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Background Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths. The current prevention and treatment situation remains critical. It is of scientific significance to explore new therapeutic agents for HCC. Objective To analyze the mechanism of wogonin on HCC by network pharmacology and to verify it in vitro. Methods The drug targets of wogonin were searched in TCMSP database, and the disease targets of HCC were collected from TTD, GenCard, OMIM, DisGent databases. The collected drug targets and disease targets were intersected as potential targets for drug intervention in diseases. R software was used for enrichment analysis of intersection targets, STRING database and Cytoscape software were used to construct protein interaction network and screen core targets. The core targets were further analyzed in GIEPA database. Finally, the preliminary analysis results were verified by in vitro experiments, including cell activity determination using CCK-8 kit, cell proliferation determination using plate clone formation experiment, cell migration determination using scoring test, protein expression level determination using Western-blotting (WB) assay. Results The AMDE characteristics of wogonin were found to be in accordance with the rules for small molecule drug formation and the toxicity analysis showed no toxicity. A total of 135 wogonin targets and 8 238 HCC targets were collected, and 113 targets were intersected. Through the analysis of the core genes of TOP10 screened by the constructed protein interaction network, it was found that the mRNA levels of CDK1 and SRC in liver cancer tissues were higher than those in normal liver tissues (P

Abstract Alzheimer’s disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the “diffuse-AD” (R1) dimension shows widespread brain atrophy, and the “MTL-AD” (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were “druggable genes” for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOE ε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction—driven by genes different from APOE—which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/ .

Abstract Background Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease (AD). This case-cohort study used targeted plasma biomarkers and large-scale proteomics to examine the biological mechanisms that allow some APOEε4 carriers to maintain normal cognitive functioning in older adulthood. Methods APOEε4 carriers and APOEε3 homozygotes enrolled in the Women’s Health Initiative Memory Study (WHIMS) from 1996 to 1999 were classified as resilient if they remained cognitively unimpaired beyond age 80, and as non-resilient if they developed cognitive impairment before or at age 80. AD pathology (Aß42/40) and neurodegeneration (NfL, tau) biomarkers, as well as 1007 proteins (Olink) were quantified in blood collected at study enrollment (on average 14 years prior) when participants were cognitively normal. We identified plasma proteins that distinguished between resilient and non-resilient APOEε4 carriers, examined whether these associations generalized to APOEε3 homozygotes, and replicated these findings in the UK Biobank. Results A total of 1610 participants were included (baseline age: 71.3 [3.8 SD] years; all White; 42% APOEε4 carriers). Compared to resilient APOEε4 carriers, non-resilient APOEε4 carriers had lower Aß42/40/tau ratio and greater NfL at baseline. Proteomic analyses identified four proteins differentially expressed between resilient and non-resilient APOEε4 carriers at an FDR-corrected P

Abstract Liposarcoma (LPS) is the second most common kind of soft tissue sarcoma, and a heterogeneous malignant tumor derived from adipose tissue. Up to now, the prognostic value of BAG1 or BAG2 in LPS has not been defined yet. Expression profiling data of LPS patients were collected from TCGA and GEO database. Survival curves were plotted to verify the outcome differences of patients based on BAG1 or BAG2 expression. Univariate and multivariate Cox regression models were used to analyze the prognostic ability of BAG1 or BAG2. Chaperone’s regulators BAG1 and BAG2 were identified as prognostic biomarkers for LPS patients, which exhibited distinct expression patterns and survival outcome prediction performances. Patients with high BAG2 expression and/or low BAG1 expression had worse prognosis. Enrichment analysis showed that BAG1 was involved in negative regulation of TGF-β signaling. Low expression of BAG1 was associated with high abundance of regulatory T cells (Tregs). The 2-gene signature model further confirmed the improved risk assessment performance of BAG1 and BAG2: high risk patients displayed poor prognosis. BAG1 and BAG2 are supposed to be potential prognostic biomarkers for LPS and have impacts on liposarcomagenesis and immune infiltration in distinctive manners, which may function as potential therapy targets (BAG1 agonists/BAG2 inhibitors) for LPS.

Abstract Progranulin (PGRN) plays a critical role in bronchial asthma and the function of various immune cells. However, the mechanisms by which PGRN influences B‐cell receptor (BCR) signaling and immunoglobulin E(IgE) production are not fully understood. The study aimed to elucidate the molecular mechanisms through which PGRN affects BCR signaling, B‐cell differentiation, and IgE production. A PGRN knockout mouse model, along with techniques including flow cytometry, the creation of a bone marrow chimeric mouse model, total internal reflection fluorescence (TIRF), and Western blot (WB) analysis is employed, to investigate the link between PGRN and various aspects of B‐cell biology. It is discovered that the absence of PGRN in mice alters peripheral B‐cell subpopulations, promotes IgE class switching in a cell‐intrinsic manner, and affects B‐cell subpopulations. Additionally, PGRN modulates B‐cell functions by regulating BCR signaling pathways, metabolic processes, and the actin cytoskeleton during early B‐cell activation. Significantly, PGRN deficiency results in diminished production of NP‐specific antibodies. Moreover, it is found that PGRN inhibits B‐cell activation and IgE production through the PGRN‐IFITM3‐STAT1 signaling pathway. The findings provide new strategies for the targeted treatment of bronchial asthma, highlighting the crucial role of PGRN in B‐cell signaling and IgE production.

Summary: Background: Brain ageing is highly heterogeneous, as it is driven by a variety of normal and neuropathological processes. These processes may differentially affect structural and functional brain ageing across individuals, with more pronounced ageing (older brain age) during midlife being indicative of later development of dementia. Here, we examined whether brain-ageing heterogeneity in unimpaired older adults related to neurodegeneration, different cognitive trajectories, genetic and amyloid-beta (Aβ) profiles, and to predicted progression to Alzheimer’s disease (AD). Methods: Functional and structural brain age measures were obtained for resting-state functional MRI and structural MRI, respectively, in 3460 cognitively normal individuals across an age range spanning 42–85 years. Participants were categorised into four groups based on the difference between their chronological and predicted age in each modality: advanced age in both (n = 291), resilient in both (n = 260) or advanced in one/resilient in the other (n = 163/153). With the resilient group as the reference, brain-age groups were compared across neuroimaging features of neuropathology (white matter hyperintensity volume, neuronal loss measured with Neurite Orientation Dispersion and Density Imaging, AD-specific atrophy patterns measured with the Spatial Patterns of Abnormality for Recognition of Early Alzheimer’s Disease index, amyloid burden using amyloid positron emission tomography (PET), progression to mild cognitive impairment and baseline and longitudinal cognitive measures (trail making task, mini mental state examination, digit symbol substitution task). Findings: Individuals with advanced structural and functional brain-ages had more features indicative of neurodegeneration and they had poor cognition. Individuals with a resilient brain-age in both modalities had a genetic variant that has been shown to be associated with age of onset of AD. Mixed brain-age was associated with selective cognitive deficits. Interpretation: The advanced group displayed evidence of increased atrophy across all neuroimaging features that was not found in either of the mixed groups. This is in line with biomarkers of preclinical AD and cerebrovascular disease. These findings suggest that the variation in structural and functional brain ageing across individuals reflects the degree of underlying neuropathological processes and may indicate the propensity to develop dementia in later life. Funding: The National Institute on Aging, the National Institutes of Health, the Swiss National Science Foundation, the Kaiser Foundation Research Institute and the National Heart, Lung, and Blood Institute.

