GeneCompass: deciphering universal gene regulatory mechanisms with a knowledge-informed cross-species foundation model.

Deciphering universal gene regulatory mechanisms in diverse organisms holds great potential for advancing our knowledge of fundamental life processes and facilitating clinical applications. However, the traditional research paradigm primarily focuses on individual model organisms and does not integrate various cell types across species. Recent breakthroughs in single-cell sequencing and deep learning techniques present an unprecedented opportunity to address this challenge. In this study, we built an extensive dataset of over 120 million human and mouse single-cell transcriptomes. After data preprocessing, we obtained 101,768,420 single-cell transcriptomes and developed a knowledge-informed cross-species foundation model, named GeneCompass. During pre-training, GeneCompass effectively integrated four types of prior biological knowledge to enhance our understanding of gene regulatory mechanisms in a self-supervised manner. By fine-tuning for multiple downstream tasks, GeneCompass outperformed state-of-the-art models in diverse applications for a single species and unlocked new realms of cross-species biological investigations. We also employed GeneCompass to search for key factors associated with cell fate transition and showed that the predicted candidate genes could successfully induce the differentiation of human embryonic stem cells into the gonadal fate. Overall, GeneCompass demonstrates the advantages of using artificial intelligence technology to decipher universal gene regulatory mechanisms and shows tremendous potential for accelerating the discovery of critical cell fate regulators and candidate drug targets.

Global risk dynamics of Borrelia miyamotoi in the context of climate change.

The impact of Borrelia miyamotoi on human health, facilitated by the expanding geographical distribution and increasing population of Ixodes ticks, remains obscure in the context of global climate change. We employed multiple models to evaluate the effect of global climate change on the risk of B. miyamotoi worldwide across various scenarios. The habitat suitability index of four primary vector tick species for B. miyamotoi, including Ixodes persulcatus, Ixodes ricinus, Ixodes pacificus and Ixodes scapularis, was projected using a boosted regression tree model, considering multiple shared socio-economic pathway scenarios over various time periods. The modelling analysis reveals that, apart from I. scapularis, future global warming will result in a northward shift in the other three vector tick species and a gradual reduction in suitable habitats. Random forest models indicate consistent changes in B. miyamotoi and its primary tick species, with potential risk areas shrinking and shifting northward, particularly in the eastern USA, northeastern and northern Europe and northeast Asia. These findings highlight the urgent need for enhanced active surveillance of B. miyamotoi infection in primary vector tick species across projected potential risk areas. The effect of climate change on B. miyamotoi distribution might have significant implications for public health decision-making regarding tick-borne pathogens.

DFT study on the mechanism of methanol dehydrogenation over RuxPy surfaces.

Methanol dehydrogenation (MD) is highly valuable in hydrogen energy production, and the introduction of nonmetals has received much attention to improve the activity and stability of the MD catalysts, but the understanding of the role of non-metallic elements in catalyzing the MD reaction is rather limited. Density functional theory (DFT) is employed to investigate the mechanism of methanol dehydrogenation on RuxPy surfaces. In this work, the P element is introduced into the Ru-based catalyst to obtain dispersed Ru sites and RuxPy (x/y = 2 : 1, 1 : 1, and 1 : 2) catalysts are designed. CH3OH adsorption, electronic structure of the catalyst, energy barriers for carbon accumulation reactions, and the mechanism of methanol decomposition are systematically calculated. The results of the effective reaction barrier (Eeffa) reveal that the order of the activity of the MD reaction is RuP(112) > Ru(0001) > Ru2P(210) > RuP2(110). The most preferable pathway on RuP(112) is pathway 1 (CH3OH* → CH3O* → CH2O* → CHO* → CO*). After the introduction of P, the weakened CO adsorption enhanced the resistance of catalysts to CO poisoning, and the activation energy of the carbon accumulation reaction increased, indicating that the anti-coking ability of the catalysts is improved. This theoretical study contributes to the design and modulation of highly active and stable metal catalysts for MD reactions.

