ALS mutations in the TIA-1 prion-like domain trigger highly condensed pathogenic structures

筋萎縮性側索硬化症（ALS）の発症機構の一端を解明 --タンパク質の高密度な凝縮構造が鍵--. 京都大学プレスリリース. 2022-09-13.T cell intracellular antigen-1 (TIA-1) plays a central role in stress granule (SG) formation by self-assembly via the prion-like domain (PLD). In the TIA-1 PLD, amino acid mutations associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) or Welander distal myopathy (WDM), have been identified. However, how these mutations affect PLD self-assembly properties has remained elusive. In this study, we uncovered the implicit pathogenic structures caused by the mutations. NMR analysis indicated that the dynamic structures of the PLD are synergistically determined by the physicochemical properties of amino acids in units of five residues. Molecular dynamics simulations and three-dimensional electron crystallography, together with biochemical assays, revealed that the WDM mutation E384K attenuated the sticky properties, whereas the ALS mutations P362L and A381T enhanced the self-assembly by inducing β-sheet interactions and highly condensed assembly, respectively. These results suggest that the P362L and A381T mutations increase the likelihood of irreversible amyloid fibrillization after phase-separated droplet formation, and this process may lead to pathogenicity

The Effects of Maxillomandibular Advancement and Genioglossus Advancement on Sleep Quality

Maxillomandibular advancement (MMA) using a standardized surgical procedure consisting of a LeFort I osteotomy and bilateral sagittal split ramus osteotomy and genioglossus advancement (GA) using a genioplasty improve airway volume, oxygen desaturation, and the AHI in patients with OSA. However, there are few reports on changes in sleep quality following MMA and GA. We assessed the effects of MMA and GA on sleep quality by comparing oxygen desaturation, AHI, and sleep architecture before and after surgery. Methods: Eight patients underwent polysomnography (PSG) and CT scan before and after surgery. Conclusions: Our study finds that %TST and %REM were both increased, while %S1 and NA both decreased. Based on these results, it appears that both the quality and quantity of sleep were improved. MMA and GA improve sleep respiratory disturbance and can also improve sleep quality

MEF/ELF4 transactivation by E2F1 is inhibited by p53

Myeloid elf-1-like factor (MEF) or Elf4 is an E-twenty-six (ETS)-related transcription factor with strong transcriptional activity that influences cellular senescence by affecting tumor suppressor p53. MEF downregulates p53 expression and inhibits p53-mediated cellular senescence by transcriptionally activating MDM2. However, whether p53 reciprocally opposes MEF remains unex-plored. Here, we show that MEF is modulated by p53 in human cells and mice tissues. MEF expression and promoter activity were suppressed by p53. While we found that MEF promoter does not contain p53 response elements, intriguingly, it contains E2F consensus sites. Subsequently, we determined that E2F1 specifically binds to MEF promoter and transactivates MEF. Nevertheless, E2F1 DNA binding and transactivation of MEF promoter was inhibited by p53 through the association between p53 and E2F1. Furthermore, we showed that activation of p53 in doxorubicin-induced senescent cells increased E2F1 and p53 interaction, diminished E2F1 recruitment to MEF promoter and reduced MEF expression. These observations suggest that p53 downregulates MEF by associating with and inhibiting the binding activity of E2F1, a novel transcriptional activator of MEF. Together with previous findings, our present results indicate that a negative regulatory mechanism exists between p53 and MEF

miR-22 represses cancer progression by inducing cellular senescence

The microRNA miR-22 targets CDK6, SIRT1, and Sp1—genes involved in regulation of the senescence program—to suppress cell growth and proliferation

Relationship between the fluorescence intensity of rhodamine-labeled orexin A and the calcium responses in cortical neurons: An in vivo two-photon calcium imaging study

Neural responses to a ligand vary widely between neurons; however, the mechanisms underlying this variation remain unclear. One possible mechanism is a variation in the number of receptors expressed in each neural membrane. Here, we synthesized a rhodamine-labeled orexin A compound, enabling us to quantify the amount of orexin binding to its receptors, OX1 and OX2, which principally couple to the Gq/11 protein. The rhodamine intensity and calcium response were measured under tetrodotoxin application from insular cortical glutamatergic neurons in Thy1-GCaMP6s transgenic mice using an in vivo two-photon microscope. Applying rhodamine-labeled orexin A (10 μM) to the cortical surface gradually and heterogeneously increased both the intensity of the rhodamine fluorescence and [Ca2+]i. Calcium responses started simultaneously with the increase in rhodamine-labeled orexin fluorescence and reached a plateau within several minutes. We classified neurons as high- and low-responding neurons based on the peak amplitude of the [Ca2+]i increase. The rhodamine fluorescence intensity was larger in the high-responding neurons than the low-responding neurons. Preapplication of SB334867 and TCS-OX2-29, OX1 and OX2 antagonists, respectively, decreased the proportion of high-responding neurons. These results suggest that the diverse receptor expression level in neural membranes is involved in mechanisms underlying varied neural responses, including [Ca2+]i increases. Keywords: Gq/11 protein, Hypocretin, Insular cortex, In vivo calcium imaging, Rhodamin