Synaptic vesicle glycoprotein 2 A in serum is an ideal biomarker for early diagnosis of Alzheimer's disease.

BACKGROUND: Previous studies have demonstrated that early intervention was the best plan to inhibit the progression of Alzheimer's disease (AD), which relied on the discovery of early diagnostic biomarkers. In this study, synaptic vesicle glycoprotein 2 A (SV2A) was examined to improve the early diagnostic efficiency in AD. METHODS: In this study, biomarker testing was performed through the single-molecule array (Simoa). A total of 121 subjects including cognitively unimpaired controls, amnestic mild cognitive impairment (aMCI), AD and other types of dementia underwent cerebrospinal fluid (CSF) SV2A testing; 430 subjects including health controls, aMCI, AD and other types of dementia underwent serum SV2A, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL) and p-tau217 testing; 92 subjects including aMCI and AD underwent both CSF SV2A and serum SV2A testing; 115 cognitively unimpaired subjects including APOE ε4 carriers and APOE ε4 non-carriers were tested for serum SV2A, GFAP, NfL and p-tau217. Then, the efficacy of SV2A for the early diagnosis of AD and its ability to identify those at high risk of AD from a cognitively unimpaired population were further analyzed. RESULTS: Both CSF and serum SV2A significantly and positively correlated with cognitive performance in patients with AD, and their levels gradually decreased with the progression of AD. Serum SV2A demonstrated excellent diagnostic efficacy for aMCI, with a sensitivity of 97.8%, which was significantly higher than those of NfL, GFAP, and p-tau217. The SV2A-positive rates ranged from 92.86 to 100% in aMCI cases that were negative for the above three biomarkers. Importantly, of all the biomarkers tested, serum SV2A had the highest positivity rate (81.82%) in individuals at risk for AD. CONCLUSIONS: Serum SV2A was demonstrated to be a novel and ideal biomarker for the early diagnosis of AD, which can effectively distinguish those at high risk of AD in cognitively unimpaired populations.

Clinical Outcomes of Anterior Cervical Decompression and Fusion Therapy for Patients With Hirayama Disease.

OBJECTIVES: To investigate the clinical outcomes of anterior cervical decompression and fusion (ACDF) surgery for the treatment of Hirayama disease (HD). METHODS: In this study, 15 patients with HD who underwent ACDF operation between March 2022 and March 2023 with complete data were retrospectively analyzed. Following the diagnosis, conservative treatment was ineffective, and thus, disease progression severely affected the quality of life (QOL) of patients. ACDF was performed in the China-Japan Friendship Hospital, and patients were regularly followed up postoperatively. The cervical range of motion (ROM), the anteroposterior and transverse diameter of the spinal cord, and their ratio was measured before and after the operation. The neurologic function of patients before and after the last follow-up was evaluated using the selected brief-Michigan Hand Questionnaire (sb-MHQ), whilst the overall therapeutic effect after the operation was evaluated using Odom's criteria. RESULTS: All patients were followed up for an average of 12 ± 4.5 (6-18) months. Dynamic X-ray displayed that the ROM of cervical vertebrae decreased from 72.73 ± 12.72° (53-97°) to 33.53° ± 10.34° (15-54°) (P < 0.001). Moreover, flexion cervical magnetic resonance imaging (MRI) performed after the operation revealed that spinal cord compression was markedly relieved, and the ratio of the anteroposterior diameter of the spinal cord to the transverse diameter increased from 0.27 ± 0.09 to 0.43 ± 0.03 (P < 0.001). At the last follow-up visit, finger extension tremor symptoms were alleviated, although they did not completely disappear. Contrastingly, muscle atrophy showed no significant improvement. Finally, the sb-MHQ score significantly increased from 17.33±1.76 preoperatively to 24.80±1.78 at the last follow-up (P<0.001). CONCLUSIONS: Our results collectively highlighted the efficacy of ACDF for the treatment of HD. This procedure can limit excessive cervical flexion and repeated compression of the spinal cord during cervical movement and considerably improve upper limb functions.

A randomized controlled trial of repetitive transcranial magnetic stimulation plus donepezil vs donepezil alone for mild to moderate cognitive impairment due to small vessel cerebrovascular disease.

