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Xinxin Niu,1,* Shuang Qiu,1,* Yafeng Zheng,2,* Li Li,1 Eryun Tian,1 Jie Liu,1 Wei Gai,2 Qing Zhang,1 Hailong Jin1 1Department of Organ Transplantation, The Third Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 2WillingMed Technology (Beijing) Co., Ltd, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qing Zhang; Hailong Jin, Department of Organ Transplantation, The Third Medical Center of Chinese PLA General Hospital, Beijing, 100039, People’s Republic of China, Email zqy6920@sina.com; jhl309@sina.comAbstract: Q fever is a zoonotic disease caused by the Gram-negative bacterium Coxiella burnetii, typically transmitted through exposure to infected animal secretions. As the clinical signs of Q-fever are largely non-specific in humans, a definitive diagnosis can often be overlooked, particularly when physicians fail to consider C. burnetii on the list of differentials. This case report describes Q-fever in a male patient who had previously undergone orthotopic liver transplantation. The patient had a sudden onset of fever and received the anti-infective moxifloxacin which proved ineffective. Despite the comprehensive laboratory tests and CT imaging that were performed, the etiology remained undetermined. The patient’s blood was subjected to metagenomic next-generation sequencing (mNGS), which identified C. burnetii, after which the patient was treated with doxycycline and recovered well. Eight literature articles on Q fever infection in solid organ transplant recipients were reviewed. To our knowledge, this is the first case of Q fever identified by mNGS in an organ transplantation patient. The case underscores the potential of mNGS has in aiding the rapid detection of rare pathogens in immunocompromised patients.Keywords: Q-fever, metagenomic next-generation sequencing, case report, liver transplant, Coxiella burnetii

The C allele of rs11136000 variant in the clusterin (CLU) gene represents the third strongest known genetic risk factor for late-onset Alzheimer's disease. However, whether this single-nucleotide polymorphism (SNP) is functional and what the underlying mechanisms are remain unclear. In this study, the CLU rs11136000 SNP is identified as a functional variant by a small-scale CRISPR-Cas9 screen. Astrocytes derived from isogenic induced pluripotent stem cells (iPSCs) carrying the "C" or "T" allele of the CLU rs11136000 SNP exhibit different CLU expression levels. TAR DNA-binding protein-43 (TDP-43) preferentially binds to the "C" allele to promote CLU expression and exacerbate inflammation. The interferon response and CXCL10 expression are elevated in cytokine-treated C/C astrocytes, leading to inhibition of oligodendrocyte progenitor cell (OPC) proliferation and myelination. Accordingly, elevated CLU and CXCL10 but reduced myelin basic protein (MBP) expression are detected in human brains of C/C carriers. Our study uncovers a mechanism underlying reduced white matter integrity observed in the CLU rs11136000 risk "C" allele carriers.

BackgroundNon-alcoholic fatty liver disease (NAFLD) and ulcerative colitis (UC) are two common health issues that have gained significant global attention. Previous studies have suggested a possible connection between NAFLD and UC, but the underlying pathophysiology remains unclear. This study investigates common genes, underlying pathogenesis mechanisms, identification of diagnostic markers applicable to both conditions, and exploration of potential therapeutic targets shared by NAFLD and UC.MethodsWe obtained datasets for NAFLD and UC from the GEO database. The DEGs in the GSE89632 dataset of the NAFLD and GSE87466 of the UC dataset were analyzed. WGCNA, a powerful tool for identifying modules of highly correlated genes, was employed for both datasets. The DEGs of NAFLD and UC and the modular genes were then intersected to obtain shared genes. Functional enrichment analysis was conducted on these shared genes. Next, we utilize the STRING database to establish a PPI network. To enhance visualization, we employ Cytoscape software. Subsequently, the Cytohubba algorithm within Cytoscape was used to identify central genes. Diagnostic biomarkers were initially screened using LASSO regression and SVM methods. The diagnostic value of ROC curve analysis was assessed to detect diagnostic genes in both training and validation sets for NAFLD and UC. A nomogram was also developed to evaluate diagnostic efficacy. Additionally, we used the CIBERSORT algorithm to explore immune infiltration patterns in both NAFLD and UC samples. Finally, we investigated the correlation between hub gene expression, diagnostic gene expression, and immune infiltration levels.ResultsWe identified 34 shared genes that were found to be associated with both NAFLD and UC. These genes were subjected to enrichment analysis, which revealed significant enrichment in several pathways, including the IL-17 signaling pathway, Rheumatoid arthritis, and Chagas disease. One optimal candidate gene was selected through LASSO regression and SVM: CCL2. The ROC curve confirmed the presence of CCL2 in both the NAFLD and UC training sets and other validation sets. This finding was further validated using a nomogram in the validation set. Additionally, the expression levels of CCL2 for NAFLD and UC showed a significant correlation with immune cell infiltration.ConclusionThis study identified a gene (CCL2) as a biomarker for NAFLD and UC, which may actively participate in the progression of NAFLD and UC. This discovery holds significant implications for understanding the progression of these diseases and potentially developing more effective diagnostic and treatment strategies.

