Fast and sensitive GCaMP calcium indicators for imaging neural populations.

Calcium imaging with protein-based indicators1,2 is widely used to follow neural activity in intact nervous systems, but current protein sensors report neural activity at timescales much slower than electrical signalling and are limited by trade-offs between sensitivity and kinetics. Here we used large-scale screening and structure-guided mutagenesis to develop and optimize several fast and sensitive GCaMP-type indicators3-8. The resulting 'jGCaMP8' sensors, based on the calcium-binding protein calmodulin and a fragment of endothelial nitric oxide synthase, have ultra-fast kinetics (half-rise times of 2 ms) and the highest sensitivity for neural activity reported for a protein-based calcium sensor. jGCaMP8 sensors will allow tracking of large populations of neurons on timescales relevant to neural computation.

Outcomes of a Double-Cup Construct to Treat Paprosky 3A and 3B Acetabular Defects at a Mean of 39 Months.

BACKGROUND: Modular reconstruction systems based on porous tantalum (PT) prosthetic components have been increasingly used for the treatment of complex acetabular bone defects in revision total hip arthroplasty. We report a novel technique that applies a revision cup as a "super-augment" to form a "double-cup" construct for Paprosky type III defects. METHODS: A retrospective review was conducted on revision total hip arthroplasty cases, comparing those treated with double-cup constructs (DC group, n = 48) to those treated with PT shells and augments (PT group, n = 48). All procedures were performed at the same institute between 2017 and 2022. Clinical outcome evaluation utilized the Harris Hip Score, Oxford Hip Score, and the 36-Item Short Form Survey. Preoperative and postoperative radiographic assessments measured hip center of rotation (COR) position and leg length discrepancy. Additionally, postoperative complications and implant survivorship were monitored during the follow-up period. RESULTS: The clinical outcomes improved substantially in both groups, which showed no significant difference in the Harris Hip Score (P = .786), the Oxford Hip Score (P = .570), and the 36-Item Short Form Survey (P = .691). Compared to the PT group, the reconstruction COR was significantly closer to the anatomic COR (vertical distance: 2.630 versus 7.355 mm, P = .0034; horizontal distance: 1.881 versus -6.413 mm, P < .0001) in Paprosky 3B type defects. Additionally, postoperative leg length discrepancy was less in the DC group (-8.252 versus -1.821 mm, P = .0008). Dislocation was the main complication in the DC group, and only 1 patient received re-revision due to repeated dislocation. The cumulative survival rate of the DC group (100%; 95% confidence interval 100) was better than the PT group (83.4%; 95% confidence interval 70.5 to 98.6) when re-revisions for aseptic loosening were the endpoint (P = .046). CONCLUSIONS: The DC is a reliable revision technique for the reconstruction of Paprosky type III bone defects. Although dislocation remains challenging, the biomechanically superior restoration achieved by this technique lowers the risk of aseptic loosening.

Shock or opportunity? Unveiling the effect of low-carbon transition on employment.

The stabilization of growth and preservation of employment are the primary objectives of the current new economic normal. Investigating whether the low-carbon transition can be an opportunity or a shock for employment expansion in green development requires thorough examination. This study utilizes multi-temporal difference-in-difference (DID) models, analyzing comprehensive panel data from China (2007-2019) to assess the impact of the Low-carbon City Pilot (LCCP) policy on employment at meso-regional and micro-firm levels. Empirical findings robustly reveal that LCCP significantly boosts employment, with average treatment effects of approximately 0.548% and 5.892% at regional and firm scales, respectively. Positive impacts vary based on ownership, location, industry type, and energy consumption within enterprises. Notably, state-owned enterprises, those in the eastern region, engaged in secondary industries, and with high energy consumption experience pronounced positive effects. Mechanism analysis further reveals that LCCP boosts employment via promoting government environmental subsidies and expanding enterprise investment scale to create more jobs. These findings provide policy recommendations for further promoting low-carbon transition and expanding employment to achieve the win-win goal of sustainable development.

Radiographic evaluation of robot-assisted versus manual total hip arthroplasty: a multicenter randomized controlled trial.

