C9orf72-derived arginine-rich poly-dipeptides impede phase modifiers

Nuclear import receptors (NIRs) not only transport RNA-binding proteins (RBPs) but also modify phase transitions of RBPs by recognizing nuclear localization signals (NLSs). Toxic arginine-rich poly-dipeptides from C9orf72 interact with NIRs and cause nucleocytoplasmic transport deficit. However, the molecular basis for the toxicity of arginine-rich poly-dipeptides toward NIRs function as phase modifiers of RBPs remains unidentified. Here we show that arginine-rich poly-dipeptides impede the ability of NIRs to modify phase transitions of RBPs. Isothermal titration calorimetry and size-exclusion chromatography revealed that proline:arginine (PR) poly-dipeptides tightly bind karyopherin-β2 (Kapβ2) at 1:1 ratio. The nuclear magnetic resonances of Kapβ2 perturbed by PR poly-dipeptides partially overlapped with those perturbed by the designed NLS peptide, suggesting that PR poly-dipeptides target the NLS binding site of Kapβ2. The findings offer mechanistic insights into how phase transitions of RBPs are disabled in C9orf72-related neurodegeneration

Cellular Basis of Tissue Regeneration by Omentum

The omentum is a sheet-like tissue attached to the greater curvature of the stomach and contains secondary lymphoid organs called milky spots. The omentum has been used for its healing potential for over 100 years by transposing the omental pedicle to injured organs (omental transposition), but the mechanism by which omentum helps the healing process of damaged tissues is not well understood. Omental transposition promotes expansion of pancreatic islets, hepatocytes, embryonic kidney, and neurons. Omental cells (OCs) can be activated by foreign bodies in vivo. Once activated, they become a rich source for growth factors and express pluripotent stem cell markers. Moreover, OCs become engrafted in injured tissues suggesting that they might function as stem cells

Non-Fasting Hypertriglyceridemia Burden as a Residual Risk of the Progression of Carotid Artery Stenosis

The relationships between repeated non-fasting triglyceride (TG) measurements and carotid stenosis progression during follow-ups have never been investigated. In 111 consecutive carotid arteries of 88 patients with ≥50% atherosclerotic stenosis on at least one side, who had ≥3 blood samples taken during ≥one-year follow-ups, clinical variables were compared between carotid arteries with and without subsequent stenosis progression. To evaluate non-fasting TG burden, a new parameter area [TG ≥ 175] was calculated by integrating non-fasting TG values ≥ 175 mg/dL (i.e., TG values minus 175) with the measurement intervals (year). Carotid stenosis progression occurred in 22 arteries (19.8%) during the mean follow-up period of 1185 days. Younger age, symptomatic stenosis, higher mean values of TG during follow-ups, the area [TG ≥ 175], mean TG values ≥ 175 mg/dL and maximum TG values ≥175 mg/dL were significant factors related to the progression on univariate analyses. The cut-off value of the area [TG ≥ 175] to discriminate carotid stenosis progression was 6.35 year-mg/dL. Multivariate analyses demonstrated that symptomatic stenosis and the area [TG ≥ 175] ≥ 6.35 year-mg/dL were independently related to carotid stenosis progression. In conclusion, the area [TG ≥ 175] was an independent risk factor for carotid stenosis progression, and this study suggests the importance to continuously control non-fasting TG levels < 175 mg/dL during follow-ups to prevent carotid stenosis progression

Structure elements can be predicted using the contact Volume among protein residues

Previously, the structure elements of dihydrofolate reductase (DHFR) were determined using comprehen­sive Ala-insertion mutation analysis, which is assumed to be a kind of protein “building blocks.” It is hypo­thesized that our comprehension of the structure elements could lead to understanding how an amino acid sequence dictates its tertiary structure. However, the comprehensive Ala-insertion mutation analysis is a time- and cost-consuming process and only a set of the DHFR structure elements have been reported so far. Therefore, developing a computational method to predict structure elements is an urgent necessity. We focused on intramolecular residue–residue contacts to predict the structure elements. We introduced a simple and effective parameter: the overlapped contact volume (CV) among the residues and calculated the CV along the DHFR sequence using the crystal structure. Our results indicate that the CV profile can recapitulate its precipitate ratio profile, which was used to define the structure elements in the Ala-insertion mutation analysis. The CV profile allowed us to predict structure elements like the experimentally determined structure elements. The strong correlation between the CV and precipitate ratio profiles indicates the importance of the intramolecular residue–residue contact in maintaining the tertiary structure. Additionally, the CVs between the structure elements are considerably more than those between a structure element and a linker or two linkers, indicating that the structure elements play a funda­mental role in increasing the intramolecular adhesion. Thus, we propose that the structure elements can be considered a type of “building blocks” that maintain and dictate the tertiary structures of proteins

Correction to Synthetic Studies on (+)-Manzamine A: Stereoselective Synthesis of the Tetracyclic Core Framework

Correction to Synthetic Studies on (+)-Manzamine A: Stereoselective Synthesis of the Tetracyclic Core Framewor

Plasma Fibulin-5 Levels as an Independent Predictor of a Poor Outcome after an Aneurysmal Subarachnoid Hemorrhage

Aneurysmal subarachnoid hemorrhage (SAH) is a poor-outcome disease with a delayed neurological exacerbation. Fibulin-5 (FBLN5) is one of matricellular proteins, some of which have been involved in SAH pathologies. However, no study has investigated FBLN5’s roles in SAH. This study was aimed at examining the relationships between serially measured plasma FBLN5 levels and neurovascular events or outcomes in 204 consecutive aneurysmal SAH patients, including 77 patients (37.7%) with poor outcomes (90-day modified Rankin Scale 3–6). Plasma FBLN5 levels were not related to angiographic vasospasm, delayed cerebral ischemia, and delayed cerebral infarction, but elevated levels were associated with severe admission clinical grades, any neurological exacerbation and poor outcomes. Receiver-operating characteristic curves indicated that the most reasonable cut-off values of plasma FBLN5, in order to differentiate 90-day poor from good outcomes, were obtained from analyses at days 4–6 for all patients (487.2 ng/mL; specificity, 61.4%; and sensitivity, 62.3%) and from analyses at days 7–9 for only non-severe patient (476.8 ng/mL; specificity, 66.0%; and sensitivity, 77.8%). Multivariate analyses revealed that the plasma FBLN5 levels were independent determinants of the 90-day poor outcomes in both all patients’ and non-severe patients’ analyses. These findings suggest that the delayed elevation of plasma FBLN5 is related to poor outcomes, and that FBLN5 may be a new molecular target to reveal a post-SAH pathophysiology