LncRNA 4930581F22Rik promotes myogenic differentiation by regulating the ERK/MAPK signaling pathway.

The skeletal muscle is the largest organ in mammals and is the primary motor function organ of the body. Our previous research has shown that long non-coding RNAs (lncRNAs) are significant in the epigenetic control of skeletal muscle development. Here, we observed progressive upregulation of lncRNA 4930581F22Rik expression during skeletal muscle differentiation. Knockdown of lncRNA 4930581F22Rik hindered skeletal muscle differentiation and resulted in the inhibition of the myogenic markers MyHC and MEF2C. Furthermore, we found that lncRNA 4930581F22Rik regulates myogenesis via the ERK/MAPK signaling pathway, and this effect could be attenuated by the ERK-specific inhibitor PD0325901. Additionally, in vivo mice injury model results revealed that lncRNA 4930581F22Rik is involved in skeletal muscle regeneration. These results establish a theoretical basis for understanding the contribution of lncRNAs in skeletal muscle development and regeneration.

Multi-layer CNN-LSTM network with self-attention mechanism for robust estimation of nonlinear uncertain systems.

Introduction: With the help of robot technology, intelligent rehabilitation of patients with lower limb motor dysfunction caused by stroke can be realized. A key factor constraining the clinical application of rehabilitation robots is how to realize pattern recognition of human movement intentions by using the surface electromyography (sEMG) sensors to ensure unhindered human-robot interaction. Methods: A multilayer CNN-LSTM prediction network incorporating the self-attention mechanism (SAM) is proposed, in this paper, which can extract and learn the periodic and trend characteristics of the sEMG signals, and realize the accurate autoregressive prediction of the human motion information. Firstly, the multilayer CNN-LSTM network utilizes the CNN layer for initial feature extraction of data, and the LSTM network is used to improve the enhancement of the historical time-series features. Then, the SAM is used to improve the global feature extraction performance and parallel computation speed of the network. Results: In comparison with existing test is carried out using actual data from five healthy subjects as well as a clinical hemiplegic patient to verify the superiority and practicality of the proposed algorithm. The results show that most of the model's prediction R > 0.9 for different motion states of healthy subjects; in the experiments oriented to the motion characteristics of patient subjects, the angle prediction results of R > 0.99 for the untrained data on the affected side, which proves that our proposed model also has a better effect on the angle prediction of the affected side. Discussion: The main contribution of this paper is to realize continuous motion estimation of ankle joint for healthy and hemiplegic individuals under non-ideal conditions (weak sEMG signals, muscle fatigue, high muscle tension, etc.), which improves the pattern recognition accuracy and robustness of the sEMG sensor-based system.

Design and assessment of a reconfigurable behavioral assistive robot: a pilot study.

Introduction: For patients with functional motor disorders of the lower limbs due to brain damage or accidental injury, restoring the ability to stand and walk plays an important role in clinical rehabilitation. Lower limb exoskeleton robots generally require patients to convert themselves to a standing position for use, while being a wearable device with limited movement distance. Methods: This paper proposes a reconfigurable behavioral assistive robot that integrates the functions of an exoskeleton robot and an assistive standing wheelchair through a novel mechanism. The new mechanism is based on a four-bar linkage, and through simple and stable conformal transformations, the robot can switch between exoskeleton state, sit-to-stand support state, and wheelchair state. This enables the robot to achieve the functions of assisted walking, assisted standing up, supported standing and wheelchair mobility, respectively, thereby meeting the daily activity needs of sit-to-stand transitions and gait training. The configuration transformation module controls seamless switching between different configurations through an industrial computer. Experimental protocols have been developed for wearable testing of robotic prototypes not only for healthy subjects but also for simulated hemiplegic patients. Results: The experimental results indicate that the gait tracking effect during robot-assisted walking is satisfactory, and there are no sudden speed changes during the assisted standing up process, providing smooth support to the wearer. Meanwhile, the activation of the main force-generating muscles of the legs and the plantar pressure decreases significantly in healthy subjects and simulated hemiplegic patients wearing the robot for assisted walking and assisted standing-up compared to the situation when the robot is not worn. Discussion: These experimental findings demonstrate that the reconfigurable behavioral assistive robot prototype of this study is effective, reducing the muscular burden on the wearer during walking and standing up, and provide effective support for the subject's body. The experimental results objectively and comprehensively showcase the effectiveness and potential of the reconfigurable behavioral assistive robot in the realms of behavioral assistance and rehabilitation training.

