Open access EEG dataset of repeated measurements from a single subject for microstate analysis.

Electroencephalography (EEG) microstate analysis is a neuroimaging analytical method that has received considerable attention in recent years and is widely used for analysing EEG signals. EEG is easily influenced by internal and external factors, which can affect the repeatability and stability of EEG microstate analysis. However, there have been few reports and publicly available datasets on the repeatability of EEG microstate analysis. In the current study, a 39-year-old healthy male underwent a total of 60 simultaneous electroencephalography and electrocardiogram measurements over a period of three months. After the EEG recording was completed, magnetic resonance imaging (MRI) was also conducted. To date, this EEG dataset has the highest number of repeated measurements for one individual. The dataset can be used to assess the stability and repeatability of EEG microstates and other analytical methods, to decode resting EEG states among subjects with open eyes, and to explore the stability and repeatability of cortical spatiotemporal dynamics through source analysis with individual MRI.

Human-multimodal deep learning collaboration in 'precise' diagnosis of lupus erythematosus subtypes and similar skin diseases.

BACKGROUND: Lupus erythematosus (LE) is a spectrum of autoimmune diseases. Due to the complexity of cutaneous LE (CLE), clinical skin image-based artificial intelligence is still experiencing difficulties in distinguishing subtypes of LE. OBJECTIVES: We aim to develop a multimodal deep learning system (MMDLS) for human-AI collaboration in diagnosis of LE subtypes. METHODS: This is a multi-centre study based on 25 institutions across China to assist in diagnosis of LE subtypes, other eight similar skin diseases and healthy subjects. In total, 446 cases with 800 clinical skin images, 3786 multicolor-immunohistochemistry (multi-IHC) images and clinical data were collected, and EfficientNet-B3 and ResNet-18 were utilized in this study. RESULTS: In the multi-classification task, the overall performance of MMDLS on 13 skin conditions is much higher than single or dual modals (Sen = 0.8288, Spe = 0.9852, Pre = 0.8518, AUC = 0.9844). Further, the MMDLS-based diagnostic-support help improves the accuracy of dermatologists from 66.88% ± 6.94% to 81.25% ± 4.23% (p = 0.0004). CONCLUSIONS: These results highlight the benefit of human-MMDLS collaborated framework in telemedicine by assisting dermatologists and rheumatologists in the differential diagnosis of LE subtypes and similar skin diseases.

Research on the characteristics of EV interior sound quality and its dynamic active control system design and development un-der accelerated driving conditions.

In order to improve the interior sound quality of Electric Vehicles (EV), solve the problem of low sense of power and comfort of the interior sound as well as the large electromagnetic excitation order noise of motor and the sharp interior sound, this article designs a dynamic active sound control system for EV under accelerated driving conditions. Firstly, by comparing and analyzing the sound spectrum characteristics of fuel vehicle (FV) and EV during acceleration, a short-time Fourier transform (STFT) is adopted to extract and synthesize the engine sound. Secondly, the influence of the engine order composition and the energy distribution in the frequency domain on the sound quality of the vehicle is analyzed, and an active control system for sound quality is proposed. And the software and hardware development of the active control sound system is completed. Finally, through real-vehicle testing and verification, the sense of comfort and power of the EV interior sound has been greatly improved during acceleration, and the total value of interior sound can meet the requirement. The sound pressure level and loudness of interior sound have been increased, and the sharpness of the sound inside the vehicle has been improved, with a maximum reduction of 1.0acum.

Down-conversion and frequency spectrum convolution of the broadband signal based on active mode-locking technology.

A multifunction processor for a broadband signal based on the active mode-locking optoelectronic oscillator (OEO) is proposed and experimentally demonstrated. The central frequency down-conversion and frequency spectrum convolution of the target broadband signal (TBS) are realized by just tuning the wavelength of the optical carrier or by the time domain product, respectively. To achieve the central frequency down-conversion of the TBS, an optical tunable delay line (OTDL) is adopted to match the delay time of the OEO loop with the repetition period of the TBS. Then the spectrum convolution of the TBS is produced by just injecting a lower frequency signal consistent with the free spectral range (FSR) of the OEO loop. Moreover, the frequency convolution repetition is also greatly increased by harmonic mode-locking injection. The equivalent bandwidth of the TBS is enlarged by ∼50 times, benefiting from the frequency convolution. The central frequency conversion flexibility and the bandwidth compatibility are also discussed in detail. This work provides a multifunction processor system and may have potential usage in multifunctional integrated radar systems.

