HISTONE DEACETYLASE 6 interaction with ABSCISIC ACID-INSENSITIVE 5 decreases apple drought tolerance.

Understanding the molecular regulation of plant response to drought is the basis of drought-resistance improvement through molecular strategies. Here, we characterized apple (Malus × domestica) histone deacetylase 6 (MdHDA6), which negatively regulates apple drought tolerance by catalyzing deacetylation on histones associated with drought-responsive genes. Transgenic apple plants over-expressing MdHDA6 were less drought-tolerant, while those with down-regulated MdHDA6 expression were more drought-resistant than nontransgenic apple plants. Transcriptomic and histone 3 acetylation (H3ac) Chromatin immunoprecipitation-seq analyses indicated that MdHDA6 could facilitate histone deacetylation on the drought-responsive genes, repressing gene expression. Moreover, MdHDA6 interacted with the abscisic acid (ABA) signaling transcriptional factor, ABSCISIC ACID-INSENSITIVE 5 (MdABI5), forming the MdHDA6-MdABI5 complex. Interestingly, MdHDA6 facilitated histone deacetylation on the drought-responsive genes regulated by MdABI5, resulting in gene repression. Furthermore, a dual-Luc experiment showed that MdHDA6 could repress the regulation of a drought-responsive gene, RESPONSIVE TO DESICCATION 29A (MdRD29A) activated by MdABI5. On the one hand, MdHDA6 can facilitate histone deacetylation and gene repression on the positive drought-responsive genes to negatively regulate drought tolerance in apple. On the other hand, MdHDA6 directly interacts with MdABI5 and represses the expression of genes downstream of MdABI5 via histone deacetylation around these genes to reduce drought tolerance. Our study uncovers a different drought response regulatory mechanism in apple based on the MdHDA6-MdABI5 complex function and provides the molecular basis for drought-resistance improvement in apple.

Association of sodium-glucose cotransporter 2 inhibitors with risk of major adverse cardiovascular events in type 2 diabetes patients with acute coronary syndrome: a propensity score­matched analysis.

BACKGROUND: This study aimed to investigate the association of sodium-glucose cotransporter 2 inhibitors (SGLT2i) use with cardiovascular (CV) clinical outcomes in type 2 diabetes (T2D) patients with acute coronary syndrome (ACS). METHODS: Data of T2D patients hospitalized for ACS at Civil Aviation General Hospital from January 2019 to December 2022 were collected. Based on SGLT2i use or not, patients were stratified as SGLT2i group and SGLT2i-free group. A 1:1 nearest-neighbor propensity score-matched (PSM) was performed to adjust for the confounding factors and facilitate the robust comparisons between groups. The first occurrence of major adverse cardiovascular events (MACE) with 1 year follow-up, which consisted of CV death, all cause death, non-fatal myocardial infarction or stroke, coronary revascularization or heart failure readmission, was assessed. Kaplan-Meier analysis and Cox regressions were conducted to evaluate the prognostic significance of SGLT2i use. Subgroup analyses were performed to assess the interaction between subgroups and SGLT2i use. RESULTS: A total of 925 patients were included, and the SGLT2i use increased from 9.9% in 2019 to 43.8% in 2022. 226 pairs were finally matched using the PSM model. During 1 year follow-up period, a total of 110 patients experienced MACE in the matched cohort, with a rate of 24.3%. Survival analyses showed cumulative incidence of MACE, CV death, and heart failure readmission in the SGLT2i group were significantly lower than the SGLT2i-free group. Additionally, the adjusted Cox analyses demonstrated that SGLT2i was associated with a 34.1% lower risk of MACE (HR 0.659, 95% CI 0.487-0.892, P = 0.007), which was primarily driven by a decrease in the risk of CV death by 12.0% (HR 0.880, 95% CI 0.7830.990, P = 0.033), and heart failure readmission by 45.5% (HR 0.545, 95% CI 0.332-0.893, P = 0.016). This MACE preventive benefit was consistent across different subgroups (P interaction > 0.05 for all comparisons). CONCLUSIONS: In T2D patients with ACS, there was a clear increasing trend in SGLT2i use. SGLT2i was associated with a significantly lower risk of MACE, driven by the decrease in the risk of CV death, and heart failure readmission. Our study confirmed real-world use and efficacy of SGLT2i in a general T2D population with ACS.

