Hepatic stellate cells (HSCs) are the primary fibrogenic cells in the liver, and their activation plays a crucial role in the development and progression of hepatic fibrosis. Here, we report that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a key modulator of HSC activation and liver fibrosis. RXRα exerts its effects by modulating calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). In addition, we demonstrate that K-80003, which binds RXRα by a unique mechanism, effectively suppresses HSC activation, proliferation, and migration, thereby inhibiting liver fibrosis in the CCl₄ and amylin liver NASH (AMLN) diet animal models. The effect is mediated by AMPKα activation, promoting mitophagy in HSCs. Mechanistically, K-80003 activates AMPKα by inducing RXRα to form condensates with CaMKKβ and AMPKα via a two-phase process. The formation of RXRα condensates is driven by its N-terminal intrinsic disorder region and requires phosphorylation by CaMKKβ. Our results reveal a crucial role of RXRα in liver fibrosis regulation through modulating mitochondrial activities in HSCs. Furthermore, they suggest that K-80003 and related RXRα modulators hold promise as therapeutic agents for fibrosis-related diseases.

Objective:To investigate the predictive value of fluid-attenuated inversion recovery (FLAIR) signal strength ratio (SIR) in onset time≤4.5 h in patients with acute ischemic stroke.Methods:A retrospective analysis was performed; 180 acute ischemic stroke patients admitted to Department of Neurology, Nanjing Hospital Affiliated to Nanjing Medical University from January 2020 to June 2023 were chosen. Hypoperfusion intensity ratio (HIR) was used to evaluate the collateral circulation (poor collateral circulation: HIR≤0.4; good collateral circulation: HIR>0.4); clinical data and imaging indexes between poor collateral circulation and good collateral circulation groups were compared. Univariate and multivariate Logistic regressions were used to analyze the influencing factors for onset time≤4.5 h in patients with acute ischemic stroke. Correlation between SIR and onset time was analyzed in patients with acute ischemic stroke. Role of HIR as agency between SIR and onset time was explored. Receiver operating characteristic (ROC) curve was used to analyze the predictive efficacy of SIR and diffusion weighted imaging (DWI)-FLAIR mismatch in onset time≤4.5 h in acute ischemic stroke patients.Results:Of the 180 patients, 100 were into the good collateral circulation group and 80 were into the poor collateral circulation group; compared with the good collateral circulation group, the poor collateral circulation group had significantly higher percentage of patients with hyperlipidemia, larger DWI infarction volume before treatment, larger perfusion weighted imaging (PWI)-DWI mismatch volume and higher SIR ( P<0.05). In these 180 patients, 76 had onset time≤4.5 h and 104 had onset time>4.5 h. Univariate Logistic regression analysis showed that hyperlipidemia, DWI infarct volume before treatment, DWI-FLAIR mismatch, HIR and SIR were influencing factors for onset time≤4.5 h in acute ischemic stroke patients ( P<0.05). Multivariate Logistic regression analysis showed that hyperlipidemia ( OR=6.654, 95% CI: 5.751-8.824, P<0.001), HIR ( OR=0.724, 95% CI: 0.521-1.321, P=0.041) and SIR ( OR=739.881, 95% CI: 383.296-14 258.065, P<0.001) were independent influencing factors for onset time≤4.5 h in acute ischemic stroke patients. Pearson correlation analysis showed that SIR was positively correlated to onset time in patients with acute ischemic stroke ( r=0.420, P<0.05), and SIR was positively correlated to onset time in patients from poor collateral circulation group ( r=0.781, P<0.05). ROC curve showed that AUC of SIR in predicting onset time≤4.5 h was 0.917 (95% CI: 0.814-1.000, P<0.001) and that of DWI-FLAIR mismatch in predicting onset time≤4.5 h was 0.530 (95% CI: 0.509-0.757, P=0.075) in poor collateral circulation group, enjoying significant difference in predictive efficacy. Conclusion:Acute ischemic stroke patients with low HIR and SIR have higher odds of onset time≤4.5 h; SIR can more accurately predict the onset time in these patients with poor collateral circulation.

