Maf1 loss regulates spinogenesis and attenuates cognitive impairment in Alzheimer's disease.

Alzheimer's disease is neurodegenerative and characterized by progressive cognitive impairment. Synaptic dysfunction appears in the early stage of Alzheimer's disease and is significantly correlated with cognitive impairment. However, the specific regulatory mechanism remains unclear. Here, we found the transcription factor Maf1 to be upregulated in Alzheimer's disease and determined that conditional knockout of Maf1 in a transgenic mouse model of Alzheimer's disease restored learning and memory function; the downregulation of Maf1 reduced the intraneuronal calcium concentration and restored neuronal synaptic morphology. We also demonstrated that Maf1 regulated the expression of NMDAR1 by binding to the promoter region of Grin1, further regulating calcium homeostasis and synaptic remodelling in neurons. Our results clarify the important role and mechanism of the Maf1-NMDAR1 signalling pathway in stabilizing synaptic structure, neuronal function and behaviour during Alzheimer's disease pathogenesis. This therefore serves as a potential diagnostic and therapeutic target for the early stage of Alzheimer's disease.

CuO Nanozymes Catalyze Cysteine and Glutathione Depletion Induced Ferroptosis and Cuproptosis for Synergistic Tumor Therapy.

The latest research identifies that cysteine (Cys) is one of the key factors in tumor proliferation, metastasis, and recurrence. The direct depletion of intracellular Cys shows a profound antitumor effect. However, using nanozymes to efficiently deplete Cys for tumor therapy has not yet attracted widespread attention. Here, a (3-carboxypropyl) triphenylphosphonium bromide-derived hyaluronic acid-modified copper oxide nanorods (denoted as MitCuOHA) are designed with cysteine oxidase-like, glutathione oxidase-like and peroxidase-like activities to realize Cys depletion and further induce cellular ferroptosis and cuproptosis for synergistic tumor therapy. MitCuOHA nanozymes can efficiently catalyze the depletion of Cys and glutathione (GSH), accompanied by the generation of H2O2 and the subsequent conversion into highly active hydroxyl radicals, thereby successfully inducing ferroptosis in cancer cells. Meanwhile, copper ions released by MitCuOHA under tumor microenvironment stimulation directly bind to lipoylated proteins of the tricarboxylic acid cycle, leading to the abnormal aggregation of lipoylated proteins and subsequent loss of iron-sulfur cluster proteins, which ultimately triggers proteotoxic stress and cell cuproptosis. Both in vitro and in vivo results show the drastically enhanced anticancer efficacy of Cys oxidation catalyzed by the MitCuOHA nanozymes, demonstrating the high feasibility of such catalytic Cys depletion-induced synergistic ferroptosis and cuproptosis therapeutic concept.

Application of superstatistical analysis on fluctuant surface shear in particle-laden turbulence boundary layer.

We report on an application of superstatistics to particle-laden turbulent flow. Four flush-mounted hot-film wall shear sensors were used to record the fluctuations of the wall shear stress in sand-laden flow. By comparing the scaling exponent in sand-free with that in sand-laden flows, we found that the sand-laden flow is more intermittent. By applying the superstatistics analysis to the friction velocity, we found that the large time scale is smaller when the flow is sand-laden. The probability density of a fluctuating energy dissipation rate measured in sand-laden flow follows a log-normal distribution with higher variances than for sand-free flow. The variance of this dissipation rate is a power law of the corresponding time scale. The prediction based on the superstatistics model is consistent with our structure function exponents [Formula: see text] for sand-free flow. Nevertheless, it overestimates [Formula: see text] for sand-laden flow, especially at higher Reynolds numbers.

γδ T cells recognize a microbial encoded B cell antigen to initiate a rapid antigen-specific interleukin-17 response.