Trends and Outcomes in Elective Pediatric Surgery During Weekends.

PURPOSE: Limited operating room availability constrains hospital scheduling capacity for elective surgical cases. Leveraging weekends for elective surgical cases could increase operative capacity but must be balanced with practical considerations. Our study aimed to characterize trends and outcomes for elective pediatric surgeries performed during weekends. METHODS: This retrospective cohort study used the Pediatric Health Information System database from 2016 to 2019 to identify surgeries in children <18 years of age from 38 hospitals. Six elective surgeries, commonly performed on the weekend, were selected for analysis. Trends in elective surgeries during weekends (Saturday or Sunday) were evaluated using the Mann-Kendall trend test. Multivariable regression models were used to compare complications and costs between weekend and weekday surgeries. RESULTS: Of the 233,266 elective surgeries evaluated, 357 (0.15%) were performed during weekend hours. The proportion of surgeries performed on weekends was stable over time (p = 0.65). Following adjustment for clinicodemographic and hospital-level factors, no differences were observed when comparing weekend to weekday surgeries in terms of surgical complications [adjusted Odds Ratio: 1.59; 95% Confidence Interval (CI): 0.65-3.90; p = 0.32] or mortality (n = 1 in cohort). Weekend surgeries were associated a small additional cost compared to weekday surgeries (ß-coefficient $312; 95% CI: $152 to $473; p < 0.01). CONCLUSION: Elective pediatric surgeries performed during weekends were uncommon, stable in occurrence, and not associated with substantial increases in complications or costs compared to weekday surgeries. Increasing surgical capacity by extending into weekend scheduling merits further assessment of patient and provider satisfaction, unexpected human resource costs, and thoughtful case selection to ensure patient safety. LEVEL OF EVIDENCE: III. TYPE OF STUDY: Retrospective Cohort Study.

Potential tumor-specific antigens and immune landscapes identification for mRNA vaccine in thyroid cancer.

Background: Tumor mRNA vaccines have been identified as a promising technology for cancer therapy in multiple cancer types, while their efficacy in thyroid cancer (THCA) is unclear. Immunotyping is strongly associated with the immune microenvironment and immune status in cancer, thus it is important in vaccination and therapeutic response. This study is to identify potential valuable antigens and novel immune subtypes of THCA for immune landscape construction, thus screening patients suitable for mRNA vaccination. Methods: The clinical information and gene expression files of 568 THCA cases were obtained from the TCGA dataset. The DNA copy number variation and the somatic mutation of THCA were visualized by the cBioPortal database. TIMER was used to investigate the immune infiltrating correlation with candidate antigens. Consensus clustering analysis was conducted to cluster data using the ConsensusClusterPlus package. The immune landscapes of THCA patients were visualized using the Monocle package. The critical hub genes for THCA mRNA vaccines were identified by WGCNA package. To validate, the immunohistochemistry and real-time quantitative PCR (RT-qPCR) were performed to detect the expression level of potential antigen for mRNA vaccine in tissue and cell lines in THCA. Results: Thymidine kinase 1 (TK1) was identified as a potential biomarker of mRNA vaccine against THCA. It was confirmed to be significantly upregulated in THCA tissues and cells lines. Moreover, three novel immune subtypes of THCA were obtained based on the expression consistency of immune-associated genes. The S2 subtype was characterized as an immunological "cold" phenotype with a high expression of immunogenic cell death modulators. S1 and S3 subtypes were immunological "hot" phenotypes with immune checkpoints upregulation. Further, the immune landscape of THCA patients was visualized and ten hub genes for mRNA vaccines were identified. Conclusion: TK1 was a tumor-specific antigen of mRNA vaccines. The patients belonging to the S2 subtype ("cold" tumor) were suitable for mRNA vaccine therapy in THCA. Notably, ten hub genes were conducted as potential biomarkers for identifying suitable patients for mRNA vaccination. These findings provided novel insights into mRNA vaccine development against THCA.

