Impaired end joining induces cardiac atrophy in a Hutchinson-Gilford progeria mouse model.

Patients with Hutchinson-Gilford progeria syndrome (HGPS) present with a number of premature aging phenotypes, including DNA damage accumulation, and many of them die of cardiovascular complications. Although vascular pathologies have been reported, whether HGPS patients exhibit cardiac dysfunction and its underlying mechanism is unclear, rendering limited options for treating HGPS-related cardiomyopathy. In this study, we reported a cardiac atrophy phenotype in the LmnaG609G/G609G mice (hereafter, HGPS mice). Using a GFP-based reporter system, we demonstrated that the efficiency of nonhomologous end joining (NHEJ) declined by 50% in HGPS cardiomyocytes in vivo, due to the attenuated interaction between γH2AX and Progerin, the causative factor of HGPS. As a result, genomic instability in cardiomyocytes led to an increase of CHK2 protein level, promoting the LKB1-AMPKα interaction and AMPKα phosphorylation, which further led to the activation of FOXO3A-mediated transcription of atrophy-related genes. Moreover, inhibiting AMPK enlarged cardiomyocyte sizes both in vitro and in vivo. Most importantly, our proof-of-concept study indicated that isoproterenol treatment significantly reduced AMPKα and FOXO3A phosphorylation in the heart, attenuated the atrophy phenotype, and extended the mean lifespan of HGPS mice by ~21%, implying that targeting cardiac atrophy may be an approach to HGPS treatment.

A p21-ATD mouse model for monitoring and eliminating senescent cells and its application in liver regeneration post injury.

Cellular senescence associates with pathological aging and tissue dysfunctions. Studies utilizing mouse models for cell lineage tracings have emphasized the importance of senescence heterogeneity in different organs and cell types. Here, we constructed a p21- (Akaluc - tdTomato - Diphtheria Toxin Receptor [DTR]) (ATD) mouse model to specifically study the undefined mechanism for p21-expressing senescent cells in the aged and liver injury animals. The successful expressions of these genes enabled in vitro flow cytometric sorting, in vivo tracing, and elimination of p21-expressing senescent cells. During the natural aging process, p21-expressing cells were found in various tissues of p21-ATD mice. Eliminating p21-expressing cells in the aged p21-ATD mice recovered their multiple biological functions. p21-ATD/Fah-/- mice, bred from p21-ATD mice and fumarylacetoacetate hydrolase (Fah)-/- mice of liver injury, showed that the majority of their senescent hepatocytes were the phenotype of p21+ rather than p16+. Furthermore, eliminating the p21-expressing hepatocytes significantly promoted the engraftment of grafted hepatocytes and facilitated liver repopulation, resulting in significant recovery from liver injury. Our p21-ATD mouse model serves as an optimal model for studying the pattern and function of p21-expressing senescent cells under the physical and pathological conditions during aging.

Jmjd4 Facilitates Pkm2 Degradation in Cardiomyocytes and Is Protective Against Dilated Cardiomyopathy.

