Rab32 facilitates Schwann cell pyroptosis in rats following peripheral nerve injury by elevating ROS levels.

BACKGROUND: Peripheral nerve injury (PNI) is commonly observed in clinical practice, yet the underlying mechanisms remain unclear. This study investigated the correlation between the expression of a Ras-related protein Rab32 and pyroptosis in rats following PNI, and potential mechanisms have been explored by which Rab32 may influence Schwann cells pyroptosis and ultimately peripheral nerve regeneration (PNR) through the regulation of Reactive oxygen species (ROS) levels. METHODS: The authors investigated the induction of Schwann cell pyroptosis and the elevated expression of Rab32 in a rat model of PNI. In vitro experiments revealed an upregulation of Rab32 during Schwann cell pyroptosis. Furthermore, the effect of Rab32 on the level of ROS in mitochondria in pyroptosis model has also been studied. Finally, the effects of knocking down the Rab32 gene on PNR were assessed, morphology, sensory and motor functions of sciatic nerves, electrophysiology and immunohistochemical analysis were conducted to assess the therapeutic efficacy. RESULTS: Silencing Rab32 attenuated PNI-induced Schwann cell pyroptosis and promoted peripheral nerve regeneration. Furthermore, our findings demonstrated that Rab32 induces significant oxidative stress by damaging the mitochondria of Schwann cells in the pyroptosis model in vitro. CONCLUSION: Rab32 exacerbated Schwann cell pyroptosis in PNI model, leading to delayed peripheral nerve regeneration. Rab32 can be a potential target for future therapeutic strategy in the treatment of peripheral nerve injuries.

Non-heavy doped pnp-AlGaN tunnel junction for an efficient deep-ultraviolet light emitting diode with low conduction voltage.

While traditional tunnel junction (TJ) light-emitting diodes (LEDs) can enhance current diffusion and increase hole injection efficiency, their reliance on highly doped AlGaN layers to improve hole tunneling efficiency results in a higher conduction voltage, adversely impacting LED device performance. This paper proposes a non-heavy doped pnp-AlGaN TJ deep ultraviolet (DUV) LED with a low conduction voltage. By inserting the TJ near the active region, between the electron blocking layer and the hole supply layer, the need for heavily doped AlGaN is circumvented. Furthermore, the LED leverages the polarization charge in the pnp-AlGaN TJ layer to decrease the electric field strength, enhancing hole tunneling effects and reducing conduction voltage. The non-heavy doped pnp-AlGaN TJ LED effectively enhances carrier concentration in the quantum well, achieving a more uniform distribution of electrons and holes, thus improving radiative recombination efficiency. Consequently, at an injection current of 120 A/cm2, compared to the traditional structure LED (without TJ), the proposed LED exhibits a 190.7% increase in optical power, a 142.8% increase in maximum internal quantum efficiency (IQE) to 0.85, and a modest efficiency droop of only 5.8%, with a conduction voltage of just 4.1V. These findings offer valuable insights to address the challenges of high heavy doped TJ and elevated conduction voltage in high-performance TJ DUV LEDs.

Clinical prognosis and related molecular features of hepatitis B-associated adolescent and young adult hepatocellular carcinoma.

BACKGROUND: Inattention has been given to the pathogenesis of adolescent and young adult (AYA) hepatocellular carcinoma (HCC). Due to the more advanced tumor progression and poorer prognosis of AYA-HCC, together with a better tolerance ability, noncirrhotic background, and a stronger willingness to treat AYA-HCC, clinical and molecular biology studies are urgent and necessary, especially for those with hepatitis B infection. METHODS: For clinical aspects, the overall survival, the recurrence-free survival, and the Cox analyses were performed. Then, functional analysis, gene clustering, metabolic-related analysis, immune infiltration and competing endogenous RNA (ceRNA) construction were carried out using whole transcriptome sequencing technique. RESULTS: Based on the clinical information of our HCC cohort, the overall survival and recurrence-free survival rates were worse in the AYA group than in the elderly group as previously described. According to our whole transcriptome sequencing results, functional analysis revealed that metabolism-related pathways as well as protein translation and endoplasmic reticulum processing were enriched. Then the hub metabolism-related genes were screened by metabolite-protein interactions (MPIs) and protein-protein interactions (PPIs). Fatty acid metabolism is a crucial component of metabolic pathways, abnormalities of which may be the reason for the worse prognosis of HBV-AYA HCC. Finally, the relationship of disrupted expression of metabolism-related genes with immune infiltration was also analyzed, and the lncRNA‒miRNA‒mRNA-related ceRNA network for HBV-AYA HCC was constructed, which may provide new cues for HBV-AHA HCC prevention. CONCLUSION: The worse prognosis and recurrence rate of HBV-AYA HCC may be related to abnormalities in metabolism-related pathways, especially disorders of fatty acid metabolism.

