanisms. Here, we established a house dust mite (house dust mite)-induced eosinophilic asthma model in BALB/c mouse, and evaluated the effects of lonicerin on it. Our results showed that lonicerin significantly reduced airway hyperresponsiveness the number of inflammatory cells (especially eosinophils) and the elevation of interleukin (IL)-4, IL-5, IL-13 and eotaxin in bronchoalveolar lavage fluid (BALF) supernatants of mice. Additionally, lonicerin also eminently blunted inflammatory infiltration and mucus secretion, as well as mRNA levels of Mucin 5AC (MUC5AC) in lung tissue. Furthermore, results of network pharmacology and molecular docking revealed that Src kinase and epidermal growth factor receptor may be the potential targets responsible for the effects of lonicerin. Finally, in vivo experiments confirmed that lonicerin inhibited activation of the Src/EGFR pathway by decreasing their phosphorylation. Taken together, the present study demonstrated that lonicerin could suppress HDM-induced eosinophilic asthma in mice through inhibiting the activation of Src/EGFR pathway, which also provides a basis for further research as a new potentially therapeutic agent for eosinophilic asthma and its underlying mechanisms in the future.

Effect of Low-Frequency Repetitive Transcranial Magnetic Stimulation on Executive Function and Its Neural Mechanism: An Event-Related Potential Study.

Objective: Executive function refers to the conscious control of thinking and behavior in psychological process. Executive dysfunction widely exists in a variety of neuropsychiatric diseases, and is closely related to the decline of daily living ability and function. This study intends to explore the effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) on executive function and its neural mechanism by using event-related potential (ERP), so as to provide basis for further study on the relationship between cerebral cortex and executive function. Methods: Task switching paradigm was used to study the cognitive flexibility in executive function. Thirty-one healthy subjects were randomly assigned to receive rTMS stimulations (1 Hz rTMS or sham rTMS) to the left dorsolateral prefrontal cortex (DLPFC) twice. The switching task and the electroencephalography EEG recordings were performed before (pre-rTMS/pre-sham rTMS) and immediately after the end of the rTMS application (post-rTMS/post-sham rTMS). Results: The analysis of RTs showed that the main effects of switching and time were statistically significant. Further analysis revealed that the RT of rTMS stimulation was longer than sham rTMS at post-stimulation. ERP analysis showed that there was a significant switching effect in frontal and central scalp location, and the P2 amplitude in switch trials was greater than that in non-switch trials. At post-stimulation, the N2 amplitude of rTMS is more negative than that of sham rTMS at non-switch trials, whereas no such difference was found at switch trials. The P3 amplitude and LPC amplitude are significantly reduced by rTMS at post-stimulation. Conclusion: Low-frequency rTMS of the left DLPFC can cause decline of cognitive flexibility in executive function, resulting in the change of N2 amplitude and the decrease of P3 and LPC components during task switching, which is of positive significance for the evaluation and treatment of executive function.

Analysis of Correlation Between White Matter Changes and Functional Responses in Post-stroke Depression.

Objective: Post-stroke depression (PSD) is one of the most common neuropsychiatric symptoms with high prevalence, however, the mechanism of the brain network in PSD and the relationship between the structural and functional network remain unclear. This research applies graph theory to structural networks and explores the relationship between structural and functional networks. Methods: Forty-five patients with acute ischemic stroke were divided into the PSD group and post-stroke without depression (non-PSD) group respectively and underwent the magnetic resonance imaging scans. Network construction and Module analysis were used to explore the structural connectivity-functional connectivity (SC-FC) coupling of multi-scale brain networks in patients with PSD. Results: Compared with non-PSD, the structural network in PSD was related to the reduction of clustering and the increase of path length, but the degree of modularity was lower. Conclusions: The SC-FC coupling may serve as a biomarker for PSD. The similarity in SC and FC is associated with cognitive dysfunction, retardation, and desperation. Our findings highlighted the distinction in brain structural-functional networks in PSD. Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT03256305, NCT03256305.

Sex Differences in the Blood Oxygen Level-Dependent Signal to Placebo Analgesia and Nocebo Hyperalgesia in Experimental Pain: A Functional MRI Study.

