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Cryo-electron microscopy (cryo-EM) of non-crystalline single particles is a biophysical technique that can be used to determine the structure of biological macromolecules and assemblies. Historically, its potential for application in drug discovery has been heavily limited by two issues: the minimum size of the structures it can be used to study and the resolution of the images. However, recent technological advances -- including the development of direct electron detectors and more effective computational image analysis techniques -- are revolutionizing the utility of cryo-EM, leading to a burst of high-resolution structures of large macromolecular assemblies. These advances have raised hopes that single-particle cryo-EM might soon become an important tool for drug discovery, particularly if they could enable structural determination for 'intractable' targets that are still not accessible to X-ray crystallographic analysis. This article describes the recent advances in the field and critically assesses their relevance for drug discovery as well as discussing at what stages of the drug discovery pipeline cryo-EM can be useful today and what to expect in the near future.

Background There is valid evidence that air pollution is associated with respiratory disease. However, few studies have quantified the short-term effects of six air pollutants on influenza-like illness (ILI). This study explores the potential relationship between air pollutants and ILI in Jinan, China. Methods Daily data on the concentration of particulate matters < 2.5 μm (PM 2.5), particulate matters < 10 μm (PM10), sulfur dioxide (SO 2 ), nitrogen dioxide (NO 2 ), carbon monoxide (CO), and ozone (O 3 ) and ILI counts from 2016 to 2017 were retrieved. The wavelet coherence analysis and generalized poisson additive regression model were employed to qualify the relationship between air pollutants and ILI risk. The effects of air pollutants on different age groups were investigated. Results A total of 81,459 ILI counts were collected, and the average concentrations of PM2.5, PM10, O 3 , CO, SO 2 and NO 2 were 67.8 μg/m 3 , 131.76 μg/ m 3 , 109.85 μg/ m 3 , 1133 μg/ m 3 , 33.06 μg/ m 3 and 44.38 μg/ m 3 , respectively. A 10 μg/ m 3 increase in concentration of PM2.5, PM10, CO at lag0 and SO 2 at lag01, was positively associated with a 1.0137 (95% confidence interval (CI) : 1.0083–1.0192), 1.0074 (95% CI : 1.0041–1.0107), 1.0288 (95% CI : 1.0127–1.0451), and 1.0008 (95% CI : 1.0003–1.0012) of the relative risk (RR) of ILI, respectively. While, O3 (lag5) was negatively associated with ILI (RR 0.9863; 95% CI : 0.9787–0.9939), and no significant association was observed with NO 2 , which can increase the incidence of ILI in the two-pollutant model. A short-term delayed impact of PM2.5, PM10, SO2 at lag02 and CO, O3 at lag05 was also observed. People aged 25–59, 5–14 and 0–4 were found to be significantly susceptible to PM2.5, PM10, CO; and all age groups were significantly susceptible to SO 2 ; People aged ≥60 year, 5–14 and 0–4 were found to be significantly negative associations with O 3 . Conclusion Air pollutants, especially PM2.5, PM10, CO and SO 2 , can increase the risk of ILI in Jinan. The government should create regulatory policies to reduce the level of air pollutants and remind people to practice preventative and control measures to decrease the incidence of ILI on pollution days.

The objective of this study was to develop multifunctional chitosan (CT) derivatives by conjugating oleic acid (OLA) and caffeic acid (CAF) to improve water solubility at neutral pH, enhance interfacial activity, and provide antioxidant protection in oil-in-water emulsions. Two CAF-incorporation strategies—1-(3-dimethylaminopropyl)-3-ethylcarbodiimide·HCl/N-hydroxysuccinimide (EDC/NHS)-mediated amide coupling and ascorbic acid/H2O2-initiated free radical grafting—were employed to functionalize the CT–OLA backbone. The CT–OLA–CAF conjugates generated via the free radical pathway exhibited markedly lower viscosity and interfacial tension than those produced through EDC/NHS coupling, thereby highlighting the respective advantages and limitations associated with these two synthesis approaches. Chemically, CAF incorporation substantially enhanced the antioxidant capacity of the conjugates—surpassing that of both CT and CT—OLA and conferred excellent protection to photo-oxidatively labile β-carotene in o/w emulsions.

