DSN signal amplification strategy based nanochannels biosensor for the detection of miRNAs.

MiRNA-21 is recognized as an important biological marker for the diagnosis, treatment, and prognosis of breast cancer. Here, we have created a nanochannel biosensor utilizing the duplex-specific nuclease (DSN) signal amplification strategy to achieve the detection of miRNAs. In this system, DNA as the capture probe was covalently immobilized on the surface of nanochannels, which hybridized with the target miRNA and forms RNA/DNA duplexes. DSN could cleave the probe DNA in RNA/DNA duplexes, recycling target miRNA, which may again hybridized with other DNA probes. After N cycles, most of the DNA probes had been cleaved, and the content of miRNA could be quantified by detecting changes in surface charge density. This biosensor can distinguish miR-21 from non-complementary miRNAs and one-base mismatched miRNAs, with reliable detection limits as low as 1 fM in PBS. In addition, we had successfully applied this method to analysis of total RNA samples in MCF-7 cells and HeLa cells, and the nanochannels had also shown excellent responsiveness and strong anti-interference ability. This new method is expected to contribute to miRNA detection in clinical diagnostics, providing a unique approach to detecting and distinguishing disease-associated molecules.

Caspase-mediated AURKA cleavage at Asp132 is essential for paclitaxel to elicit cell apoptosis.

Background: Aurora kinase A (AURKA) is a potent oncogene that is often aberrantly expressed during tumorigenesis, and is associated with chemo-resistance in various malignancies. However, the role of AURKA in chemo-resistance remains largely elusive. Methods: The cleavage of AURKA upon viral infection or apoptosis stimuli was assesed by immunoblotting assays in several cancer cells or caspase deficient cell line models. The effect of AURKA cleavage at Asp132 on mitosis was explored by live cell imaging and immunofluorescence staining experiments. The role of Asp132-cleavage of AURKA induced by the chemotherapy drug paclitaxel was investigated using TUNEL, immunohistochemistry assay in mouse tumor xenograft model and patient tissues. Results: The proteolytic cleavage of AURKA at Asp132 commonly occurs in several cancer cell types, regardless of viral infection or apoptosis stimuli. Mechanistically, caspase 3/7/8 cleave AURKA at Asp132, and the Asp132-cleaved forms of AURKA promote cell apoptosis by disrupting centrosome formation and bipolar spindle assembly in metaphase during mitosis. The AURKAD132A mutation blocks the expression of cleaved caspase 3 and EGR1, which leads to reduced therapeutic effects of paclitaxel on colony formation and malignant growth of tumor cells in vitro and in vivo using a murine xenograft model and cancer patients. Conclusions: This study reveals that caspase-mediated AURKAD132 proteolysis is essential for paclitaxel to elicit cell apoptosis and indicates that AURKAD132 is a potential key target for chemotherapy.

Platinum nanowires/MXene nanosheets/porous carbon ternary nanocomposites for in situ monitoring of dopamine released from neuronal cells.

Dopamine is an important neurotransmitter in the body and closely related to many neurodegenerative diseases. Therefore, the detection of dopamine is of great significance for the diagnosis and treatment of diseases, screening of drugs and unraveling of relevant pathogenic mechanisms. However, the low concentration of dopamine in the body and the complexity of the matrix make the accurate detection of dopamine challenging. Herein, an electrochemical sensor is constructed based on ternary nanocomposites consisting of one-dimensional Pt nanowires, two-dimensional MXene nanosheets, and three-dimensional porous carbon. The Pt nanowires exhibit excellent catalytic activity due to the abundant grain boundaries and highly undercoordinated atoms; MXene nanosheets not only facilitate the growth of Pt nanowires, but also enhance the electrical conductivity and hydrophilicity; and the porous carbon helps induce significant adsorption of dopamine on the electrode surface. In electrochemical tests, the ternary nanocomposite-based sensor achieves an ultra-sensitive detection of dopamine (S/N = 3) with a low limit of detection (LOD) of 28 nM, satisfactory selectivity and excellent stability. Furthermore, the sensor can be used for the detection of dopamine in serum and in situ monitoring of dopamine release from PC12 cells. Such a highly sensitive nanocomposite sensor can be exploited for in situ monitoring of important neurotransmitters at the cellular level, which is of great significance for related drug screening and mechanistic studies.