BACKGROUND: The effectiveness of robot-assisted surgery remains contentious due to the lack of high-quality randomized controlled trials (RCTs) to elevate the level of evidence. We aimed to evaluate the postoperative radiographic outcomes of robot-assisted (RAS-THA) versus manual (M-THA) total hip arthroplasty. METHODS: This multicenter RCT was performed from March 1, 2021 to December 1, 2021. Patients were randomly assigned to routine M-THA or to RAS-THA that used the TRex-RS orthopedic joint surgical navigation system. The primary outcome was to compare the acetabular component orientation, femoral stem alignment, femoral canal fill ratio, and leg length discrepancy between RAS-THA and M-THA using postoperative radiography. Subgroup analyses of the two groups stratified by surgical approach, gender, and BMI were also conducted. RESULTS: Seventy-three participants were randomly allocated to the RAS-THA group, while seventy-two participants were assigned to the M-THA group. Compared to the M-THA group, the RAS-THA group exhibited less variability in the preoperative planning of the vertical center of rotation (VCOR; P < 0.001), demonstrated a significant advantage in femoral stem alignment (P = 0.004), and showed pronounced decreases in inequality and in the variability in leg length discrepancy (P < 0.001). There was no significant difference in the Lewinnek safe-zone ratio (P = 0.081) and the femoral canal fill ratio (P > 0.05) between the two groups. Further subgroup analysis also showed that the RAS-THA group had fewer horizontal center of rotation (HCOR) and leg length differences when stratified by surgical approach, gender, and overweight status. CONCLUSION: This RCT found that, regardless of the surgical approach, gender, or body mass index, RAS-THA can effectively improve the postoperative VCOR and significantly reduce the variability of leg length difference. RAS-THA should be considered an effective method to enhance surgical precision by achieving less variability in challenging patients with leg length discrepancies. TRIAL REGISTRATION: ChiCTR2100044124.

Identification of the shared gene signatures and molecular pathways in systemic lupus erythematosus and diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) incidence is higher in systemic lupus erythematosus (SLE) patients than the general population, but the molecular mechanisms behind this link remain ambiguous. The aim of this study was to investigate shared gene signatures and molecular pathways between SLE and DLBCL. METHODS: We procured expression profiles of SLE and DLBCL from public databases and identified common differentially expressed genes (DEGs). Functional pathway enrichment and protein-protein interaction (PPI) analyses were performed on these shared genes. The molecular complex detection technology (MCODE) and eXtreme Gradient Boosting (XGBoost) machine learning algorithm were used to select core shared genes, followed by Gene Set Enrichment Analysis (GSEA) and immune infiltration analysis. RESULTS: We identified 54 DEGs as shared genes, among which CD177, CEACAM1, GPR84 and IFIT3 were identified as core shared genes. These genes showed strong associations with inflammatory and immune response pathways. We found a significant positive correlation between GPR84 and IFIT3 expression levels and the immune microenvironment. Decreased expression levels of GPR84 and IFIT3 were linked to enhanced immune therapy sensitivity, potentially due to lower dysregulation scores during low expression. We also discovered that TP53 mutations might elevate CD177 and GPR84 expression and that reduced expression levels of GPR84 and IFIT3 were linked with better overall survival and progression-free survival in DLBCL patients. CONCLUSIONS: Our study provides valuable insights into the shared molecular mechanisms underpinning the pathogenesis of SLE and DLBCL. These findings could potentially offer new biomarkers and therapeutic targets for SLE and DLBCL.

The star target in SLE: IL-17.

PURPOSE: The purpose of this review is to discuss the significance of IL-17 in SLE and the potential of IL-17-targeted therapy. BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs and tissues throughout the body. It is characterized by overactive B and T cells and loss of immune tolerance to autoantigens. Interleukin-17 (IL-17) is a cytokine that promotes inflammation and has been implicated in the pathogenesis of several autoimmune diseases as well as inflammatory diseases. In in vitro cellular experiments in lupus susceptible mice or SLE patients, there is substantial evidence that IL-17 is a highly promising therapeutic target. METHODS: We searched papers from PubMed database using the search terms, such as interleukin-17, systemic lupus erythematosus, treatment targets, T cells, lupus nephritis, and other relevant terms. RESULTS: We discuss in this paper the molecular mechanisms of IL-17 expression, Th17 cell proliferation, and the relationship between IL-17 and Th17. The significance of IL-17 in SLE and the potential of IL-17-targeted therapy are further discussed in detail. CONCLUSION: IL-17 has a very high potential for the development as a star target in SLE.

