Exploring the gut microbiota mediated biotransformation of Senecio scandens Buch.-Ham.: Insights from metabolite spectrum with UHPLC-Q-Orbitrap HRMS and bioinformatics analysis of gut microbiota metabolites.

Senecio scandens Buch.-Ham., a traditional Chinese medicine commonly used clinically, exhibits various pharmacological properties, including anti-inflammatory, anti-tumor, antiviral, and antibacterial activities. However, its water extracts' chemical components and metabolites are inadequately understood, limiting further research. In this study, the chemical components and metabolism processes of Senecio scandens, both in vivo (plasma, feces, urine, and bile) and in vitro (gut microbiota and liver microsomes), were characterized based on ultra-high performance liquid chromatography coupled with hybrid quadrupole-orbitrap high-resolution mass spectrometry. Additionally, metabolites detectable in fecal samples and intestinal microbiota incubated but absent in liver microsomes were identified as characteristic metabolites of intestinal microbiota. The targets of the characteristic metabolites of intestinal microbiota were collected, followed by exploration of potential pathways through KEGG enrichment analysis. As a result, a total of 133 chemical components were preliminarily identified, including 35 organic acids, 21 alkaloids, 19 flavonoids and their glycosides, 17 phenylpropanoids, 10 jacaranda ketones, and 31 other compounds. Notably, 12 of these were potentially novel compounds. In addition, 39 prototype components in rats and 109 metabolites were identified and characterized, including 102 in vivo and 52 metabolites in vitro (51 in rat gut microbiota and 24 in rat liver microsomes). The main metabolic pathways include oxidation, reduction, hydrolysis, methylation, glucuronidation, sulfonation, and acetylation reactions. Furthermore, KEGG enrichment analysis revealed that the characteristic metabolites of intestinal microbiota may be related to the ErbB, FoxO, mTOR, and MAPK signaling pathways, exhibiting anti-inflammatory and anti-tumor effects. In summary, the chemical components and metabolites of Senecio scandens were comprehensively identified using a rapid and accurate method, providing a scientific basis for the in-depth study of the material basis and its clinical application of Senecio scandens.

Phase separation of SPIN1 through its IDR facilitates histone methylation readout and tumorigenesis.

Spindlin1 (SPIN1) is a unique multivalent histone modification reader that plays a role in ribosomal RNA transcription, chromosome segregation, and tumorigenesis. However, the function of the extended N-terminal region of SPIN1 has remained unclear. Here, we discovered that SPIN1 can form phase-separated and liquid-like condensates both in vitro and in vivo through its N-terminal intrinsically disordered region (IDR). The phase separation of SPIN1 recruits the histone methyltransferase MLL1 to the same condensates and enriches the H3K4 methylation marks. This process also facilitates the binding of SPIN1 to H3K4me3 and activates tumorigenesis-related genes. Moreover, SPIN1-IDR enhances the genome-wide chromatin binding of SPIN1 and facilitates its localization to genes associated with the MAPK signaling pathway. These findings provide new insights into the biological function of the IDR in regulating SPIN1 activity and reveal a previously unrecognized role of SPIN1-IDR in histone methylation readout. Our study uncovers the crucial role of appropriate biophysical properties of SPIN1 in facilitating gene expression and links phase separation to tumorigenesis, which provides a new perspective for understanding the function of SPIN1.

Draft genome sequences of antibiotic-resistant Serratia and Enterobacter species isolated from imported fresh produce in Georgia, USA.

Imported foods play an essential role in food security and in fulfilling consumer demand. However, these foods can also carry antibiotic-resistant bacteria, which might be introduced into the country of importation. Here, we report the draft genomes of antibiotic-resistant bacteria that were isolated from imported fresh produce in Georgia, USA.

Risk of candidiasis associated with interleukin-17 inhibitors: Implications and management.

