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Zhuoyuan Zhang,1,2,* Dan Liu,1,2,* Rui Lv,1,2,* Haoyan Zhao,1,2,* Tianjing Li,1,2 Yutao Huang,2 Zhicheng Tian,2 Xiangyu Gao,2 Peng Luo,2 Xin Li3 1Biochemistry and Molecular Biology, College of Life Science, Northwest University, Xi’an, 710127, People’s Republic of China; 2Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, People’s Republic of China; 3Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng Luo; Xin Li, Email pengluo@fmmu.edu.cn; li_xin_mail@126.comPurpose: Neuroinflammation occurs in response to central nervous system (CNS) injury, infection, stimulation by toxins, or autoimmunity. We previously analyzed the downstream molecular changes in HT22 cells (mouse hippocampal neurons) upon lipopolysaccharide (LPS) stimulation. We detected elevated expression of Fibrillarin (FBL), a nucleolar methyltransferase, but the associated proinflammatory mechanism was not systematically elucidated. The aim of this study was to investigate the underlying mechanisms by which FBL affects neuroinflammation.Methods: RT-real-time PCR, Western blotting and immunofluorescence were used to assess the mRNA and protein expression of FBL in HT22 cells stimulated with LPS, as well as the cellular localization and fluorescence intensity of FBL. BAY-293 (a son of sevenless homolog 1 (SOS1) inhibitor), SR11302 (an activator protein-1 (AP-1) inhibitor) and KRA-533 (a KRAS agonist) were used to determine the molecular mechanisms underlying the effect of FBL. AP-1 was predicted to be the target protein of FBL by molecular docking analysis, and validation was performed with T-5224 (an AP-1 inhibitor). In addition, the downstream signaling pathways of FBL were identified by transcriptome sequencing and verified by RT-real-time PCR.Results: LPS induced FBL mRNA and protein expression in HT22 cells. In-depth mechanistic studies revealed that when we inhibited c-Fos, AP-1, and SOS1, FBL expression decreased, whereas FBL expression increased when KRAS agonists were used. In addition, the transcript levels of inflammatory genes in the NF-kB signaling pathway (including CD14, MYD88, TNF, TRADD, and NFKB1) were elevated after the overexpression of FBL.Conclusion: LPS induced the expression of FBL in HT22 cells through the RAS/MAPK signaling pathway, and FBL further activated the NF-kB signaling pathway, which promoted the expression of relevant inflammatory genes and the release of cytokines. The present study reveals the mechanism by which FBL promotes neuroinflammation and offers a potential target for the treatment of neuroinflammation.Keywords: FBL, neuroinflammation, LPS, molecular docking, transcriptome sequencing

Jie Zhao,1 Fang Xu,2 Wanying Xu,1 Rong Lv,1 Juan Wang,3 Xufeng Yang1 1Department of Geriatrics, Suzhou Ninth People’s Hospital, Soochow University, Suzhou, Jiangsu, 215200, People’s Republic of China; 2Department of Obstetrics and Gynecology, Suzhou Wujiang District Hospital of Traditional Chinese Medicine, Suzhou, Jiangsu, 215200, People’s Republic of China; 3Department of Endocrine, Suzhou Ninth People’s Hospital, Soochow University, Suzhou, Jiangsu, 215200, People’s Republic of ChinaCorrespondence: Xufeng Yang, Department of Geriatrics, Suzhou Ninth People’s Hospital, Soochow University, No. 2666 Ludang Road, Suzhou, Jiangsu, 215200, People’s Republic of China, Tel/Fax +86 0512-82881332, Email yangxufeng2013@163.comBackground and Purpose: High-mobility group box-1 (HMGB1) is a useful biomarker for disease severity stratification and prognosis prediction. We aim to explore whether the circulating HMGB1 concentrations are associated with the white matter lesions (WMLs) burden in stroke patients.Methods: Between 2022 June and December 2022, patients with acute ischemic stroke were prospectively enrolled. HMGB1 levels were measured by an enzyme-linked immunosorbent assay after admission for all patients. The WMLs severity was assessed by the Fazekas scale. We dichotomized patients into those with moderate–severe WMLs (Fazekas score 3– 6) versus those with none–mild WMLs (Fazekas score 0– 2). Furthermore, based on the severity of periventricular WMLs (PWMLs) and deep WMLs (DWMLs), patients were categorized as none–mild (Fazekas score 0– 1) or moderate–severe (Fazekas score 2– 3).Results: A total of 287 participants (mean age: 64.9 years; 157 male) were analyzed. The median serum HMGB1 levels were 7.3 ng/mL (interquartile, 4.3 ng/mL– 12.3 ng/mL). After adjustment for potential confounders, elevated HMGB1 levels were associated with the presence of moderate–severe WMLs (first quartile vs fourth quartile, odds ratio [OR], 4.101; 95% confidence interval [CI], 1.948– 8.633; P = 0.001) and moderate–severe PWMLs (first quartile vs fourth quartile, OR, 9.181; 95% CI, 4.078– 20.671; P = 0.001). Similar results were found when the HMGB1 levels were analyzed as a continuous variable.Conclusion: This study demonstrated that increased HMGB1 levels were associated with the severity of WMLs, mainly in the periventricular region.Keywords: ischemic stroke, high-mobility-group box 1, white matter lesions, inflammation