Abstract Background Trans-sutural distraction osteogenesis (TSDO) involves the application of distraction force to facial sutures to stimulate osteogenesis. Gli1+ cells in the cranial sutures play an important role in bone growth. However, whether Gli1+ cells in facial sutures differentiate into bone under distraction force is unknown. Methods 4-week-old Gli1ER/Td and C57BL/6 mice were used to establish a TSDO model to explore osteogenesis of zygomaticomaxillary sutures. A Gli1+ cell lineage tracing model was used to observe the distribution of Gli1+ cells and explore the role of Gli1+ cells in facial bone remodeling. Results Distraction force promoted bone remodeling during TSDO. Fluorescence and two-photon scanning images revealed the distribution of Gli1+ cells. Under distraction force, Gli1-lineage cells proliferated significantly and co-localized with Runx2+ cells. Hedgehog signaling was upregulated in Gli1+ cells. Inhibition of Hedgehog signaling suppresses the proliferation and osteogenesis of Gli1+ cells induced by distraction force. Subsequently, the stem cell characteristics of Gli1+ cells were identified. Cell-stretching experiments verified that mechanical force promoted the osteogenic differentiation of Gli1+ cells through Hh signaling. Furthermore, immunofluorescence staining and RT-qPCR experiments demonstrated that the primary cilia in Gli1+ cells exhibit Hedgehog-independent mechanosensitivity, which was required for the osteogenic differentiation induced by mechanical force. Conclusions Our study indicates that the primary cilia of Gli1+ cells sense mechanical stimuli, mediate Hedgehog signaling activation, and promote the osteogenic differentiation of Gli1+ cells in zygomaticomaxillary sutures.

Abstract Recent advances in single-cell immune profiling have enabled the simultaneous measurement of transcriptome and T cell receptor (TCR) sequences, offering great potential for studying immune responses at the cellular level. However, integrating these diverse modalities across datasets is challenging due to their unique data characteristics and technical variations. Here, to address this, we develop the multimodal generative model mvTCR to fuse modality-specific information across transcriptome and TCR into a shared representation. Our analysis demonstrates the added value of multimodal over unimodal approaches to capture antigen specificity. Notably, we use mvTCR to distinguish T cell subpopulations binding to SARS-CoV-2 antigens from bystander cells. Furthermore, when combined with reference mapping approaches, mvTCR can map newly generated datasets to extensive T cell references, facilitating knowledge transfer. In summary, we envision mvTCR to enable a scalable analysis of multimodal immune profiling data and advance our understanding of immune responses.

Abstract Background Perioperative hypotension is frequently observed following the initiation of general anesthesia administration, often associated with adverse outcomes. This study assessed the effect of subclavian vein (SCV) diameter combined with perioperative fluid therapy on preventing post-induction hypotension (PIH) in patients with lower ASA status. Methods This two-part study included patients aged 18 to 65 years, classified as ASA physical status I or II, and scheduled for elective surgery. The first part (Part I) included 146 adult patients, where maximum SCV diameter (dSCVmax), minimum SCV diameter (dSCVmin), SCV collapsibility index (SCVCI) and SCV variability (SCVvariability) assessed using ultrasound. PIH was determined by reduction in mean arterial pressure (MAP) exceeding 30% from baseline measurement or any instance of MAP

At the beginning of the 2019 coronavirus disease (COVID-19) pandemic, airway allergic diseases such as asthma and allergic rhinitis (AR) were considered as risk factors for COVID-19, as they would aggravate symptoms. With further research, more and more literature has shown that airway allergic disease may not be a high-risk factor, but may be a protective factor for COVID-19 infection, which is closely related to its low-level expression of the ACE2 receptor and the complex cytokines network as underlying molecular regulatory mechanisms. In addition, steroid hormones and age factors could not be ignored. In this review, we have summarized some current evidence on the relationship between COVID-19 and allergic rhinitis to highlight the underlying mechanisms of COVID-19 infection and provide novel insights for its prevention and treatment. The key findings show that allergic rhinitis and its related molecular mechanisms may have a protective effect against COVID-19 infection.

Metal-organic frameworks (MOFs) are favored in the fields of adsorption, separation, catalysis, electrochemistry, and magnetism due to their advantages of large specific surface area, high porosity, controllable pore size adjustment, and dispersion of metal active sites. The application of MOFs involves multiple fields, which requires that MOFs have good water stability, as gaseous and liquid water inevitably exist in industrial processes. In this paper, the research status of the stability of MOFs in aqueous solutions was reviewed in recent years, including the design and synthesis, the influencing factors, and the applications of MOFs in water stability.

Abstract Background Although blood-based biomarkers have been identified as cost-effective and scalable alternatives to PET and CSF markers of neurodegenerative disease, little is known about how these biomarkers predict future brain atrophy and cognitive decline in cognitively unimpaired individuals. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether plasma biomarkers of Alzheimer’s disease (AD) pathology (amyloid-β [Aβ42/40], phosphorylated tau [pTau-181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal brain volume loss and cognitive decline. Additionally, we determined whether sex, APOEε4 status, and plasma amyloid-β status modified these associations. Methods Plasma biomarkers were measured using Quanterix SIMOA assays. Regional brain volumes were measured by 3T MRI, and a battery of neuropsychological tests assessed five cognitive domains. Linear mixed effects models adjusted for demographic factors, kidney function, and intracranial volume (MRI analyses) were completed to relate baseline plasma biomarkers to baseline and longitudinal brain volume and cognitive performance. Results Brain volume analyses included 622 participants (mean age ± SD: 70.9 ± 10.2) with an average of 3.3 MRI scans over 4.7 years. Cognitive performance analyses included 674 participants (mean age ± SD: 71.2 ± 10.0) with an average of 3.9 cognitive assessments over 5.7 years. Higher baseline pTau-181 was associated with steeper declines in total gray matter volume and steeper regional declines in several medial temporal regions, whereas higher baseline GFAP was associated with greater longitudinal increases in ventricular volume. Baseline Aβ42/40 and NfL levels were not associated with changes in brain volume. Lower baseline Aβ42/40 (higher Aβ burden) was associated with a faster decline in verbal memory and visuospatial performance, whereas higher baseline GFAP was associated with a faster decline in verbal fluency. Results were generally consistent across sex and APOEε4 status. However, the associations of higher pTau-181 with increasing ventricular volume and memory declines were significantly stronger among individuals with higher Aβ burden, as was the association of higher GFAP with memory decline. Conclusions Among cognitively unimpaired older adults, plasma biomarkers of AD pathology (pTau-181) and astrogliosis (GFAP), but not neuronal injury (NfL), serve as markers of future brain atrophy and cognitive decline.

