Disruption in the regulation of casein kinase 2 in circadian rhythm leads to pathological states: cancer, diabetes and neurodegenerative disorders.

Introduction: Circadian rhythm maintains the sleep-wake cycle in biological systems. Various biological activities are regulated and modulated by the circadian rhythm, disruption of which can result in onset of diseases. Robust rhythms of phosphorylation profiles and abundances of PERIOD (PER) proteins are thought to be the master keys that drive circadian clock functions. The role of casein kinase 2 (CK2) in circadian rhythm via its direct interactions with the PER protein has been extensively studied; however, the exact mechanism by which it affects circadian rhythms at the molecular level is not known. Methods: Here, we propose an extended circadian rhythm model in Drosophila that incorporates the crosstalk between the PER protein and CK2. We studied the regulatory role of CK2 in the dynamics of PER proteins involved in circadian rhythm using the stochastic simulation algorithm. Results: We observed that variations in the concentration of CK2 in the circadian rhythm model modulates the PER protein dynamics at different cellular states, namely, active, weakly active, and rhythmic death. These oscillatory states may correspond to distinct pathological cellular states of the living system. We find molecular noise at the expression level of CK2 to switch normal circadian rhythm to any of the three above-mentioned circadian oscillatory states. Our results suggest that the concentration levels of CK2 in the system has a strong impact on its dynamics, which is reflected in the time evolution of PER protein. Discussion: We believe that our findings can contribute towards understanding the molecular mechanisms of circadian dysregulation in pathways driven by the PER mutant genes and their pathological states, including cancer, obesity, diabetes, neurodegenerative disorders, and socio-psychological disease.

Frequency Of Vaginal Birth After Caesarean Section And Its Fetomaternal Outcome.

BACKGROUND: Vaginal birth after caesarean section (VBAC) is associated with reduced blood loss and transfusions, fewer infections, and fewer thromboembolic events as compared to caesarean delivery. The current rate of repeat caesarean after one previous caesarean is above the WHO standard of 15%. We aimed to determine the occurrence of VBAC and to determine the occurrence of feto-maternal outcomes in successful VBAC cases so that trials of VBAC can be given to carefully selected patients to reduce the rate of repeat caesarean section. METHODS: The Combined Military Hospital (CMH) Rawalpindi's Obstetrics and Gynaecology department conducted this cross-sectional study from March 20 to September 19, 2021. After obtaining ethical committee approval, data was collected using a non-probability, consecutive sampling technique from 150 patients on a self-developed structured proforma. Patients between the age range of 20-35 years with a history of previous lower segment caesarean section, having gestational age between 37-41 weeks and who presented in spontaneous labour were included in this study. After taking informed consent, all women were given a trial of labour and the outcome of the trial was noted. Women were followed for the feto-maternal outcomes. The gathered information was analysed using SPSS version 25.0. Post-stratification, a p-value of 0.05 or lower on the chi-square test was deemed statistically significant. RESULTS: Following a C-section, 28.67% of patients experienced successful vaginal births. PPH was found in 2.32%, scar dehiscence in 0.0%, low birth weight babies in 16.28%, APGAR score <7 at 1 minute was 23.26% and NICU admission as 9.30% in women undergoing vaginal birth after caesarean section. CONCLUSIONS: Appropriate selection of patients for the trial of VBAC can help reduce the higher rate of repeat caesarean section after a previous caesarean section and increase the chances of successful vaginal birth.

Potentiating the Antitumor Activity of Cytotoxic T Cells via the Transmembrane Domain of IGSF4 That Increases TCR Avidity.

A robust T-cell response is an important component of sustained antitumor immunity. In this respect, the avidity of TCR in the antigen-targeting of tumors is crucial for the quality of the T-cell response. This study reports that the transmembrane (TM) domain of immunoglobulin superfamily member 4 (IGSF4) binds to the TM of the CD3 ζ-chain through an interaction between His177 and Asp36, which results in IGSF4-CD3 ζ dimers. IGSF4 also forms homo-dimers through the GxxVA motif in the TM domain, thereby constituting large TCR clusters. Overexpression of IGSF4 lacking the extracellular (IG4ΔEXT) domain potentiates the OTI CD8+ T cells to release IFN-γ and TNF-α and to kill OVA+-B16F10 melanoma cells. In animal models, IG4ΔEXT significantly reduces B16F10 tumor metastasis as well as tumor growth. Collectively, the results indicate that the TM domain of IGSF4 can regulate TCR avidity, and they further demonstrate that TCR avidity regulation is critical for improving the antitumor activity of cytotoxic T cells.

Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1.

Correct temporal and spatial control of actin dynamics is essential for the cytotoxic T cell effector function against tumor cells. However, little is known whether actin engineering in tumor-targeted T cells can enhance their antitumor responses, thereby potentiating the adoptive T cell therapy. Here, we report that TAGLN2, a 22-KDa actin-stabilizing protein which is physically associated with lymphocyte function-associated antigen-1 (LFA-1), potentiates the OTI TCR CD8+ T cells to kill the intercellular adhesion molecule-1 (ICAM-1)-positive/OVA-presenting E0771 cells, but not ICAM-1-negative OVA-B16F10 cells, suggesting an 'inside-out' activation of LFA-1, which causes more efficient immunological synapse formation between T cells and tumor cells. Notably, recombinant TAGLN2 fused with the protein transduction domain (TG2P) overcame the disadvantages of viral gene delivery, leading to a significant reduction in tumor growth in mice. TG2P also potentiated the CD19-targeted, chimeric antigen receptor (CAR)-modified T cells to kill Raji B-lymphoma cells. Our findings indicate that activating the TAGLN2-actin-LFA-1 axis is an effective strategy to potentiate the adoptive T-cell immunotherapy.