Patent foramen ovale closure in ischemic stroke patients with and without thrombophilia: a systematic review and meta-analyses.

Ischemic stroke patients with thrombophilia and patient foramen ovale (PFO) may have an increased risk of recurrent stroke and transient ischemic attack (TIA), and may benefit from PFO closure. However, screening for thrombophilia is not routinely performed and the impact of thrombophilia on prognosis after PFO closure is uncertain. We aim to compare the risk of recurrent stroke and TIA after PFO closure in patients with thrombophilia versus those without. We performed a systematic review and meta-analyses of the literature, with a comprehensive literature search performed on 12 January 2023. Studies comparing the outcomes of patients with and without thrombophilia after PFO closure were included. The primary outcome evaluated was a recurrence of acute cerebrovascular event (ACE), a composite of recurrent ischemic stroke and recurrent TIA. The secondary outcomes included recurrent ischemic stroke only or TIA only. A total of 8 cohort studies were included, with a total of 3514 patients. There was an increased risk of stroke/TIA in patients with thrombophilia compared to those without thrombophilia after PFO (OR: 1.42, 95% CI: 1.01-1.99, I2 = 50%). The association between risk of TIA only (OR: 1.36, 95% CI: 0.77-2.41, I2 = 0%) and stroke only (OR: 1.09, 95% CI: 0.54-2.21, I2 = 0%) with thrombophilia did not reach statistical significance. There is an increased risk of recurrent cerebral ischemia event in patients with thrombophilia compared to those without thrombophilia after PFO closure. Future large prospective studies are necessary to characterise the risk and benefits of PFO closure, as well as the appropriate medical treatment to reduce the risk of recurrent stroke and TIA in this high-risk population.

Development and validation of a model for predicting upstage in minimally invasive lung adenocarcinoma in Chinese people.

BACKGROUND: Sublobar resection for ground-glass opacity became a recommend surgery choice supported by the JCOG0804/JCOG0802/JCOG1211 results. Sublobar resection includes segmentectomy and wedge resection, wedge resection is suitable for non-invasive lesions, but in clinical practice, when pathologists are uncertain about the intraoperative frozen diagnosis of invasive lesions, difficulty in choosing the appropriate operation occurs. The purpose of this study was to analyze how to select invasive lesions with clinic-pathological characters. METHODS: A retrospective study was conducted on 134 cases of pulmonary nodules diagnosed with minimally invasive adenocarcinoma by intraoperative freezing examination. The patients were divided into two groups according to intraoperative frozen results: the minimally invasive adenocarcinoma group and the at least minimally invasive adenocarcinoma group. A variety of clinical features were collected. Chi-square tests and multiple regression logistic analysis were used to screen out independent risk factors related to pathological upstage, and then ROC curves were established. In addition, an independent validation set included 1164 cases was collected. RESULTS: Independent risk factors related to pathological upstage were CT value, maximum tumor diameter, and frozen result of AL-MIA. The AUC of diagnostic mode was 71.1% [95%CI: 60.8-81.3%]. The independent validation included 1164 patients, 417 (35.8%) patients had paraffin-based pathology of invasive adenocarcinoma. The AUC of diagnostic mode was 75.7% [95%CI: 72.9-78.4%]. CONCLUSIONS: The intraoperative frozen diagnosis was AL-MIA, maximum tumor diameter larger than 15 mm and CT value is more than - 450Hu, highly suggesting that the lung GGO was invasive adenocarcinoma which represent a higher risk to recurrence. For these patients, sublobectomy would be insufficient, lobectomy or complementary treatment is encouraged.

Dihydroartemisinin alleviates doxorubicin-induced cardiotoxicity and ferroptosis by activating Nrf2 and regulating autophagy.

Although the use of Doxorubicin (Dox) is extensive in the treatment of malignant tumor, the toxic effects of Dox on the heart can cause myocardial injury. Therefore, it is necessary to find an alternative drug to alleviate the Dox-induced cardiotoxicity. Dihydroartemisinin (DHA) is a semisynthetic derivative of artemisinin, which is an active ingredient of Artemisia annua. The study investigates the effects of DHA on doxorubicin-induced cardiotoxicity and ferroptosis, which are related to the activation of Nrf2 and the regulation of autophagy. Different concentrations of DHA were administered by gavage for 4 weeks in mice. H9c2 cells were pretreated with different concentrations of DHA for 24 h in vitro. The mechanism of DHA treatment was explored through echocardiography, biochemical analysis, real-time quantitative PCR, western blotting analysis, ROS/DHE staining, immunohistochemistry, and immunofluorescence. In vivo, DHA markedly relieved Dox-induced cardiac dysfunction, attenuated oxidative stress, alleviated cardiomyocyte ferroptosis, activated Nrf2, promoted autophagy, and improved the function of lysosomes. In vitro, DHA attenuated oxidative stress and cardiomyocyte ferroptosis, activated Nrf2, promoted clearance of autophagosomes, and reduced lysosomal destruction. The changes of ferroptosis and Nrf2 depend on selective degradation of keap1 and recovery of lysosome. We found for the first time that DHA could protect the heart from the toxic effects of Dox-induced cardiotoxicity. In addition, DHA significantly alleviates Dox-induced ferroptosis through the clearance of autophagosomes, including the selective degradation of keap1 and the recovery of lysosomes.