Identifying habitat modification by Chinese pangolin in subtropical forests of southern China.

The excavation of Chinese pangolin (Manis pentadactyla) is expected to alter habitat heterogeneity and thus affect the functioning and structure of forest ecosystems. In this study, the bioturbation of Chinese pangolin on forest soils in three regions (Heping, Tianjingshan, and Wuqinzhang) across Guangdong province was quantified. Overall, a mean of 2.66 m3·ha-1 and 83.1 m2·ha-1 of burrows and bare mounds, respectively, was excavated by Chinese pangolin; the disturbed soils had significantly lower water content and P, C, available N concentrations, but higher bulk density, pH, and microbial abundance than those undisturbed soils. The unevenness of habitat heterogeneity improvement was mainly ascribed to the stronger soil disturbance caused in resting burrows by pangolins. Patterns of altering habitat heterogeneity were site-specific, with high-intensity soil disturbance occurring most in shrubs, meadows, steep habitats at high elevations, and mountain tops in Heping, while in broad-leaved, coniferous and mixed coniferous and broad-leaved forests away from human settlements in Tianjingshan and upper mountains at high elevations far away from roads and human settlements in Wuqinzhang. Road networks are the main interference for the burrow distribution in Heping and Wuqinzhang and should be programmed.

Alterations in neural circuit dynamics between the limbic network and prefrontal/default mode network in patients with generalized anxiety disorder.

BACKGROUND: Widespread functional alterations have been implicated in patients with generalized anxiety disorder (GAD). However, most studies have primarily focused on static brain network features in patients with GAD. The current research focused on exploring the dynamics within functional brain networks among individuals diagnosed with GAD. METHODS: Seventy-five participants were divided into patients with GAD and healthy controls (HCs), and resting-state functional magnetic resonance imaging data were collected. The severity of symptoms was measured using the Hamilton Anxiety Scale and the Patient Health Questionnaire. Co-activation pattern (CAP) analysis, centered on the bed nucleus of the stria terminalis, was applied to explore network dynamics. The capability of these dynamic characteristics to distinguish between patients with GAD and HCs was evaluated using a support vector machine. RESULTS: Patients with GAD exhibited disruptions in the limbic-prefrontal and limbic-default-mode network circuits. Particularly noteworthy was the marked reduction in dynamic indicators such as occurrence, EntriesFromBaseline, ExitsToBaseline, in-degree, out-degree, and resilience. Moreover, these decreased dynamic features effectively distinguished the GAD group from the HC in this study. CONCLUSIONS: The current findings revealed the underlying brain networks associated with compromised emotion regulation in individuals with GAD. The dynamic reduction in connectivity between the limbic-default mode network and limbic-prefrontal networks could potentially act as a biomarker and therapeutic target for GAD in the future.

Impact of high-fat diet on ovarian epigenetics: Insights from altered intestinal butyric acid levels.

Objective: To investigate the effects of a high-fat diet (HFD) on the gut bacterium Roseburia intestinalis and butyric acid levels, and to assess their impact on ovarian function and epigenetic markers in mice. Methods: A total of 20 female ICR mice aged 4 weeks were randomly assigned to two groups and fed either a control diet (CD) or an HFD for 36 weeks. Post-intervention, ileal contents were analyzed for the quantification of butyric acid using ELISA, while feces were obtained for Roseburia intestinalis expression assessment via qPCR. Histological evaluations of intestinal and ovarian tissues included H&E and Alcian Blue-Periodic Acid Schiff (AB-PAS) staining, alongside immunohistochemical analysis for F4/80, and immunofluorescent detection of Occludin, ZO-1, 5 mC, and H3K36me3. Ovarian health was assessed through follicle counts and morphological evaluations. Statistical analyses were performed using GraphPad Prism 8.0, with P < 0.05 considered significant. Results: After 36 weeks, the HFD group showed significantly higher body weight compared to the CD group (P < 0.01). The HFD led to a decrease in Roseburia intestinalis and butyric acid levels, a reduction in intestinal goblet cells, and an increase in intestinal inflammation. Histological analyses revealed impaired ovarian follicular development and enhanced inflammation in the HFD mice, with immunofluorescent staining showing downregulation of the ovarian epigenetic markers 5 mC and H3K36me3. Conclusion: Our study demonstrates that long-term HFD negatively impacts ovarian function and epigenetic regulation. We found decreased levels of the gut bacterium Roseburia intestinalis and its metabolite, butyric acid, which contribute to these adverse effects. Additionally, the associated intestinal inflammation and compromised mucosal barrier may contribute to these adverse outcomes on female reproductive health.