Objective To evaluate and analyze the resting-state MRI data of patients with chronic subjective tinnitus via the multilayer brain functional network and to find the relevant node parameters with certain dynamic characteristics.Methods A total of 28 chronic subjective tinnitus patients(tinnitus group)and 39 sex,age,and education-matched healthy volunteers(control group)were included.After completing relevant otologic and neuropsychiatric tests for all subjects,3.0T MRI data were collected.Data preprocessing,dynamic functional connection analysis,multilayer modularization and network switching rate were performed.Correlation analysis between MRI data results and clinical data were further conducted.Results There was no significant difference in terms of Q between tinnitus group and control group(P＞0.05).Compared with the control group,the network switching rate of bilateral anterior cingulate gyrus(P＜0.001)and right hippocampus(P＜0.01)was significantly decreased in the tinnitus group.Additionally,the network switching rate of right hippocampus was negatively correlated with the duration of tinnitus(r=-0.503,P=0.006).Conclusion Based on using multilayer brain functional network method,the signal regulations in anterior cingulate gyrus and hippocampus in chronic subjective tinnitus patients is changed,while the alteration of hippocampus may be related to the duration of disease.

Objective:To investigate the alterations of multilayer network and dynamic causal connectivity in patients with bilateral sudden sensorineural hearing loss.Methods:The hearing ability, neural-scale data and resting-state functional magnetic resonance imaging(fMRI)data of 60 patients with bilateral sudden sensorineural hearing loss from the Department of Otolaryngology and 60 healthy controls from Physical Examination Center, Nanjing First Hospital were collected from January 2022 to January 2024. Multilayer brain network analysis was computed to identify the nodes with abnormal switching rate. Then these abnormal nodes were used as regions of interest (ROIs) in the subsequent dynamic causal model analysis. The SPSS 26.0 software was used to analyze causal connectivity between two groups based on independent-sample Mann-Whitney U test. And Pearson correlation coefficients between fMRI results and clinical parameters were calculated. Results:Pure tone audiometry test showed that the left and right hearing thresholds of bilateral sudden sensorineural hearing loss were significantly higher than those of healthy controls( Z=-9.460, -9.462, both P<0.01). The score of depressive emotion in patients with bilateral sudden hearing loss was 6.00(2.00, 9.00).Multilayer brain network analysis showed that the switching rates in the left superior frontal gyrus (0.073(0.049, 0.102), Z=3.603, P<0.001), left anterior cingulate gyrus (0.077(0.044, 0.105), Z=3.189, P=0.001), right hippocampus (0.080(0.045, 0.116), Z=3.616, P<0.001), left para-hippocampal gyrus (0.080(0.043, 0.108), Z=3.577, P<0.001), left superior parietal gyrus (0.079(0.047, 0.103), Z=3.160, P=0.002), and right inferior parietal gyrus (0.078(0.043, 0.105), Z=3.396, P<0.001) in patients with bilateral sudden sensorineural hearing loss were lower that those in healthy controls. These six brain areas were used as ROIs to compute dynamic causal model analysis, and the results showed that the connection strength from left superior frontal gyrus to the left para-hippocampal gyrus in patients with bilateral sudden sensorineural hearing loss was significantly higher than that in healthy controls ( Z=-2.593, P<0.05). Additionally, enhanced connectivity from left superior frontal gyrus to the left para-hippocampal gyrus was positively correlated with duration of hearing loss ( r=0.376, P=0.003). Conclusions:Bilateral sudden sensorineural hearing loss patients have decreased switching rates in many brain areas, and the causal connectivity from left superior frontal gyrus to the left para-hippocampal gyrus is enhanced.

Intracranial atherosclerotic stenosis (ICAS) is the main cause of patients with stroke in China. How to accurately detect and identify vulnerable plaques through imaging examinations, and strengthen the prediction and prevention of ischemic stroke in patients with ICAS, is a key clinical problem that needs to be solved, and is also a current challenge. With the application of magnetic resonance vascular wall imaging in ICAS, imaging examinations provide useful information on the vascular structure and plaque stability at the stenosis in addition to the degree of stenosis. It has improved the ability to evaluate ICAS and promoted its development towards more accurate diagnosis and treatment.

