Cell-specific Nav1.6 knockdown reduced astrocyte-derived Aß by reverse Na+-Ca2+ transporter-mediated autophagy in alzheimer-like mice.

INTRODUCTION: Nav1.6 is closely related to the pathology of Alzheimer's Disease (AD), and astrocytes have recently been identified as a significant source of ß-amyloid (Aß). However, little is known about the connection between Nav1.6 and astrocyte-derived Aß. OBJECTIVE: This study explored the crucial role of Nav1.6 in mediated astrocyte-derived Aß in AD and knockdown astrocytic Nav1.6 alleviates AD progression by promoting autophagy and lysosome-APP fusion. METHODS: A mouse model for astrocytic Nav1.6 knockdown was constructed to study the effects of astrocytic Nav1.6 on amyloidosis. The role of astrocytic Nav1.6 on autophagy and lysosome-APP(amyloid precursor protein) fusion was used by transmission electron microscope, immunostaining, western blot and patch clamp. Glial cell activation was detected using immunostaining. Neuroplasticity and neural network were assessed using patch-clamp, Golgi stain and EEG recording. Behavioral experiments were performed to evaluate cognitive defects. RESULTS: Astrocytic Nav1.6 knockdown reduces amyloidosis, alleviates glial cell activation and morphological complexity, improves neuroplasticity and abnormal neural networks, as well as promotes learning and memory abilities in APP/PS1 mice. Astrocytic Nav1.6 knockdown reduces itself-derived Aß by promoting lysosome- APP fusion, which is related to attenuating reverse Na+-Ca2+ exchange current thus reducing intracellular Ca2+ to facilitate autophagic through AKT/mTOR/ULK pathway. CONCLUSION: Our findings unveil the crucial role of astrocyte-specific Nav1.6 in reducing astrocyte-derived Aß, highlighting its potential as a cell-specific target for modulating AD progression.

Protocol to detect telomerase activity in adult mouse hippocampal neural progenitor cells using the telomeric repeat amplification protocol assay.

Changes in telomerase activity and telomere length contribute to aging-related decline. Investigating telomerase in aging models provides insights into related pathologies. Here, we present a protocol to detect telomerase activity in adult mouse hippocampal neural progenitor cells using the telomeric repeat amplification protocol assay. We describe steps for isolating and expanding aged mouse hippocampal neural progenitor cells (NPCs) and assessing telomerase using a non-radioactive technique. The protocol emphasizes the significance of understanding telomerase activity in NPCs for neurogenesis and age-related diseases.

Stepwise targeted strategies for improving neurological function by inhibiting oxidative stress levels and inflammation following ischemic stroke.

Ischemia-reperfusion injury is caused by excessive production of reactive oxygen species (ROS) and inflammation accompanied by ischemic injury symptoms and blood-brain barrier (BBB) dysfunction. This causes neuronal damage, for which no effective treatments or drugs exist. Herein, we provided a stepwise targeted drug delivery strategy and successfully prepared multifunctional ORD@SHp@ANG nanoparticles (NPs) that consist of a stroke homing peptide (DSPE-PEG2000-SHp), BBB-targeting peptide (DSPE-PEG2000-ANG), and ROS-responsive Danshensu (salvianic acid A) chain self-assembly. ORD@SHp@ANG NPs effectively crossed the BBB by ANG peptide and selectively targeted the ischemic brain sites using stroke-homing peptide. The results showed that ORD@SHp@ANG NPs can effective at scavenging ROS, and protect SH-SY5Y cells from oxidative damage in vitro. Furthermore, ORD@SHp@ANG NPs showed excellent biocompatibility. These NPs recognized brain endothelial cells and crossed the BBB, regulated the transformation of microglia into the anti-inflammatory phenotype, and inhibited the production of inflammatory factors in a rat ischemia-reperfusion model, thereby reducing cerebral infarction, neuronal apoptosis and preserving BBB integrity. Sequencing revealed that ORD@SHp@ANG NPs promote cell proliferation, activate immune responses, suppress inflammatory responses, and ameliorate ischemic stroke. In conclusion, this study reports a simple and promising drug delivery strategy for managing ischemic stroke.