Zhongyu Fan,1– 4,* Yunliang Guo,1– 3,* Xunyao Hou,1– 3 Renjun Lv,5 Shanjing Nie,1– 3 Song Xu,1– 3 Jian Chen,1– 3 Yan Hong,1– 3 Shuo Zhao,6 Xueping Liu1– 3 1Department of Geriatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 2Department of Geriatric Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 3Anti-Aging Monitoring Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 4Shandong Provincial Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of China; 5The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu, People’s Republic of China; 6Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xueping LiuDepartment of Geriatric Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of ChinaEmail Liuxueping1962@163.comBackground: Few reports have implied electrophysiological alterations and neurocognitive abnormalities in patients with cerebral small vessel disease (CSVD), while no investigation is available regarding emotional processing. In the present study, pre-attentive processing of facial expressions was compared between CSVD sufferers and healthy controls using expression-related visual mismatch negativity (EMMN) as the indicator.Methods: A total of 22 CSVD patients (12 males) and 21 age-matched healthy controls (12 males) were recruited for neuropsychological and emotional assessments, as well as electroencephalogram recording and analysis. We employed an expression-related oddball paradigm to investigate automatic emotional processing, and a series of schematic emotional faces (neutral, happy, sad) unrelated to subject’s task were present in the test to avoid low-level processing of facial features.Results: Although the distinctions of neuropsychological (MoCA and MMSE), emotional (GAD-7 and PHQ-9) and behavioral parameters (reaction time to target stimuli and response accuracy) did not reach significant levels, mean amplitudes of sad EMMN in time intervals of 150– 250 ms and 250– 350 ms were remarkably reduced in CSVD patients compared with healthy controls, but not for happy EMMN. Furthermore, in the control group, sad EMMN was demonstrated to be larger (more negative) than happy EMMN, while this interesting phenomenon disappeared in the CSVD group.Conclusion: Our findings confirmed selective impairment of processing expressions which were task-irrelevant in CSVD patients, without the existence of negative bias (sad superiority) effect. The efficacy of EMMN as an electrophysiological evaluation marker of CSVD should be taken into account in future investigations.Keywords: cerebral small vessel disease, expression-related visual mismatch negativity, pre-attentive processing of facial expressions, negative bias effect

Shanjing Nie,1– 3 Chao Shen,1,2 Yunliang Guo,1– 3 Xunyao Hou,1– 3 Yan Hong,1– 3 Song Xu,1– 3 Renjun Lv,4 Xueping Liu1– 3 1Department of Geriatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 2Department of Geriatric Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 3Anti-Aging Monitoring Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, People’s Republic of China; 4Shandong Provincial Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Xueping LiuDepartment of Senile Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, People’s Republic of ChinaEmail Liuxueping1962@163.comBackground: Cerebral small vessel disease is the primary cause of cognitive impairment. Therefore, early recognition is of great significance. Some studies have shown that asymptomatic cerebral small vessel disease (aCSVD) patients have abnormal neurocognitive function, but this is not readily apparent at the initial stage. The objective of this paper was to assess visual spatial attention by event-related potential (ERP) examination and to analyze the relationship between ERP data and clinical characteristics in patients with aCSVD.Methods: We selected 25 aCSVD patients and enrolled 23 age-matched normal subjects as the control group. We measured the latency and amplitude of original/corresponding differential ERP components using the modified visual oddball paradigm, which included a standard stimulus, target stimulus, and new stimulus. Additionally, we selected aberrant ERP components to study the correlations between the ERP data and clinical characteristics of the patients with aCSVD.Results: We found not only lower amplitude but also significantly longer P3 latency in the aCSVD patients. The above results were further verified by analyzing the different components (target minus standard and novel minus standard) of P3. Furthermore, abnormal ERPs in the aCSVD patients were closely related to the changes observed with imaging.Conclusion: It was demonstrated that the speed and capability of processing visual spatial information was impaired in aCSVD patients compared with healthy controls. Thus, ERP examination could detect the presence of attentional deficits and might become a rapid and sensitive method for the early diagnosis of aCSVD. However, its availability needs further investigation.Keywords: asymptomatic cerebral small vessel, event-related potential, cognitive impairment, P3, visual spatial attention impairment

