Thermal Capacitance (Slug) Calorimeter Theory Including Heat Losses and Other Decaying Processes

A mathematical model, termed the Slug Loss Model, has been developed for describing thermal capacitance (slug) calorimeter behavior when heat losses and other decaying processes are not negligible. This model results in the temperature time slope taking the mathematical form of exponential decay. When data is found to fit well to this model, it allows a heat flux value to be calculated that corrects for the losses and may be a better estimate of the cold wall fully catalytic heat flux, as is desired in arc jet testing. The model was applied to the data from a copper slug calorimeter inserted during a particularly severe high heating rate arc jet run to illustrate its use. The Slug Loss Model gave a cold wall heat flux 15% higher than the value of 2,250 W/sq cm obtained from the conventional approach to processing the data (where no correction is made for losses). For comparison, a Finite Element Analysis (FEA) model was created and applied to the same data, where conduction heat losses from the slug were simulated. The heat flux determined by the FEA model was found to be in close agreement with the heat flux determined by the Slug Loss Model

Novel therapeutic strategies targeting HIV integrase

Integration of the viral genome into host cell chromatin is a pivotal and unique step in the replication cycle of retroviruses, including HIV. Inhibiting HIV replication by specifically blocking the viral integrase enzyme that mediates this step is an obvious and attractive therapeutic strategy. After concerted efforts, the first viable integrase inhibitors were developed in the early 2000s, ultimately leading to the clinical licensure of the first integrase strand transfer inhibitor, raltegravir. Similarly structured compounds and derivative second generation integrase strand transfer inhibitors, such as elvitegravir and dolutegravir, are now in various stages of clinical development. Furthermore, other mechanisms aimed at the inhibition of viral integration are being explored in numerous preclinical studies, which include inhibition of 3' processing and chromatin targeting. The development of new clinically useful compounds will be aided by the characterization of the retroviral intasome crystal structure. This review considers the history of the clinical development of HIV integrase inhibitors, the development of antiviral drug resistance and the need for new antiviral compounds

Enthalpy By Energy Balance for Aerodynamic Heating Facility at NASA Ames Research Center Arc Jet Complex

The NASA Ames Research Center (ARC) Arc Jet Facilities' Aerodynamic Heating Facility (AHF) has been instrumented for the Enthalpy By Energy Balance (EB2) method. Diagnostic EB2 data is routinely taken for all AHF runs. This paper provides an overview of the EB2 method implemented in the AHF. The chief advantage of the AHF implementation over earlier versions is the non-intrusiveness of the instruments used. For example, to measure the change in cooling water temperature, thin film 1000 ohm Resistance Temperature Detectors (RTDs) are used with an Anderson Current Loop (ACL) as the signal conditioner. The ACL with 1000 ohm RTDs allows for very sensitive measurement of the increase in temperature (Delta T) of the cooling water to the arc heater, which is a critical element of the EB2 method. Cooling water flow rates are measured with non-intrusive ultrasonic flow meters

Dolutegravir Interactions with HIV-1 Integrase-DNA: Structural Rationale for Drug Resistance and Dissociation Kinetics

<div><p>Signature HIV-1 integrase mutations associated with clinical raltegravir resistance involve 1 of 3 primary genetic pathways, Y143C/R, Q148H/K/R and N155H, the latter 2 of which confer cross-resistance to elvitegravir. In accord with clinical findings, in vitro drug resistance profiling studies with wild-type and site-directed integrase mutant viruses have shown significant fold increases in raltegravir and elvitegravir resistance for the specified viral mutants relative to wild-type HIV-1. Dolutegravir, in contrast, has demonstrated clinical efficacy in subjects failing raltegravir therapy due to integrase mutations at Y143, Q148 or N155, which is consistent with its distinct in vitro resistance profile as dolutegravir’s antiviral activity against these viral mutants is equivalent to its activity against wild-type HIV-1. Kinetic studies of inhibitor dissociation from wild-type and mutant integrase-viral DNA complexes have shown that dolutegravir also has a distinct off-rate profile with dissociative half-lives substantially longer than those of raltegravir and elvitegravir, suggesting that dolutegravir’s prolonged binding may be an important contributing factor to its distinct resistance profile. To provide a structural rationale for these observations, we constructed several molecular models of wild-type and clinically relevant mutant HIV-1 integrase enzymes in complex with viral DNA and dolutegravir, raltegravir or elvitegravir. Here, we discuss our structural models and the posited effects that the integrase mutations and the structural and electronic properties of the integrase inhibitors may have on the catalytic pocket and inhibitor binding and, consequently, on antiviral potency in vitro and in the clinic.</p> </div

2D structures of (A) dolutegravir, (B) raltegravir and (C) elvitegravir.

<p>Red ovals encircle the oxygen atoms that chelate the divalent metal cations in the active site; green ovals encircle the halobenzyl groups; and blue boxes encircle the approximate regions of the scaffolds that can accommodate positive charge after chelation of the metals. The purple circles at (B) encircle raltegravir’s gem-dimethyl (small circle) and oxadiazole groups, and the purple oval at (C) encircles elvitegravir’s 1-hydroxymethyl-2-methylpropyl group.</p

Structural models of (A) Q148H/G140S and (B) N155H HIV-1 integrase with U5 LTR DNA and dolutegravir.

<p>(A) The Q148H/G140S mutations are predicted to disrupt the structure of the flexible active-site loop, displacing the 3₁₀ helix away from the DDE motif and weakening the H-bond interaction between the backbone CO of Q148H and the backbone NH of E152. (B) The N155H mutation is predicted to disrupt the structure of the α4 helix, widen the base of the catalytic pocket, alter the placement of at least the Mg²⁺ ion coordinated to residues D64 and E152 and alter the conformation of the terminal 3′ adenosine forming part of the pocket. Molecular representations and coloring schemes are described in Figure 2.</p

Structural model of Q148R HIV-1 integrase with U5 LTR DNA.

<p>The side chain of residue Q148R was modeled interacting with the side chain of E152 and in this conformation the residue may interfere with the binding of elvitegravir. Molecular representations and coloring schemes as described in Figure 2.</p

Structural models of HIV-1 integrase with U5 LTR DNA and (A, B) raltegravir, (C) elvitegravir or (D) dolutegravir.

<p>For raltegravir, the terminal 3′ adenylate is depicted in 2 distinct conformations: panel 2A shows the published conformer and panel 2B shows an alternative conformer that is also consistent with the observed electron density. Raltegravir, elvitegravir and dolutegravir are in stick representation with carbon, nitrogen, oxygen, fluorine and chlorine atoms colored gray, blue, red, cyan and green, respectively. A select subset of amino acids and nucleotides is depicted and labeled with residue type and number (numbering schemes as listed in Figure S1); all residues are in stick representation with carbon atoms colored by secondary structure/chain and nitrogen and oxygen atoms colored blue and red, respectively. The Mg²⁺ ions are represented as small yellow spheres with coordinate bonds to the inhibitors depicted as dashed yellow lines.</p

CCDC 1953060: Experimental Crystal Structure Determination

Related Article: Michael J. Celestine, Mark A.W. Lawrence, Olivier Schott, Vincent Picard, Garry S. Hanan, Emily M. Marquez, Chekeyl G. Harold, Cole T. Kuester, Blaise A. Frenzel, Christopher G. Hamaker, Sean E. Hightower, Colin D. McMillen, Alvin A. Holder|2021|Inorg.Chim.Acta|517|120195|doi:10.1016/j.ica.2020.12019