Histone deacetylase MdHDA6 is an antagonist in regulation of transcription factor MdTCP15 to promote cold tolerance in apple.

Understanding the molecular regulation of plant cold response is the basis for cold resistance germplasm improvement. Here, we revealed that the apple histone deacetylase MdHDA6 can perform histone deacetylation on cold-negative regulator genes and repress their expression, leading to the positive regulation of cold tolerance in apples. Moreover, MdHDA6 directly interacts with the transcription factor MdTCP15. Phenotypic analysis of MdTCP15 transgenic apple lines and wild types reveals that MdTCP15 negatively regulates cold tolerance in apples. Furthermore, we found that MdHDA6 can facilitate histone deacetylation of MdTCP15 and repress the expression of MdTCP15, which positively contributes to cold tolerance in apples. Additionally, the transcription factor MdTCP15 can directly bind to the promoter of the cold-negative regulator gene MdABI1 and activate its expression, and it can also directly bind to the promoter of the cold-positive regulator gene MdCOR47 and repress its expression. However, the co-expression of MdHDA6 and MdTCP15 can inhibit MdTCP15-induced activation of MdABI1 and repression of MdCOR47, suggesting that MdHDA6 suppresses the transcriptional regulation of MdTCP15 on its downstream genes. Our results demonstrate that histone deacetylase MdHDA6 plays an antagonistic role in the regulation of MdTCP15-induced transcriptional activation or repression to positively regulate cold tolerance in apples, revealing a new regulatory mechanism of plant cold response.

The positive feedback regulatory loop of miR160-Auxin Response Factor 17-HYPONASTIC LEAVES 1 mediates drought tolerance in apple trees.

Drought stress tolerance is a complex trait regulated by multiple factors. Here, we demonstrate that the miRNA160-Auxin Response Factor 17 (ARF17)-HYPONASTIC LEAVES 1 module is crucial for apple (Malus domestica) drought tolerance. Using stable transgenic plants, we found that drought tolerance was improved by higher levels of Mdm-miR160 or MdHYL1 and by decreased levels of MdARF17, whereas reductions in MdHYL1 or increases in MdARF17 led to greater drought sensitivity. Further study revealed that modulation of drought tolerance was achieved through regulation of drought-responsive miRNA levels by MdARF17 and MdHYL1; MdARF17 interacted with MdHYL1 and bound to the promoter of MdHYL1. Genetic analysis further suggested that MdHYL1 is a direct downstream target of MdARF17. Importantly, MdARF17 and MdHYL1 regulated the abundance of Mdm-miR160. In addition, the Mdm-miR160-MdARF17-MdHYL1 module regulated adventitious root development. We also found that Mdm-miR160 can move from the scion to the rootstock in apple and tomato (Solanum lycopersicum), thereby improving root development and drought tolerance of the rootstock. Our study revealed the mechanisms by which the positive feedback loop of Mdm-miR160-MdARF17-MdHYL1 influences apple drought tolerance.

Reductions in Depression and Anxiety Among Autistic Adults Participating in an Intervention to Promote Healthy Relationships.

IMPORTANCE: Some autistic adults experience depression and anxiety related to their social relationships. There is a need for evidence-based occupational therapy interventions that decrease depression and anxiety and improve the health of social relationships for autistic adults. OBJECTIVE: To determine the feasibility and preliminary effectiveness of the Healthy Relationships on the Autism Spectrum (HEARTS) intervention, a six-session, group-based psychoeducational intervention for the improvement of relationship health. DESIGN: One-group pretest-posttest design with a 3-mo follow-up after baseline. SETTING: United States; online intervention through community organization. PARTICIPANTS: Fifty-five adults, ages 20 to 43 yr, with a professional or self-diagnosis of autism and the capacity to independently participate in an online, group-based, participatory class. INTERVENTION: Participants received 6 90-min weekly sessions that addressed healthy relationship topics, including recognizing abuse, meeting people, maintaining relationships, setting interpersonal boundaries, neurohealth for relationships, and ending relationships. A psychoeducational approach that provided education and involved guided discovery and strategy acquisition was used. OUTCOMES AND MEASURES: All measures were self-administered through an online survey. Depression and anxiety were assessed using instruments from the Patient-Reported Outcomes Measurement Information System. RESULTS: Fifty-five participants completed the intervention. Postintervention scores revealed statistically significant improvements in depression and anxiety. CONCLUSIONS AND RELEVANCE: HEARTS is a promising intervention for improving depression and anxiety among autistic adults and should be investigated further. What This Article Adds: HEARTS offers a potentially effective, nonpharmacological, psychoeducational group-based intervention option to promote healthy relationships for autistic adults. Positionality Statement: This article uses identity-first language (autistic person) in accordance with the preference of autistic self-advocates (Autistic Self Advocacy Network, 2020; Kenny et al., 2016; Lord et al., 2022).