A study of the effects of screen exposure on the neuropsychological development in children with autism spectrum disorders based on ScreenQ.

PURPOSE: To investigate the relationship between multi-dimensional aspects of screen exposure and autistic symptoms, as well as neuropsychological development in children with ASD. METHODS: We compared the ScreenQ and Griffiths Development Scales-Chinese Language Edition (GDS-C) of 636 ASD children (40.79 ± 11.45 months) and 43 typically developing (TD) children (42.44 ± 9.61 months). Then, we analyzed the correlations between ScreenQ and Childhood Autism Rating Scale (CARS), and GDS-C. We further used linear regression model to analyze the risk factors associated with high CARS total scores and low development quotients (DQs) in children with ASD. RESULTS: The CARS of children with ASD was positively correlated with the ScreenQ total scores and "access, frequency, co-viewing" items of ScreenQ. The personal social skills DQ was negatively correlated with the "access, frequency, content, co-viewing and total scores" of ScreenQ. The hearing-speech DQ was negatively correlated with the "frequency, content, co-viewing and total scores" of ScreenQ. The eye-hand coordination DQ was negatively correlated with the "frequency and total scores" of ScreenQ. The performance DQ was negatively correlated with the "frequency" item of ScreenQ. CONCLUSION: ScreenQ can be used in the study of screen exposure in children with ASD. The higher the ScreenQ scores, the more severe the autistic symptoms tend to be, and the more delayed the development of children with ASD in the domains of personal-social, hearing-speech and eye-hand coordination. In addition, "frequency" has the greatest impact on the domains of personal social skills, hearing-speech, eye-hand coordination and performance of children with ASD.

Portable and Flexible Hydrogel Sensor for On-Site Atrazine Assay on Agricultural Products.

There is growing attention focused toward the problems of ecological sustainability and food safety raised from the abuse of herbicides, which underscores the need for the development of a portable and reliable sensor for simple, rapid, and user-friendly on-site analysis of herbicide residues. Herein, a novel multifunctional hydrogel composite is explored to serve as a portable and flexible sensor for the facile and efficient analysis of atrazine (ATZ) residues. The hydrogel electrode is fabricated by doping graphite-phase carbon nitride (g-C3N4) into the aramid nanofiber reinforced poly(vinyl alcohol) hydrogel via a simple solution-casting procedure. Benefiting from the excellent electroactivity and large specific surface area of the solid nanoscale component, the prepared hydrogel sensor is capable of simple, rapid, and sensitive detection of ATZ with a detection limit down to 0.002 ng/mL and per test time less than 1 min. After combination with a smartphone-controlled portable electrochemical analyzer, the flexible sensor exhibited satisfactory analytical performance for the ATZ assay. We further demonstrated the applications of the sensor in the evaluation of the ATZ residues in real water and soil samples as well as the user-friendly on-site point-of-need detection of ATZ residues on various agricultural products. We envision that this flexible and portable sensor will open a new avenue on the development of next-generation analytical tools for herbicide monitoring in the environment and agricultural products.

Smart diabetic foot ulcer scoring system.

Current assessment methods for diabetic foot ulcers (DFUs) lack objectivity and consistency, posing a significant risk to diabetes patients, including the potential for amputations, highlighting the urgent need for improved diagnostic tools and care standards in the field. To address this issue, the objective of this study was to develop and evaluate the Smart Diabetic Foot Ulcer Scoring System, ScoreDFUNet, which incorporates artificial intelligence (AI) and image analysis techniques, aiming to enhance the precision and consistency of diabetic foot ulcer assessment. ScoreDFUNet demonstrates precise categorization of DFU images into "ulcer," "infection," "normal," and "gangrene" areas, achieving a noteworthy accuracy rate of 95.34% on the test set, with elevated levels of precision, recall, and F1 scores. Comparative evaluations with dermatologists affirm that our algorithm consistently surpasses the performance of junior and mid-level dermatologists, closely matching the assessments of senior dermatologists, and rigorous analyses including Bland-Altman plots and significance testing validate the robustness and reliability of our algorithm. This innovative AI system presents a valuable tool for healthcare professionals and can significantly improve the care standards in the field of diabetic foot ulcer assessment.

