Generation of sub-100†fs vortices from a Kerr-lens mode-locked Hermite-Gaussian Yb:CALGO oscillator.

Mode-locked oscillators with high-order transverse modes are excellent platforms for generating femtosecond optical vortices with high average power and good propagation stability. These have important applications in diverse fields such as optical communication, strong-field physics, and laser processing. So far, generating vortex pulses with ultrashort pulse duration remains a challenge. In this Letter, we report a Kerr-lens mode-locked Yb:CALGO laser oscillator delivering Hermite-Gaussian (HG) pulses with a pulse duration of 86 fs using a non-collinear pumping technique. 91 fs optical vortex pulses were generated by using a cylindrical-lens mode converter. To the best of our knowledge, this is the shortest pulse duration ever obtained from a diode pumped solid-state mode-locked oscillator with a pure high-order Hermite-Gaussian mode. The phase structures of the generated femtosecond vortices are characterized.

The role of NLRP3 inflammasome-mediated neuroinflammation in chronic noise-induced impairment of learning and memory ability.

BACKGROUND: Noise pollution pervades daily working and living environment, becoming a serious public health problem. In addition to causing auditory impairment, noise independently contributes to cognitive decline as a risk factor. Though neuroinflammation plays an important role in noise-induced cognitive deficits, the mechanisms underlying noise-induced neuroinflammation in the hippocampus are still poorly understood. Glial hyperactivation of the NLRP3 inflammasome contributes to various neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). However, whether the NLRP3 inflammasome plays a role in noise-induced cognitive impairment remains to be further investigated. METHODS: Adult male Wistar rats were exposed to 100 dB white noise (4 h/day) for 30 days with or without injection of the NLRP3 inhibitor MCC950 (10 mg/kg/day). The Morris water maze (MWM) test and the open field test (OFT) were performed to evaluate learning and memory ability of rats. HE staining was used to explore hippocampal pathological changes, while immunohistochemical staining was employed to evaluate the number and morphology of microglia and astrocytes. The mRNA levels of the NLRP3 inflammasome in the hippocampus were examined by Real-time PCR. The protein levels of NLRP3 inflammasome, inflammatory cytokines, p-Tau-S396, and amyloid-ß (Aß) 42 in the hippocampus were examined by Western blot. Immunofluorescence was used to observe the distribution of NLRP3 in glial cells and neurons, and the assembly of the NLRP3 inflammasome. RESULTS: We found that noise exposure induced learning and memory impairment in rats, mainly related to the activation of microglia and astrocytes in hippocampus region. Noise exposure increased the protein levels of p-Tau-S396, Aß42, ionized calcium binding adapter molecule 1 (Iba-1), glial fibrillary acidic protein (GFAP), interleukin (IL)-1ß, IL-18, and tumor necrosis factor-α (TNF-α) in hippocampus. Furthermore, the hippocampus of noise-exposed rats showed elevated protein levels of NLRP3, ASC and cleaved caspase-1. The co-labeled immunofluorescence levels of Iba-1 or GFAP with NLRP3 significantly increased in the dentate gyrus (DG) region of the hippocampus. NLRP3 inhibitor MCC950 intervention reversed chronic noise-induced activation of NLRP3 inflammasome, AD-like pathologies and impairment of learning and memory in rats. CONCLUSIONS: The NLRP3 inflammasome-mediated neuroinflammation played an essential role in chronic noise-induced cognitive dysfunction. These results provide novel strategies for the prevention and treatment of cognitive deficits caused by chronic noise.

Systemic identification of functionally conserved lncRNA metabolic regulators in human and mouse livers.

BACKGROUND & AIMS: Unlike protein-coding genes, the majority of human long non-coding RNAs (lncRNAs) lack conservation based on their sequences, posing a challenge for investigating their role in a pathophysiological context for clinical translation. This study explores the hypothesis that non-conserved lncRNAs in human and mouse livers may share similar metabolic functions, giving rise to functionally conserved lncRNA metabolic regulators (fcLMRs). METHODS: We developed a sequence-independent strategy to select putative fcLMRs, and performed extensive analysis to determine the functional similarities of putative human and mouse LMR pairs (h/mLMRs). RESULTS: We found that several pairs of putative fcLMRs share similar functions in regulating gene expression. We further demonstrated that a pair of fcLMRs, h/mLMR1, robustly regulated triglyceride levels by modulating the expression of a similar set of lipogenic genes. Mechanistically, h/mLMR1 binds to PABPC1, a regulator of protein translation, via short motifs on either lncRNA with divergent sequences but similar structures. This interaction inhibits protein translation, activating an amino acid-mTOR-SREBP1 axis to regulate lipogenic gene expression. Intriguingly, PABPC1-binding motifs on each lncRNA fully rescued the functions of their corresponding LMRs in the opposite species. Given the elevated expression of h/mLMR1 in humans and mice with hepatic steatosis, the PABPC1-binding motif on hLMR1 emerges as a potential non-conserved human drug target whose functions can be fully validated in a physiologically relevant setting before clinical studies. CONCLUSIONS: Our study supports that fcLMRs represent a novel and prevalent biological phenomenon, and deep phenotyping of genetic mLMR mouse models constitutes a powerful approach to understand the pathophysiological role of lncRNAs in the human liver.

