BACKGROUND:Paclitaxel produces a chronic, glove-stocking neuropathy that is frequently accompanied by anxiety and depression. However, the neural circuits and molecular signals driving this pain-affect comorbidity remain unclear. METHODS:Chemotherapy-induced neuropathic pain (CINP) was established by paclitaxel injections in male rats. Mechanical and thermal sensitivity and negative emotional behaviors were assessed using behavioral tests. Parabrachial nucleus (PBN)-central amygdala (CeA) projections were traced with viral vectors, and optogenetics was used to manipulate PBN terminals. Prodynorphin (PDYN) and κ-opioid receptor (KOR) mRNA levels were quantified by reverse transcription quantitative polymerase chain reaction (RT-qPCR). RESULTS:CINP rats developed persistent pain hypersensitivity and negative emotional behaviors, accompanied by increased CeA c-Fos and PDYN expression without changes in KOR mRNA. Intra-CeA administration of the KOR antagonist Navacaprant alleviated both pain and negative emotional behaviors. Optogenetic inhibition of the PBN-CeA pathway reduced CeA activation, attenuated pain hypersensitivity, and improved negative emotional behaviors, whereas pathway activation elicited both changes in naïve rats. Chronic inhibition of this pathway lowered CeA PDYN mRNA levels in CINP rats. CONCLUSION:The PBN-CeA pathway contributes to paclitaxel-induced neuropathic pain and anxiety-like behavior, and is associated with increased dynorphin expression in the CeA. Targeting this pathway or its downstream KOR may provide a therapeutic strategy for chemotherapy-related sensory and affective disturbances.

BACKGROUND:Chronic liver diseases caused by metabolic, viral, and mixed etiologies frequently converge on fibrosis and cirrhosis; however, the extent to which fibrogenic mechanisms are shared across etiologies versus disease-specific remains incompletely defined. METHODS:Four GEO datasets were analyzed: GSE135251 (NAFLD-related fibrosis), GSE84044 (HBV-related fibrosis), GSE197112 (mixed-etiology fibrosis), and GSE14323 (cirrhosis versus normal). Differential expression analysis was performed separately within each dataset using DESeq2 for RNA-seq and limma for microarray data. Shared genes were identified by cross-dataset intersection. For downstream network and ordination analyses, gene-level matrices were harmonized across platforms and batch-adjusted using ComBat, with PCA before and after correction provided in the supporting information. WGCNA and random forest were then applied to the integrated matrix, and the final seven hub genes were defined as genes supported by recurrent differential expression, co-expression prioritization, and random forest feature importance. The final seven-gene hub panel was further used for exploratory age-stratified visualization and regression analysis. Functional enrichment, miRNA-mRNA mapping, PPI analysis, PCoA, UMAP, RT-qPCR, and western blotting were performed. RESULTS:Across the four cohorts, 434-787 differentially expressed genes were identified per dataset, and 26 genes were consistently upregulated across all etiologies. Enrichment analyses converged on extracellular matrix organization, TGF-β, PI3K-Akt, MAPK, and Wnt-related signaling. The final seven hub genes were MAOA, LOC102724200, SLC16A3, GPM6B, CST7, MT3, and ZNF142. Exploratory age analyses in the age-annotated GSE84044 cohort suggested that a subset of the final seven hub genes varied with age; however, these findings should be interpreted cautiously because age metadata were not uniformly available across all public cohorts. RT-qPCR in 10 fibrotic and 10 nonfibrotic liver tissues confirmed upregulation of the seven hub genes, and western blotting supported increased protein abundance of CST7, MT3, SLC16A3, and MAOA. CONCLUSIONS:This integrative analysis identifies both shared and etiology-associated transcriptional programs in liver fibrosis and defines a multistep strategy for prioritizing conserved hub genes. The seven validated hub genes represent candidate biomarkers for fibrotic liver injury, whereas the exploratory age-related findings based on this seven-gene panel remain hypothesis-generating. This workflow may support future cross-platform transcriptomic studies of hepatic fibrosis.