The application of interleukin-17 (IL-17) inhibitors, including secukinumab, ixekizumab, brodalumab, and bimekizumab, are associated with elevated risk of candidiasis. These medications interfere with the IL-17 pathway, which is essential for maintaining mucosal barriers and coordinating the immune response against Candida species. The observational data and clinical trials demonstrate the increased incidence of candidiasis in individuals treated with IL-17 inhibitors. Brodalumab and bimekizumab pose a greater risk than secukinumab in eliciting candidiasis, whereas the data regarding ixekizumab are equivocal. Higher doses and prolonged treatment duration of IL-17 inhibitors increase the risk of candidiasis by compromising the immune response against Candida species. Prior to prescribing IL-17 inhibitors, healthcare professionals should comprehensively evaluate patients' medical histories and assess their risk factors. Patients should be educated on the signs and symptoms of candidiasis to facilitate early detection and intervention. Future research should focus on identifying the risk factors associated with candidiasis in patients receiving IL-17 inhibitors. Prospective studies and long-term surveillance are required to explore the impact of specific inhibitors on the incidence and severity of candidiasis and to evaluate the effectiveness of combination therapies, such as concurrent use of IL-17 inhibitors and prophylactic antifungal agents.

Interleukin inhibitors and the associated risk of candidiasis.

Interleukins (ILs) are vital in regulating the immune system, enabling to combat fungal diseases like candidiasis effectively. Their inhibition may cause enhanced susceptibility to infection. IL inhibitors have been employed to control autoimmune diseases and inhibitors of IL-17 and IL-23, for example, have been associated with an elevated risk of Candida infection. Thus, applying IL inhibitors might impact an individual's susceptibility to Candida infections. Variations in the severity of Candida infections have been observed between individuals with different IL inhibitors, necessitating careful consideration of their specific risk profiles. IL-1 inhibitors (anakinra, canakinumab, and rilonacept), IL-2 inhibitors (daclizumab, and basiliximab), and IL-4 inhibitors (dupilumab) have rarely been associated with Candida infection. In contrast, tocilizumab, an inhibitor of IL-6, has demonstrated an elevated risk in the context of coronavirus disease 2019 (COVID-19) treatment, as evidenced by a 6.9% prevalence of candidemia among patients using the drug. Furthermore, the incidence of Candida infections appeared to be higher in patients exposed to IL-17 inhibitors than in those exposed to IL-23 inhibitors. Therefore, healthcare practitioners must maintain awareness of the risk of candidiasis associated with using of IL inhibitors before prescribing them. Future prospective studies need to exhaustively investigate candidiasis and its associated risk factors in patients receiving IL inhibitors. Implementing enduring surveillance methods is crucial to ensure IL inhibitors safe and efficient utilization of in clinical settings.

The Internal Anatomy and Water Current System of Cambrian Archaeocyaths of South China.

Archaeocyaths are a group of extinct filter feeders that flourished in the early Cambrian period and occupied an important position in the evolution of basal fauna and the early marine ecosystem. However, the detailed morphological and anatomical information of this group are still unclear due to insufficient fossil material and limited experimental analyses. Here, we report exquisitely preserved phosphatized archaeocyathan fossil cups, ca. 515 million years old, from the top of the Shuijingtuo Formation (Series 2, Stage 3) and the Xiannüdong Formation (Series 2, Stage 3) of the Yangtze Platform, South China. Detailed observation of their external morphology via scanning electron microscopy (SEM) and micro-computed tomography (Micro-CT) analysis revealed detailed information of their internal structure. They have a typical double-walled cup, with the perforated inner and outer walls concentrically distributed, but the structure between the two walls differs. The inverted cone-shaped cups have radially distributed septa between the walls. Perforated septa connect the two walls. The low and columnar cups have canals between the two walls, forming the network. These pores and cavities constitute an important component of the water current system (pumping and filtering water with a network of canals and chambers) and influence the process of filtration in the cup. In comparison to traditional thin-section analysis, the combination of SEM and Micro-CT analysis on phosphatized archaeocyaths presented in this study further explored the detailed internal structure and finely reconstructed the microscopic overall morphology and anatomy, which provide important information to help us understand the systematic taxonomy, anatomy, and morphology of archaeocyaths during the Cambrian period.

A high-affinity fluorescent probe for human uridine-disphosphate glucuronosyltransferase 1A9 function monitoring under environmental pollutant exposure.

