Small molecule inhibitors of clathrin-mediated endocytosis are highly desired for the dissection of membrane trafficking pathways in the lab and for potential use as anti-infectives in the clinic. One inhibition strategy is to prevent clathrin from contacting adaptor proteins so that clathrin-mediated endocytosis cannot occur. “Pitstop” compounds have been developed that block only one of the four functional interaction sites on the N-terminal domain of clathrin heavy chain. Despite this limitation, Pitstop 2 causes profound inhibition of clathrin-mediated endocytosis. In this study, we probed for non-specific activity of Pitstop 2 by examining its action in cells expressing clathrin heavy chain harbouring mutations in the N-terminal domain interaction sites. We conclude that the inhibition observed with this compound is due to non-specificity, i.e. it causes inhibition away from its proposed mode of action. We recommend that these compounds be used with caution in cells and that they should not be used to conclude anything of the function of clathrin's N-terminal domain.
These findings emphasize that the chance of ocular complication is less when accidental cannulation occurs at the superficial temporal artery compared with injury to the supratrochlear or the supraorbital arteries as the terminal branches of the ophthalmic artery. Ultrasound can assist in the identification and evaluation of all the arteries at risk, thus avoiding the occurrence of vascular complications.
Activating mutations of Ras genes are often observed in cancer. The protein products of the three Ras genes are almost identical. However, for reasons that remain unclear, KRAS is far more frequently mutated than the other Ras isoforms in cancer and RASopathies. We have quantified HRAS, NRAS, KRAS4A and KRAS4B protein abundance across a large panel of cell lines and healthy tissues. We observe consistent patterns of KRAS > NRAS»HRAS protein expression in cells that correlate with the rank order of Ras mutation frequencies in cancer. Our data provide support for the model of a sweet-spot of Ras dosage mediating isoform-specific contributions to cancer and development. We suggest that in most cases, being the most abundant Ras isoform correlates with occupying the sweet-spot and that HRAS and NRAS expression is usually insufficient to promote oncogenesis when mutated. However, our results challenge the notion that rare codons mechanistically underpin the predominance of KRAS mutant cancers. Finally, direct measurement of mutant versus wildtype KRAS protein abundance revealed a frequent imbalance that may suggest additional non-gene duplication mechanisms for optimizing oncogenic Ras dosage.
Most nerve communications reported in the literature were found between the terminal branches. This study aimed to clarify and classify patterns of proximal communications between the buccal branches (BN) of the facial nerve and the infraorbital nerve (ION).The superficial musculoaponeurotic system protects any communication sites from conventional dissections. Based on this limitation, the soft tissues of each face were peeled off the facial skull and the facial turn-down flap specimens were dissected from the periosteal view. Dissection was performed in 40 hemifaces to classify the communications in the sublevator space. Communication site was measured from the ala of nose.A double communication was the most common type found in 62.5% of hemifaces. Triple and single communications existed in 25% and 10% of 40 hemiface specimens, respectively. One hemiface had no communication. The most common type of communication occurred between the lower trunk of the BN of the facial nerve and the lateral labial (fourth) branch of the ION (70% in 40 hemifaces). Communication site was deep to the levator labii superioris muscle at 16.2 mm from the nasal ala. Communications between the motor and the sensory nerves in the midface may be important to increase nerve endurance and to compensate functional loss from injury.Proximal communications between the main trunks of the facial nerve and the ION in the midface exist in every face. This implies some specific functions in normal individuals. Awareness of these nerves is essential in surgical procedure in the midface.
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