Oxytocin has been found to modulate and improve pain in humans, but the mechanisms underlying these antinociceptive properties, especially in visceral hypersensitivity, are still unclear. Irritable bowel syndrome (IBS) models were established by colorectal distention in newborn rats aged 8 to 14 days, and visceral hypersensitivity was assessed using electromyogram (EMG). Oxytocin or saclofen was administered intrathecally to evaluate visceral hypersensitivity in the rats. The protein expressions of oxytocin receptor (OTR), γ-aminobutyric acid type B1 receptor (GABAB1), and transient receptor potential vanilloid 1 (TRPV1) in the lumbosacral spinal cord regions were measured. IBS rats exhibited a unique spinal cord molecular signature comprising decreased OTR/GABAB1 and increased TRPV1 expression. Intrathecal oxytocin treatment not only normalized these molecular alterations (increasing GABAB1 while decreasing TRPV1) but also ameliorated visceral pain behaviors. Crucially, this therapeutic effect was fully reversed by GABAB1 inhibition, establishing the necessity of intact GABAergic signaling for oxytocin-mediated analgesia. Collectively, these findings indicate that oxytocin relieves visceral hypersensitivity through the regulation of GABAB1 and TRPV1 in the spinal cord of IBS rats.

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder characterized by visceral hypersensitivity and prominent affective symptoms, yet molecular regulators that coordinate these dimensions remain poorly defined. Histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase implicated in neuronal plasticity and inflammatory signaling, has been linked to pain-related conditions, but its relevance to IBS is unclear. Here, we used optogenetics to selectively stimulate projection terminals from the parabrachial nucleus (PBN) or basolateral amygdala (BLA) within the central amygdala (CeA). Activation of PBN-CeA terminals exacerbated visceral hypersensitivity and anxiety-like behaviors, whereas activation of BLA-CeA terminals alleviated these phenotypes. Notably, pro-nociceptive PBN-CeA stimulation increased HDAC6 expression, while the anti-nociceptive BLA-CeA stimulation decreased it. To probe downstream pathways, we combined bioinformatic analyses with intracranial pharmacological intervention and found that intra-CeA infusion of the highly selective HDAC6 inhibitor ACY-738 alleviated visceral pain and negative affect-like behaviors in IBS-like rats. These behavioral improvements were accompanied by reduced synaptic and neuroimmune alterations in the CeA and decreased phosphorylation of p38 MAPK and ERK1/2. Importantly, ACY-738 also attenuated the exacerbation of pain and negative affect induced by pro-nociceptive PBN-CeA stimulation. Together, these findings suggest that CeA HDAC6 contributes to circuit state-associated alterations underlying pain-affect comorbidity and may serve as a potential therapeutic target in IBS.

Purpose:This study aimed to evaluate the association between the relative decline rate of HBsAg at week 12 (HBsAg R) and achieving HBsAg clearance in patients with compensated HBV-related cirrhosis. Patients and Methods:This study included 174 patients with compensated hepatitis B-related cirrhosis receiving pegylated interferon-alpha and nucleos(t)ide analogue therapy. HBsAgR was defined as (week-12 HBsAg - baseline HBsAg) / baseline HBsAg, where a more negative value indicates greater decline. To identify stable predictors, we employed the Boruta machine learning algorithm for feature selection. The association between HBsAgR and HBsAg clearance at 48 weeks was assessed using multivariable logistic regression and ROC analysis. Model stability was internally validated using Bootstrap resampling with 1,000 iterations. Results:HBsAgR was identified as a stable factor associated with HBsAg clearance. After adjustment, each one-unit increase in HBsAgR was associated with a 53% lower odds of clearance (aOR=0.47; 95% CI: 0.28-0.79), indicating that greater HBsAg decline (more negative HBsAgR) was associated with higher clearance probability. ROC analysis showed an AUC of 0.746. The optimal cutoff value of HBsAgR was -0.56585, which corresponds to a 56.6% decline in HBsAg from baseline at week 12. Patients with HBsAgR less than -0.56585 (ie, a decline greater than 56.6%) were associated with a higher probability of HBsAg clearance, yielding a sensitivity of 76.19% and specificity of 73.33%. Bootstrap validation showed minimal optimism (difference: -0.001). Conclusion:HBsAgR is strongly associated with HBsAg clearance at week 48 in patients with hepatitis B-related cirrhosis, and may serve as a useful modicification of treatment strategies for this population.