Uridine-disphosphate glucuronosyltransferase 1A9 (UGT1A9), an important detoxification and inactivation enzyme for toxicants, regulates the exposure level of environmental pollutants in the human body and induces various toxicological consequences. However, an effective tool for high-throughput monitoring of UGT1A9 function under exposure to environmental pollutants is still lacking. In this study, 1,3-dichloro-7-hydroxy-9,9-dimethylacridin-2(9H)-one (DDAO) was found to exhibit excellent specificity and high affinity towards human UGT1A9. Remarkable changes in absorption and fluorescence signals after reacting with UGT1A9 were observed, due to the intramolecular charge transfer (ICT) mechanism. Importantly, DDAO was successfully applied to monitor the biological functions of UGT1A9 in response to environmental pollutant exposure not only in microsome samples, but also in living cells by using a high-throughput screening method. Meanwhile, the identified pollutants that disturb UGT1A9 functions were found to significantly influence the exposure level and retention time of bisphenol S/bisphenol A in living cells. Furthermore, the molecular mechanism underlying the inhibition of UGT1A9 by these pollutant-derived disruptors was elucidated by molecular docking and molecular dynamics simulations. Collectively, a fluorescent probe to characterize the responses of UGT1A9 towards environmental pollutants was developed, which was beneficial for elucidating the health hazards of environmental pollutants from a new perspective.

ARTC1-mediated VAPB ADP-ribosylation regulates calcium homeostasis.

Mono-ADP-ribosylation (MARylation) is a post-translational modification that regulates a variety of biological processes, including DNA damage repair, cell proliferation, metabolism, and stress and immune responses. In mammals, MARylation is mainly catalyzed by ADP-ribosyltransferases (ARTs), which consist of two groups: ART cholera toxin-like (ARTCs) and ART diphtheria toxin-like (ARTDs, also known as PARPs). The human ARTC (hARTC) family is composed of four members: two active mono-ADP-ARTs (hARTC1 and hARTC5) and two enzymatically inactive enzymes (hARTC3 and hARTC4). In this study, we systematically examined the homology, expression, and localization pattern of the hARTC family, with a particular focus on hARTC1. Our results showed that hARTC3 interacted with hARTC1 and promoted the enzymatic activity of hARTC1 by stabilizing hARTC1. We also identified vesicle-associated membrane protein-associated protein B (VAPB) as a new target of hARTC1 and pinpointed Arg50 of VAPB as the ADP-ribosylation site. Furthermore, we demonstrated that knockdown of hARTC1 impaired intracellular calcium homeostasis, highlighting the functional importance of hARTC1-mediated VAPB Arg50 ADP-ribosylation in regulating calcium homeostasis. In summary, our study identified a new target of hARTC1 in the endoplasmic reticulum and suggested that ARTC1 plays a role in regulating calcium signaling.

Newborn Girl Presenting With Erythema and Blisters.

A female child presents for 3-year follow-up with erythema, vesicles, and bullae present since birth and an increasing number of annular hyperkeratotic plaques and palmoplantar hyperkeratosis. What is your diagnosis?

Identification of Plasma Biomarkers in Drug-Naïve Schizophrenia Using Targeted Metabolomics.

OBJECTIVE: Schizophrenia (SCZ) is a severe psychiatric disorder with unknown etiology and lacking specific biomarkers. Herein, we aimed to explore plasma biomarkers relevant to SCZ using targeted metabolomics. METHODS: Sixty drug-naïve SCZ patients and 36 healthy controls were recruited. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale. We analyzed the levels of 271 metabolites in plasma samples from all subjects using targeted metabolomics, and identified metabolites that differed significantly between the two groups. Then we evaluated the diagnostic power of the metabolites based on receiver operating characteristic curves, and explored metabolites associated with the psychotic symptoms in SCZ patients. RESULTS: Twenty-six metabolites showed significant differences between SCZ patients and healthy controls. Among them, 12 metabolites were phosphatidylcholines and cortisol, ceramide (d18:1/22:0), acetylcarnitine, and γ-aminobutyric acid, which could significantly distinguish SCZ from healthy controls with the area under the curve (AUC) above 0.7. Further, a panel consisting of the above 4 metabolites had an excellent performance with an AUC of 0.867. In SCZ patients, phosphatidylcholines were positively related with positive symptoms, and cholic acid was positively associated with negative symptoms. CONCLUSION: Our study provides insights into the metabolite alterations associated with SCZ and potential biomarkers for its diagnosis and symptom severity assessment.

The relationship between inflammatory markers, clinical characteristics, and cognitive performance in drug-naïve patients with schizophrenia.