Bacterial heat shock protein: A new crosstalk between T lymphocyte and macrophage via JAK2/STAT1 pathway in bloodstream infection.

Bloodstream infection (BSI) refers to the infection of blood by pathogens. Severe immune response to BSI can lead to sepsis, a systemic infection leading to multiple organ dysfunction, coupled with drug resistance, mortality, and limited clinical treatment options. This work aims to further investigate the new interplay between bacterial exocrine regulatory protein and host immune cells in the context of highly drug-resistant malignant BSI. Whether interfering with related regulatory signaling pathways can reverse the inflammatory disorder of immune cells. In-depth analysis of single-cell sequencing results in Septic patients for potential immunodeficiency factors. Analysis of key proteins enriched by host cells and key pathways using proteomics. Cell models and animal models validate the pathological effects of DnaK on T cells, MAITs, macrophages, and osteoclasts. The blood of patients was analyzed for the immunosuppression of T cells and MAITs. We identified that S. maltophilia-DnaK was enriched in immunodeficient T cells. The activation of the JAK2/STAT1 axis initiated the exhaustion of T cells. Septic patients with Gram-negative bacterial infections exhibited deficiencies in MAITs, which correspond to IFN-γ. Cellular and animal experiments confirmed that DnaK could facilitate MAIT depletion and M1 polarization of macrophages. Additionally, Fludarabine mitigated M1 polarization of blood, liver, and spleen in mice. Interestingly, DnaK also repressed osteoclastogenesis of macrophages stimulated by RANKL. S.maltophilia-DnaK prompts the activation of the JAK2/STAT1 axis in T cells and the M1 polarization of macrophages. Targeting the DnaK's crosstalk can be a potentially effective approach for treating the inflammatory disorder in the broad-spectrum drug-resistant BSI.

Direct visual observation of pedal motion-dependent flexibility of single covalent organic frameworks.

Flexible covalent organic frameworks (COFs) have been studied for applications containing sorption, selective separation, and catalysis. How to correlate the microscopic structure with flexibility in COFs is a great challenge. Herein, we visually track the flexible deformation behaviors of single COF-300 and COF-300-AR particles in response to solvent vapour guests with dark-field microscopy (DFM) in an in operando manner. COF-300-AR with freely-rotating C-N single bonds are synthesized by the reduction of imine-based COF-300 consisting of rigid C=N double bonds without changing topological structure and crystallinity. Unexpectedly, we observe that the flexible deformation of COF-300 is extremely higher than that of COF-300-AR despite it bears many C-N single bonds, clearly illustrating the apparent flexibility decrease of COF-300 after reduction. The high spatiotemporal resolution of DFM enables the finding of inter-particle variations of the flexibility among COF-300 crystals. Experimental characterizations by variable-temperature X-ray diffraction and infrared spectroscopy as well as theoretical calculations demonstrate that the flexible deformation of COF-300 is ascribed to the pedal motion around rigid C=N double bonds. These observations provide new insights into COF flexibility.

Complete 3D Relationships Extraction Modality Alignment Network for 3D Dense Captioning.