The purpose of the study was to investigate the role of the long non-coding RNA (lncRNA)_RT1-CE10 and its molecular mechanisms in chronic visceral pain of rats with irritable bowel syndrome (IBS). Sprague-Dawley (SD) rats were exposed to colorectal distention (CRD) stimulation at a pressure of 60 mmHg for 1 min from 8 to 14 days after birth. The visceral hypersensitivity was assessed by measuring electromyographic (EMG) responses of external oblique muscle to CRD at 40 mmHg and 60 mmHg when the rats were 6 weeks old. The expression of lncRNA_RT1-CE10, Iba-1 and MHCII in the spinal cord was detected by RT-qPCR or Western blot. After intrathecal injection of minocycline (an inhibitor of microglia), the expression of Iba-1, MHCII and the visceral hypersensitivity were determined by Western blot and EMG, respectively. After intrathecal injection of AAV-lncRT1-CE10 and AAV-shlncRT1-CE10, the expression of Iba-1 and MHCII was examined by Western blot, respectively. The results showed that the expression of lncRNA_RT1-CE10 was decreased in the spinal cord of IBS rats, while the expression of Iba-1 and MHCII was increased. Inhibition of microglial activation by minocycline attenuated visceral hypersensitivity in IBS rats. Over-expression of lncRNA_RT1-CE10 decreased the Iba-1 and MHCⅡ levels in IBS rats, while knockdown of lncRNA_RT1-CE10 increased the Iba-1 and MHCⅡ levels in control rats. Collectively, these results demonstrate that lncRNA_RT1-CE10 attenuates visceral hypersensitivity by inhibiting microglial activation in IBS rats.

Objective:This study investigated the differential roles of Locus Coeruleus-Infralimbic cortex (LC-IL) and Locus Coeruleus-Prelimbic cortex (LC-PL) circuits in comorbid mechanical hyperalgesia and anxiety-like emotions in male rats with chronic post-surgical pain (CPSP). Methods:A total of 100 adult male Sprague-Dawley rats were randomly divided into 10 groups (n=10/group). Group included LC activation (sham+ChR2, sham+mch), LC-IL inhibition/activation (CPSP+NpHR, CPSP+mch; sham+ChR2, sham+mch), and LC-PL inhibition/activation (CPSP+NpHR, CPSP+mch; sham+ChR2, sham+mch). Using the skin/muscle incision and retraction procedure to establish CPSP or sham surgery. Optogenetic viruses (ChR2 for activation, NpHR for inhibition) or control virus (mCherry) were injected into the LC, with optical fibers implanted in the LC, IL, or PL. After 4 weeks of viral expression, blue or yellow light stimulation was applied. Mechanical paw withdrawal threshold was measured by Von-Frey filaments. Anxiety-like emotions was assessed by open field test and elevated plus maze. Results:Blue light irradiation of the LC region and LC-IL neural circuit both induced mechanical hyperalgesia and anxiety-like emotions in the rats. Yellow light irradiation of the LC-IL neural circuit alleviated mechanical hyperalgesia and anxiety-like emotions in CPSP model rats. Blue or yellow light irradiation of the LC-PL neural circuit had no significant effect on mechanical hyperalgesia or anxiety-like emotions in the rats. Conclusion:The LC-IL circuit specifically regulates comorbid mechanical hyperalgesia and anxiety-like emotions in male CPSP rats, while the LC-PL circuit does not. These findings identify a sex-specific circuit mechanism and a potential therapeutic target for CPSP.