Increasing evidence implicates that inflammatory factors do play a crucial role in the pathophysiology of schizophrenia. However, the association between inflammatory markers and different symptom dimensions and cognitive function of schizophrenia remains unclear. A total of 140 drug-naïve patients with schizophrenia and 69 healthy controls matched for age and gender were enrolled. Peripheral blood plasma concentrations of S-100 calcium-binding protein B (S100B), neutrophil gelatinase-associated lipocalin (NGAL), and interferon-γ (IFN-γ) were detected by enzyme-linked immunosorbent assay (ELISA). Psychotic symptoms were measured using the Positive and Negative Syndrome Scale (PANSS), and cognitive function was assessed by the MATRICS Consensus Cognitive Battery (MCCB). Compared with healthy controls, patients with schizophrenia had significantly worse cognitive function and lower levels of NGAL and IFN-γ (P < 0.001). In schizophrenia, plasma NGAL and IFN-γ levels negatively correlated with positive symptom scores (all P < 0.05). There was a positive correlation between plasma levels of NGAL and IFN-γ with visual learning, neurocognition, and MCCB total score (all P < 0.05). We found that NGAL levels (ß = 0.352, t = 5.553, 95% CI 0.228-0.477, P < 0.001) and negative symptoms subscale scores (ß = - 0.321, OR = 0.725, 95% CI 648-0.811, P < 0.001) were independently associated with the MCCB total score. Further, binary logistic regression analysis indicated that the concentrations of NGAL (ß = - 0.246, OR = 0.782, 95% CI 0.651-0.939, P = 0.008) were independently associated with the diagnosis of schizophrenia. There was a positive correlation between NGAL and IFN-γ levels and MCCB total score in schizophrenia. NGAL level was an independent protective factor for cognitive function and an independent risk factor for the diagnosis of schizophrenia.

Integrated Bioinformatic Analyses Reveal Immune Molecular Markers and Regulatory Networks for Cerebral Ischemia-Reperfusion.

BACKGROUND: Cerebral ischemia-reperfusion injury (CIR) following a stroke results in secondary damage and is a leading cause of adult disability. The present study aimed to identify hub genes and networks in CIR to explore potential therapeutic agents for its treatment. METHODS: Differentially expressed genes based on the GSE23163 dataset were identified, and weighted gene co-expression network analysis was performed to explore co-expression modules associated with CIR. Hub genes were identified by intersecting immune gene profiles, differentially expressed genes, and modular genes. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway, and transcription factor-microRNA-gene regulatory network analyses were then conducted in selected crucial modules. Subsequently, their expression levels in animal models were verified using real-time quantitative polymerase chain reaction and Western blotting. Finally, potential drug molecules were screened for, and molecular docking simulations were performed to identify potential therapeutic targets. RESULTS: Seven hub genes-namely, Ccl3, Ccl4, Ccl7, Cxcl1, Hspa1a, Cd14, and Socs3-were identified. Furthermore, we established a protein interaction network using the STRING database and found that the core genes selected through the cytohubba plugin remained consistent. Animal experiments showed that at the transcriptional level, all seven genes showed significant differences (p < 0.001, fold change vs sham, 5-200). At the translational level, however, only Ccl3, Ccl4, Ccl7, Hspa1a, and Socs3 showed significant differences, while Cxcl1 and Cd14 did not. Nifedipine, with the highest predicted score, was identified as a therapeutic agent and successfully docked with the protein encoded by the hub genes. CONCLUSIONS: The expression of Ccl3, Ccl4, Ccl7, Hspa1a, and Socs3 was significantly different in CIR tissues compared to normal tissues both at the transcriptional and translational levels. Systems biology approaches indicated that these could be possible CIR marker genes, providing a stepping stone for further experimental studies.

First Report of Small Skeletal Fossils from the Upper Guojiaba Formation (Series 2, Cambrian), Southern Shaanxi, South China.

A small skeletal fossil assemblage is described for the first time from the bioclastic limestone interbeds of the siltstone-dominated Guojiaba Formation, southern Shaanxi, China. The carbonate-hosted fossils include brachiopods (Eohadrotreta zhujiahensis, Eohadrotreta zhenbaensis, Spinobolus sp., Kuangshanotreta malungensis, Kyrshabaktella sp., Lingulellotreta yuanshanensis, Eoobolus incipiens, and Eoobolus sp.), sphenothallids (Sphenothallus sp.), archaeocyaths (Robustocyathus sp. and Yukonocyathus sp.), bradoriids (Kunmingella douvillei), chancelloriids sclerites (Onychia sp., Allonnia sp., Diminia sp., Archiasterella pentactina, and Chancelloria cf. eros), echinoderm plates, fragments of trilobites (Eoredlichia sp.), and hyolithelminths. The discovery of archaeocyaths in the Guojiaba Formation significantly extends their stratigraphic range in South China from the early Tsanglangpuian at least to the late Chiungchussuan. Thus, the Guojiaba Formation now represents the lowest known stratigraphic horizon where archaeocyath fossils have been found in the southern Shaanxi area. The overall assemblage is most comparable, in terms of composition, to Small skeletal fossil (SSF) assemblages from the early Cambrian Chengjiang fauna recovered from the Yu'anshan Formation in eastern Yunnan Province. The existing position that the Guojiaba Formation is correlated with Stage 3 in Cambrian Series 2 is strongly upheld based on the fossil assemblage recovered in this study.