Uridine diphosphate glucosyltransferase is vital for fenpropathrin resistance in Bombyx mori (Lepidoptera).

The silkworm (Bombyx mori) is an important model lepidopteran insect and can be used to identify pesticide resistance-related genes of great significance for biological control of pests. Uridine diphosphate glucosyltransferases (UGTs), found in all organisms, are the main secondary enzymes involved in the metabolism of heterologous substances. However, it remains uncertain if silkworm resistance to fenpropathrin involves UGT. This study observes significant variations in BmUGT expression among B. mori strains with variable fenpropathrin resistance post-feeding, indicating BmUGT's role in fenpropathrin detoxification. Knockdown of BmUGT with RNA interference and overexpression of BmUGT significantly decreased and increased BmN cell activity, respectively, indicating that BmUGT plays an important role in the resistance of silkworms to fenpropathrin. In addition, fenpropathrin residues were significantly reduced after incubation for 12 h with different concentrations of a recombinant BmUGT fusion protein. Finally, we verified the conservation of UGT to detoxify fenpropathrin in Spodoptera exigua: Its resistance to fenpropathrin decreased significantly after knocking down SeUGT. In a word, UGT plays an important role in silkworm resistance to fenpropathrin by directly degrading the compound, a function seen across other insects. The results of this study are of great significance for breeding silkworm varieties with high resistance and for biological control of pests.

Sleep and internalizing problems in primary school children with attention-deficit hyperactivity disorder.

BACKGROUND: Internalizing and externalizing problems have received great attention, and children with ADHD exhibit high rates of comorbid internalizing and externalizing disorders. This study aimed to explore the relationship between sleep and internalizing problems in children with attention-deficit hyperactivity disorder (ADHD) and the probable mediating role of externalizing problems. METHODS: A total of 203 primary school children diagnosed with ADHD for the first time were recruited for this study. Children with ADHD were evaluated by Children's Sleep Habits Questionnaire (CSHQ), Strengths and Difficulties Questionnaire (SDQ). Internalizing problems were represented by emotional symptoms and peer problems of SDQ, and externalizing problems were represented by conduct problems and hyperactivity-inattention problems of SDQ. Multi-step linear regression analysis was used to investigate the mediating effect of externalizing problems on the relationship between sleep and internalizing problems. RESULTS: Sleep in children with ADHD was associated with emotional problems in internalizing problems, and conduct problems in externalizing problems mediated the association between sleep and emotional problems. CONCLUSION: For children with ADHD, when it is difficult to identify internalizing problems, especially emotional problems, we can take sleep and externalizing problems as clues to improve our clinical ability to recognize and deal with emotional problems. IMPACT: 1. We first explored the possible mediating role of conduct problems between sleep and emotional problems in primary school children with ADHD. 2. When it is difficult to identify internalizing problems, especially emotional problems, we can take sleep and externalizing problems as clues to improve our clinical ability to recognize emotional problems for children with ADHD. 3. For children with ADHD with potential internalizing problems, especially emotional problems, interventions for their sleep and externalizing problems may be the possible methods to deal with.

Chronic sleep fragmentation impairs brain interstitial clearance in young wildtype mice.

Accumulating evidence shows that most chronic neurological diseases have a link with sleep disturbances, and that patients with chronically poor sleep undergo an accelerated cognitive decline. Indeed, a single-night of sleep deprivation may increase metabolic waste levels in cerebrospinal fluid. However, it remains unknown how chronic sleep disturbances in isolation from an underlying neurological disease may affect the glymphatic system. Clearance of brain interstitial waste by the glymphatic system occurs primarily during sleep, driven by multiple oscillators including arterial pulsatility, and vasomotion. Herein, we induced sleep fragmentation in young wildtype mice and assessed the effects on glymphatic activity and cognitive functions. Chronic sleep fragmentation reduced glymphatic function and impaired cognitive functions in healthy mice. A mechanistic analysis showed that the chronic sleep fragmentation suppressed slow vasomotion, without altering cardiac-driven pulsations. Taken together, results of this study document that chronic sleep fragmentation suppresses brain metabolite clearance and impairs cognition, even in the absence of disease.

Comparative transcriptomic analysis reveals the molecular changes of acute pancreatitis in experimental models.