Abstract Sensory impairment and brain atrophy is common among older adults, increasing the risk of dementia. Yet, the degree to which multiple co-occurring sensory impairments (MSI across vision, proprioception, vestibular function, olfactory, and hearing) are associated with brain morphometry remain unexplored. Data were from 208 cognitively unimpaired participants (mean age 72 ± 10 years; 59% women) enrolled in the Baltimore Longitudinal Study of Aging. Multiple linear regression models were used to estimate cross-sectional associations between MSI and regional brain imaging volumes. For each additional sensory impairment, there were associated lower orbitofrontal gyrus and entorhinal cortex volumes but higher caudate and putamen volumes. Participants with MSI had lower mean volumes in the superior frontal gyrus, orbitofrontal gyrus, superior parietal lobe, and precuneus compared to participants with

Abstract Background Muscle and bone are physiologically interconnected, but joint changes of muscle and bone with aging, and whether the muscle‐bone changes are different by sex and by country has been little studied. We examined longitudinal associations of bone mineral density (BMD) and muscle mass or muscle strength in community‐dwelling 65 years or older in the United States and Japan. Methods The present analytic sample included 1129 women and men from the Baltimore Longitudinal Study of Aging (BLSA) (mean age, 74.5 ± 7.5 years; women, 49.8%) and 1998 women and men from the National Institute for Longevity Sciences‐Longitudinal Study of Aging (NILS‐LSA) (mean age, 70.0 ± 4.5 years; women, 51.4%). Median follow‐up was 4.6 (min‐max, 0–15.4) years in the BLSA and 4.0 (min‐max, 0–13.4) years in the NILS‐LSA. We selected visits at which participants had BMD (whole body, pelvic, femoral neck, trochanter, and Ward's triangle BMDs) and muscle mass [appendicular lean mass, (ALM)] measured by DXA scan. In each bone site, we ran cohort‐specific bivariate linear mixed‐effects models adjusted for baseline age, sex, body height, body weight, fat mass, education year, and smoking status. Race was an additional adjustment in the BLSA. Additionally, we performed sex‐specific analyses. Results In the BLSA, the rate of change in ALM positively correlated with the rate of change in the whole body (rho = 0.30, P 0.05). In the NILS‐LSA, ALM positively correlated with the rate of change in all bone sites (rho ranged from 0.20 to 0.71, P

Abstract Gene‐editing technology shows great potential in glioblastoma (GBM) therapy. Due to the complexity of GBM pathogenesis, a single gene‐editing‐based therapy is unlikely to be successful; therefore, a multi‐gene knockout strategy is preferred for effective GBM inhibition. Here, a non‐invasive, biodegradable brain‐targeted CRISPR/Cas12a nanocapsule is used that simultaneously targeted dual oncogenes, EGFR and PLK1, for effective GBM therapy. This cargo nanoencapsulation technology enables the CRISPR/Cas12a system to achieve extended blood half‐life, efficient blood‐brain barrier (BBB) penetration, active tumor targeting, and selective release. In U87MG cells, the combinatorial gene editing system resulted in 61% and 33% knockout of EGFR and PLK1, respectively. Following systemic administration, the CRISPR/Cas12a system demonstrated promising brain tumor accumulation that led to extensive EGFR and PLK1 gene editing in both U87MG and patient‐derived GSC xenograft mouse models with negligible off‐target gene editing detected through NGS. Additionally, CRISPR/Cas12a nanocapsules that concurrently targeted the EGFR and PLK1 oncogenes showed superior tumor growth suppression and significantly improved the median survival time relative to nanocapsules containing single oncogene knockouts, signifying the potency of the multi‐oncogene targeting strategy. The findings indicate that utilization of the CRISPR/Cas12a combinatorial gene editing technique presents a practical option for gene therapy in GBM.

Abstract Background Postoperative sore throat (POST) is an unpleasant outcome that can occur as a result of tracheal intubation in adults. Increased pressure from the endotracheal tube (ETT) cuff often leads to local mucosal injury, resulting in sore throat. The purpose of this study was to compare the effect of two different ETT cuff pressure monitoring systems vs. no cuff pressure monitoring on the incidence and severity of POST in adults. Methods One hundred and fourteen ASA I-III patients of either gender, aged 18–65 years, and undergoing surgery requiring endotracheal intubation were included in this study. Patients were randomized into three groups: control (C), cuff pressure gauge (G), and automated cuff controller (A). The ETT cuff pressure was not monitored intraoperatively in group C but was monitored using a cuff pressure gauge and an automated cuff controller in groups G and A, respectively. Postoperatively, patients were assessed at 2, 24, and 48 h for the presence and severity of POST, hoarseness and cough. Results One hundred and eleven patients completed the study. POST occurred in 40.5% of the patients in group G (n = 37) (p = 0.013) and 23.7% of the patients in group A (n = 38) (p

Abstract Propelled by the structure of water oxidation co-catalysts in natural photosynthesis, molecular co-catalysts have long been believed to possess the developable potential in artificial photosynthesis. However, the interfacial complexity between light absorber and molecular co-catalyst limits its structural stability and charge transfer efficiency. To overcome the challenge, a supramolecular scaffold with the [FeCl4] catalytic units is reported, which undergo a water-nucleophilic attack of the water oxidation reaction, while the supramolecular matrix can be in-situ grown on the surface of photoelectrode through a simple chemical polymerization to be a strongly coupled interface. A well-defined BiVO4 photoanode hybridized with [FeCl4] units in polythiophene reaches 4.72 mA cm−2 at 1.23 VRHE, which also exhibits great stability for photoelectrochemical seawater splitting due to the restraint on chlorine evolution reaction by [FeCl4] units and polythiophene. This work provides a novel solution to the challenge of the interface charge transfer of molecular co-catalyst hybridized photoelectrode.

With the popularity of Internet applications, a large amount of Internet behavior log data is generated. Abnormal behaviors of corporate employees may lead to internet security issues and data leakage incidents. To ensure the safety of information systems, it is important to research on anomaly prediction of Internet behaviors. Due to the high cost of labeling big data manually, an unsupervised generative model–Anomaly Prediction of Internet behavior based on Generative Adversarial Networks (APIBGAN), which works only with a small amount of labeled data, is proposed to predict anomalies of Internet behaviors. After the input Internet behavior data is preprocessed by the proposed method, the data-generating generative adversarial network (DGGAN) in APIBGAN learns the distribution of real Internet behavior data by leveraging neural networks’ powerful feature extraction from the data to generate Internet behavior data with random noise. The APIBGAN utilizes these labeled generated data as a benchmark to complete the distance-based anomaly prediction. Three categories of Internet behavior sampling data from corporate employees are employed to train APIBGAN: (1) Online behavior data of an individual in a department. (2) Online behavior data of multiple employees in the same department. (3) Online behavior data of multiple employees in different departments. The prediction scores of the three categories of Internet behavior data are 87.23%, 85.13%, and 83.47%, respectively, and are above the highest score of 81.35% which is obtained by the comparison method based on Isolation Forests in the CCF Big Data & Computing Intelligence Contest (CCF-BDCI). The experimental results validate that APIBGAN predicts the outlier of Internet behaviors effectively through the GAN, which is composed of a simple three-layer fully connected neural networks (FNNs). We can use APIBGAN not only for anomaly prediction of Internet behaviors but also for anomaly prediction in many other applications, which have big data infeasible to label manually. Above all, APIBGAN has broad application prospects for anomaly prediction, and our work also provides valuable input for anomaly prediction-based GAN.