3D dense captioning aims to semantically describe each object detected in a 3D scene, which plays a significant role in 3D scene understanding. Previous works lack a complete definition of 3D spatial relationships and the directly integrate visual and language modalities, thus ignoring the discrepancies between the two modalities. To address these issues, we propose a novel complete 3D relationship extraction modality alignment network, which consists of three steps: 3D object detection, complete 3D relationships extraction, and modality alignment caption. To comprehensively capture the 3D spatial relationship features, we define a complete set of 3D spatial relationships, including the local spatial relationship between objects and the global spatial relationship between each object and the entire scene. To this end, we propose a complete 3D relationships extraction module based on message passing and self-attention to mine multi-scale spatial relationship features and inspect the transformation to obtain features in different views. In addition, we propose the modality alignment caption module to fuse multi-scale relationship features and generate descriptions to bridge the semantic gap from the visual space to the language space with the prior information in the word embedding, and help generate improved descriptions for the 3D scene. Extensive experiments demonstrate that the proposed model outperforms the state-of-the-art methods on the ScanRefer and Nr3D datasets.

Novel tumor therapy strategies targeting endoplasmic reticulum-mitochondria signal pathways.

Organelles form tight connections through membrane contact sites, thereby cooperating to regulate homeostasis and cell function. Among them, the contact between endoplasmic reticulum (ER), the main intracellular calcium storage organelles, and mitochondria has been recognized for decades, and its main roles in the ion and lipid transport, ROS signaling, membrane dynamic changes and cellular metabolism are basically determined. At present, many tumor chemotherapeutic drugs rely on ER-mitochondrial calcium signal to function, but the mechanism of targeting resident molecules at the mitochondria-associated endoplasmic reticulum membranes (MAM) to sensitize traditional chemotherapy and the new tumor therapeutic targets identified based on the signal pathways on the MAM have not been thoroughly discussed. In this review, we highlight the key roles of various signaling pathways at the ER-mitochondria contact site in tumorigenesis and focus on novel anticancer therapy strategies targeting potential targets at this contact site.

A pilot study on pyroptosis related genes in peripheral blood mononuclear cells of non-small cell lung cancer patients.

OBJECTIVE: To investigate the GSDMD, CASP1, CASP4 and CASP5 expression in peripheral blood mononuclear cells of non-small cell lung cancer patients and analyze their clinical significance. METHODS: 71 non-small cell lung cancer patients were selected as the study group and 50 healthy individuals as the control group. The GSDMD, CASP1, CASP4 and CASP5 expression in peripheral blood mononuclear cells of the two groups were detected by real-time fluorescence quantitative PCR. The GSDMD, CASP1, CASP4, CASP5 expression and their relationship with the clinical characteristics of the patients were analyzed. RESULTS: Compared with the control group, the GSDMD, CASP4 and CASP5 expression in PBMCs of lung cancer patients was significantly higher(P < 0.05). Lymph node metastasis had significant difference with the CASP4 and GSDMD expression (P < 0.05); tumor volume had significant difference with CASP1 and CASP5 expression (P < 0.05). The areas under predictive ROC curve of the GSDMD, CASP1, CASP4, and CASP5 mRNA expression were 0.629(P < 0.05), 0.574(p > 0.05), 0.701(P < 0.05) and 0.628(P < 0.05), the sensitivity values were 84.5%, 67.6% 43.7%, and 84.3%;the specificity values were 42%, 52%, 84% and 64%, respectively. CONCLUSION: GSDMD, CASP1, CASP4 and CASP5 gene expression are highly increased in PBMCs of non-small cell lung cancer patients and their expression are closely related to the clinical characteristics of patients. The early enhanced pyroptosis-related gene expression may be potential molecular markers for early diagnosis of non-small cell lung cancer.

IMPA2 blocks cervical cancer cell apoptosis and induces paclitaxel resistance through p53-mediated AIFM2 regulation.