OBJECTIVE: Placebo as well as nocebo responses are widely found in scientific research and clinical practice. Growing evidence suggests sex differences in placebo as well as nocebo responses. However, data concerning this question are still insufficient. This study examined whether the BOLD signals of two responses, as measured with functional MRI (fMRI), differ by sex under conditions of equivalent experimental pain perception. METHOD: Thirty-one healthy volunteers (14 female) underwent two fMRI scans, once during a placebo intervention and once during a nocebo intervention, pseudorandomly ordered, in an acute lower back pain (ALBP) model. We collected visual analog scale (VAS) data after each scanning. fMRI data from different sex groups were subjected to functional connectivity (FC) analysis and behavioral correlation analysis (BCA). RESULTS: The results showed statistical differences in VAS scores between male and female participants, in both placebo and nocebo responses. Both groups also showed reduced FC in the pain-associated network of the placebo response and elevated FC in the pain-related network of the nocebo response. However, in the placebo condition, male participants displayed increased FC in the ventromedial prefrontal cortex, parahippocampal gyrus (PHP), and posterior cingulate cortex (PCC), while female participants showed increased FC in the dorsolateral prefrontal cortex, hippocampal gyrus (HP), and insular cortex (IC). In the nocebo condition, male participants showed decreased FC in the PCC and HP, while female participants displayed decreased FC in the mid-cingulate cortex, thalamus (THS), and HP. The BCA results of the two groups were also different. CONCLUSION: We found that the endogenous opioid system and reward circuit play a key role in sex differences of placebo response and that anxiety and its secondary reactions may cause the sex differences of nocebo response.

The Inhibitory Effect of Emotional Conflict Control on Memory Retrieval.

Evidence is mounting that emotional conflict is mainly resolved by the rostral anterior cingulate inhibiting the processing of emotional distractors. However, this theory has not been verified from the perspective of memory retrieval. This experiment aimed to explore the offline effect of emotional conflict processing on memory retrieval. We adopted a modified encoding-retrieval paradigm to explore this issue. Participants' electroencephalography (EEG) signal were also collected. A face-word Stroop task was used to create the congruency factor. In addition, an old/new judgment task was used to evaluate the recognition performance. During the retrieval phase, the response time of the incongruent condition was longer and the recognition accuracy was lower compared with congruent and neutral conditions in the behavioral data. For event-related potentials (ERP), we detected two well-established old/new effects related to memory retrieval under both neutral and emotional conditions: the frontal negativity (FN400) related to familiarity-driven recognition and the late posterior negativity (LPN) related to reconstructive processing or evaluation of retrieval outcomes. More importantly, the old/new effects were missing for incongruent condition during the early stage of FN400 (300-400 ms). Besides, for LPN (700-900 ms), the old/new effects of the incongruent condition are greater than the congruent condition. The results prove that the encoding phase's emotional congruency factor has a regulatory effect on the retrieval phase's early familiarity processing and evaluation of retrieval outcomes. Our data confirm the inhibitory effect of emotional conflict control on memory retrieval and support the emotional conflict control mechanism found in previous studies.

Personality differences in brain network mechanisms for placebo analgesia and nocebo hyperalgesia in experimental pain: a functional magnetic resonance imaging study.

BACKGROUND: Placebo and nocebo responses have been increasingly gaining the attention of clinical and scientific researchers. Inconsistent conclusions from current studies indicate that different factors potentially affect both placebo and nocebo responses. Increasing evidence suggests that personality differences may affect the mechanisms of both two responses. In the present work, we explored the characteristics of neural signals of placebo and nocebo responses based on functional connectivity (FC) analysis and Granger causality analysis (GCA). METHODS: A total of 34 healthy participants received conditional induction training to establish placebo and nocebo responses. Every participant completed the following experimental workflow, including scanning of baseline, experimental low back pain model establishment, scanning of acute pain status, and scanning of placebo response or nocebo response. We collect visual analogue scale (VAS) data after each scanning. Functional magnetic resonance imaging (fMRI) data from different personality groups were subjected to FC analysis and multivariate GCA (mGCA). RESULTS: Pain scores for placebo and nocebo responses were statistically different across different personality. There are also statistically differences in the neural signals of two responses across different personality. CONCLUSIONS: The findings of the present study indicated that extroverted and introverted participants are likely to experience placebo analgesic effects and nocebo hyperalgesia effects, respectively. Both extroverted and introverted participants showed significant changes in brain networks under placebo response. Variation in emotional control and ventromedial prefrontal cortex inactivity may constitute the bulk of the personality differences in placebo analgesia. Differences in the regulation of the sensory conduction system (SCS) and release of the emotional circuit could be important factors affecting personality differences in nocebo hyperalgesia.

lncRNA CASC9 sponges miR­758­3p to promote proliferation and EMT in bladder cancer by upregulating TGF­ß2.

