Actl6a (actin-like protein 6A, also known as Baf53a or Arp4) is a subunit shared by multiple complexes including esBAF, INO80, and Tip60-p400, whose main components (Brg1, Ino80, and p400, respectively) are crucial for the maintenance of embryonic stem cells (ESCs). However, whether and how Actl6a functions in ESCs has not been investigated. ESCs originate from the epiblast (EPI) that is derived from the inner cell mass (ICM) in blastocysts, which also give rise to primitive endoderm (PrE). The molecular mechanisms for EPI/PrE specification remain unclear. In this study, we provide the first evidence that Actl6a can protect mouse ESCs (mESCs) from differentiating into PrE. While RNAi knockdown of Actl6a, which appeared highly expressed in mESCs and downregulated during differentiation, induced mESCs to differentiate towards the PrE lineage, ectopic expression of Actl6a was able to repress PrE differentiation. Our work also revealed that Actl6a could interact with Nanog and Sox2 and promote Nanog binding to pluripotency genes such as Oct4 and Sox2. Interestingly, cells depleted of p400, but not of Brg1 or Ino80, displayed similar PrE differentiation patterns. Mutant Actl6a with impaired ability to bind Tip60 and p400 failed to block PrE differentiation induced by Actl6a dysfunction. Finally, we showed that Actl6a could target to the promoters of key PrE regulators (e.g., Sall4 and Fgf4), repressing their expression and inhibiting PrE differentiation. Our findings uncover a novel function of Actl6a in mESCs, where it acts as a gatekeeper to prevent mESCs from entering into the PrE lineage through a Yin/Yang regulating pattern.
Background: Dido1 plays important roles in development. Results: Dido1 inhibition led to ES cell differentiation, and its expression promoted ES cell self-renewal. Conclusion: Dido1 participates in ES cell maintenance and forms feedback and feedforward loops with canonical ES cell factors such as Nanog and Oct4. Significance: Dido1 represents a new factor in the ES cell regulatory circuitry for maintaining self-renewal of ES cells.
Brain tumors have been proved challenging to treat. Here, we present a promising alternative by developing an implantable ultrasound-powered tumor treating device (UP-TTD) that electromagnetically disrupts the rapid division of cancer cells without any adverse effects on normal neurons, thereby safely inhibiting brain cancer recurrence. In vitro and in vivo experiments confirmed the significant therapeutic effect of the UP-TTD, with ~58% inhibition on growth rate of clinical tumor cells and ~78% reduction of cancer area in tumor-bearing rats. This UP-TTD is wireless ultrasound-powered, chip-sized, lightweight, and easy to operate on complex surfaces, with a largely boosting therapeutic efficiency and reducing energy consumption. Meanwhile, various treatment parameters could be tuned from the UP-TTD without increasing its size or adding circuits on the integrated chip. The tuning process was simulated and discussed, showing an excellent agreement with the experimental data. The encouraging results of the UP-TTD raise the possibility of a new modality for brain cancer treatment.
Background/Aims: The age-bilirubin-international normalized ratio-creatinine (ABIC) score, which is a predictive model commonly used for alcoholic hepatitis, has not yet been studied in acute-on-chronic hepatitis B liver failure (HBV-ACLF). We aimed to investigate the predictive value of the ABIC score in patients with HBV-ACLF. Methods: This retrospective study involved 398 patients diagnosed with HBV-ACLF, who were divided into a training cohort of 305 patients and a validation cohort of 93 patients. Univariate and multivariate Cox regression models were used to determine risk factors for mortality. Area under the receiver operating characteristic curve (AUC) was calculated to estimate and compare the predictive values of different prognostic scores. Results: The ABIC score was significantly higher in the death group of the training cohort than in its survival group. Independent risk factors for mortality identified by multivariate Cox analysis included blood urea nitrogen, ABIC score, and Chronic Liver Failure Consortium Organ Failure (CLIF-C OF) score. For predicting 1- and 3-month mortality, AUC was higher for the ABIC score than for the Model for End-stage Liver Diseases (MELD) score (0.732 vs. 0.653, P < 0.05, 0.695 vs. 0.619, P < 0.05, respectively), CLIF-C OF score (0.693, P=0.353, 0.656, P=0.341, respectively), and Child-Pugh score (0.675, P=0.189, 0.656, P=0.300, Respectively). Patients with ABIC score > 9.44 had reduced 1- and 3-month survival rates. Conclusion: ABIC score is superior to MELD score in predicting short-term survival in HBV-ACLF patients. ABIC score > 9.44 predicts high short-term mortality risk in HBV-ACLF patients.
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