BACKGROUND: A large portion of idiopathic and familial dilated cardiomyopathy (DCM) cases have no obvious causal genetic variant. Although altered response to metabolic stress has been implicated, the molecular mechanisms underlying the pathogenesis of DCM remain elusive. The JMJD family proteins, initially identified as histone deacetylases, have been shown to be involved in many cardiovascular diseases. Despite their increasingly diverse functions, whether JMJD family members play a role in DCM remains unclear. METHODS: We examined Jmjd4 expression in patients with DCM, and conditionally deleted and overexpressed Jmjd4 in cardiomyocytes in vivo to investigate its role in DCM. RNA sequencing, metabolites profiling, and mass spectrometry were used to dissect the molecular mechanism of Jmjd4-regulating cardiac metabolism and hypertrophy. RESULTS: We found that expression of Jmjd4 is significantly decreased in hearts of patients with DCM. Induced cardiomyocyte-specific deletion of Jmjd4 led to spontaneous DCM with severely impaired mitochondrial respiration. Pkm2, the less active pyruvate kinase compared with Pkm1, which is normally absent in healthy adult cardiomyocytes but elevated in cardiomyopathy, was found to be drastically accumulated in hearts with Jmjd4 deleted. Jmjd4 was found mechanistically to interact with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, which is dependent on hydroxylation of K66 of Pkm2 by Jmjd4. By enhancing the enzymatic activity of the abundant but less active Pkm2, TEPP-46, a Pkm2 agonist, showed a significant therapeutic effect on DCM induced by Jmjd4 deficiency, and heart failure induced by pressure overload, as well. CONCLUSIONS: Our results identified a novel role of Jmjd4 in maintaining metabolic homeostasis in adult cardiomyocytes by degrading Pkm2 and suggest that Jmjd4 and Pkm2 may be therapeutically targeted to treat DCM, and other cardiac diseases with metabolic dysfunction, as well.

PDZD8-mediated lipid transfer at contacts between the ER and late endosomes/lysosomes is required for neurite outgrowth.

Membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and late endosomes/lysosomes (LE/lys) are emerging as critical hubs for diverse cellular events, and changes in their extents are linked to severe neurological diseases. While recent studies show that the synaptotagmin-like mitochondrial-lipid-binding (SMP) domain-containing protein PDZD8 may mediate the formation of ER-LE/lys MCSs, the cellular functions of PDZD8 remain largely elusive. Here, we attempt to investigate the lipid transfer activities of PDZD8 and the extent to which its cellular functions depend on its lipid transfer activities. In accordance with recent studies, we demonstrate that PDZD8 is a protrudin (ZFYVE27)-interacting protein and that PDZD8 acts as a tether at ER-LE/lys MCSs. Furthermore, we discover that the SMP domain of PDZD8 binds glycerophospholipids and ceramides both in vivo and in vitro, and that the SMP domain can transport lipids between membranes in vitro. Functionally, PDZD8 is required for LE/lys positioning and neurite outgrowth, which is dependent on the lipid transfer activity of the SMP domain.

Thrombospondin 1 and Reelin act through Vldlr to regulate cardiac growth and repair.

Adult mammalian cardiomyocytes have minimal cell cycle capacity, which leads to poor regeneration after cardiac injury such as myocardial infarction. Many positive regulators of cardiomyocyte cell cycle and cardioprotective signals have been identified, but extracellular signals that suppress cardiomyocyte proliferation are poorly understood. We profiled receptors enriched in postnatal cardiomyocytes, and found that very-low-density-lipoprotein receptor (Vldlr) inhibits neonatal cardiomyocyte cell cycle. Paradoxically, Reelin, the well-known Vldlr ligand, expressed in cardiac Schwann cells and lymphatic endothelial cells, promotes neonatal cardiomyocyte proliferation. Thrombospondin1 (TSP-1), another ligand of Vldlr highly expressed in adult heart, was then found to inhibit cardiomyocyte proliferation through Vldlr, and may contribute to Vldlr's overall repression on proliferation. Mechanistically, Rac1 and subsequent Yap phosphorylation and nucleus translocation mediate the regulation of the cardiomyocyte cell cycle by TSP-1/Reelin-Vldlr signaling. Importantly, Reln mutant neonatal mice displayed impaired cardiomyocyte proliferation and cardiac regeneration after apical resection, while cardiac-specific Thbs1 deletion and cardiomyocyte-specific Vldlr deletion promote cardiomyocyte proliferation and are cardioprotective after myocardial infarction. Our results identified a novel role of Vldlr in consolidating extracellular signals to regulate cardiomyocyte cell cycle activity and survival, and the overall suppressive TSP-1-Vldlr signal may contribute to the poor cardiac repair capacity of adult mammals.