Recovery of superior frontal gyrus cortical thickness and resting-state functional connectivity in abstinent heroin users after 8 months of follow-up.

Compared with healthy controls, heroin users (HUs) show evidence of structural and functional brain alterations. However, little is known about the possibility of brain recovery after protracted heroin abstinence. The purpose of this study was to investigate whether brain recovery is possible after protracted abstinence in HUs. A total of 108 subjects with heroin addiction completed structural and functional scans, and 61 of those subjects completed 8-month follow-up scans. Resting-state data and 3D-T1 MR images were collected for all participants, first at baseline and again after 8 months. Cognitive function and craving were measured by the Trail Making Test-A (TMT-A) and Visual Analog Scale for Craving, respectively. The cortical thickness and resting-state functional connectivity (RSFC) differences were then analyzed and compared between baseline and follow-up, and correlations were obtained between neuroimaging and behavioral changes. HUs demonstrated improved cognition (shorter TMT-A time) and reduced craving at the follow-up (HU2) relative to baseline (HU1), and the cortical thickness in the bilateral superior frontal gyrus (SFG) was significantly greater at HU2 than at HU1. Additionally, the RSFC of the left SFG with the inferior frontal gyrus (IFG), insula, and nucleus accumbens and that of the right SFG with the IFG, insula and orbitofrontal cortex (OFC) were increased at HU2. The changes in TMT-A time were negatively correlated with the RSFC changes between the left SFG and the bilateral IFG, the bilateral caudate, and the right insula. The changes in craving were negatively correlated with the RSFC changes between the left OFC and the bilateral SFG. Our results demonstrated that impaired frontal-limbic neurocircuitry can be partially restored, which might enable improved cognition as well as reduced craving in substance-abusing individuals. We provided novel scientific evidence for the partial recovery of brain circuits implicated in cognition and craving after protracted abstinence.

Integrating ATAC-seq and RNA-seq Reveals the Dynamics of Chromatin Accessibility and Gene Expression in Apple Response to Drought.

Drought resistance in plants is influenced by multiple signaling pathways that involve various transcription factors, many target genes, and multiple types of epigenetic modifications. Studies on epigenetic modifications of drought focus on DNA methylation and histone modifications, with fewer on chromatin remodeling. Changes in chromatin accessibility can play an important role in abiotic stress in plants by affecting RNA polymerase binding and various regulatory factors. However, the changes in chromatin accessibility during drought in apples are not well understood. In this study, the landscape of chromatin accessibility associated with the gene expression of apple (GL3) under drought conditions was analyzed by Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq) and RNA-seq. Differential analysis between drought treatment and control identified 23,466 peaks of upregulated chromatin accessibility and 2447 peaks of downregulated accessibility. The drought-induced chromatin accessibility changed genes were mainly enriched in metabolism, stimulus, and binding pathways. By combining results from differential analysis of RNA-seq and ATAC-seq, we identified 240 genes with higher chromatin accessibility and increased gene expression under drought conditions that may play important functions in the drought response process. Among them, a total of nine transcription factor genes were identified, including ATHB7, HAT5, and WRKY26. These transcription factor genes are differentially expressed with different chromatin accessibility motif binding loci that may participate in apple response to drought by regulating downstream genes. Our study provides a reference for chromatin accessibility under drought stress in apples and the results will facilitate subsequent studies on chromatin remodelers and transcription factors.