BACKGROUND: Cognitive impairment due to small vessel cerebrovascular disease (SVCVD) results in 35% to 67% of vascular dementia, which may be overlooked by healthcare providers due to its insidious onset. SVCVD involves chronic cerebral ischemia and hypoperfusion, endothelial dysfunction, and blood-brain barrier disruption, as well as interstitial fluid reflux obstruction. OBJECTIVES: The purpose of this study was to investigate the clinical efficacy of repetitive transcranial magnetic stimulation (rTMS) combined with donepezil hydrochloride (vs donepezil alone) in the treatment of mild-to-moderate cognitive impairment in patients with SVCVD. MATERIAL AND METHODS: A cohort of 115 individuals with mild-to-moderate cognitive impairment due to SVCVD was purposefully selected and subsequently randomized into two groups: a test group and a control group. The test group received a combination of repetitive transcranial magnetic stimulation (rTMS) and oral donepezil hydrochloride (10 mg/day), while the control group received oral donepezil alone (10 mg/day). The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) scores were evaluated in both groups prior to and following the intervention. RESULTS: Following 6 weeks of treatment, both groups demonstrated an enhancement in cognitive function. However, a statistically significant difference was observed between the test group and the control group (P < .05 on both the MMSE and the MOCA), favouring the test group. CONCLUSIONS: Compared to donepezil hydrochloride alone, the combination of repetitive transcranial magnetic stimulation (rTMS) and donepezil hydrochloride has a significantly greater effect on enhancing cognitive function among individuals experiencing mild-to-moderate cognitive impairment resulting from SVCVD.

IL-17A promotes the progression of Alzheimer's disease in APP/PS1 mice.

BACKGROUND: Alzheimer's disease (AD), which is the most common cause of dementia in elderly individuals, is a progressive neurodegenerative disorder. Neuroinflammation, which is an immune response that is activated by glial cells in the central nervous system, plays an important role in neurodegenerative diseases. Many studies have shown that interleukin-17A (IL-17A) plays an important role in AD, but research on the pathological effects of IL-17A on AD is limited. METHODS: We report the effect of IL-17A on AD progression in APPswe/PS1dE9 (APP/PS1) mice, which are the most widely used AD model mice. The BV2 cell line, which is a microglial cell line derived from C57/BL6 mice, was used to establish a cell model to verify the role of IL-17A in neuroinflammation at the cellular level. The HT22 hippocampal neuronal cell line was used to investigate the relationship between IL-17A and Aß deposition. RESULTS: In this research, we found that IL-17A promotes the progression of AD in the APP/PS1 mouse model. The role of IL-17A in neuroinflammation is related to tumour necrosis factor (TNF)-α. Circulating IL-17A stimulates the secretion of TNF-α by microglia through the Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signalling pathway, thus exacerbating neuroinflammation. In addition, intraperitoneal injection of IL-17A antibody (IL17Ab) significantly improved the cognitive function of APP/PS1 mice. CONCLUSIONS: IL-17A increased TNF-α levels in the brain and exacerbated neuroinflammation through the TLR4/NF-κB signalling pathway and microglial activation in APP/PS1 mice. Moreover, IL-17A promoted the progression of AD by enhancing neuroinflammation, inhibiting microglial phagocytosis, and promoting the deposition of ß-amyloid 42 in AD model mice.

Downregulation of Krüppel-like factor 14 accelerated cellular senescence and aging.

Aging has been considered as a risk factor in many diseases, thus, comprehensively understanding the cellular and molecular mechanisms of delayed aging is important. Here we investigated whether Krüppel-like factor 14 (KLF14) is a suppressor of cellular senescence and aging. In our research, KLF14 levels significantly decreased not only in the lymphocytes of healthy people but also in the cells and tissues of mice with aging. We performed in vitro and in vivo experiments on cells and mice to reveal the function of KLF14 in aging. KLF14 deficiency facilitates cellular senescence and aging-related pathologies in C57BL/6J mice, whereas KLF14 overexpression attenuates cellular senescence. Mechanistically, KLF14 delays aging by binding to the POLD1 promoter to positively regulate POLD1 expression. Remarkably, cellular senescence mediated by KLF14 downregulation could be alleviated by POLD1 expression. In addition, perhexiline, an agonist of KLF14, could delay cellular senescence and aging-related pathologies in senescence-accelerated P8 mice by inducing POLD1 expression, as perhexiline could enhance the effect of KLF14's transcription activation to POLD1 by elevating the binding level of KLF14 to the POLD1 promoter. Our data indicate that KLF14 might be a critical element in aging by upregulating POLD1 expression, indicating that the activation of KLF14 may delay aging and aging-associated diseases.