High-order exciton complexes induced by an interlayer carrier transfer in 2D van der Waals heterostructures.

High-order correlated excitonic states, such as biexciton, charged biexciton, and polaron, hold a promising platform in contemporary quantum and nonlinear optics due to their large Bohr radii and thus strong nonlinear interactions. The recently found 2D TMDs further give such excitonic states additional valley properties, with bound state of excitons in opposite valleys in momentum spaces. Despite great efforts that have been made on emission properties of excitonic states, their absorption features, especially the ultrafast absorption dynamics, are rarely reported. Here, we reported the enhanced optical absorption of the high-order charged-excitonic states in monolayer WS2, including singlet, triplet, and semidark trions (3-particle state), and charged biexcitons (5-particle state), by utilizing the interlayer charge transfer-induced photo-doping effect in the graphene-WS2 heterostructure. Depending on recombination rates of doping electrons, absorption intensities of charged complexes exhibit ultrafast decay dynamics, with lifetimes of several picoseconds. Due to many-body interaction, both increasing pump intensity and lattice temperature can broaden these fine excitonic absorption peaks and even reverse the shape of the transient absorption spectrum.

Mitochondrial DNA release via the mitochondrial permeability transition pore activates the cGAS-STING pathway, exacerbating inflammation in acute Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is an immune vasculitis of unknown origin, characterized by transient inflammation. The activation of the cGAS-STING pathway, triggered by mitochondrial DNA (mtDNA) release, has been implicated in the onset of KD. However, its specific role in the progression of inflammation during KD's acute phase remains unclear. METHODS: We measured mtDNA and 2'3'-cGAMP expression in KD patient serum using RT-qPCR and ELISA. A murine model of KD was induced by injecting Lactobacillus casei cell wall extract (LCWE), after which cGAS-STING pathway activation and inflammatory markers were assessed via immunohistochemistry, western blot, and RT-qPCR. Human umbilical vein endothelial cells (HUVECs) were treated with KD serum and modulators of the cGAS-STING pathway for comparative analysis. Mitochondrial function was evaluated using Mitosox staining, mPTP opening was quantified by fluorescence microscopy, and mitochondrial membrane potential (MMP) was determined with JC-1 staining. RESULTS: KD patient serum exhibited increased mtDNA and 2'3'-cGAMP expression, with elevated levels of pathway-related proteins and inflammatory markers observed in both in vivo and in vitro models. TEM confirmed mitochondrial damage, and further studies demonstrated that inhibition of mPTP opening reduced mtDNA release, abrogated cGAS-STING pathway activation, and mitigated inflammation. CONCLUSION: These findings indicate that mtDNA released through the mPTP is a critical activator of the cGAS-STING pathway, contributing significantly to KD-associated inflammation. Targeting mtDNA release or the cGAS-STING pathway may offer novel therapeutic approaches for KD management.