Identification of the tumor metastasis-related tumor subgroups overexpressed NENF in triple-negative breast cancer by single-cell transcriptomics.

Tumor metastasis is a continuous and dynamic process and is a major cause of tumor-related death in triple-negative breast cancer. However, this biological process remains largely unknown in triple-negative breast cancer. The emergence of single-cell sequencing enables a deeper understanding of the tumor microenvironment and provides a new strategy for discovering the potential mechanism of tumor metastasis. Herein, we integrated the single-cell expression profiling of primary and metastatic triple-negative breast cancer by Seurat package. Nine tumor cell subgroups were identified. Enrichment analysis suggested tumor subgroups (C0, C4) were associated with tumor metastasis with poor prognosis in TNBC. Weighted gene co-expression network was constructed and identified NENF was a metastasis-related gene. Subsequently, RT-qPCR, Immunohistochemistry, and western blot confirmed NENF is highly expressed in TNBC tissues. And cell function assays indicated NENF promote cell invasion and migration through regulating EMT in TNBC. Finally, TIDE and Connectivity Map database suggest the candidate drugs for targeting NENF. In conclusion, our findings provide a new insight into the progression and metastasis of TNBC and uncover NENF may be a prognostic biomarker and potential therapy targets.

Neighborhood Racial and Ethnic Predominance, Child Opportunity, and Violence-Related Mortality among Children and Adolescents in Chicago.

Our objective was to determine whether Child Opportunity Index (COI), a measure of neighborhood socioeconomic and built environment specific to children, mediated the relationship of census tract Black or Hispanic predominance with increased rates of census tract violence-related mortality. The hypothesis was that COI would partially mediate the relationship. This cross-sectional study combined data from the American Community Survey 5-year estimates, the COI 2.0, and the Illinois Violent Death Reporting System 2015-2019 for the City of Chicago. Individuals ages 0-19 years were included. The primary exposure was census tract Black, Hispanic, White, and other race predominance (> 50% of population). The primary outcome was census tract violence-related mortality. A mediation analysis was performed to evaluate the role of COI as a potential mediator. Multivariable logistic regression modeling census tract violence-related mortality demonstrated a direct effect of census tract Black predominance (adjusted odds ratio [aOR] 2.59, 95% confidence interval [CI] 1.30-5.14) on violence-related mortality compared to White predominance. There was no association of census tract Hispanic predominance with violence-related mortality compared to White predominance (aOR 1.57, 95% CI 0.88-2.84). Approximately 64.9% (95% CI 60.2-80.0%) of the effect of census tract Black predominance and 67.9% (95% CI 61.2-200%) of the effect of census tract Hispanic predominance on violence-related mortality was indirect via COI. COI partially mediated the effect of census tract Black and Hispanic predominance on census tract violence-related mortality. Interventions that target neighborhood social and economic factors should be considered to reduce violence-related mortality among children and adolescents.

Epidemiological characteristics of ventilator-associated pneumonia in neurosurgery: A 10-year surveillance study in a Chinese tertiary hospital.

Background: Ventilator-associated pneumonia (VAP) is a significant and common health concern. The epidemiological landscape of VAP is poorly understood in neurosurgery patients. This study aimed to explore the epidemiology of VAP in this population and devise targeted surveillance, treatment, and control efforts. Methods: A 10-year retrospective study spanning 2011 to 2020 was performed in a large Chinese tertiary hospital. Surveillance data was collected from neurosurgical patients and analyzed to map the demographic and clinical characteristics of VAP and describe the distribution and antimicrobial resistance profile of leading pathogens. Risk factors associated with the presence of VAP were explored using boosted regression tree (BRT) models. Results: Three hundred ten VAP patients were identified. The 10-year incidence of VAP was 16.21 per 1000 ventilation days. All-cause mortality was 6.1%. The prevalence of gram-negative bacteria, fungi, and gram-positive bacteria among the 357 organisms isolated from VAP patients was 86.0%, 7.6%, and 6.4%, respectively; most were multidrug-resistant organisms. Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa were the most common pathogens. The prevalence of carbapenem-resistant A. baumannii, P. aeruginosa, and K. pneumoniae was high and increased over time in the study period. The BRT models revealed that VAP was associated with number of days of ventilator use (relative contribution, 47.84 ± 7.25), Glasgow Coma Scale score (relative contribution, 24.72 ± 5.67), and tracheotomy (relative contribution, 21.50 ± 2.69). Conclusions: Our findings provide a better understanding of the epidemiology of VAP and its risk factors in neurosurgery patients.