Functional connectivity profiles of the default mode and visual networks reflect temporal accumulative effects of sustained naturalistic emotional experience.

Determining and decoding emotional brain processes under ecologically valid conditions remains a key challenge in affective neuroscience. The current functional Magnetic Resonance Imaging (fMRI) based emotion decoding studies are mainly based on brief and isolated episodes of emotion induction, while sustained emotional experience in naturalistic environments that mirror daily life experiences are scarce. Here we used 12 different 10-minute movie clips as ecologically valid emotion-evoking procedures in n = 52 individuals to explore emotion-specific fMRI functional connectivity (FC) profiles on the whole-brain level at high spatial resolution (432 parcellations including cortical and subcortical structures). Employing machine-learning based decoding and cross validation procedures allowed to investigate FC profiles contributing to classification that can accurately distinguish sustained happiness and sadness and that generalize across subjects, movie clips, and parcellations. Both functional brain network-based and subnetwork-based emotion classification results suggested that emotion manifests as distributed representation of multiple networks, rather than a single functional network or subnetwork. Further, the results showed that the Visual Network (VN) and Default Mode Network (DMN) associated functional networks, especially VN-DMN, exhibited a strong contribution to emotion classification. To further estimate the temporal accumulative effect of naturalistic long-term movie-based video-evoking emotions, we divided the 10-min episode into three stages: early stimulation (1∼200 s), middle stimulation (201∼400 s), and late stimulation (401∼600 s) and examined the emotion classification performance at different stimulation stages. We found that the late stimulation contributes most to the classification (accuracy=85.32%, F1-score=85.62%) compared to early and middle stimulation stages, implying that continuous exposure to emotional stimulation can lead to more intense emotions and further enhance emotion-specific distinguishable representations. The present work demonstrated that sustained happiness and sadness under naturalistic conditions are presented in emotion-specific network profiles and these expressions may play different roles in the generation and modulation of emotions. These findings elucidated the importance of network level adaptations for sustained emotional experiences during naturalistic contexts and open new venues for imaging network level contributions under naturalistic conditions.

Increased Small Ubiquitin-like Modifier-Activating Enzyme SAE1 Promotes Hepatocellular Carcinoma by Enhancing mTOR SUMOylation.

SUMOylation, one of the most important posttranslational modifications of proteins, plays an essential role in various biological processes; however, enzymes that control SUMOylation in hepatocellular carcinoma (HCC) are still unclear. Comprehensive exploration of the expression and clinical significance of SUMO enzymes in HCC would be of great value. Here, we obtained the gene expression profile of each small ubiquitin-like modifier (SUMO) protein and the corresponding clinical information from The Cancer Genome Atlas. We found that all SUMO enzymes were significantly increased in HCC tissues compared with that in adjacent nontumorous tissues. We identified a 6-gene prognostic signature, including SAE1, PIAS2, PIAS3, SENP3, SENP5, and UBC9, that could effectively predict the overall survival in patients with HCC. Specifically, SAE1 was the most valuable prognostic indicator. In 282 clinical samples, we found that SAE1 was closely related to the clinicopathologic parameters and prognosis of patients with HCC. In vitro and in vivo studies showed that SAE1 knockdown inhibits the proliferation, migration, and invasion of HCC cells. Mechanistically, we confirmed that SAE1 plays a role in driving HCC progression, which is largely dependent on the SUMOylation of mTOR signaling. In conclusion, our study revealed that the expression of SUMO enzymes, especially SAE1, is highly associated with HCC development and acts as a promising prognostic predictor.

HDAC3 Controls Liver Homeostasis More by Facilitating Deoxyribonucleic Acid Damage Repair than by Regulating Transcription in Hepatocytes.