Multimodal imaging evaluation of early neurological deterioration following acute ischemic stroke.

Background: Early neurologic deterioration occurs in up to one-third of patients with acute ischemic stroke (IS), often leading to poor functional outcomes. At present, few studies have applied amide proton transfer (APT) imaging to the evaluation of early neurological deterioration (END). This study analyzed the value of computed tomography perfusion (CTP) combined with multimodal magnetic resonance imaging (MRI) in patients with acute IS with END. Methods: This retrospective study included patients with acute IS who were admitted to the neurology inpatient department in a tertiary hospital from October 2021 to June 2023. Patients with acute IS underwent CTP within 24 hours of stroke onset and MRI [arterial spin labeling (ASL), susceptibility-weighted imaging (SWI), and APT] within 7 days. END was defined as an elevation of ≥2 points on the National Institute of Health Stroke Scale (NIHSS) within 7 days of stroke onset. Univariable and multivariable analyses were used to compare clinical and imaging biomarkers in patients with acute IS with and without END. The performance of potential biomarkers in distinguishing between the two groups was evaluated using receiver operating characteristic (ROC) curve analysis. Results: Among the 70 patients with acute IS, 20 (29%) had END. After conducting univariable analysis, variables were selected for entry into a binary logistic regression analysis based on our univariable analysis results, previous research findings, clinical experience, and methodological standards. The results indicated that relative cerebral blood volume (CBV) on CTP, relative cerebral blood flow (CBF) on ASL, and relative signal intensity on amide proton transfer-weighted (APTw) imaging were independent risk factors for END. The areas under the ROC curves for these risk factors were 0.710 [95% confidence interval (CI): 0.559-0.861, P=0.006], 0.839 (95% CI: 0.744-0.933, P<0.001), and 0.804 (95% CI: 0.676-0.932, P<0.001), respectively. The combined area under the curve (AUC), sensitivity, and specificity of the four indices (0.941, 100%, and 78%, respectively) were higher than those of the four indices alone. Conclusions: CTP combined with multi-modal MRI better evaluated hemodynamics, tissue metabolism, and other relevant patient information, providing an objective basis for the clinical assessment of patients with acute IS with END and facilitating the development of accurate and personalized treatment plans.

Cascade CRISPR/Cas12a and DSN for the electrochemical biosensing of miR-1246 in BC-derived exosomes.

MiR-1246 in breast cancer-derived exosomes was a promising biomarker for early diagnosis of breast cancer(BC). However, the low abundance, high homology and complex background interference make the accurate quantitative detection of miR-1246 facing great challenges. In this study, we developed an electrochemical biosensor based on the subtly combined of CRISPR/Cas12a, double-stranded specific nuclease(DSN) and magnetic nanoparticles(MNPs) for the detection of miR-1246 in BC-derived exosomes. Ascribed to the good synergistic effect of DSN, Cas12a and MNPs, the developed electrochemical biosensor exhibited excellent performance with the linear range from 500 aM to 5 pM, and the detection limit as low down to about 50 aM. The target-specific triggered enzyme-digest activity of DSN and Cas12a system, as well as the powerful separation ability of MNPs ensure the high specificity of developed electrochemical biosensor which can distinguish single base mismatches. In addition, the developed electrochemical biosensor has been successfully applied to detect miR-1246 in blood-derived exosomes and realize distinguishing the BC patients from the healthy individuals. It is expected that the well-designed biosensing platform will open up new avenues for clinical liquid biopsy and early screening of breast cancer, as well as provide deeper insights into clinical oncology treatment.