[Effect of Pien Tze Huang against EV71].

This study aims to investigate the inhibitory effect of Pien Tze Huang(PZH) on enterovirus 71(EV71). To be speci-fic, chemiluminescence method was adopted to evaluate the toxicity of PZH to African green monkey kidney(Vero) cells and human rhabdomyosarcoma(RD) cells, and cytopathic effect(CPE) method to assess the inhibition on EV71-GFP reporter virus and EV71 C4 wild-type virus. The results showed that PZH had low cytotoxicity to Vero cells and RD cells, with the half-maximal cytotoxic concentration(CC_(50)) of about 0.691 3-0.879 2 mg·mL~(-1) for the two. In addition, PZH can effectively inhibit the replication of EV71 within the non-cytotoxic concentration range, and dose-dependently alleviate the cytopathic changes caused by virus infection, with the half-maximal effective concentration(EC_(50)) of 0.009 2-0.106 3 mg·mL~(-1). On the basis of the above results, the green fluorescent protein(GFP), indirect immunofluorescence assay(IFA), and median tissue culture infective dose(TCID_(50)) were employed to assess and verify the anti-EV71-GFP and anti-EV71 C4 activity of PZH. The results demonstrated that PZH can dose-dependently lower the expression of GFP by EV71-GFP and structural protein VP-1 by EV71 C4 and decrease the production of progeny infectious viruses. The EC_(50) of PZH for EV71-GFP and EV71 C4 was about 0.006 0-0.006 2 mg·mL~(-1) and 0.006 6-0.025 6 mg·mL~(-1), respectively. This study suggested that PZH may exert antiviral activity by acting on EV71 and interfering with the expression of VP-1. At the moment, there is still a lack of specific anti-EV71 drugs. This study proposed a new idea for the symptomatic treatment of EV71 infections such as hand-foot-mouth disease and verified an effective drug for the treatment of EV71 infections.

Genome-wide analysis of SET-domain group histone methyltransferases in apple reveals their role in development and stress responses.

BACKGROUND: Histone lysine methylation plays an important role in plant development and stress responses by activating or repressing gene expression. Histone lysine methylation is catalyzed by a class of SET-domain group proteins (SDGs). Although an increasing number of studies have shown that SDGs play important regulatory roles in development and stress responses, the functions of SDGs in apple remain unclear. RESULTS: A total of 67 SDG members were identified in the Malus×domestica genome. Syntenic analysis revealed that most of the MdSDG duplicated gene pairs were associated with a recent genome-wide duplication event of the apple genome. These 67 MdSDG members were grouped into six classes based on sequence similarity and the findings of previous studies. The domain organization of each MdSDG class was characterized by specific patterns, which was consistent with the classification results. The tissue-specific expression patterns of MdSDGs among the 72 apple tissues in the different apple developmental stages were characterized to provide insight into their potential functions in development. The expression profiles of MdSDGs were also investigated in fruit development, the breaking of bud dormancy, and responses to abiotic and biotic stress; the results indicated that MdSDGs might play a regulatory role in development and stress responses. The subcellular localization and putative interaction network of MdSDG proteins were also analyzed. CONCLUSIONS: This work presents a fundamental comprehensive analysis of SDG histone methyltransferases in apple and provides a basis for future studies of MdSDGs involved in apple development and stress responses.

Brain responses to drug cues predict craving changes in abstinent heroin users: A preliminary study.