Background and purposeIncreased cough sensitivity is the key pathophysiological mechanism of chronic cough. Although previous studies have focused on peripheral airway receptor sensitization, the role of the central nervous system—particularly the hypothalamic paraventricular nucleus (PVN)—remains unclear. Whether substance P (SP)–expressing PVN neurons contribute to cough hypersensitivity remains unknown.MethodsThree-week-old Hartley guinea pigs were divided into three groups: citric acid (CA), saline control (SA), and blank control (CON). A cough hypersensitivity model was induced by inhalation of 0.4 mol/L citric acid. Cough sensitivity was assessed using a capsaicin challenge, with the C5 threshold defined as the lowest capsaicin concentration inducing ≥5 coughs. Locomotor activity was evaluated using the open-field test. Airway inflammation and goblet cell hyperplasia were examined by HE and PAS staining. SP and c-Fos expression in the PVN were detected by immunofluorescence and Western blot. HSV retrograde tracing was used to analyze the PVN-airway neural pathway associated with cough hypersensitivity.ResultsCompared with the control groups, guinea pigs in the CA group exhibited a time-dependent increase in cough frequency and enhanced cough sensitivity, as indicated by a reduction in the C5 threshold. Histological analysis revealed increased inflammatory cell infiltration and goblet cell hyperplasia in the airways of the CA group. SP and c-Fos expression, along with the proportion of SP/Fos double-labeled neurons in the PVN, were significantly increased in the CA group (all P < 0.05). Viral tracing confirmed the presence of HSV-positive neurons in the PVN, supporting a neural connection between the PVN and the airways.ConclusionActivation of SP-expressing neurons in the PVN is associated with cough hypersensitivity and suggests the presence of a potential PVN–airway neural pathway. These findings provide a theoretical basis for the development of central-targeted therapies for chronic cough.

Parathyroidectomy (PTX) improves left ventricular structure and geometry in patients with uremic secondary hyperparathyroidism (SHPT). This single-center retrospective study followed 131 patients through December 31, 2022, and compared echocardiographic parameters before surgery and one year postoperatively. PTX significantly reduced the proportion of patients with moderate-to-severe left ventricular hypertrophy. Additionally, 26.19

ABSTRACT Background The 5‐year survival rate for hepatocellular carcinoma (HCC) is stage‐dependent, yet existing models lack accuracy in predicting hepatitis B virus‐associated HCC (HBV‐HCC). We therefore aimed to develop and validate an interpretable machine learning (ML) model integrating multidimensional biomarkers for HBV‐HCC risk stratification. Methods This retrospective multicenter study included 3568 participants (1872 HBV‐infected and 1696 HBV‐HCC). Patients from Mengchao Hepatobiliary Hospital were divided into training and validation sets (3:1 ratio), while those from Eastern Hepatobiliary Surgery Hospital and the First Affiliated Hospital of Xiamen University formed the external validation set. Five key predictors were identified through random forest, LASSO regression, and XGBoost methods. Seven ML models were evaluated using area under the curve (AUC), sensitivity, specificity, accuracy, and F1‐score, with the top model compared against previous models (GALAD, C‐GALAD, C‐GALAD II, and ASAP). Results Key predictors were log10DCP (mean SHAP value 1.784), log10HBVDNA (1.063), log10ALT (0.753), AFP‐L3% (0.444), and log10AFP (0.392). The XGBoost model achieved AUCs of 0.985 (95% CI: 0.981–0.989) in the training set, 0.978 (0.969–0.987) in the validation set, and 0.942 (0.911–0.973) in the external validation set. XGBoost significantly outperformed previous models in both the training and validation sets (DeLong test; p < 0.001). In the external validation set, XGBoost demonstrated superior individualized risk prediction accuracy (IDI = 0.228), net clinical benefit, calibration, and high‐risk patient identification compared to the ASAP model. An interactive web tool was developed to facilitate clinical implementation. Conclusions We developed a novel diagnostic model for HBV‐HCC that demonstrates higher accuracy in identifying HBV‐HCC compared to existing models.

Irritable bowel syndrome (IBS) is characterized by chronic visceral pain and anxiety comorbidity, yet the central mechanisms linking gut signals to persistent pain–emotion dysregulation remain unclear. This study investigated whether hippocampal Lipocalin-2 (LCN2) drives neuronal ferroptosis to mediate visceral hypersensitivity and anxiety-like behaviors in a neonatal rat IBS model. Using a colorectal distension model, we conducted behavioral tests, molecular assays, and electron microscopy. IBS-like rats exhibited upregulated hippocampal LCN2 expression, predominantly in neurons, alongside ferroptosis hallmarks including increased ACSL4, decreased GPX4, elevated Fe2⁺ and MDA levels, and mitochondrial damage. Inhibition of ferroptosis reversed visceral pain and anxiety-like behaviors. LCN2 knockdown in the hippocampal CA1 region alleviated IBS-related phenotypes, while LCN2 overexpression in normal rats induced similar behavioral and ferroptotic changes. These findings identify a novel LCN2–ferroptosis axis in hippocampal neurons that critically mediates gut–brain dysregulation in IBS. Our study provides the first causal evidence linking LCN2-driven ferroptosis to visceral pain–anxiety comorbidity, offering new mechanistic insights and potential therapeutic targets for IBS and related gut–brain disorders.