γδ T cells contribute uniquely to immune competence. Nevertheless, how they function remains an enigma. It is unclear what most γδ T cells recognize, what is required for them to mount an immune response, and how the γδ T cell response is integrated into host immune defense. Here, we report that a noted B cell antigen, the algae protein phycoerythrin (PE), is a murine and human γδ T cell antigen. Employing this specificity, we demonstrated that antigen recognition activated naive γδ T cells to make interleukin-17 and respond to cytokine signals that perpetuate the response. High frequencies of antigen-specific γδ T cells in naive animals and their ability to mount effector response without extensive clonal expansion allow γδ T cells to initiate a swift, substantial response. These results underscore the adaptability of lymphocyte antigen receptors and suggest an antigen-driven rapid response in protective immunity prior to the maturation of classical adaptive immunity.

Association of HMOX-1 with sporadic Alzheimer's disease in southern Han Chinese.

BACKGROUND AND PURPOSE: The aim of this study was to discover the associations between HMOX-1 and Alzheimer's disease (AD). METHODS: A total of 500 AD patients and 500 healthy controls were recruited in this study. Polymer chain reaction was used. RESULTS: There was a statistically significant difference between AD patients and controls in both the dominant and recessive models of HMOX-1 rs2071746 after adjustment for age, gender and education (dominant model: p = 0.047, odds ratio [OR] 1.34, 95% confidence interval [CI] 1.00-1.78, adjusted; recessive model: p = 0.049, OR 1.34, 95% CI 1.00-1.80, adjusted). There was also a trend for an association between the dominant model and late-onset AD after adjustment for age, gender and education (dominant model: p = 0.084, OR 1.37, 95% CI 0.96-1.95, adjusted). CONCLUSIONS: We found an association between the dominant and recessive models of HMOX1 rs2071746 and AD.

Exploring the liver fibrosis induced by deltamethrin exposure in quails and elucidating the protective mechanism of resveratrol.

Deltamethrin (DLM) is widely used in agriculture and the prevention of human insect-borne diseases. However, the molecular mechanism of DLM induced liver injury remains unclear to date. This study investigated the potential molecular mechanism that DLM induced liver fibrosis in quails. Japanese quails received resveratrol (500 mg/kg) daily with or without DLM (45 mg/kg) exposure for 12 weeks. Histopathology, transmission electron microscopy, biochemical indexes, TUNEL, quantitative real-time PCR, and western blot analysis were performed. DLM exposure induced hepatic steatosis, oxidative stress, inflammation, and apoptosis. Most importantly, the Nrf2/TGF-ß1/Smad3 signaling pathway played an important role on DLM-induced liver fibrosis in quails. Interestingly, the addition of resveratrol, an Nrf2 activator, alleviates oxidative stress and inflammation response by activating Nrf2, thereby inhibits the liver fibrosis induced by DLM in quails. Collectively, these findings demonstrate that chronic exposure to DLM induces oxidative stress via the Nrf2 expression inhibition and apoptosis, and then results in liver fibrosis in quails by the activation of NF-κB/TNF-α and TGF-ß1/Smad3 signaling pathway.

Association between ZNF184 and symptoms of Parkinson's disease in southern Chinese.

STUDY OBJECTIVES: The aim was to investigate the association between ZNF184 and symptoms of Parkinson's disease (PD) in southern Chinese. METHODS: A total of 241 PD patients were recruited in this study. All patients were evaluated by Sniffin' Sticks 16 (SS-16), Hamilton anxiety rating scale and Hamilton depression rating scale, 39-item Parkinson's disease Questionnaire (PDQ-39) and MDS-Unified PD Rating Scale (MDS-UPDRS). Symptoms were also recorded. RESULTS: There was association of rapid eye movement sleep behavior disorder (RBD) under additive, dominant and overdominant model (p 0.039, additive; p 0.028, dominant; p 0.044, overdominant). We also found the association of excessive daytime sleepiness under the dominant model, the association of urgent urination or urinary incontinence under the recessive model and the association of sensitive to hot under the overdominant model (excessive daytime sleepiness: p 0.032, dominant; p 0.038, dominant; urgent urination or urgent incontinence: p 0.027, recessive; sensitive to hot: p, 0.027, overdominant). CONCLUSIONS: ZNF184 rs9468199 was associated with the presence of RBD, excessive daytime sleepiness, urgent urination or urgent incontinence and sensitive to hot.