Spliceosome rearrangements facilitated by RNA helicase PRP16 before catalytic step two of splicing are poorly understood. Here we report a 3D cryo-electron microscopy structure of the human spliceosomal C complex stalled directly after PRP16 action (C*). The architecture of the catalytic U2–U6 ribonucleoprotein (RNP) core of the human C* spliceosome is very similar to that of the yeast pre-Prp16 C complex. However, in C* the branched intron region is separated from the catalytic centre by approximately 20 Å, and its position close to the U6 small nuclear RNA ACAGA box is stabilized by interactions with the PRP8 RNase H-like and PRP17 WD40 domains. RNA helicase PRP22 is located about 100 Å from the catalytic centre, suggesting that it destabilizes the spliced mRNA after step two from a distance. Comparison of the structure of the yeast C and human C* complexes reveals numerous RNP rearrangements that are likely to be facilitated by PRP16, including a large-scale movement of the U2 small nuclear RNP. The cryo-EM structure of the splicing intermediate known as the C* complex from human. Structure of the spliceosomal C* complex Recent years have seen substantial progress in understanding the structure of various intermediates of the splicing process. Two groups, led by Reinhard Lührmann and Kiyoshi Nagai, now describe the cryo-electron microscopy structures (from human and yeast cells, respectively) of the splicing intermediate known as the C* complex. The notable feature observed in this complex, relative to the preceding catalytic intermediate (the C complex), is a remodelling that positions the branch-site adenosine and the branched intron out of the catalytic core, opening up space for the 3′ exon to dock in preparation for exon ligation.

The U4/U6.U5 triple small nuclear ribonucleoprotein (tri-snRNP) is a major spliceosome building block. We obtained a three-dimensional structure of the 1.8-megadalton human tri-snRNP at a resolution of 7 angstroms using single-particle cryo–electron microscopy (cryo-EM). We fit all known high-resolution structures of tri-snRNP components into the EM density map and validated them by protein cross-linking. Our model reveals how the spatial organization of Brr2 RNA helicase prevents premature U4/U6 RNA unwinding in isolated human tri-snRNPs and how the ubiquitin C-terminal hydrolase–like protein Sad1 likely tethers the helicase Brr2 to its preactivation position. Comparison of our model with cryo-EM three-dimensional structures of the Saccharomyces cerevisiae tri-snRNP and Schizosaccharomyces pombe spliceosome indicates that Brr2 undergoes a marked conformational change during spliceosome activation, and that the scaffolding protein Prp8 is also rearranged to accommodate the spliceosome's catalytic RNA network.

For the sake of energy preservation, bacteria, upon transition to stationary phase, tone down their protein synthesis. This process is favored by the reversible binding of small stress-induced proteins to the ribosome to prevent unnecessary translation. One example is the conserved bacterial ribosome silencing factor (RsfS) that binds to uL14 protein onto the large ribosomal subunit and prevents its association with the small subunit. Here we describe the binding mode of Staphylococcus aureus RsfS to the large ribosomal subunit and present a 3.2 Å resolution cryo-EM reconstruction of the 50S-RsfS complex together with the crystal structure of uL14-RsfS complex solved at 2.3 Å resolution. The understanding of the detailed landscape of RsfS-uL14 interactions within the ribosome shed light on the mechanism of ribosome shutdown in the human pathogen S. aureus and might deliver a novel target for pharmacological drug development and treatment of bacterial infections. Upon transition to stationary phase or upon stress, bacteria limit protein synthesis through small inhibitory proteins that bind the ribosome. Here the authors decipher the interaction mode of the bacterial ribosome silencing factor (RsfS) at atomic details to provide an in depth view of how it shutdowns ribosomes.

Background Seasonal influenza and other respiratory tract infections are serious public health problems that need to be further addressed and investigated. Internet search data are recognized as a valuable source for forecasting influenza or other respiratory tract infection epidemics. However, the selection of internet search data and the application of forecasting methods are important for improving forecasting accuracy. The aim of the present study was to forecast influenza epidemics based on the long short-term memory neural network (LSTM) method, Baidu search index data, and the influenza-like-illness (ILI) rate. Methods The official weekly ILI% data for northern and southern mainland China were obtained from the Chinese Influenza Center from 2018 to 2021. Based on the Baidu Index, search indices related to influenza infection over the corresponding time period were obtained. Pearson correlation analysis was performed to explore the association between influenza-related search queries and the ILI% of southern and northern mainland China. The LSTM model was used to forecast the influenza epidemic within the same week and at lags of 1–4 weeks. The model performance was assessed by evaluation metrics, including the mean square error (MSE), root mean square error (RMSE) and mean absolute error (MAE). Results In total, 24 search queries in northern mainland China and 7 search queries in southern mainland China were found to be correlated and were used to construct the LSTM model, which included the same week and a lag of 1–4 weeks. The LSTM model showed that ILI% + mask with one lag week and ILI% + influenza name were good prediction modules, with reduced RMSE predictions of 16.75% and 4.20%, respectively, compared with the estimated ILI% for northern and southern mainland China. Conclusions The results illuminate the feasibility of using an internet search index as a complementary data source for influenza forecasting and the efficiency of using the LSTM model to forecast influenza epidemics.

