A junctional PACSIN2/EHD4/MICAL-L1 complex coordinates VE-cadherin trafficking for endothelial migration and angiogenesis

Angiogenic sprouting relies on collective migration and coordinated rearrangements of endothelial leader and follower cells. VE-cadherin-based adherens junctions have emerged as key cell-cell contacts that transmit forces between cells and trigger signals during collective cell migration in angiogenesis. However, the underlying molecular mechanisms that govern these processes and their functional importance for vascular development still remain unknown. We previously showed that the F-BAR protein PACSIN2 is recruited to tensile asymmetric adherens junctions between leader and follower cells. Here we report that PACSIN2 mediates the formation of endothelial sprouts during angiogenesis by coordinating collective migration. We show that PACSIN2 recruits the trafficking regulators EHD4 and MICAL-L1 to the rear end of asymmetric adherens junctions to form a recycling endosome-like tubular structure. The junctional PACSIN2/EHD4/MICAL-L1 complex controls local VE-cadherin trafficking and thereby coordinates polarized endothelial migration and angiogenesis. Our findings reveal a molecular event at force-dependent asymmetric adherens junctions that occurs during the tug-of-war between endothelial leader and follower cells, and allows for junction-based guidance during collective migration in angiogenesis.

A Case of Small-Cell Neuroendocrine Carcinoma of the Gallbladder in a Background of High-Grade Biliary Intraepithelial Neoplasia

Introduction/Objective Neuroendocrine carcinoma (NEC) of the gallbladder is a very rare neoplasia comprising 4% of all malignant gallbladder neoplasms. Most of NECs show molecular accumulation of TP53, while KRAS mutations are rare. Approximately 40% of Biliary intraepithelial neoplasia (BilIN) cases are associated by KRAS mutations as an early molecular event, whereas TP53 mutation appears to be a late molecular event. Methods We report a case of a 62-year-old male who presented to emergency department for evaluation of abdominal pain associated with vomiting. Imaging studies demonstrated a distended gallbladder with small amount of pericholecystic fluid along with 5 mm calculus at the gallbladder neck consistent with symptomatic cholelithiasis and acute cholecystitis. No mass lesion was radiologically identified. A laparoscopic cholecystectomy was performed. Grossly, there was a thickened area of mucosa at the distal body-fundus, measuring 5.0 x 4.5 cm. Multiple calculi were present. On histology, thickened area showed sheets and nests of moulded small cells with hyperchromatic nuclei, brisk mitotic activity and confluent necrosis. A diagnosis of small-cell NEC is established, and confirmed by positive immunoreactivity to neuroendocrine markers (CD56, Synaptophysin) and epithelial markers (CK7 and CAM5.2). Multiple foci of high-grade BilIN were noted. Subsequent entire submission of the gallbladder revealed no adenocarcinoma present. The pathologic stage was pT2a pNX. Conclusion In conclusion, this rare gallbladder carcinoma is found incidentally in a patient with acute cholecystitis symptoms and no clinical proof of mass lesion. In addition, there is a background of high-grade BilIN, which shares the molecular pathway of small-cell NEC. Therefore, awareness of such coexistence of these two pathologic entities in the same gallbladder, is essential to alert pathologists to look for the poorly-prognosis small cell NEC, whenever BilIN is encountered in random section of a gallbladder.

Sialidase Activity in Human Blood Serum Has a Distinct Seasonal Pattern: A Pilot Study

Desialylation—loss of terminal sialic acid residues from glycoconjugates catalyzed by sialidases—is involved in many human diseases and is considered a key molecular event of atherosclerosis onset. Desialylated low-density lipoproteins with atherogenic properties have been detected in human blood previously. However, there is currently no consensus on the origin of desialylation activity in the bloodstream. Here, we suggest viral intervention as a possible explanation. In order to address our hypothesis, we studied seasonal patterns of blood serum sialidase enzymatic activity and designed an approach to detect and quantify viral sialidase genetic presence. Increased sialidase activity in autumn-winter combined with detectable levels of influenza virus sialidase mRNA suggests exogenous viral sialidase as a viable component of desialylation in human blood, providing new insights on the molecular background of atherogenesis.

A transcriptional roadmap for 2C-like–to–pluripotent state transition

In mouse embryonic stem cell (ESC), a small cell population displays totipotent features by expressing a set of genes that are transiently active in 2-cell–stage embryos. These 2-cell–like (2C-like) cells spontaneously transit back into the pluripotent state. We previously dissected the transcriptional dynamics of the transition from pluripotency to the totipotent 2C-like state and identified factors that modulate the process. However, how 2C-like cells transit back into the pluripotent state remains largely unknown. In this study, we analyzed the transcriptional dynamics from the 2C-like state to pluripotent ESCs and identified an intermediate state. The intermediate state characterized by two-wave step up-regulation of pluripotent genes is different from the one observed during the 2C-like entry transition. Nonsense-mediated Dux mRNA decay plays an important role in the 2C-like state exit. Thus, our study not only provides a transcriptional roadmap for 2C-like–to–pluripotent state transition but also reveals a key molecular event driving the transition.