Visceral hypersensitivity is a hallmark feature of irritable bowel syndrome (IBS), yet its underlying mechanisms remain incompletely understood. In the present study, we found that miRNA-let7b5p was downregulated in the spinal cord of IBS model rats induced by neonatal colorectal distension. Concurrently, microglia exhibited a shift toward a pro-inflammatory M1 phenotype and selectively engulfed inhibitory synapses, resulting in impaired GABAergic neuronal function and disruption of the excitatory/inhibitory balance. Intrathecal administration of a miRNA-let7b5p agomir suppressed M1-type microglial activation in the spinal cord, reduced pro-inflammatory cytokine levels, and alleviated visceral hypersensitivity, whereas antagomir treatment induced visceral hypersensitivity in control rats. Mechanistically, MAP3K3 was identified as a direct target of miRNA-let7b5p, and its knockdown recapitulated the protective effects conferred by miRNA upregulation. Collectively, these findings demonstrate that miRNA-let7b5p attenuates IBS-associated visceral hypersensitivity by downregulating MAP3K3, thereby inhibiting spinal microglial activation and restoring GABAergic neuronal function. This study provides novel insights into the pathogenesis of IBS-related visceral hypersensitivity and highlights a potential therapeutic target for drug development.

Introduction:Irritable bowel syndrome (IBS) is a prevalent chronic functional gastrointestinal disorder characterized by visceral hypersensitivity (VH), affecting over 10% of the global population. Current treatments for IBS have notable limitations, highlighting the need for novel therapeutic strategies to address chronic visceral pain and associated comorbidities. Objectives: This study aimed to investigate whether bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) can alleviate chronic visceral pain in IBS and to explore the underlying molecular mechanisms, with a specific focus on the Nrf-2/HO-1 oxidative stress pathway. Methods:High-quality BMSC-Exos were isolated and characterized. In vitro, their neuroprotective effects were assessed in oxidatively stressed neurons. In vivo, IBS model rats received intrathecal injections of BMSC-Exos, and their effects on visceral pain sensitivity and anxiety-like behaviors were evaluated. Spinal cord tissues were analyzed to determine modulation of the Nrf-2/HO-1 pathway. Results:In vitro studies demonstrated that BMSC-Exos effectively rescued oxidative stress-induced neuronal damage. In IBS rats, intrathecally administered BMSC-Exos were internalized by spinal cord neurons, significantly reducing visceral hypersensitivity and anxiety-like behaviors. Mechanistically, BMSC-Exos upregulated the Nrf-2/HO-1 antioxidant pathway, mitigating oxidative stress-induced neuronal damage. Conclusion:These findings demonstrate that BMSC-Exos alleviate chronic visceral pain and comorbid anxiety in IBS rats, likely through Nrf-2/HO-1-mediated oxidative stress reduction in spinal neurons. These results highlight BMSC-Exos as a promising acellular therapeutic strategy for IBS, offering potential applications for this debilitating disorder.

Irritable bowel syndrome (IBS) is characterized by chronic visceral pain, but its molecular mechanisms remain controversial, hindering effective treatment. This research is to investigate the role of lncRNA RT1-CE10 in chronic visceral pain associated with IBS and to elucidate the underlying molecular mechanisms. An IBS rat model was developed in rats, and RNA-Seq analysis was conducted to assess lncRNA RT1-CE10 expression. The subcellular localization of lncRNA RT1-CE10 and its co-localization with ATP1a3 in spinal cord neurons were examined. AAV was used to over-express lncRNA RT1-CE10 in the spinal cord to study its effects on ATP1a3 levels and pain response, with knockdown experiments to evaluate the impact of reduced lncRNA RT1-CE10. The RNA-Seq analysis revealed a significant down-regulation of lncRNA RT1-CE10 in IBS rats. The lncRNA was found to be expressed in both the cytoplasm and the nucleus and to co-localize with ATP1a3 in spinal cord neurons. Over- expression of lncRNA RT1-CE10 via AAV-lncRT1-CE10 increased ATP1a3 levels and alleviated visceral pain response, while knockdown of lncRNA RT1-CE10 decreased ATP1a3 levels and enhanced visceral pain response. Additionally, a marked decrease in ATP1a3 expression was observed in the spinal cords of IBS rats. Modulating ATP1a3 expression either through over-expression or knockdown could alleviate or aggravate chronic visceral pain, respectively. LncRNA RT1-CE10, which is lowly expressed in the spinal cord of IBS rats, interacts with ATP1a3 and influences chronic visceral pain. These findings could lead to the development of targeted therapeutic interventions for IBS.

