A Test of a New Model for the Origin of Primary Kinetic Hydrogen Isotope Effect

Semi-classical transitional state theory and Bell model with a H-tunneling correction are the traditional basis for the understanding of the hydrogen kinetic isotope effects (KIEs). However, they fail to explain many observations in H-transfer reactions. The major reason is that they do not consider the role of the heavy atom motions in the H-transfer chemistry. Marcus-like model is a phenomenological model which treats H as a wave between vibrational donor and acceptor and can explain the observations from temperature independence of KIEs for the wild-type enzymes (∆Ea = EaD - EaH = 0) and temperature dependence of KIE’s in mutated enzymes (∆Ea > 0). Within this new model, KIE originates from different H/D wave-function overlap between activated reactant and product at all possible donor-acceptor distances (DAD’s) sampled by the heavy atom motions. In this work, two hypotheses were recognized from this model, which link structure/DAD to KIEs and the temperature dependency of the KIEs. They are, (1) a shorter DAD is required for D-tunneling than for H-tunneling, and (2) the more rigid the reaction centers the weaker will be the temperature dependence of the 1° KIEs, i.e. a smaller ∆Ea. A series of hydride transfer reactions of NADH/NAD+ analogs in acetonitrile were designed to systematically investigate the hypotheses. Experiments studied electronic, steric, and temperature effects on kinetics and produced rate constants ranging from 105 to 1.0 M-1s-1, KIE’s from 2.5 to 5.31, and ∆Ea’s from nearly 0 to 1.19 kcal/mol. It was found that H- and D-tunneling processes use different tunneling-ready state electronic structures. It was also found that the ∆Ea increases as the rigidity of the donor-acceptor centers decreases. The latter results replicate the trend of ∆Ea’s observed from enzymes to mutated enzymes and have opened a new research direction that studies structure – ∆Ea relationship. Results support the two hypotheses, and thus are consistent with the Marcus-like H-tunneling model

Rip It, Stitch It, Click It: A Chemist’s Guide to VLP Manipulation

Viruses are some of nature’s most ubiquitous self-assembled molecular containers. Evolutionary pressures have created some incredibly robust, thermally and enzymatically resistant containers to transport delicate genetic information safely. Virus-like particles (VLPs) are human-engineered non-infectious systems that inherit the parent virus’ ability to self-assemble under controlled conditions while being non-infectious. VLPs and plant-based viral nanoparticles are becoming increasingly popular in medicine as their self-assembly properties are exploitable for applications ranging from diagnostic tools to targeted drug delivery. Understanding the basic structure and principles underlying the assembly of higher-order structures has allowed researchers to disassemble (rip it), functionalize (click it), and reassemble (stitch it) these systems on demand. This review focuses on the current toolbox of strategies developed to manipulate these systems by ripping, stitching, and clicking to create new technologies in the biomedical space

Mean dietary salt intake in Nepal: A population survey with 24-hour urine collections.

High salt (sodium chloride) intake raises blood pressure and increases the risk of developing hypertension, a major risk factor for cardiovascular disease. Little is known about salt intake in Nepal, and no study has estimated salt consumption from 24‐hour urinary sodium excretion. Participants (n = 451) were recruited from the Community‐Based Management of Non‐Communicable Diseases in Nepal (COBIN) cohort in 2018. Salt intake was estimated by analyzing 24‐hour urinary sodium excretion. Multivariate linear regression was used to estimate differences in salt intake. The mean (±SD) age and salt intake were 49.6 (±9.8) years and 13.3 (±4.7) g/person/d, respectively. Higher salt intake was significantly associated with male gender (β for female = −2.4; 95% CI: −3.3, −1.4) and younger age (β (10 years) = −1.4; 95% CI: −1.4, −0.5) and higher BMI (β = 0.1; 95% CI: 0.0, 0.2). A significant association was also found between increase in systolic blood pressure and higher salt intake (β = 0.3; 95% CI: 0.0, 0.7). While 55% reported that they consumed just the right amount of salt, 98% were consuming more than the WHO recommended salt amount (<5 g/person/d). Daily salt intake in this population was over twice the limit recommended by the WHO, suggesting a substantial need to reduce salt intake in this population. It also supports the need of global initiatives such as WHO's Global Hearts Initiative SHAKE technical package and Resolves to Save Lives for sodium reduction in low‐ and middle‐income countries like Nepal

A Scalable Synthesis of Adjuvanting Antigen Depots Based on Met-al-Organic Frameworks

Vaccines have saved countless lives by preventing and even irradicating infectious diseases. Commonly used subunit vaccines comprising one or multiple recombinant proteins isolated from a pathogen demonstrate a better safety profile than live or attenuated vaccines. However, the immunogenicity of these vaccines is weak, and therefore, subunit vaccines require a series of doses to achieve sufficient immunity against the pathogen. Here, we show that the biomimetic mineralization of the inert model antigen, ovalbumin (OVA), in zeolitic imidazolate framework-8 (ZIF-8) significantly improves the humoral immune response over three bolus doses of OVA (OVA 3×). Encapsulation of OVA in ZIF-8 (OVA@ZIF) demonstrated higher serum antibody titers against OVA than OVA 3×. OVA@ZIF vaccinated mice displayed higher populations of germinal center (GC) B cells and IgG1+ GC B cells as opposed to OVA 3×, indicative of class-switching recombination. We show that the mechanism of this phenomenon is at least partly owed to the metalloimmunological effects of the zinc metal as well as the sustained release of OVA from the ZIF-8 composite. The system acts as an antigen reservoir for antigen-presenting cells to traffic into the draining lymph node, enhancing the humoral response. Lastly, our model system OVA@ZIF is produced quickly at the gram scale in a laboratory setting, sufficient for up to 20,000 vaccine doses