Near-Infrared Voltage Nanosensors Enable Real-Time Imaging of Neuronal Activities in Mice and Zebrafish.

Optical voltage sensors with the ability to monitor neuronal activities are invaluable tools for studying information processing of the brain. However, the current genetically encoded voltage indicators usually require high-power visible light for excitation and are limited to genetically addressable model animals. Here, we report a near-infrared (NIR)-excited nongenetic voltage nanosensor that achieves stable recording of neuronal membrane potential in intact animals. The nanosensor is composed of a Förster resonance energy transfer (FRET) pair, the outer membrane-anchored upconversion nanoparticle (UCNP), and the membrane-embedded dipicrylamine (DPA). The negative charge of DPA allows membrane potential fluctuation to affect the distance between the DPA and UCNP, therefore changing the FRET efficiency. Consequently, the emission intensity of the nanosensor can report the membrane potential. Using the nanosensor, we monitor not only electrically evoked changes in the membrane potential of cultured cells but also sensory responses of neurons in intact zebrafish and brain state-modulated subthreshold activities of cortical neurons in intact mice.

miR-193b promotes cell proliferation by targeting Smad3 in human glioma.

Studies have shown that several miRNAs play important roles in regulating a variety of cellular processes in gliomas. In these reports, upregulation of miR-193b has been found to be associated with a poor prognosis for glioma, but its functional mechanism in glioma remains unclear. This study investigates the roles of miR-193b in glioma tumor growth. We first showed that the expression of miR-193b was elevated in both glioma samples and glioma cells. Furthermore, downregulation of miR-193b by inhibitors was statistically correlated with a decrease in cell growth and a restored G1 accumulation. Luciferase assay and Western blot analysis revealed that Smad3 is a direct target of miR-193b. To prove that miR-193b regulated cell growth through the transforming growth factor-ß (TGF-ß) pathway in glioma cells by regulating Smad3, we tested endogenous targets of the TGF-ß pathway by measuring the accumulation of p21 mRNAs after downregulation of miR-193b. The results confirmed that induction of p21 was promoted by miR-193b inhibitors in glioma cells, although this induction disappeared when Smad3 was knocked down with siRNA. Moreover, downregulation of Smad3 mitigates the miR-193b suppression of glioma proliferation. In conclusion, these results suggest that miR-193b regulated cell growth in glioma through the TGF-ß pathway by regulating Smad3. Thus, our study indicates that miR-193b promotes cell proliferation by targeting Smad3 in human glioma, which may serve as a potentially useful target for development of miRNA-based therapies in the future.

Total Hip Arthroplasty Combined with Proximal Femoral Reconstruction Effectively Treats Severe Hip Deformities: A Novel Osteotomy Technique.

OBJECTIVE: Total hip arthroplasty (THA) combined with proximal femoral reconstruction is a novel osteotomy technique developed to address severe hip deformities. There is a paucity of robust clinical and radiological evidence regarding the outcomes of this novel osteotomy technique. This study aimed to evaluate the clinical and radiological outcomes of THA combined with proximal femoral reconstruction during the early follow-up. METHODS: This is a retrospective case series of 63 hips who underwent THA combined with proximal femoral reconstruction at a single institution between January 2020 and July 2023. The mean age of patients was 39.6 ± 12.6 years. The mean follow-up was 25.6 ± 3.8 months. Surgical characteristics and perioperative variables were evaluated to assess the efficacy of this technique. Harris hip score (HHS) was utilized to evaluate hip function. Leg length discrepancy (LLD) was evaluated in X-ray. The incidence of major adverse events including deep vein thrombosis (DVT), osteolysis, nonunion of the osteotomy, intraoperative femoral fracture, and infection was also evaluated. Paired-samples t-test was used to compare preoperative and postoperative HHS and LLD. RESULTS: The mean operative time was 125.1 min. The mean size of the acetabular components used was 45.2 mm, and the stem size was 7.5. The primary friction interface was ceramic-on-ceramic, accounting for 92.1% of cases. The average length of hospital stay was 8.5 days. The mean cost of treatment was 46,296.0 Yuan. There was a significant improvement in postoperative HHS (p < 0.001) and LLD (p < 0.001) compared to preoperative values. The incidence of deep venous thrombosis was 4.8%; osteolysis rates for the cup and stem were 4.8% and 6.4%, respectively. The non-union and dislocation rates were 1.6% and 3.2%, respectively. There was no incidence of postoperative infection. CONCLUSION: The novel osteotomy surgical procedure yields reliable and impressive clinical and radiological outcomes, with minimal complications. We advocate for its use in complex primary THA cases involving severe proximal femoral deformities.