Realveolarization with inhalable mucus-penetrating lipid nanoparticles for the treatment of pulmonary fibrosis in mice.

The stemness loss-associated dysregeneration of impaired alveolar type 2 epithelial (AT2) cells abolishes the reversible therapy of idiopathic pulmonary fibrosis (IPF). We here report an inhalable mucus-penetrating lipid nanoparticle (LNP) for codelivering dual mRNAs, promoting realveolarization via restoring AT2 stemness for IPF treatment. Inhalable LNPs were first formulated with dipalmitoylphosphatidylcholine and our in-house-made ionizable lipids for high-efficiency pulmonary mucus penetration and codelivery of dual messenger RNAs (mRNAs), encoding cytochrome b5 reductase 3 and bone morphogenetic protein 4, respectively. After being inhaled in a bleomycin model, LNPs reverses the mitochondrial dysfunction through ameliorating nicotinamide adenine dinucleotide biosynthesis, which inhibits the accelerated senescence of AT2 cells. Concurrently, pathological epithelial remodeling and fibroblast activation induced by impaired AT2 cells are terminated, ultimately prompting alveolar regeneration. Our data demonstrated that the mRNA-LNP system exhibited high protein expression in lung epithelial cells, which markedly extricated the alveolar collapse and prolonged the survival of fibrosis mice, providing a clinically viable strategy against IPF.

The development of the QM/MM interface and its application for the on-the-fly QM/MM nonadiabatic dynamics in JADE package: Theory, implementation, and applications.

Understanding the nonadiabatic dynamics of complex systems is a challenging task in computational photochemistry. Herein, we present an efficient and user-friendly quantum mechanics/molecular mechanics (QM/MM) interface to run on-the-fly nonadiabatic dynamics. Currently, this interface consists of an independent set of codes designed for general-purpose use. Herein, we demonstrate the ability and feasibility of the QM/MM interface by integrating it with our long-term developed JADE package. Tailored to handle nonadiabatic processes in various complex systems, especially condensed phases and protein environments, we delve into the theories, implementations, and applications of on-the-fly QM/MM nonadiabatic dynamics. The QM/MM approach is established within the framework of the additive QM/MM scheme, employing electrostatic embedding, link-atom inclusion, and charge-redistribution schemes to treat the QM/MM boundary. Trajectory surface-hopping dynamics are facilitated using the fewest switches algorithm, encompassing classical and quantum treatments for nuclear and electronic motions, respectively. Finally, we report simulations of nonadiabatic dynamics for two typical systems: azomethane in water and the retinal chromophore PSB3 in a protein environment. Our results not only illustrate the power of the QM/MM program but also reveal the important roles of environmental factors in nonadiabatic processes.

Single-cell transcriptome atlas of testes from mice with high-fat diets.

Obesity is accompanied by multiple known health risks and increased morbidity, and obese men display reduced reproductive health. However, the impact of obesity on the testes at the molecular levels remain inadequately explored. This is partially attributed to the lack of monitoring tools for tracking alterations within cell clusters in testes associated with obesity. Here, we utilized single-cell RNA sequencing to analyze over 70,000 cells from testes of obese and lean mice, and to study changes related to obesity in non-spermatogenic cells and spermatogenesis. The Testicular Library encompasses all non-spermatogenic cells and spermatogenic cells spanning from spermatogonia to spermatozoa, which will significantly aid in characterizing alterations in cellular niches and the testicular microenvironment during high-fat diet (HFD)-induced obesity. This comprehensive dataset is indispensable for studying how HFD disrupts cell-cell communication networks within the testis and impacts alterations in the testicular microenvironment that regulate spermatogenesis. Being the inaugural dataset of single-cell RNA-seq in the testes of diet-induced obese (DIO) mice, this holds the potential to offer innovative insights and directions in the realm of single-cell transcriptomics concerning male reproductive injury associated with HFD.

[Real-time Detection Method for Motion Artifact of Photoplethysmography Signals Based on Decision Trees].