Abstract Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer’s disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217. Here, we examined the diagnostic utility of plasma p-tau212. In five cohorts (n = 388 participants), plasma p-tau212 showed high performances for AD diagnosis and for the detection of both amyloid and tau pathology, including at autopsy as well as in memory clinic populations. The diagnostic accuracy and fold changes of plasma p-tau212 were similar to those for p-tau217 but higher than p-tau181 and p-tau231. Immunofluorescent staining of brain tissue slices showed prominent p-tau212 reactivity in neurofibrillary tangles that co-localized with p-tau217 and p-tau202/205. These findings support plasma p-tau212 as a peripherally accessible biomarker of AD pathophysiology.

With the wide application of a modular multilevel converter in various power conversion fields, submodule open-circuit fault diagnostics have attracted increasing attention, as some of the existing diagnosis methods have a single function and limited localization speed. Therefore, a simplified and innovative multifunctional hybrid machine learning-based fault diagnosis strategy for the submodules is proposed. Starting from the output characteristics of the faulty submodule, the eigenvalues of the bridge arm current and submodule capacitor voltage during faults are extracted, and the eigenvalues are utilized for fault detection and location via the integration of improved supervised learning and unsupervised learning. Finally, the effectiveness of the proposed method is verified by simulated and experimental results in a three-phase modular multilevel converter topology. In addition, it can diagnose multiple fault types and achieve a high fault identification probability.

Objectives: To scrutinize the therapeutic efficiency and safety profile of lenvatinib, accompanied by the programmed cell death protein-1 (PD-1) monoclonal antibody, and interventional treatment in managing intermediate-stage hepatocellular carcinoma. Methods: Retrospective analysis was performed on clinical data from 93 patients suffering from intermediate to advanced hepatocellular carcinoma, treated at our institution from May 2018 to April 2020. Patients were divided based on the therapeutic regimen: 43 cases constituted the control group receiving lenvatinib plus transhepatic artery chemoembolization (TACE), while the remaining 50 cases in the study group were managed with lenvatinib, PD-1 monoclonal antibody, and TACE. Outcome measures included therapeutic efficacy, tumor markers (carcinoembryonic antigen [CEA], alpha-fetoprotein [AFP], α-L-fucosidase [AFU], carbohydrate antigen 199 [CA199]), immune response indices (CD3+, CD4+, CD8+, CD4+/CD8+ ratio), pertinent cytokine levels (vascular endothelial growth factor [VEGF], matrix metalloproteinase-9 [MMP-9], basic fibroblast growth factor [aFGF], acidic fibroblast growth factor [bFGF]), quality of life (as per Quality of Life Assessment Scale for Cancer Patients [QOL-LC] scores), adverse effects, and survival rates. Results: The study group exhibited a significantly enhanced total effective rate compared to the control group (74.00% vs 53.49%, P .05). Moreover, the study group reported significantly higher 1-, 2-, and 3-year survival rates than the control group ( P

Abstract Obesity, a worldwide epidemic in recent years, is mainly due to the uncontrolled development of adipose tissues, which includes adipocyte hypertrophy and hyperplasia. Adipocyte differentiation is a process involving multiple transcription factor cascades, and the exact mechanism has not yet been defined. As a bHLH transcription factor, Twist1 exerts its activity by forming homo- or heterodimers with other factors. In this study, we showed Twist1 restricts adipogenesis through PPARγ. Expression of various differentiation markers (including PPARγ and adiponectin) and triglyceride-containing lipid droplets were decreased with overexpression of Twist1. Pathway enrichment analysis of RNA-seq data showed that differentially expressed genes (DEGs) caused by Twist1 overexpression were significantly related to lipolysis and PPARγ signaling. This implicates that Twist1 plays important regulatory roles in these processes. ChIP and dual luciferase assays showed that Twist1 could bind either PPARγ or adiponectin promoter to repress their respective transcription or directly to PPARγ protein to regulate its transcriptional activity. Furthermore, Twist1 directly interacted RXRα, which usually forms heterodimer with PPARγ to regulate adipogenesis. Taken together, our results suggest that Twist1 is an inhibitory modulator of adipogenesis and its function is likely through direct interaction with PPARγ protein or its gene promoter.

Abstract The resolution of SARS-CoV-2 replication hinges on cell-mediated immunity, wherein CD8+ T cells play a vital role. Nonetheless, the characterization of the specificity and TCR composition of CD8+ T cells targeting non-spike protein of SARS-CoV-2 before and after infection remains incomplete. Here, we analyzed CD8+ T cells recognizing six epitopes from the SARS-CoV-2 nucleocapsid (N) protein and found that SARS-CoV-2 infection slightly increased the frequencies of N-recognizing CD8+ T cells but significantly enhanced activation-induced proliferation compared to that of the uninfected donors. The frequencies of N-specific CD8+ T cells and their proliferative response to stimulation did not decrease over one year. We identified the N222-230 peptide (LLLDRLNQL, referred to as LLL thereafter) as a dominant epitope that elicited the greatest proliferative response from both convalescent and uninfected donors. Single-cell sequencing of T cell receptors (TCR) from LLL-specific CD8+ T cells revealed highly restricted Vα gene usage (TRAV12-2) with limited CDR3α motifs, supported by structural characterization of the TCR–LLL–HLA-A2 complex. Lastly, transcriptome analysis of LLL-specific CD8+ T cells from donors who had expansion (expanders) or no expansion (non-expanders) after in vitro stimulation identified increased chromatin modification and innate immune functions of CD8+ T cells in non-expanders. These results suggests that SARS-CoV-2 infection induces LLL-specific CD8+ T cell responses with a restricted TCR repertoire.

Abstract Prostate cancer (PC) is one of the most common cancers in men and becoming the second leading cause of cancer fatalities. At present, the lack of effective strategies for prognosis of PC patients is still a problem to be solved. Therefore, it is significant to identify potential gene signatures for PC patients’ prognosis. Here, we summarized 71 different prognostic gene signatures for PC and concluded 3 strategies for signature construction after extensive investigation. In addition, 14 genes frequently appeared in 71 different gene signatures, which enriched in mitotic and cell cycle. This review provides extensive understanding and integrated analysis of current prognostic signatures of PC, which may help researchers to construct gene signatures of PC and guide future clinical treatment.

Abstract Backgrounds Predicting medications is a crucial task in intelligent healthcare systems, aiding doctors in making informed decisions based on electronic medical records (EMR). However, medication prediction faces challenges due to complex relations within heterogeneous medical data. Existing studies primarily focus on the supervised mining of hierarchical relations between homogeneous codes in medical ontology graphs, such as diagnosis codes. Few studies consider the valuable relations, including synergistic relations between medications, concurrent relations between diseases, and therapeutic relations between medications and diseases from historical EMR. This limitation restricts prediction performance and application scenarios. Methods To address these limitations, we propose KAMPNet, a multi-sourced medical knowledge augmented medication prediction network. KAMPNet captures diverse relations between medical codes using a multi-level graph contrastive learning framework. Firstly, unsupervised graph contrastive learning with a graph attention network encoder captures implicit relations within homogeneous medical codes from the medical ontology graph, generating knowledge augmented medical code embedding vectors. Then, unsupervised graph contrastive learning with a weighted graph convolutional network encoder captures correlative relations between homogeneous or heterogeneous medical codes from the constructed medical codes relation graph, producing relation augmented medical code embedding vectors. Finally, the augmented medical code embedding vectors, along with supervised medical code embedding vectors, are fed into a sequential learning network to capture temporal relations of medical codes and predict medications for patients. Results Experimental results on the public MIMIC-III dataset demonstrate the superior performance of our KAMPNet model over several baseline models, as measured by Jaccard, F1 score, and PR-AUC for medication prediction. Conclusions Our KAMPNet model can effectively capture the valuable relations between medical codes inherent in multi-sourced medical knowledge using the proposed multi-level graph contrastive learning framework. Moreover, The multi-channel sequence learning network facilitates capturing temporal relations between medical codes, enabling comprehensive patient representations for downstream tasks such as medication prediction.