The long noncoding RNA cancer susceptibility candidate 9 (CASC9) has been revealed to be an oncogenic gene in several types of cancer, and high CASC9 expression is related to tumorigenesis and cancer progression. However, the role of CASC9 in bladder cancer (BC), particularly during epithelial­mesenchymal transition (EMT), has not been characterized. RT­qPCR, EdU, CCK­8, wound scratch, Transwell and flow cytometric assays were performed to detect CASC9 expression, miR­758­3p expression and their functions in BC. RNA FISH was used to detect CASC9 subcellular localization. Luciferase reporter assay, RT­qPCR assay and western blotting were used to explore the relationship of CASC9, miR­758­3p and TGF­ß2. In the present study, it was revealed that CASC9 regulated EMT in BC. CASC9 expression was significantly upregulated in BC cell lines and specimens compared to that in adjacent normal bladder tissues. Upregulated CASC9 was associated with increased invasion ability and poor prognosis of BC. CASC9 knockdown inhibited BC cell proliferation, migration and invasion. Furthermore, a bioinformatics study and luciferase reporter assays revealed that CASC9 functioned as a ceRNA for miR­758­3p. CASC9 inhibited microRNA (miR)­758­3p activity and resulted in the de­suppression of its target transforming growth factor (TGF)­ß2. TGF­ß signaling driven by TGF­ß2 was crucial for CASC9 to promote EMT in BC. Collectively, these results indicated that CASC9 sponged miR­758­3p to regulate the expression of TGF­ß2, which activated the TGF­ß signaling pathway and promoted proliferation and EMT in BC.

Personality Differences of Brain Networks in Placebo Analgesia and Nocebo Hyperalgesia: A Psychophysiological Interaction (PPI) Approach in fMRI.

It is generally believed that the placebo response can elicit an analgesic effect, whilst the nocebo response can elicit a hyperalgesia effect in pain. Placebo analgesia and nocebo hyperalgesia effects are increasing concerns for researchers. Growing evidence suggests personality differences have an impact on both placebo and nocebo effects. However, previous studies have not reached a unified conclusion. We designed this study to explore the personality differences of functional magnetic resonance imaging (fMRI) signals in placebo response and nocebo response by using psychophysiological interaction (PPI) analysis. 30 healthy subjects underwent conditioning induction training to establish expectations of placebo effect and nocebo effect, and then, all subjects completed the following experimental procedures: (1) baseline scanning, (2) acute pain model establishment, (3) pain status scanning, and (4) pseudorandom scanning of block design of placebo response or nocebo response. Behavioral data were collected after each scan. The results of this study showed that (1) there were significant differences of VAS placebo intervention between the extrovert group and the introvert group (p = 0.004); (2) there were significant differences of VAS nocebo intervention between the extrovert group and the introvert group (p = 0.011); (3) there were significant differences between the VAS placebo intervention and VAS pain status (baseline) in both the extrovert group (p < 0.001) and the introvert group (p = 0.001); (4) there were significant differences between the VAS nocebo intervention and VAS pain status (baseline) in both the extrovert group (p = 0.008) and the introvert group (p < 0.001). Moreover, there were significant differences in the brain network for placebo and nocebo responses between different personalities. We found that (1) deactivation differences of the pain-related network and limbic system play an important role in personality differences associated with placebo analgesia and (2) differences of control of anxiety and activation of dorsolateral prefrontal cortex may cause the personality differences observed in nocebo hyperalgesia.

TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer's disease mice.

Triggering receptor expressed on myeloid cells 2 (TREM2) has been shown with a neuroprotective function against inflammation and neuronal injury in Alzheimer's disease (AD). However, the TREM2 induced anti-inflammatory mechanism is still not well known. In this study it has been demonstrated that the expression of TREM2 was upregulated in hippocampus of 5xFAD mice, whereas TREM2 knock-out mediated by AAV significantly increased the levels of pro-inflammatory cytokines and aggravated cognitive defect. Additionally, FoxO3a, a downstream member of the PI3K/AKT pathway, could be activated by TREM2 defect via the PI3K/AKT signaling in 5xFAD mice. That suggests TREM2-induced protection is associated with the PI3K-FoxO3a axis. On the contrary, overexpression of TREM2 alleviated the LPS-induced inflammatory response and induced M2 phenotype microglia in vitro. This phenomenon can be abolished by applying the PI3K inhibitor LY294002, suggesting FoxO3a not only participates in TREM2-induced anti-inflammation response, but is also involved in regulating the phenotype of microglia. Taken together, our results show that the protective functions of TREM2, both in inflammatory response and cognitive impairment as well as in the decrease of M1 phenotype microglia, are related to PI3K/AKT/FoxO3a signaling pathway in AD mice.

Resveratrol mediates mechanical allodynia through modulating inflammatory response via the TREM2-autophagy axis in SNI rat model.

BACKGROUND: Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms. METHODS: A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanical allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, lentivirus coding TREM2 was intrathecally injected into SNI rats to activate TREM2, and the pain behavior was detected by the von Frey test. Furthermore, 3-methyladenine (3-MA, an autophagy inhibitor) was applied to study the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, and immunofluorescence. RESULTS: The TREM2 expression and number of the microglial cells were significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1ß, interleukin-6, and tumor necrosis factor-α in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-MA in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia. CONCLUSIONS: Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.