By controlling DNA damage repair and regulating gene transcription, the critical epigenetic regulator histone deacetylase 3 (HDAC3) plays pivotal roles in liver cancer and liver regeneration; however, the role of HDAC3 in liver homeostasis has not been fully elucidated. In this study, we found that HDAC3-deficient livers developed a defective morphology and metabolism with an increasing degree of DNA damage in the hepatocytes along the portal-central axis of the lobule. Most strikingly, in the Alb-CreERT:Hdac3-/- mice, it was demonstrated that HDAC3 ablation did not impair liver homeostasis in terms of histologic characteristics, function, proliferation, or gene profiles prior to the profound accumulation of DNA damage. Next, we identified that the hepatocytes in the portal area, which carried less DNA damage than those in the central area, repopulated the hepatic lobule by active regeneration and movement toward the center. As a result, the liver became more viable after each surgery. Furthermore, in vivo tracing of keratin-19-expressing hepatic progenitor cells, which lacked HDAC3, showed that the hepatic progenitor cells gave rise to newly generated periportal hepatocytes. In hepatocellular carcinoma, HDAC3 deficiency impaired DNA damage response and enhanced radiotherapy sensitivity in vitro and in vivo. Taken together, we demonstrated that HDAC3 deficiency interferes with liver homeostasis, which is more dependent on the accumulation of DNA damage in hepatocytes than on transcriptional dysregulation. Our findings support the hypothesis that selective HDAC3 inhibition has the potential to augment the effect of chemoradiotherapy aimed at inducing DNA damage in cancer therapy.

Hepatocyte-specific HDAC3 ablation promotes hepatocellular carcinoma in females by suppressing Foxa1/2.

BACKGROUND: Hepatocellular carcinoma (HCC), the most common primary liver cancer, prevails mainly in males and has long been attributed to androgens and higher circumstantial levels of interleukin-6 (IL-6) produced by resident hepatic macrophages. METHODS: Constitutively hepatocyte-specific histone deacetylase 3 (HDAC3)-deficient (HDAC3LCKO) mice and constitutively hepatocyte-specific HDAC3 knockout and systemic IL-6 simultaneously ablated (HDAC3LCKO& IL-6-/-) mice were used in our study to explore the causes of sex differences in HCC. Additionally, we performed human HCC tissues with an IHC score. Correlation analysis and linear regression plots were constructed to reveal the association between HDAC3 and its candidate genes. To further elucidate that HDAC3 controls the expression of Foxa1/2, we knocked down HDAC3 in HUH7 liver cancer cells. RESULTS: We observed a contrary sex disparity, with an earlier onset and higher incidence of HCC in female mice when HDAC3 was selectively ablated in the liver. Loss of HDAC3 led to constant liver injury and the spontaneous development of HCC. Unlike the significant elevation of IL-6 in male mice at a very early age, female mice exhibit stable IL-6 levels, and IL-6 ablation did not eliminate the sex disparity in hepatocarcinogenesis in HDAC3-deficient mice. Oestrogen often protects the liver when combined with oestrogen receptor alpha (ERα); however, ovariectomy in HDAC3-ablated female mice significantly delayed tumourigenesis. The oestrogen-ERα axis can also play a role in tumour promotion in the absence of Foxa1 and Foxa2 in the receptor complex. Loss of HDAC3 profoundly reduced the expression of both Foxa1 and Foxa2 and impaired the binding between Foxa1/2 and ERα. Furthermore, a more frequent HDAC3 decrease accompanied by the simultaneous Foxa1/2 decline was found in female HCC compared to that in male HCC. CONCLUSION: In summary, we reported that loss of HDAC3 reduces Foxa1/2 and thus promotes HCC development in females in an oestrogen-dependent manner.

Analysis of the expression and prognostic significance of DDK complex in Hepatocarcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) remains one of the most common and lethal malignancies worldwide. Although DBF4-dependent kinase (DDK) complex composed of CDC7 kinase and its regulatory subunit DBF4 has been shown to be overexpressed in primary tumors and promotes tumor development, while its role and prognostic value in HCC remain largely unknown. In the present study, the expression of DBF4 and CDC7 and their relationship with clinical characteristics were comprehensively analyzed. METHODS: The mRNA expression profiles of HCC and the corresponding clinical data of HCC patients were downloaded from TCGA and GEO databases, respectively. The differences in DBF4 and CDC7 expression in tumor tissues and adjacent normal tissues were analyzed. HCC-derived tissue microarray (TMA) was used to evaluate and score the expression of CDC7 by immunohistochemistry (IHC) staining. The Kaplan-Meier method and the Cox regression method were used to analyze the relationship between overall survival and clinical characteristics of the patients. Gene set enrichment analysis (GSEA) was used to analyze the pathway enrichment of DBF4 and CDC7. RESULTS: DBF4 and CDC7 had similar expression patterns in HCC patients. Detailly, compared with adjacent tissues, both mRNA and protein of DBF4 and CDC7 were significantly higher in HCC, and their expression was positively correlated with AJCC_T stage, clinical stage and G stage (grade) of liver cancer patients, and higher DBF4 or CDC7 expression predicted a worse prognosis in HCC patients with shorter overall survival (OS), recurrence-free survival (RFS), disease-specific survival (DSS) and progress-free survival (PFS). Cox regression analysis suggested that both DBF4 and CDC7 were independent risk factors for the prognosis of HCC patients in TCGA dataset. GSEA suggested that both DBF4 and CDC7 were positively correlated with cell cycle and DNA replication. Finally, the prognostic value of CDC7 was furtherly confirmed by TMA-based IHC staining results. CONCLUSIONS: Our study showed that DDK complex was significantly increased in HCC. Both DBF4 and CDC7 may be potential diagnostic and prognostic markers for HCC, and high expression of DDK members predicts a worse prognosis in patients with HCC, which may be associated with high tumor cell proliferation rate.