Multiple assessments of non-inferiority trials with ordinal endpoints.

Non-inferiority (NI) trials are implemented when there is a practical demand to search for alternatives to standard therapies, such as to reduce side effects. An experimental treatment is considered non-inferior to the standard treatment when it exhibits clinically non-significant loss of efficacy. Ordinal categorical responses are frequently observed in clinical trials. It has been reported that responses measured using an ordinal scale produce more informative analysis than when responses collapse into binary outcomes. We study the NI trials using ordinal endpoints. We propose a latent variable model for ordinal categorical responses. Based on the proposed latent variable model, the mean efficacy of the different treatments is denoted by the corresponding mean parameter of the underlying continuous distributions. A two-step procedure is proposed for model identification and parameter estimation. A non-inferiority analysis can then be conducted based on the latent variable model and the corresponding estimation procedure. We also develop a method and an algorithm to produce an optimal sample size configuration based on the proposed testing procedure. Two clinical examples are provided for demonstrative purposes.

A meta-analysis on the association between obstructive sleep apnea and periodontitis.

PURPOSE: The present meta-analysis aimed to evaluate quantitively the recent scientific evidence regarding the association between obstructive sleep apnea (OSA) and periodontitis. METHODS: Databases searched were PubMed, EMBASE, Scopus, and Web of Science. Publications were included according to the inclusion criteria. The following outcomes were evaluated: the prevalence of periodontitis, probing depth (PD), clinical attachment loss (CAL), the percentage of sites with bleeding on probing (BOP), plaque index (PI), and gingival index (GI). The statistical analysis was processed using the software STATA. RESULTS: Thirteen eligible studies comprising a total of 31,800 patients were included. The meta-analysis showed an increased prevalence of periodontitis in OSA populations compared to controls. Both PD and CAL were increased in OSA populations compared with controls. (Prevalence of periodontitis: OR 2.348; 95%CI 2.221-2.482; PD: SMD = 0.681, 95% CI: 0.062-1.301, Z = 2.61, P = 0.031; CAL: SMD = 0.694, 95% CI: 0.167-1.22, Z = 2.58, P = 0.01). The study also found significantly increased BOP in patients with OSA after heterogeneity was clarified. (SMD = 0.357, 95% CI: 0.079-0.635, Z = 2.52, P = 0.012). CONCLUSIONS: The findings suggest that OSA was associated with an increased prevalence of periodontitis.

AHNAK Contributes to Hepatocellular Carcinoma Growth by Interacting with IGF-1R.

Neuroblast differentiation-associated protein AHNAK, a large structural scaffold protein, remains mysterious in biological processes. AHNAK plays a suppressive or progressive role in different types of cancers. To investigate the role of the AHNAK in hepatocellular carcinoma (HCC), cell viability assays were performed to determine the cell proliferation of the stable AHNAK-knockdown HepG2 cell line; co-immunoprecipitation (Co-IP) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) were performed on HCC and matched paracancerous (MPC) tissues. The Metascape platform was used for enrichment analyses; the "ComplexHeatmap" package was applied for cluster analyses and visualization. Co-IP, Western botting and immunofluorescence double staining were performed to assess the interactions between AHNAK and insulin-like growth factor 1 receptor (IGF-1R). AHNAK silencing reduced the viability of HepG2 cells; the interactome in HCC and MPC tissues enriched 204 pathways and processes, which partially reflected the signature of HCC field cancerization. AHNAK could co-localize and interact with IGF-1R. These results suggested that the AHNAK complex contributes to HCC growth, potentially by interacting with IGF-1R.

Integrated multi-omics approach revealed cellular senescence landscape.