Renjun Lv,1– 5 Shanjing Nie,1– 4 Zhenhua Liu,6 Yunliang Guo,1– 4 Yue Zhang,7 Song Xu,1– 4 Xunyao Hou,1– 4 Jian Chen,1– 4 Yingjuan Ma,8 Zhongyu Fan,1– 5 Xueping Liu1– 4 1Department of Geriatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, People’s Republic of China; 2Department of Geriatric Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, People’s Republic of China; 3Anti-Aging Monitoring Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, People’s Republic of China; 4Department of Anti-Aging, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, People’s Republic of China; 5Shandong Provincial Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250021, Shandong, People’s Republic of China; 6Center of Sleep Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong, People’s Republic of China; 7Department of Geriatric Neurology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, People’s Republic of China; 8Department of Otolaryngology Head and Neck Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of ChinaCorrespondence: Xueping Liu Tel +86-53168777165Email Liuxueping1962@163.comAim: Obstructive sleep apnea syndrome (OSAS) is a prevalent chronic disease characterized by sleep fragmentation and intermittent hypoxemia. Several studies suggested that electrophysiological changes and neurocognitive abnormalities occurred in OSAS patients. In this study, we compared automatic processing of emotional facial expressions schematic in OSAS patients and matched healthy controls via assessing expression-related mismatch negativity (EMMN).Methods: Twenty-two OSAS patients (mean age 44.59 years) and twenty-one healthy controls (mean age 42.71 years) were enrolled in this study. All participants underwent Montreal Cognitive Assessment (MoCA) scale test and polysomnographic recording. An expression-related oddball paradigm was used to elicit EMMN and the electroencephalogram was recorded and analyzed. Furthermore, Pearson’s correlations were calculated to discuss the correlation between neuropsychological test scores, clinical variables and electrophysiological data.Results: Compared with healthy controls, OSAS sufferers demonstrated significantly reduced EMMN mean amplitudes within corresponding time intervals, regardless of happy or sad conditions. Meanwhile, we observed that amplitude of sad EMMN was larger (more negative) than happy EMNN in healthy controls, while not in patients. Moderate correlations were found between MoCA test scores, sleep parameters and EMMN amplitudes.Conclusion: Our findings suggested pre-attentive dysfunction of processing emotional facial expressions in patients with OSAS, without the existence of negative bias effect. Moreover, correlation analysis showed that clinical characteristics of OSAS patients could affect EMMN amplitudes. Further studies on the advantages of EMMN as clinical and electrophysiological indicators of OSAS are warranted.Keywords: OSAS, EMMN, facial expressions, pre-attentive processing, negative bias effect

Qingqing Yin,1,2 Xiaojuan Ji,3 Renjun Lv,1 Jin-Jing Pei,4 Yifeng Du,5 Chao Shen,1 Xunyao Hou1 1Department of Geriatric Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, People’s Republic of China; 2Department of Geriatric Neurology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, People’s Republic of China; 3Department of Geriatrics, Beijing Jishuitan Hospital, Beijing 100035, People’s Republic of China; 4Stress Research Institute, Stockholm University, Stockholm 10691, Sweden; 5Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, People’s Republic of ChinaCorrespondence: Chao ShenDepartment of Geriatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, People’s Republic of ChinaTel +86-53168776133Email 7938911@163.comXunyao HouDepartment of Geriatrics, Department of Geriatric Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, People’s Republic of ChinaTel +86-53168777165Email hxy6074@163.comAbstract: Alzheimer’s disease (AD) is a neurodegenerative disease that mainly occurs in old age and involves progressive cognitive impairment. AD has become a major global issue for public health, with approximately 24 million people currently affected by the disease. Estimates indicted that this number will quadruple by 2050. Because of the high incidence of AD, there is an urgent need to develop new strategies to diagnose and treat AD. Many recent studies have indicated the multiple, yet somewhat controversial, roles of exosomes in AD. Although the underlying mechanisms by which exosomes play a role in AD are still unknown, current evidence suggests that exosomes can carry and spread toxic amyloid-beta, and hyperphosphorylated tau, between cells, and then induce apoptosis, thus contributing to the loss of neurons. In addition, exosomes appear to possess the ability to reduce brain amyloid-beta, and tau hyperphosphorylation, and transfer neuroprotective substances between neural cells. The accumulating data brings hope that the application of exosomes may be helpful for early diagnostics and the identification of new therapeutic targets for AD. Here, we summarized the various roles of exosomes, and how they might relate to the pathogenesis of AD. We also highlight the potential application of exosomes as a therapeutic option in AD therapy.Keywords: exosomes, alzheimer’s disease, biomarker, mesenchymal stem cells, therapeutic strategy

