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"Grandy, David"
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Discovery and multimerization of cross-reactive single-domain antibodies against SARS-like viruses to enhance potency and address emerging SARS-CoV-2 variants
Coronaviruses have been the causative agent of three epidemics and pandemics in the past two decades, including the ongoing COVID-19 pandemic. A broadly-neutralizing coronavirus therapeutic is desirable not only to prevent and treat COVID-19, but also to provide protection for high-risk populations against future emergent coronaviruses. As all coronaviruses use spike proteins on the viral surface to enter the host cells, and these spike proteins share sequence and structural homology, we set out to discover cross-reactive biologic agents targeting the spike protein to block viral entry. Through llama immunization campaigns, we have identified single domain antibodies (VHHs) that are cross-reactive against multiple emergent coronaviruses (SARS-CoV, SARS-CoV-2, and MERS). Importantly, a number of these antibodies show sub-nanomolar potency towards all SARS-like viruses including emergent CoV-2 variants. We identified nine distinct epitopes on the spike protein targeted by these VHHs. Further, by engineering VHHs targeting distinct, conserved epitopes into multi-valent formats, we significantly enhanced their neutralization potencies compared to the corresponding VHH cocktails. We believe this approach is ideally suited to address both emerging SARS-CoV-2 variants during the current pandemic as well as potential future pandemics caused by SARS-like coronaviruses.
Journal Article
Dopamine D2-Like Receptors and Behavioral Economics of Food Reinforcement
Previous studies suggest dopamine (DA) D2-like receptor involvement in the reinforcing effects of food. To determine contributions of the three D2-like receptor subtypes, knockout (KO) mice completely lacking DA D2, D3, or D4 receptors (D2R, D3R, or D4R KO mice) and their wild-type (WT) littermates were exposed to a series of fixed-ratio (FR) food-reinforcement schedules in two contexts: an open economy with additional food provided outside the experimental setting and a closed economy with all food earned within the experimental setting. A behavioral economic model was used to quantify reinforcer effectiveness with food pellets obtained as a function of price (FR schedule value) plotted to assess elasticity of demand. Under both economies, as price increased, food pellets obtained decreased more rapidly (ie, food demand was more elastic) in DA D2R KO mice compared with WT littermates. Extinction of responding was studied in two contexts: by eliminating food deliveries and by delivering food independently of responding. A hyperbolic model quantified rates of extinction. Extinction in DA D2R KO mice occurred less rapidly compared with WT mice in both contexts. Elasticity of food demand was higher in DA D4R KO than WT mice in the open, but not closed, economy. Extinction of responding in DA D4R KO mice was not different from that in WT littermates in either context. No differences in elasticity of food demand or extinction rate were obtained in D3R KO mice and WT littermates. These results indicate that the D2R is the primary DA D2-like receptor subtype mediating the reinforcing effectiveness of food.
Journal Article
Antihypertensive effect of etamicastat in dopamine D2 receptor-deficient mice
Abnormalities of the D
R gene (DRD2) play a role in the pathogenesis of human essential hypertension; variants of the DRD2 have been reported to be associated with hypertension. Disruption of Drd2 (D
) in mice increases blood pressure. The hypertension of D
mice has been related, in part, to increased sympathetic activity, renal oxidative stress, and renal endothelin B receptor (ETBR) expression. We tested in D
mice the effect of etamicastat, a reversible peripheral inhibitor of dopamine-β-hydroxylase that reduces the biosynthesis of norepinephrine from dopamine and decreases sympathetic nerve activity. Blood pressure was measured in anesthetized D
mice treated with etamicastat by gavage, (10 mg/kg), conscious D
mice, and D
littermates, and mice with the D
R selectively silenced in the kidney, treated with etamicastat in the drinking water (10 mg/kg per day). Tissue and urinary catecholamines and renal expression of selected G protein-coupled receptors, enzymes related to the production of reactive oxygen species, and sodium transporters were also measured. Etamicastat decreased blood pressure both in anesthetized and conscious D
mice and mice with renal-selective silencing of D
R to levels similar or close to those measured in D
littermates. Etamicastat decreased cardiac and renal norepinephrine and increased cardiac and urinary dopamine levels in D
mice. It also normalized the increased renal protein expressions of ETBR, NADPH oxidase isoenzymes, and urinary 8-isoprostane, as well as renal NHE3 and NCC, and increased the renal expression of D
R but not D
R in D
mice. In conclusion, etamicastat is effective in normalizing the increased blood pressure and some of the abnormal renal biochemical alterations of D
mice.