JNK3 inhibitors as promising pharmaceuticals with neuroprotective properties.

The intensive study and investigation of neuroprotective therapy for central nervous system (CNS) diseases is ongoing. Due to shared mechanisms of neurodegeneration, a neuroprotective approach might offer benefits across multiple neurological disorders, despite variations in symptoms or injuries. C-Jun N-terminal Kinase 3 (JNK3) is found primarily in the CNS and is involved in physiological processes such as brain development, synapse formation, and memory formation. The potential of JNK3 as a target for pharmacological development holds promise for advancing neuroprotective therapies. Developing small molecule JNK3 inhibitors into drugs with neuroprotective qualities could facilitate neuronal restoration and self-repair. This review focuses on elucidating key neuroprotective mechanisms, exploring the interplay between neurodegenerative diseases and neuroprotection, and discussing advancements in JNK3 inhibitor drug development.

Natural products for combating multidrug resistance in cancer.

Cancer cells frequently develop resistance to chemotherapeutic therapies and targeted drugs, which has been a significant challenge in cancer management. With the growing advances in technologies in isolation and identification of natural products, the potential of natural products in combating cancer multidrug resistance has received substantial attention. Importantly, natural products can impact multiple targets, which can be valuable in overcoming drug resistance from different perspectives. In the current review, we will describe the well-established mechanisms underlying multidrug resistance, and introduce natural products that could target these multidrug resistant mechanisms. Specifically, we will discuss natural compounds such as curcumin, resveratrol, baicalein, chrysin and more, and their potential roles in combating multidrug resistance. This review article aims to provide a systematic summary of recent advances of natural products in combating cancer drug resistance, and will provide rationales for novel drug discovery.

Prediction value of pericoronary fat attenuation index for coronary in-stent restenosis.

OBJECTIVES: As a novel imaging marker, pericoronary fat attenuation index (FAI) reflects the local coronary inflammation which is one of the major mechanisms for in-stent restenosis (ISR). We aimed to validate the ability of pericoronary FAI to predict ISR in patients undergoing percutaneous coronary intervention (PCI). MATERIALS AND METHODS: Patients who underwent coronary CT angiography (CCTA) before PCI within 1 week between January 2017 and December 2019 at our hospital and had follow-up invasive coronary angiography (ICA) or CCTA were enrolled. Pericoronary FAI was measured at the site where stents would be placed. ISR was defined as ≥ 50% diameter stenosis at follow-up ICA or CCTA in the in-stent area. Multivariable analysis using mixed effects logistic regression models was performed to test the association between pericoronary FAI and ISR at lesion level. RESULTS: A total of 126 patients with 180 target lesions were included in the study. During 22.5 months of mean interval time from index PCI to follow-up ICA or CCTA, ISR occurred in 40 (22.2%, 40/180) stents. Pericoronary FAI was associated with a higher risk of ISR (adjusted OR = 1.12, p = 0.028). The optimum cutoff was - 69.6 HU. Integrating the dichotomous pericoronary FAI into current state of the art prediction model for ISR improved the prediction ability of the model significantly (△area under the curve = + 0.064; p = 0.001). CONCLUSION: Pericoronary FAI around lesions with subsequent stent placement is independently associated with ISR and could improve the ability of current prediction model for ISR. CLINICAL RELEVANCE STATEMENT: Pericoronary fat attenuation index can be used to identify the lesions with high risk for in-stent restenosis. These lesions may benefit from extra anti-inflammation treatment to avoid in-stent restenosis. KEY POINTS: • Pericoronary fat attenuation index reflects the local coronary inflammation. • Pericoronary fat attenuation index around lesions with subsequent stents placement can predict in-stent restenosis. • Pericoronary fat attenuation index can be used as a marker for future in-stent restenosis.

Determinants of device success after transcatheter aortic valve replacement in patients with type-0 bicuspid aortic stenosis.

