Control of COVID-19 Outbreaks under Stochastic Community Dynamics, Bimodality, or Limited Vaccination.

Reaching population immunity against COVID-19 is proving difficult even in countries with high vaccination levels. Thus, it is critical to identify limits of control and effective measures against future outbreaks. The effects of nonpharmaceutical interventions (NPIs) and vaccination strategies are analyzed with a detailed community-specific agent-based model (ABM).

5-Azacytidine inhaled dry powder formulation profoundly improves pharmacokinetics and efficacy for lung cancer therapy through genome reprogramming.

Background: Epigenetic therapy through demethylation of 5-methylcytosine has been largely ineffective in treating lung cancer, most likely due to poor tissue distribution with oral or subcutaneous delivery of drugs such as 5-azacytidine (5AZA). An inhalable, stable dry powder formulation of 5AZA was developed.

Methods: Pharmacokinetics of inhaled dry powder and aqueous formulations of 5AZA were compared to an injected formulation.

Acute hypothalamo-pituitary-adrenal axis response to LPS-induced endotoxemia: expression pattern of kinin type B1 and B2 receptors.

Bradykinin (BK) and des-Arg9-BK are pro-inflammatory mediators acting via B2 (B2R) and B1 (B1R) receptors, respectively. We investigated the role of B2R and B1R in lipopolysaccharide (LPS)-induced hypothalamo-pituitary-adrenal (HPA) axis activation in SD rats. LPS given intraperitoneally (ip) up-regulated B1R mRNA in the hypothalamus, both B1R and B2R were up-regulated in pituitary and adrenal glands.

NMR characterization of an S-linked glucuronide metabolite of the potent, novel, nonsteroidal progesterone agonist tanaproget.

Tanaproget is a first-in-class nonsteroidal progesterone receptor agonist that is being investigated for use in contraception. A major in vitro and in vivo metabolite of tanaproget formed in humans was initially characterized as a glucuronide of tanaproget. However, whether the glucuronide was linked to the nitrogen or sulfur of the benzoxazine-2-thione group in tanaproget could not be determined by liquid chromatography/mass spectrometry (LC/MS) and LC-tandem mass spectrometry analysis.

Integrity profiling of high throughput screening hits using LC-MS and related techniques.

Integrity profiling of HTS hits is valuable for verification of the hit identity and purity. This provides early discovery researchers with more confident SAR theories. Methodology for integrity profiling of HTS hits must be high throughput, consume little material, and selectively provide structure-based data.

Automated accurate mass data processing using a gas chromatograph/time-of-flight mass spectrometer in drug discovery.

A gas chromatograph/time-of-flight (GCT) mass spectrometer, with high mass measurement accuracy to within 5 ppm, has been used for the automated accurate mass analysis of multicomponent mixtures and drug discovery compounds. A multicomponent mixture was analyzed several times over the course of a week to assess the reproducibility and ruggedness of the automated method while operating the GCT in electron ionization mode. For example, the data for 31 radical cations generated via electron ionization was processed using automated software (i.

Integrated high capacity solid phase extraction-MS/MS system for pharmaceutical profiling in drug discovery.

A method is described for use in analysis of samples from pharmaceutical profiling of early drug discovery compounds. The method consists of a high capacity autosampler which injects samples into one of two solid phase extraction columns operated in parallel for alternating trapping, washing and elution into a tandem quadrupole mass spectrometer operated in multiple reaction monitoring (MRM) MS/MS mode. A primary method, which is useful for 80-90% of compounds, and a secondary method, which is useful for a majority of the remaining compounds, are described.

Determination of rat oral bioavailability of soy-derived phytoestrogens using an automated on-column extraction procedure and electrospray tandem mass spectrometry.

In recent years, consumption of herbal supplements as an alternative to pharmaceutical drug therapy has increased. For example, with the health claims labeling which describes the link between soy-protein and a reduced risk of coronary heart disease (CHD), the consumption of soy and soy-derived phytoestrogens has increased dramatically. That being said, the oral bioavailability of only a few soy phytoestrogens such as Daidzein and Genestein have been previously estimated.

Open-access liquid chromatography/mass spectrometry in a drug discovery environment.