BACKGROUND: Loss of control over drug intake occurring in drug addiction is believed to result from disruption of reward circuits, including reduced responsiveness to natural rewards (e.g., monetary, sex) and heightened responsiveness to drug reward. Yet few studies have assessed reward deficiency and related brain responses in abstinent heroin users with opioid use disorder, and less is known whether the brain responses can predict cue-induced craving changes following by prolonged abstinence. METHOD: 31 heroin users (age: 44.13±7.68 years, male: 18 (58%), duration of abstinence: 85.2 ± 52.5 days) were enrolled at a mandatory detoxification center. By employing a cue-reactivity paradigm including three types of cues (drug, sexual, neutral), brain regional activations and circuit-level functional coupling were extracted. Among the 31 heroin users, 15 were followed up longitudinally to assess cue induced craving changes in the ensuing 6 months. RESULTS: One way analysis of variance results showed that heroin users have differential brain activations to the three cues (neutral, drug and sexual) in the left dorsolateral prefrontal cortex (DLPFC), insula, orbiotofrontal cortex (OFC) and the bilateral thalamus. Drug cue induced greater activations in left DLPFC, insula and OFC compared to sexual cue. The psychophysiological interactions (PPI) analysis revealed negative couplings of the left DLPFC and the left OFC, bilateral thalamus, putamen in heroin users during drug cue exposure. In the 6-month follow-up study, both drug cue induced activation of the left DLPFC and the functional coupling of the left DLPFC-bilateral thalamus at baseline was correlated with craving reductions, which were not found for sexual cues. CONCLUSION: Our preliminary study provided novel evidence for the reward deficiency theory of opioid use disorder. Our findings also have clinical implications, as drug cue induced activation of the left DLPFC and functional coupling of left DLPFC-bilateral thalamus may be potential neuroimaging markers for craving changes during prolonged abstinence. Evidently, the findings in the current preliminary study should be confirmed by large sample size in the future.

Reduced thalamic resting-state functional connectivity and impaired cognition in acute abstinent heroin users.

As a critical component of cortico-striato-thalamo-cortical loop in addiction, our understanding of the thalamus in impaired cognition of heroin users (HU) has been limited. Due to the complex thalamic connection with cortical and subcortical regions, thalamus was divided into prefrontal (PFC), occipital (OC), premotor, primary motor, sensory, temporal, and posterior parietal association subregions according to white matter tractography. We adopted seven subregions of bilateral thalamus as regions of interest to systematically study the implications of distinct thalamic nuclei in acute abstinent HU. The volume and resting-state functional connectivity (RSFC) differences of the thalamus were investigated between age-, gender-, and alcohol-matched 37 HU and 33 healthy controls (HCs). Trail making test-A (TMT-A) was adopted to assess cognitive function deficits, which were then correlated with neuroimaging findings. Although no significant different volumes were found, HU group showed decreased RSFC between left PFC_thalamus and middle temporal gyrus as well as between left OC_thalamus and inferior frontal gyrus and supplementary motor area relative to HCs. Meanwhile, the higher TMT-A scores in HU were negatively correlated with PFC_thalamic RSFC with inferior temporal gyrus, fusiform, and precuneus. Craving scores were negatively correlated with OC_thalamic RSFC with accumbens, hippocampus, and insula. Opiate Withdrawal Scale scores were negatively correlated with left PFC/OC_thalamic RSFC with orbitofrontal cortex and medial PFC. We indicated two thalamus subregions separately involvement in cognitive control and craving to reveal the implications of thalamic subnucleus in pathology of acute abstinent HU.

AnGong NiuHuang (AGNH) pill attenuated traumatic brain injury through regulating NF-κB/Nlrp3 axis and glycerophospholipid metabolism.

BACKGROUND: Traumatic brain injury (TBI), especially neuroinflammation after TBI persists for a long time and causes significant neurodegenerative pathologies and neuropsychiatric problems. PURPOSE: In this study, the neuroprotective effect of AnGong NiuHuang (AGNH) on TBI was investigated and the mechanism was revealed by integrating multiple omics. METHODS: The rats with TBI were administrated with AGNH for 5 consecutive days and the effect was evaluated by using modified neurologic severity score (mNSS), brain edema, H&E staining, Nissl staining and TUNEL staining. The mechanism was revealed by using RNA sequencing (RNA-seq) and metabolomic analysis. The inflammatory factors, apoptosis-related proteins and identified vital targets were validated by enzyme-linked immunosorbent assay, western blotting and immunofluorescence staining. RESULTS: Administration of AGNH decreased mNSS, brain edema, brain structure damage, but increased Nissl body density in the rats with TBI. Additionally, AGNH reduced IL-1ß, IL-17A, TNF-α, MMP9, MCP-1, IL-6, Bax and TUNEL staining,but elevated Bcl2 level. Integrating transcriptomic analysis and metabolomic analysis identified vital targets and critical metabolic pathways. Importantly, AGNH treatment reduced the expression of TLR4, MYD88, NLRP3, BTK, IL-18 and Caspase 1 as well as glycerophospholipid metabolism-related protein AGPAT2 and PLA2G2D, and decreased the nuclear translocation of NF-κB p65 in the brain of TBI rats. Additionally, AGNH increased phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylserine (PS), phosphatidylethanolamine (PE), but decreased 1-acyl-sn-glycero-3-phosphocholine (LysoPC) in the metabolic pathway of glycerophospholipid metabolism. CONCLUSION: Taken together, AGNH inhibited NF-κB/NLRP3 axis to suppress neuroinflammation, cell apoptosis and pyroptosis, and improved metabolic pathways of glycerophospholipid metabolism after TBI.