Background: Clinical evidence of transcatheter aortic valve replacement in patients with type-0 bicuspid aortic valve was relatively scarce. Aims: Our goal was to explore determinants of device success after transcatheter aortic valve replacement in patients with type-0 bicuspid aortic valve morphology. Methods: In this retrospective multicenter analysis, we included 59 patients with symptomatic severe aortic stenosis with type-0 bicuspid aortic valve morphology who underwent transcatheter aortic valve replacement. Type-0 bicuspid aortic valve was identified with multidetector computed tomography scans. The technical success rate was 89.8%, and the device success rate was 81.4%. Patients were divided into a device success group and a device failure group according to Valve Academic Research Consortium- 3 criteria. Results: When we compared the two groups, we found that the ellipticity index of the aortic root and the presence of bulky calcifications at the commissure were statistically different (ellipticity index 35.7 ± 1.7 vs. 29.7 ± 1.1, p = 0.018; bulky calcification at the commissure, 54.5% vs. 4.5%, p < 0.001). Further multivariate logistic analysis showed that bulky calcification at the commissure had a negative correlation with device success (odds ratio 0.030, 95% confidence interval 0.003-0.285, p = 0.002). Yet there was no statistical correlation between the ellipticity index and device success (odds ratio 0.818, 95% confidence interval 0.667-1.003, p = 0.053). Conclusions: The presence of bulky calcifications at the commissure is negatively correlated with device success after transcatheter aortic valve replacement in patients with type-0 bicuspid aortic valve.

Recent Advances in Anti-Atherosclerosis and Potential Therapeutic Targets for Nanomaterial-Derived Drug Formulations.

Atherosclerosis, the leading cause of death worldwide, is responsible for ≈17.6 million deaths globally each year. Most therapeutic drugs for atherosclerosis have low delivery efficiencies and significant side effects, and this has hampered the development of effective treatment strategies. Diversified nanomaterials can improve drug properties and are considered to be key for the development of improved treatment strategies for atherosclerosis. The pathological mechanisms underlying atherosclerosis is summarized, rationally designed nanoparticle-mediated therapeutic strategies, and potential future therapeutic targets for nanodelivery. The content of this study reveals the potential and challenges of nanoparticle use for the treatment of atherosclerosis and highlights new effective design ideas.

An intestinal sphingolipid confers intergenerational neuroprotection.

In animals, maternal diet and environment can influence the health of offspring. Whether and how maternal dietary choice impacts the nervous system across multiple generations is not well understood. Here we show that feeding Caenorhabditis elegans with ursolic acid, a natural plant product, improves axon transport and reduces adult-onset axon fragility intergenerationally. Ursolic acid provides neuroprotection by enhancing maternal provisioning of sphingosine-1-phosphate, a bioactive sphingolipid. Intestine-to-oocyte sphingosine-1-phosphate transfer is required for intergenerational neuroprotection and is dependent on the RME-2 lipoprotein yolk receptor. Sphingosine-1-phosphate acts intergenerationally by upregulating the transcription of the acid ceramidase-1 (asah-1) gene in the intestine. Spatial regulation of sphingolipid metabolism is critical, as inappropriate asah-1 expression in neurons causes developmental axon outgrowth defects. Our results show that sphingolipid homeostasis impacts the development and intergenerational health of the nervous system. The ability of specific lipid metabolites to act as messengers between generations may have broad implications for dietary choice during reproduction.

Residual Risk in Non-ST-Segment Elevation Acute Coronary Syndrome: Quantitative Plaque Analysis at Coronary CT Angiography.