Background: Targeted combined immunotherapy (TCI) has shown certain antitumor effects in patients with unresectable hepatocellular carcinoma(uHCC), but only a subset of patients benefit. This study aims to develop a Transformer-based radiomics model to predict the objective response to combined therapy in patients with uHCC. Methods: This multicenter, retrospective study involved 264 HCC patients who underwent contrast-enhanced MRI prior to immunotherapy. The patients were divided into a training cohort(n=180) and a validation cohort(n=84). Using a multi-instance learning approach, tumor lesions in multi-sequence MRI were segmented into cross-sectional images, and features were extracted using the ResNet50 model. The Transformer model was then trained to predict the objective response rate (ORR). The prediction process was visualized using Grad-CAM and SHAP algorithms. Model performance was assessed using ROC and DCA curves, while survival analysis was conducted using Kaplan-Meier curves. Results: Among 264 patients, one achieved complete response (0.4%), 64 experienced partial response (24.2%). The ORR was 26.1% in the training group and 21.4% in the validation group. The model demonstrated high predictive accuracy, achieving a perfect area under the curve (AUC) of 1.000. Further validation using screenshot-based model inputs revealed an AUC of 0.929 (95% CI: 0.904, 0.947), confirming the model's clinical applicability. Kaplan-Meier analysis indicated that objective responders experienced better overall survival (OS) in both the training set (HR: 0.50, 95% CI: 0.27, 0.90) and the validation set (HR: 0.28, 95% CI: 0.08, 0.91). Conclusion: The deep learning framework combining ResNet50 and Transformer has proven its clinical applicability in predicting and assessing the efficacy of targeted combination immunotherapy in unresectable hepatocellular carcinoma, providing crucial guidance for clinical treatment decisions.

Accumulating evidences suggest dysfunctions in the hippocampus are associated with chronic pain. Nevertheless, the role of hippocampal circuitry in pain memories and emotional responses is not yet fully understood. In this study, we utilized a comprehensive approach that combined electromyography (EMG), photochemical genetic techniques, and anxiety-related behavioral paradigms to investigate the involvement of dorsal hippocampus (DH) and ventral hippocampus (VH) in visceral sensitivity and anxiety behaviors in male rats. Our results demonstrated that IBS-like rats exhibited comorbid visceral hypersensitivity and anxiety, along with the number of activated neurons in the VH was higher than that in the DH. Manipulation of glutamatergic neurons in the hippocampus was identified as a crucial mechanism underlying the mediation of both visceral sensitivity and anxiety behaviors. Specifically, optogenetic activation of the DH induced both visceral hypersensitivity and anxiety, while activation of the VH induced anxiety but did not affect visceral sensitivity. Conversely, chemogenetic inhibition of the DH reduced both visceral hypersensitivity and anxiety, whereas inhibition of the VH alleviated anxiety but did not alleviate visceral hypersensitivity in IBS-like rats. Our study highlights the important role of early life stress in inducing visceral hypersensitivity and anxiety, and further elucidates the distinct functional contributions of the DH and VH to these behavioral changes. These findings provide a theoretical basis for the diagnosis and treatment of IBS, and suggest that targeting specific hippocampal neuron subtypes may represent a promising therapeutic approach.

