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Dysregulation of pre-mRNA alternative splicing (AS) is closely associated with cancers. However, the relationships between the AS and classic oncogenes/tumor suppressors are largely unknown. Here we show that the deletion of tumor suppressor PTEN alters pre-mRNA splicing in a phosphatase-independent manner, and identify 262 PTEN-regulated AS events in 293T cells by RNA sequencing, which are associated with significant worse outcome of cancer patients. Based on these findings, we report that nuclear PTEN interacts with the splicing machinery, spliceosome, to regulate its assembly and pre-mRNA splicing. We also identify a new exon 2b in GOLGA2 transcript and the exon exclusion contributes to PTEN knockdown-induced tumorigenesis by promoting dramatic Golgi extension and secretion, and PTEN depletion significantly sensitizes cancer cells to secretion inhibitors brefeldin A and golgicide A. Our results suggest that Golgi secretion inhibitors alone or in combination with PI3K/Akt kinase inhibitors may be therapeutically useful for PTEN-deficient cancers. Cytoplasmic PTEN is a tumor suppressor that antagonises PI3K signalling. Here, the authors show that nuclear PTEN can interact with the spliceosomal proteins and drive pre-mRNA splicing in a phosphatase-independent manner, in particular, PTEN depletion promotes Golgi extension and secretion through GOLGA2 exon skipping.

Objectives: Resilience to pain is a protective factor against aversive pain outcomes, such as suicide. Religiosity as a cornerstone of resilience has been found to be associated with reduced risk of suicidality in chronic pain. However, affiliations to different religions have displayed differences in suicide risk. This study focuses on the roles of pain resilience and Dao religion in mitigating suicidal experience in individuals with chronic pain. Methods: This study adopted a mixed‐method approach. A preliminary investigation was conducted regarding the internal consistency and construct validity of the translated version of the pain resilience scale (PRS). Qualitative data were collected through interviews with individuals experiencing chronic pain. Levels of PRS and gender were included in the logistic regression on the probability of suicide attempts. The role of Dao practice was qualitatively analyzed through narrative analysis. Results: Among the 24 participants, 14 were affiliated with the Dao religion; therefore, the transcripts of these 14 interviews were analyzed. Individuals with moderate scores on the PRS were 11.60 times less likely to have attempted suicide than those with low PRS scores. The likelihood further decreased by 38.7 times in those with high PRS scores. Four themes emerged from the qualitative interviews. The participants experienced a burden from pain, made efforts to please the deities in exchange for better pain control, continuously adjusted to pain, and ultimately developed a new perspective on the relationship between their religion and pain. Many individuals have engaged in Dao rituals to try to alleviate their physical and psychological pain. Most participants tended to offer a religious interpretation of enlightening moments after surviving a suicide attempt. Discussion: This study illustrates how pain resilience and Dao religious practices mitigate suicidality in chronic pain. Trial Registration: ClinicalTrials.gov identifier: NCT05148364.

To evaluate the “flow void” diameter in patients with pregnancy-related diseases with and without uterine AVMs and assess the diagnostic performance of unenhanced MRI for uterine AVMs. From May 2014 to April 2019, 79 patients with pregnancy-related diseases were included, including 36 with and 43 without uterine AVMs confirmed by DSA. On MRI, the diameter of the most prominent “flow void” (hereinafter referred to as fv-D) was measured and compared between patients with and without uterine AVMs. The diagnostic performance of fv-D was estimated with receiver operating characteristic curves. The “flow void” sign was observed in patients with and without uterine AVMs (P > 0.05). The fv-D was significantly larger in patients with uterine AVMs in the myometrium and parametrium than in patients without uterine AVMs (P < 0.0001). The fv-D achieved a reliable diagnostic performance in the myometrium (sensitivity 80.6%, specificity 60.5%, negative predictive value 78.8%, positive predictive value 63%, AUC 0.727, cut-off: > 1.33 mm) and parametrium (sensitivity 97.2%, specificity 67.4%, negative predictive value 96.7%, positive predictive value 71.4%, AUC 0.881, cut-off > 2.6 mm). On MRI, fv-D could diagnose uterine AVMs. The fv-D had a much higher diagnostic efficiency in the parametrium than in the myometrium. The parametrium fv-D greatly improved the diagnostic sensitivity and provides a more accurate, noninvasive method of investigating possible uterine AVMs.