Gut microbiota changes in patients with Alzheimer's disease spectrum based on 16S rRNA sequencing: a systematic review and meta-analysis.

Background: The gut microbiota (GM) is hypothesized to play roles in Alzheimer's disease (AD) pathogenesis. In recent years, many GM composition and abundance investigations in AD patients have been conducted; however, despite this work, some results remain controversial. Therefore, we conducted a systematic review and meta-analysis using 16S ribosomal RNA (16S rRNA) sequencing to explore GM alterations between patients with AD spectrum and healthy controls (HCs). Methods: A systematic and comprehensive literature search of PubMed, Web of Science, Embase, the Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine disc database, WanFang database and Social Sciences Citation Index databases was conducted from inception to January 2023. Inclusion and exclusion criteria were strictly defined, and two researchers independently screened and extracted information from selected studies. Data quality were evaluated according to the "Cochrane system evaluator manual" and pooled data were comprehensively analyzed using Stata 14 software with standardized mean differences (SMDs) and 95% confidence intervals (95% CIs) used to measure effect sizes. Also, geographical heterogeneity effects (related to cohorts) on GM abundance were examined based on subgroup meta-analyses if sufficient studies reported outcomes. Finally, publication bias was assessed using funnel plots. Results: Out of 1566 articles, 13 studies involving 581 patients with AD spectrum and 445 HCs were deemed eligible and included in our analysis. In summary, a decreased microbiota alpha diversity and a significantly distinct pattern of clustering with regard to beta diversity were observed in AD spectrum patients when compared with HCs. Comparative analyses revealed a decreased Ruminococcus, Faecalibacterium, Lachnospira, Dialister, Lachnoclostridium, and Roseburia abundance in AD spectrum patients while Phascolarctobacterium, Lactobacillus, and Akkermansia muciniphila were more enriched in patients when compared to HCs. Furthermore, regional variations may have been in play for intestinal microbes such as Bacteroides, Bifidobacterium, and Alistipes. Conclusion: Our meta-analysis identified alterations in GM abundance in patients with AD spectrum, with 12 genera from four major phyla significantly associated with AD. Moreover, we provided evidence for region-specific alterations in Bacteroides, Bifidobacterium, and Alistipes abundance. These findings may have profound implications for the development of innovative GM-based strategies to prevent and treat AD. Systematic review registration: https://doi.org/10.37766/inplasy2024.6.0067, identifier INPLASY202460067.

Explore the shared molecular mechanism between dermatomyositis and nasopharyngeal cancer by bioinformatic analysis.