PPG (photoplethysmography) holds significant application value in wearable and intelligent health devices. However, during the acquisition process, PPG signals can generate motion artifacts due to inevitable coupling motion, which diminishes signal quality. In response to the challenge of real-time detection of motion artifacts in PPG signals, this study analyzed the generation and significant features of PPG signal interference. Seven features were extracted from the pulse interval data, and those exhibiting notable changes were filtered using the dual-sample Kolmogorov-Smirnov test. The real-time detection of motion artifacts in PPG signals was ultimately based on decision trees. In the experimental phase, PPG signal data from 20 college students were collected to formulate the experimental dataset. The experimental results demonstrate that the proposed method achieves an average accuracy of (94.07±1.14)%, outperforming commonly used motion artifact detection algorithms in terms of accuracy and real-time performance.

Multi-risk factors joint prediction model for risk prediction of retinopathy of prematurity.

Purpose: Retinopathy of prematurity (ROP) is a retinal vascular proliferative disease common in low birth weight and premature infants and is one of the main causes of blindness in children.In the context of predictive, preventive and personalized medicine (PPPM/3PM), early screening, identification and treatment of ROP will directly contribute to improve patients' long-term visual prognosis and reduce the risk of blindness. Thus, our objective is to establish an artificial intelligence (AI) algorithm combined with clinical demographics to create a risk model for ROP including treatment-requiring retinopathy of prematurity (TR-ROP) infants. Methods: A total of 22,569 infants who underwent routine ROP screening in Shenzhen Eye Hospital from March 2003 to September 2023 were collected, including 3335 infants with ROP and 1234 infants with TR-ROP among ROP infants. Two machine learning methods of logistic regression and decision tree and a deep learning method of multi-layer perceptron were trained by using the relevant combination of risk factors such as birth weight (BW), gestational age (GA), gender, whether multiple births (MB) and mode of delivery (MD) to achieve the risk prediction of ROP and TR-ROP. We used five evaluation metrics to evaluate the performance of the risk prediction model. The area under the receiver operating characteristic curve (AUC) and the area under the precision-recall curve (AUCPR) were the main measurement metrics. Results: In the risk prediction for ROP, the BW + GA demonstrated the optimal performance (mean ± SD, AUCPR: 0.4849 ± 0.0175, AUC: 0.8124 ± 0.0033). In the risk prediction of TR-ROP, reasonable performance can be achieved by using GA + BW + Gender + MD + MB (AUCPR: 0.2713 ± 0.0214, AUC: 0.8328 ± 0.0088). Conclusions: Combining risk factors with AI in screening programs for ROP could achieve risk prediction of ROP and TR-ROP, detect TR-ROP earlier and reduce the number of ROP examinations and unnecessary physiological stress in low-risk infants. Therefore, combining ROP-related biometric information with AI is a cost-effective strategy for predictive diagnostic, targeted prevention, and personalization of medical services in early screening and treatment of ROP.

Integrated analysis of microbiome and host transcriptome unveils correlations between lung microbiota and host immunity in bronchoalveolar lavage fluid of pneumocystis pneumonia patients.

OBJECTIVE: The lung microbiota of patients with pulmonary diseases is disrupted and impacts the immunity. The microbiological and immune landscape of the lungs in patients with pneumocystis pneumonia (PCP) remains poorly understood. METHODS: Multi-omics analysis and machine learning were performed on bronchoalveolar lavage fluid to explore interaction between the lung microbiota and host immunity in PCP. Then we constructed a diagnostic model using differential genes with LASSO regression and validated by qPCR. The immune infiltration analysis was performed to explore the landscape of lung immunity in patients with PCP. RESULTS: Patients with PCP showed a low alpha diversity of lung microbiota, accompanied by the elevated abundance of Firmicutes, and the differential expressed genes (DEGs) analysis displayed a downregulation of MAPK signaling. The MAPK10, TGFB1, and EFNA3 indicated a potential to predict PCP (AUC = 0.86). The lung immune landscape in PCP showed the lower levels of naïve CD4+ T cells and activated dendritic cells. The correlation analysis of the MAPK signaling pathway-related DEGs and the differential microorganisms at the level of phylum showed that the Firmicutes was negatively correlated with these DEGs. CONCLUSION: We profiled the characteristics of lung microbiota and immune landscape in PCP, which may contribute to elucidating the mechanism of PCP.