Cellular senescence is a complex multifactorial biological phenomenon that plays essential roles in aging, and aging-related diseases. During this process, the senescent cells undergo gene expression altering and chromatin structure remodeling. However, studies on the epigenetic landscape of senescence using integrated multi-omics approaches are limited. In this research, we performed ATAC-seq, RNA-seq and ChIP-seq on different senescent types to reveal the landscape of senescence and identify the prime regulatory elements. We also obtained 34 key genes and deduced that NAT1, PBX1 and RRM2, which interacted with each other, could be the potential markers of aging and aging-related diseases. In summary, our work provides the landscape to study accessibility dynamics and transcriptional regulations in cellular senescence. The application of this technique in different types of senescence allows us to identify the regulatory elements responsible for the substantial regulation of transcription, providing the insights into molecular mechanisms of senescence.

Bioinformatics Identification of Aberrantly Methylated Differentially Expressed Genes Associated with Arteriosclerosis by Integrative Analysis of Gene Expression and DNA Methylation Datasets.

The prognosis of patients with advanced arteriosclerosis is bleak due to the lack of understanding of arteriosclerosis. Epigenetics-based DNA methylation plays an important role in the pathogenesis of arteriosclerosis. Hence, we aimed to identify the epigenetics-related aberrantly methylated differentially expressed genes (AMDEGs) in arteriosclerosis. A gene expression dataset and DNA methylation dataset were downloaded from the Gene Expression Omnibus database, and AMDEGs were identified on the basis of the relationship between methylation and expression. Subsequently, the expression levels of candidate hub genes were detected in human peripheral blood mononuclear cells (PBMCs) from atherosclerotic patients and control subjects by RT-qPCR and Western blot. Lastly, the methylation level of the target gene was detected using the MassARRAY method. In the present study, the hypermethylated and downregulated genes were mainly involved in vascular smooth muscle contraction. The hypomethylated and upregulated genes were markedly associated with immune-inflammatory processes. Following validation, LMOD1 was identified as the target gene, which was hypermethylated and downregulated in arteriosclerosis. The methylation levels of CpG sites in LMOD1 promoter were detected to be elevated in the PBMCs of atherosclerotic patients. In conclusion, AMDEGs identified in the present study may assist in understanding the pathogenesis of arteriosclerosis. LMOD1 exhibits potential as a promising diagnostic and therapeutic biomarker for arteriosclerosis.

Krüppel-like factor 5 accelerates the pathogenesis of Alzheimer's disease via BACE1-mediated APP processing.

BACKGROUND: The deposition of ß-amyloid (Aß) in the brain plays a major role in the pathogenesis of Alzheimer's disease (AD). Aß is generated via amyloid precursor protein (APP) cleavage through the amyloidogenic pathway. In this pathway, ß-secretase (BACE1) is the first and rate-limiting enzyme. Its expression increases through an unknown mechanism in patients with AD. Thus, the key regulatory mechanism of BACE1 in the AD process should be revealed to understand the pathogenesis of AD and explore the key treatment targets of AD. METHODS: Here, APPswe/PS1dE9 (APP/PS1) mice were employed to observe the Krüppel-like factor 5 (KLF5) and BACE1 levels in the serum and brain tissues. HT22 cells were used to explore the relationship between KLF5 and BACE1. RESULTS: In this study, KLF5 was found to be a novel transcription factor that positively regulated BACE1 by binding to the BACE1 promoter. The KLF5 levels significantly increased not only in the CSF and serum of patients with AD but also in the brain tissue of APP/PS1 mice. They were closely related to cognitive capacity. KLF5 accelerated APP amyloidogenic metabolism and promoted Aß synthesis through BACE1. Silencing BACE1 could block the KLF5-induced amyloidogenic process of APP. ML264 ameliorated the cognitive deficits and slowed down APP amyloidogenic cleavage in APP/PS1 mice. CONCLUSION: The findings above suggest that upregulation of KLF5 might be a critical element in AD progression by accelerating BACE1-mediated APP amyloidogenic cleavage. The inhibition of KLF5 or the combined inhibitory effect of KLF5 and the BACE1 promoter might be a potential strategy to prevent AD pathogenesis.