In response to the relatively limited research on health evaluation and prediction of the entire system of mine hoists, a health evaluation index system and comment set for mine hoists have been established. The health evaluation and prediction system for mine hoists has been designed. A fuzzy comprehensive evaluation method for the health of mine hoists is proposed to address the issues of insufficient utilization of monitoring data from various components of mine hoists, and the inability of health evaluation results to meet actual production needs. The method introduces relative degradation degree to characterize the health of different types of indicators of the hoist. The method uses health degree to quantify the health of mine hoists. The fuzzy comprehensive evaluation method is used to calculate the health of mine hoists. The analytic hierarchy process (AHP) is improved by replacing the 1-9 scale with an exponential scale to reduce computational complexity. The method uses CRITIC objective weighting method and combines subjective and objective weights to calculate the comprehensive weights of each subsystem and indicator. Based on the fuzzy comprehensive evaluation calculation process and the maximum membership principle, the health evaluation results and fault causes of the mine hoist are obtained. On the basis of the health evaluation results of the mine hoist, the Harris hawks (HHO) algorithm is used to optimize the important parameters of the support vector regression (SVR) model. The HHO-SVR model is constructed to predict the health of the mine hoist, improving the accuracy of the health prediction results. The experimental results show that the fuzzy comprehensive evaluation method can accurately evaluate the health of the hoist. Compared with particle swarm optimization support vector regression (PSO-SVR), genetic algorithm optimization support vector regression (GA-SVR), and grey wolf algorithm optimization support vector regression (GWO-SVR) models, the prediction results of the HHO-SVR model are closer to the actual values and have better prediction performance.

Abstract Significant advancements have been made in recent years in the development of highly sophisticated skin organoids. Serving as three-dimensional models that mimic human skin, these organoids have evolved into complex structures and are increasingly recognized as effective alternatives to traditional culture models and human skin due to their ability to overcome the limitations of two-dimensional systems and ethical concerns. The inherent plasticity of skin organoids allows for their construction into physiological and pathological models, enabling the study of skin development and dynamic changes. This review provides an overview of the pivotal work in the progression from 3D layered epidermis to cyst-like skin organoids with appendages. Furthermore, it highlights the latest advancements in organoid construction facilitated by state-of-the-art engineering techniques, such as 3D printing and microfluidic devices. The review also summarizes and discusses the diverse applications of skin organoids in developmental biology, disease modelling, regenerative medicine, and personalized medicine, while considering their prospects and limitations.

Electric vehicles (EVs) have been widely considered an essential element to contribute to green and smart transportation, which will further enhance the development of smart cities. Hong Kong, as one of the largest metropolises in the world, has promoted the deployment of EVs for both the private and public transportation sectors over the past decade, with substantial financial subsidies and encouraging policy incentives. With the rapid penetration of EVs, especially in the market of private passenger cars, Hong Kong may face the challenge of insufficient charging facilities in the next few years. As such, the research study aims to develop a mathematical model using a topological method to map out feasible locations for new EV charging facilities on Ap Lei Chau Island, to construct a small Python program to optimize the mapping process of these feasible locations, and to estimate energy consumption and associated economic analysis to foster the spatial planning of EV charging facility networks. In conclusion, optimal locations for new charging facilities for EVs have been revealed to match the rapid growth of EV usage and facilitate the emergence of green and smart transportation.

Abstract. In the field of plastic and reconstructive surgery, the loss of organs or tissues caused by diseases or injuries has resulted in challenges, such as donor shortage and immunosuppression. In recent years, with the development of regenerative medicine, the decellularization-recellularization strategy seems to be a promising and attractive method to resolve these difficulties. The decellularized extracellular matrix contains no cells and genetic materials, while retaining the complex ultrastructure, and it can be used as a scaffold for cell seeding and subsequent transplantation, thereby promoting the regeneration of diseased or damaged tissues and organs. This review provided an overview of decellularization-recellularization technique, and mainly concentrated on the application of decellularization-recellularization technique in the field of plastic and reconstructive surgery, including the remodeling of skin, nose, ears, face, and limbs. Finally, we proposed the challenges in and the direction of future development of decellularization-recellularization technique in plastic surgery.

The problem of traffic flow forecasting has multi-source heterogeneity.The traffic flow in the future is not only related to the flow at the previous moment, but also affected by heterogeneous spatio-temporal data such as the relationship between urban regions, weather conditions and POI (point of interest).To solve this problem, a traffic flow prediction model based on multi-source heterogeneous spatio-temporal data fusion was proposed, which was called MHFSTNet (multi-source heterogeneous fusion spatio-temporal network).Firstly, this model used clustering methods to obtain different traffic patterns in urban areas, and utilized various methods such as concatenation, weight addition, and attention mechanism to integrate spatio-temporal data of multiple modalities, including traffic flow, location relationships between urban areas, weather, POI and the time of day.Deep learning methods were used to uniformly model heterogeneous data and predict traffic flow in the future.Experiments were conducted on three real-world traffic datasets, TaxiBJ, TaxiNYC and BikeNYC datasets.The results showed that MHF-STNet achieved the best performance compared with some classic traffic flow prediction models, which verified the effectiveness of MHF-STNet for unified modeling of heterogeneous spatio-temporal data.

Abstract EZH2 is the catalytic subunit of the histone methyltransferase Polycomb Repressive Complex 2 (PRC2), and its somatic activating mutations drive lymphoma, particularly the germinal center B‐cell type. Although PRC2 inhibitors, such as tazemetostat, have demonstrated anti‐lymphoma activity in patients, the clinical efficacy is not limited to EZH2‐mutant lymphoma. In this study, Activin A Receptor Type 1 (ACVR1), a type I Bone Morphogenetic Protein (BMP) receptor, is identified as critical for the anti‐lymphoma efficacy of PRC2 inhibitors through a whole‐genome CRISPR screen. BMP6, BMP7, and ACVR1 are repressed by PRC2‐mediated H3K27me3, and PRC2 inhibition upregulates their expression and signaling in cell and patient‐derived xenograft models. Through BMP‐ACVR1 signaling, PRC2 inhibitors robustly induced cell cycle arrest and B cell lineage differentiation in vivo. Remarkably, blocking ACVR1 signaling using an inhibitor or genetic depletion significantly compromised the in vitro and in vivo efficacy of PRC2 inhibitors. Furthermore, high levels of BMP6 and BMP7, along with ACVR1, are associated with longer survival in lymphoma patients, underscoring the clinical relevance of this study. Altogether, BMP‐ACVR1 exhibits anti‐lymphoma function and represents a critical PRC2‐repressed pathway contributing to the efficacy of PRC2 inhibitors.