BACKGROUND: Acute pancreatitis (AP) encompasses a spectrum of pancreatic inflammatory conditions, ranging from mild inflammation to severe pancreatic necrosis and multisystem organ failure. Given the challenges associated with obtaining human pancreatic samples, research on AP predominantly relies on animal models. In this study, we aimed to elucidate the fundamental molecular mechanisms underlying AP using various AP models. AIM: To investigate the shared molecular changes underlying the development of AP across varying severity levels. METHODS: AP was induced in animal models through treatment with caerulein alone or in combination with lipopolysaccharide (LPS). Additionally, using Ptf1α to drive the specific expression of the hM3 promoter in pancreatic acinar cells transgenic C57BL/6J- hM3/Ptf1α(cre) mice were administered Clozapine N-oxide to induce AP. Subsequently, we conducted RNA sequencing of pancreatic tissues and validated the expression of significantly different genes using the Gene Expression Omnibus (GEO) database. RESULTS: Caerulein-induced AP showed severe inflammation and edema, which were exacerbated when combined with LPS and accompanied by partial pancreatic tissue necrosis. Compared with the control group, RNA sequencing analysis revealed 880 significantly differentially expressed genes in the caerulein model and 885 in the caerulein combined with the LPS model. Kyoto Encyclopedia of Genes and Genomes enrichment analysis and Gene Set Enrichment Analysis indicated substantial enrichment of the TLR and NOD-like receptor signaling pathway, TLR signaling pathway, and NF-κB signaling pathway, alongside elevated levels of apoptosis-related pathways, such as apoptosis, P53 pathway, and phagosome pathway. The significantly elevated genes in the TLR and NOD-like receptor signaling pathways, as well as in the apoptosis pathway, were validated through quantitative real-time PCR experiments in animal models. Validation from the GEO database revealed that only MYD88 concurred in both mouse pancreatic tissue and human AP peripheral blood, while TLR1, TLR7, RIPK3, and OAS2 genes exhibited marked elevation in human AP. The genes TUBA1A and GADD45A played significant roles in apoptosis within human AP. The transgenic mouse model hM3/Ptf1α(cre) successfully validated significant differential genes in the TLR and NOD-like receptor signaling pathways as well as the apoptosis pathway, indicating that these pathways represent shared pathological processes in AP across different models. CONCLUSION: The TLR and NOD receptor signaling pathways play crucial roles in the inflammatory progression of AP, notably the MYD88 gene. Apoptosis holds a central position in the necrotic processes of AP, with TUBA1A and GADD45A genes exhibiting prominence in human AP.

A sustainable balance between innovation and risk: How the "right to science" affects China's medical biotechnology regulatory policy.

Medical biotechnology is at the forefront of scientific progress, with humanity facing a critical juncture during the pandemic. However, to maximize these benefits, governments face the complex challenge of reconciling innovation and risk. A sustainable balance is critical, as extreme measures such as blanket bans on biotechnology research could hamper progress, while unfettered research could pose an existential threat. The need for effective regulation has become apparent in the context of recent controversies surrounding pharmaceutical biotechnology. Governments face the challenge of reconciling precaution with innovation, necessitating a dual strategy fostering both principles. This paper explores the delicate dynamics of innovation and risk in pharmaceutical biotechnology, focusing on the evolving landscape in Europe, the U.S., and, notably, China. At the same time, we delve into the regulatory landscape and examine the role of the "right to science" in shaping Chinese policy. This paper further applies the right to science that has received the interests of medical biotechnology regulatory policymakers: understanding the role of scientific claims in regulating emerging technologies and analyzing the impact of major regulations on the ability to sustainably balance innovation and risk. We believe that a comprehensive global effort is needed to harmonize these two principles, highlighting the imperative of responsible governance in steering the trajectory of this powerful scientific frontier. The insights gained from the Chinese experience offer valuable implications for global policymakers facing similar challenges.

Comparison of the efficacy of parent-mediated NDBIs on developmental skills in children with ASD and fidelity in parents: a systematic review and network meta-analysis.