ABI3 Is a Novel Early Biomarker of Alzheimer's Disease.

BACKGROUND: The Abi3 gene has been suggested to be an important regulator of microglia during Alzheimer's disease (AD), but the diagnostic power of ABI3 in neurodegenerative disease has rarely been reported. OBJECTIVE: The aim of this study was to evaluate the diagnostic value of ABI3 in AD patients. METHODS: ELISAs were used to measure the ABI3 level in the serum and cerebrospinal fluid (CSF) of AD patients as well as in the serum of APP/PS1 mice. RT-PCR and western blot were further performed to detect the expression levels of ABI3 in peripheral blood mononuclear cells (PBMCs) of AD subjects as well as in the hippocampus and cortical tissue of APP/PS1 mice. The correlation of cognitive ability with ABI3 level was estimated by linear regression analysis. Moreover, the diagnostic value of ABI3 for AD was assessed with ROC analysis. RESULTS: The ABI3 levels all decreased significantly in the serum, CSF, and PBMCs of AD patients and showed a good diagnostic performance. In addition, the ABI3 levels were observed to decrease markedly in the hippocampus from 5-month-old mice, but the dramatic change only appeared in the cortical tissue in the 9-month-old APP/PS1 mice. The ABI3 levels in serum and in the hippocampus of APP/PS1 mice were significantly correlated with cognitive capacity. CONCLUSION: These results demonstrated that ABI3 in serum, CSF, and PBMCs could be a novel early diagnostic biomarker of AD. Moreover, ABI3 had potential to be a novel tracer marker in hippocampus of early AD.

Interferon-Induced Transmembrane Protein 3 Expression Upregulation Is Involved in Progression of Hepatocellular Carcinoma.

PURPOSE: Interferon-induced transmembrane protein 3 (IFITM3) is a key signaling molecule regulating cell growth in some tumors, but its function and mechanism in hepatocellular carcinoma (HCC) remain unknown. Our study investigated the relationship between the expression of IFITM3 and HCC development. Material and Methods. IFITM3 expression was identified via multiple gene expression databases and investigated in HCC tissue samples. Then, PLC/PRF/5 cells were transfected with lentivirus to knock down and overexpress the expression of IFITM3. IFITM3 expression, cell proliferation, and migration were detected by qRT-PCR, western blotting, QuantiGene Plex 2.0 assay, immunohistochemistry, CCK-8, and wound healing tests. RNA-seq technology identified the PI3K/AKT/mTOR pathway as an IFITM3-related signaling pathway for investigation. RESULTS: IFITM3 expression was higher in HCC tissues than in adjacent normal tissues, and the level of IFITM3 was higher in HCC tissues with low differentiation and metastatic potential than in those with high/medium differentiation and without metastatic potential. A higher RNA level of IFITM3 was found in samples with IFITM3 rs12252-CC genotype rather than the TT genotype. Knockdown of IFITM3 in PLC/PRF/5 cells inhibited cell proliferation and migration, blocked the expression of the PI3K/AKT/mTOR signaling pathway, and decreased the expression of vimentin. The results were opposite with the overexpression of IFITM3. CONCLUSION: Upregulation of IFITM3 plays a role in the development of HCC. Possibly through regulating HCC cell proliferation and migration, these effects are associated with the PI3K/AKT/mTOR signaling pathway. Upregulation of IFITM3 is also associated with the IFITM3 rs12252-CC genotype.

CTCF Mediates Replicative Senescence Through POLD1.

POLD1, the catalytic subunit of DNA polymerase δ, plays a critical role in DNA synthesis and DNA repair processes. Moreover, POLD1 is downregulated in replicative senescence to mediate aging. In any case, the components of age-related downregulation of POLD1 expression have not been fully explained. In this article, we elucidate the mechanism of the regulation of POLD1 at the transcription level and found that the transcription factor CCCTC-binding factor (CTCF) was bound to the POLD1 promoter area in two sites. The binding level of CTCF for the POLD1 promoter appeared to be related to aging and was confirmed to be positively controlled by the CTCF level. Additionally, cell senescence characteristics were detected within the cells transfected with short hairpin RNA (shRNA)-CTCF, pLenti-CMV-CTCF, shRNA-POLD1, and pLenti-CMV-POLD1, and the results showed that the CTCF may contribute to the altered expression of POLD1 in aging. In conclusion, the binding level of CTCF for the POLD1 promoter intervened by an age-related decrease in CTCF and downregulated the POLD1 expression in aging. Moreover, the decrease in CTCF-mediated POLD1 transcription accelerates the progression of cell aging.

