Dynamics of the Destruction and Rebuilding of a Dipole Gap in Glasses

After a strong electric bias field was applied to a glass sample at temperatures in the millikelvin range its AC-dielectric constant increases and then decays logarithmically with time. For the polyester glass mylar we have observed the relaxation of the dielectric constant back to its initial value for several temperatures and histories of the bias field. Starting from the dipole gap theory we have developed a model suggesting that the change of the dielectric constant after transient application of a bias field is only partly due to relaxational processes. In addition, non-adiabatic driving of tunneling states (TSs) by applied electric fields causes long lasting changes in the dielectric constant. Moreover, our observations indicate that at temperatures below 50 mK the relaxation of TSs is caused primarily by interactions between TSs.Comment: 4 pages, 4 figures, submitted to PR

Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer.

Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration-resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways. We hypothesized that these Sigma1-mediated responses could be exploited to suppress AR protein levels and activity. Here we demonstrate that treatment with a small-molecule Sigma1 inhibitor prevented 5α- dihydrotestosterone-mediated nuclear translocation of AR and induced proteasomal degradation of AR and ARV, suppressing the transcriptional activity and protein levels of both full-length and splice-variant AR. Consistent with these data, RNAi knockdown of Sigma1 resulted in decreased AR levels and transcriptional activity. Furthermore, Sigma1 physically associated with ARV7 and A

Correlated Persistent Tunneling Currents in Glasses

Low temperature properties of glasses are derived within a generalized tunneling model, considering the motion of charged particles on a closed path in a double-well potential. The presence of a magnetic induction field B violates the time reversal invariance due to the Aharonov-Bohm phase, and leads to flux periodic energy levels. At low temperature, this effect is shown to be strongly enhanced by dipole-dipole and elastic interactions between tunneling systems and becomes measurable. Thus, the recently observed strong sensitivity of the electric permittivity to weak magnetic fields can be explained. In addition, superimposed oscillations as a function of the magnetic field are predicted.Comment: 4 page

Dynamics of Highly Supercooled Liquids:Heterogeneity, Rheology, and Diffusion

Highly supercooled liquids with soft-core potentials are studied via molecular dynamics simulations in two and three dimensions in quiescent and sheared conditions.We may define bonds between neighboring particle pairs unambiguously owing to the sharpness of the first peak of the pair correlation functions. Upon structural rearrangements, they break collectively in the form of clusters whose sizes grow with lowering the temperature $T$. The bond life time $\tau_b$, which depends on $T$ and the shear rate \gdot, is on the order of the usual structural or $\alpha$ relaxation time $\tau_{\alpha}$ in weak shear \gdot \tau_{\alpha} \ll 1, while it decreases as 1/\gdot in strong shear \gdot\tau_{\alpha} \gg 1 due to shear-induced cage breakage. Accumulated broken bonds in a time interval ($\sim 0.05\tau_b$) closely resemble the critical fluctuations of Ising spin systems. For example, their structure factor is well fitted to the Ornstein-Zernike form, which yields the correlation length $\xi$ representing the maximum size of the clusters composed of broken bonds. We also find a dynamical scaling relation, $\tau_b \sim \xi^{z}$, valid for any $T$ and \gdot with $z=4$ in two dimensions and $z=2$ in three dimensions. The viscosity is of order $\tau_b$ for any $T$ and \gdot, so marked shear-thinning behavior emerges. The shear stress is close to a limiting stress in a wide shear region. We also examine motion of tagged particles in shear in three dimensions. The diffusion constant is found to be of order $\tau_b^{-\nu}$ with $\nu=0.75 \sim 0.8$ for any $T$ and \gdot, so it is much enhanced in strong shear compared with its value at zero shear. This indicates breakdown of the Einstein-Stokes relation in accord with experiments. Some possible experiments are also proposed.Comment: 20pages (including figures

The natural stilbenoid (-)-hopeaphenol inhibits cellular entry of SARS-CoV-2 USA-WA1/2020, B.1.1.7, and B.1.351 variants

Antivirals are urgently needed to combat the global SARS-CoV-2/COVID- 19 pandemic, supplement existing vaccine efforts, and target emerging SARS-CoV-2 variants of concern. Small molecules that interfere with binding of the viral spike receptor binding domain (RBD) to the host angiotensin-converting enzyme II (ACE2) receptor may be effective inhibitors of SARS-CoV-2 cell entry. Here, we screened 512 pure compounds derived from natural products using a high-throughput RBD/ACE2 binding assay and identified (-)-hopeaphenol, a resveratrol tetramer, in addition to vatalbinoside A and vaticanol B, as potent and selective inhibitors of RBD/ACE2 binding and viral entry. For example, (-)-hopeaphenol disrupted RBD/ACE2 binding with a 50% inhibitory concentration (IC50) of 0.11 mM, in contrast to an IC50 of 28.3 mM against the unrelated host ligand/receptor binding pair PD-1/PD-L1 (selectivity index, 257.3). When assessed against the USA-WA1/2020 variant, (-)-hopeaphenol also inhibited entry of a VSVDG-GFP reporter pseudovirus expressing SARS-CoV-2 spike into ACE2-expressing Vero-E6 cells and in vitro replication of infectious virus in cytopathic effect and yield reduction assays (50% effective concentrations [EC50s], 10.2 to 23.4 mM) without cytotoxicity and approaching the activities of the control antiviral remdesivir (EC50s, 1.0 to 7.3 mM). Notably, (-)-hopeaphenol also inhibited two emerging variants of concern, B.1.1.7/Alpha and B.1.351/Beta in both viral and spike-containing pseudovirus assays with similar or improved activities over the USA-WA1/2020 variant. These results identify (-)-hopeaphenol and related stilbenoid analogues as potent and selective inhibitors of viral entry across multiple SARS-CoV-2 variants of concern

Some like it cold: biocatalysis at low temperatures

In the last few years, increased attention has been focused on a class of organisms called psychrophiles. These organisms, hosts of permanently cold habitats, often display metabolic fluxes more or less comparable to those exhibited by mesophilic organisms at moderate temperatures. Psychrophiles have evolved by producing, among other peculiarities, "cold-adapted" enzymes which have the properties to cope with the reduction of chemical reaction rates induced by low temperatures. Thermal compensation in these enzymes is reached, in most cases, through a high catalytic efficiency associated, however, with a low thermal stability. Thanks to recent advances provided by X-ray crystallography, structure modelling, protein engineering and biophysical studies, the adaptation strategies are beginning to be understood. The emerging picture suggests that psychrophilic enzymes are characterized by an improved flexibility of the structural components involved in the catalytic cycle, whereas other protein regions, if not implicated in catalysis, may be even more rigid than their mesophilic counterparts. Due to their attractive properties, i.e., a high specific activity and a low thermal stability, these enzymes constitute a tremendous potential for fundamental research and biotechnological applications. (C) 2003 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved