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Based on single-cell sequencing of the hippocampi of 5× familiar Alzheimer's disease (5× FAD) and wild type mice at 2-, 12-, and 24-month of age, we found an increased percentage of microglia in aging and Alzheimer's disease (AD) mice. Blood brain barrier injury may also have contributed to this increase. Immune regulation by microglia plays a major role in the progression of aging and AD, according to the functions of 41 intersecting differentially expressed genes in microglia. Signaling crosstalk between C−C motif chemokine ligand (CCL) and major histocompatibility complex-1 bridges intercellular communication in the hippocampus during aging and AD. The amyloid precursor protein (APP) and colony stimulating factor (CSF) signals drive 5× FAD to deviate from aging track to AD occurrence among intercellular communication in hippocampus. Microglia are involved in the progression of aging and AD can be divided into 10 functional types. The strength of the interaction among microglial subtypes weakened with aging, and the CCL and CSF signaling pathways were the fundamental bridge of communication among microglial subtypes.

Abstract Introduction Objective observational studies have shown that basal metabolic rate (BMR) decreases in patients with Alzheimer’s disease (AD), but the causal relationship between BMR and AD has not been established. We determined the causal relationship between BMR and AD by two-way Mendelian randomization (MR) and investigated the impact of factors associated with BMR on AD. Methods We obtained BMR (n = 454,874) and AD from a large genome-wide association study (GWAS) database (21,982 patients with AD, 41,944 controls). The causal relationship between AD and BMR was investigated using two-way MR. Additionally, we identified the causal relationship between AD and factors related with BMR, hyperthyroidism (hy/thy) and type 2 diabetes (T2D), height and weight. Results BMR had a causal relationship with AD [451 single nucleotide polymorphisms (SNPs), odds ratio (OR) 0.749, 95% confidence intervals (CIs) 0.663–0.858, P = 2.40E-03]. There was no causal relationship between hy/thy or T2D and AD (P > 0.05). The bidirectional MR showed that there was also a causal relationship between AD and BMR (OR 0.992, Cls 0.987–0.997, N SNPs18, P = 1.50E−03). BMR, height and weight have a protective effect on AD. Based on MVMR analysis, we found that genetically determined height and weight may be adjusted by BMR to have a causal effect on AD, not height and weight themselves. Conclusion Our study showed that higher BMR reduced the risk of AD, and patients with AD had a lower BMR. Because of a positive correlation with BMR, height and weight may have a protective effect on AD. The two metabolism-related diseases, hy/thy and T2D, had no causal relationship with AD.

IntroductionCognitive impairment is the main symptom of Alzheimer's disease (AD). Accumulating evidence implicate that immunity plays an important role in AD. Here, we investigated the effect of Qi-fu-yin (QFY) on cognitive impairment and cytokine secretion of 5xFAD mice.MethodsWe used 2.5-month-old 5xFAD transgenic mice for behavioral tests to observe the changes in cognitive function after QFY treatment. After the behavioral experiment, the whole brain, cortex and plasma of each mouse were collected for soluble Aβ analysis, immunohistochemical experiment and cytokine analysis.ResultsHere we found that the treatment of QFY ameliorated the ability of object recognition, passive avoidance responses and the ability of spatial learning and memory in 5xFAD mice. The deposits of β1 − 42 and Aβ1 − 40 were alleviated and the ration of Aβ1 − 42/Aβ1 − 40 was decrease in the plasma and brain of 5xFAD mice administrated with QFY. The administration of QFY promoted the secretion of anti-inflammatory cytokines, IL-5, IL-10 and G-CSF, and reduced the content of proinflammatory cytokines IFN-γ in plasma of 5xFAD mice. Notably, we found that the treatment of QFY decreased the concentration of CCL11 in the brain and plasma of 5xFAD mice.ConclusionThis suggested that QFY improved cognition and reduced Aβ deposits in 5xFAD mice by regulating abnormal immunity in 5xFAD mice. QFY may be as a potential therapeutic agent for AD.