Brand pattern design is an important part of brand image building. This paper proposes a fractal method for visual communication and brand pattern design, combining fractal theory with a computer to generate Julia fractal graphics and apply them to brand pattern design. The grayscale covariance matrix is utilized for texture analysis to address the issue of difficult fractal processing. Meanwhile, the DEA method was applied to measure the economic efficiency of the brand design process based on visual communication art. Three input indicators and two output indicators were selected to construct the DEA performance measurement system, and based on the study of the fractal effect of pattern design, the brand design of hotel brand Group A was taken as the research object to compare and analyze the DEA efficiency and influence of similar brands. From the perspective of brand pattern design, the average value of the brand influence score of Group A from 2017 to 2020 is 0.4515, the overall average value of the brand influence score of the sample hotel group is 0.5154, and the brand influence score of A fails to reach the average level. The brand design of Group A is still insufficient to fully reflect the influence of the brand.

Autophagy plays a critical role in the physiology and pathophysiology of hepatocytes. High level of homocysteine (Hcy) promotes autophagy in hepatocytes, but the underlying mechanism is still unknown. Here, we investigate the relationship between Hcy-induced autophagy level and the expression of nuclear transcription factor EB (TFEB). The results show that Hcy-induced autophagy level is mediated by upregulation of TFEB. Silencing of TFEB decreases the level of autophagy-related protein LC3BII/I and increases p62 expression level in hepatocytes after exposure to Hcy. Moreover, the effect of Hcy on the expression of TFEB is regulated by hypomethylation of the TFEB promoter catalyzed by DNA methyltransferase 3b (DNMT3b). In summary, this study shows that Hcy can activate autophagy by inhibiting DNMT3b-mediated DNA methylation and upregulating TFEB expression. These findings provide another new mechanism for Hcy-induced autophagy in hepatocytes.

Abstract This article reviewed our experience of Chinese nasal reconstruction over 12 years and evaluated the effect of expanded forehead flap both aesthetically and functionally. The special skin type and other anatomic features of Chinese patients was understood thoroughly during the treatment. This article thus catered for the need of multiracial nasal reconstruction. We analyzed existing clinical data and demonstrated a typical case in detail. The postoperative result supported our strategy which advocated the extensive application of expanded forehead flap, together with flip scar flap as the internal lining. The features of Chinese patients also prompted the use of costal and auricular cartilage. Emerging technology like 3D-printing would benefit nasal reconstruction from more aspects.

BackgroundWith the development of nuclear energy, spent nuclear fuel reprocessing has generated high-level liquid waste (HLLW) containing large quantities of minor actinides (e.g., Np, Am, and Cm). N,N,N',N'-tetraoctyl-diglycolamide (TODGA), an amide ether extraction agent, has immense potential for the extraction and separation of actinides from HLLW. However, HLLW is characterized by high radioactivity, which can destroy the molecular structure of TODGA and diminish its extraction capacity. In addition, the type of organic medium selected to dilute TODGA has a significant impact on its extraction ability and radiolysis.PurposeThis study aims to evaluate the gamma radiolysis and extraction performance of TODGA in a kerosene medium.MethodsFirstly, several experimental reagent systems were prepared. Organic phase: 50 mmol∙L-1 TODGA/kerosene; aqueous phase: 0~4 mol∙L-1 HNO3; absorbed doses: 5~1 000 kGy by a 60Co gamma-irradiator (3.7×1015 Bq) at room temperature; absorbed dose rates: 0.6 kGy∙h-1 (5~15 kGy) and 5.8 kGy∙h-1 (50~1 000 kGy). Then, ultra-performance liquid chromatography (UPLC) and mass spectrometer were used to identify the components in the organic phase and assess the relative concentrations of TODGA and radiolysis products before and after irradiation. Lanthanides (substitutes for actinides) and alkaline earth metals were extracted using TODGA at different absorbed doses (5~100 kGy) and the concentration of metal ions for extraction was 100 μg∙mL-1 in 3 mol∙L-1 HNO3. Finally, after extraction and dilution, the aqueous phase was detected using an inductively coupled plasma-optical emission spectrometer to estimate the lanthanide and alkaline earth metal concentrations.ResultsThe experimental results indicate that the concentration of TODGA steadily increases with increasing concentrations of HNO3 at a radiation dose of 1 000 kGy. The radiolysis rate of TODGA in the acid-free solution is >80%. Compared to the acid-free solution, the degree of radiolysis can be inhibited at approximately 8% (adding 0.5~3 mol∙L-1 HNO3) and 18% (adding 4 mol∙L-1 HNO3). Moreover, with an increase in the absorbed doses, the concentration of TODGA decreases in the studied systems. The radiolysis rate of TODGA is estimated to be 10%~40% when the absorbed dose was less than 100 kGy. However, it increases dramatically and reaches over 70% at 1 000 kGy. Breaking the ether bond results in the radiolysis of TODGA, generating two types of radiolysis products (C18H37NO2 and C18H37NO). HNO3 alters the radiolysis path, and breaking of the octyl side chain occurs with the appearance of another radiolysis product (C28H56N2O3). TODGA exhibits extremely poor extraction affinity for Sr, and the extraction rate decreases from 25% to non-extraction at an absorbed dose of 100 kGy. However, TODGA achieves approximately 100% lanthanide extraction (Ce, Eu, and Dy).ConclusionsTODGA has low radiation resistance in a kerosene medium at an absorbed dose of 1 000 kGy. Its radiolysis can be inhibited by the addition of HNO3; a higher concentration of HNO3 leads to a stronger inhibitory effect. The radiolysis of TODGA is insignificant within a 100 kGy absorbed dose, particularly in the range of 50~100 kGy. The molecular structure of TODGA is susceptible to breaking of its ether bond owing to gamma rays or radicals produced by kerosene. These findings demonstrate that TODGA can maintain the ability to extract lanthanides after irradiation at an absorbed dose of up to 100 kGy. Thus, it can be inferred that TODGA has a good extraction capacity for actinides in kerosene under the studied conditions.

Background: This study aimed to review treatments and evaluate the aesthetic outcomes, complications, and reoperation rates regarding surgical correction for a postoperative contracted nose. Methods: PubMed, MEDLINE, and Embase databases were searched for studies detailing aesthetic outcomes and complications of surgical correction of a contracted nose. Surgical procedures, adjuvant treatment, outcomes, and complications were synthesized and analyzed. Results: Nine articles encompassing 376 patients were included in the systematic review, and six articles (198 participants) were included in the meta-analysis. The most frequently used graft material was the autologous rib cartilage (61.1%). Surgical procedures were heterogeneous in these studies. The nasolabial angle reduced by 9.52° (95% confidence interval (CI): (−11.95, −7.09), P

Once a popular injectable filler, polyacrylamide hydrogel (PAAG) has been banned in China since 2006 due to its unclear safety and long-term complications. However, it is still being used worldwide because of its huge commercial profit, leading to emerging complications and an urgent need for standardized clinical management. This review aimed to assess the properties, safety, and complications of PAAG and treatment strategies for its removal.