BACKGROUND: Recently, studies on behavioral interventions for autism have gained popularity. Naturalistic Developmental Behavior Interventions (NDBIs) are among the most effective, evidence-based, and widely used behavior interventions for autism. However, no research has been conducted on which of the several NDBI methods is most effective for parents and children with autism spectrum disorders. Therefore, we conducted a network meta-analysis to compare the specific effects of each type of parental-mediated NDBI on children's developmental skills and parent fidelity. METHODS: PubMed, Embase, Cochrane Library, Medline, Web of Science, China National Knowledge Infrastructure (CNKI), CINAHL, and Wanfang databases were searched from inception to August 30, 2023. A total of 32 randomized controlled trial studies that examined the efficacy of different NDBIs were included. RESULTS: Parents of children with ASD who received Pivotal Response Treatment (PRT) reported significant improvements in their children's social skills (SUCRA, 74.1%), language skills (SUCRA, 88.3%), and parenting fidelity (SUCRA, 99.5%). Moreover, parents who received Early Start Denver Model (ESDM) reported significant improvements in their children's language (SMD = 0.41, 95% CI: 0.04, 0.79) and motor skills (SMD = 0.44, 95% CI: 0.09, 0.79). In terms of the efficacy of improving parent fidelity, the results showed that the Improving Parents as Communication Teachers (ImPACT) intervention significantly improved parent fidelity when compared with the treatment-as-usual group (TAU) (SMD = 0.90, 95% CI: 0.39, 1.42) and the parental education intervention (PEI) (SMD = 1.10, 95% CI:0.28, 1.91).There was a difference in parent fidelity among parents who received PRT(SMD = 3.53, 95% CI: 2.26, 4.79) or ESDM(SMD = 1.42, 95% CI: 0.76, 2.09) training compared with PEI. CONCLUSION: In conclusion, this study revealed that parents can achieve high fidelity with the ImPACT intervention, and it can serve as an early first step for children newly diagnosed with ASD. It also showed that parent-mediated ESDM is effective in improving language and motor skills for children with ASD and can be used as part of the second stage of parent training. Parent-mediated PRT can also be used as a third stage of parent training with sufficient training intensity to further improve language, social, and motor skills.

ALPL regulates pro-angiogenic capacity of mesenchymal stem cells through ATP-P2X7 axis controlled exosomes secretion.

BACKGROUND: Early-onset bone dysplasia is a common manifestation of hypophosphatasia (HPP), an autosomal inherited disease caused by ALPL mutation. ALPL ablation induces prototypical premature bone ageing characteristics, resulting in impaired osteogenic differentiation capacity of human bone marrow mesenchymal stem cells (hBMMSCs). As angiogenesis is tightly coupled with osteogenesis, it also plays a necessary role in sustaining bone homeostasis. We have previously observed a decrease in expression of angiogenesis marker gene CD31 in the metaphysis of long bone in Alpl+/- mice. However, the role of ALPL in regulation of angiogenesis in bone has remained largely unknown. METHODS: Exosomes derived from Normal and HPP hBMMSCs were isolated and identified by ultracentrifugation, transmission electron microscopy, and nanoparticle size measurement. The effects of ALPL on the angiogenic capacity of hBMMSCs from HPP patients were assessed by immunofluorescence, tube formation, wound healing and migration assay. exo-ELISA and Western Blot were used to evaluate the exosomes secretion of hBMMSCs from HPP, and the protein expression of VEGF, PDGFBB, Angiostatin and Endostatin in exosomes respectively. RESULTS: We verified that ALPL ablation resulted in impaired pro-angiogenic capacity of hBMMSCs, accounting for reduced migration and tube formation of human umbilical vein endothelial cells, as the quantities and proteins composition of exosomes varied with ALPL expression. Mechanistically, loss of function of ALPL enhanced ATP release. Additional ATP, in turn, led to markedly elevated level of ATP receptor P2X7, which consequently promoted exosomes secretion, resulting in a decreased capacity to promote angiogenesis. Conversely, inhibition of P2X7 increased the angiogenic induction capacity by preventing excessive release of anti-angiogenic exosomes in ALPL deficient-hBMMSCs. CONCLUSION: The ALPL-ATP axis regulates the pro-angiogenic ability of hBMMSCs by controlling exosomes secretion through the P2X7 receptor. Thus, P2X7 may be proved as an effective therapeutic target for accelerating neovascularization in ALPL-deficient bone defects.

Novel peripheral blood mononuclear cell mRNA signature for IFN-beta therapy responsiveness prediction in multiple sclerosis.