Association between fatigue and motor progression in Parkinson's disease in southern Chinese.

STUDY OBJECTIVES: The aim was to investigate whether fatigue could predict the development of motor symptoms of Parkinson's disease (PD) in a southern Chinese population. METHODS: In total, 246 PD patients were recruited. All patients were evaluated by Fatigue Severity Scale (FSS), Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale, and Unified PD Rating Scale provided by Movement Disorders Society (MDS-UPDRS). MDS-UPDRS was re-evaluated after 2 years. RESULTS: FSS scores were associated with total score and subparts of MDS-UPDRS (total: p 0.039, p 0.030, adjusted; part III: p 0.022, p 0.016, adjusted). CONCLUSIONS: The symptom of subjective fatigue could predict the progression of PD.

Planar Position Sensor Based on Mono Sensing Electrode and Hybrid-Frequency Excitation.

A new way of measuring planar position for micrometric and sub-micrometric applications is presented with a mono sensing electrode and hybrid-frequency excitation. The sensing theory and operation principle are described and summarized, and a printed circuit board (PCB) sensor prototype is built and tested. It is shown by the experimental results that a very simple structure and geometric relationship are achieved. Meanwhile, displacement sensitivity on an order of 1.50 mV per micron and measurement repeatability better than 0.002 mm are easily fulfilled for a square zone of 256 mm², making it a valuable alternative measurement device candidate for flexible and low-cost planar position detection.

Dl-3-n-butylphthalide improves stroke outcomes after focal ischemic stroke in mouse model by inhibiting the pyroptosis-regulated cell death and ameliorating neuroinflammation.

Recent studies have highlighted the involvement of pyroptosis-mediated cell death and neuroinflammation in ischemic stroke (IS) pathogenesis. DL-3-n-butylphthalide (NBP), a synthesized compound based on an extract from seeds of Apium graveolens, possesses a broad range of biological effects. However, the efficacy and the underlying mechanisms of NBP in IS remain contentious. Herein, we investigated the therapeutic effects of NBP and elucidated its potential mechanisms in neuronal cell pyroptosis and microglia inflammatory responses. Adult male mice underwent permanent distal middle cerebral artery occlusion (dMCAO), followed by daily oral gavage of NBP (80 mg/kg) for 1, 7, or 21 consecutive days. Gene Expression Omnibus (GEO) dataset of IS patients peripheral blood RNA sequencing was analyzed to identify differentially expressed pyroptosis-related genes (PRGs) during the ischemic process. Our results suggested that NBP treatment effectively alleviated brain ischemic damage, resulting in decreased neurological deficit scores, reduced infarct volume, and improved neurological and behavioral functions. RNA sequence data from human unveiled upregulated PRGs in IS. Subsequently, we observed that NBP downregulated pyroptosis-associated markers at days 7 and 21 post-modeling, at both the protein and mRNA levels. Additionally, NBP suppressed the co-localization of pyroptosis markers with neuronal cells to variable degrees and simultaneously mitigated the accumulation of activated microglia. Overall, our data provide novel evidence that NBP treatment significantly attenuates ischemic brain damage and promotes recovery of neurological function in the early and recovery phases after IS, probably by negatively regulating the pyroptosis cell death of neuronal cells and inhibiting toxic neuroinflammation in the central nervous system.

Altered local and systemic immune profiles underlie lymph node metastasis in breast cancer patients.