The clinical use of remote parameter testing during cardiac implantable electronic devices implantation procedures: a single center, randomized, open-label, non-inferiority trial.

Background: A novel non-contact system for remote parameter testing and reprogramming offers an alternative method for assessing device parameters during cardiac implantable electronic devices (CIEDs) implantation without the need for physical contact with the manufacturer's clinical service technician. The safety and feasibility of using this system in CIEDs implantation procedures remains to be determined. Objective: Evaluate the safety and feasibility of remote parameter testing in CIEDs implantation procedures. Methods: A single center, randomized, open-label, non-inferiority trial (ChiCTR2200057587) was conducted to compare the two approaches for interrogating CIEDs during implantation procedures: routine interrogation performed by on-site technicians or remote interrogation performed by technicians using the 5G-Cloud Technology Platform. Patients aged ≥18 years and elected to receive CIEDs were eligible for inclusion. The primary endpoint was the completion rate of the parameter test. Safety and efficiency were evaluated in all randomly assigned participants. Results: A total of 480 patients were finally enrolled and were randomly assigned to routine group (n = 240) or remote group (n = 240). The primary endpoint was achieved by 100% in both groups (P = 0.0060 for noninferiority). The parameters of sensing, threshold, and impedance regarding the right atrium, right ventricle, and left ventricle had no statistical significance between the two groups (P > 0.05). Procedure time, parameter testing time, and both duration and dose of x-ray irradiation were not significantly different between the two groups (P > 0.05). Shut-open door frequency was significantly higher in the routine group than the remote group [6.00 (4.00, 8.00) vs. 0, P < 0.0001]. Notably, no clinical or technical complications were observed in the remote group. Conclusions: Remote parameter testing is safe and feasible across various devices implantation procedures. The utilization of remote parameter testing and reprogramming could represent an innovative approach to improve healthcare accessibility and unlock the full potential of secondary centers in managing CIEDs. The Registration Identification: ChiCTR2200057587.

Research on the parameter design and calibration and control of EV in-vehicle active sound generation system.

In order to improve the interior sound quality of electric vehicles (EVs) under acceleration and uniform speed conditions, to balance the comfort and dynamics of the interior sound, and to improve the accuracy and performance of the active sound generation system (ASGS), this article carries out the research related to the parameter design, sound calibration, evaluation methodology, and control system of the EV ASGS. Propose an in-vehicle sound design method focusing on three dimensions, including engine order composition, spectral energy distribution, and sound amplitude enhancement in the typical speed range, and determine the in-vehicle sound design scheme and the total sound value target. Focus on the sound parameter design, calibration and evaluation methods of EV ASGS considering the frequency response characteristics of the loudspeaker, sound amplitude control accuracy, sound quality, and psychoacoustic parameters, clarify the active sound parameter settings of EVs, complete the analysis of sound extraction methods, complete the engine order sound fitting, and design the ASGS of the EV interior by combining the subjective and objective evaluations. Develop the control software and hardware of the ASGS, complete the construction and accuracy verification of the ASGS based on the in-vehicle sound system, and realize the sound calibration of the ASGS under the static conditions of the real vehicle and the verification of the target achievement. The real-vehicle test shows that the ASGS reduces the sharpness of 1.0 acum and 0.52 acum under acceleration and constant speed conditions, respectively, and improves the comfort and dynamics of in-vehicle sound. The objective and subjective evaluation results show that the parameter design, selection and accuracy of the sound calibration and evaluation methods of the ASGS in the EV determines the accuracy and effect of the ASGS.

Hammerhead-type FXR agonists induce an enhancer RNA Fincor that ameliorates nonalcoholic steatohepatitis in mice.