Sleep, as the basis for regular body functioning, can affect human health. Poor sleep conditions can lead to various physical ailments, such as poor immunity, memory loss, slow cognitive development, and cardiovascular diseases. Along the increasing stress in society comes with a growing surge in conditions associated with sleep disorders. Studies have shown that sleep stages are essential for the body’s memory, immune system, and brain functioning. Therefore, automatic sleep stage classification is of great medical practice importance as a basis for monitoring sleep conditions. Although previous research into the classification of sleep stages has been promising, several challenges remain to be addressed: (1) The EEG signal is a non-smooth signal with harrowing feature extraction and high requirements for model accuracy. (2) Some existing network models suffer from overfitting and gradient descent. (3) Correlation between long time sequences is challenging to capture. This paper proposes NAMRTNet, a deep model architecture based on the original single-channel EEG signal to address these challenges. The model uses a modified ResNet network to extract features from sub-epochs of individual epochs, a lightweight attention mechanism normalization-based attention module (NAM) to suppress insignificant features, and a temporal convolutional network (TCN) network to capture dependencies between features of long time series. The recognition rate of 20-fold cross-validation with the NAMRTNet model for Fpz-cz channel data in the public sleep dataset Sleep-EDF was 86.2%. The experimental results demonstrate the network’s superiority in this paper, surpassing some state-of-the-art techniques in different evaluation metrics. Furthermore, the total time to train the network was 5.1 h, which was much less than the training time of other models.

BackgroundAlzheimer's disease (AD) is a heterogeneous pathological disease with genetic background accompanied by aging. This inconsistency is present among molecular subtypes, which has led to diagnostic ambiguity and failure in drug development. We precisely distinguished patients of AD at the transcriptome level.MethodsWe collected 1,240 AD brain tissue samples collected from the GEO dataset. Consensus clustering was used to identify molecular subtypes, and the clinical characteristics were focused on. To reveal transcriptome differences among subgroups, we certificated specific upregulated genes and annotated the biological function. According to RANK METRIC SCORE in GSEA, TOP10 was defined as the hub gene. In addition, the systematic correlation between the hub gene and “A/T/N” was analyzed. Finally, we used external data sets to verify the diagnostic value of hub genes.ResultsWe identified three molecular subtypes of AD from 743 AD samples, among which subtypes I and III had high-risk factors, and subtype II had protective factors. All three subgroups had higher neuritis plaque density, and subgroups I and III had higher clinical dementia scores and neurofibrillary tangles than subgroup II. Our results confirmed a positive association between neurofibrillary tangles and dementia, but not neuritis plaques. Subgroup I genes clustered in viral infection, hypoxia injury, and angiogenesis. Subgroup II showed heterogeneity in synaptic pathology, and we found several essential beneficial synaptic proteins. Due to presenilin one amplification, Subgroup III was a risk subgroup suspected of familial AD, involving abnormal neurogenic signals, glial cell differentiation, and proliferation. Among the three subgroups, the highest combined diagnostic value of the hub genes were 0.95, 0.92, and 0.83, respectively, indicating that the hub genes had sound typing and diagnostic ability.ConclusionThe transcriptome classification of AD cases played out the pathological heterogeneity of different subgroups. It throws daylight on the personalized diagnosis and treatment of AD.

Amphioxus species are considered living fossils and are important in the evolutionary study of chordates and vertebrates. To explore viral homologous sequences, a high-quality annotated genome of the Beihai amphioxus (Branchiostoma belcheri beihai) was examined using virus sequence queries. In this study, 347 homologous fragments (HFs) of viruses were identified in the genome of B. belcheri beihai, of which most were observed on 21 genome assembly scaffolds. HFs were preferentially located within protein-coding genes, particularly in their CDS regions and promoters. A range of amphioxus genes with a high frequency of HFs is proposed, including histone-related genes that are homologous to the Histone or Histone H2B domains of viruses. Together, this comprehensive analysis of viral HFs provides insights into the neglected role of viral integration in the evolution of amphioxus.