Opioid-Sparing Anesthesia Versus Opioid-Free Anesthesia for the Prevention of Postoperative Nausea and Vomiting after Laparoscopic Bariatric Surgery: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Patients who undergo laparoscopic bariatric surgery (LBS) are susceptible to postoperative nausea and vomiting (PONV). Opioid-free anesthesia (OFA) or opioid-sparing anesthesia (OSA) protocols have been proposed as solutions; however, differences between the 2 alternative opioid protocols for anesthesia maintenance in obese patients remain uncertain. A network meta-analysis was conducted to compare the impacts of OFA and OSA on PONV. METHODS: Systematic searches were conducted using Embase, PubMed, MEDLINE, and Cochrane Library databases to identify randomized controlled trials (RCTs) comparing OFA and OSA strategies. After screening according to the inclusion and exclusion criteria, we used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the credibility of the evidence. The main concern of this review was the difference between OFA and OSA in reducing PONV. The primary outcome was any PONV occurrence within 24 hours. Secondary outcomes included postoperative pain intensity, opioid consumption, opioid-related adverse events, and length of hospital stay. RESULTS: Fifteen RCTs involving 1310 patients were identified for a network meta-analysis from 1776 articles that compared OFA, OSA, and traditional opioid-based anesthesia (OBA) strategies in LBS. Twelve RCTs (80%) with 922 participants (70%) were eligible for the occurrence of PONV. These included 199 (22%) patients who received OFA and 476 (52%) and 247 (27%) patients who received OSA and OBA, respectively. OFA was more effective at reducing PONV (relative risks [RR], 0.6, 95% confidence interval [CI], 0.5-0.9, moderate-quality evidence) compared to OSA. No differences were observed in postoperative pain control or opioid consumption between the OFA and OSA strategies (very low-to high-quality evidence). Notably, OFA is associated with a higher risk of bradycardia than OSA (RR, 2.6, 95% CI, 1.2-5.9, moderate-quality evidence). CONCLUSIONS: OFA is more effective than OSA in reducing the occurrence of PONV during the early postoperative period of LBS, although it may associate with an increased risk of bradycardia. Patients who received either opioid-alternative strategy demonstrated similar effects in reducing postoperative opioid consumption and alleviating pain intensity.

Obesity-induced downregulation of miR-192 exacerbates lipopolysaccharide-induced acute lung injury by promoting macrophage activation.

BACKGROUND: Macrophage activation may play a crucial role in the increased susceptibility of obese individuals to acute lung injury (ALI). Dysregulation of miRNA, which is involved in various inflammatory diseases, is often observed in obesity. This study aimed to investigate the role of miR-192 in lipopolysaccharide (LPS)-induced ALI in obese mice and its mechanism of dysregulation in obesity. METHODS: Human lung tissues were obtained from obese patients (BMI ≥ 30.0 kg/m2) and control patients (BMI 18.5-24.9 kg/m2). An obese mouse model was established by feeding a high-fat diet (HFD), followed by intratracheal instillation of LPS to induce ALI. Pulmonary macrophages of obese mice were depleted through intratracheal instillation of clodronate liposomes. The expression of miR-192 was examined in lung tissues, primary alveolar macrophages (AMs), and the mouse alveolar macrophage cell line (MH-S) using RT-qPCR. m6A quantification and RIP assays helped determine the cause of miR-192 dysregulation. miR-192 agomir and antagomir were used to investigate its function in mice and MH-S cells. Bioinformatics and dual-luciferase reporter gene assays were used to explore the downstream targets of miR-192. RESULTS: In obese mice, depletion of macrophages significantly alleviated lung tissue inflammation and injury, regardless of LPS challenge. miR-192 expression in lung tissues and alveolar macrophages was diminished during obesity and further decreased with LPS stimulation. Obesity-induced overexpression of FTO decreased the m6A modification of pri-miR-192, inhibiting the generation of miR-192. In vitro, inhibition of miR-192 enhanced LPS-induced polarization of M1 macrophages and activation of the AKT/ NF-κB inflammatory pathway, while overexpression of miR-192 suppressed these reactions. BIG1 was confirmed as a target gene of miR-192, and its overexpression offset the protective effects of miR-192. In vivo, when miR-192 was overexpressed in obese mice, the activation of pulmonary macrophages and the extent of lung injury were significantly improved upon LPS challenge. CONCLUSIONS: Our study indicates that obesity-induced downregulation of miR-192 expression exacerbates LPS-induced ALI by promoting macrophage activation. Targeting macrophages and miR-192 may provide new therapeutic avenues for obesity-associated ALI.

Oral health self-management barriers among rural older adults in Guangxi, China: A qualitative study.

