Deciphering of interactions between platinated DNA and HMGB1 by hydrogen/deuterium exchange mass spectrometry

A high mobility group box 1 (HMGB1) protein has been reported to recognize both 1,2-intrastrand crosslinked DNA by cisplatin (1,2-cis-Pt-DNA) and monofunctional platinated DNA using trans-[PtCl2(NH3)(thiazole)] (1-trans-PtTz-DNA). However, the molecular basis of recognition between the trans-PtTz-DNA and HMGB1 remains unclear. In the present work, we described a hydrogen/deuterium exchange mass spectrometry (HDX-MS) method in combination with docking simulation to decipher the interactions of platinated DNA with domain A of HMGB1. The global deuterium uptake results indicated that 1-trans-PtTz-DNA bound to HMGB1a slightly tighter than the 1,2-cis-Pt-DNA. The local deuterium uptake at the peptide level revealed that the helices I and II, and loop 1 of HMGB1a were involved in the interactions with both platinated DNA adducts. However, docking simulation disclosed different H-bonding networks and distinct DNA-backbone orientations in the two Pt-DNA-HMGB1a complexes. Moreover, the Phe37 residue of HMGB1a was shown to play a key role in the recognition between HMGB1a and the platinated DNAs. In the cis-Pt-DNA-HMGB1a complex, the phenyl ring of Phe37 intercalates into a hydrophobic notch created by the two platinated guanines, while in the trans-PtTz-DNA-HMGB1a complex the phenyl ring appears to intercalate into a hydrophobic crevice formed by the platinated guanine and the opposite adenine in the complementary strand, forming a penta-layer π–π stacking associated with the adjacent thymine and the thiazole ligand. This work demonstrates that HDX-MS associated with docking simulation is a powerful tool to elucidate the interactions between platinated DNAs and proteins

Learning to Skip for Language Modeling

Overparameterized large-scale language models have impressive generalization performance of in-context few-shot learning. However, most language models allocate the same amount of parameters or computation to each token, disregarding the complexity or importance of the input data. We argue that in language model pretraining, a variable amount of computation should be assigned to different tokens, and this can be efficiently achieved via a simple routing mechanism. Different from conventional early stopping techniques where tokens can early exit at only early layers, we propose a more general method that dynamically skips the execution of a layer (or module) for any input token with a binary router. In our extensive evaluation across 24 NLP tasks, we demonstrate that the proposed method can significantly improve the 1-shot performance compared to other competitive baselines only at mild extra cost for inference

Patterns and Distributions of Urban Expansion in Global Watersheds

Abstract Understanding urban expansion at the watershed scale is important because watersheds are important carriers of ecological and environmental impacts. However, current analyses are mainly restricted to administrative units only. Here, we used a long‐term multitemporal data set of urban land to quantify the spatiotemporal trends in the extent and form of urban expansion from 1992 to 2016 in endorheic and exoreic watersheds, globally. Overall, urban expansion in 70% of watersheds (154/220) showed a decelerating trend. The average urban expansion speed of these watersheds in the last 6 years was approximately half of that in the last 24 years. Urban expansion speed in endorheic watersheds lagged behind the counterparts in exoreic watersheds, with the former approximately 1/4 of the latter. More importantly, the pattern of urban expansion in endorheic watersheds was following the low‐density and sprawling trend in exoreic watersheds, which could exert far‐reaching impacts on the sustainability of endorheic watersheds located in arid lands. These findings suggest the need to look beyond administrative city boundaries for land use planning and policies in the context of watershed management

Effects of vertebral number variations on carcass traits and genotyping of Vertnin candidate gene in Kazakh sheep

Objective The vertebral number is associated with body length and carcass traits, which represents an economically important trait in farm animals. The variation of vertebral number has been observed in a few mammalian species. However, the variation of vertebral number and quantitative trait loci in sheep breeds have not been well addressed. Methods In our investigation, the information including gender, age, carcass weight, carcass length and the number of thoracic and lumbar vertebrae from 624 China Kazakh sheep was collected. The effect of vertebral number variation on carcass weight and carcass length was estimated by general linear model. Further, the polymorphic sites of Vertnin (VRTN) gene were identified by sequencing, and the association of the genotype and vertebral number variation was analyzed by the one-way analysis of variance model. Results The variation of thoracolumbar vertebrae number in Kazakh sheep (18 to 20) was smaller than that in Texel sheep (17 to 21). The individuals with 19 thoracolumbar vertebrae (T13L6) were dominant in Kazakh sheep (79.2%). The association study showed that the numbers of thoracolumbar vertebrae were positively correlated with the carcass length and carcass weight, statistically significant with carcass length. To investigate the association of thoracolumbar vertebrae number with VRTN gene, we genotyped the VRTN gene. A total of 9 polymorphic sites were detected and only a single nucleotide polymorphism (SNP) (rs426367238) was suggested to associate with thoracic vertebral number statistically. Conclusion The variation of thoracolumbar vertebrae number positively associated with the carcass length and carcass weight, especially with the carcass length. VRTN gene polymorphism of the SNP (rs426367238) with significant effect on thoracic vertebral number could be as a candidate marker to further evaluate its role in influence of thoracolumbar vertebral number