RNF167-mediated ubiquitination of Tollip inhibits TNF-α-triggered NF-κB and MAPK activation.

Toll-interacting protein (Tollip) is a multifunctional regulator in cellular activities. However, whether its functions are subjected to post-translational modifications remains elusive. Here, we identified ubiquitination as a post-translational modification on Tollip. We found that Tollip interacted with ring finger protein 167 (RNF167) through its C-terminal coupling of ubiquitin to ER degradation (CUE) domain, and RNF167 functioned as the potential E3 ligase to attach K33-linked poly-ubiquitin chains to the Lys235 (K235) site of Tollip. Furthermore, we discovered Tollip could inhibit TNF-α-induced nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) activation, and substitution of Lys235 on Tollip to arginine failed to suppress TNF-α-NF-κB/MAPK (JNK) cascades, revealing the role of Tollip and its ubiquitination in NF-κB/MAPK pathways. Thus, our study reveals the novel biological function of Tollip and RNF167-dependent ubiquitination of Tollip in TNF-α signaling.

Phosphoproteomic and proteomic profiling in post-infarction chronic heart failure.

Background: Post-infarction chronic heart failure is the most common type of heart failure. Patients with chronic heart failure show elevated morbidity and mortality with limited evidence-based therapies. Phosphoproteomic and proteomic analysis can provide insights regarding molecular mechanisms underlying post-infarction chronic heart failure and explore new therapeutic approaches. Methods and results: Global quantitative phosphoproteomic and proteomic analysis of left ventricular tissues from post-infarction chronic heart failure rats were performed. A total of 33 differentially expressed phosphorylated proteins (DPPs) and 129 differentially expressed proteins were identified. Bioinformatic analysis indicated that DPPs were enriched mostly in nucleocytoplasmic transport and mRNA surveillance pathway. Bclaf1 Ser658 was identified after construction of Protein-Protein Interaction Network and intersection with Thanatos Apoptosis Database. Predicted Upstream Kinases of DPPs based on kinase-substrate enrichment analysis (KSEA) app showed 13 kinases enhanced in heart failure. Proteomic analysis showed marked changes in protein expression related to cardiac contractility and metabolism. Conclusion: The present study marked phosphoproteomics and proteomics changes in post-infarction chronic heart failure. Bclaf1 Ser658 might play a critical role in apoptosis in heart failure. PRKAA1, PRKACA, and PAK1 might serve as potential therapeutic targets for post-infarction chronic heart failure.

Health care needs and health services utilization of people with spinal cord injury living in Jiangsu and Sichuan provinces of China: a cross-sectional community survey.

PURPOSE: We aimed to investigate health care needs, health service utilization, and their socio-economic and health-related determinants in people with spinal cord injury (SCI) living in Jiangsu and Sichuan Provinces of China. MATERIALS AND METHODS: A total of 1355 participants with SCI living in the community were recruited using a multi-stage stratified random sample and surveyed by telephone or online. Outcomes evaluated included the presence of health care needs, mode of health service utilization, and specific provider types seen within 12 months preceding the survey. RESULTS: The prevalence of healthcare needs was 92%. Needs were higher in Sichuan (98%) as compared to Jiangsu (80%). Of those in need of health care, 38% reported not having utilized care, more in Sichuan (39%) than in Jiangsu (37%). In Jiangsu, inpatient care was more often used than in Sichuan (46% vs. 27%), while in Sichuan outpatient services were utilized more often (33% vs. 17%). On average, 1.6 provider types were seen, with Sichuan reporting fewer different provider types. CONCLUSIONS: Considerable differences in the prevalence of health care needs and service utilization patterns were found between provinces, mostly in favour of the economically more developed Jiangsu Province.Implications for RehabilitationPeople with low income, particularly those below the World Bank poverty line for middle-income countries, had increased health care needs but utilized health care less often.Moreover, environmental barriers contributed significantly to unmet health care needs.This implies the necessity to provide better accessible and more affordable rehabilitation services for people with spinal cord injury (SCI) in China such as community-based rehabilitation programming.Policies for alleviation of poverty in the case of SCI including insurance for catastrophic health expenditure should also be reviewed and adapted where applicable.

