RNA-Mediated Feedback Control of Transcriptional Condensates.

Regulation of biological processes typically incorporates mechanisms that initiate and terminate the process and, where understood, these mechanisms often involve feedback control. Regulation of transcription is a fundamental cellular process where the mechanisms involved in initiation have been studied extensively, but those involved in arresting the process are poorly understood. Modeling of the potential roles of RNA in transcriptional control suggested a non-equilibrium feedback control mechanism where low levels of RNA promote condensates formed by electrostatic interactions whereas relatively high levels promote dissolution of these condensates. Evidence from in vitro and in vivo experiments support a model where RNAs produced during early steps in transcription initiation stimulate condensate formation, whereas the burst of RNAs produced during elongation stimulate condensate dissolution. We propose that transcriptional regulation incorporates a feedback mechanism whereby transcribed RNAs initially stimulate but then ultimately arrest the process.

Transcription factors interact with RNA to regulate genes.

Transcription factors (TFs) orchestrate the gene expression programs that define each cell's identity. The canonical TF accomplishes this with two domains, one that binds specific DNA sequences and the other that binds protein coactivators or corepressors. We find that at least half of TFs also bind RNA, doing so through a previously unrecognized domain with sequence and functional features analogous to the arginine-rich motif of the HIV transcriptional activator Tat. RNA binding contributes to TF function by promoting the dynamic association between DNA, RNA, and TF on chromatin. TF-RNA interactions are a conserved feature important for vertebrate development and disrupted in disease. We propose that the ability to bind DNA, RNA, and protein is a general property of many TFs and is fundamental to their gene regulatory function.

Contribution of the Fetal Cardiac Axis and V-Sign Angle in First-Trimester Screening for Major Cardiac Defects.

OBJECTIVE: To estimate the potential value of fetal assessment for the cardiac axis (CAx) and V-sign angle (VSA) in the first trimester in the prediction of fetal major cardiac defects. METHODS: A cohort study was conducted from December 2015 to June 2016. Patients with singleton pregnancies and crown-rump length from 45 to 84 mm were recruited to undergo nuchal translucency sonography. The CAx on the 4-chamber view and the VSA on the 3-vessel and trachea view with Doppler mapping were measured. The estimated performance of different combinations of increased fetal nuchal translucency, CAx, and VSA in screening for major cardiac defects was examined. RESULTS: The study population of fetuses included 30 fetuses with major cardiac defects and 1538 normal fetuses. The CAx and VSA were 30° to 60° and 30° to 40°, respectively, according to the 2.5th and 97.5th percentiles in normal fetuses. When cases of isolated septal wall defects and an isolated right aortic arch were excluded, nuchal translucency above the 95th percentile, an abnormal CAx, and an abnormal VSA were observed in 63.3% (19 of 30), 63.3% (19 of 30), and 66.7% (20 of 30) of fetuses with major cardiac defects, respectively, and in 4.6% (71 of 1538), 2.0% (30 of 1538), and 5.6% (86 of 1538) of those without cardiac defects. Either an abnormal CAx or VSA was found in 93.3% (28 of 30) of the fetuses with cardiac defects and in 7.3% (113 of 1538) of those without cardiac defects. CONCLUSION: Assessment of the CAx and VSA is helpful in defining a population at risk for major cardiac defects in the first trimester.

Improvement in early detection of orofacial clefts using the axial view of the maxilla.

OBJECTIVES: To evaluate the performance of the maxilla in the axial view in detection of orofacial clefts (OC) compared with the retronasal triangle (RNT) in the coronal view and palatine line in the sagittal view at the early stage of gestation. METHODS: A total of 2982 fetuses (including 315 twins) were enrolled for the first-trimester screening in this prospective study. The maxilla in the axial view, palatine line in the sagittal view, and RNT in the coronal view were scanned by 2-dimensional ultrasound. RESULTS: Excluded 103 cases lost to follow-up, 2879 fetuses were analyzed in our study. Obtaining rates of the satisfactory image of the maxilla in the axial view, RNT in the coronal view, and palatine line in the sagittal view were 95.2%, 93.8%, and 98.2% respectively. Abnormal axial view of the maxilla, coronal view of the RNT, and sagittal view of the palatine line were observed in 100% (8/8), 75% (6/8), and 50% (4/8) of the CLP cases respectively. CONCLUSIONS: The study demonstrates that using the axial view of maxilla in the diagnosis of OC is feasible and improved the detection of OC compared with the sagittal view of the palatine line and coronal view of the RNT in the first trimester.

Fetoscopy-guided bipolar cord coagulation in selective fetal reduction with complicated monochorionic diamniotic twins: a prospective cohort study.

OBJECTIVE: To assess the feasibility of fetoscopy-guided bipolar umbilical cord coagulation for selective fetal reduction in complicated monochorionic diamniotic (MCDA) twin pregnancies. METHODS: MCDA twins undergoing fetoscopy-guided bipolar cord coagulation (BCC) were enrolled prospectively between December 2015 to March 2020 in a fetal medicine center. RESULTS: Twenty-three cases undergoing fetoscopy-guided BCC were finally analyzed, including 11 cases for type 2 selective intrauterine growth restriction, 4 cases for twin-twin transfusion syndrome, and 8 cases for a severe discordant anomaly. The overall survival rate was 78.3% (18/23). CONCLUSIONS: Fetoscopy-guided BCC is effective for selective fetal reduction in complicated monochorionic twin pregnancies.

The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance.

Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We report here that IR is incorporated into dynamic clusters at the plasma membrane, in the cytoplasm and in the nucleus of human hepatocytes and adipocytes. Insulin stimulation promotes further incorporation of IR into these dynamic clusters in insulin-sensitive cells but not in insulin-resistant cells, where both IR accumulation and dynamic behavior are reduced. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue IR accumulation and the dynamic behavior of these clusters. This rescue is associated with metformin's role in reducing reactive oxygen species that interfere with normal dynamics. These results indicate that changes in the physico-mechanical features of IR clusters contribute to insulin resistance and have implications for improved therapeutic approaches.