Brainformers: Trading Simplicity for Efficiency

Transformers are central to recent successes in natural language processing and computer vision. Transformers have a mostly uniform backbone where layers alternate between feed-forward and self-attention in order to build a deep network. Here we investigate this design choice and find that more complex blocks that have different permutations of layer primitives can be more efficient. Using this insight, we develop a complex block, named Brainformer, that consists of a diverse sets of layers such as sparsely gated feed-forward layers, dense feed-forward layers, attention layers, and various forms of layer normalization and activation functions. Brainformer consistently outperforms the state-of-the-art dense and sparse Transformers, in terms of both quality and efficiency. A Brainformer model with 8 billion activated parameters per token demonstrates 2x faster training convergence and 5x faster step time compared to its GLaM counterpart. In downstream task evaluation, Brainformer also demonstrates a 3% higher SuperGLUE score with fine-tuning compared to GLaM with a similar number of activated parameters. Finally, Brainformer largely outperforms a Primer dense model derived with NAS with similar computation per token on fewshot evaluations

Peroxo Species Formed in the Bulk of Silicate Cathodes

Oxygen redox in Li‐rich oxides may boost the energy density of lithium‐ion batteries by incorporating oxygen chemistry in solid cathodes. However, oxygen redox in the bulk usually entangles with voltage hysteresis and oxygen release, resulting in a prolonged controversy in literature on oxygen transformation. Here, we report spectroscopic evidence of peroxo species formed and confined in silicate cathodes amid oxygen redox at high voltage, accompanied by Co$^{2+}$/Co$^{3+}$ redox dominant at low voltage. First‐principles calculations reveal that localized electrons on dangling oxygen drive the O‐O dimerization. The covalence between the binding cation and the O‐O dimer determines the degree of electron transfer in oxygen transformation. Dimerization induces irreversible structural distortion and slow kinetics. But peroxo formation can minimize the voltage drop and volume expansion in cumulative cationic and anionic redox. These findings offer insights into oxygen redox in the bulk for the rational design of high‐energy‐density cathodes

X-ray Absorption Spectroscopy Combined with Time-Dependent Density Functional Theory Elucidates Differential Substitution Pathways of Au(I) and Au(III) with Zinc Fingers

A combination of two elements’ (Au, Zn) X-ray absorption spectroscopy (XAS) and time-dependent density functional theory (TD-DFT) allowed the elucidation of differential substitution pathways of Au(I) and Au(III) compounds reacting with biologically relevant zinc fingers (ZnFs). Gold L3-edge XAS probed the interaction of gold and the C-terminal Cys2HisCys finger of the HIV-1 nucleocapsid protein NCp7, and the Cys2His2 human transcription factor Sp1. The use of model compounds helped assign oxidation states and the identity of the gold-bound ligands. The computational studies accurately reproduced the experimental XAS spectra and allowed the proposition of structural models for the interaction products at early time points. The direct electrophilic attack on the ZnF by the highly thiophilic Au(I) resulted in a linear P–Au–Cys coordination sphere after zinc ejection whereas for the Sp1, loss of PEt3 results in linear Cys–Au–Cys or Cys–Au–His arrangements. Reactions with Au(III) compounds, on the other hand, showed multiple binding modes. Prompt reaction between [AuCl(dien)]2+ and [Au(dien)(DMAP)]3+ with Sp1 showed a partially reduced Au center and a final linear His–Au–His coordination. Differently, in the presence of NCp7, [AuCl(dien)]2+ readily reduces to Au(I) and changes from square-planar to linear geometry with Cys–Au–His coordination, while [Au(dien)(DMAP)]3+ initially maintains its Au(III) oxidation state and square-planar geometry and the same first coordination sphere. The latter is the first observation of a “noncovalent” interaction of a Au(III) complex with a zinc finger and confirms early hypotheses that stabilization of Au(III) occurs with N-donor ligands. Modification of the zinc coordination sphere, suggesting full or partial zinc ejection, is observed in all cases, and for [Au(dien)(DMAP)]3+ this represents a novel mechanism for nucleocapsid inactivation. The combination of XAS and TD-DFT presents the first direct experimental observation that not only compound reactivity, but also ZnF core specificity, can be modulated on the basis of the coordination sphere of Au(III) compounds.This work was supported by National Science Foundation NSF CHE-1413189, and São Paulo Research Foundation (FAPESP) 2013/20334-0 and 2015/9905-1, Brazilian Federal Agency, for the Support and Evaluation of Graduate Education (CAPES), CAPES/PVES 154/2012 and 0580/2013. We thank the Brazilian Synchrotron Light Laboratory for the beamtime and the XAFS1 and XAFS2 staff for the support. We especially thank Anna Paula Sotero and Carlos Doro Neto for the technical support at the synchrotron beamlines. F.A.L. acknowledges the National Council for Scientific and Technological Development (CNPq) for the productivity grant 311270/2015-8″. C.A. acknowledges support from FAPESP 2013/20334-0 and Brazilian Synchrotron Light Laboratory LNLS 1-XAFS1-17707 and LNLS2 research project 2015 0089. R.B. acknowledges support from the Icelandic Research Fund, Grant No. 141218051, and the University of Iceland Research Fund