NMR Structure and Dynamics of a Designed Water-Soluble Transmembrane Domain of Nicotinic Acetylcholine Receptor

The nicotinic acetylcholine receptor (nAChR) is an important therapeutic target for a wide range of pathophysiological conditions, for which rational drug designs often require receptor structures at atomic resolution. Recent proof-of-concept studies demonstrated a water-solubilization approach to structure determination of membrane proteins by NMR (Slovic et al., PNAS, 101: 1828–1833, 2004; Ma et al., PNAS, 105: 16537–42, 2008). We report here the computational design and experimental characterization of WSA, a water-soluble protein with ~ 83% sequence identity to the transmembrane (TM) domain of the nAChR α1 subunit. Although the design was based on a low-resolution structural template, the resulting high-resolution NMR structure agrees remarkably well with the recent crystal structure of the TM domains of the bacterial Gloeobacter violaceuspentameric ligand-gated ion channel (GLIC), demonstrating the robustness and general applicability of the approach. NMR T2 dispersion measurements showed that the TM2 domain of the designed protein was dynamic, undergoing conformational exchange on the NMR timescale. Photoaffinity labeling with isoflurane and propofol photolabels identified a common binding site in the immediate proximity of the anesthetic binding site found in the crystal structure of the anesthetic-GLIC complex. Our results illustrate the usefulness of high-resolution NMR analyses of water-solubilized channel proteins for the discovery of potential drug binding sites

Nano-enabled bioanalytical approaches to ultrasensitive detection of low abundance single nucleotide polymorphisms

Single nucleotide polymorphisms (SNPs) constitute the most common types of genetic variations in the human genome. A number of SNPs have been linked to the development of life threatening diseases including cancer, cardiovascular diseases and neurodegenerative diseases. The ability for ultrasensitive and accurate detection of low abundant disease-related SNPs in bodily fluids (e.g. blood, serum, etc.) holds a significant value in the development of non-invasive future biodiagnostic tools. Over the past two decades, nanomaterials have been utilized in a myriad of biosensing applications due to their ability of detecting extremely low quantities of biologically important biomarkers with high sensitivity and accuracy. Of particular interest is the application of such technologies in the detection of SNPs. The use of various nanomaterials, coupled with different powerful signal amplification strategies, has paved the way for a new generation of ultrasensitive SNP biodiagnostic assays. Over the past few years, several ultrasensitive SNP biosensors capable of detecting specific targets down to the ultra-low regimes (ca. aM and below) and therefore holding great promises for early clinical diagnosis of diseases have been developed. This mini review will highlight some of the most recent, significant advances in nanomaterial-based ultrasensitive SNP sensing technologies capable of detecting specific targets on the attomolar (10-18 M) regime or below. In particular, the design of novel, powerful signal amplification strategies that hold the key to the ultrasensitivity is highlighted

DeepSeek LLM: Scaling Open-Source Language Models with Longtermism

The rapid development of open-source large language models (LLMs) has been truly remarkable. However, the scaling law described in previous literature presents varying conclusions, which casts a dark cloud over scaling LLMs. We delve into the study of scaling laws and present our distinctive findings that facilitate scaling of large scale models in two commonly used open-source configurations, 7B and 67B. Guided by the scaling laws, we introduce DeepSeek LLM, a project dedicated to advancing open-source language models with a long-term perspective. To support the pre-training phase, we have developed a dataset that currently consists of 2 trillion tokens and is continuously expanding. We further conduct supervised fine-tuning (SFT) and Direct Preference Optimization (DPO) on DeepSeek LLM Base models, resulting in the creation of DeepSeek Chat models. Our evaluation results demonstrate that DeepSeek LLM 67B surpasses LLaMA-2 70B on various benchmarks, particularly in the domains of code, mathematics, and reasoning. Furthermore, open-ended evaluations reveal that DeepSeek LLM 67B Chat exhibits superior performance compared to GPT-3.5

Effect of Water-to-Cement Ratio on Cracking Resistance of Concrete at Early Age in Restrained Ring Specimens

Nowadays, low water-to-cement (w/c) ratio has been put into widespread use in engineering practice. However, low w/c ratio may give rise to high self-desiccation, which may lead to the decrease of early-age cracking resistance. Investigating the impact of w/c ratio on cracking resistance is utterly meaningful to understand the cracking mechanism of concrete better. However, the corresponding investigations remain lacking, especially when the ring test is utilized. Ring tests for three concrete mixtures with different w/c ratios were conducted to investigate the early-age cracking resistance of concrete from multiple parameters in the present study. Results showed that: (1) the development rate of shrinkage of concrete for Mixture W50 was slower than Mixture W33 and W40; (2) the value and development rate of residual stress of concrete decreased when the w/c ratio increased; (3) the relaxed stress for all mixtures developed rapidly at very early age, and reached the maximum quickly; (4) the cracking resistance of concrete increased as the w/c ratio increased at early age.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Progress on Sensory Quality and Chemical Composition of Kombucha

Kombucha is a functional beverage made from sugared tea fermented by yeasts, acetic acid bacteria and lactic acid bacteria. In recent years, with the improvement of people's health awareness, Kombucha with health benefits has received widespread attention from all over the world. In this review, the chemical composition of Kombucha, including organic acids, tea polyphenols and aromatic substances, and the sensory quality, including appearance, aroma and taste are summarized. The effects of different fermentation parameters on the chemical composition and sensory quality of Kombucha are discussed. Besides, the interactions between those two are drawn. The information gathered in this review could help us to better understand the sensory quality of Kombucha and the biochemical causes of its formation. Furthermore, it would provide a theoretical basis to the product stability, quality improvement and variety innovation of Kombucha

In situ interfacial architecture of lithium vanadate-based cathode for printable lithium batteries

Summary: Most Li3VO4 anodes are obtained by pre-architecture methods in which Li3VO4 anode materials are prepared with more than six key processes including high-temperature annealing and long preparation time. Herein, we propose an in situ post-architecture strategy including Li3VO4-precursor solution (ink) preparation and then annealing at 250°C. The integrated Li3VO4 based electrode not only possesses good electrical conductivity and porous microstructure but also has superior stability because of Cu anchoring and inclusion by in situ catalysis. The integrated electrode demonstrates a high reversible capacity (865 mA h g−1 at 0.2 A g−1) and good cyclability (100% capacity retention after 200 cycles at 1 A g−1). More importantly, the post-architecture electrode has a high energy density of 773.8 Wh kg−1, much higher than reported Li3VO4-based materials, as well as most cathodes. Therefore, the electrode could be used to the printable cathode of low-voltage high-energy-density lithium batteries