BACKGROUND: Dermatomyositis (DM) is prone to nasopharyngeal carcinoma (NPC), but the mechanism is unclear. This study aimed to explore the potential pathogenesis of DM and NPC. METHODS: The datasets GSE46239, GSE142807, GSE12452, and GSE53819 were downloaded from the GEO dataset. The disease co-expression module was obtained by R-package WGCNA. We built PPI networks for the key modules. ClueGO was used to analyze functional enrichment for the key modules. DEG analysis was performed with the R-package "limma". R-package "pROC" was applied to assess the diagnostic performance of hub genes. MiRNA-mRNA networks were constructed using MiRTarBase and miRWalk databases. RESULTS: The key modules that positively correlated with NPC and DM were found. Its intersecting genes were enriched in the negative regulation of viral gene replication pathway. Similarly, overlapping down-regulated DEGs in DM and NPC were also enriched in negatively regulated viral gene replication. Finally, we identified 10 hub genes that primarily regulate viral biological processes and type I interferon responses. Four key genes (GBP1, IFIH1, IFIT3, BST2) showed strong diagnostic performance, with AUC>0.8. In both DM and NPC, the expression of key genes was correlated with macrophage infiltration level. Based on hub genes' miRNA-mRNA network, hsa-miR-146a plays a vital role in DM-associated NPC. CONCLUSIONS: Our research discovered pivot genes between DM and NPC. Viral gene replication and response to type I interferon may be the crucial bridge between DM and NPC. By regulating hub genes, MiR-146a will provide new strategies for diagnosis and treatment in DM complicated by NPC patients. For individuals with persistent viral replication in DM, screening for nasopharyngeal cancer is necessary.

Biodegradable flow-diverting device for the treatment of intracranial aneurysm: short-term results of a rabbit experiment.

INTRODUCTION: One main complication of a flow-diverting device (FD) in treating intracranial aneurysm is stenosis of parent artery (PA) or occlusion of side branches. The use of a biodegradable device may satisfy the need for aneurysm occlusion and eliminate potential complications. METHODS: Twenty elastase-induced aneurysm rabbit models were divided into three groups: in group 1 (n = 7), polyglycolic acid FDs (PGA-FDs) were implanted across the necks of aneurysms and the abdominal aortas (AA), covering the ostium of a lumbar artery; in group 2 (n = 7), the PGA-FDs were replaced by metal FDs; and in group 3 (n = 6), the PGA-FDs were only implanted across the necks of aneurysms. Animals in group 3 underwent angiography at 6 weeks; those in groups 1 and 2 underwent angiography at 3 months. The status of aneurysm embolization and patency of side branches were assessed. RESULTS: Complete aneurysm occlusion rates in groups 1 and 3 were 83.3 and 66.7 %, respectively, compared with 0 % in group 2. No side branch occlusions were noted. PA neointimal hyperplasia was minimal, and there were no significant differences between groups 1 and 2 (P = 0.233). The neointimal coverage ratio of the branch ostium in AA in group 1 was not significantly different from that in group 2 (P = 0.605). The neointima comprised predominantly smooth muscle cells and collagen fibers. CONCLUSIONS: The PGA-FD was an effective device for the treatment of aneurysms and was safe for side branches at the 3-month follow-up.

Changes in Chinese early adolescents' group orientation and mental health from before to during the COVID-19 pandemic.

Adolescence is a critical period for formulating and developing value orientations. The COVID-19 pandemic has dramatically restricted people's lives, potentially leading adolescents to reevaluate what they prioritize in life (i.e., their values) and affecting their mental health. Previous studies suggest that Chinese early adolescents' group orientation is negatively associated with mental health more strongly in rural than in urban, whereas this rural-urban differs may vary after the outbreak of the pandemic. To examine potential changes in group orientation, mental health, and their associations during the pandemic, two cross-sectional surveys of ninth-grade students in the same three school were conducted in rural and urban China in 2019 and 2021. The results showed that compared with students before the pandemic (2019, N = 516, 48.8% girls, Mage = 14.87 years), students during the pandemic (2021, N = 655, 48.1% girls, Mage = 14.80 years) displayed lower group orientation such as group responsibility and rule abiding of rural students, and higher loneliness and depressive symptoms. Social equality, group responsibility and rule abiding were all significantly negatively associated with loneliness and depressive symptoms. Those negative associations were stronger in the urban regions than in the rural region. Follow-up invariance analysis revealed that this rural-urban difference in the relations between social equality, group responsibility, and rule abiding and mental health problems was only significant during (and not before) the pandemic. The protective effect of group orientation on mental health seems to be weakened only in rural contexts. The results suggest that significant changes in macrolevel contexts may play an important role in shaping adolescents' value orientation and mental health.

Identification of NETs-related biomarkers and molecular clusters in systemic lupus erythematosus.