AbstractLgr5+ intestinal stem cells (ISCs) are crucial for the intestinal epithelium renewal and regeneration after injury. However, the mechanism underlying the interplay between Wnt and BMP signaling in this process is not fully understood. Here we report that Bcl11b, which is downregulated by BMP signaling, enhances Wnt signaling to maintain Lgr5+ ISCs and thus promotes the regeneration of the intestinal epithelium upon injury. Loss of Bcl11b function leads to a significant decrease of Lgr5+ ISCs in both intestinal crypts and cultured organoids. Mechanistically, BMP suppresses the expression of Bcl11b, which can positively regulate Wnt target genes by inhibiting the function of the Nucleosome Remodeling and Deacetylase (NuRD) complex and facilitating the β-catenin-TCF4 interaction. Bcl11b can also promote intestinal epithelium repair after injuries elicited by both irradiation and DSS-induced inflammation. Furthermore, Bcl11b deletion prevents proliferation and tumorigenesis of colorectal cancer cells. Together, our findings suggest that BMP suppresses Wnt signaling via Bcl11b regulation, thus balancing homeostasis and regeneration in the intestinal epithelium.

Evidence indicates that microglial G protein-coupled receptor kinase 2 (GRK2) is a key regulator of the transition from acute to chronic pain mediated by microglial products via the p38 mitogen-activated protein kinase (MAPK) pathway in the spinal cord dorsal horn (SCDH). Increasing studies have shown that autophagic dysfunction in the SCDH and neuroinflammation in the hippocampus underlie NeP. However, whether GRK2/p38MAPK and autophagic flux in the SCDH and hippocampal neuroinflammation are involved in NeP and depression comor-bidity has not been determined. Here, we explored the effects of high-voltage pulsed radiofrequency (PRF) (85 V-PRF; HV-PRF) to the dorsal root ganglion (DRG) on pain phenotypes in Wistar male rats with spared nerve injury (SNI) and the underlying mechanisms. The exacerbation of pain phenotypes was markedly relieved by PRF-DRG. The SNI-induced reduction in GRK2 expression, elevation of p-p38 MAPK levels in the SCDH, and increase in IL-1 beta and TNF-alpha levels in the hippocampus were reversed by PRF, which was accompanied by an increase in autophagic flux in spinal microglia. The beneficial effect of 85 V-PRF was superior to that of 45 V-PRF. In addition, the improvements elicited by 85 V-PRF were reversed by intrathecal injection of GRK2 antisense oligonucleotide, and these changes were accompanied by GRK2 downregulation and p-p38 upregulation in the SCDH, increased pro-inflammatory factor levels in the hippocampus, and excessive autophagy in spinal micro-glia. In conclusion, our data indicate that the application of HV-PRF to the DRG could serve as an excellent therapeutic technique for regulating neuroimmunity and neuroinflammation to relieve pain phenotypes.

A multivariate predictive model was constructed using baseline and 12-week clinical data to evaluate the rate of clearance of hepatitis B surface antigen (HBsAg) at the 48-week mark in patients diagnosed with chronic hepatitis B who are receiving treatment with pegylated interferon α (PEG-INFα). The study cohort comprised CHB patients who received pegylated interferon treatment at Mengchao Hepatobiliary Hospital, Fujian Medical University, between January 2019 and April 2024. Predictor variables were identified (LASSO), followed by multivariate analysis and logistic regression analysis. Subsequently, predictive models were developed via logistic regression, random forest (RF), gradient boosting decision tree (GBDT), extreme gradient boosting (XGBoost), and support vector machine (SVM) algorithms. The efficacy of these models was assessed through various performance metrics, including the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and F1 score. This study included a total of 224 individuals diagnosed with chronic hepatitis B. The variables baseline log2(HBsAg), gender, age, neutrophil count at week 12, HBsAg decline rate at week 12, and HBcAb at week 12 were closely associated with functional cure and were included in the predictive model. In the validation term, the logistic regression model had an AUC of 0.858, which was better than that of the other machine learning models (AUC = 0.858,F1 = 0.753). Consequently, this model was selected for the development of the predictive tool. The combined use of the baseline log2(HBsAg) value, HBsAg decline rate at week 12, gender, neutrophil count at week 12, and age can serve as a foundational predicting model for anticipating the clearance of HBsAg in individuals with chronic hepatitis B who are receiving PEG-INFα therapy.