BACKGROUND: Objective: To understand the barriers associated with self-management of oral health among rural older adults in Guangxi, and to explore the high incidence of oral problems. This information will assist in the formulation of relevant strategies to solve the oral health problems in this population. METHODS: Taking a phenomenological approach, the current status of, and barriers to, oral health self-management in rural older adults from different regions of Guangxi were explored. Participants were purposively selected and interviewed face-to-face. RESULTS: The interviews yielded four overarching themes and six corresponding sub-themes pertaining to barriers in oral health self-management. These included: (1) Older adults' understanding of oral health and disease, perceptions of oral health and their oral health behaviours; (2) Problems in accessing oral health information; (3) Role of family support; and (4) Barriers to healthcare that included access to dental services, oral treatment experience and financial burden of access to dental care. CONCLUSION: Rural older adults in Guangxi face oral health self-management barriers. Improving access to oral healthcare services and changing existing oral health perceptions and habits may assist them in overcoming self-management challenges.

Association Between the Blood Glucose Value at PACU Discharge and Postoperative Hypoglycemia in Nondiabetic Patients With Hyperglycemia After Hysteroscopic Surgery: A Retrospective Cohort Study.

PURPOSE: The target glycemic control for nondiabetic patients in the postanesthesia care unit (PACU) after hysteroscopic surgery remains unclear. Our goal is to determine the optimal level of glycemic control by finding the relationship between blood glucose level (BGL) leaving the PACU and postoperative hypoglycemia in nondiabetic patients. DESIGN: This retrospective cohort study was conducted at a comprehensive tertiary hospital in Chongqing, China between June 2018 and December 2020. METHODS: The target independent and dependent variables were BGL leaving the PACU and postoperative hypoglycemia, respectively. The primary outcome was the incidence of hypoglycemia. Logistic regression was used to explore the association between discharge BGL and hypoglycemia. The optimal glycemic control range was determined by using the receiver operating characteristic (ROC) curve. FINDINGS: Prior to insulin use, BGL in the insulin-using subgroup might be as high as 20 mmol/L. Hypoglycemia was related to the BGL while leaving the PACU (odds ratio (OR) 0.37 [95% confidence interval (CI) 0.22 to 0.65]). The best cut-off value (12.95 mmol/L) was determined by fitting the ROC curve. CONCLUSIONS: If severe hyperglycemia develops during hysteroscopic surgery in individuals with 5% glucose as the mediator of uterine distention, the recommendation is to maintain blood glucose above 12.95 mmol/L when treated with insulin.

[Effect of polymethoxylated flavonoids on glucose and lipid metabolism in rat model of obesity induced by a high-fat diet].

This study established a rat model of obesity by using a high-fat diet(HFD) to explore the effect of polymethoxylated flavonoids on glucose and lipid metabolism in the model rats and decipher the role and mechanism of polymethoxylated flavonoids in mitigating obesity. Thirty normal SD rats were selected and randomized into normal, model, ezetimibe(0.1 mg·kg~(-1)), and polymethoxylated flavonoids(62.5 mg·kg~(-1) and 125 mg·kg~(-1)) groups based on the body weight. Except the normal group receiving a conventional diet, the other groups received a HFD. Rats were administrated with corresponding doses of drugs by gavage. During the administration period, the body weight of each group of rats was regularly weighed, and the serum lipid and glucose levels were measured by a fully automated biochemical analyzer. Islet homeostasis and serum levels of obesity factors were measured by ELISA. The 16S rRNA high-throughput sequencing was employed to study the gut microbiota. Hematoxylin-eosin staining was employed to observe the histomorphology of white fat, brown fat, and pancreas. After the wet weights of white fat and brown fat were measured, the organ index was calculated. Immunohistochemistry and Western blot were employed to determine the protein levels. The results showed that polymethoxylated flavonoids reduced the body weight and Lee's index and improved blood lipid levels of the model rats. Polymethoxylated flavonoids reduced blood glucose and insulin secretion, increased insulin responsiveness, and alleviated insulin resistance. In addition, polymethoxylated flavonoids regulated the serum levels of obesity factors and reduced the weights and indexes of white fat and brown fat, the diameter of white adipocytes, and the number of fat vacuoles in brown fat and pancreatic islet cells. The intervention with polymethoxylated flavonoids increased the diversity of gut microbiota in the model rats, increasing the beneficial bacteria associated with glucose and lipid metabolism and reduced the harmful bacteria at the genus level. In addition, polymethoxylated flavonoids up-regulated the protein levels of glucose transporter 4(GLUT4), phosphorylated AMP-activated protein kinase(p-AMPK), peroxisome proliferator-activated receptor gamma coactivator-1α(PGC-1α), and uncoupling protein 1(UCP1). In summary, polymethoxylated flavonoids may increase the body utilization of glucose and lipids by regulating the homeostasis of insulin, the serum levels of obesity factors, the diversity of gut microbiota, and the expression of mitochondrial metabolism-related proteins in brown adipocytes, thereby mitigating obesity in rats.