CsPbBrxCl3-x Solid Solutions: Understanding the Relationship between Lattice Expansion and Optical Properties.

All-inorganic halide perovskite semiconductors have received extensive attention due to their excellent photoelectronic conversion efficiency. Prior studies have reported on compounds CsPbBr3 and CsPbCl3. However, the transition phases between them have not been systematically studied. Here, a series of large-size single crystals of CsPbBrxCl3-x (x = 0-3) were successfully grown by the Bridgman method, which proves that the Br and Cl atoms can be miscible in any proportion in the solid solution system, and the change of lattice parameters conforms to Vegard's law. Also, the bandgap and light emission were studied. It is found that the band gap (2.90-2.29 eV) and photoluminescence characteristics (from blue light to green light) can be effectively tuned by adjusting the content of the Br atom. These results provide valuable guidance for the development and optimization of photoelectronic semiconductors that can meet different practical demands.

Status and influencing factors of nurses' burnout: A cross-sectional study during COVID-19 regular prevention and control in Jiangsu Province, China.

Background: Chinese nurses working with immense stress may have issues with burnout during COVID-19 regular prevention and control. There were a few studies investigating status of burnout and associated factors among Chinese nurses. However, the relationships remained unclear. Objectives: To investigate status and associated factors of nurses' burnout during COVID-19 regular prevention and control. Methods: 784 nurses completed questionnaires including demographics, Generalized Anxiety Disorder-7, Patient Health Questionnaire-9, Insomnia Severity Index, Impact of Event Scale-revised, Perceived Social Support Scale, Connor-Davidson Resilience Scale, General Self-efficacy Scale and Maslach Burnout Inventory. Results: 310 (39.5%), 393 (50.1%) and 576 (73.5%) of respondents were at high risk of emotional exhaustion (EE), depersonalization (DP) and reduced personal accomplishment (PA). The risk of EE, DP and reduced PA were moderate, high and high. Nurses with intermediate and senior professional rank and title and worked >40 h every week had lower scores in EE. Those worked in low-risk department reported lower scores in PA. Anxiety, post-traumatic stress disorder (PTSD), self-efficacy and social support were influencing factors of EE and DP, while social support and resilience were associated factors of PA. Conclusion: Chinese nurses' burnout during COVID-19 regular prevention and control was serious. Professional rank and title, working unit, weekly working hours, anxiety, PTSD, self-efficacy, social support and resilience were associated factors of burnout.

Degradation of TRIM32 is induced by RTA for Kaposi's sarcoma-associated herpesvirus lytic replication.

TRIM32 is often aberrantly expressed in many types of cancers. Kaposi's sarcoma-associated herpesvirus (KSHV) is linked with several human malignancies, including Kaposi's sarcoma and primary effusion lymphomas (PELs). Increasing evidence has demonstrated the crucial role of KSHV lytic replication in viral tumorigenesis. However, the role of TRIM32 in herpesvirus lytic replication remains unclear. Here, we reveal that the expression of TRIM32 is upregulated by KSHV in latency, and reactivation of KSHV lytic replication leads to the inhibition of TRIM32 in PEL cells. Strikingly, RTA, the master regulator of lytic replication, interacts with TRIM32 and dramatically promotes TRIM32 for degradation via the proteasome systems. Inhibition of TRIM32 induces cell apoptosis and in turn inhibits the proliferation and colony formation of KSHV-infected PEL cells and facilitates the reactivation of KSHV lytic replication and virion production. Thus, our data imply that the degradation of TRIM32 is vital for the lytic activation of KSHV and is a potential therapeutic target for KSHV-associated cancers. IMPORTANCE: TRIM32 is associated with many cancers and viral infections; however, the role of TRIM32 in viral oncogenesis remains largely unknown. In this study, we found that the expression of TRIM32 is elevated by Kaposi's sarcoma-associated herpesvirus (KSHV) in latency, and RTA (the master regulator of lytic replication) induces TRIM32 for proteasome degradation upon viral lytic reactivation. This finding provides a potential therapeutic target for KSHV-associated cancers.

Strain rate-dependent failure mechanics of the intervertebral disc under tension/compression and constitutive analysis.