Population Pharmacokinetics and Exposure-Response Relationship of Zimberelimab in Chinese Patients with Advanced Tumors.

This study aimed to establish a population pharmacokinetic (PopPK) model using data from 2 clinical trials of zimberelimab, evaluate the pharmacokinetics (PKs) of zimberelimab, explore the feasibility of 360 mg once every 3 weeks (Q3W) and 480 mg once every 4 weeks (Q4W) as alternative dosage regimens, and analyze the exposure-response relationship of the efficacy and safety of zimberelimab for advanced tumors. The PKs of zimberelimab were described using the 2-compartment model with time-dependent nonlinear elimination. The prediction-corrected visual predictive check was used to evaluate the model's predictive value on blood drug concentrations. In total, 2165 PK observations from 321 participants were included. The PopPK model demonstrated a high level of concordance between the observed data and the predicted values, indicative of a robust fit to the PK data of zimberelimab. The PK variables were similar for the 240 mg once every 2 weeks, 360 mg Q3W, and 480 mg Q4W regimens. No covariates significantly affecting the PK variables in the final model were found. The exposure variables of zimberelimab have no obvious correlations with efficacy and safety, and 360 mg Q3W and 480 mg Q4W are worthy of further study. This study establishes a PopPK model and analyzes the exposure-response relationship of zimberelimab, which helps to explore the potential for alternative dosing regimens and offers a foundation for optimizing therapeutic strategies for advanced cancer patients through simulation-based methods.

Traditional Chinese medicine Pien-Tze-Huang ameliorates LPS-induced sepsis through bile acid-mediated activation of TGR5-STAT3-A20 signalling.

Pien Tze Huang (PZH), a class I nationally protected traditional Chinese medicine (TCM), has been used to treat liver diseases such as hepatitis; however, the effect of PZH on the progression of sepsis is unknown. Here, we reported that PZH attenuated lipopolysaccharide (LPS)-induced sepsis in mice and reduced LPS-induced production of proinflammatory cytokines in macrophages by inhibiting the activation of mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signalling. Mechanistically, PZH stimulated signal transducer and activator of transcription 3 (STAT3) phosphorylation to induce the expression of A20, which could inhibit the activation of NF-κB and MAPK signalling. Knockdown of the bile acid (BA) receptor G protein-coupled bile acid receptor 1 (TGR5) in macrophages abolished the effects of PZH on STAT3 phosphorylation and A20 induction, as well as the LPS-induced inflammatory response, suggesting that BAs in PZH may mediate its anti-inflammatory effects by activating TGR5. Consistently, deprivation of BAs in PZH by cholestyramine resin reduced the effects of PZH on the expression of phosphorylated-STAT3 and A20, the activation of NF-κB and MAPK signalling, and the production of proinflammatory cytokines, whereas the addition of BAs to cholestyramine resin-treated PZH partially restored the inhibitory effects on the production of proinflammatory cytokines. Overall, our study identifies BAs as the effective components in PZH that activate TGR5-STAT3-A20 signalling to ameliorate LPS-induced sepsis.

Acute exacerbation prediction of COPD based on Auto-metric graph neural network with inspiratory and expiratory chest CT images.