A simple and rapid method for fabrication of concentration gradient generators on microfluidic devices on poly (methyl methacrylate) (PMMA) substrate using a flexible and low cost CO2 laser system is proposed. The effects of the laser power and the cutting speed on the depth, width and aspect ratio of the microchannels machined into the PMMA substrate were studied. Laser power was set from 10 to 30 W and laser scanning speed was set from 7 to 27 mm/s in the experiment. The results show the depth of the microchannels increases with the increase of the laser power at the same laser velocity; however, the depth of the microchannel decreases with the increase of the laser velocity at the same laser power. At the same laser power, the width reaches the maximum when the laser velocity is 10mm/s. So when the laser velocity is at 5 to 10mm/s, the width increases with the increase of laser velocity. When the laser velocity is at 10 to 27 mm/s, the width decreases with the increase of laser velocity. The PMMA substrate with microfluidic channels are encapsulated using a hot-press bonding technique. The experimental results show that obvious concentration gradient could be easily obtained in the device. [ABSTRACT FROM AUTHOR]

CO2 laser cutting is an advanced processing technology which can, with the assistance of computer-aided design (CAD) graphics, cut a variety of shapes on the surfaces of many polymer sheets. This work aims to analyse the effect of laser power, scanning speed, focal distance and number of cut passes on the surface roughness of polystyrene (PS) microchannels with CO2 laser cutting process. There are several experiments designed and the results were analysed by an orthogonal experimental method. Finally, optimal power, speed, focal distance and number of cut passes were obtained: laser power of 10 W; laser cutting speed of 8 mm/s; focal distance of 8 mm; and three cut passes, respectively. The experimental results show that the greatest influence factor is the number of cut passes. In the optimal case, the arithmetical mean roughness (Ra) can reach as little as 0.861 μm. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of the study was to explore the role and mechanism of circHIPK3 in atherosclerosis. MATERIALS AND METHODS: AS model was constructed in vivo and in vitro for high fat-fed and ox-LDL treatment. RT-PCR was used to assess the level of circHIPK3. The autophagy level of HUVECs was detected by Western blot, transmission electron microscopy, and LC3II fluorescence intensity. HUVECs lipid accumulation was assessed by oil red staining. Luciferase assay was performed to verify the relationship of circRNA and miRNA, miRNA, and target gene. RESULTS: The expression of circHIPK3 was downregulated in HFD mice, and ox-LDL treated HUVECs. The level of autophagy was decreased in AS, which was reversed by overexpression of circHIPK3. Meanwhile, forced expression of circHIPK3 would reduce the accumulation of lipid in HUVECs. CONCLUSIONS: CircHIPK3 could inhibit lipid content in ox-LD-treated HUVECs via activating autophagy. This progression mechanism may target the miR-190b/ATG7 signal pathway, which indicates a suitable role in the pathogenesis of atherosclerosis. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of this study was to clarify the potential function of transforming growth factor-β1/serum/glucocorticoid-regulated kinase 1 (TGF-β1/SGK1) pathway in diabetic nephropathy-induced tubulointerstitial fibrosis. MATERIALS AND METHODS: Type 2 diabetes mellitus (T2DM) model was successfully established in rats by high-sucrose-high-fat diet combined with streptozotocin (STZ) induction. Subsequently, blood glucose level, renal function and pathological changes in kidneys of T2DM and control rats were evaluated. Western blot and quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) were conducted to determine the protein and mRNA expression levels of TGF-β1, SGK1, fibronectin (FN) and α-smooth muscle actin (α-SMA) in rat kidney tissues, respectively. RESULTS: Blood glucose (BG), glycosylated hemoglobin (GHb), serum creatinine (Scr) and blood urea nitrogen (BUN) in T2DM rats were significantly higher than those of control rats (p<0.05). The morphology of glomeruli and renal tubules in rats of control group were normal. In contrast, T2DM rats showed significant lesions in glomeruli, renal tubules, and renal interstitium. Furthermore, the relative expression levels of TGF-β1, SGK1, FN, and α-SMA in kidney tissues of T2DM rats were remarkably higher than those of controls (p<0.05). CONCLUSIONS: The TGF-β1/SGK1 pathway is closely related to tubulointerstitial fibrosis in T2DM rats. [ABSTRACT FROM AUTHOR]

B Introduction: b Chronic lymphocytic leukemia (CLL) is less common in Han Chinese compared with persons of Europeans. As expected, PFS and OS were better in CLL patients receiving immunochemotherapy and targeted therapy than those receiving chemotherapy. B Results: b In this cohort, the median age of patients at diagnosis was 61(20-92) years, which was younger than that for Western CLL patients (65-70 years). [Extracted from the article]