Cancer-mediated immune dysfunction contributes to tumor progression and correlates with patient outcome. Metastasis to tumor draining lymph nodes (TDLNs) is an important step in breast cancer progression and is used to predict patient outcome and survival. Although lymph nodes are important immune organs, the role of immune cells in TDLNs has not been thoroughly investigated. We hypothesized that the host immune response in node negative (NN) patients is more intact and thereby can resist tumor invasion compared to node positive (NP) patients. As such, lymph node metastasis requires breakdown of the host immune response in addition to escape of cancer cells from the tumor. To investigate the immunological differences between NN and NP breast cancer patients, we purified and profiled immune cells from the three major compartments where cancer and immune cells interact: tumor, TDLNs and peripheral blood. Significant down-regulation of genes associated with immune-related pathways and up-regulation of genes associated with tumor-promoting pathways was consistently observed in NP patients' TDLNs compared to NN patients. Importantly, these signatures were seen even in NP patients' tumor-free TDLNs, suggesting that such immune changes are not driven solely by local tumor invasion. Furthermore, similar patterns were also observed in NP patients' tumor and blood immune cells, suggesting that immunological differences between NN and NP patients are systemic. Together, these findings suggest that alterations in overall immune function may underlie risk for LN metastasis in breast cancer patients.

Loss of SV2A promotes human neural stem cell apoptosis via p53 signaling.

This study investigated the role of synaptic vesicle protein 2A (SV2A) in the regulation of human induced pluripotent stem cell-derived neural stem cells (NSCs). SV2A was highly expressed in NSCs. SV2A knockdown promotes apoptosis, which was associated with an upregulation of genes involved in p53 signaling as determined by transcriptome analysis. Treatment with the small molecule p53 inhibitor pifithrin-α reversed the promotion of NSC apoptosis induced by loss of SV2A. These results demonstrate that SV2A plays an important role in regulating NSC survival via the p53 signaling pathway.

Gut microbiota-associated taurine metabolism dysregulation in a mouse model of Parkinson's disease.

IMPORTANCE: PD is recognized as a multisystem disease concerning GI dysfunction and microbiota dysbiosis but still lacks ideal therapies. Recently, aberrant microbiota-derived metabolites are emerging as important participants in PD etiology. However, the alterations of gut microbiota community and serum untargeted metabolite profile have not been fully investigated in a PD mice model. Here, we discover sharply reduced levels of Lactobacillus and taurine in MPTP-treated mice. Moreover, Lactobacillus, Adlercreutzia, and taurine-related metabolites showed the most significant correlation with pathological and GI performance of PD mice. The abundances of microbial transporter and enzymes participating in the degeneration of taurine were disturbed in PD mice. Most importantly, taurine supplement ameliorates MPTP-induced motor deficits, DA neuron loss, and microglial activation. Our data highlight the impaired taurine-based microbiome-metabolism axis during the progression of PD and reveal a novel and previously unrecognized role of genera in modulating taurine metabolism.

Learning a simulation-based visual policy for real-world peg in unseen holes.

This paper proposes a learning-based visual peg-in-hole that enables training with several shapes in simulation and adapting to arbitrary unseen shapes in the real world with minimal sim-to-real cost. The core idea is to decouple the generalization of the sensory-motor policy from the design of a fast-adaptable perception module and a simulated generic policy module. The framework consists of a segmentation network (SN), a virtual sensor network (VSN), and a controller network (CN). Concretely, the VSN is trained to measure the pose of the unseen shape from a segmented image. After that, given the shape-agnostic pose measurement, the CN is trained to achieve a generic peg-in-hole. Finally, when applying to real unseen holes, we only have to fine-tune the SN required by the simulated VSN + CN. To further minimize the transfer cost, we propose to automatically collect and annotate the data for the SN after one-minute human teaching. Simulated and real-world results are presented under the configuration of eye-to/in-hand. An electric vehicle charging system with the proposed policy inside achieves a 10/10 success rate in 2-3 s, using only hundreds of auto-labeled samples for the SN transfer.

Curcumin-driven reprogramming of the gut microbiota and metabolome ameliorates motor deficits and neuroinflammation in a mouse model of Parkinson's disease.