The clinical use of fat grafts for breast reconstruction post-mastectomy or radiotherapy has the disadvantages of limited retention and survival rates. To solve this problem, adipose-derived stem cells (ADSCs) have been suggested as an alternative cell source for breast reconstruction, because they are simple to access, have low immunogenicity, and support the survival of mature adipose grafts. However, despite their outstanding properties, the use of ADSCs in patients with breast cancer is controversial, and the oncological safety of this method has been questioned. The biological effects of ADSCs on breast cancer are complex, and clinical research on ADSC-assisted fat grafting is limited. Here, we review the current experimental findings on the effects of ADSCs on breast cancer, mainly focusing on the role of ADSCs in breast cancer proliferation and growth processes, such as epithelial-mesenchymal transition (EMT) and angiogenesis. We also discuss the safety of ADSCs in clinical breast reconstruction.

Abstract The recent developments related to the black hole information paradox have brought us a confusing object: the replica wormhole. We are trying to better understand the object from the viewpoint of the thermo-mixed double and spontaneous symmetry breaking. In this paper, we show that the replica wormhole can be regarded as a transition between different degenerate vacua, and the corresponding gravitational partition function should be controlled by the manifold of the degenerate vacua. We also check the wormhole partition function in two-dimensional Jackiw–Teitelboim gravity and show that the wormhole saddle is indeed controlled by the dimension of the degenerate vacua. Moreover, it is suggested that the replica wormhole geometries connecting different vacua can be related to the measurement process of soft hair that compares different vacuum configurations.

Dynamic multi-objective big data optimization problems (DMBDOPs) are challenging because of the difficulty of dealing with large-scale decision variables and continuous problem changes. In contrast to classical multi-objective optimization problems, DMBDOPs are still not intensively explored by researchers in the optimization field. At the same time, there is lacking a software framework to provide algorithmic examples to solve DMBDOPs and categorize benchmarks for relevant studies. This paper presents a metaheuristic software framework for DMBDOPs to remedy these issues. The proposed framework has a lightweight architecture and a decoupled design between modules, ensuring that the framework is easy to use and has enough flexibility to be extended and modified. Specifically, the framework now integrates four basic dynamic metaheuristic algorithms, eight test suites of different types of optimization problems, as well as some performance indicators and data visualization tools. In addition, we have proposed an experience reuse method, speeding up the algorithm’s convergence. Moreover, we have implemented parallel computing with Apache Spark to enhance computing efficiency. In the experiments, algorithms integrated into the framework are tested on the test suites for DMBDOPs on an Apache Hadoop cluster with three nodes. The experience reuse method is compared to two restart strategies for dynamic metaheuristics.

Abstract Introduction It is unclear how rates of white matter microstructural decline differ between normal aging and abnormal aging. Methods Diffusion MRI data from several well‐established longitudinal cohorts of aging (Alzheimer's Disease Neuroimaging Initiative [ADNI], Baltimore Longitudinal Study of Aging [BLSA], Vanderbilt Memory & Aging Project [VMAP]) were free‐water corrected and harmonized. This dataset included 1723 participants (age at baseline: 72.8 ± 8.87 years, 49.5% male) and 4605 imaging sessions (follow‐up time: 2.97 ± 2.09 years, follow‐up range: 1–13 years, mean number of visits: 4.42 ± 1.98). Differences in white matter microstructural decline in normal and abnormal agers was assessed. Results While we found a global decline in white matter in normal/abnormal aging, we found that several white matter tracts (e.g., cingulum bundle) were vulnerable to abnormal aging. Conclusions There is a prevalent role of white matter microstructural decline in aging, and future large‐scale studies in this area may further refine our understanding of the underlying neurodegenerative processes. HIGHLIGHTS Longitudinal data were free‐water corrected and harmonized. Global effects of white matter decline were seen in normal and abnormal aging. The free‐water metric was most vulnerable to abnormal aging. Cingulum free‐water was the most vulnerable to abnormal aging.

Abstract INTRODUCTION White matter hyperintensities (WMHs) increase with age and contribute to cognitive and motor function decline. Energy costs for mobility worsen with age, as the energetic cost of walking increases and energetic capacity declines. We examined the cross‐sectional associations of multiple measures of walking energetics with WMHs in mid‐ to late‐aged adults. METHODS A total of 601 cognitively unimpaired adults (mean age 66.9 ± 15.3 years, 54% women) underwent brain magnetic resonance imaging scans and completed standardized slow‐ and peak‐paced walking assessments with metabolic measurement (V̇O2). T1‐weighted scans and fluid‐attenuated inversion recovery images were used to quantify WMHs. Separate multivariable linear regression models examined associations adjusted for covariates. RESULTS Lower slow‐paced V̇O2 (B = 0.07; P = 0.030), higher peak‐paced V̇O2 (B = –0.10; P = 0.007), and lower cost‐to‐capacity ratio (B = .12; P < 0.0001) were all associated with lower WMH volumes. DISCUSSION The cost‐to‐capacity ratio, which describes the percentage of capacity required for ambulation, was the walking energetic measure most strongly associated with WMHs.

Nasal defects can be reconstructed with a nasolabial perforator flap, resulting in good aesthetic outcomes based on the facial subunit principle, owing to the combined advantages of the traditional nasolabial flap and the perforator flap. However, the localization of perforators makes the clinical application of a nasolabial perforator flap difficult. This review aims to provide a comprehensive summary of the nasolabial perforator flap from anatomical, methodological, and clinical application aspects, intending to provide plastic surgeons with a reference on conducting nasal reconstruction with a nasolabial perforator flap.

Abstract Background Both Alzheimer’s disease (AD) genetic risk factors and indices of cognitive reserve (CR) influence risk of cognitive decline, but it remains unclear whether they interact. This study examined whether a CR index score modifies the relationship between AD genetic risk factors and long-term cognitive trajectories in a large sample of individuals with normal cognition. Methods Analyses used data from the Preclinical AD Consortium, including harmonized data from 5 longitudinal cohort studies. Participants were cognitively normal at baseline (M baseline age = 64 years, 59% female) and underwent 10 years of follow-up, on average. AD genetic risk was measured by (i) apolipoprotein-E (APOE) genetic status (APOE-ε2 and APOE-ε4 vs. APOE-ε3; N = 1819) and (ii) AD polygenic risk scores (AD-PRS; N = 1175). A CR index was calculated by combining years of education and literacy scores. Longitudinal cognitive performance was measured by harmonized factor scores for global cognition, episodic memory, and executive function. Results In mixed-effects models, higher CR index scores were associated with better baseline cognitive performance for all cognitive outcomes. APOE-ε4 genotype and AD-PRS that included the APOE region (AD-PRSAPOE) were associated with declines in all cognitive domains, whereas AD-PRS that excluded the APOE region (AD-PRSw/oAPOE) was associated with declines in executive function and global cognition, but not memory. There were significant 3-way CR index score × APOE-ε4 × time interactions for the global (p = 0.04, effect size = 0.16) and memory scores (p = 0.01, effect size = 0.22), indicating the negative effect of APOE-ε4 genotype on global and episodic memory score change was attenuated among individuals with higher CR index scores. In contrast, levels of CR did not attenuate APOE-ε4-related declines in executive function or declines associated with higher AD-PRS. APOE-ε2 genotype was unrelated to cognition. Conclusions These results suggest that APOE-ε4 and non-APOE-ε4 AD polygenic risk are independently associated with global cognitive and executive function declines among individuals with normal cognition at baseline, but only APOE-ε4 is associated with declines in episodic memory. Importantly, higher levels of CR may mitigate APOE-ε4-related declines in some cognitive domains. Future research is needed to address study limitations, including generalizability due to cohort demographic characteristics.