In order to study the effects of inlet sweepback angle on the cavitation performance of inducers based on the Reynolds N-S equation, RNG k-ε turbulent model, and Schnerr and Sauer cavitation model, a three-dimensional numerical calculation is employed to study the flow characteristics of a certain LNG pump. Laws of the variation of cavitation performance, head, and efficiency with the change of sweepback were studied. Numerical analysis of the eight inducer projects with a sweepback angle from 120° to 290° was carried out. The results show that the cavitation bubbles first appear at the suction surface near the inlet side. With the decrease of net positive suction head (NPSHa), the bubbles spread to the outlet side of the inducer and the pressure surface. Finally, they fill the entire channel. When the inducer sweepback angle increases from 120° to 270°, the NPSHr of the pump reduces gradually, that is to say that the anti-cavitation performance of the pump has been improved. However, the NPSHr of the pump increases gradually when the inducer sweepback angle increases from 270° to 290°. In other words, there is an optimal sweepback from 120° to 290°, and efficiency and head of pump tend to be stable near the optimal sweepback.

In order to study the influence of blade outlet cutting width on hydrodynamic excitation noise of the centrifugal pump with low specific speed, five schemes are used to perform V-shaped cutting on the outlet of the impeller blade are studied in this study. Based on Lighthill acoustic analogy, combining computational fluid dynamics and computational acoustics, RNG k-ε turbulence model is used to calculate internal unsteady flow field of the centrifugal pump, and the acoustic solution is based on the flow field calculation. The results show that the pressure pulsation can reflect the sound pressure level to a certain extent; proper cutting of the blade outlet can improve the flow state of the rear cavity of the centrifugal pump and make the flow uniform; the V-shaped cutting of the blade outlet also can reduce the dynamic and static interference between the impeller outlet and the volute tongue, effectively reducing the sound pressure level of the internal sound field, when the blade outlet cutting width is a / b 2 = 33.33%, the inlet sound pressure level and the outlet sound pressure level are decreased by 4.8% and 7.2%, respectively. In terms of internal sound field, the sound pressure level at the outlet of the pump is obviously higher than that at the inlet.

Aging is a natural biological process associated with cognitive decline and neuroendocrine–immune system changes; the neuroendocrine–immune system plays crucial role in brain aging and neurodegeneration, and it is essential to discern beneficial attempts to delay the aging progress based on immunological aging. In this study, we have investigated the effects of Traditional Chinese Medicine (TCM)—Liuwei Dihuang decoction (LW)—and donepezil, memantine, and melatonin on cognitive decline in aging mice. The aged SAMR1 mice received oral administration of donepezil (1mg/kg), memantine (10 mg/kg), melatonin (10 mg/kg), and LW (10 g/kg) for 3 months. A shuttle box, Morris water maze, and elevated-zero maze were performed to assess cognitive function, and flowcytometry, Luminex, and radioimmunoassay were performed to measure the lymphocyte subsets, inflammatory factors, and hormones. We observed that survival days of mice was increased with melatonin and LW, the anxiety behavior was significantly improved by memantine, melatonin, and LW treatment, active avoidance responses significantly improved by LW, donepezil, and memantine, the spatial learning ability was significantly improved by donepezil, and LW and melatonin were beneficial to the spatial memory of old mice. For immune function, LW increased CD4+ and CD4+CD28+ cells and reduced TNF-α, IL-1β, and G-CSF in plasma, and it also promoted the secretion of anti-inflammatory factors IL-4, IL-5, and IL-10 by regulating the active of Th2 cells in spleen. Donepezil and memantine exerted protective effects against CD4+CD28+ cell decrease caused by aging and reduced the pro-inflammatory factors TNF-α, IL-1β, and G-CSF in plasma. Melatonin could reverse CD8+CD28+ cell imbalances and increased B cells. For endocrine factors, LW increased TSH levels in the pituitary, and melatonin increased the GH level in blood. Our findings indicated that LW improved the cognitive decline in aging mice, and this might be associated with modulation of the active T cells and HPG axis hormones as well as increasing anti-inflammatory factors. Meanwhile, donepezil and memantine have advantages in regulating adaptive immunity, melatonin has advantages in the regulation of B cells and pituitary hormones, and LW exhibits a better effect on neuroendocrine immune function compared with the others from a holistic point of view. LW might be a potential therapeutic strategy for anti-aging-related syndromes, and it can also provide a value on medication guidance about drug combinations or treatment in clinic.