ß-Cyclodextrin functionalized 3D reduced graphene oxide composite-based electrochemical sensor for the sensitive detection of dopamine.

A three-dimensional reduced graphene oxide nanomaterial with ß-cyclodextrin modified glassy carbon electrode (3D-rGO/ß-CD/GCE) was constructed and used to detect the electrochemical behavior of dopamine (DA). The nanocomposite materials were characterized by scanning electron microscopy (SEM), infrared spectrometry (FT-IR), Raman spectrogram and thermogravimetric analysis (TGA), which showed that ß-CD was well modified on 3D graphene with a porous structure. The electrochemical properties of different modified electrodes were investigated by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), proving the highest electron transfer rate of the 3D-rGO/ß-CD modified electrode. The experimental conditions such as scan rate, pH, enrichment time and layer thickness were optimized. Under the best experimental conditions, DA was detected by differential pulse voltammetry (DPV) by 3D-rGO/ß-CD/GCE with excellent electrocatalytic ability and satisfactory recognition ability, resulting in a wide linear range of 0.5-100 µM and a low detection limit (LOD) of 0.013 µM. The modified electrode based on 3D-rGO/ß-CD nanocomposites is promising in the field of electrochemical sensors due to its high sensitivity and other excellent properties.

A meta-analysis of the effectiveness of Yangxue Qingnao granules for the treatment of chronic cerebral circulation insufficiency.

OBJECTIVE: Yangxue Qingnao granules (YXQNG), which translates to granules that tonify the blood and clear liver heat, are widely available in China for the treatment of Chronic Cerebral Circulation Insufficiency (CCCI). This systematic review aimed to evaluate the effectiveness and safety of YXQNG in treating CCCI. METHODS: PubMed, the Cochrane Central Register of Controlled Trials, Embase, the Chinese National Knowledge Infrastructure, and the Wanfang Database were searched from their inception to February 2019. Randomized controlled trials of YXQNG used alone or in combination with other drugs against a placebo, with no intervention or used with other drugs in CCCI patients were identified. The reviewers identified studies, extracted data, and assessed the quality of the evidence, independently and in duplicate. The Cochrane risk of bias assessment tool was used for quality assessment. RESULTS: A total of 31 RCTs and 2,877 patients were selected. The meta-analysis indicated that the ratio between the combined RR of the total effective rate and the 95% confidential interval (95% CI) was 1.21 (1.17, 1.26). The combined MD of transcranial Doppler (TCD) detecting carotid artery, vertebral artery, and basilar artery blood flows (95% CI), respectively, were 8.84 (5.83, 11.85), 4.72 (3.71, 5.73), and 3.89 (3.03, 4.76). The combined MD of plasma viscosity and fibrinogen, respectively, were -0.35 (-0.40, -0.30) and -0.81 (-1.12, -0.50). Serious adverse effects were not reported in all the included trials. CONCLUSION: This systematic review revealed that YXQNG could increase cerebral blood flow in patients with CCCI and improve their symptoms, with no serious adverse effects. Since the literature reviewed was affected by factors such as lower quality of the included studies, the systematic evaluation's conclusion is not very reliable. Thus, more rigorously designed trials are needed.

Characterization of the chromatin accessibility in an Alzheimer's disease (AD) mouse model.

