Centering Equity in the Nation's Weather, Water, and Climate Services.

Water, weather, and climate affect everyone. However, their impacts on various communities can be very different based on who has access to essential services and environmental knowledge. Structural discrimination, including racism and other forms of privileging and exclusion, affects people's lives and health, with ripples across all sectors of society. In the United States, the need to equitably provide weather, water, and climate services is uplifted by the Justice40 Initiative (Executive Order 14008), which mandates 40% of the benefits of certain federal climate and clean energy investments flow to disadvantaged communities. To effectively provide such services while centering equity, systemic reform is required. Reform is imperative given increasing weather-related disasters, public health impacts of climate change, and disparities in infrastructure, vulnerabilities, and outcomes. It is imperative that those with positional authority and resources manifest responsibility through (1) recognition, inclusion, and prioritization of community expertise; (2) the development of a stronger and more representative and equitable workforce; (3) communication about climate risk in equitable, relevant, timely, and culturally responsive ways; and (4) the development and implementation of new models of relationships between communities and the academic sector.

Microbial N-demethylation: biotransformation and recovery of a drug metabolite.

A total of 39 microbes were screened for the ability to selectively N-demethylate (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1H-1,2,4-triazol-5-yl)aminopyrimidin-5-yl)-3,5-dihydroxy-hept-6-enoic acid (I), a potential drug for lowering blood cholesterol levels. Two Streptomyces species were found to carry out the desired N-demethylation. Bioconversion by Streptomyces griseus A.T.C.C. 13273 and product recovery were scaled up to the multi-gram level.

Enzymatic C-4 deacetylation of 10-deacetylbaccatin III.

Second-generation paclitaxel analogues that require replacement of the C-4 acetate by other substituents are in development. An enzyme able to specifically remove the C-4 acetate from paclitaxel could simplify preparation of the analogues. Several strains were isolated from soil samples that contain enzyme activities able to 4-deacetylate 10-DAB (10-deacetylbaccatin III). Selection was made using plates containing 10-DAB as the sole carbon source and screening colonies for deacetylation of 10-DAB. Two strains initially isolated were identified as Rhodococcus sp. and deposited with the A.T.C.C. (Manassas, VA, U.S.A.) as strains 202191 and 202192. Whole cells were able to convert 10-DAB into 4,10-DDAB (4-deacetyl-10-deacetylbaccatin III) in 90% yield. The enzyme activity in these strains was not effective with paclitaxel and 10-deacetylpaclitaxel, although 4,10-DDAB was produced from baccatin III. The activity in these strains was associated with an insoluble fraction of cell extracts. Several additional isolates were obtained that were identified as variants of Stenotrophomonas maltophilia, and a soluble C-4 deacetylase was purified approx. 218-fold from one of them. The activity of this enzyme was limited to 10-DAB, and the enzyme was not effective with paclitaxel or baccatin III.

Influence of formaldehyde impurity in polysorbate 80 and PEG-300 on the stability of a parenteral formulation of BMS-204352: identification and control of the degradation product.

The purpose of this study was to identify a degradation product formed in the clinical parenteral formulation of BMS-204352, investigate the role of excipients in its formation, and develop a strategy to minimize/control its formation. The degradant was identified as the hydroxy methyl derivative (formaldehyde adduct, BMS-215842) of the drug substance based upon liquid chromatography/mass spectroscopy (LC/MS), liquid chromatography/mass spectroscopy/mass spectroscopy (LC/MS/MS), nuclear magnetic resonance (NMR), and chromatographic comparison to an authentic sample of hydroxymethyl degradation product, BMS-215842. An assay method for the detection of formaldehyde based on HPLC quantitation of formaldehyde dinitrophenylhydrazone was developed to quantitate its levels in various Polysorbate 80 and PEG 300 excipient lots. A direct relationship between the levels of formaldehyde in the excipients and the formation of the hydroxymethyl degradant was found. To confirm the hypothesis that the formaldehyde impurity in these two excipients contributed to the formation of the hydroxymethyl degradant, several clinical formulation lots were spiked with formaldehyde equivalent to 1, 10, and 100 mg/g of BMS-204352. A correlation was found between the formaldehyde level and the quantity of the hydroxymethyl degradant formed upon storage at 5 and 25 degrees C. From these experiments, a limit test on the formaldehyde content in polysorbate 80 and PEG 300 can be set as part of a strategy to limit the formation of the degradation product.