Abstract Background Handelin is a bioactive compound from Chrysanthemum indicum L. that improves motor function and muscle integrity during aging in Caenorhabditis elegans. This study aimed to further evaluate the protective effects and molecular mechanisms of handelin in a mouse muscle atrophy model induced by cachexia and aging. Methods A tumour necrosis factor (TNF)‐α‐induced atrophy model was used to examine handelin activity in cultured C2C12 myotubes in vitro. Lipopolysaccharide (LPS)‐treated 8‐week‐old model mice and 23‐month‐old (aged) mice were used to examine the therapeutic effects of handelin on cachexia‐ and aging‐induced muscle atrophy, respectively, in vivo. Protein and mRNA expressions were analysed by Western blotting, ELISA and quantitative PCR, respectively. Skeletal muscle mass was measured by histological analysis. Results Handelin treatment resulted in an upregulation of protein levels of early (MyoD and myogenin) and late (myosin heavy chain, MyHC) differentiation markers in C2C12 myotubes (P

The regenerative capacity of muscle, which primarily relies on anabolic processes, diminishes with age, thereby reducing the effectiveness of therapeutic interventions aimed at treating age-related muscle atrophy. In this study, we observed a decline in the expression of methionine adenosine transferase 2A (MAT2A), which synthesizes S-adenosylmethionine (SAM), in the muscle tissues of both aged humans and mice. Considering MAT2A’s critical role in anabolism, we hypothesized that its reduced expression contributes to the impaired regenerative capacity of aging skeletal muscle. Mimicking this age-related reduction in the MAT2A level, either by reducing gene expression or inhibiting enzymatic activity, led to inhibiting their differentiation into myotubes. In vivo, inhibiting MAT2A activity aggravated BaCl2-induced skeletal muscle damage and decreased the number of satellite cells, whereas supplementation with SAM improved these effects. RNA-sequencing analysis further revealed that the Fas cell surface death receptor (Fas) gene was upregulated in Mat2a-knockdown C2C12 cells. Suppressing MAT2A expression or activity elevated Fas protein levels and increased the proportion of apoptotic cells. Additionally, inhibition of MAT2A expression or activity increased p53 expression. In conclusion, our findings demonstrated that impaired MAT2A expression or activity compromised the regeneration and repair capabilities of skeletal muscle, partially through p53–Fas-mediated apoptosis.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with no cure. Huge efforts have been made to develop anti-AD drugs in the past decades. However, all drug development programs for disease-modifying therapies have failed. Possible reasons for the high failure rate include incomplete understanding of complex pathophysiology of AD, especially sporadic AD (sAD), and species difference between humans and animal models used in preclinical studies. In this study, sAD is modeled using human induced pluripotent stem cell (hiPSC)-derived 3D brain organoids. Because the blood-brain barrier (BBB) leakage is a well-known risk factor for AD, brain organoids are exposed to human serum to mimic the serum exposure consequence of BBB breakdown in AD patient brains. The serum-exposed brain organoids are able to recapitulate AD-like pathologies, including increased amyloid beta (Aβ) aggregates and phosphorylated microtubule-associated tau protein (p-Tau) level, synaptic loss, and impaired neural network. Serum exposure increases Aβ and p-Tau levels through inducing beta-secretase 1 (BACE) and glycogen synthase kinase-3 alpha / beta (GSK3α/β) levels, respectively. In addition, single-cell transcriptomic analysis of brain organoids reveals that serum exposure reduced synaptic function in both neurons and astrocytes and induced immune response in astrocytes. The human brain organoid-based sAD model established in this study can provide a powerful platform for both mechanistic study and therapeutic development in the future.