Comparative analysis of intestinal microbiota composition and transcriptome in diploid and triploid Carassius auratus.

Polyploidy and the microbiome are crucial factors in how a host organism responds to disease. However, little is known about how triploidization and microbiome affect the immune response and disease resistance in the fish host. Therefore, this study aims to identify the relationship between intestinal microbiota composition, transcriptome changes, and disease resistance in triploid Carassius auratus (3nCC). In China's central Dongting lake water system, diploid (2nCC) and triploid Carassius auratus were collected, then 16S rRNA and mRNA sequencing were used to examine the microbes and gene expression in the intestines. 16S rRNA sequencing demonstrated that triploidization altered intestinal richness, as well as the diversity of commensal bacteria in 3nCC. In addition, the abundance of the genus Vibrio in 3nCC was increased compared to 2nCC (P < 0.05). Furthermore, differential expression analysis of 3nCC revealed profound up-regulation of 293 transcripts, while 324 were down-regulated. Several differentially expressed transcripts were related to the immune response pathway in 3nCC, including NLRP3, LY9, PNMA1, MR1, PELI1, NOTCH2, NFIL3, and NLRC4. Taken together, triploidization can alter bacteria composition and abundance, which can in turn result in changes in expression of genes. This study offers an opportunity for deciphering the molecular mechanism underlying disease resistance after triploidization.

Fiber-coupled silicon carbide divacancy magnetometer and thermometer.

Divacancy in silicon carbide has become an important solid-state system for quantum metrologies. To make it more beneficial for practical applications, we realize a fiber-coupled divacancy-based magnetometer and thermometer simultaneously. First, we realize an efficient coupling between the divacancy in a silicon carbide slice with a multimode fiber. Then the optimization of the power broadening in optically detected magnetic resonance (ODMR) of divacancy is performed to obtain a higher sensing sensitivity of 3.9 µT/Hz1/2. We then use it to detect the strength of an external magnetic field. Finally, we use the Ramsey methods to realize a temperature sensing with a sensitivity of 163.2 mK/Hz1/2. The experiments demonstrate that the compact fiber-coupled divacancy quantum sensor can be used for multiple practical quantum sensing.

Fiber-integrated silicon carbide silicon-vacancy-based magnetometer.

Silicon vacancies in silicon carbide have drawn much attention for various types of quantum sensing. However, most previous experiments are realized using confocal scanning systems, which limits their practical applications. In this work, we demonstrate a compact fiber-integrated silicon carbide silicon-vacancy-based magnetometer at room temperature. First, we effectively couple the silicon vacancy in a tiny silicon carbide slice with an optical fiber tip and realize the readout of the spin signal through the fiber at the same time. We then study the optically detected magnetic resonance spectra at different laser and microwave powers, obtaining an optimized magnetic field sensitivity of 12.3 µT/Hz 12. Based on this, the magnetometer is used to measure the strength and polar angle of an external magnetic field. Through these experiments, we have paved the way for fiber-integrated silicon-vacancy-based magnetometer applications in practical environments, such as geophysics and biomedical sensing.