Background Lipid-rich plaques detected with intravascular imaging are associated with adverse cardiovascular events in patients with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS). But evidence about the prognostic implication of coronary CT angiography (CCTA) in NSTE ACS is limited. Purpose To assess whether quantitative variables at CCTA that reflect lipid content in nonrevascularized plaques in individuals with NSTE ACS might be predictors of subsequent nonrevascularized plaque-related major adverse cardiovascular events (MACEs). Materials and Methods In this multicenter prospective cohort study, from November 2017 to January 2019, individuals diagnosed with NSTE ACS (excluding those at very high risk) were enrolled and underwent CCTA before invasive coronary angiography (ICA) within 1 day. Lipid core was defined as areas with attenuation less than 30 HU in plaques. MACEs were defined as cardiac death, myocardial infarction, hospitalization for unstable angina, and revascularization. Participants were followed up at 6 months, 12 months, and annually thereafter for at least 3 years (ending by July 2022). Multivariable analysis using Cox proportional hazards regression models was performed to determine the association between lipid core burden, lipid core volume, and future nonrevascularized plaque-related MACEs at both the participant and plaque levels. Results A total of 342 participants (mean age, 57.9 years ± 11.1 [SD]; 263 male) were included for analysis with a median follow-up period of 4.0 years (IQR, 3.6-4.4 years). The 4-year nonrevascularized plaque-related MACE rate was 23.9% (95% CI: 19.1, 28.5). Lipid core burden (hazard ratio [HR], 12.6; 95% CI: 4.6, 34.3) was an independent predictor at the participant level, with an optimum threshold of 2.8%. Lipid core burden (HR, 12.1; 95% CI: 6.6, 22.3) and volume (HR, 11.0; 95% CI: 6.5, 18.4) were independent predictors at the plaque level, with an optimum threshold of 7.2% and 10.1 mm3, respectively. Conclusion In NSTE ACS, quantitative analysis of plaque lipid content at CCTA independently predicted participants and plaques at higher risk for future nonrevascularized plaque-related MACEs. Chinese Clinical Trial Registry no. ChiCTR1800018661 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Tavakoli and Duman in this issue.

Recent advances in biomimetic nanodelivery systems: New brain-targeting strategies.

In recent years, brain diseases have seriously threatened human health due to their high morbidity and mortality. Achieving efficient drug delivery to provide satisfactory therapeutic outcomes is currently the greatest challenge in treating brain diseases. The main challenges are the structural peculiarities of the brain and the inability to transport drugs across the blood-brain barrier. Biomimetic nanodelivery systems (BNDSs) applied to the brain have been extensively developed in the preclinical phase to surmount these challenges. Considering the inherent properties of BNDSs, the substantially enhanced ability of BNDS to carry therapeutic agents and their higher selectivity toward lesions offer new opportunities for developing safe and effective therapies. This review summarizes brain-targeting nanotherapies, particularly advanced therapies with biomimetic nano-assistance. Prospects for developing BNDSs and the challenges of their clinical translation are discussed. Understanding and implementing biomimetic nanotherapies may facilitate the development of new targeted strategies for brain disorders.

Contactin-6-deficient male mice exhibit the abnormal function of the accessory olfactory system and impaired reproductive behavior.

INTRODUCTION: Contactin-6 (CNTN6), also known as NB-3, is a neural recognition molecule and a member of the contactin subgroup of the immunoglobulin superfamily. Gene encoding CNTN6 is expressed in many regions of the neural system, including the accessory olfactory bulb (AOB) in mice. We aim to determine the effect of CNTN6 deficiency on the function of the accessory olfactory system (AOS). METHODS: We examined the effect of CNTN6 deficiency on the reproductive behavior of male mice through behavioral experiments such as urine sniffing and mate preference tests. Staining and electron microscopy were used to observe the gross structure and the circuitry activity of the AOS. RESULTS: Cntn6 is highly expressed in the vomeronasal organ (VNO) and the AOB, and sparsely expressed in the medial amygdala (MeA) and the medial preoptic area (MPOA), which receive direct and/or indirect projections from the AOB. Behavioral tests to examine reproductive function in mice, which is mostly controlled by the AOS, revealed that Cntn6-/- adult male mice showed less interest and reduced mating attempts toward estrous female mice in comparison with their Cntn6+/+ littermates. Although Cntn6-/- adult male mice displayed no obvious changes in the gross structure of the VNO or AOB, we observed the increased activation of granule cells in the AOB and the lower activation of neurons in the MeA and the MPOA as compared with Cntn6+/+ adult male mice. Moreover, there were an increased number of synapses between mitral cells and granule cells in the AOB of Cntn6-/- adult male mice as compared with wild-type controls. CONCLUSION: These results indicate that CNTN6 deficiency affects the reproductive behavior of male mice, suggesting that CNTN6 participated in normal function of the AOS and its ablation was involved in synapse formation between mitral and granule cells in the AOB, rather than affecting the gross structure of the AOS.