Interferon-beta (IFN-ß) is one of the classical drugs for immunomodulatory therapy in relapsing-remitting multiple sclerosis (RRMS) patients, but the drug responsiveness of different patients varies. Currently, there is no valid model to predict IFN-ß responsiveness. This research attempted to develop an IFN-ß responsiveness prediction model based on mRNA expression in RRMS patient peripheral blood mononuclear cells. Peripheral blood mononuclear cell mRNA expression datasets including 50 RRMS patients receiving IFN-ß treatment were obtained from GEO. Among the datasets, 24 cases from GSE24427 were included in a training set, and 18 and 9 cases from GSE19285 and GSE33464, respectively, were adopted as two independent test sets. In the training set, blood samples were collected immediately before first, second, month 1, 12, and 24 IFN-ß injection, and the mRNA expression data at four time points, namely, two days, one month, one year and two years after the onset of IFN-ß treatment, were compared with pre-treatment data to identify IFN-stimulated genes (ISGs). The ISGs at the one-month time point were used to construct the drug responsiveness prediction model. Next, the drug responsiveness model was verified in the two independent test sets to examine the performance of the model in predicting drug responsiveness. Finally, we used CIBERSORTx to estimate the content of cell subtypes in samples and evaluated whether differences in the proportions of cell subtypes were related to differences in IFN-ß responsiveness. Among the four time points, one month was the time point when the training set GSE24427 and test set GSE33464 had the highest number of ISGs. Functional analysis showed that these one-month ISGs were enriched in biological functions such as the innate immune response, type-I interferon signalling pathway, and other IFN-ß-associated functions. Based on these ISGs, we obtained a four-factor prediction model for IFN-ß responsiveness including MX1, MX2, XAF1, and LAMP3. In addition, the model demonstrated favourable predictive performance within the training set and two external test sets. A higher proportion of activated NK cells and lower naive CD4/total CD4 ratio might indicate better drug responsiveness. This research developed a polygene-based biomarker model that could predict RRMS patient IFN-ß responsiveness in the early treatment period. This model could probably help doctors screen out patients who would not benefit from IFN-ß treatment early and determine whether a current treatment plan should be continued.

Endothelial ELABELA improves post-ischemic angiogenesis by upregulating VEGFR2 expression.

BACKGROUND: Post-ischemic angiogenesis is critical for perfusion recovery and tissue repair. ELABELA (ELA) plays an essential role in embryonic heart development and vasculogenesis. However, the mechanism of ELA on post-ischemic angiogenesis is poorly characterized. METHODS: We first assessed ELA expression after hind limb ischemia (HLI) in mice. We then established a HLI model in tamoxifen-inducible endothelial-ELA-specific knockout mice (ELAECKO) and assessed the rate of perfusion recovery, capillary density, and VEGFR2 pathway. Knockdown of ELA with lentivirus or siRNA and exogenous addition of ELA peptides were employed to analyze the effects of ELA on angiogenic capacity and VEGFR2 pathway in endothelial cells in vitro. The serum levels of ELA in healthy people and patients with type 2 diabetes mellitus (T2DM) and diabetic foot ulcer (DFU) were detected by a commercial ELISA kit. RESULTS: In murine HLI models, ELA was significantly up-regulated in the ischemic hindlimb. Endothelial-specific deletion of ELA impaired perfusion recovery and angiogenesis. In physiologic conditions, no significant difference in VEGFR2 expression was found between ELAECKO mice and ELAWT mice. After ischemia, the expression of VEGFR2, p-VEGFR2, and p-AKT was significantly lower in ELAECKO mice than in ELAWT mice. In cellular experiments, the knockdown of ELA inhibited endothelial cell proliferation and tube formation, and the addition of ELA peptides promoted proliferation and tube formation. Mechanistically, ELA upregulated the expression of VEGFR2, p-VEGFR2, and p-AKT in endothelial cells under hypoxic conditions. In clinical investigations, DFU patients had significantly lower serum levels of ELA compared to T2DM patients. CONCLUSION: Our results indicated that endothelial ELA is a positive regulator of post-ischemic angiogenesis via upregulating VEGFR2 expression. Targeting ELA may be a potential therapeutic option for peripheral arterial diseases.

Bombyx mori voltage-dependent anion-selective channel induces programmed cell death to defend against Bombyx mori nucleopolyhedrovirus infection.

BACKGROUND: Voltage-dependent anion-selective channels (VDACs) serve as pore proteins within the mitochondrial membrane, aiding in the regulation of cell life and cell death. Although the occurrence of cell death is crucial for defense against virus infection, the function played by VDAC in Bombyx mori, in response to the influence of Bombyx mori nucleopolyhedrovirus (BmNPV), remains unclear. RESULTS: BmVDAC was found to be relatively highly expressed both during embryonic development, and in the Malpighian tubule and midgut. Additionally, the expression levels of BmVDAC were found to be different among silkworm strains with varying levels of resistance to BmNPV, strongly suggesting a connection between BmVDAC and virus infection. To gain further insight into the function of BmVDAC in BmNPV, we employed RNA interference (RNAi) to silence and overexpress it by pIZT/V5-His-mCherry. The results revealed that BmVDAC is instrumental in developing the resistance of host cells to BmNPV infection in BmN cell-line cells, which was further validated as likely to be associated with initiating programmed cell death (PCD). Furthermore, we evaluated the function of BmVDAC in another insect, Spodoptera exigua. Knockdown of the BmVDAC homolog in S. exigua, SeVDAC, made the larvae more sensitive to BmNPV. CONCLUSION: We have substantiated the pivotal role of BmVDAC in conferring resistance against BmNPV infection, primarily associated with the initiation of PCD. The findings of this study shine new light on the molecular mechanisms governing the silkworm's response to BmNPV infection, thereby supporting innovative approaches for pest biocontrol. © 2024 Society of Chemical Industry.