Cervical cancer continues to be a concern, and the prognosis of locally advanced cervical cancer remains poor. IMPA2 was previously identified as a potential oncogene and regulator of tumor apoptosis. In this study, we aim to further elucidate the underlying mechanisms of IMPA2 gene in the regulation of cervical cancer apoptosis. First, we identify AIFM2 as an upregulated gene in IMPA2-silenced cervical cancer cells, and inhibition of AIFM2 reverses IMPA2 knockdown-induced apoptosis. Further study reveals that AIFM2 regulates cell apoptosis in a mitochondrial-dependent manner with a redistribution of mitochondrial membrane potential and intracellular Ca 2+ levels. However, the analysis of the STRING database and our experimental results show that AIFM2 has little effect on cervical cancer progression and survival. Further mechanistic study demonstrates that IMPA2 and AIFM2 silencing inhibits apoptosis by activating p53. Meanwhile, the knockdown of IMPA2 enhances the chemosensitivity of cervical cancer cells by strengthening paclitaxel-induced apoptosis. Based on the above results, the IMPA2/AIFM2/p53 pathway may be a new molecular mechanism for paclitaxel treatment of cervical cancer and an effective strategy to enhance the sensitivity of cervical cancer cells to paclitaxel. Our findings display a novel function of IMPA2 in regulating cell apoptosis and paclitaxel resistance mediated by a disturbance of AIFM2 and p53 expression, potentially making it a novel therapeutic target for cervical cancer treatment.

T cells: an emerging cast of roles in bipolar disorder.

Bipolar disorder (BD) is a distinctly heterogeneous and multifactorial disorder with a high individual and social burden. Immune pathway dysregulation is an important pathophysiological feature of BD. Recent studies have suggested a potential role for T lymphocytes in the pathogenesis of BD. Therefore, greater insight into T lymphocytes' functioning in patients with BD is essential. In this narrative review, we describe the presence of an imbalance in the ratio and altered function of T lymphocyte subsets in BD patients, mainly in T helper (Th) 1, Th2, Th17 cells and regulatory T cells, and alterations in hormones, intracellular signaling, and microbiomes may be potential causes. Abnormal T cell presence explains the elevated rates of comorbid inflammatory illnesses in the BD population. We also update the findings on T cell-targeting drugs as potentially immunomodulatory therapeutic agents for BD disease in addition to classical mood stabilizers (lithium, valproic acid). In conclusion, an imbalance in T lymphocyte subpopulation ratios and altered function may be involved in the development of BD, and maintaining T cell immune homeostasis may provide an overall therapeutic benefit.

Messenger RNA electroporated hepatitis B virus (HBV) antigen-specific T cell receptor (TCR) redirected T cell therapy is well-tolerated in patients with recurrent HBV-related hepatocellular carcinoma post-liver transplantation: results from a phase I trial.

BACKGROUND AND AIMS: Liver transplantation (LT) is the primary curative option for cirrhotic patients with early-stage hepatocellular carcinoma (HCC). However, tumor recurrence occurs in 15-20% of cases with unfavorable prognosis. We have developed a library of T cell receptors (TCRs) specific for different hepatitis B virus (HBV) antigens, restricted by different molecules of human leucocyte antigen (HLA)-class I, to redirect T cells against HBV antigens (Banu in Sci Rep 4:4166, 2014). We further demonstrated that these transiently functional T cells specific for HBV obtained through messenger RNA (mRNA) electroporation can eliminate HCC cells expressing HBV antigens in vitro and in vivo (Kah in J Clin Invest 127:3177-3188, 2017). A phase I clinical trial for patients with HCC recurrence post-liver transplant was conducted to assess the safety, tolerability, and anti-tumor efficacy of transiently functional HBV-TCR T cells. Here, we report the clinical findings with regard to the safety and anti-tumor efficacy of mRNA electroporated HBV-specific TCR-T cells. (ClinicalTrials.gov identifier: NCT02719782). PATIENTS AND METHODS: A total of six patients with HBV-positive recurrent HCC post-liver transplant and HLA-matched to TCR targeting hepatitis B surface antigen (HBsAg) or hepatitis B core antigen (HBcAg) (HLA-A*02:01/HBsAg, HLA-A*11:01/HBcAg, HLA-B*58:01/HBsAg or HLA-C*08:01/HBsAg) were enrolled in this study. The primary objective was to assess the safety of short-lived mRNA electroporated HBV-TCR T cells based on the incidence and severity of the adverse event (AE) graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.0. The secondary objective was to determine the effectiveness of HBV-TCR T cells as per RECIST 1.1 criteria. Patients were followed up for survival for 2 years post-end of treatment. RESULTS: The median age of the six patients was 35.5 years (range: 28-47). The median number of HBV-TCR T cell infusions administered was 6.5 (range: 4-12). The treatment-related AE included grade 1 pyrexia. This study reported no cytokine release syndrome nor neurotoxicity. One patient remained alive and five were deceased at the time of the data cutoff (30 April 2020). CONCLUSION: This study has demonstrated that multiple infusions of mRNA electroporated HBV-specific TCR T cells were well-tolerated in patients with HBV-positive recurrent HCC post-liver transplant.

