Cell entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by its surface glycoprotein, Spike. The S1 subunit of Spike contains the N-terminal domain (NTD) and the receptor-binding domain (RBD), which mediates recognition of the host cell receptor angiotensinconverting enzyme 2 (ACE2). The S2 subunit drives fusion

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The importance of Notch signaling pathway in the regulation of vascular development and angiogenesis is suggested by the expression of Notch receptors and ligands in vascular endothelial cells (ECs) and the observed vascular phenotypes in mutants of Notch receptors or ligands, especially Dll4. DLL4 is specifically expressed in arterial ECs during development, and haploinsufficiency is embryonically lethal in mice. To address the role of Dll4 in vascular development, we produced mDll4 conditionally overexpressed transgenic mice that were crossed with constitutive recombinase cre lines. Double transgenic embryos displayed grossly enlarged dorsal aortae (DA) and died before embryonic day 10.5 (E10.5), showing a variable degree of premature arteriovenous fusion. Veins displayed ectopic expression of arterial markers. Other defects included reduced vascular sprouting, EC proliferation, and migration. mDll4 overexpression also inhibited VEGF signaling and increased fibronectin accumulation around the vessels. In vitro and in vivo studies of DLL4-FL (Dll4-full-length) in ECs recapitulate many of the mDll4 transgenics findings, including decreased tube formation, reduced vascular branching, fewer vessels, increased pericyte recruitment, and increased fibronectin expression. These results establish the role of Dll4 in arterial identity determination, and regulation of angiogenesis subject to dose and location. IntroductionArterial versus venous differentiation has long been thought to be mainly dependent on physical factors such as blood pressure and oxygen concentration. Recently, however, the identification of several genes that are specifically expressed in arterial or venous endothelial cells (ECs) well before the onset of circulation seems to indicate an important role for genetic determination of ECs in the primary differentiation events between arteries and veins. Among these genes are Eph-B4, specifically expressed in venous ECs [1][2][3] and Ephrin-B2, 1,3,4 Notch1, 5 Notch4 6 and Dll4 7 , among others, which are specifically expressed in arterial ECs.Dll4 is the only Notch ligand known to have an expression pattern similar to Notch1 and Notch4 in the vascular system, being likewise restricted to the arterial endothelium. Mutation studies in zebrafish have shown that Notch homologues are the earliest genes expressed in an endothelial arterial specific fashion and regulate arterial and venous endothelial differentiation downstream of vascular endothelial growth factor (Vegf) and sonic-hedgehog (Shh) and upstream of the ephrin pathway. 8 There is growing evidence, in both zebrafish and mouse, that Notch function is essential in the establishment of the arterial endothelial cell fate. [8][9][10] In this context, the ligand Dll4, given its arterial specific expression pattern and striking loss-of-function phenotype 10 appears to play a pivotal role.In the present study we investigated the role of Dll4 in mammalian vascular development by producing and characterizing murine gain-offunction mutants. To achieve genera...

To assess the role of the p53 tumor suppressor gene in skin carcinogenesis by UV radiation, mice constitutively lacking one or both copies of the functional p53 gene were compared to wild-type mice for their susceptibility to UV carcinogenesis. Heterozygous mice showed greatly increased susceptibility to skin cancer induction, and homozygous p53 knockout mice were even more susceptible. Accelerated tumor development in the heterozygotes was not associated with loss of the remaining wild-type allele of p53, as reported for tumors induced by other carcinogens, but in many cases was associated with UV-induced mutations in p53. Tumors arose on the ears and dorsal skin of mice of all three genotypes, and homozygous knockout mice also developed ocular tumors, mainly melanomas. Skin tumors in the p53 knockout mice were predominately squamous cell carcinomas and were associated with premalignant lesions resembling actinic keratoses, whereas those in the heterozygous and wild-type mice were mainly sarcomas. These results demonstrate the importance of p53 in protecting against UV-induced cancers, particularly in the eye and epidermis.