Background and Objectives: Attentional bias (AB) for addictive substances is a feature of attention found in individuals with substance misuse or diagnosed with substance use disorders. When AB exists, the attention of the addicted individual may be quickly oriented to cues related to the addictive substance or be maintained on these cues for a longer time. AB toward opioids was found in Western samples of smokers with chronic noncancer pain. The level of AB was dose-responsive. However, similar studies in the Taiwanese population are lacking. This study compared the patterns of AB for opioid analgesics in Taiwanese participants with chronic noncancer pain to that of individuals without pain. This study aimed to investigate if AB toward opioids is presented in Taiwanese heavy smokers who are on long-term opioid therapy for pain control. Materials and Methods: Participants were grouped into chronic noncancer pain smokers, chronic pain nonsmokers, and smokers without pain, according to smoking habits and whether or not on long-term opioid therapy for pain control. Each participant completed demographic questionnaires, mood scales, and the opioid-related visual probe task. Differences in AB among the groups were compared using a three-way analysis of covariance controlling for daily cigarette consumption. Results: Chronic noncancer pain smokers (n = 17) and chronic pain nonsmokers (n = 16) displayed more severe levels of depression, anxiety, and pain, compared to smokers without pain (n = 28). Only did chronic pain nonsmokers show significant AB for opioid cues that were displayed for a short time. Analysis on reaction time found that smokers without pain consistently responded faster to the tasks. No difference in reaction time was found between the pain groups. Conclusions: The current study did not fully replicate findings from studies that were based in Western countries. Formulary availability and regulatory limitations might have affected patient’s perception of prescription opioids in Taiwan. However, chronic pain nonsmokers exhibited initial orientation toward opioid-related cues when daily cigarette consumption was accounted for. According to previous research, this AB for shortly displayed opioid cues can be associated with the expectation of pain relief. The current finding also indicated general psychomotor retardation in individuals who were on long-term use of opioids.

Background and Objectives: Local anesthetics administered via epidural catheters have evolved from intermittent top-ups to simultaneous administration of continuous epidural infusion (CEI) and patient-controlled epidural analgesia (PCEA) using the same device. The latest programmed intermittent epidural bolus (PIEB) model is believed to create a wider and more even distribution of analgesia inside the epidural space. The switch from CEI + PCEA to PIEB + PCEA in our department began in 2018; however, we received conflicting feedback regarding workload from the quality assurance team. This study aimed to investigate the benefits and drawbacks of this conversion, including the differences in acute pain service (APS) staff workload, maternal satisfaction, side effects, and complications before and after the changeover. Materials and Methods: Items from the APS records included total delivery time, average local anesthetic dosage, and the formerly mentioned items. The incidence of side effects, the association between the duration of delivery and total dosage, and hourly medication usage in the time subgroups of the CEI and PIEB groups were compared. The staff workload incurred from rescue bolus injection, catheter adjustment, and dosage adjustment was also analyzed. Results: The final analysis included 214 and 272 cases of CEI + PCEA and PIEB + PCEA for labor analgesia, respectively. The total amount of medication and average hourly dosage were significantly lower in the PIEB + PCEA group. The incidences of dosage change, manual bolus, extra visits per patient, and lidocaine use for rescue bolus were greater in the PIEB + PCEA group, indicating an increased staff workload. However, the two groups did not differ in CS rates, labor time, maternal satisfaction, and side effects. Conclusions: This study revealed that while PIEB + PCEA maintained the advantage of decreasing total drug doses, it inadvertently increased the staff burden. Increased workload might be a consideration in clinical settings when choosing between different methods of PCEA.

Vacuolar protein sorting 33B (VPS33B) is important for intracellular vesicular trafficking process and protein interactions, which is closely associated with the arthrogryposis, renal dysfunction, and cholestasis syndrome. Our previous study has shown a crucial role of Vps33b in regulating metabolisms of bile acids and lipids in hepatic Vps33b deficiency mice with normal chow, but it remains unknown whether VPS33B could contribute to cholestatic liver injury. In this study we investigated the effects of hepatic Vps33b deficiency on bile acid metabolism and liver function in intrahepatic cholestatic mice. Cholestasis was induced in Vps33b hepatic knockout and wild-type male mice by feeding 1% CA chow diet for 5 consecutive days. We showed that compared with the wild-type mice, hepatic Vps33b deficiency greatly exacerbated CA-induced cholestatic liver injury as shown in markedly increased serum ALT, AST, and ALP activities, serum levels of total bilirubin, and total bile acid, as well as severe hepatocytes necrosis and inflammatory infiltration. Target metabolomics analysis revealed that hepatic Vps33b deficiency caused abnormal profiles of bile acids in cholestasis mice, evidenced by the upregulation of conjugated bile acids in serum, liver, and bile. We further demonstrated that the metabolomics alternation was accompanied by gene expression changes in bile acid metabolizing enzymes and transporters including Cyp3a11 , Ugt1a1 , Ntcp , Oatp1b1 , Bsep , and Mrp2 . Overall, these results suggest a crucial role of hepatic Vps33b deficiency in exacerbating cholestasis and liver injury, which is associated with the altered metabolism of bile acids.