Validation of reference genes for the normalization of the RT-qPCR in peripheral blood mononuclear cells of septic patients.

Objective: To screen and validate reference genes suitable for gene mRNA expression study in peripheral blood mononuclear cells (PBMCs) between septic patients and healthy controls (HC). Methods: Total RNA in PBMCs was extracted and RT-qPCR was used to determine the mRNA expression profiles of 9 candidate genes, including ACTB, B2M, GAPDH, GUSB, HPRT1, PGK1, RPL13A, SDHA and YWHAZ. The genes expression stabilities were assessed by both geNorm and NormFinder software. Results: YWHAZ was the most stable gene among the 9 candidate genes evaluated by both geNorm and NormFinder in mixed and sepsis groups. The most stable gene combination in mixed group analyzed by geNorm was the combination of GAPDH, PKG1 and YWHAZ, while that in sepsis group was the combination of ACTB, PKG1 and YWHAZ. Conclusion: Our first systematic analysis of the reference genes in PBMC of septic patients suggested YWHAZ was the best candidate. The combination of ACTB, PKG1 and YWHAZ could improve RT-qPCR accuracy in septic patients. Our results identified the most stable reference genes to standardize RT-qPCR of sepsis patients, which can serve as a useful tool for gene function exploration in the future.

Candida parapsilosis infection after double-lung transplantation in a patient with pulmonary fibrosis caused by COVID-19.

Pulmonary fibrosis is a complication in patients with coronavirus disease 2019 (COVID-19). Extensive pulmonary fibrosis is a severe threat to patients' life and lung transplantation is last resort to prolong the life of patients. We reported a case of critical type COVID-19 patient, though various treatment measures were used, including anti-virus, anti-infection, improving immunity, convalescent plasma, prone position ventilation, and airway cleaning by fiber-optic bronchoscope, although his COVID-19 nucleic acid test turned negative, the patient still developed irreversible extensive pulmonary fibrosis, and respiratory mechanics suggested that lung compliance could not be effectively recovered. After being assisted by ventilator and extracorporeal membrane oxygenation for 73 days, he finally underwent double-lung transplantation. On the 2nd day after the operation, the alveolar lavage fluid of transplanted lung was examined by cytomorphology, and the morphology of alveolar epithelial cells was intact and normal. On the 20th day post-transplantation, the chest radiograph showed a large dense shadow in the middle of the right lung. On the 21st day, the patient underwent fiber-optic bronchoscopy, yeast-like fungal spores were found by cytomorphological examination from a brush smear of the right bronchus, which was confirmed as Candida parapsilosis infection by fungal culture. He recovered well due to the careful treatment and nursing in our hospital. Until July 29, 96 days after transplantation, the patient was recovery and discharged from hospital.

Adverse effects of chronic ammonia stress on juvenile oriental river prawn (Macrobrachium nipponense) and alteration of glucose and ammonia metabolism.