The use of open-access mass spectrometry to monitor synthetic chemistry reactions, and also the integrity and purity of new chemical entities, has been a part of the medicinal chemist's tool-box for more than 5 years. Originally in our group at Wyeth Research there were two open-access methods available to the chemists, flow injection analysis (FIA) and liquid chromatography/mass spectrometry (LC/MS). The FIA method was approximately 3 min long, while the LC/MS method was approximately 20 min long (including an 8 min gradient).

Differential effects of estradiol and estradiol-BSA conjugates.

The steroid 17beta-estradiol (E2) acts to modulate transcription through classical nuclear estrogen receptors (ER-alpha and ER-beta). However, E2 also induces a number of rapid responses (<10 min) within cells, including cells devoid of classical ERs, consistent with the presence of a membrane receptor for E2. Membrane impermeable steroids, typically bovine serum albumin (BSA) conjugates, are commonly used to characterize these non-genomic actions of E2 to exclude the involvement of nuclear ERs.

Negative ion fast-atom bombardment tandem mass spectrometry to determine sulfate and linkage position in glycosaminoglycan-derived disaccharides.

Negative ion fast-atom bombardment tandem mass spectrometry has been used in the analysis of monosulfated. disaccharides. These commercially obtained disaccharides have been enzymatically prepared from glycosaminoglycans using polysaccharide lyases.

Cyclodextrin sulfates: characterization as polydisperse and amorphous mixtures.

Alpha- and beta-cyclodextrins and their hydroxypropyl derivatives were converted by the reaction with chlorosulfonic acid in pyridine to the corresponding sulfates. Cyclodextrin sulfates were shown by fast-atom bombardment mass spectrometry (negative ion mode, triethanolamine matrix) to be mixtures with nearly symmetrical distributions of degree of substitution by sulfate groups and by powder X-ray diffraction to be amorphous. Thus, in these aspects, cyclodextrin sulfates are similar to the potent drug solubilizers hydroxypropylcyclodextrins.

Plasma serine in schizophrenics and controls measured by gas chromatography-mass spectrometry.

In several previous studies, we reported significantly higher plasma serine concentrations in psychotic (and schizophrenic) subjects compared with nonpsychotic and control subjects. In those studies, we used a gas chromatography technique to assay the amino acids. Perry and Hanson (1985), using cation-exchange chromatography to assay plasma amino acids, found no differences in the plasma serine concentrations of controls compared with schizophrenic patients.

Intracellular chloride activity in cultured mesangial cells.

Glomerular mesangial cells require Cl ions for the development of a variety of metabolic and functional properties. In the present study the electrochemical distribution for Cl- was examined in cultured rat mesangial cells with Cl(-)-sensitive intracellular microelectrodes. It was determined that the intracellular Cl activity exceeded the levels predicted for a passively distributed ion.

Structural variation in the antithrombin III binding site region and its occurrence in heparin from different sources.

A tetrasaccharide possessing a biosynthetically permissible structural variability in and adjacent to the antithrombin III (ATIII) binding site has been isolated from heparin lyase depolymerized bovine lung heparin by using strong anion-exchange high-pressure liquid chromatography (SAX-HPLC). On the basis of two-dimensional 500-MHz 1H NMR experiments, including phase-sensitive correlated spectroscopy (COSY) and rotating frame nuclear Overhauser enhancement spectroscopy (ROESY), and fast-atom bombardment mass spectrometry (FAB-MS), the primary structure of this tetrasaccharide was unambiguously established as delta UAp2S (1----4)-alpha-D-GlcNp2S6S(1----4)-beta-D-GlcAp(1----4)-alph a-D-GlcNp2S3S6S (where delta UA represents 4-deoxy-alpha-L-threo-hex-4-enopyranosyluronic acid). The 1H NMR ROESY experiment proved to be particularly valuable in offering sequence information.

Sequence analysis of highly sulfated, heparin-derived oligosaccharides using fast atom bombardment mass spectrometry.

Heparin, a polydisperse, sulfated copolymer of 1----4 linked glucosamine and uronic acid residues, has been used clinically as an anticoagulant for half a century. Despite a yearly use of over 50 million doses in the U.S.