Background: Parkinson's disease (PD) is a common neurodegenerative disorder, accompanied by motor deficits as well as gastrointestinal dysfunctions. Recent studies have proved that the disturbance of gut microbiota and metabolism contributes to the pathogenesis of PD; however, the mechanisms underlying these effects have yet to be elucidated. Curcumin (CUR) has been reported to provide neuroprotective effects on neurological disorders and modulate the gut flora in intestinal-related diseases. Therefore, it is of significant interest to investigate whether CUR could exert a protective effect on PD and whether the effect of CUR is dependent on the intestinal flora and subsequent changes in metabolites. Methods: In this study, we investigated the neuroprotective effects of CUR on a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). 16S rRNA sequencing was performed to explore the profile of the gut microbiota among controls, MPTP-treated mice and CUR-treated mice. Then, antibiotic treatment (ABX) and fecal microbiota transplantation (FMT) experiments were conducted to examine the role of intestinal microbes on the protective effects of CUR in PD mice. Furthermore, ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS)-based metabolomics analysis was used to identify the landscape of the CUR-driven serum metabolome. Finally, Pearson's analysis was conducted to investigate correlations between the gut flora-metabolite axis and CUR-driven neuroprotection in PD. Results: Our results showed that CUR intervention effectively improved motor deficits, glial cell activation, and the aggregation of α-synuclein (α-syn) in MPTP-treated mice. 16S rRNA sequencing showed elevated abundances of Muribaculaceae, Lactobacillaceae, Lachnospiraceae and Eggerthellaceae but depleted abundances of Aerococcaceae and Staphylococcaceae in CUR-treated mice when compared with MPTP mice. ABX and FMT experiments further confirmed that the gut microbiota was required for CUR-induced protection in PD mice. Serum metabolomics analysis showed that CUR notably upregulated the levels of tyrosine, methionine, sarcosine and creatine. Importantly, strong correlations were identified among crucial taxa (Aerococcaceae, Staphylococcaceae, Muribaculaceae, Lactobacillaceae, Lachnospiraceae and Eggerthellaceae), pivotal metabolites (tyrosine, methionine, sarcosine and creatine) and the motor function and pathological results of mice. CUR treatment led to a rapid increase in the brain levels of tyrosine and levodopa (dopa) these changes were related to the abundances of Lactobacillaceae and Aerococcaceae. Conclusions: CUR exerts a protective effect on the progression of PD by modulating the gut microbiota-metabolite axis. Lactobacillaceae and Aerococcaceae, along with key metabolites such as tyrosine and dopa play a dominant role in CUR-associated neuroprotection in PD mice. Our findings offer unique insights into the pathogenesis and potential treatment of PD.

High-Density Lipoprotein Cholesterol and the Risk of First Ischemic Stroke in a Chinese Hypertensive Population.

BACKGROUND AND PURPOSE: Elevated high-density lipoprotein cholesterol (HDL-C) levels have displayed protection against cardiovascular disease. However, the association between specific lipoprotein classes and first ischemic stroke (IS) has not been well defined, particularly in higher-risk hypertensive populations. Our study evaluated the associations of HDL-C with first IS in a Chinese hypertensive population. METHODS: The study population was obtained from a community-based cohort study of hypertension in Lianyungang and Rongcheng, China. A nested case-control design was used that included 2463 identified first IS cases and 2463 controls matched by age ± 1 year, sex, and region. RESULTS: After adjusting for potential confounders, HDL-C was inversely associated with first IS (adjusted odds ratio [aOR]: 0.91; 95% confidence interval [CI]: 0.85-0.98). HDL-C levels of at least 65.4 mg/dL displayed a significant protective effect for first IS (aOR: 0.82; 95% CI: 0.69-0.98). Conversely, adverse effects of first IS were observed for low-density lipoprotein cholesterol (LDL-C) levels ≥138.1 mg/dL (aOR: 1.20; 95% CI: 1.02-1.42) and triglyceride (TG) levels ≥140.8 mg/dL (aOR: 1.27; 95% CI: 1.09-1.49). The risk associations of LDL-C and TG with first IS were attenuated in the presence of high HDL-C (≥53.0 mg/dL); an increased risk of first IS was only found in the presence of low HDL-C (<53.0 mg/dL) when LDL-C (aOR: 1.66; 95% CI: 1.19-2.31) and TG (aOR: 1.47; 95% CI: 1.17-1.84) were combined with HDL-C for analysis. CONCLUSION: In this community-based Chinese hypertensive population, higher HDL-C was a significant protective factor of first IS. These data add to the evidence describing the relationship between lipids and IS and suggest that HDL-C maybe is a marker of IS risk in Chinses hypertensive population.