Generation of High-Density High-Polarization Positrons via Single-Shot Strong Laser-Foil Interaction.

We put forward a novel method for producing ultrarelativistic high-density high-polarization positrons through a single-shot interaction of a strong laser with a tilted solid foil. In our method, the driving laser ionizes the target, and the emitted electrons are accelerated and subsequently generate abundant γ photons via the nonlinear Compton scattering, dominated by the laser. These γ photons then generate polarized positrons via the nonlinear Breit-Wheeler process, dominated by a strong self-generated quasistatic magnetic field B^{S}. We find that placing the foil at an appropriate angle can result in a directional orientation of B^{S}, thereby polarizing positrons. Manipulating the laser polarization direction can control the angle between the γ photon polarization and B^{S}, significantly enhancing the positron polarization degree. Our spin-resolved quantum electrodynamics particle-in-cell simulations demonstrate that employing a laser with a peak intensity of about 10^{23} W/cm^{2} can obtain dense (≳10^{18} cm^{-3}) polarized positrons with an average polarization degree of about 70% and a yield of above 0.1 nC per shot. Moreover, our method is feasible using currently available or upcoming laser facilities and robust with respect to the laser and target parameters. Such high-density high-polarization positrons hold great significance in laboratory astrophysics, high-energy physics, and new physics beyond the standard model.

Increased Two-Hour Post-Load Plasma Glucose Fluctuation Corresponds with Worse Clinical Prognoses among Acute Ischemic Stroke Patients without a History of Diabetes Mellitus.

INTRODUCTION: This study aimed to evaluate the relationship between 2-h post-load minus fasting plasma glucose (2hPG-FPG) and 1-year clinical outcomes, such as death, stroke recurrence, and modified Rankin Scale (mRS) ≥2-3 among acute ischemic stroke (AIS) patients without diabetes mellitus (DM) history. METHODS: 1,214 AIS patients without DM history, obtained from ACROSS-China, were divided into 4 quartiles, based on 2hPG-FPG measurements obtained 14 days post-admission. Four models were constructed using multivariate Cox and logistic regression analyses, based on the inclusion of age, gender, trial of ORG 10172 in acute stroke treatment, NIH Stroke Scale scores (model 1), plus 10 other clinical parameters (model 2), plus newly diagnosed DM (NDDM) post-admission (model 3), plus 2hPG and FPG (model 4). Associations found from those 4 models between 2hPG-FPG and 1-year clinical outcomes were confirmed via stratification, multiplicative interaction, sensitivity, and restricted cubic spline analyses. RESULTS: The highest quartile of 2hPG-FPG, after adjusting for variables, such as stroke severity (model 2), was independently associated with death, stroke recurrence, and mRS ≥2-3 (odds ratio [OR] = 3.95, 2.96, 4.15, and 4.83, respectively, all p < 0.0001). Increased 2hPG-FPG remained independently associated with mRS ≥2-3 in models 3-4, as well as increased mRS ≥2 under stratification analyses among both non-NDDM and NDDM patients. CONCLUSION: 2hPG-FPG is a relatively specific indicator of poorer 1-year clinical prognoses among AIS patients, independent of NDDM, 2hPG, and FPG post-hospital admission. Therefore, the oral glucose tolerance test could be a useful approach for detecting a higher likelihood for developing poorer prognoses among patients without DM history.

Characterization of LTr1 derived from cruciferous vegetables as a novel anti-glioma agent via inhibiting TrkA/PI3K/AKT pathway.