Yemazhui () ameliorates lipopolysaccharide-induced acute lung injury modulation of the toll-like receptor 4/nuclear factor kappa-B/nod-like receptor family pyrin domain-containing 3 protein signaling pathway and intestinal flora in rats.

OBJECTIVE: To investigate the impact of Yemazhui (Herba Eupatorii Lindleyani, HEL) against lipopolysaccharide (LPS)-induced acute lung injury (ALI) and explore its underlying mechanism in vivo. METHODS: The chemical constituents of HEL were analyzed by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry method. Then, HEL was found to suppress LPS-induced ALI in vivo. Six-week-old male Sprague-Dawley rats were randomly divided into 6 groups: control, LPS, Dexamethasone (Dex), HEL low dose 6 g/kg (HEL-L), HEL medium dose 18 g/kg (HEL-M) and HEL high dose 54 g/kg (HEL-H) groups. The model rats were intratracheally injected with 3 mg/kg LPS to establish an ALI model. Leukocyte counts, lung wet/dry weight ratio, as well as myeloperoxidase (MPO) activity were determined followed by the detection with hematoxylin and eosin staining, enzyme linked immunosorbent assay, quantitative real time polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence. Besides, to explore the effect of HEL on ALI-mediated intestinal flora, we performed 16s rRNA sequencing analysis of intestinal contents. RESULTS: HEL attenuated LPS-induced inflammation in lung tissue and intestinal flora disturbance. Mechanism study indicated that HEL suppressed the lung coefficient and wet/dry weight ratio of LPS-induced ALI in rats, inhibited leukocytes exudation and MPO activity, and improved the pathological injury of lung tissue. In addition, HEL reduced the expression of tumor necrosis factor-alpha, interleukin-1beta (IL-1ß) and interleukin-6 (IL-6) in bronchoalveolar lavage fluid and serum, and inhibited nuclear displacement of nuclear factor kappa-B p65 (NF-κBp65). And 18 g/kg HEL also reduced the expression levels of toll-like receptor 4 (TLR4), myeloid differentiation factor 88, NF-κBp65, phosphorylated inhibitor kappa B alpha (phospho-IκBα), nod-like receptor family pyrin domain-containing 3 protein (NLRP3), IL-1ß, and interleukin-18 (IL-18) in lung tissue, and regulated intestinal flora disturbance. CONCLUSIONS: In summary, our findings revealed that HEL has a protective effect on LPS-induced ALI in rats, and its mechanism may be related to inhibiting TLR4/ NF-κB/NLRP3 signaling pathway and improving intestinal flora disturbance.

Altered intra- and inter-network brain functional connectivity associated with prolonged screen time in pre-school children with autism spectrum disorder.

Prolonged screen time (ST) has adverse effects on autistic characteristics and language development. However, the mechanisms underlying the effects of prolonged ST on the neurodevelopment of children with autism spectrum disorder (ASD) remain unclear. Neuroimaging technology may help to further explain the role of prolonged ST in individuals with ASD. This study included 164 cases, all cases were divided into low-dose ST exposure (LDE group 108 cases) and high-dose ST exposure (HDE group 56 cases) based on the average ST of all subjects. Spatial independent component analysis (ICA) was used to identify resting state networks (RSNs) and investigate intra- and inter-network alterations in ASD children with prolonged ST. We found that the total Childhood Autism Rating Scale (CARS) scores in the HDE group were significantly higher than those in the LDE group (36.2 ± 3.1 vs. 34.6 ± 3.9, p = 0.008). In addition, the developmental quotient (DQ) of hearing and language in the HDE group were significantly lower than those in the LDE group (31.5 ± 13.1 vs. 42.5 ± 18.5, p < 0.001). A total of 13 independent components (ICs) were identified. Between-group comparison revealed that the HDE group exhibited decreased functional connectivity (FC) in the left precuneus (PCUN) of the default mode network (DMN), the right middle temporal gyrus (MTG) of the executive control network (ECN), and the right median cingulate and paracingulate gyri (MCG) of the attention network (ATN), compared with the LDE group. Additionally, there was an increase in FC in the right orbital part of the middle frontal gyrus (ORBmid) of the salience network (SAN), compared with the LDE group. The inter-network analysis revealed increased FC between the visual network (VN) and basal ganglia (BG) and decreased FC between the sensorimotor network (SMN) and DMN, SMN and ATN, SMN and auditory network (AUN), and DMN and SAN in the HDE group, compared with the LDE group. There was a significant negative correlation between altered FC values in MTG and total CARS scores in subjects (r = - 0.18, p = 0.018).  Conclusion: ASD children with prolonged ST often exhibit lower DQ of language development and more severe autistic characteristics. The alteration of intra- and inter-network FC may be a key neuroimaging feature of the effect of prolonged ST on neurodevelopment in ASD children.  Clinical trial registration: ChiCTR2100051141. What is Known: • Prolonged ST has adverse effects on autistic characteristics and language development. • Neuroimaging technology may help to further explain the role of prolonged ST in ASD. What is New: • This is the first study to explore the impact of ST on intra- and inter-network FC in children with ASD. • ASD children with prolonged ST have atypical changes in intra- and inter-brain network FC.