Ammonia is one of the common stress factors in aquaculture. However, the effect of chronic ammonia exposure in juvenile oriental river prawn (Macrobrachium nipponense) is currently unexplored. This study explored the effects of chronic ammonia on juvenile healthy oriental river prawns. Fifty prawns (0.123 ± 0.003 g) were exposed to 0, 5, and 15 mg/L total ammonia nitrogen (TAN) in triplicates for 28 days. The effects of chronic ammonia challenge were evaluated on growth, antioxidant capacity, hepatopancreas and gill morphology, and glucose and ammonia metabolism. The results showed that, the chronic ammonia exposure reduced significantly survival rate and weight gain of prawns. The prawns exposed to 15 mg/L ammonia had induced oxidative stress. However, the prawn exposed to 15 mg/L ammonia had significantly lower aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and acid phosphatase activities in the serum. Furthermore, exposure of prawns to 15 mg/L ammonia increased the activities of hexokinase, pyruvate kinase, pyruvate and lactic acid content, and glutamine synthase activity. However, the prawns exposed to 15 mg/L ammonia, reduced succinic dehydrogenase, 6-phosphogluconic dehydrogenase, phosphoenolpyruvate carboxykinase, glutamate synthase, and glutamate dehydrogenase activities but increased ammonia content in serum. The exposure of ammonia deformed lumen, damaged basement membrane and decreased secretory cells in the hepatopancreas, disordered gill epithelial and pillar cells, and caused gill filament base vacuolation. Our study indicates that chronic ammonia stress impairs growth performance, tissue morphology, induces oxidative stress, and alters glucose and ammonia metabolism in juvenile oriental river prawns.

Role of lncRNA Has2os in Skeletal Muscle Differentiation and Regeneration.

Long non-coding RNAs (lncRNAs) regulate a series of physiological processes and play an important role in development, metabolism and disease. Our previous studies showed that lncRNAs involved in skeletal muscle differentiation. Here, we demonstrated that lncRNA Has2os is highly expressed in skeletal muscle and significantly elevated during skeletal cell differentiation. The knockdown of Has2os inhibited myocyte fusion and impeded the expression of the myogenic factors MyHC and Mef2C. Mechanically, Has2os regulates skeletal muscle differentiation by inhibiting the JNK/MAPK signaling pathway. Furthermore, we also revealed that Has2os is involved in the early stage of regeneration after muscle injury, and the JNK/MAPK signaling pathway is activated at both protein and mRNA levels during early repair. Our results demonstrate the new function of lncRNA Has2os, which plays crucial roles during skeletal muscle differentiation and muscle regeneration, providing a basis for the therapy of lncRNA-related muscle diseases.

Ultra-Light GO@KGM Aerogels for Oil-Water Separation Based on CVD Modification.

Nowadays, oil pollution of water caused by illegal discharges or accidental events occurs frequently, and the waste of resources and environmental pollution cannot be ignored, so effective oil-water separation methods are needed to cope with such incidents. To solve these problems, this paper investigated an aerogel made from a plant polysaccharide, konjac glucomannan (KGM), supplemented with graphene oxide (GO), to improve the mechanical properties. Finally, a hydrophobic layer was attached to the surface and interior of the aerogel via chemical vapor deposition to improve its selectivity toward oil. Through a series of characterization methods such as infrared, X-ray photoelectron spectroscopy, and X-ray diffraction, it was demonstrated that KGM and GO were successfully cross-linked, resulting in excellent mechanical properties and directional absorption properties on oil. This composite polysaccharide aerogel could absorb oil 48 times its own weight. In addition, due to its strong mechanical properties, the gel can be reused many times, and the maximum recovery rate can be maintained at 96% after 10 cycles. Furthermore, the absorption of oil from water was conducted in a continuous mode, demonstrating the diversity of application scenarios. Generally, the results observed in this work have shown that the KGM aerogels have great potential for applications in oil-water separation.

Cost-Effectiveness of Linaclotide Compared to Osmotic Laxatives in the Treatment of Irritable Bowel Syndrome with Constipation in China.