Chronic obstructive pulmonary disease (COPD) is a widely prevalent disease with significant mortality and disability rates and has become the third leading cause of death globally. Patients with acute exacerbation of COPD (AECOPD) often substantially suffer deterioration and death. Therefore, COPD patients deserve special consideration regarding treatment in this fragile population for pre-clinical health management. Based on the above, this paper proposes an AECOPD prediction model based on the Auto-Metric Graph Neural Network (AMGNN) using inspiratory and expiratory chest low-dose CT images. This study was approved by the ethics committee in the First Affiliated Hospital of Guangzhou Medical University. Subsequently, 202 COPD patients with inspiratory and expiratory chest CT Images and their annual number of AECOPD were collected after the exclusion. First, the inspiratory and expiratory lung parenchyma images of the 202 COPD patients are extracted using a trained ResU-Net. Then, inspiratory and expiratory lung Radiomics and CNN features are extracted from the 202 inspiratory and expiratory lung parenchyma images by Pyradiomics and pre-trained Med3D (a heterogeneous 3D network), respectively. Last, Radiomics and CNN features are combined and then further selected by the Lasso algorithm and generalized linear model for determining node features and risk factors of AMGNN, and then the AECOPD prediction model is established. Compared to related models, the proposed model performs best, achieving an accuracy of 0.944, precision of 0.950, F1-score of 0.944, ad area under the curve of 0.965. Therefore, it is concluded that our model may become an effective tool for AECOPD prediction.

Xinshubao tablet rescues cognitive dysfunction in a mouse model of vascular dementia: Involvement of neurogenesis and neuroinflammation.

Vascular dementia (VaD) represents a severe cognitive dysfunction syndrome closed linked to cardiovascular function. In the present study, we assessed the potential of Xinshubao tablet (XSB), a traditional Chinese prescription widely used for cardiovascular diseases, to mitigate neuropathological damage in a mouse model of VaD and elucidated the underlying mechanisms. Our findings revealed that oral administration of XSB rescued the cardiac dysfunction resulting from bilateral common carotid artery stenosis (BCAS), improved the cerebral blood flow (CBF) and cognitive function, reduced white matter injury, inhibited excessive microglial and astrocytic activation, stimulated hippocampal neurogenesis, and reduced neural apoptosis in the brains of BCAS mice. Mechanistically, RNA-seq analysis indicated that XSB treatment was significantly associated with neuroinflammation, vasculature development, and synaptic transmission, which were further confirmed by q-PCR assays. Western blot results revealed that XSB treatment hindered the nuclear translocation of nuclear factor-κB (NF-κB), thereby suppressing the NF-κB signaling pathway. These results collectively demonstrated that XSB could ameliorate cognitive dysfunction caused by BCAS through regulating CBF, reducing white matter lesions, suppressing glial activation, promoting neurogenesis, and mitigating neuroinflammation. Notably, the NF-κB signaling pathway emerged as a pivotal player in this mechanism.

Transcriptomics and Metabolomics Unveil the Neuroprotection Mechanism of AnGong NiuHuang (AGNH) Pill Against Ischaemic Stroke Injury.

As a famous prescription in China, AnGong NiuHuang (AGNH) pill exerts good neuroprotection for ischaemic stroke (IS), but its mechanism is still unclear. In this study, the neuroprotection of AGNH was evaluated in the rat IS model which were established with the surgery of middle cerebral artery occlusion (MCAO), and the potential mechanism was elucidated by transcriptomic analysis and metabolomic analysis. AGNH treatment obviously decreased the infarct volume and Zea-Longa 5-point neurological deficit scores, improved the survival percentage of rats, regional cerebral blood flow (rCBF), and rat activity distance and activity time. Transcriptomics showed that AGNH exerted its anti-inflammatory effects by affecting the regulatory network including Tyrobp, Syk, Tlr2, Myd88 and Ccl2 as the core. Integrating transcriptomics and metabolomics identified 8 key metabolites regulated by AGNH, including L-histidine, L-serine, L-alanine, fumaric acid, malic acid, and N-(L-arginino) succinate, 1-pyrroline-4-hydroxy-2-carboxylate and 1-methylhistamine in the rats with IS. Additionally, AGNH obviously reduced Tyrobp, Syk, Tlr2, Myd88 and Ccl2 at both the mRNA and protein levels, decreased IL-1ß, KC-GRO, IL-13, TNF-α, cleaved caspase 3 and p65 nucleus translocation, but increased IκBα expression. Network pharmacology analysis showed that quercetin, beta-sitosterol, baicalein, naringenin, acacetin, berberine and palmatine may play an important role in protecting against IS. Taken together, this study reveals that AGNH reduced neuroinflammation and protected against IS by inhibiting Tyrobp/Syk and Tlr2/Myd88, as well as NF-κB signalling pathway and regulating multiple metabolites.