Objective: Glial cells are involved in the analgesic effect of electroacupuncture (EA) in rats with chronic neurological pain. The objective of this study was to observe the role of neuronal-glial interaction and glutamate (Glu) transporters in EA-induced acute neck pain relief in rats. Materials and Methods: Male rats were placed into the following 5 groups: control, model, EA Futu (LI18), EA Hegu (LI4)-Neiguan (PC6), and EA Zusanli (ST36)-Yanglingquan (GB34). The incisional neck pain model was established by making a longitudinal incision along the midline of the neck. The thermal pain threshold (TPT) was measured using a radiation heat detector. The immunoactivities of glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba-1), neurokinin 1 receptor (NK-1R), Glu aspartate transporter (GLAST), and Glu transporter-1 (GLT-1) in the dorsal horns of the cervico-spinal cord (C2–C5) were detected using immunofluorescence histochemistry. The expression levels of GFAP, Iba-1, GLAST, and GLT-1 mRNAs were determined using quantitative real-time polymerase chain reaction (PCR). Results: The TPT and levels of mRNAs expression and immunoactivity GLT-1 and GLAST were significantly decreased, and those of Iba-1 and GFAP were significantly increased in the model group than those of the control group (P < 0.05). The activated microgliacytes were gathered around the NK-1R positive neurons, and co-expression of NK-1R and astrocytes was observed in the model group. EA LI18 significantly increased the TPT and expression of GLAST and GLT-1 mRNAs(P < 0.05), and notably decreased the number of Iba-1 positive cells and Iba-l mRNA expression (P < 0.05), whereas GLAST and GLT-1 antagonists inhibited the analgesic effect of EA LI18. However, these effects, except for the downregulation of Iba-1 mRNA, were not observed in the EA ST36-GB34 group. Fewer NK-1R-positive neurons were visible in the spinal DHs in the EA LI18 group, and the co-expression of NK-1R and astrocytes was also lower than that in the three EA groups. Conclusion: EA of LI18 had an analgesic effect in rats with neck incisions, which may be related to it’s functions in suppressing the neuronal-glial cell interaction through NK-1R and upregulating the expression of GLAST and GLT-1 in the spinal DHs.

Background/Objectives: Pain resilience (PR) may be associated with different coping skills, resulting in differences in pain outcomes. This study aimed to understand the role of PR in dictating the choice of coping methods. Methods: This study completed a preliminary validation of the Mandarin Chinese version of the Pain Resilience Scale (PRS-C) with online survey data (n = 46). Further, we conducted interviews with individuals with chronic low back pain (n = 24). Results: The PRS-C psychometric properties were assessed using a confirmatory factor analysis. The interviews explored pain history, treatment experiences, and coping strategies and were analyzed thematically. The validated PRS-C (10 items) demonstrated satisfactory psychometric properties. The interview results showed that participants who scored lower were more likely to adopt disengagement rather than engagement coping strategies. Qualitative data revealed three themes explaining why and how participants in this collectivist social framework chose their coping methods. Conclusions: The findings suggest that while participants tried to understand their pain and treatment experiences, the cognitive appraisal construct in PR influenced some of the coping experiences. However, deeply influenced by Confucianism and Buddhism, participants also expressed factors beyond the scope of individual fortitudes, such as the relationship with a higher power that significantly influenced their coping behaviors.

Autogenic processes are widely found in various sedimentary systems and they play an important role in the depositional evolution and corresponding sedimentary architecture. However, autogenic processes are often affected by changing allogenic factors and are difficult to be identified and analyzed from modern and ancient records. Through the flume tank experiment under constant boundary conditions, the depositional process, evolution principles, and the sedimentary architecture of a river-dominated delta was presented, and a corresponding sedimentary architecture model was constructed. The evolution of river-dominated delta controlled only by autogenic process is obviously periodic, and each autogenic cycle can be divided into an initial progradational stage, a middle retrogratational stage, and a late aggradational–progradational stage. In the initial progradational stage, one feeder channel incised into the delta plain, mouth bar(s) was formed in front of the channel mouth, and small-scale crevasse splays were formed on the delta plain. In the middle retrogradational stage, the feeder channel was blocked by the mouth bar(s) which grew out of water at the end of the initial stage, and a set of large-scale distributary splay complexes were formed on the delta plain. These distributary splay complexes were retrogradationally overlapped due to the continuous migration of the bifurcation point of the feeder channel. In the late aggradational–progradational stage, the feeder channel branched into several radial distributary channels, overlapped distributary channels were formed on the delta plain, and terminal lobe complexes were formed at the end of distributary channels. The three sedimentary layers formed in the three stages constituted an autogenic succession. The experimental delta consisted of six autogenic depositional successions. Dynamic allocation of accommodation space and the following adaptive sediments filling were the two main driving factors of the autogenic evolution of deltas.