Timely and accurate fault diagnosis for a lithium-ion battery pack is critical to ensure its safety. However, the early fault of a battery pack is difficult to detect because of its unobvious fault effect and nonlinear time-varying characteristics. In this paper, a fault diagnosis method based on relative entropy and state of charge (SOC) estimation is proposed to detect fault in lithium-ion batteries. First, the relative entropies of the voltage, temperature and SOC of battery cells are calculated by using a sliding window, and the cumulative sum (CUSUM) test is adopted to achieve fault diagnosis and isolation. Second, the SOC estimation of the short-circuit cell is obtained, and the short-circuit resistance is estimated for a quantitative analysis of the short-circuit fault. Furthermore, the effectiveness of our method is validated by multiple fault tests in a thermally coupled electrochemical battery model. The results show that the proposed method can accurately detect different types of faults and evaluate the short-circuit fault degree by resistance estimation. The voltage/temperature sensor fault is detected at 71 s/58 s after faults have occurred, and a short-circuit fault is diagnosed at 111 s after the fault. In addition, the standard error deviation of short-circuit resistance estimation is less than 0.12 Ω/0.33 Ω for a 5 Ω/10 Ω short-circuit resistor.

ApoE4, a strong genetic risk factor for Alzheimer disease, has been associated with increased risk for severe COVID-19. However, it is unclear whether ApoE4 alters COVID-19 susceptibility or severity, and the role of direct viral infection in brain cells remains obscure. We tested the neurotropism of SARS-CoV2 in human-induced pluripotent stem cell (hiPSC) models and observed low-grade infection of neurons and astrocytes that is boosted in neuron-astrocyte co-cultures and organoids. We then generated isogenic ApoE3/3 and ApoE4/4 hiPSCs and found an increased rate of SARS-CoV-2 infection in ApoE4/4 neurons and astrocytes. ApoE4 astrocytes exhibited enlarged size and elevated nuclear fragmentation upon SARS-CoV-2 infection. Finally, we show that remdesivir treatment inhibits SARS-CoV2 infection of hiPSC neurons and astrocytes. These findings suggest that ApoE4 may play a causal role in COVID-19 severity. Understanding how risk factors impact COVID-19 susceptibility and severity will help us understand the potential long-term effects in different patient populations.

Brain organoid models have greatly facilitated our understanding of human brain development and disease. However, key brain cell types, such as microglia, are lacking in most brain organoid models. Because microglia have been shown to play important roles in brain development and pathologies, attempts have been made to add microglia to brain organoids through co-culture. However, only short-term microglia-organoid co-cultures can be established, and it remains challenging to have long-lasting survival of microglia in organoids to mimic long-term residency of microglia in the brain. In this study, we developed an adhesion brain organoid (ABO) platform that allows prolonged culture of brain organoids (greater than a year). Moreover, the long-term (LT)-ABO system contains abundant astrocytes and can support prolonged survival and ramification of microglia. Furthermore, we showed that microglia in the LT-ABO could protect neurons from neurodegeneration by increasing synaptic density and reducing p-Tau level and cell death in the LT-ABO. Therefore, the microglia-containing LT-ABO platform generated in this study provides a promising human cellular model for studying neuron-glia and glia-glia interactions in brain development and the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. Human iPSC-based modeling using microglia-containing long-term adhesion brain organoids reveals the role of microglia in supporting neuronal growth and function, as well as protecting neurons from neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Usnea has various pharmacological properties, including anti-inflammatory, antitumor, antioxidant, antiviral, and cardiovasculoprotective effects.Aim of the study: To investigate the potential mechanisms underlying the anti-atherosclerosis (AS) activity of Usnea ethanol extract (UEE) via the regulation of intestinal flora.Materials and Methods: The chemical composition of UEE was determined using ultra-performance liquid chromatography with quadrupole exactive orbitrap mass spectrometry (UPLC-Q-EOMS). Thirty-six male Sprague–Dawley rats were divided into six groups. A high-fat diet and intraperitoneal vitamin D3 injections were used to establish a rat model of AS. After 4 weeks of treatment with UEE, hematoxylin–eosin staining was performed to evaluate the pathomorphology of the aorta, liver, and colon. The composition and diversity of the rat intestinal flora were determined using high-throughput 16S rRNA sequencing. Enzyme-linked immunosorbent assays were used to measure the levels of plasma trimethylamine oxide (TMAO), serum bile acid (BA), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), lipopolysaccharide (LPS), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). The protein expression of cholesterol 7α-hydroxylase (CYP7A1) and flavin monooxygenase 3 (FMO3) in the liver and zonula occludens-1 (ZO-1) and occludin in colon tissue was detected via western blotting.Results: Forty-four compounds were identified in UEE. In the rat model of AS, UEE significantly prevented calcium deposition; decreased the serum levels of TC, TG, LDL-C, LPS, TNF-α, and IL-6; and increased the serum level of HDL-C. Additionally, all UEE dosages decreased the relative abundance of Verrucomicrobiota while increased that of Bacteroidetes. FMO3 protein expression and TMAO levels decreased, whereas CYP7A1 protein expression and BA levels increased. The absorption of intestinal-derived LPS was minimized. Furthermore, the protein expression of ZO-1 and occludin was upregulated.Conclusion: UEE ameliorated AS. The underlying mechanism was the reversal of imbalances in the intestinal flora by Usnea, thereby inhibiting calcium deposition, abnormal lipid metabolism, and inflammatory response.