Early pirfenidone treatment enhances lung function in idiopathic pulmonary fibrosis patients.

This editorial comments on the study by Lei et al investigating the efficacy of early treatment with pirfenidone on the lung function of patients with idiopathic pulmonary fibrosis (IPF) published. This study evaluates the efficacy of early treatment with pirfenidone on lung function in patients with IPF. The early and advanced stages of IPF are defined, highlighting the drug's benefits. While prior research indicates pirfenidone's effectiveness in advanced IPF, this study focuses on its advantages in early stages. The study emphasizes the importance of computed tomography imaging alongside biochemical data and lung function tests for a comprehensive analysis of symptom relief. Results show that early intervention with pirfenidone significantly reduces disease progression and preserves lung function, underscoring its potential as a critical treatment strategy in early IPF.

Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader.

Selective degradation of cyclin-dependent kinases 12 and 13 (CDK12/13) emerges as a new potential therapeutic approach for triple-negative breast cancer (TNBC) and other human cancers. While several proteolysis-targeting chimera (PROTAC) degraders of CDK12/13 were reported, none are orally bioavailable. Here, we report the discovery of ZLC491 as a potent, selective, and orally bioavailable CDK12/13 PROTAC degrader. The compound effectively degraded CDK12 and CDK13 with DC50 values of 32 and 28 nM, respectively, in TNBC MDA-MB-231 cells. Global proteomic assessment and mechanistic studies revealed that ZLC491 selectively induced CDK12/13 degradation in a cereblon- and proteasome-dependent manner. Furthermore, the molecule efficiently suppressed transcription and expression of long genes, predominantly a subset of genes associated with DNA damage response, and significantly inhibited proliferation of multiple TNBC cell lines. Importantly, ZLC491 achieved an oral bioavailability of 46.8% in rats and demonstrated potent in vivo degradative effects on CDK12/13 in an MDA-MB-231 xenografted mouse model.

Changes in insulin utilization in China from 2020 to 2022.

AIM: To assess the variation in patterns of use of insulin and other antidiabetic medicines across China, both geographically and over time. MATERIALS AND METHODS: Nationally, we calculated the relative change in antidiabetic medicine purchases between the first and last quarters of 2020 through 2022 based on the number of defined daily doses procured per quarter. We used annual data to analyse differences in antidiabetic medicine use and patterns across seven regions of China. Considering large regional variations, we used multifactor linear regression to preliminarily explore the possible factors influencing this variation. RESULTS: Nationally, the procurement of antidiabetic medicines and insulin increased from 2020 to 2022, while the proportion of insulin among antidiabetic medicines remained stable at approximately 22%. Among all insulins, premixed insulin (human) was ranked first. Of the three subgroups of insulin, analogues were the most preferred and had the largest procurement, but different categories showed different trends in terms of purchases and proporation. Regionally, the growth rate of antidiabetic medicines, the proportion of insulin procurement and the preferred types of insulin across the seven regions were different. Regarding preliminary influencing factors, the level of education and owning a domestically funded producer had a positive effect on insulin procurement. CONCLUSIONS: From 2020 to 2022, the procurement of insulin increased, which may be due to the increased attention for diabetes from the country and residents.However, the proportion of insulin among all antidiabetic medicines was essentially unchanged, while the use of some non-insulin hypoglycemic drugs increased significantly, especially the SGLT2i and GLP-1 RA. Given the economic and cultural diversity, Insulin procurement and utilization patterns varied greatly across the regions. Owning domestic enterprises potentially influences the procurement of insulin. Enhancing education to further improve the self-management of patients with diabetes is essential.