Long-term efficacy and safety of anticoagulant for cavernous transformation of the portal vein cirrhotic patient with extrahepatic portal vein obstruction.

BACKGROUND/AIMS: Cavernous transformation of the portal vein (CTPV) in cirrhotic patients with extrahepatic portal vein obstruction (EHPVO) was a relatively rare disease and had no consensus on the treatment. Our study aimed to explore the value of anticoagulation with warfarin treatment for CTPV cirrhotic patients with EHPVO. METHODS: From January 2015 to December 2019, the clinical characteristics of cirrhotic patients who were diagnosed as CTPV with EHPVO were retrospectively analyzed. Eligible patients were distributed into the anticoagulation group (n = 46) and control group (n = 38). The change of portal vein thrombosis, hepatic decompensation, survival and adverse events were evaluated between the two groups. RESULTS: The median follow-up of our patients was 51 months in the anticoagulation group and 44 months in the control group. The progress rate of the portal vein was higher in patients from the control groups (n = 12) than in patients from the anticoagulation group (n = 4, p = 0.008). There was no significant difference between the partial recanalization rate and stable rate between the two groups. Patients in anticoagulation group developed less hepatic decompensation than those in control group (13.0% vs 34.2%, p = 0.021). The Kaplan-Meier curve showed that patients in the anticoagulation group had a better prognosis than patients in the control group (P < 0.022). There were no serious complications due to warfarin treatment. CONCLUSION: For CTPV cirrhotic patients with EHPVO, anticoagulation with warfarin treatment was effective and safe. Anticoagulants could prevent portal vein thrombosis progression, hepatic decompensation and death. In addition, our results showed little benefit of anticoagulants on thrombosis recanalization.

Relationship between alexithymia, loneliness, resilience and non-suicidal self-injury in adolescents with depression: a multi-center study.

OBJECTIVE: Non-suicidal self-injury (NSSI) behaviors are prevalent in adolescents and have adverse effects on physical and mental health. However, little is known about the relationship between NSSI and alexithymia, or the underlying mechanisms that could explain this relationship. This study aimed to elucidate the current status of NSSI in adolescent depression, and analyze the relationship between alexithymia, loneliness, resilience, and adolescent depression with NSSI, so as to provide a theoretical basis for psychotherapeutic interventions. METHOD: The study sample involved inpatients and outpatients from 12 hospitals across China and adolescents with depression who met the DSM-5 diagnostic criteria for depression episode. The following scales were used: The Functional Assessment of Self-Mutilation, Toronto Alexithymia Scale, UCLA Loneliness Scale, and Connor Davidson Resilience Scale. RESULTS: The detection rate of NSSI in adolescents with depression from 2021.01.01-2022.01.01 was 76.06% (1782/2343). Spearman's correlation analysis revealed a significant correlation between alexithymia, loneliness, resilience and NSSI in depressed adolescents, and the results of the non-parametric test showed that the differences between the two groups for each factor were statistically significant. Binary logistic regression results showed that alexithymia (B = 0.023, p = 0.003, OR = 1.023, 95% CI: 1.008-1.038) and depression (B = 0.045, p < 0.001, OR = 1.046, 95% CI: 1.026-1.066) are risk factors for NSSI, resilience (B = - 0.052, p < 0.001, OR = 0.949, 95% CI: 0.935 - 0.964) is a protective factor for NSSI. Alexithymia directly predicted NSSI and also indirectly influenced NSSI through the mediated effect of resilience. Loneliness moderates the first half of the path of this mediated model. CONCLUSION: The present study confirms a moderated mediation effect: Alexithymia can have an impact on NSSI behaviors in depressed adolescents through the mediating role of resilience. Loneliness, as a moderating variable, moderated the first half of the pathway of the mediating model. We discuss perspectives for future research and interventions based on the findings of the study.