INTRODUCTION: Linaclotide, a selective agonist of guanylate cyclase C, was highly recommended for the treatment of irritable bowel syndrome with constipation (IBS-C). However, the cost-effectiveness of linaclotide in Chinese is not known, and this study aimed to assess the cost-effectiveness of linaclotide for patients with IBS-C. METHODS: An economic evaluation was conducted with a Markov model from a societal perspective. The Markov model was structured to simulate the discontinuation and continuation of medication in IBS-C patients in clinical practice, as well as the revisit and non-visit of non-responding patients. The cycle of the model was 4 weeks, and the time horizon was 1 year. The efficacy data in the model was from the risk ratios obtained by the meta-analysis and the calculation of the response rate of the three medications. The utility, discontinuation rate of the medication, and revisit rate data were from published literature, while the cost data were obtained from experts' opinions and published literature. A series of sensitivity analyses was performed on parameters potentially having impact on the model outputs. RESULTS: The QALYs (quality-adjusted life years) gained for 1-year treatment with linaclotide, polyethylene glycol, and lactulose were 0.821, 0.795, and 0.781, respectively. The corresponding total costs were CNY 7,721 (USD 1,120), CNY 8,797 (USD 1,276) and CNY 9,481 (USD 1,375). In both comparisons, linaclotide was dominant. Compared with polyethylene glycol and lactulose, the likelihood of linaclotide being cost-effective was 100% for both, using 1 times per capita GDP per QALY as willingness-to-pay threshold. CONCLUSIONS: IBS-C seriously affects the quality of life of patients with IBS-C, and linaclotide can improve symptoms and quality of life at less cost.

Whole genome analysis identifies intra-serotype recombinants and positive selection sites of dengue virus in mainland China from 2015 to 2020.

Immune pressure can select for escape mutants that can become epidemiologically relevant. Thus, surveillance of recombinants and positively selected mutants of the dengue virus (DENV) are vital for preventing and controlling the dengue fever outbreak. However, little is known about recombinants and positively selected mutants of circulating DENV strains in mainland China. In this study, those variants with recombination and adaptive evolutionary sites of circulating DENV strains were identified during 2015-2020. Phylogenetic analysis showed that the DENV-2 was the dominant epidemic serotype, and the dengue epidemic in China was closely related to the imported virus from Southeast Asian countries. Recombination analysis based on 291 complete genomes of naturally circulating DENV identified 10 new intra-serotype recombinant variants. Two or three recombination regions in a single dengue isolate were also observed. The breakpoints of recombinants were distributed in different regions of the genome. In particular, two recombinant strains (strain DENV-4/China/YN/15DGR394 (2015) and XLLM10666) with extremely large exchange fragments were detected. This large-scale gene fragment exchange (eight genomic regions) of strain DENV-4/China/YN/15DGR394 (2015) with substitutions at both the 5' and 3' ends of the genome, had never been described before. Moreover, selection pressure analyses revealed seven positive selection sites located in regions encoding the NS1, NS3 and NS5 proteins. Overall, this study is the first to report ten specific intra-serotype recombinants and seven positive selection sites of Chinese epidemic strains of DENV, which highlight their significance for DENV surveillance and effective control.

Conditional Knockout of Pdha1 in Mouse Hippocampus Impairs Cognitive Function: The Possible Involvement of Lactate.

Background and Purpose: Neurodegenerative diseases are associated with metabolic disturbances. Pyruvate dehydrogenase E1 component subunit alpha (PDHA1) is an essential component in the process of glucose metabolism, and its deficiency exists in various diseases such as Alzheimer's disease (AD), epilepsy, Leigh's syndrome, and diabetes-associated cognitive decline. However, the exact role of PDHA1 deficiency in neurodegenerative diseases remains to be elucidated. In this study, we explored the effect of PDHA1 deficiency on cognitive function and its molecular mechanism. Methods: A hippocampus-specific Pdha1 knockout (Pdha1 -/-) mouse model was established, and behavioral tests were used to evaluate the cognitive function of mice. Transmission electron microscopy (TEM) was performed to observe the morphological changes of the hippocampus. The lactate level in the hippocampus was measured. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting were used to explore the possible mechanism of the effect of PDHA1 on cognition. Results: Pdha1 knockout damaged the spatial memory of mice and led to the ultrastructural disorder of hippocampal neurons. Lactate accumulation and abnormal lactate transport occurred in Pdha1 -/- mice, and the cyclic AMP-protein kinase A-cAMP response element-binding protein (cAMP/PKA/CREB) pathway was inhibited. Conclusion: Lactate accumulation caused by PDHA1 deficiency in the hippocampus may impair cognitive function by inhibiting the cAMP/PKA/CREB pathway.