Neutrophil extracellular traps (NETs) is an important process involved in the pathogenesis of systemic lupus erythematosus (SLE), but the potential mechanisms of NETs contributing to SLE at the genetic level have not been clearly investigated. This investigation aimed to explore the molecular characteristics of NETs-related genes (NRGs) in SLE based on bioinformatics analysis, and identify associated reliable biomarkers and molecular clusters. Dataset GSE45291 was acquired from the Gene Expression Omnibus repository and used as a training set for subsequent analysis. A total of 1006 differentially expressed genes (DEGs) were obtained, most of which were associated with multiple viral infections. The interaction of DEGs with NRGs revealed 8 differentially expressed NRGs (DE-NRGs). The correlation and protein-protein interaction analyses of these DE-NRGs were performed. Among them, HMGB1, ITGB2, and CREB5 were selected as hub genes by random forest, support vector machine, and least absolute shrinkage and selection operator algorithms. The significant diagnostic value for SLE was confirmed in the training set and three validation sets (GSE81622, GSE61635, and GSE122459). Additionally, three NETs-related sub-clusters were identified based on the hub genes' expression profiles analyzed by unsupervised consensus cluster assessment. Functional enrichment was performed among the three NETs subgroups, and the data revealed that cluster 1 highly expressed DEGs were prevalent in innate immune response pathways while that of cluster 3 were enriched in adaptive immune response pathways. Moreover, immune infiltration analysis also revealed that innate immune cells were markedly infiltrated in cluster 1 while the adaptive immune cells were upregulated in cluster 3. As per our knowledge, this investigation is the first to explore the molecular characteristics of NRGs in SLE, identify three potential biomarkers (HMGB1, ITGB2, and CREB5), and three distinct clusters based on these hub biomarkers.

Decoding the mitochondrial connection: development and validation of biomarkers for classifying and treating systemic lupus erythematosus through bioinformatics and machine learning.

BACKGROUND: Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disease characterized by clinical and pathological diversity. Mitochondrial dysfunction has been identified as a critical pathogenetic factor in SLE. However, the specific molecular aspects and regulatory roles of this dysfunction in SLE are not fully understood. Our study aims to explore the molecular characteristics of mitochondria-related genes (MRGs) in SLE, with a focus on identifying reliable biomarkers for classification and therapeutic purposes. METHODS: We sourced six SLE-related microarray datasets (GSE61635, GSE50772, GSE30153, GSE99967, GSE81622, and GSE49454) from the Gene Expression Omnibus (GEO) database. Three of these datasets (GSE61635, GSE50772, GSE30153) were integrated into a training set for differential analysis. The intersection of differentially expressed genes with MRGs yielded a set of differentially expressed MRGs (DE-MRGs). We employed machine learning algorithms-random forest (RF), support vector machine (SVM), and least absolute shrinkage and selection operator (LASSO) logistic regression-to select key hub genes. These genes' classifying potential was validated in the training set and three other validation sets (GSE99967, GSE81622, and GSE49454). Further analyses included differential expression, co-expression, protein-protein interaction (PPI), gene set enrichment analysis (GSEA), and immune infiltration, centered on these hub genes. We also constructed TF-mRNA, miRNA-mRNA, and drug-target networks based on these hub genes using the ChEA3, miRcode, and PubChem databases. RESULTS: Our investigation identified 761 differentially expressed genes (DEGs), mainly related to viral infection, inflammatory, and immune-related signaling pathways. The interaction between these DEGs and MRGs led to the identification of 27 distinct DE-MRGs. Key among these were FAM210B, MSRB2, LYRM7, IFI27, and SCO2, designated as hub genes through machine learning analysis. Their significant role in SLE classification was confirmed in both the training and validation sets. Additional analyses included differential expression, co-expression, PPI, GSEA, immune infiltration, and the construction of TF-mRNA, miRNA-mRNA, and drug-target networks. CONCLUSIONS: This research represents a novel exploration into the MRGs of SLE, identifying FAM210B, MSRB2, LYRM7, IFI27, and SCO2 as significant candidates for classifying and therapeutic targeting.

Comparing clinical characteristics of systemic sclerosis with or without interstitial lung disease: A cross-sectional study from a single center of the Chinese Rheumatism Data Center.