The nuclear receptor, farnesoid X receptor (FXR/NR1H4), is increasingly recognized as a promising drug target for metabolic diseases, including nonalcoholic steatohepatitis (NASH). Protein-coding genes regulated by FXR are well known, but whether FXR also acts through regulation of long non-coding RNAs (lncRNAs), which vastly outnumber protein-coding genes, remains unknown. Utilizing RNA-seq and global run-on sequencing (GRO-seq) analyses in mouse liver, we found that FXR activation affects the expression of many RNA transcripts from chromatin regions bearing enhancer features. Among these we discovered a previously unannotated liver-enriched enhancer-derived lncRNA (eRNA), termed FXR-induced non-coding RNA (Fincor). We show that Fincor is specifically induced by the hammerhead-type FXR agonists, including GW4064 and tropifexor. CRISPR/Cas9-mediated liver-specific knockdown of Fincor in dietary NASH mice reduced the beneficial effects of tropifexor, an FXR agonist currently in clinical trials for NASH and primary biliary cholangitis (PBC), indicating that amelioration of liver fibrosis and inflammation in NASH treatment by tropifexor is mediated in part by Fincor. Overall, our findings highlight that pharmacological activation of FXR by hammerhead-type agonists induces a novel eRNA, Fincor, contributing to the amelioration of NASH in mice. Fincor may represent a new drug target for addressing metabolic disorders, including NASH.

Non-alcoholic steatohepatitis, also known as NASH, is a severe condition whereby fat deposits around the liver lead to inflammation, swelling, scarring and lasting damage to the organ. Despite being one of the leading causes of liver-related deaths worldwide, the disease has no approved treatment. A protein known as Farnesoid X receptor (or FXR) is increasingly being recognized as a promising drug target for non-alcoholic steatohepatitis. Once activated, FXR helps to regulate the activity of DNA regions which are coding for proteins important for liver health. However, less is known about how FXR may act on non-coding regions, the DNA sequences that do not generate proteins but can be transcribed into RNA molecules with important biological roles. In response, Chen et al. investigated whether FXR activation of non-coding RNAs could be linked to the clinical benefits of hammerhead FXR agonists, a type of synthetic compounds that activates this receptor. To do so, genetic analyses of mouse livers were performed to identify non-coding RNAs generated when FXR was activated by the agonist. These experiments revealed that agonist-activated FXR induced a range of non-coding RNAs transcribed from DNA sequences known as enhancers, which help to regulate gene expression. In particular, hammerhead FXR agonists led to the production of a liver-specific enhancer RNA called Fincor. Additional experiments using tropifexor, a hammerhead FXR agonist currently into clinical trials, showed that this investigational new drug had reduced benefits in a mouse model of non-alcoholic steatohepatitis with low Fincor levels. This suggested that this enhancer RNA may play a key role in mediating the clinical benefits of hammerhead FXR agonists, encouraging further research into its role and therapeutic value.

Comparison of three methods for collecting interstitial fluid from subcutaneous tissue in mini pigs.

Interstitial fluid, owing to its similarity to blood components and higher sensitivity and specificity, finds widespread application in disease diagnosis and tumor marker detection. However, collecting interstitial fluid, particularly from the deep subcutaneous connective tissue, remains challenging.•This study aimed to compare three different collection methods - push-pull perfusion, multi-filament nylon thread implantation, and tissue centrifugation - for collecting interstitial fluid from the subcutaneous connective tissue layer of mini-pigs. High-performance ion chromatography was employed to analyze the conventional cation components in the samples and compare ion composition analysis between the different methods.•Results indicated that while the distribution of conventional cations in the interstitial fluid collected by the three methods was generally consistent, there were slight variations in the detection rates and concentrations of different ions. Hence, suitable collection methods should be selected based on the ions or collection sites of interest.

Abiotic natural attenuation of 1,2,3-trichloropropane by natural magnetite under O2 perturbation.

1,2,3-Trichloropropane (TCP) is an emerging groundwater pollutant, but there is a lack of reported studies on the abiotic natural attenuation of TCP by iron minerals. Furthermore, perturbation by O2 is common in the shallow subsurface by both natural and artificial processes. In this study, natural magnetite was selected as the reactive iron mineral to investigate its role in the degradation of TCP under O2 perturbation. The results indicated that the mineral structural Fe(II) on magnetite reacted with dissolved oxygen to generate O2-· and HO·. Both O2-· and HO· contributed to TCP degradation, with O2-· playing a more important role. After 56 days of reaction, 66.7% of TCP was completely dechlorinated. This study revealed that higher magnetite concentrations, smaller magnetite particle sizes, and lower initial TCP concentrations favored TCP degradation. The presence of <10 mg/L natural organic matter (NOM) did not affect TCP degradation. These findings significantly advance our understanding of the abiotic natural attenuation mechanisms facilitated by iron minerals under O2 perturbation, providing crucial insights for the study of natural attenuation.

Semi-automatic proximal humeral trabecular bone density assessment tool: technique application and clinical validation.