Effectiveness and safety of transcatheter aortic valve replacement in elderly people with severe aortic stenosis with different types of heart failure.

BACKGROUND: Impaired left ventricular function is an independent predictor of adverse clinical outcomes in patients with aortic stenosis. The aim of this study is to evaluate the short-term changes of echocardiographic parameters, New York Heart Association (NYHA) class and B-type natriuretic peptide (BNP) level and adverse events amongst patients with heart failure (HF) after transcatheter aortic valve replacement (TAVR) procedure. METHODS: This was a retrospective cohort study conducted at affiliated Yantai Yuhuangding Hospital of Qingdao University between September 2017 and September 2022. TAVR cases were stratified into three groups [heart failure with reduced ejection fraction (HFrEF), heart failure with mildly reduced ejection fraction (HFmrEF), heart failure with preserved ejection fraction (HFpEF)] by left ventricular ejection fraction (LVEF). Baseline characteristics, changes in echocardiographic parameters (1 week and 1 month), BNP (1 month), and NYHA class (6 months) post-TAVR were compared across the three groups. Meanwhile, we observed the adverse events of the patients after TAVR. RESULTS: A total of 96 patients were included, of whom 15 (15.6%) had HFrEF, 15 (15.6%) had HFmrEF, and 66 (68.8%) had HFpEF. Compared to the HFpEF subgroup, patients in the HFrEF subgroup were younger (p < 0.05), and with a higher BNP (p < 0.05). The left ventricular end-diastolic dimension (LVEDD) in HFrEF group decreased significantly after TAVR. HFmrEF and HFrEF patients showed significant improvements in LVEF after TAVR. The pulmonary artery systolic pressure (PASP), aortic valve peak gradient (AVPG) and aortic valve peak gradient (Vmax) decreased significantly 1 month after TAVR in all three groups compared to the baseline (all p < 0.05). BNP significantly reduced in HFrEF group compared to HFpEF patients after TAVR (p < 0.05). The majority of patients experienced an improvement at least one NYHA class in all three groups 6 months post-TAVR. There is no significant increase in the risk of adverse events in the HFrEF group. CONCLUSIONS: Patients who underwent TAVR achieved significant improvements in BNP, NYHA class, LVEDD, LVEF, and PASP across the three HF classes, with a more rapid and pronounced improvement in the HFrEF and HFmrEF groups. Complication rates were low in the different HF groups. There is no significant increase in the risk of periprocedural complications in the HFrEF and HFmrEF groups.

LDL-C: An Important Independent Risk Factor for New-Onset Heart Block in Patients with Severe Aortic Stenosis and Heart Failure after TAVR.

Background: Transcatheter aortic valve replacement (TAVR) is an effective alternative treatment for patients with aortic stenosis (AS) who have intermediate to high surgical risk or who are inoperable. However, the incidence of conduction abnormalities is high after TAVR, which can reduce the effectiveness of the surgery. Our research objective is to explore the risk factors of new-onset conduction abnormalities after TAVR, providing reference value for clinical doctors to better prevent and treat conduction abnormalities. Methods: Patients who underwent TAVR were divided into those who developed heart block and those who did not. Baseline clinical characteristics, cardiac structural parameters, procedural characteristics, electrocardiogram (ECG) changes before and after TAVR ( △ = postoperative minus preoperative), and surgical complications were compared. Logistic regression was applied to identify significant risk factors for new-onset heart block. Results: We studied 93 patients, of whom 34.4% developed heart blocks. Univariate logistic regression showed that prior history of malignancy, atrial fibrillation, preoperative high-level total cholesterol and low-density lipoprotein cholesterol (LDL-C), △ HR, △ QRS interval, △ QT interval, and △ QTc interval were risk factors of new-onset heart block after TAVR. Multivariate analysis showed that preoperative high-level LDL-C and △ QRS interval remained significant independent risk factors after adjusting for potential confounds. Conclusions: Heart block is the most common complication of TAVR, and its significant independent risk factors include high-level LDL-C and △ QRS interval.

p38 MAPK Endogenous Inhibition Improves Neurological Deficits in Global Cerebral Ischemia/Reperfusion Mice.

