Mutagenic Activation of Glutathione Peroxidase-4: Approaches toward Rational Design of Allosteric Drugs.

Glutathione peroxidase 4 (GPX4) reduces lipid hydroperoxides in lipid membranes, effectively inhibiting iron-dependent cell death or ferroptosis. The upregulation of the enzyme by the mutations at residues D21 and D23 has been suggested to be associated with higher protein activity, which confers more protection against neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases. Therefore, it has become an attractive target for treating and preventing neurodegenerative diseases. However, identifying means of mimicking the beneficial effects of these mutations distant from the active site constitutes a formidable challenge in moving toward therapeutics. In this study, we explore using molecular dynamics simulations to computationally map the conformational and energetic landscape of the wild-type GPX4 protein and three mutant variants to identify the allosteric networks of the enzyme. We present the conformational dynamic profile providing the desired signature behavior of the enzyme. We also discuss the implications of these findings for drug design efforts.

Extinction in a hyperdiverse endemic Hawaiian land snail family and implications for the underestimation of invertebrate extinction.

The International Union for Conservation of Nature (IUCN) Red List includes 832 species listed as extinct since 1600, a minuscule fraction of total biodiversity. This extinction rate is of the same order of magnitude as the background rate and has been used to downplay the biodiversity crisis. Invertebrates comprise 99% of biodiversity, yet the status of a negligible number has been assessed. We assessed extinction in the Hawaiian land snail family Amastridae (325 species, IUCN lists 33 as extinct). We did not use the stringent IUCN criteria, by which most invertebrates would be considered data deficient, but a more realistic approach comparing historical collections with modern surveys and expert knowledge. Of the 325 Amastridae species, 43 were originally described as fossil or subfossil and were assumed to be extinct. Of the remaining 282, we evaluated 88 as extinct and 15 as extant and determined that 179 species had insufficient evidence of extinction (though most are probably extinct). Results of statistical assessment of extinction probabilities were consistent with our expert evaluations of levels of extinction. Modeling various extinction scenarios yielded extinction rates of 0.4-14.0% of the amastrid fauna per decade. The true rate of amastrid extinction has not been constant; generally, it has increased over time. We estimated a realistic average extinction rate as approximately 5%/decade since the first half of the nineteenth century. In general, oceanic island biotas are especially susceptible to extinction and global rate generalizations do not reflect this. Our approach could be used for other invertebrates, especially those with restricted ranges (e.g., islands), and such an approach may be the only way to evaluate invertebrates rapidly enough to keep up with ongoing extinction.

Yukawa interactions and supersymmetric electroweak baryogenesis.

We analyze the quantum transport equations for supersymmetric electroweak baryogenesis including previously neglected bottom and tau Yukawa interactions and show that they imply the presence of a previously unrecognized dependence of the cosmic baryon asymmetry on the spectrum of third generation quark and lepton superpartners. For fixed values of the CP-violating phases in the supersymmetric theory, the baryon asymmetry can vary in both magnitude and sign as a result of the squark and slepton mass dependence. For light, right-handed top and bottom quark superpartners, the baryon number creation can be driven primarily by interactions involving third generation leptons and their superpartners.

High density preheating effects on Q-ball decays and inflation in the minimal supersymmetric standard model.

Nonperturbative preheating decay of postinflationary condensates often results in a high density, low momenta, nonthermal gas. In the case where the nonperturbative classical evolution also leads to Q balls, this effect shields them from instant dissociation, and may radically change the thermal history of the Universe. For example, in a large class of inflationary scenarios, motivated by the minimal supersymmetric standard model and its embedding in string theory, the reheat temperature changes by a multiplicative factor of 10(12).