Abstract Binary code similarity detection (BCSD) is a task of detecting similarity of binary functions which are not available to the corresponding source code. It has been widely utilized to facilitate various kinds of crucial security analysis in software engineering. Because of the complexity of the program compilation process, identifying binary code similarity presents tough challenges. The most sensible binary similarity detector relies on a robust vector representation of binary code. However, few BCSD approaches are suitable to form vector representations for analyzing similarities between binaries, which may not only diverge in semantics but also in structures. And the existing solutions which only depend on hands-on feature engineering to form feature vectors, fail to take into consideration the relationships between instructions. To resolve these problems, we propose a novel and unified approach called DeepDual-SD that aims to combine the dual attributes (semantic and structural attribute). More specifically, DeepDual-SD consists of two branches, in which one text-based feature representation is driven by semantic attribute learning to exploit instruction semantics, another graph-based feature representation for structural attribute learning to investigate structural differences. Meanwhile deep embedding (DE) technology is utilized to map this information into low-dimensional vector representation. In addition, to get together the dual attributes, a fusion mechanism based on gate architecture is designed for learning to pay proper attention between the two attribute-aware embeddings. Experimental verifications are conducted on Openssl and Debian datasets for several tasks, including cross-compiler, cross-architecture and cross-version scenarios. The results demonstrate that our method outperforms the state-of-the-art BCSD methods in different scenarios in terms of detection accuracy.

Abstract Objective White matter damage is a feature of Alzheimer's disease, yet little is known about how facets of the Alzheimer's disease process relate to key features of white matter structure. We examined the association of Alzheimer's disease (Aß42/40 ratio; pTau181), neuronal injury (NfL), and reactive astrogliosis (GFAP) biomarkers with MRI measures of myelin content and axonal density. Methods Among cognitively normal participants in the BLSA and GESTALT studies who received MRI measures of myelin content (defined by myelin water fraction [MWF]) and axonal density (defined by neurite density index [NDI]), we quantified plasma levels of Aβ42, Aβ40, pTau181, NfL, and GFAP. Linear regression models adjusted for demographic variables were used to relate these plasma biomarker levels to the MRI measures. Results In total, 119 participants received MWF imaging (age: 56 [SD 21]), of which 43 received NDI imaging (age: 50 [SD 18]). We found no relationship between plasma biomarkers and total brain myelin content. However, secondary analysis found higher GFAP was associated with lower MWF in the temporal lobes (ß = −0.13; P = 0.049). Further, higher levels of NfL (ß = −0.22; P = 0.009) and GFAP (ß = −0.29; P = 0.002) were associated with lower total brain axonal density. Secondary analyses found lower Aβ42/40 ratio and higher pTau181 were also associated with lower axonal density, but only in select brain regions. These results remained similar after additionally adjusting for cardiovascular risk factors. Interpretation Plasma biomarkers of neuronal injury and astrogliosis are associated with reduced axonal density and region‐specific myelin content. Axonal loss and demyelination may co‐occur with neurodegeneration and astrogliosis ahead of clinically meaningful cognitive decline.

Accumulating evidence has shown that the apoptosis of trophoblast cells plays an important role in the pathogenesis of preeclampsia, and an intricate interplay between DNA methylation and polycomb group (PcG) protein-mediated gene silencing has been highlighted recently. Here, we provide evidence that the expression of nervous system polycomb 1 (NSPc1), a BMI1 homologous polycomb protein, is significantly elevated in trophoblast cells during preeclampsia, which accelerates trophoblast cell apoptosis. Since NSPc1 acts predominantly as a transcriptional inactivator that specifically represses HOXA11 expression in trophoblast cells during preeclampsia, we further show that NSPc1 is required for DNMT3a recruitment and maintenance of the DNA methylation in the HOXA11 promoter in trophoblast cells during preeclampsia. In addition, we find that the interplay of DNMT3a and NSPc1 represses the expression of HOXA11 and promotes trophoblast cell apoptosis. Taken together, these results indicate that the cooperation between NSPc1 and DNMT3a reduces HOXA11 expression in preeclampsia pathophysiology, which provides novel therapeutic approaches for targeted inhibition of trophoblast cell apoptosis during preeclampsia pathogenesis.

Nephrolithiasis is a highly prevalent disease worldwide that is associated with significant suffering, renal failure, and cost for the healthcare system. A patient with nephrolithiasis was found to have SLC6A20 variation. SLC6A20 gene in human is located on chromosome 3p21.3, which is a member of SLC6 family of membrane transporters and the product of this gene expression is transporter protein of sub-amino acid transporter system. The previous studies have reported that the mutation of SLC6A20 may cause hyperglycinuria or iminoglycinuria which may lead to nephrolithiasis. The object was to investigate the relationship between nephrolithiasis and SLC6A20 through pedigree genetic analysis. To explore whether the SLC6A20 mutation can cause hereditary nephrolithiasis, and provide evidence for further research. The urine and blood were collected from the patients for compositional analysis. DNA sequencing was applied to analyze the gene mutation. Labial gland and kidney biopsy were conducted for pathological analysis. As a result we reported a rare family case of nephrolithiasis accompanied by primary Sjogren’s syndrome and investigated it by examining the family members with whole exome gene sequencing technology and detecting 20 different amino acids and 132 kinds of organic acids in the urine with gas chromatography-mass spectrometry. We discovered that the proband and her mother had hyperglycinuria and the proband (Ⅱ2), her sister (Ⅱ3), and mother (Ⅰ1) were found to carry the SLC6A20 gene exon NM_020208.3 sequence c.1072T > C heterozygous mutation, and the other family members (Ⅰ2, Ⅱ1, Ⅱ4, Ⅲ1, Ⅲ2) did not carry the genetic mutation. As a conclusion, the heterozygous mutation of SLC6A20 (c.1072T > C) might be contributed to hyperglycinuria and the formation of nephrolithiasis.

Long noncoding RNAs (lncRNAs) are increasingly being implicated as key regulators of cell proliferation, apoptosis, and differentiation. However, the molecular mechanisms of specific lncRNAs in the context of hypertrophic scar remain largely unclear. Here, we find that the lncRNA FPASL (fibroblast proliferation-associated LncRNA) is downregulated in HS, and FPASL reduces fibroblast proliferation and colony formation and blocks cell cycle progression. Using GO annotation enrichment analysis along with AZC (a specific inhibitor of DNA methylation), we identify that DNA methylation is responsible for downregulating FPASL in hypertrophic scar. Subsequent studies demonstrate that high expression of DNMT3b inhibits FPASL expression in HS. Mechanistic study reveals a significant increase in fibroblast proliferation after transfection with LNA-FPASL, which is further inhibited by knockdown of DNMT3b. Thus, our study reveals that DNMT3b mediates hypermethylation of the lncRNA FPASL promoter and the downregulation of lncRNA FPASL promotes fibroblast proliferation in hypertrophic scar.