Increased GABAergic development in iPSC-derived neurons from patients with sporadic Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, and the underlying molecular mechanisms of this neurodegenerative disorder are still unclear. γ-Aminobutyric acid (GABA) neurons play an essential role in the excitatory/inhibitory (E/I) balance in the brain, and the GABAergic system may contribute to the pathogenesis of AD. We used human induced pluripotent stem cells (iPSCs) generated from sporadic AD (SAD) patients to analyze the phenotype and transcriptional profiles of SAD iPSC-derived neural cells. We observed reduced neurogenesis and increased astrogenesis in SAD neural differentiation. We discovered elevated levels of GABA, glutamate decarboxylase 67 (GAD67), and vesicular GABA transporter (vGAT) in SAD neurons that indicated increased GABAergic development. Gene expression profiling of SAD neural cultures showed upregulation of the GABAergic signaling pathway and downregulation of the neurogenesis pathway. We presumed that the GABAergic transmission system might be enhanced in SAD neurons, as an early pathological change of SAD, which provides a novel target and new direction for the development of more effective therapeutic strategies.

Derivation of induced pluripotent stem cells TUSMi006 from an 87-year old Chinese Han Alzheimer's disease patient carrying GRINB and SORL1 mutations.

A 87-year old Alzheimer's Disease(AD) male patient donated his Peripheral blood mononuclear cells (PBMC). The non-integrating episomal vector system was used to reprogram PBMCs with the human OKSM transcription factors. The pluripotency of transgene-free iPSCs was confirmed by immunocytochemistry for pluripotency markers and by the ability of the iPSCs to differentiate spontaneously into 3 germ layers in vitro. In addition, the iPSC line displayed a normal karyotype. Our model might offer a good platform to further study the pathological mechanisms, to identify early biomarkers, and also for drug testing studies in AD.

Establishment of TUSMi004-A, an induced pluripotent stem cell (iPSC) line from a 32-year old Chinese Han patient with Obsessive-Compulsive Disorder (OCD).

A 32-year old Obsessive-Compulsive Disorder (OCD) male patient donated his Peripheral blood mononuclear cells (PBMC). The non-integrating episomal vector system used to reprogram PBMCs with the human OKSM transcription factors. The pluripotency of transgene-free iPSCs was confirmed by immunocytochemistry for pluripotency markers and by the ability of the iPSCs to differentiate spontaneously into 3 germ layers in vitro. In addition, the iPSC line displayed a normal karyotype. Our model might offer a good platform to further study the pathological mechanisms, to identify early biomarkers, and also for drug testing studies in OCD. Resource Table.

Establishment of TUSMi005-A, an induced pluripotent stem cell (iPSC) line from a 32-year old Chinese Han patient with Bipolar Disorder (BD).

A 32-year old Bipolar Disorder (BD) male patient donated his Peripheral blood mononuclear cells (PBMC). The non-integrating episomal vector system used to reprogram PBMCs with the human OKSM transcription factors. The pluripotency of transgene-free iPSCs was confirmed by immunocytochemistry for pluripotency markers and by the ability of the iPSCs to differentiate spontaneously into 3 germ layers in vitro. In addition, the iPSC line displayed a normal karyotype. Our model might offer a good platform to further study the pathological mechanisms, to identify early biomarkers, and also for drug testing studies in BD. Resource table.