DDInter 2.0: an enhanced drug interaction resource with expanded data coverage, new interaction types, and improved user interface.

Drug interactions pose significant challenges in clinical practice, potentially leading to adverse drug reactions, reduced efficacy, and even life-threatening consequences. As polypharmacy becomes increasingly common, the risk of harmful drug interactions rises, underscoring the need for comprehensive and user-friendly drug interaction resources to ensure patient safety. To address these concerns and support healthcare professionals in optimizing drug therapy, we present DDInter 2.0, a significantly expanded and enhanced update to our drug interaction database. This new version incorporates additional interaction types, including drug-food interactions (DFIs), drug-disease interactions (DDSIs), and therapeutic duplications, providing a more complete resource for clinical decision-making. The updated database covers 2310 drugs, with 302 516 drug-drug interaction (DDI) records accompanied by 8398 distinct, high-quality mechanism descriptions and management recommendations. DDInter 2.0 also includes 857 DFIs, 8359 DDSIs and 6033 therapeutic duplication records, each supplemented with detailed information and guidance. Furthermore, the enhanced user interface and advanced filtering options in this second release facilitate easy access to and analysis of the comprehensive drug interaction data. By providing healthcare professionals and researchers with a more complete and user-friendly resource, DDInter 2.0 aims to support clinical decision-making and ultimately improve patient outcomes. DDInter 2.0 is freely accessible at https://ddinter2.scbdd.com.

FGL1: a novel biomarker and target for non-small cell lung cancer, promoting tumor progression and metastasis through KDM4A/STAT3 transcription mechanism.

Non-small cell lung cancer (NSCLC) is characterized by a high incidence rate and poor prognosis worldwide. A deeper insight into the pathogenesis of NSCLC and identification of novel therapeutic targets are essential to improve the prognosis of NSCLC. In this study, we revealed that fibrinogen-like protein 1 (FGL1) promotes proliferation, migration, and invasion of NSCLC cells. Mechanistically, we found that Stat3 acts as a transcription factor and can be recruited to the FGL1 promoter, enhancing FGL1 promoter activity. Lysine-specific demethylase 4A (KDM4A) interacts with Stat3 and facilitates the removal of methyl groups from H3K9me3, thereby enhancing Stat3-mediated transcription of FGL1. Furthermore, we observed that Stat3 and KDM4A promote NSCLC cell proliferation, migration, and invasion partly by upregulating FGL1 expression. Additionally, the expression of FGL1 was significantly higher in cancer tissues (n = 90) than in adjacent non-cancerous tissues (n = 90). Furthermore, patients with high FGL1 expression had a shorter overall survival (OS) compared to those with low FGL1 expression. We measured the expression levels of FGL1 on circulating tumor cells (CTCs) in 65 patients and found that patients with a dynamic decrease in FGL1 expression on CTCs exhibited a better therapeutic response. These findings suggest that the dynamic changes in FGL1 expression can serve as a potential biomarker for predicting treatment efficacy in NSCLC. Overall, this study revealed the significant role and regulatory mechanisms of FGL1 in the development of NSCLC, suggesting its potential as a therapeutic target for patients with NSCLC. Future studies should provide more personalized and effective treatment options for patients with NSCLC to improve clinical outcomes.

Dynamic regulation of alternative polyadenylation by PQBP1 during neurogenesis.