Development and Comparison of Time Series Models in Predicting Severe Fever with Thrombocytopenia Syndrome Cases - Hubei Province, China, 2013-2020.

Introduction: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the SFTS virus, which has a high mortality rate. Predicting the number of SFTS cases is essential for early outbreak warning and can offer valuable insights for establishing prevention and control measures. Methods: In this study, data on monthly SFTS cases in Hubei Province, China, from 2013 to 2020 were collected. Various time series models based on seasonal auto-regressive integrated moving average (SARIMA), Prophet, eXtreme Gradient Boosting (XGBoost), and long short-term memory (LSTM) were developed using these historical data to predict SFTS cases. The established models were evaluated and compared using mean absolute error (MAE) and root mean squared error (RMSE). Results: Four models were developed and performed well in predicting the trend of SFTS cases. The XGBoost model outperformed the others, yielding the closest fit to the actual case numbers and exhibiting the smallest MAE (2.54) and RMSE (2.89) in capturing the seasonal trend and predicting the monthly number of SFTS cases in Hubei Province. Conclusion: The developed XGBoost model represents a promising and valuable tool for SFTS prediction and early warning in Hubei Province, China.

Chronic noise exposure induces Alzheimer's disease-like neuropathology and cognitive impairment via ferroptosis in rat hippocampus.

BACKGROUND: Chronic noise exposure poses a remarkable public health concern, drawing attention to its impacts on the brain. Ferroptosis is involved in several brain-related diseases. However, the role of ferroptosis in the effects of chronic noise on the brain remains elusive. This study aimed to investigate the effects of chronic noise exposure on the brain and elucidate the underlying mechanisms. METHODS: A chronic noise-induced cognitive impairment model in rats was constructed and validated. The pathological state and ferroptosis level of the rat hippocampus were determined using Western blotting and immunohistochemistry. Bioinformatics was employed to investigate the interrelationship between chronic noise exposure and genes. Genetic relationships were analyzed using Mendelian randomization (MR) analysis. Cytoscape was employed for the prediction of upstream molecular and drug targets. RESULTS: In vivo experiments revealed that chronic noise exposure could induce Alzheimer's disease (AD)-like neuropathological changes in rat hippocampus and cognitive impairment. Moreover, protein markers indicative of ferroptosis and levels of lipid peroxidation were quantified to elucidate underlying mechanisms. Thereafter, oxidative stress- and ferroptosis-related differentially expressed genes (DEGs) underwent functional enrichment and PPI network analyses. Additionally, 8 genes with diagnostic significance were identified. In MR analysis, retinoic acid receptor responder 2 (Rarres2) gene exhibited a negative genetic relationship with AD. CONCLUSIONS: Chronic noise exposure could induce AD-like neuropathological changes and cognitive impairment via ferroptosis. The results of MR analysis indicated that Rarres2 gene may act as a protective factor in AD. This gene may be upstream of ferroptosis and serve as a target for the prevention and treatment of chronic noise-induced cognitive impairment.

Unlocking the potential: advancements and future horizons in ROR1-targeted cancer therapies.

While receptor tyrosine kinase-like orphan receptor 1 (ROR1) is typically expressed at low levels or absent in normal tissues, its expression is notably elevated in various malignant tumors and conditions, including chronic lymphocytic leukemia (CLL), breast cancer, ovarian cancer, melanoma, and lung adenocarcinoma. This distinctive feature positions ROR1 as an attractive target for tumor-specific treatments. Currently, several targeted drugs directed at ROR1 are undergoing clinical development, including monoclonal antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor T-cell therapy (CAR-T). Additionally, there are four small molecule inhibitors designed to bind to ROR1, presenting promising avenues for the development of PROTAC degraders targeting ROR1. This review offers updated insights into ROR1's structural and functional characteristics, embryonic development implications, cell survival signaling pathways, and evolutionary targeting strategies, all of which have the potential to advance the treatment of malignant tumors.

Gcn2 structurally mimics and functionally repurposes the HisRS enzyme for the integrated stress response.