PURPOSE: This study aimed to apply a newly developed semi-automatic phantom-less QCT (PL-QCT) to measure proximal humerus trabecular bone density based on chest CT and verify its accuracy and precision. METHODS: Subcutaneous fat of the shoulder joint and trapezius muscle were used as calibration references for PL-QCT BMD measurement. A self-developed algorithm based on a convolution map was utilized in PL-QCT for semi-automatic BMD measurements. CT values of ROIs used in PL-QCT measurements were directly used for phantom-based quantitative computed tomography (PB-QCT) BMD assessment. The study included 376 proximal humerus for comparison between PB-QCT and PL-QCT. Two sports medicine doctors measured the proximal humerus with PB-QCT and PL-QCT without knowing each other's results. Among them, 100 proximal humerus were included in the inter-operative and intra-operative BMD measurements for evaluating the repeatability and reproducibility of PL-QCT and PB-QCT. RESULTS: A total of 188 patients with 376 shoulders were involved in this study. The consistency analysis indicated that the average bias between proximal humerus BMDs measured by PB-QCT and PL-QCT was 1.0 mg/cc (agreement range - 9.4 to 11.4; P > 0.05, no significant difference). Regression analysis between PB-QCT and PL-QCT indicated a good correlation (R-square is 0.9723). Short-term repeatability and reproducibility of proximal humerus BMDs measured by PB-QCT (CV: 5.10% and 3.41%) were slightly better than those of PL-QCT (CV: 6.17% and 5.64%). CONCLUSIONS: We evaluated the bone quality of the proximal humeral using chest CT through the semi-automatic PL-QCT system for the first time. Comparison between it and PB-QCT indicated that it could be a reliable shoulder BMD assessment tool with acceptable accuracy and precision. This study developed and verify a semi-automatic PL-QCT for assessment of proximal humeral bone density based on CT to assist in the assessment of proximal humeral osteoporosis and development of individualized treatment plans for shoulders.

High-Efficiency Thermal-Shock Resistance Enabled by Radiative Cooling and Latent Heat Storage.

Radiative cooling technology is well known for its subambient temperature cooling performance under sunlight radiation. However, the intrinsic maximum cooling power of radiative cooling limits the performance when the objects meet the thermal shock. Here, a dual-function strategy composed of radiative cooling and latent heat storage simultaneously enabling the efficient subambient cooling and high-efficiency thermal-shock resistance performance is proposed. The electrospinning and absorption-pressing methods are used to assemble the dual-function cooler. The high sunlight reflectivity and high mid-infrared emissivity of radiative film allow excellent subambient temperature of 5.1 °C. When subjected the thermal shock, the dual-function cooler demonstrates a pinning effect of huge temperature drop of 39 °C and stable low-temperature level by isothermal heat absorption compared with the traditional radiative cooler. The molten phase change materials provide the heat-time transfer effect by converting thermal-shock heat to the delayed preservation. This strategy paves a powerful way to protect the objects from thermal accumulation and high-temperature damage, expanding the applications of radiative cooling and latent heat storage technologies.

PTGS2: A potential immune regulator and therapeutic target for chronic spontaneous urticaria.

AIMS: Chronic spontaneous urticaria (CSU) is a common and debilitating skin disease that is difficult to control with existing treatments, and the pathogenesis of CSU has not been fully revealed. The aim of this study was to explore the underlying mechanisms of CSU and identify potential treatments. MATERIALS AND METHODS: Microarray datasets of CSU were obtained from Gene Expression Omnibus database. Differentially expressed genes between skin lesions of CSU and normal controls (LNS-DEGs) were identified, and the enrichment analyses of LNS-DEGs were performed. Hub genes of LNS-DEGs were selected by protein-protein interaction analysis. The co-expression and transcriptional regulatory networks of hub genes were conducted using GeneMANIA and TRRUST database, respectively. CIBERSORT was utilized for immune cell infiltration analysis. Experimental validation was performed by ß-hexosaminidase release examination and passive cutaneous anaphylaxis (PCA) mouse model. KEY FINDINGS: A total of 247 LNS-DEGs were identified, which were enriched in cell migration, cell chemotaxis, and inflammatory pathways such as TNF and interleukin (IL) -17 signaling pathway. Among LNS-DEGs, seven upregulated (PTGS2, CCL2, IL1B, CXCL1, IL6, VCAM1, ICAM1) and one downregulated hub gene (PECAM1) were selected. Immune infiltration analysis identified eight different immune cells, such as activated/resting mast cells and neutrophils. Furthermore, PTGS2, encoding cyclooxygenase 2 (COX2), was selected for further validation. COX2 inhibitor, celecoxib, significantly inhibited mast cell degranulation, and reduced vascular permeability and inflammatory cytokine expression in PCA mouse model. SIGNIFICANCE: PTGS2 may be a potential regulator of immunity and inflammation in CSU. Targeting PTGS2 is a new perspective for CSU treatment.