COPD stage detection: leveraging the auto-metric graph neural network with inspiratory and expiratory chest CT images.

Chronic obstructive pulmonary disease (COPD) is a common lung disease that can lead to restricted airflow and respiratory problems, causing a significant health, economic, and social burden. Detecting the COPD stage can provide a timely warning for prompt intervention in COPD patients. However, existing methods based on inspiratory (IN) and expiratory (EX) chest CT images are not sufficiently accurate and efficient in COPD stage detection. The lung region images are autonomously segmented from IN and EX chest CT images to extract the 1 , 781 × 2 lung radiomics and 13 , 824 × 2 3D CNN features. Furthermore, a strategy for concatenating and selecting features was employed in COPD stage detection based on radiomics and 3D CNN features. Finally, we combine all the radiomics, 3D CNN features, and factor risks (age, gender, and smoking history) to detect the COPD stage based on the Auto-Metric Graph Neural Network (AMGNN). The AMGNN with radiomics and 3D CNN features achieves the best performance at 89.7 % of accuracy, 90.9 % of precision, 89.5 % of F1-score, and 95.8 % of AUC compared to six classic machine learning (ML) classifiers. Our proposed approach demonstrates high accuracy in detecting the stage of COPD using both IN and EX chest CT images. This method can potentially establish an efficient diagnostic tool for patients with COPD. Additionally, we have identified radiomics and 3D CNN as more appropriate biomarkers than Parametric Response Mapping (PRM). Moreover, our findings indicate that expiration yields better results than inspiration in detecting the stage of COPD.

Immunomodulatory Function of Pien Tze Huang in T Cell-Mediated Anti-tumor Activity against B16-F10, MC38 and Hep1-6 Tumor Models.

OBJECTIVE: To investigate the anti-tumor effects of Pien Tze Huang (PZH) in mouse models of B16-F10 melanoma, MC38 colorectal cancer, Hep1-6 hepatocellular carcinoma and chemically induced hepatocellular carcinoma model. METHODS: Various tumor models, including B16-F10, MC38 and Hep1-6 tumor hypodermic inoculation models, B16-F10 and Hep1-6 pulmonary metastasis models, Hep1-6 orthotopic implantation model, and chemically induced hepatocellular carcinoma model, were utilized to evaluate the anti-tumor function of PZH. Tumor growth was assessed by measuring tumor size and weight of solid tumors isolated from C57BL/6 mice. For cell proliferation and death of tumor cells in vitro, as well as T cell activation markers, cytokine production and immune checkpoints analysis, single-cell suspensions were prepared from mouse spleen, lymph nodes, and tumors after PZH treatment. RESULTS: PZH demonstrated significant therapeutic efficacy in inhibiting tumor growth (P<0.01). Treatment with PZH resulted in a reduction in tumor size in subcutaneous MC38 colon adenocarcinoma and B16-F10 melanoma models, and decreased pulmonary metastasis of B16-F10 melanoma and Hep1-6 hepatoma (P<0.01). However, in vitro experiments showed that PZH only had slight impact on the cell proliferation and survival of tumor cells (P>0.05). Nevertheless, PZH exhibited a remarkable ability to enhance T cell activation and the production of interferon gamma, tumor necrosis factor alpha, and interleukin 2 in CD4+ T cells in vitro (P<0.01 or P<0.05). Importantly, PZH substantially inhibited T cell exhaustion and boosted cytokine production by tumor-infiltrating CD8+ T cells (P<0.01 or P<0.05). CONCLUSION: This study has confirmed a novel immunomodulatory function of PZH in T cell-mediated anti-tumor immunity, indicating that PZH holds promise as a potential therapeutic agent for cancer treatment.