Protein kinase Gcn2 attenuates protein synthesis in response to amino acid starvation while stimulating translation of a transcriptional activator of amino acid biosynthesis. Gcn2 activation requires a domain related to histidyl-tRNA synthetase (HisRS), the enzyme that aminoacylates tRNAHis. While evidence suggests that deacylated tRNA binds the HisRS domain for kinase activation, ribosomal P-stalk proteins have been implicated as alternative activating ligands on stalled ribosomes. We report crystal structures of the HisRS domain of Chaetomium thermophilum Gcn2 that reveal structural mimicry of both catalytic (CD) and anticodon-binding (ABD) domains, which in authentic HisRS bind the acceptor stem and anticodon loop of tRNAHis. Elements for forming histidyl adenylate and aminoacylation are lacking, suggesting that Gcn2HisRS was repurposed for kinase activation, consistent with mutations in the CD that dysregulate yeast Gcn2 function. Substituting conserved ABD residues well positioned to contact the anticodon loop or that form a conserved ABD-CD interface impairs Gcn2 function in starved cells. Mimicry in Gcn2HisRS of two highly conserved structural domains for binding both ends of tRNA-each crucial for Gcn2 function-supports that deacylated tRNAs activate Gcn2 and exemplifies how a metabolic enzyme is repurposed to host new local structures and sequences that confer a novel regulatory function.

Carbon Quantum Dot-Functionalized Dermis-Derived Transparent Electronic Skin for Multimodal Human Motion Signal Monitoring and Construction of Self-Powered Triboelectric Nanogenerator.

Electronic skin (e-skin) is considered as a highly promising interface for human-computer interaction systems and wearable electronic devices. Through elaborate design and assembly of various materials, it possesses multiple characteristics similar to human skin, including remarkable flexibility, stretchability, sensitivity to temperature and humidity, biocompatibility, and efficient interfacial ion/electron transport capabilities. Here, we innovatively integrate multifunctional carbon quantum dots (CQDs), which exhibit conductivity, antibacterial properties, ultraviolet absorption, and fluorescence emission, with poly(acrylic acid) and glycerin (Gly) into a three-dimensional network structure of natural goatskin collagen fibers. Through a top-down design strategy enhanced by hydrogen bond reconstruction, we successfully fabricated a novel transparent e-skin (PAC-eSkin). This e-skin exhibited significant tensile properties (4.94 MPa of tensile strength and 263.42% of a maximum breaking elongation), while also possessing Young's modulus similar to human skin (2.32 MPa). It is noteworthy that the functionalized CQDs used was derived from discarded goat hair, and the addition of Gly gave PAC-eSkin excellent antifreezing and moisturizing properties. Due to the presence of ultrasmall CQDs, which creates efficient ion/electron transport channels within PAC-eSkin, it could rapidly sense human motion and physiological signals (with a gauge factor (GF) of 1.88). Furthermore, PAC-eSkin had the potential to replace traditional electrode patches for real-time monitoring of electrocardiogram, electromyogram, and electrooculogram signals, with a higher SNR (signal-to-noise ratio) of 25.1 dB. Additionally, the customizable size and shape of PAC-eSkin offer vast possibilities for the construction of single-electrode triboelectric nanogenerator systems. We have reason to believe that the design and development of this transparent e-skin based on CQDs-functionalized dermal collagen matrices can pave a new way for innovations in human-computer interaction interfaces and their sensing application in diverse scenarios.

Causal effects of noise and air pollution on multiple diseases highlight the dual role of inflammatory factors in ambient exposures.

BACKGROUND: Noise and air pollution are significant environmental threats with proven adverse health effects. However, the causality between these ambient exposures and disease is still largely unknown. This study aims to provide genetic evidence for this gap and investigates the dual role of inflammatory factors, emphasizing the need for integrated public health strategies. METHODS: We included noise and air pollution as exposures, 91 inflammatory factors as mediators, and 26 diseases as outcomes. We explored causal relationships using Mendelian randomization. To ensure the reliability, we screened single nucleotide polymorphisms (SNPs) closely associated with exposure as instrumental variables (IVs), and assessed the pleiotropy and heterogeneity of these IVs. RESULTS: Our results suggest that "Hearing difficulty/problems with background noise" increases the risk of hypertension, bronchitis, and menopause; loud music exposure frequency increases the risk of bronchitis; noisy workplace raises the risk of hypertension, coronary heart disease, narcolepsy, and irritable bowel syndrome; NO2 increases the risk of myocardial infarction and chronic heart failure; NOx increases the risk of pneumonia and inflammatory diseases of female pelvic organs; and PM10 increases the risk of myocardial infarction, narcolepsy, and type 2 diabetes; PM2.5-10 increases the risk of developing pneumonia and type 2 diabetes. Furthermore, we found that nine inflammatory factors play a mediating role, of which four play a mediating role in increasing the risk of morbidity and eight play a mediating role in protection against ambient exposures. Finally, we selected SNPs significantly associated with exposure and outcome for enrichment analysis. CONCLUSIONS: This study provides the first genetic evidence linking noise and air pollution to various diseases, highlighting the dual mediating role of inflammatory factors. Our findings align with the "One Health" framework, emphasizing the interconnectedness of environmental and human health. Integrated public health strategies considering these complex biological responses are essential for promoting overall well-being.