Atrial cardiomyocytes contribute to the inflammatory status associated with atrial fibrillation in right heart disease.

AIMS: Right heart disease (RHD), characterized by right ventricular (RV) and atrial (RA) hypertrophy, and cardiomyocytes' (CM) dysfunctions have been described to be associated with the incidence of atrial fibrillation (AF). Right heart disease and AF have in common, an inflammatory status, but the mechanisms relating RHD, inflammation, and AF remain unclear. We hypothesized that right heart disease generates electrophysiological and morphological remodelling affecting the CM, leading to atrial inflammation and increased AF susceptibility. METHODS AND RESULTS: Pulmonary artery banding (PAB) was surgically performed (except for sham) on male Wistar rats (225-275 g) to provoke an RHD. Twenty-one days (D21) post-surgery, all rats underwent echocardiography and electrophysiological studies (EPS). Optical mapping was performed in situ, on Langendorff-perfused hearts. The contractility of freshly isolated CM was evaluated and recorded during 1 Hz pacing in vitro. Histological analyses were performed on formalin-fixed RA to assess myocardial fibrosis, connexin-43 levels, and CM morphology. Right atrial levels of selected genes and proteins were obtained by qPCR and Western blot, respectively. Pulmonary artery banding induced severe RHD identified by RV and RA hypertrophy. Pulmonary artery banding rats were significantly more susceptible to AF than sham. Compared to sham RA CM from PAB rats were significantly elongated and hypercontractile. Right atrial CM from PAB animals showed significant augmentation of mRNA and protein levels of pro-inflammatory interleukin (IL)-6 and IL1ß. Sarcoplasmic-endoplasmic reticulum Ca2+-ATPase-2a (SERCA2a) and junctophilin-2 were decreased in RA CM from PAB compared to sham rats. CONCLUSIONS: Right heart disease-induced arrhythmogenicity may occur due to dysfunctional SERCA2a and inflammatory signalling generated from injured RA CM, which leads to an increased risk of AF.

Investigating the synergy of Shikonin and Valproic acid in inducing apoptosis of osteosarcoma cells via ROS-mediated EGR1 expression.

BACKGROUND: Osteosarcoma is the most prevalent malignant bone tumour with a poor prognosis. Shikonin (SHK) is derived from the traditional Chinese medicine Lithospermum that has been extensively studied for its notable anti-tumour effects, including for osteosarcoma. However, its application has certain limitations. Valproic acid (VPA) is a histone deacetylase inhibitor (HDACI) that has recently been employed as an adjunctive therapeutic agent that allows chromatin to assume a more relaxed state, thereby enhancing anti-tumour efficacy. PURPOSE: This study was aimed to investigate the synergistic anti-tumour efficacy of SHK in combination with VPA and elucidate its underlying mechanism. METHODS/STUDY DESIGN: CCK-8 assays were utilized to calculate the combination index. Additional assays, including colony formation, acridine orange/ethidium bromide double fluorescent staining, and flow cytometry, were employed to evaluate the effects on osteosarcoma cells. Wound healing and transwell assays were utilized to assess cell mobility. RNA sequencing, PCR, and Western blot analyses were conducted to uncover the underlying mechanism. Rescue experiments were performed to validate the mechanism of apoptotic induction. The impact of SHK and VPA combination treatment on primary osteosarcoma cells was also assessed. Finally, in vivo experiments were conducted to validate its anti-tumour effects and mechanism. RESULTS: The combination of SHK and VPA synergistically inhibited the proliferation and migration of osteosarcoma cells in vitro and induced apoptosis in these cells. Through a comprehensive analysis involving RNA sequencing, PCR, Western blot, and rescue experiments, we have substantiated our hypothesis that the combination of SHK and VPA induced apoptosis via the ROS-EGR1-Bax axis. Importantly, our in vivo experiments corroborated these findings, demonstrating the potential of the SHK and VPA combination as a promising therapeutic approach for osteosarcoma. CONCLUSION: The combination of SHK and VPA exerted an anti-tumour effect by inducing apoptosis through the ROS-EGR1-Bax pathway. Repurposing the old drug VPA demonstrated its effectiveness as an adjunctive therapeutic agent for SHK, enhancing its anti-tumour efficacy and revealing its potential value. Furthermore, our study expanded the application of natural compounds in the anti-tumour field and overcame some of their limitations through combination therapy. Finally, we enhanced the understanding of the mechanistic pathways linking reactive oxygen species (ROS) accumulation and apoptosis in osteosarcoma cells. Additionally, we elucidated the role of EGR1 in osteosarcoma cells, offering novel strategies and concepts for the treatment of osteosarcoma.

