No abstract

The India‐Eurasia collision zone is the largest deforming region on the planet; direct measurements of present‐day deformation from Global Positioning System (GPS) have the potential to discriminate between competing models of continental tectonics. But the increasing spatial resolution and accuracy of observations have only led to increasingly complex realizations of competing models. Here we present the most complete, accurate, and up‐to‐date velocity field for India‐Eurasia available, comprising 2576 velocities measured during 1991–2015. The core of our velocity field is from the Crustal Movement Observation Network of China‐I/II: 27 continuous stations observed since 1999; 56 campaign stations observed annually during 1998–2007; 1000 campaign stations observed in 1999, 2001, 2004, and 2007; 260 continuous stations operating since late 2010; and 2000 campaign stations observed in 2009, 2011, 2013, and 2015. We process these data and combine the solutions in a consistent reference frame with stations from the Global Strain Rate Model compilation, then invert for continuous velocity and strain rate fields. We update geodetic slip rates for the major faults (some vary along strike), and find that those along the major Tibetan strike‐slip faults are in good agreement with recent geological estimates. The velocity field shows several large undeforming areas, strain focused around some major faults, areas of diffuse strain, and dilation of the high plateau. We suggest that a new generation of dynamic models incorporating strength variations and strain‐weakening mechanisms is required to explain the key observations. Seismic hazard in much of the region is elevated, not just near the major faults.

The p53 tumor suppressor requires tetramerization to function as an initiator of cell cycle arrest and/or apoptosis. Children in southern Brazil that exhibit an elevated incidence of adrenocortical carcinoma (ACC) harbor an Arg 337 to His mutation within the tetramerization domain of p53 (p53-R337H; 35 of 36 patients). The mutant tetramerization domain (p53tet-R337H) adopts a native-like fold but is less stable than the wild type domain (p53tet-wt). Furthermore, the stability of p53tet-R337H is highly sensitive to pH in the physiological range; this sensitivity correlates with the protonation state of the mutated His 337. These results demonstrate a pH-sensitive molecular defect of p53 (R337H), suggesting that pH-dependent p53 dysfunction is the molecular basis for these cases of ACC in Brazilian children.

Disordered proteins are highly prevalent in biological systems, they control myriad signaling and regulatory processes, and their levels and/or cellular localization are often altered in human disease. In contrast to folded proteins, disordered proteins, due to conformational heterogeneity and dynamics, are not considered viable drug targets. We challenged this paradigm by identifying through NMR-based screening small molecules that bound specifically, albeit weakly, to the disordered cell cycle regulator, p27Kip1 (p27). Two groups of molecules bound to sites created by transient clusters of aromatic residues within p27. Conserved chemical features within these two groups of small molecules exhibited complementarity to their binding sites within p27, establishing structure-activity relationships for small molecule:disordered protein interactions. Finally, one compound counteracted the Cdk2/cyclin A inhibitory function of p27 in vitro, providing proof-of-principle that small molecules can inhibit the function of a disordered protein (p27) through sequestration in a conformation incapable of folding and binding to a natural regulatory target (Cdk2/cyclin A).

-In this study, the chemical and mineral composition and trace elements in royal jelly (RJ) and worker jelly (WJ) and in royal jelly on particular days (only-2-day RJ [O2d], only-3-day RJ [O3d] and only-4-day RJ [O4d]) were determined. Significant differences in levels of moisture, protein, 10-hydroxy-2-decenoic acid (10-HDA), fructose (F) and glucose (G) were found between the RJ and WJ samples. The nutrient content was significantly higher in samples on O2d than the O3d and O4d samples. The results of this study add to the current knowledge of the nutritional value of RJ and WJ. These results also imply a strong relationship between nutritional effects and polyphenism in honey bees.chemical / composition / royal jelly / worker jelly

No abstract

The pulse is a key biomedical signal containing various human physiological and pathological information highly related to cardiovascular diseases. Pulse signals are often collected from the radial artery based on Traditional Chinese Medicine, or by using flexible pressure sensors. However, the wrist wrapped with a flexible pressure sensor exhibits unstable signals under hand motion because of the concave surface of the wrist. By contrast, fingertips have a convex surface and therefore show great promises in stable and long‐term pulse monitoring. Despite the promising potential, the fingertip pulse signal is weak, calling for highly sensitive detecting devices. Here, a highly sensitive and flexible iontronic pressure sensor with a linear sensitivity of 13.5 kPa−1, a swift response, and remarkable stability over 5000 loading/unloading cycles is developed. This sensor enables stable and high‐resolution detection of pulse waveform under both static condition and finger motion. Fingertip pulse waveforms from subjects of different genders, age, and health conditions are collected and analyzed, suggesting that fingertip pulse information is highly similar to that of the radial artery. This work justifies that fingertip is an ideal platform for pulse signals monitoring, which would be a competitive alternative to existing complex health monitoring systems.

Mercaptopurine and thioguanine, two of the most widely used antileukemic agents, exert their cytotoxic, therapeutic effects by being incorporated into DNA as deoxy-6-thioguanosine. However, the molecular mechanism(s) by which incorporation of these thiopurines into DNA translates into cytotoxicity is unknown. The solution structure of thioguanine-modified duplex DNA presented here shows that the effects of the modification on DNA structure were subtle and localized to the modified base pair. Specifically, thioguanine existed in the keto form, formed weakened Watson-Crick hydrogen bonds with cytosine and caused a modest ϳ10°o pening of the modified base pair toward the major groove. In contrast, thioguanine significantly altered base pair dynamics, causing an ϳ80-fold decrease in the base pair lifetime with cytosine compared with normal guanine. This perturbation was consistent with the ϳ6°C decrease in DNA melting temperature of the modified oligonucleotide, the 1.13 ppm upfield shift of the thioguanine imino proton resonance, and the large increase in the exchange rate of the thioguanine imino proton with water. Our studies provide new mechanistic insight into the effects of thioguanine incorporation into DNA at the level of DNA structure and dynamics, provide explanations for the effects of thioguanine incorporation on the activity of DNA-processing enzymes, and provide a molecular basis for the specific recognition of thioguanine-substituted sites by proteins. These combined effects likely cooperate to produce the cellular responses that underlie the therapeutic effects of thiopurines.