Advanced 3D-Printed Potassium Ammonium Vanadate/rGO Aerogel Cathodes for Durable and High-Capacity Potassium-Ion Batteries.

A 3D-printed oxygen-vacancy-rich potassium ammonium vanadate/reduced graphene oxide (KNVOv/rGO) microlattice aerogel is designed for the cathode in high-performance K-ion batteries (KIBs). The 3D-printed KNVOv/rGO electrode with periodic submillimeter microchannels and interconnected printed filaments is composed of highly dispersed KNVOv nanobelts, wrinkled graphene nanoflakes, and abundant micropores. The well-defined 3D porous microlattice structure of the rGO backbone not only provides the interconnected conductive 3D network and the required mechanical robustness but also facilitates the penetration of the liquid electrolyte into inner active sites, consequently ensuring a stable electrochemical environment for K-ion intercalation/deintercalation within the KNVOv nanobelts. The 3D-printed KNVOv/rGO microlattice aerogel electrode has a high discharge capacity of 109.3 mAh g-1 with a capacity retention rate of 92.6% after 200 cycles at 50 mA g-1 and maintains a discharge capacity of 75.8 mAh g-1 after 2000 cycles at 500 mA g-1. The flexible pouch-type KIB battery consisting of the 3D-printed KNVOv/rGO has good mechanical durability and retains a high specific capacity under different forms of deformation such as bending and folding. The results provide valuable insights into the integration of advanced 3D-printed electrode materials into K-ion batteries and the design of flexible and wearable energy storage devices.

Single-shot probing of sub-picosecond solid-to-overdense-plasma dynamics.

A single-shot near-infrared probing method has been developed to characterize the formation and evolution of the pre-plasma dynamics over sub-picosecond timescales, which is essential for the societal applications of laser-accelerated ion technologies.

Is chronic kidney disease associated with osteoarthritis? The United States national health and nutrition examination survey 2011-2020.

OBJECTIVE: Chronic kidney disease (CKD) and osteoarthritis (OA) represent two frequently seen disorders among the general population, and they share several similar risk factors. The present work focused on assessing the relation of CKD with OA. METHODS: This cohort study included 26,280 eligible participants aged ≥ 20 years who had valid data on CKD and OA from the National Health and Nutrition Examination Survey (NHANES) 2011-2020. The association between CKD and OA was studied by logistic regression, adjusting for demographics, body mass index (BMI), socioeconomic factors, physical activity, ever smoking, alcohol using, diabetes status and hypertension status. RESULTS: Among the participants of this study, 26.69% of OA patients had concurrent CKD, whereas this proportion was only 13.83% among non-OA patients.CKD was related to OA[OR:2.269 (95%CI:2.266-2.271), p < 0.01] and the relation was of significance [OR:1.031 (95%CI:1.030-1.033),p < 0.01] following adjustments. In subgroup analyses based on age, the relation between osteoarthritis and chronic kidney disease remained significant, and in the subgroup analyses based on gender the previously mentioned relation between OA and CKD showed opposite directions in men [OR:0.869(95%CI0.867-0.871), p < 0.01] and women [OR:1.178(95%CI1.177-1.180), p < 0.01]. CONCLUSIONS: In the present 10-year large-scale national-wide survey, OA is closely related to CKD, and women with OA showed a higher risk of developing CKD compared to men. This study suggests that the relationship between OA and CKD deserves further investigation, and we suggest that patients with OA need to pay extra attention to their own kidney health.

Unveiling the Regulatory Role of LncRNA MYU in Hypoxia-Induced Angiogenesis via the miR-23a-3p Axis in Endothelial Cells.

Background: Angiogenesis is essential for various physiological and pathological processes, such as embryonic development and cancer cell proliferation, migration, and invasion. Long noncoding RNAs (lncRNAs) play pivotal roles in normal homeostasis and disease processes by regulating gene expression through various mechanisms, including competing endogenous RNAs (ceRNAs) of target microRNAs (miRNAs). The lncRNA MYU is known to promote prostate cancer proliferation via the miR-184/c-Myc regulatory axis and to be upregulated in vascular endothelial cells under hypoxic conditions, which often occurs in solid tumors. In the present study, we investigated whether MYU might affect cancer growth by regulating angiogenesis in vascular endothelial cells under hypoxia. Methods: The expression of MYU-regulated miR-23a-3p and interleukin-8 (IL-8) in HUVEC cell lines was examined using qRT-PCR. The CCK-8 assay, EdU assay, wound-healing assay, and tube-formation assay were used to assess the effects of MYU on cell proliferation, migration, and tube formation of HUVEC cells in vitro. The dual-luciferase reporter assay was performed to examine the effects of miR-23a-3p on MYU and IL-8 expression. Results: We found that the overexpression of MYU and knockdown of miR-23a-3p in human umbilical vein endothelial cells (HUVECs) under hypoxia promoted cell proliferation, migration, and tube formation. Mechanistically, MYU was shown to bind competitively to miR-23a-3p, thereby preventing miR-23a-3p binding to the 3' untranslated region of IL-8 mRNA. In turn, increased production of pro-angiogenic IL-8 promoted HUVEC proliferation, migration, and tube formation under hypoxia. Conclusion: This study identified a new role for lncRNA MYU as a ceRNA for miR-23a-3p and uncovered a novel MYU-miR-23a-3p-IL-8 regulatory axis for angiogenesis. MYU and/or miR-23a-3p may thus represent new targets for the treatment of hypoxia-related diseases by promoting angiogenesis.

Structural basis of NEAT1 lncRNA maturation and menRNA instability.

NEAT1 long noncoding RNA orchestrates paraspeckle assembly and impacts tumorigenesis, fertility and immunity. Its maturation requires RNase P cleavage yielding an unstable transfer RNA-like multiple endocrine neoplasia-ß tRNA-like transcript (menRNA) due to CCACCA addition. Here we report the crystal structure of human menRNA, which partially mimics tRNAs to drive RNase P and ELAC2 processing. Biophysical analyses uncover an RNA-centric, riboswitch-like mechanism whereby the nascent CCA reshapes the RNA folding landscape and propels a spontaneous conformational isomerization that directs repeat CCA addition, marking the menRNA and defective tRNAs for degradation.

STimage-1K4M: A histopathology image-gene expression dataset for spatial transcriptomics.

Recent advances in multi-modal algorithms have driven and been driven by the increasing availability of large image-text datasets, leading to significant strides in various fields, including computational pathology. However, in most existing medical image-text datasets, the text typically provides high-level summaries that may not sufficiently describe sub-tile regions within a large pathology image. For example, an image might cover an extensive tissue area containing cancerous and healthy regions, but the accompanying text might only specify that this image is a cancer slide, lacking the nuanced details needed for in-depth analysis. In this study, we introduce STimage-1K4M, a novel dataset designed to bridge this gap by providing genomic features for sub-tile images. STimage-1K4M contains 1,149 images derived from spatial transcriptomics data, which captures gene expression information at the level of individual spatial spots within a pathology image. Specifically, each image in the dataset is broken down into smaller sub-image tiles, with each tile paired with 15,000 - 30,000 dimensional gene expressions. With 4,293,195 pairs of sub-tile images and gene expressions, STimage-1K4M offers unprecedented granularity, paving the way for a wide range of advanced research in multi-modal data analysis an innovative applications in computational pathology, and beyond.

Structural basis of tRNA recognition by the widespread OB fold.

The widespread oligonucleotide/oligosaccharide-binding (OB)-fold recognizes diverse substrates from sugars to nucleic acids and proteins, and plays key roles in genome maintenance, transcription, translation, and tRNA metabolism. OB-containing bacterial Trbp and yeast Arc1p proteins are thought to recognize the tRNA elbow or anticodon regions. Here we report a 2.6 Å co-crystal structure of Aquifex aeolicus Trbp111 bound to tRNAIle, which reveals that Trbp recognizes tRNAs solely by capturing their 3' ends. Structural, mutational, and biophysical analyses show that the Trbp/EMAPII-like OB fold precisely recognizes the single-stranded structure, 3' terminal location, and specific sequence of the 3' CA dinucleotide - a universal feature of mature tRNAs. Arc1p supplements its OB - tRNA 3' end interaction with additional contacts that involve an adjacent basic region and the tRNA body. This study uncovers a previously unrecognized mode of tRNA recognition by an ancient protein fold, and provides insights into protein-mediated tRNA aminoacylation, folding, localization, trafficking, and piracy.