Objective:To investigate the resting state functional connectivity changes of the " triple network model" composed of salient network (SN), executive control network (ECN) and default mode network (DMN) in patients with acute mild traumatic brain injury (mTBI).Methods:From August 2020 to December 2021, forty-five acute mTBI patients (mTBI group) and 40 healthy controls (HC group) with matched sex, age, and education were included.The Montreal cognitive assessment (MoCA) scale was used to evaluate the cognitive status of all subjects.The resting state network (RNS) was established based on independent component analysis (ICA), and the SN, ECN and DMN were extracted, then functional network connectivity (FNC) was analyzed.Subsequently, the correlation between functional connectivity abnormalities and the performance of cognitive impairment was analyzed.SPSS 19.0 was used for statistical analysis and double sample t test was used for comparison between the tow groups. Results:Compared with HC group, mTBI group had enhanced functional connectivity between SN(L-insula) (MNI: x, y, z=-36, 15, 0, t=3.693)and ECN (left superior parietal gyrus, L-SPG) (MNI: x, y, z=-33, -69, 54, t=3.333)(FDR adjust, P<0.05), and decreased functional connectivity between DMN(left superior frontal gyrus, L-SFG) (MNI: x, y, z=-30, 30, 42, t=-4.063)and DMN(L-angular gyrus)(MNI: x, y, z=-21, -66, 33, t=-4.101)(FDR adjust, P<0.05). For FNC analysis, functional network connectivity in SN(IC26)-DMN(IC8) was enhanced in the acute mTBI group and decreased between SN(IC26)-DMN(IC12) and ECN(IC3)-DMN(IC12). The changes of left superior parietal gyrus functional connection were negatively correlated with MoCA score ( r=-0.627, P<0.01), and SN (IC26) -DMN(IC12) connection was positively correlated with MoCA score ( r=0.411, P=0.005). Conclusions:In patients with acute mTBI, the resting functional connectivity changes within and between the networks of the " triple network model" composed of SN, ECN and DMN, and is related to the decline of cognitive function.This will help to better understand the neuropathological mechanism of acute mTBI and post-traumatic cognitive impairment, and may become an effective imaging marker for identifying and predicting cognitive impairment after mTBI.

Objective To analyze the demographic data,CT characteristics,treatment methods and follow-up results of patients with spontaneous isolated dissection of celiac artery(SIDCA)and to explore the selection of treatment strategy for SIDCA.Methods Medical records of 31 patients diagnosed as SIDCA were selected.The patients were divided into 2 groups,symptomatic group and asymptotic group.Demographic data,morbidity season,CT characteristics(type,distance of the entry site from the origin of the artery,dissection length,compression rate of the true lumen,branches involvement,organ ischemia,coexisting vasculopathy),treatment methods,and follow-up results were analyzed.Results Thirty-one patients were identified by CT contrast scan,22 were symptomatic and 9 were asymptomatic.22 patients were first diagnosed in cooler season,compared with 9 patients in warmer season(22 vs 9,Fisher's exact test,P=0.029).The difference between symptomatic and asymptomatic groups about branches involvement in patients was significant(8/14 vs 0/9,Fisher's exact test,P=0.007).Treatment included observation in 24,endovascular intervention in 6 patients and surgical repair in 1 patient.No patient required bowel resection.The mean follow-up period was 13.75 months.Except for 2 patients,the condition of the remaining patients improved or stabilized during follow-up.Conclusion The difference between symptomatic and asymptomatic groups about branches involvement in patients is significant.Initial conservative treatment may be adequate for patients without end organ malperfusion or aneurysm formation or aneurysm rupture in SIDCA.Additionally,during the cooler season,visceral artery should be observed carefully on abdominal contrast CT,especially in the patient with abdominal pain,to avoid misdiagnosis.

Objective:To investigate the relationship between wall shear stress (WSS) and the degree of lumen stenosis and plaque characteristics in patients with atherosclerotic stenosis in the middle brain.Methods:Thirty-four patients with moderate to severe unilateral middle cerebral artery stenosis in Nanjing First Hospital from June 2020 to June 2021 were analyzed retrospectively. All patients underwent routine magnetic resonance imaging and vascular wall imaging to obtain plaque parameters such as plaque area, remodeling mode and remodeling index. Based on magnetic resonance angiography, a computational fluid dynamics model was established to simulate the local hemodynamics near the lesion and quantify WSS. The patients were divided into high WSS group and low WSS group according to the median WSS. The differences of clinical baseline data, degree of lumen stenosis and plaque characteristics between the two groups were compared. Pearson correlation analysis was used to calculate the correlation between WSS and lumen stenosis and plaque characteristics.Results:A total of 34 patients were included in this study, 17 in the high WSS group and 17 in the low WSS group. Compared with the low WSS group, the plasma homocysteine level in the high WSS group was lower [(11.10±4.96) μmol/L vs (16.97±6.98) μmol/L, t=-2.83, P=0.010], the degree of stenosis was lower (0.56±0.05 vs 0.66±0.08, t=-4.54, P<0.001), and the proportion of positive lumen remodeling was higher (12/17 vs 4/17, P=0.015). Pearson correlation analysis showed that the degree of lumen stenosis was negatively correlated with WSS ( r=-0.44, P=0.011), and the plaque area was not correlated with WSS. Conclusions:WSS in middle cerebral artery stenosis is related to the degree of lumen stenosis and the mode of vascular remodeling. Higher WSS has poor stability, but lower WSS is more likely to cause lumen stenosis.

Objective:To investigate the local consistency of inferior colliculus and ventrolateral orbital cortex by resting-state functional magnetic resonance imaging (fMRI) in rats with noise induced deafness and its relationship with anxiety- and depression-like behavior.Methods:Twenty-four clean grade male four-weeks old SD rats were randomly divided into noise group and control group with 12 rats in each group.Rats in the noise group were exposed to 122 dB broadband strong noise for 2 hours to induce severe bilateral hearing loss, while rats in the control group were placed in a quiet environment. Hearing thresholds were assessed by auditory brainstem response (ABR) test. The open field test (OFT) was conducted to examine anxiety-depression related behavior, and the local consistency in the rat brain was evaluated by fMRI.SPM12 software was used to process fMRI data, and Pearson correlation analysis was conducted by SPSS 22.0 software to calculate the correlation between fMRI data and behavior.Results:The results of ABR showed that the full band hearing threshold of rats in the noise group was higher than that of rats in the control group ((85.417±6.463) dB, (20.083±8.853) dB, t=46.168, P<0.001). And compared with control group, the rats in the noise group showed obvious anxiety-depression-like behavior in the open field test, that was, low activity level.The results of OFT showed that the total distance ((39.912±5.696) m, (47.993±10.820)m, t=-2.289, P=0.032), average moving speed ((13.306±1.900)cm/s, (15.998±3.607)cm/s, t=-2.290, P=0.032) and standing times ((13.333±5.960), (23.500±7.323), t=-3.730, P=0.001) of the rats in the noise group were all lower than those in the control group. Compared with the control group, the local consistency of hypothalamus in the noise group was significantly enhanced, while the local consistency of ventrolateral orbital cortex was significantly reduced, and the abnormal neural activity was lateralized. The correlation analysis showed that the neural activity of the inferior colliculus was negatively correlated with the total distance of rats in the noise group moving in the open field( r=-0.691, P=0.013), while the neural activity of the ventrolateral orbital cortex was not significantly correlated with the anxiety-depression-like behavior in the open field. Conclusions:The neural activity of inferior colliculus is closely related to anxious-depression behavior in rats with noise-induced deafness, while the ventrolateral orbital cortex may be related with other behaviors.

Intracranial atherosclerotic lesions are a common cause of ischemic stroke. Hemodynamics plays an important role in the formation and development of atherosclerosis and the risk assessment of clinical ischemic stroke events. As an evaluation method of cerebral hemodynamics, computational fluid dynamics can intuitively obtain hemodynamic parameters and provide valuable information for clinical diagnosis and treatment. This article reviews the application progress of computational fluid dynamics in evaluating peripheral hemodynamics of intracranial atherosclerotic lesions.