Cerebral ischemia/reperfusion (I/R) injury is a complex pathophysiological process that can lead to neurological function damage and the formation of cerebral infarction. The p38 MAPK pathway has attracted considerable attention in cerebral I/R injury (IRI), but little research has been carried out on its direct role in vivo. In this study, to observe the effects of p38 MAPK endogenous inhibition on cerebral IRI, p38 heterozygous knockdown (p38KI/+) mice were used. We hypothesized that p38 signaling might be involved in I/R injury and neurological damage reduction and that neurological behavioral deficits improve when p38 MAPK is inhibited. First, we examined the neurological damage and neurological behavioral deficit effects of I/R injury in WT mice. Cerebral I/R injury was induced by the bilateral common carotid artery occlusion (BCCAO) method. The cerebral infarction area and volume were assessed and analyzed by 2,3,5-triphenyltetrazolium chloride (TTC) staining. p38 MAPK and caspase-3 were detected by western blotting. Neuronal apoptosis was measured using TUNEL staining. Neurological deficits were detected by behavioral testing. Furthermore, to assess whether these neuroprotective effects occurred when p38 MAPK was inhibited, p38 heterozygous knockdown (p38KI/+) mice were used. We found that p38 MAPK endogenous inhibition rescued hippocampal cell apoptosis, reduced ischemic penumbra, and improved neurological behavioral deficits. These findings showed that p38 MAPK endogenous inhibition had a neuroprotective effect on IRI and that p38 MAPK may be a potential therapeutic target for cerebral IRI.

Intrinsic Optical Spatial Differentiation Enabled Quantum Dark-Field Microscopy.

By solving the Maxwell's equations in Fourier space, we find that the cross-polarized component of the dipole scattering field can be written as the second-order spatial differentiation of the copolarized component. This differential operation can be regarded as intrinsic which naturally arises as consequence of the transversality of electromagnetic fields. By introducing the intrinsic spatial differentiation into heralded single-photon microscopy imaging technique, it makes the structure of pure-phase object clearly visible at low photon level, avoiding any biophysical damages to living cells. Based on the polarization entanglement, the switch between dark-field imaging and bright-field imaging is remotely controlled in the heralding arm. This research enriches both fields of optical analog computing and quantum microscopy, opening a promising route toward a nondestructive imaging of living biological systems.

Identifying New Ligands for JNK3 by Fluorescence Thermal Shift Assays and Native Mass Spectrometry.

The c-Jun N-terminal kinases (JNKs) are evolutionary highly conserved serine/threonine kinases. Numerous findings suggest that JNK3 is involved in the pathogenesis of neurodegenerative diseases, so the inhibition of JNK3 may be a potential therapeutic intervention. The identification of novel compounds with promising pharmacological properties still represents a challenge. Fluorescence thermal shift screening of a chemically diversified lead-like scaffold library of 2024 pure compounds led to the initial identification of seven JNK3 binding hits, which were classified into four scaffold groups according to their chemical structures. Native mass spectrometry validated the interaction of 4 out of the 7 hits with JNK3. Binding geometries and interactions of the top 2 hits were evaluated by docking into a JNK3 crystal structure. Hit 5 had a K d of 21 µM with JNK3 suggested scaffold 5-(phenylamino)-1H-1,2,3-triazole-4-carboxamide as a novel and selective JNK3 binder.

Reducing Nav1.6 expression attenuates the pathogenesis of Alzheimer's disease by suppressing BACE1 transcription.