BACKGROUND: The intervertebral disc exhibits not only strain rate dependence (viscoelasticity), but also significant asymmetry under tensile and compressive loads, which is of great significance for understanding the mechanism of lumbar disc injury under physiological loads. OBJECTIVE: In this study, the strain rate sensitive and tension-compression asymmetry of the intervertebral disc were analyzed by experiments and constitutive equation. METHOD: The Sheep intervertebral disc samples were divided into three groups, in order to test the strain rate sensitive mechanical behavior, and the internal displacement as well as pressure distribution. RESULTS: The tensile stiffness is one order of magnitude smaller than the compression stiffness, and the logarithm of the elastic modulus is approximately linear with the logarithm of the strain rate, showing obvious tension-compression asymmetry and rate-related characteristics. In addition, the sensitivity to the strain rate is the same under these two loading conditions. The stress-strain curves of unloading and loading usually do not coincide, and form a Mullins effect hysteresis loop. The radial displacement distribution is opposite between the anterior and posterior region, which is consistent with the stress distribution. By introducing the damage factor into ZWT constitutive equation, the rate-dependent viscoelastic and weakening behavior of the intervertebral disc can be well described.

Dysregulation of Gut Microbiota-Derived Neuromodulatory Amino Acid Metabolism in Human Immunodeficiency Virus-Associated Neurocognitive Disorder: An Integrative Metagenomic and Metabolomic Analysis.

OBJECTIVE: Although accumulating evidence implicating altered gut microbiota in human immunodeficiency virus (HIV) infection and neurodegenerative disorders; however, the association between dysbiosis of the gut microbiota and metabolites in the pathogenesis of HIV-associated neurocognitive disorder (HAND) remains unclear. METHODS: Fecal and plasma samples were obtained from 3 cohorts (HAND, HIV-non-HAND, and healthy controls), metagenomic analysis and metabolomic profiling were performed to investigate alterations in the gut microbial composition and circulating metabolites in HAND. RESULTS: The gut microbiota of people living with HIV (PLWH) had an increased relative abundance of Prevotella and a decreased relative abundance of Bacteroides. In contrast, Prevotella and Megamonas were substantially decreased, and Bacteroides and Phocaeicola were increased in HAND patients. Moreover, untargeted metabolomics identified several neurotransmitters and certain amino acids associated with neuromodulation, and the differential metabolic pathways of amino acids associated with neurocognition were depleted in HAND patients. Notably, most neuromodulatory metabolites are associated with an altered abundance of specific gut bacteria. INTERPRETATION: Our findings provide new insights into the intricate interplay between the gut and microbiome-brain axis in the pathogenesis of HAND, highlighting the potential for developing novel therapeutic strategies that specifically target the gut microbiota. ANN NEUROL 2024;96:306-320.

Stimulation of tumoricidal immunity via bacteriotherapy inhibits glioblastoma relapse.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor characterized by invasive behavior and a compromised immune response, presenting treatment challenges. Surgical debulking of GBM fails to address its highly infiltrative nature, leaving neoplastic satellites in an environment characterized by impaired immune surveillance, ultimately paving the way for tumor recurrence. Tracking and eradicating residual GBM cells by boosting antitumor immunity is critical for preventing postoperative relapse, but effective immunotherapeutic strategies remain elusive. Here, we report a cavity-injectable bacterium-hydrogel superstructure that targets GBM satellites around the cavity, triggers GBM pyroptosis, and initiates innate and adaptive immune responses, which prevent postoperative GBM relapse in male mice. The immunostimulatory Salmonella delivery vehicles (SDVs) engineered from attenuated Salmonella typhimurium (VNP20009) seek and attack GBM cells. Salmonella lysis-inducing nanocapsules (SLINs), designed to trigger autolysis, are tethered to the SDVs, eliciting antitumor immune response through the intracellular release of bacterial components. Furthermore, SDVs and SLINs administration via intracavitary injection of the ATP-responsive hydrogel can recruit phagocytes and promote antigen presentation, initiating an adaptive immune response. Therefore, our work offers a local bacteriotherapy for stimulating anti-GBM immunity, with potential applicability for patients facing malignancies at a high risk of recurrence.