Malignant glioma is the most fatal, invasive brain cancer with limited treatment options. Our previous studies show that 2-(indol-3-ylmethyl)-3,3'-diindolylmethane (LTr1), a major metabolite of indole-3-carbinol (I3C) derived from cruciferous vegetables, produces anti-tumour effect against various tumour cell lines. In this study we characterized LTr1 as a novel anti-glioma agent. Based on screening 134 natural compounds and comparing the candidates' efficacy and toxicity, LTr1 was selected as the lead compound. We showed that LTr1 potently inhibited the viability of human glioma cell lines (SHG-44, U87, and U251) with IC50 values of 1.97, 1.84, and 2.03 µM, respectively. Furthermore, administration of LTr1 (100,300 mg· kg-1 ·d-1, i.g. for 18 days) dose-dependently suppressed the tumour growth in a U87 xenograft nude mouse model. We demonstrated that LTr1 directly bound with TrkA to inhibit its kinase activity and the downstream PI3K/AKT pathway thus inducing significant S-phase cell cycle arrest and apoptosis in SHG-44 and U87 cells by activating the mitochondrial pathway and inducing the production of reactive oxygen species (ROS). Importantly, LTr1 could cross the blood-brain barrier to achieve the therapeutic concentration in the brain. Taken together, LTr1 is a safe and promising therapeutic agent against glioma through inhibiting TrkA/PI3K/AKT pathway.

Cytoarchitecture of Mudskipper (Boleophthalmus pectinirostris) Brain.

Mudskippers are intertidal burrowing fish with unique living habits. So far, studies on the cytoarchitecture of the brain in fish with such behaviors remain limited. Therefore, documenting the neuroanatomy of this animal is of interest because of its unique characteristics. In this study, we examined the cytoarchitecture of mudskipper (Boleophthalmus pectinirostris) brain and investigated whether it has any peculiarities in its brain structures. In general, the basic composition, morphology, and organization of mudskipper brain do not vary markedly from those of other teleosts. The main differences appear in the telencephalon and diencephalon. In addition to Nissl staining, immunostainings for catecholaminergic and cholinergic systems were performed to help identify certain nuclei. The results showed that the number of subdivisions of the central division of pallium, lateral division of pallium, and medial division of pallium were different with other teleost species. In addition, some diencephalic nuclei, including the nucleus subglomerulosus, lateral thalamic nucleus, and intermediate superficial pretectal nucleus, were absent, which suggests the corresponding functions, such as visual or gustatory function, are less developed or specialized in B. pectinirostris. These results will provide a fundamental neuroanatomical basis for future studies on neuroendocrine regulation of behavior in intertidal burrowing fish.

Design and Validation of a Novel Evaluation Scale to Predict Inpatient Large Vessel Occlusion Strokes: Clinical Assessment Stroke Severity for Inpatient Scale.

OBJECTIVES: A large quantity of ischemic stroke events occur in patients hospitalized for non-stroke-related reason. No scale has been developed to identify the large vessel occlusion (LVO) among inpatient stroke alerts. We aimed to develop a novel evaluation scale to predict LVO from in-hospital stroke alerts. METHODS: Data from consecutive in-hospital stroke alerts were analyzed at a single high volume stroke center between January 2016 and October 2020. We developed a predictive scale based on the first half of patients (training group) using multivariate logistic regression and evaluated it in the remaining half of patients (validation group) adopting receiver operating curve. Receiver operating characteristics of the scale were analyzed to evaluate its value for the detection of LVO. RESULTS: A total of 243 patients were enrolled for further study, among them, 94 (38.7%) had confirmed LVO. Three risk factors independently predicted the presence of LVO: recent cardiac or pulmonary procedure (1 point), neurological deficit scale (≥1: 2 points), and history of atrial fibrillation (1 point). The CAPS scale was generated based on predictive factors and demonstrated highly effective discrimination in identifying the presence of LVO in the training group (area under curve = 0.956) and the validation group (area under curve = 0.940). When the score ≥2, CAPS scale showed 97.9% sensitivity, 79.2% specificity, 74.8% positive predictive value, and 98.3% negative predictive value for discriminating LVO. CONCLUSIONS: CAPS scale was developed for identifying LVO among inpatient stroke alerts with high sensitivity and specificity, which may help to quickly prompt responses by appropriate stroke teams.