Background: We aimed to compare the clinical characteristics of patients with systemic sclerosis (SSc) with or without interstitial lung disease (ILD) to identify relationships with the presence of ILD in SSc at a single center in China. Methods: A cross-sectional study was conducted using retrospective data from the Chinese Rheumatology Data Center. Patients diagnosed with SSc at the Second Affiliated Hospital of Nanchang University between 2013 and 2022 were included. Demographic and clinical characteristics were compared between patients with SSc with and without ILD. Logistic regression analyses were performed to explore these associations. Results: A total of 227 patients with SSc were included (male:female ratio = 1:4.82), of which 121 (53.3%) were accompanied with ILD. SSc patients with ILD had a higher percentage of diffuse cutaneous systemic sclerosis (dcSSc), sclerodactyly, loss of finger pad, muscle involvement, left ventricular diastolic dysfunction (LVDD), and pulmonary hypertension (PAH), elevated Krebs von den Lungen-6 (KL-6), and elevated ferritin than those without ILD, and a higher modified Rodnan skin score (mRSS), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) (all P < 0.05). Antinuclear antibody (ANA) and anti-scleroderma-70 (anti-Scl-70) positivity was presented frequently in SSc patients with ILD, while SSc patients without ILD were more often anti-centromere antibody (ACA) positive (all P < 0.05). On the multivariable analysis, muscle involvement [OR 2.551 (95% CI 1.054-6.175), P = 0.038], LVDD [OR 2.360 (95% CI 1.277-4.361), P = 0.006], PAH [OR 9.134 (95% CI 2.335-35.730), P = 0.001], dcSSc [OR 2.859 (95% CI 1.489-5.487), P = 0.002], PLR [OR 1.005 (95% CI 1.001-1.008), P = 0.020], elevated KL-6 [OR 2.033 (95% CI 1.099-3.763), P = 0.024], and anti-Scl-70 [OR 3.101 (95% CI 1.647-5.840), P < 0.001] were statistically significant associations with SSc patients with ILD. Conclusion: Systemic sclerosis was found mainly in females. Several important differences in clinical and laboratory characteristics have been demonstrated between SSc patients with or without ILD. Muscle involvement, LVDD, PAH, dcSSc, PLR, elevated KL-6, and Anti-Scl-70 antibody may be associated with SSc in patients with ILD.

Molecular Signatures of Mitochondrial Complexes Involved in Alzheimer's Disease via Oxidative Phosphorylation and Retrograde Endocannabinoid Signaling Pathways.

Objective: The inability to intervene in Alzheimer's disease (AD) forces the search for promising gene-targeted therapies. This study was aimed at exploring molecular signatures and mechanistic pathways to improve the diagnosis and treatment of AD. Methods: Microarray datasets were collected to filter differentially expressed genes (DEGs) between AD and nondementia controls. Weight gene correlation network analysis (WGCNA) was employed to analyze the correlation of coexpression modules with AD phenotype. A global regulatory network was established and then visualized using Cytoscape software to determine hub genes and their mechanistic pathways. Receiver operating characteristic (ROC) analysis was conducted to estimate the diagnostic performance of hub genes in AD prediction. Results: A total of 2,163 DEGs from 13,049 background genes were screened in AD relative to nondementia controls. Among the six coexpression modules constructed by WGCNA, DEGs of the key modules with the strongest correlation with AD were extracted to build a global regulatory network. According to the Maximal Clique Centrality (MCC) method, five hub genes associated with mitochondrial complexes were chosen. Further pathway enrichment analysis of hub genes, such as oxidative phosphorylation and retrograde endocannabinoid signaling, was identified. According to the area under the curve (AUC) of about 70%, each hub gene exhibited a good diagnostic performance in predicting AD. Conclusions: Our findings highlight the perturbation of mitochondrial complexes underlying AD onset, which is mediated by molecular signatures involved in oxidative phosphorylation (COX5A, NDUFAB1, SDHB, UQCRC2, and UQCRFS1) and retrograde endocannabinoid signaling (NDUFAB1) pathways.