Neuroinflammation is often accompanied by central nervous system (CNS) injury seen in various CNS diseases, with no specific treatment. Drug repurposing is a strategy of finding new uses for approved or investigational drugs, and can be enabled by the Library of Integrated Network-based Cellular Signatures (LINCS), a large drug perturbation database. In this study, the signatures of Lipopolysaccharide (LPS) were compared with the signatures of compounds contained in the LINCS dataset. To the top 100 compounds obtained, the Quantitative Structure-Activity Relationship (QSAR)-based tool admetSAR was used to identify the top 10 candidate compounds with relatively high blood–brain barrier (BBB) penetration. Furthermore, the seventh-ranked compound, dutasteride, a 5-α-reductase inhibitor, was selected for in vitro and in vivo validation of its anti-neuroinflammation activity. The results showed that dutasteride significantly reduced the levels of IL-6 and TNF-α in the supernatants of LPS-stimulated BV2 cells, and decreased the levels of IL-6 in the hippocampus and plasma, and the number of activated microglia in the brain of LPS administration mice. Furthermore, dutasteride also attenuated the cognitive impairment caused by LPS stimulation in mice. Taken together, this study demonstrates that the LINCS dataset-based drug repurposing strategy is an effective approach, and the predicted candidate, dutasteride, has the potential to ameliorate LPS-induced neuroinflammation and cognitive impairment.

Based on the Reynolds-averaged Navier–Stokes equations of relative coordinates and the RNG k-ε turbulence model, using our SIMPLE algorithm, we performed numerical simulations for an AP1000 nuclear main pump model with water as the medium. By changing the size of the tongue blend in the annular casing, seven different schemes were designed. Three-dimensional numerical simulations were conducted for the flow within the pump under various settings, and the flow characteristics of the annular casing using different tongue blends were obtained. The results show that for different operating conditions, there is a specific tongue blend that optimizes pump performance. Based on the calculation results, a larger tongue blend leads to a larger flow rate. Off-design conditions caused flow instability, which in turn caused the tongue blend to have a certain impact on the performance of the impeller. However, the performance of the pump was not primarily affected by changes in the impeller performance, but was instead affected by the performance of the annular casing, which was itself affected by tongue blend. When changing the tongue blend, the change in static pressure and total pressure of the annular casing was larger under the condition of 0.6 Q d and was smaller under the conditions of 1.0 Q d and 1.4 Q d . The turbulent kinetic energy in the annular casing changed mainly in the tongue impact zone and outlet diffuser under the condition of 1.0 Q d ; furthermore, the turbulent kinetic energy in the whole of the annular casing demonstrated significant changes under the conditions of 0.6 Q d and 1.4 Q d .