Vestibular compensation is the natural process of recovery that occurs with acute peripheral vestibular lesion. Here, we summarize the current understanding of the mechanisms underlying vestibular compensation, focusing on the role of the medial vestibular nucleus (MVN), the central hub of the vestibular system, and its associated neural networks. The disruption of neural activity balance between the bilateral MVNs underlies the vestibular symptoms after unilateral vestibular damage, and this balance disruption can be partially reversed by the mutual inhibitory projections between the bilateral MVNs, and their top‐down regulation by other brain regions via different neurotransmitters. However, the detailed mechanism of how MVN is involved in vestibular compensation and regulated remains largely unknown. A deeper understanding of the vestibular neural network and the neurotransmitter systems involved in vestibular compensation holds promise for improving treatment outcomes and developing more effective interventions for vestibular disorders. [ABSTRACT FROM AUTHOR]

The regenerative capacity of muscle, which primarily relies on anabolic processes, diminishes with age, thereby reducing the effectiveness of therapeutic interventions aimed at treating age-related muscle atrophy. In this study, we observed a decline in the expression of methionine adenosine transferase 2A (MAT2A), which synthesizes S-adenosylmethionine (SAM), in the muscle tissues of both aged humans and mice. Considering MAT2A's critical role in anabolism, we hypothesized that its reduced expression contributes to the impaired regenerative capacity of aging skeletal muscle. Mimicking this age-related reduction in the MAT2A level, either by reducing gene expression or inhibiting enzymatic activity, led to inhibiting their differentiation into myotubes. In vivo, inhibiting MAT2A activity aggravated BaCl2-induced skeletal muscle damage and decreased the number of satellite cells, whereas supplementation with SAM improved these effects. RNA-sequencing analysis further revealed that the Fas cell surface death receptor (Fas) gene was upregulated in Mat2a-knockdown C2C12 cells. Suppressing MAT2A expression or activity elevated Fas protein levels and increased the proportion of apoptotic cells. Additionally, inhibition of MAT2A expression or activity increased p53 expression. In conclusion, our findings demonstrated that impaired MAT2A expression or activity compromised the regeneration and repair capabilities of skeletal muscle, partially through p53–Fas-mediated apoptosis. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a common neurodegenerative disease. More evidence has shown that gut microbiota is closely associated with AD. Also, studies have shown that the distribution of gut microbiota vary in different sections of the intestine. In this study, a rat model of AD was established using a bilateral intraventricular injection of β-amyloid (1-42) [Aβ (1-42)], and the behavior of rats, hippocampal Aβ (1-42) deposition, and the ileal and colonic microbiota in each group were analyzed. We observed that the model rats had obvious memory and cognitive impairment, increased Aβ (1-42) deposition, indicating that the AD model was successfully established. Through 16S rRNA-sequencing analysis, we found that α diversity, β diversity, and dominant microbiota in the ileum and colon of normal rats were significantly different, showing spatial heterogeneity. Additionally, the surgery and injection of Aβ (1-42) caused various degrees of disturbances in the ileal and colonic microbiota of rats. These findings provide new insights for the study of the gut microbiota of AD rats and help advance the development of therapeutic strategies for intervening AD through the gut microbiota.