Effectiveness on level of consciousness of non-invasive neuromodulation therapy in patients with disorders of consciousness: a systematic review and meta-analysis.

Background: Disorders of consciousness (DoC) commonly occurs secondary to severe neurological injury. A considerable volume of research has explored the effectiveness of different non-invasive neuromodulation therapy (NINT) on awaking therapy, however, equivocal findings were reported. Objective: The aim of this study was to systematically investigate the effectiveness on level of consciousness of different NINT in patients with DoC and explore optimal stimulation parameters and characteristics of patients. Methods: PubMed, Embase, Web of Science, Scopus, and Cochrane central register of controlled trials were searched from their inception through November 2022. Randomized controlled trials, that investigated effectiveness on level of consciousness of NINT, were included. Mean difference (MD) with 95% confidence interval (CI) was evaluated as effect size. Risk of bias was assessed with revised Cochrane risk-of-bias tool. Results: A total of 15 randomized controlled trials with 345 patients were included. Meta-analysis was performed on 13 out of 15 reviewed trials indicating that transcranial Direct Current Stimulation (tDCS), Transcranial Magnetic Stimulation (TMS), and median nerve stimulation (MNS) all had a small but significant effect (MD 0.71 [95% CI 0.28, 1.13]; MD 1.51 [95% CI 0.87, 2.15]; MD 3.20 [95%CI: 1.45, 4.96]) on level of consciousness. Subgroup analyses revealed that patients with traumatic brain injury, higher initial level of consciousness (minimally conscious state), and shorter duration of prolonged DoC (subacute phase of DoC) reserved better awaking ability after tDCS. TMS also showed encouraging awaking effect when stimulation was applied on dorsolateral prefrontal cortex in patients with prolonged DoC. Conclusion: tDCS and TMS appear to be effective interventions for improving level of consciousness of patients with prolonged DoC. Subgroup analyses identified the key parameters required to enhance the effects of tDCS and TMS on level of consciousness. Etiology of DoC, initial level of consciousness, and phase of DoC could act as significant characteristics of patients related to the effectiveness of tDCS. Stimulation site could act as significant stimulation parameter related to the effectiveness of TMS. There is insufficient evidence to support the use of MNS in clinical practice to improve level of consciousness in patients with coma. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=337780, identifier: CRD42022337780.

Uni-Dock: GPU-Accelerated Docking Enables Ultralarge Virtual Screening.

Molecular docking, a structure-based virtual screening method, is a reliable tool to enrich potential bioactive molecules from molecular databases. With the rapid expansion of compound library sizes, the speed of existing molecular docking programs becomes less than adequate to meet the demand for screening ultralarge libraries containing tens of millions or billions of molecules. Here, we propose Uni-Dock, a GPU-accelerated molecular docking program that supports various scoring functions including vina, vinardo, and ad4. Uni-Dock achieves more than 1000-fold speedup with high accuracy compared with the AutoDock Vina running in single CPU core, outperforming reported GPU-accelerated docking programs including AutoDock-GPU and Vina-GPU based on head-to-head experiments. Uni-Dock docks molecules in batches simultaneously using concurrent threads of each molecule. The data flow between GPU and CPU is optimized to eliminate CPU hotspots and maximize GPU utility. Additionally, Uni-Dock also supports hydrogen bond biased docking for all scoring functions and can be migrated to multiple GPUs of different architectures and manufacturers. We analyzed the improved performance of Uni-Dock on the CASF-2016 and DUD-E datasets and recommend three combinations of hyperparameters corresponding to different docking scenarios. To demonstrate Uni-Dock's capability on routinely screening ultralarge libraries, we performed hierarchical virtual screening experiments with Uni-Dock on the Enamine Diverse REAL druglike set containing 38.2 million molecules to a popular target KRAS G12D in 12 h using 100 NVIDIA V100 GPUs. To the best of our knowledge, Uni-Dock should be the fastest GPU-accelerated docking program to date.