Down-Regulation of Insulin Like Growth Factor 1 Involved in Alzheimer's Disease via MAPK, Ras, and FoxO Signaling Pathways.

The inability to halt or even delay the course of Alzheimer's disease (AD) forces the development of new molecular signatures and therapeutic strategies. Insulin like growth factor 1 (IGF1) is a promising target for AD treatment, yet exact mechanisms of AD ascribed to IGF1 remain elusive. Herein, gene expression profiles of 195 samples were analyzed and 19,245 background genes were generated, among which 4,424 differentially expressed genes (DEGs) were overlapped between AD/control and IGF1-low/high groups. Based on such DEGs, seven co-expression modules were established by weight gene correlation network analysis (WGCNA). The turquoise module had the strongest correlation with AD and IGF1-low expression, the DEGs of which were enriched in GABAergic synapse, long-term potentiation, mitogen-activated protein kinase (MAPK), Ras, and forkhead box O (FoxO) signaling pathways. Furthermore, cross-talking pathways of IGF1, including MAPK, Ras, and FoxO signaling pathways were identified in the protein-protein interaction network. According to the area under the curve (AUC) analysis, down-regulation of IGF1 exhibited good diagnostic performance in AD prediction. Collectively, our findings highlight the involvement of low IGF1 in AD pathogenesis via MAPK, Ras, and FoxO signaling pathways, which might advance strategies for the prevention and therapy of AD based on IGF1 target.

Downregulation of PIK3CB Involved in Alzheimer's Disease via Apoptosis, Axon Guidance, and FoxO Signaling Pathway.

OBJECTIVE: To investigate the molecular function of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta (PIK3CB) underlying Alzheimer's disease (AD). METHODS: RNA sequencing data were used to filtrate differentially expressed genes (DEGs) in AD/nondementia control and PIK3CB-low/high groups. An unbiased coexpression network was established to evaluate module-trait relationships by using weight gene correlation network analysis (WGCNA). Global regulatory network was constructed to predict the protein-protein interaction. Further cross-talking pathways of PIK3CB were identified by functional enrichment analysis. RESULTS: The mean expression of PIK3CB in AD patients was significantly lower than those in nondementia controls. We identified 2,385 DEGs from 16,790 background genes in AD/control and PIK3CB-low/high groups. Five coexpression modules were established using WGCNA, which participated in apoptosis, axon guidance, long-term potentiation (LTP), regulation of actin cytoskeleton, synaptic vesicle cycle, FoxO, mitogen-activated protein kinase (MAPK), and vascular endothelial growth factor (VEGF) signaling pathways. DEGs with strong relation to AD and low PIK3CB expression were extracted to construct a global regulatory network, in which cross-talking pathways of PIK3CB were identified, such as apoptosis, axon guidance, and FoxO signaling pathway. The occurrence of AD could be accurately predicted by low PIK3CB based on the area under the curve of 71.7%. CONCLUSIONS: These findings highlight downregulated PIK3CB as a potential causative factor of AD, possibly mediated via apoptosis, axon guidance, and FoxO signaling pathway.

DNA vaccines targeting amyloid-ß oligomer ameliorate cognitive deficits of aged APP/PS1/tau triple-transgenic mouse models of Alzheimer's disease.

The amyloid-ß (Aß) oligomer, rather than the Aß monomer, is considered to be the primary initiator of Alzheimer's disease. It was hypothesized that p(Aß3-10)10-MT, the recombinant Aß3-10 gene vaccine of the Aß oligomer has the potential to treat Alzheimer's disease. In this study, we intramuscularly injected the p(Aß3-10)10-MT vaccine into the left hindlimb of APP/PS1/tau triple-transgenic mice, which are a model for Alzheimer's disease. Our results showed that the p(Aß3-10)10-MT vaccine effectively reduced Aß oligomer levels and plaque deposition in the cerebral cortex and hippocampus, decreased the levels tau protein variants, reduced synaptic loss, protected synaptic function, reduced neuron loss, and ameliorated memory impairment without causing any cerebral hemorrhaging. Therefore, this novel DNA vaccine, which is safe and highly effective in mouse models of Alzheimer's disease, holds a lot of promise for the treatment of Alzheimer's disease in humans.