This research aimed to modify polysaccharides extracted from the edible mushroom Tremella fuciformis with gallic acid (GA) and to complex them with zinc ions. The functionalities of the modified Tremella fuciformis polysaccharides (TFPs) were investigated. Regarding antioxidant activity, TFP-GA demonstrated effective scavenging activity against DPPH radicals, nitric oxide, and hydrogen peroxide. Additionally, TFP-GA exhibited superior reducing ability toward Fe3+ and enhanced chelating activity toward Fe2+ compared to unmodified TFP. Notably, the TFP-GA conjugate outperformed GA in Fe2+-chelating activity. In terms of antimicrobial activity, the TFP-GA-Zn complex showed significantly improved antimicrobial effectiveness against S. aureus and E. coli compared to TFP-GA.

Epicoccum latusicollum is a fungus that causes a severe foliar disease on flue-cured tobacco in southwest China, resulting in significant losses in tobacco yield and quality. To better understand the organism, researchers investigated its optimal growth conditions and metabolic versatility using a combination of traditional methods and the Biolog Phenotype MicroArray technique. The study found that E. latusicollum exhibited impressive metabolic versatility, being able to metabolize a majority of carbon, nitrogen, sulfur, and phosphorus sources tested, as well as adapt to different environmental conditions, including broad pH ranges and various osmolytes. The optimal medium for mycelial growth was alkyl ester agar medium, while oatmeal agar medium was optimal for sporulation, and the optimum temperature for mycelial growth was 25°C. The lethal temperature was 40°C. The study also identified arbutin and amygdalin as optimal carbon sources and Ala-Asp and Ala-Glu as optimal nitrogen sources for E. latusicollum . Furthermore, the genome of E. latusicollum strain T41 was sequenced using Illumina HiSeq and Pacific Biosciences technologies, with 10,821 genes predicted using Nonredundant, Gene Ontology, Clusters of Orthologous Groups, Kyoto Encyclopedia of Genes and Genomes, and SWISS-PROT databases. Analysis of the metabolic functions of phyllosphere microorganisms on diseased tobacco leaves affected by E. latusicollum using the Biolog Eco microplate revealed an inability to efficiently metabolize a total of 29 carbon sources, with only tween 40 showing some metabolizing ability. The study provides new insights into the structure and function of phyllosphere microbiota and highlights important challenges for future research, as well as a theoretical basis for the integrated control and breeding for disease resistance of tobacco Epicoccus leaf spot. This information can be useful in developing new strategies for disease control and management, as well as enhancing crop productivity and quality.

Triple-negative breast cancer (TNBC) is traditionally considered a glycolytic tumor with a poor prognosis while lacking targeted therapies. Here we show that high expression of dihydrolipoamide S-succinyltransferase (DLST), a tricarboxylic acid (TCA) cycle enzyme, predicts poor overall and recurrence-free survival among TNBC patients. DLST depletion suppresses growth and induces death in subsets of human TNBC cell lines, which are capable of utilizing glutamine anaplerosis. Metabolomics profiling reveals significant changes in the TCA cycle and reactive oxygen species (ROS) related pathways for sensitive but not resistant TNBC cells. Consequently, DLST depletion in sensitive TNBC cells increases ROS levels while N-acetyl-L-cysteine partially rescues cell growth. Importantly, suppression of the TCA cycle through DLST depletion or CPI-613, a drug currently in clinical trials for treating other cancers, decreases the burden and invasion of these TNBC. Together, our data demonstrate differential TCA-cycle usage in TNBC and provide therapeutic implications for the DLST-dependent subsets.Shen and Korm et al. investigate the role of dihydrolipoamide S-succinyltransferase (DLST), a tricarboxylic acid (TCA) cycle enzyme, in the metabolic heterogeneity of triple negative breast cancer (TNBC) cell lines. They show that either depletion or inhibition of DLST in the dependent cells leads to decreased invasion and metastasis in vitro and in vivo.