Aberrant increases in neuronal network excitability may contribute to cognitive deficits in Alzheimer's disease (AD). However, the mechanisms underlying hyperexcitability of neurons are not fully understood. Voltage-gated sodium channels (VGSC or Nav), which are involved in the formation of excitable cell's action potential and can directly influence the excitability of neural networks, have been implicated in AD-related abnormal neuronal hyperactivity and higher incidence of spontaneous non-convulsive seizures. Here, we have shown that the reduction of VGSC α-subunit Nav1.6 (by injecting adeno-associated virus (AAV) with short hairpin RNA (shRNA) into the hippocampus) rescues cognitive impairments and attenuates synaptic deficits in APP/PS1 transgenic mice. Concurrently, amyloid plaques in the hippocampus and levels of soluble Aß are significantly reduced. Interfering with Nav1.6 reduces the transcription level of ß-site APP-cleaving enzyme 1 (BACE1), which is Aß-dependent. In the presence of Aß oligomers, knockdown of Nav1.6 reduces intracellular calcium overload by suppressing reverse sodium-calcium exchange channel, consequently increasing inactive NFAT1 (the nuclear factor of activated T cells) levels and thus reducing BACE1 transcription. This mechanism leads to a reduction in the levels of Aß in APP/PS1 transgenic mice, alleviates synaptic loss, improves learning and memory disorders in APP/PS1 mice after downregulating Nav1.6 in the hippocampus. Our study offers a new potential therapeutic strategy to counteract hippocampal hyperexcitability and subsequently rescue cognitive deficits in AD by selective blockade of Nav1.6 overexpression and/or hyperactivity.

TRIM32 Deficiency Impairs the Generation of Pyramidal Neurons in Developing Cerebral Cortex.

Excitatory-inhibitory imbalance (E/I) is a fundamental mechanism underlying autism spectrum disorders (ASD). TRIM32 is a risk gene genetically associated with ASD. The absence of TRIM32 causes impaired generation of inhibitory GABAergic interneurons, neural network hyperexcitability, and autism-like behavior in mice, emphasizing the role of TRIM32 in maintaining E/I balance, but despite the description of TRIM32 in regulating proliferation and differentiation of cultured mouse neural progenitor cells (NPCs), the role of TRIM32 in cerebral cortical development, particularly in the production of excitatory pyramidal neurons, remains unknown. The present study observed that TRIM32 deficiency resulted in decreased numbers of distinct layer-specific cortical neurons and decreased radial glial cell (RGC) and intermediate progenitor cell (IPC) pool size. We further demonstrated that TRIM32 deficiency impairs self-renewal of RGCs and IPCs as indicated by decreased proliferation and mitosis. A TRIM32 deficiency also affects or influences the formation of cortical neurons. As a result, TRIM32-deficient mice showed smaller brain size. At the molecular level, RNAseq analysis indicated reduced Notch signalling in TRIM32-deficient mice. Therefore, the present study indicates a role for TRIM32 in pyramidal neuron generation. Impaired generation of excitatory pyramidal neurons may explain the hyperexcitability observed in TRIM32-deficient mice.

An Experimental Study on Properties of Pre-Coated Aggregates Grouting Asphalt Concrete for Bridge Deck Pavement.

Epoxy asphalt concrete, mortar asphalt concrete and Gussasphalt concrete are commonly used types of deck pavement materials in bridge deck pavement engineering. However, achieving the high-temperature stability and anti-fatigue performance of the deck pavement materials is still challenging. In order to reduce the rutting and cracking risks of the asphalt mixture, this paper proposed pre-coated aggregates grouting asphalt concrete (PGAC) for bridge deck pavement. Laboratory tests were conducted to determine the optimum grouting materials and to evaluate the mechanical performances of the PGAC material. Test results showed that the mechanical properties for PGAC with grouting material of high-viscosity-modified asphalt binder blending with mineral filler were superior to that of GMA-10 used for the Hong Kong-Zhuhai-Macau Bridge deck pavement. Microstructural analysis showed that the PGAC had a more stable skeleton structure compared to other typical aggregate mixtures. This study highlights the performances of the proposed PGAC and sheds light on the deck pavement material improvement of both high-temperature stability and anti-fatigue performance that could be achieved.