Growing evidence shows that the neuroendocrine immunomodulation (NIM) network plays an important role in maintaining and modulating body function and the homeostasis of the internal environment. The disequilibrium of NIM in the body is closely associated with many diseases. In the present study, we first collected a core dataset of NIM signaling molecules based on our knowledge and obtained 611 NIM signaling molecules. Then, we built a NIM molecular network based on the MetaCore database and analyzed the signaling transduction characteristics of the core network. We found that the endocrine system played a pivotal role in the bridge between the nervous and immune systems and the signaling transduction between the three systems was not homogeneous. Finally, employing the forest algorithm, we identified the molecular hub playing an important role in the pathogenesis of rheumatoid arthritis (RA) and Alzheimer’s disease (AD), based on the NIM molecular network constructed by us. The results showed that GSK3B, SMARCA4, PSMD7, HNF4A, PGR, RXRA, and ESRRA might be the key molecules for RA, while RARA, STAT3, STAT1, and PSMD14 might be the key molecules for AD. The molecular hub may be a potentially druggable target for these two complex diseases based on the literature. This study suggests that the NIM molecular network in this paper combined with the forest algorithm might provide a useful tool for predicting drug targets and understanding the pathogenesis of diseases. Therefore, the NIM molecular network and the corresponding online tool will not only enhance research on complex diseases and system biology, but also promote the communication of valuable clinical experience between modern medicine and Traditional Chinese Medicine (TCM).

To achieve accurate detection of tuberculosis (TB) areas in chest radiographs, we design a chest X-ray TB area detection algorithm. The algorithm consists of two stages: the chest Xray TB classification network (CXTCNet) and the chest X-ray TB area detection network (CXTDNet). CXTCNet is used to judge the presence or absence of TB areas in chest X-ray images, thereby excluding the influence of other lung diseases on the detection of TB areas. It can reduce false positives in the detection network and improve the accuracy of detection results. In CXTCNet, we propose a channel attention mechanism (CAM) module and combine it with DenseNet. This module enables the network to learn more spatial and channel features information about chest X-ray images, thereby improving network performance. CXTDNet is a design based on a sparse object detection algorithm (Sparse R-CNN). A group of fixed learnable proposal boxes and learnable proposal features are using for classification and location. The predictions of the algorithm are output directly without non-maximal suppression post-processing. Furthermore, we use CLAHE to reduce image noise and improve image quality for data preprocessing. Experiments on dataset TBX11K show that the accuracy of the proposed CXTCNet is up to 99.10%, which is better than most current TB classification algorithms. Finally, our proposed chest X-ray TB detection algorithm could achieve AP of 45.35% and AP50 of 74.20%. We also establish a chest X-ray TB dataset with 304 sheets. And experiments on this dataset showed that the accuracy of the diagnosis was comparable to that of radiologists. We hope that our proposed algorithm and established dataset will advance the field of TB detection. [ABSTRACT FROM AUTHOR]

Glycosylation is one of the most common eukaryotic post-translational modifications, and aberrant glycosylation has been linked to many diseases. However, glycosylation and glycome analysis is a significantly challenging task. Although several lines of evidence have indicated that protein glycosylation is defective in Alzheimer's disease (AD), only a few studies have focused on AD glycomics. The etiology of AD is unclear and there are no effective disease-modifying treatments for AD. In this study, we found that the object recognition memory, passive avoidance, and spatial learning and memory of senescence-accelerated mouse prone 8 (SAMP8) strain, an AD animal model, were deficient, and LW-AFC, which was prepared from the traditional Chinese medicine prescription Liuwei Dihuang decoction, showed beneficial effects on the deterioration of cognitive capability in SAMP8 mice. Forty-three and 56 N-glycan were identified in the cerebral cortex and serum of SAMP8 mice, respectively. The N-glycan profile in SAMP8 mice was significantly different from that of senescence accelerated mouse resistant 1 (SAMR1) strains, the control of SAMP8 mice. Treatment with LW-AFC modulated the abundance of 21 and 6 N-glycan in the cerebral cortex and serum of SAMP8 mice, respectively. The abundance of (Hex)3(HexNAc)5(Fuc)1(Neu5Ac)1 and (Hex)2(HexNAc)4 decreased in the cerebral cortex and serum of SAMP8 mice compared with SAMR1 mice, decreases that were significantly correlated with learning and memory measures. The administration of LW-AFC could reverse or increase these levels in SAMP8 mice. These results indicated that the effects of LW-AFC on cognitive impairments in SAMP8 mice might be through modulation of N-glycan patterns, and LW-AFC may be a potential anti-AD agent. [ABSTRACT FROM AUTHOR]