BACKGROUND: The pathological hallmarks of Alzheimer's disease (AD) involve alterations in the expression of numerous genes associated with transcriptional levels, which are determined by chromatin accessibility. Here, the landscape of chromatin accessibility was studied to understand the outline of the transcription and expression of AD-associated metabolism genes in an AD mouse model. METHODS: The assay for transposase-accessible chromatin by sequencing (ATAC-seq) was used to investigate the AD-associated chromatin reshaping in the APPswe/PS1dE9 (APP/PS1) mouse model. ATAC-seq data in the hippocampus of 8-month-old APP/PS1 mice were generated, and the relationship between chromatin accessibility and gene expression was analyzed in combination with RNA sequencing. Gene ontology (GO) analysis was applied to elucidate biological processes and signaling pathways altered in APP/PS1 mice. Critical transcription factors were identified; alterations in chromatin accessibility were further confirmed using chromatin immunoprecipitation assays. RESULTS: We identified 1690 increased AD-associated chromatin-accessible regions in the hippocampal tissues of APP/PS1 mice. These regions were enriched in genes related to diverse signaling pathways, including the PI3K-Akt, Hippo, TGF-ß, and Jak-Stat signaling pathways, which play essential roles in regulating cell proliferation, apoptosis, and inflammatory responses. A total of 1003 decreased chromatin-accessible regions were considered to be related with declined AD-associated biological processes including cellular response to hyperoxia and insulin stimulus, synaptic transmission, and positive regulation of autophagy. In the APP/PS1 hippocampus, 1090 genes were found to be upregulated and 1081 downregulated. Interestingly, enhanced ATAC-seq signal was found in approximately 740 genes, with 43 exhibiting upregulated mRNA levels. Several genes involved in AD development were found to have a significantly increased expression in APP/PS1 mice compared to controls, including Sele, Clec7a, Cst7, and Ccr6. The signatures of numerous transcription factors, including Olig2, NeuroD1, TCF4, and NeuroG2, were found enriched in the AD-associated accessible chromatin regions. The transcription-activating marks of H3K4me3 and H3K27ac were also found increased in the promoters of these genes. These results indicate that the mechanism for the upregulation of genes could be attributed to the enrichment of open chromatin regions with transcription factors motifs and the histone marks H3K4me3 and H3K27ac. CONCLUSION: Our study reveals that alterations in chromatin accessibility may be an initial mechanism in AD pathogenesis.

Limbic encephalitis associated with AMPA receptor and CRMP5 antibodies: A case report and literature review.

AIMS: AMPA receptor (AMPAR) and CRMP5 antibodies are relatively uncommon in limbic encephalitis, and patients with both antibodies are rare. We recently treated such a patient, but the patient died after active treatment. To further understand this disease, we conducted a case report and literature review. DISCUSSIONS: To date, five encephalitis patients, including our patient, have been found to be positive for AMPAR and CRMP5 antibodies. The male-to-female ratio of the reported cases is 4:1, and the age range is 26 and 62 years old. All five patients presented with various neuropsychiatric symptoms, including insomnia, abnormal behavior, seizures, extrapyramidal symptoms, and autonomic dysfunction. Four patients had tumors (three invasive thymomas and one suspected lymphoma), and three cases died within a short period of time. No tumor was detected in one of the patients during the follow-up period; however, after active treatment, the outcome was poor, and the patient developed cachexia. One patient had good response to immunotherapy and tumor therapy and successfully returned to work. CONCLUSIONS: The prognosis of encephalitis associated with AMPAR and CRMP5 antibodies is worse than that of the encephalitis associated with AMPAR antibodies alone. The most likely cause is that this encephalitis is more likely to be accompanied by malignant tumors, leading to a poor prognosis. In addition, it may also be due to some synergistic mechanisms between the two antibodies. Further studies aimed at the prognosis of this type of encephalitis are warranted.

Publisher Correction: Alpha-fetoprotein inhibits autophagy to promote malignant behaviour in hepatocellular carcinoma cells by activating PI3K/AKT/mTOR signalling.

The article published with errors in the authors' information. The correct ordering and designations for corresponding /first authors are shown here.

Author Correction: Alpha-fetoprotein inhibits autophagy to promote malignant behaviour in hepatocellular carcinoma cells by activating PI3K/AKT/mTOR signalling.

The correct ordering and designations for corresponding/first authors are as follows: Shanshan Wang1,2*, Mingyue Zhu3, Qiaoyun Wang3, Yuli Hou4, Lei Li5, Honglei Weng6, Yan Zhao4, Dexi Chen1,2, Junli Guo3, Huiguo Ding#5, Mengsen Li#3.