Long non‐coding RNAs (lncRNAs) have emerged as crucial regulators in the central nervous system, yet their role in vestibular compensation remains elusive. To address this knowledge gap, we employed unilateral labyrinthectomy (UL) in rats to establish animal models of peripheral vestibular dysfunction. Utilizing ribonucleic acid sequencing (RNA‐seq), we comprehensively analysed the expression profiles of genes dysregulated in the medial vestibular nucleus (MVN) of these rats at distinct time points: 4 h, 4 days, and 14 days post‐UL. Through trans‐target prediction analysis integrating differentially co‐expressed messenger RNAs (mRNAs) and lncRNAs, we constructed lncRNA‐mRNA regulatory networks. Validation of selected mRNAs and lncRNAs was performed using RT‐qPCR. Our RNA‐seq analysis revealed significant aberrant expression of 3054 lncRNAs and 1135 mRNAs compared to control samples. By applying weighted gene co‐expression network analysis (WGCNA), we identified 11 co‐expressed modules encompassing all genes. Notably, within the MEmagenta module, we observed an initial upregulation of differentially expressed genes (DEGs) at 4 h, followed by downregulation at 4‐ and 14‐days post‐UL. Our findings indicated that 3068 lncRNAs positively regulated 1259 DEGs, while 1482 lncRNAs negatively regulated 433 DEGs in the MVN. The RT‐qPCR results corroborated the RNA‐seq data, validating our findings. This study offers novel insights into the lncRNA‐mRNA expression landscape during vestibular compensation, paving the way for further exploration of lncRNA functions in this context. [ABSTRACT FROM AUTHOR]

Timely and accurate fault diagnosis for a lithium-ion battery pack is critical to ensure its safety. However, the early fault of a battery pack is difficult to detect because of its unobvious fault effect and nonlinear time-varying characteristics. In this paper, a fault diagnosis method based on relative entropy and state of charge (SOC) estimation is proposed to detect fault in lithium-ion batteries. First, the relative entropies of the voltage, temperature and SOC of battery cells are calculated by using a sliding window, and the cumulative sum (CUSUM) test is adopted to achieve fault diagnosis and isolation. Second, the SOC estimation of the short-circuit cell is obtained, and the short-circuit resistance is estimated for a quantitative analysis of the short-circuit fault. Furthermore, the effectiveness of our method is validated by multiple fault tests in a thermally coupled electrochemical battery model. The results show that the proposed method can accurately detect different types of faults and evaluate the short-circuit fault degree by resistance estimation. The voltage/temperature sensor fault is detected at 71 s/58 s after faults have occurred, and a short-circuit fault is diagnosed at 111 s after the fault. In addition, the standard error deviation of short-circuit resistance estimation is less than 0.12 Ω/0.33 Ω for a 5 Ω/10 Ω short-circuit resistor. [ABSTRACT FROM AUTHOR]

Abstract The two major limitations in the application of SnO2 for lithium-ion battery (LIB) anodes are the large volume variations of SnO2 during repeated lithiation/delithiation processes and a large irreversible capacity loss during the first cycle, which can lead to a rapid capacity fade and unsatisfactory initial Coulombic efficiency (ICE). To overcome these limitations, we developed composites of ultrafine SnO2 nanoparticles and in situ formed Co(CoSn) nanocrystals embedded in an N-doped carbon matrix using a Co-based metal–organic framework (ZIF-67). The formed Co additives and structural advantages of the carbon-confined SnO2/Co nanocomposite effectively inhibited Sn coarsening in the lithiated SnO2 and mitigated its structural degradation while facilitating fast electronic transport and facile ionic diffusion. As a result, the electrodes demonstrated high ICE (82.2%), outstanding rate capability (~ 800 mAh g−1 at a high current density of 5 A g−1), and long-term cycling stability (~ 760 mAh g−1 after 400 cycles at a current density of 0.5 A g−1). This study will be helpful in developing high-performance Si (Sn)-based oxide, Sn/Sb-based sulfide, or selenide electrodes for LIBs. In addition, some metal organic frameworks similar to ZIF-67 can also be used as composite templates.

Pluripotent stem cells (PSCs) hold significant promise in regenerative medicine due to their unlimited capacity for self-renewal and potential to differentiate into every cell type in the body. One major barrier to the use of PSCs is their potential risk for tumor initiation following differentiation and transplantation in vivo. In the current study we sought to evaluate the role of the tumor suppressor Pten in murine PSC neoplastic progression. Using eight functional assays that have previously been used to indicate PSC adaptation or transformation, Pten null embryonic stem cells (ESCs) failed to rate as significant in five of them. Instead, our data demonstrate that the loss of Pten causes the emergence of a small number of aggressive, teratoma-initiating embryonic carcinoma cells (ECCs) during differentiation in vitro, while the remaining 90-95% of differentiated cells are non-tumorigenic. Furthermore, our data show that the mechanism by which Pten null ECCs emerge in vitro and cause tumors in vivo is through increased survival and self-renewal, due to failed repression of the transcription factor Nanog.