Schisandrin A alleviates renal fibrosis by inhibiting PKCß and oxidative stress.

BACKGROUND: Renal fibrosis is a common pathway that drives the advancement of numerous kidney maladies towards end-stage kidney disease (ESKD). Suppressing renal fibrosis holds paramount clinical importance in forestalling or retarding the transition of chronic kidney diseases (CKD) to renal failure. Schisandrin A (Sch A) possesses renoprotective effect in acute kidney injury (AKI), but its effects on renal fibrosis and underlying mechanism(s) have not been studied. STUDY DESIGN: Serum biochemical analysis, histological staining, and expression levels of related proteins were used to assess the effect of PKCß knockdown on renal fibrosis progression. Untargeted metabolomics was used to assess the effect of PKCß knockdown on serum metabolites. Unilateral Ureteral Obstruction (UUO) model and TGF-ß induced HK-2 cells and NIH-3T3 cells were used to evaluate the effect of Schisandrin A (Sch A) on renal fibrosis. PKCß overexpressed NIH-3T3 cells were used to verify the possible mechanism of Sch A. RESULTS: PKCß was upregulated in the UUO model. Knockdown of PKCß mitigated the progression of renal fibrosis by ameliorating perturbations in serum metabolites and curbing oxidative stress. Sch A alleviated renal fibrosis by downregulating the expression of PKCß in kidney. Treatment with Sch A significantly attenuated the upregulated proteins levels of FN, COL-I, PKCß, Vimentin and α-SMA in UUO mice. Moreover, Sch A exhibited a beneficial impact on markers associated with oxidative stress, including MDA, SOD, and GSH-Px. Overexpression of PKCß was found to counteract the renoprotective efficacy of Sch A in vitro. CONCLUSION: Sch A alleviates renal fibrosis by inhibiting PKCß and attenuating oxidative stress.

Are Sandwich Vertebrae Prone to Refracture After Percutaneous Vertebroplasty or Kyphoplasty? A Meta-Analysis.

BACKGROUND: The formation of sandwiched vertebrae (SDVs) after percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP) has become a common phenomenon. Whether SDVs are more likely to fracture is still controversial. Therefore, we conducted a meta-analysis to provide medical evidence for whether SDVs are more prone to refracture than non-SDVs (NSDVs) after PVP or PKP. METHODS: This study was conducted in accordance with the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Several databases, including PubMed, Embase, Medline databases, China National Knowledge Infrastructure, Wanfang, and Weipu, were thoroughly searched for relevant studies included from any point up until June 2022. Statistical analyses were performed using Revman 5.4. RESULTS: A total of 4052 individuals from 9 studies were enrolled. Overall, patients with SDV presented more risk to have refracture than patients with NSDV (OR = 1.57, P = 0.04). The incidences of refracture were comparable between the 2 cohorts in studies with a follow-up time less than 3 years (OR = 1.28, P = 0.49). However, patients with SDV were more prone to have refracture than patients with NSDV in studies with a follow-up time longer than 3 years (OR = 1.92, P = 0.009). Moreover, patients with SDV were more likely to have refracture than patients with NSDV in studies that involved both PVP and PKP (OR = 1.62, P = 0.002). In addition, age, low bone density, and postoperative kyphosis angle of sandwich fracture segments >10° were independent factors to predict refracture. CONCLUSIONS: Patients with SDV were more likely to have refracture after PVP or PKP, especially when the follow-up time was longer than 3 years.