KCNH6 is essential for insulin secretion by regulating intracellular ER Ca2+ store.

Appropriate Ca2+ concentration in the endoplasmic reticulum (ER), modulating cytosolic Ca2+ signal, serves significant roles in physiological function of pancreatic ß cells. To maintaining ER homeostasis, Ca2+ movement across the ER membrane is always accompanied by a simultaneous K+ flux in the opposite direction. KCNH6 was proven to modulate insulin secretion by controlling plasma membrane action potential duration and intracellular Ca2+ influx. Meanwhile, the specific function of KCNH6 in pancreatic ß-cells remains unclear. In this study, we found that KCNH6 exhibited mainly ER localization and Kcnh6 ß-cell-specific knockout (ßKO) mice suffered from abnormal glucose tolerance and impaired insulin secretion in adulthood. ER Ca2+ store was overloaded in islets of ßKO mice, which contributed to ER stress and ER stress-induced apoptosis in ß cells. Next, we verified that ethanol treatment induced increases in ER Ca2+ store and apoptosis in pancreatic ß cells, whereas adenovirus-mediated KCNH6 overexpression in islets attenuated ethanol-induced ER stress and apoptosis. In addition, tail-vein injections of KCNH6 lentivirus rescued KCNH6 expression in ßKO mice, restored ER Ca2+ overload and attenuated ER stress in ß cells, which further confirms that KCNH6 protects islets from ER stress and apoptosis. These data suggest that KCNH6 on the ER membrane may help to stabilize intracellular ER Ca2+ stores and protect ß cells from ER stress and apoptosis. In conclusion, our study reveals the protective potential of KCNH6-targeting drugs in ER stress-induced diabetes.

MXene-Integrated Solid-Solid Phase Change Composites for Accelerating Solar-Thermal Energy Storage and Electric Conversion.

The high thermal storage density of phase change materials (PCMs) has attracted considerable attention in solar energy applications. However, the practicality of PCMs is often limited by the problems of leakage, poor solar-thermal conversion capability, and low thermal conductivity, resulting in low-efficiency solar energy storage. In this work, a new system of MXene-integrated solid-solid PCMs is presented as a promising solution for a solar-thermal energy storage and electric conversion system with high efficiency and energy density. The composite system's performance is enhanced by the intrinsic photo-thermal behavior of MXene and the heterogeneous phase transformation properties of PCM molecular chains. The optimal composites system has an impressive solar thermal energy storage efficiency of up to 94.5%, with an improved energy storage capacity of 149.5 J g-1 , even at a low MXene doping level of 5 wt.%. Additionally, the composite structure shows improved thermal conductivity and high thermal cycling stability. Furthermore, a proof-of-concept solar-thermal-electric conversion device is designed based on the optimized M-SSPCMs and commercial thermoelectric generators, which exhibit excellent energy conversion efficiency. The results of this study highlight the potential of the developed PCM composites in high-efficiency solar energy utilization for advanced photo-thermal systems.

4-PBA exerts brain-protective effects against sepsis-associated encephalopathy in a mouse model of sepsis.

