Substrate Turnover Dynamics Guide Ketol-Acid Reductoisomerase Redesign for Increased Specific Activity.

The task of adapting enzymes for specific applications is often hampered by our incomplete ability to tune and tailor catalytic functions, particularly when seeking increased activity. Here, we develop and demonstrate a rational approach to address this challenge, applied to ketol-acid reductoisomerase (KARI), which has uses in industrial-scale isobutanol production. While traditional structure-based computational enzyme redesign strategies typically focus on the enzyme-bound ground state (GS) and transition state (TS), we postulated that additionally treating the underlying dynamics of complete turnover events that connect and pass through both states could further elucidate the structural properties affecting catalysis and help identify mutations that lead to increased catalytic activity.

Multidimensional hydrogel models reveal endothelial network angiocrine signals increase glioblastoma cell number, invasion, and temozolomide resistance.

Glioblastoma (GBM) is the most common primary malignant brain tumor. The tissue microenvironment adjacent to vasculature, termed the perivascular niche, has been implicated in promoting biological processes involved in glioblastoma progression such as invasion, proliferation, and therapeutic resistance. However, the exact nature of the cues that support tumor cell aggression in this niche is largely unknown.

Evaluation of a combined tetravalent diphtheria, tetanus, whole-cell pertussis and hepatitis B candidate vaccine administered to healthy infants according to a three-dose vaccination schedule.

A vaccine combining hepatitis B with diphtheria, tetanus and whole-cell Bordetella pertussis (DTPwHBV) would facilitate the attainment of universal vaccination of infants against hepatitis B. A candidate vaccine was administered to 42 infants beginning at 7-15 weeks of age. Antibodies were measured from pre- and postvaccination blood samples.