ACE2, the Receptor that Enables Infection by SARS-CoV-2: Biochemistry,Structure, Allostery and Evaluation of the Potential Development of ACE2 Modulators

Angiotensin converting enzyme 2 (ACE2) is the human receptor that interacts with the spike protein of coronaviruses, including the one that produced the 2020 coronavirus pandemic (COVID-19). Thus, ACE2 is a potential target for drugs that disrupt the interaction of human cells with SARS-CoV-2 to abolish infection. There is also interest in drugs that inhibit or activate ACE2, that is, for cardiovascular disorders or colitis. Compounds binding at alternative sites could allosterically affect the interaction with the spike protein. Herein, we review biochemical, chemical biology, and structural information on ACE2, including the recent cryoEM structures of full-length ACE2. We conclude that ACE2 is very dynamic and that allosteric drugs could be developed to target ACE2. At the time of the 2020 pandemic, we suggest that available ACE2 inhibitors or activators in advanced development should be tested for their ability to allosterically displace the interaction between ACE2 and the spike protein.     

Transjugular intrahepatic portosystemic shunts (TIPS) in children

The transjugular intrahepatic portosystemic shunt procedure is an accepted treatment for adults with complications of portal hypertension. We performed a retrospective review of all pediatric TIPS placements performed at the University of California, San Francisco between 1990 and 1996. Twelve procedures were attempted in nine children, with a mean age (+/- SD) of 9.4 +/- 3.9 years (range, 5 to 15 years) and a mean weight of 31 +/- 18 kg (range, 16 to 70 kg). The indications for TIPS placement were portal hypertension complicated by chronic variceal hemorrhage not controlled with sclerotherapy (n = 7) and hypersplenism with thrombocytopenia (n = 2). TIPS placement was successfully completed initially in seven of nine (78%) patients. Unfavorable vascular anatomy was the cause of failure in two cases. The seven patients who underwent successful TIPS placement were followed up for an average of 136 days (range, 1 to 800 days); two still have patent shunts, three underwent liver transplantation, one had a splenorenal shunt after stenosis, and one died of underlying liver disease. Variceal bleeding was controlled in four of five patients who successfully underwent TIPS placement. Shunt occlusion occurred in four patients; patency was restored by transjugular shunt revision in three, and a splenorenal shunt was performed in one.     

Animal models of bacterial gastritis: the role of host, bacterial species and duration of infection on severity of gastritis

Gastric bacteria from cheetahs with gastritis were used to inoculate specific-pathogen free kittens and conventional mice. Helicobacter sp. and Gastrospirillum sp. colonized kittens, while only Gastrospirillum sp. colonized mice. In kittens, both bacterial species induced mild lymphofolliclar gastritis which did not change over the course of the 11 months observation period. In mice, Gastrospirillum sp. induced lymphoplasmacytic and follicular gastritis which increased in severity over 6 months and persisted for the 12 month observation period. Gastric ulcers and gastric mucosal hypertrophy were present in chronically infected mice. These results indicate that host but not bacterial factors influence the severity of gastritis, and that in mice, bacterial gastritis increases in severity with time and may lead to gastric ulceration in some individuals.     

The role of perspective in the accessibility of goals during reading.

An implicit assumption of several causal reasoning models is that readers adopt the goals of a narrative's protagonist during text comprehension. In apparent violation of this assumption, readers participating in Experiment 1 of the present study drew inferences relevant to a protagonist's goal even when that goal was already satisfied from the perspective of the protagonist. In Experiments 2 and 3, participants were explicitly asked to view the text situation from the point of view of the protagonist. In this case, the goals of the reader and the protagonist should be the same. In these experiments, participants focused on the goals of the protagonist only when those goals had not been satisfied from the perspective of the protagonist. These results are discussed in terms of reader- and character-based perspectives and in terms of text characteristics that cue perspective taking. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Ubiquitin expression in inclusion body myositis. An immunohistochemical study

Ubiquitin has been shown by immunohistochemical studies to be a component of many of the filamentous inclusion bodies that are known in neuropathology. In the current study, we examined the expression of ubiquitin in 14 cases of typical inclusion body myositis, in skeletal muscle specimens from four cases of typical amyotrophic lateral sclerosis, and in muscle specimens from three normal controls. In the cases of inclusion body myositis, rimmed vacuoles were ubiquitin immunoreactive in all cases. Intrasarcoplasmic inclusions were positive in the nine cases that had them. In four cases, there were positive intranuclear inclusions, and in seven, there was homogeneous staining of nuclei. Atrophic fibers and necrotic fibers were positive in 11 and nine cases, respectively. In the cases of amyotrophic lateral sclerosis, atrophic fibers were positive in three cases, and focal nuclear staining was seen in two. In one of the three control cases, a few atrophic fibers had faint sarcoplasmic positivity; no other staining was seen. We conclude that ubiquitin is a component of the inclusions that characterize inclusion body myositis. However, ubiquitin expression in skeletal muscle disease is not pathognomonic of inclusion body myositis.