BACKGROUND: Neuroinflammation assumes a pivotal role in both the etiological underpinnings and the dynamic progression of sepsis-associated encephalopathy (SAE). The occurrence of cognitive deficits with SAE is associated with neuroinflammation. 4-phenyl butyrate (4-PBA) may control inflammation by inhibiting endoplasmic reticulum stress (ERS). The primary objective of this investigation is to scrutinize the effectiveness of 4-PBA in mitigating neuroinflammation induced by lipopolysaccharides (LPS) and its consequent impact on cognitive function decline. METHODS: LPS-injected mice with SAE and LPS-treated BV2 cell were established to serve as experimental paradigms, both contributing to the investigative framework of the study. Cognitive functions were assessed by behavioral tests. Hippocampal neuronal damage was assessed using Golgi staining and Nissl staining. Quantitative PCR assay and immunofluorescence were used to analyze neuroinflammation. Mitochondrial function was examined using transmission electron microscopy. Protein expression analysis was conducted through the application of western blotting methodology, serving as the investigative approach to elucidate molecular signatures in the experimental framework. Endoplasmic reticulum and mitochondrial calcium flow were detected using flow cytometry. To delve deeper into the mechanistic intricacies, the administration of 4µ8c was employed to selectively impede the IRE1α/Xbp1s pathway, constituting a strategic intervention aimed at elucidating underlying regulatory processes. RESULT: Expression levels of ERS-related proteins exhibited a significant upregulation in hippocampal tissues of LPS-treated mice when compared to wild-type (WT) counterparts. The administration of 4-PBA notably ameliorated memory deficits in LPS-treated mice. Furthermore, 4-PBA treatment was found to alleviate oxidative stress and neuroinflammation. Mechanistically, the IRE1α/Xbp1s-Ca2+ signaling pathway played a crucial role in mediating the beneficial effects of mitigating oxidative stress and maintaining mitochondrial calcium homeostasis, with inhibition of the IRE-related pathway displaying opposing effects. CONCLUSION: Our results suggest that administration of 4-PBA treatment significantly attenuates ERS, alleviates cognitive decline, reduces inflammatory damage, and restores mitochondrial dynamics via the IRE1α/Xbp1s-Ca2+-associated pathway, which provides a new potential therapeutic approach to SAE.

The role of cellular senescence in profibrillatory atrial remodeling associated with cardiac pathology.

AIMS: Cellular senescence is a stress-related or aging response believed to contribute to many cardiac conditions; however, its role in atrial fibrillation (AF) is unknown. Age is the single most important determinant of the risk of AF. The present study was designed to: 1) Evaluate AF-susceptibility and senescence-marker expression in rat models of aging and myocardial infarction (MI); 2) Study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI-rats; 3) Assess senescence markers in human atrial tissue as a function of age and the presence of AF. METHODS AND RESULTS: AF-susceptibility was studied with programmed electrical stimulation. Gene and protein expression was evaluated by immunoblot or immunofluorescence (protein) and digital-PCR or RT-qPCR (mRNA). A previously-validated senolytic combination, dasatinib and quercetin (D + Q), (or corresponding vehicle) was administered from the time of sham or MI surgery through 28 days later. Experiments were performed blinded to treatment-assignment. Burst pacing-induced AF was seen in 100% of aged rats, 87.5% of young MI-rats and 10% of young-control rats (P≤0.001 vs. each). Conduction velocity was slower in aged (both left atrium, LA and right atrium, RA) and young-MI (LA) rats versus young-control rats (P≤0.001 vs. each). Atrial fibrosis was greater in aged (LA and RA) and young-MI (LA) versus young-control rats (P < 0.05 for each). Senolytic therapy reduced AF-inducibility in MI-rats (from 8/9 rats, 89% in MI-vehicle, to 0/9 rats, 0% in MI-D + Q, P < 0.001) and attenuated LA-fibrosis. Double staining suggested that D + Q acts by clearing senescent myofibroblasts and endothelial cells. In human atria, senescence-markers were upregulated in older (≥ 70 years) and longstanding-AF patients versus individuals ≤ 60 and sinus-rhythm controls respectively. CONCLUSIONS: Our results point to a potentially significant role of cellular senescence in AF pathophysiology. Modulating cell senescence might provide a basis for novel therapeutic approaches to AF.

DSM: Deep sequential model for complete neuronal morphology representation and feature extraction.

The full morphology of single neurons is indispensable for understanding cell types, the basic building blocks in brains. Projecting trajectories are critical to extracting biologically relevant information from neuron morphologies, as they provide valuable information for both connectivity and cell identity. We developed an artificial intelligence method, deep sequential model (DSM), to extract concise, cell-type-defining features from projections across brain regions. DSM achieves more than 90% accuracy in classifying 12 major neuron projection types without compromising performance when spatial noise is present. Such remarkable robustness enabled us to efficiently manage and analyze several major full-morphology data sources, showcasing how characteristic long projections can define cell identities. We also succeeded in applying our model to both discovering previously unknown neuron subtypes and analyzing exceptional co-expressed genes involved in neuron projection circuits.