Journal Article
The Speed of Light
Light -- our experience of light, our measurement of light, and the notion that light speed is constant -- can be understood to mark our interface with the cosmos. David A. Grandy's book moves from the scientific to the existential, from Einstein to Merleau-Ponty, from light as a phenomenon to light as that which is constitutive of reality. To measure the speed of light is to measure something about the way we are measured or blended into the cosmos, and that universal blending predetermines our measurement of light speed in favor of a universal or constant value. It's quite a trip, one aimed at scientists who have pondered light speed constancy, philosophers inclined to question the idea that mind and world are distinct, and scientifically or philosophically inclined persons who enjoy stretching themselves in new ways.
eBook
Hexamerization of Anti-SARS CoV IgG1 Antibodies Improves Neutralization Capacity
The SARS-CoV-2 pandemic and particularly the emerging variants have deepened the need for widely available therapeutic options. We have demonstrated that hexamer-enhancing mutations in the Fc region of anti-SARS-CoV IgG antibodies lead to a noticeable improvement in IC 50 in both pseudo and live virus neutralization assay compared to parental molecules. We also show that hexamer-enhancing mutants improve C1q binding to target surface. To our knowledge, this is the first time this format has been explored for application in viral neutralization and the studies provide proof-of-concept for the use of hexamer-enhanced IgG1 molecules as potential anti-viral therapeutics.
Journal Article
An Astroglia-Linked Dopamine D2-Receptor Action in Prefrontal Cortex
Typical neuroleptic drugs elicit their antipsychotic effects mainly by acting as antagonists at dopamine D2 receptors. Much of this activity is thought to occur in the cerebral cortex, where D2 receptors are found largely in inhibitory GABAergic neurons. Here we confirm this localization at the electron microscopic level, but additionally show that a subset of cortical interneurons with low or undetectable expression of D2 receptor isoforms are surrounded by astrocytic processes that strongly express D2 receptors. Ligand binding of isolated astrocyte preparations indicate that cortical astroglia account for approximately one-third of the total D2 receptor binding sites in the cortex, a proportion that we found conserved among rodent, monkey, and human tissues. Further, we show that the D2 receptor-specific agonist, quinpirole, can induce Ca2+elevation in isolated cortical astrocytes in a pharmacologically reversible manner, thus implicating this receptor in the signaling mechanisms by which astrocytes communicate with each other as well as with neurons. The discovery of D2 receptors in astrocytes with a selective anatomical relationship to interneurons represents a neuron/glia substrate for cortical dopamine action in the adult cerebral cortex and a previously unrecognized site of action for antipsychotic drugs with affinities at the D2 receptor.
Journal Article
Choice for response alternatives differing in reinforcement frequency in dopamine D2 receptor mutant and Swiss-Webster mice
Rationale
A previous study showed that dopamine (DA) D
2
receptors (D
2
Rs) are involved in the reinforcing effectiveness of food, but the specific involvement of DA D
2
Rs in choice among food reinforcers remains unclear.
Objectives
The current study used genetic and pharmacological approaches to assess the role of D
2
Rs in choice among food-reinforcement frequencies using the generalized matching law (GML), which specifies that logged response and time allocation ratios vary linearly with logged reinforcer ratios.
Methods
Congenic D
2
R knockout (KO) and wild-type (WT) mice were exposed to concurrent variable-interval schedules of reinforcement with scheduled relative-reinforcement rates from 4:1 to 1:4. Effects of the D
2
R antagonist (−)-eticlopride (0.1–1.0 mg/kg) were assessed in Swiss-Webster mice.
Results
Response and time allocation ratios were related to obtained reinforcement ratios as predicted by the GML. GML fits accounted for ≥92 % of the variance in allocation ratios and did not differ in D
2
R KO and WT mice. Similarly, there were no significant effects of (−)-eticlopride dose on GML fits, despite effects on overall response rates.
Conclusions
The current results demonstrate that neither deletion nor acute blockade of D
2
Rs affects choice among response alternatives varying in food-reinforcement frequencies. Because previously published results suggest a role of D
2
Rs in choice between response alternatives differing in reinforcer magnitude and delay or magnitude and probability, the current findings suggest that D
2
Rs play a role in choice only among certain parameters of reinforcement. Furthermore, these findings suggest parameters of reinforcement may only be fungible in a complex manner.
Journal Article