Alternative polyadenylation (APA) is a critical post-transcriptional process that generates mRNA isoforms with distinct 3' untranslated regions (3' UTRs), thereby regulating mRNA localization, stability, and translational efficiency. Cell-type-specific APA extensively shapes the diversity of the cellular transcriptome, particularly during cell fate transition. Despite its recognized significance, the precise regulatory mechanisms governing cell-type-specific APA remain unclear. In this study, we uncover PQBP1 as an emerging APA regulator that actively maintains cell-specific APA profiles in neural progenitor cells (NPCs) and delicately manages the equilibrium between NPC proliferation and differentiation. Multi-omics analysis shows that PQBP1 directly interacts with the upstream UGUA elements, impeding the recruitment of the CFIm complex and influencing polyadenylation site selection within genes associated with the cell cycle. Our findings elucidate the molecular mechanism by which PQBP1 orchestrates dynamic APA changes during neurogenesis, providing valuable insights into the precise regulation of cell-type-specific APA and the underlying pathogenic mechanisms in neurodevelopmental disorders.

Assessing national trends in indications for pediatric total thyroidectomy.

PURPOSE: The most common indications for total thyroidectomy (TT) in children are malignancy and thyrotoxicosis due to Graves' disease (GD). However, the incidence of patients with GD among patients undergoing TT is unknown. This study aims to examine trends in pediatric TT. MATERIALS AND METHODS: The US Agency for Health Research and Quality Healthcare Cost and Utilization Project (HCUP) Kids' Inpatient Database (KID) was queried to identify patients who underwent TT between 1997 and 2019. Weighted national estimates were obtained. Statistical analysis was completed using univariate logistic regression and one-sided Mann-Kendall Test. RESULTS: An estimated 4803 pediatric patients underwent TT within the study years. GD was the indication in 25 % of cases. Mann-Kendall testing showed a trend toward an increasing proportion of TT for GD without reaching statistical significance (z = 1.3609, S = 12, p = 0.0688). Statistically significant univariate associations were found among those who underwent thyroidectomy for GD compared to other indications, as they were more likely to be female (ß = 0.286, 95 % CI [0.058, 0.514], p = 0.014), Black, or Hispanic (ß = 1.392 [1.064, 1.721], p < 0.001; and ß = 0.562 [0.311, 0.814], p < 0.001, respectively). Additionally, they were less likely to have private insurance (ß = -0.308 [-1.076, -0.753], p = 0.002) and more likely to live in a ZIP code associated with a median household income below the 50th percentile (ß = 0.190 [0.012, 0.369], p = 0.036). The associations with the female sex, Black race, and Hispanic race persisted in multivariate analysis. CONCLUSION: GD appears to be an increasingly prevalent indication for TT. Patient characteristics differ from those who undergo TT for other diagnoses.

Telomere-to-telomere Citrullus super-pangenome provides direction for watermelon breeding.

To decipher the genetic diversity within the cucurbit genus Citrullus, we generated telomere-to-telomere (T2T) assemblies of 27 distinct genotypes, encompassing all seven Citrullus species. This T2T super-pangenome has expanded the previously published reference genome, T2T-G42, by adding 399.2 Mb and 11,225 genes. Comparative analysis has unveiled gene variants and structural variations (SVs), shedding light on watermelon evolution and domestication processes that enhanced attributes such as bitterness and sugar content while compromising disease resistance. Multidisease-resistant loci from Citrullus amarus and Citrullus mucosospermus were successfully introduced into cultivated Citrullus lanatus. The SVs identified in C. lanatus have not only been inherited from cordophanus but also from C. mucosospermus, suggesting additional ancestors beyond cordophanus in the lineage of cultivated watermelon. Our investigation substantially improves the comprehension of watermelon genome diversity, furnishing comprehensive reference genomes for all Citrullus species. This advancement aids in the exploration and genetic enhancement of watermelon using its wild relatives.

Spatiotemporal changes in Netrin/Dscam1 signaling dictate axonal projection direction in Drosophila small ventral lateral clock neurons.

Axon projection is a spatial- and temporal-specific process in which the growth cone receives environmental signals guiding axons to their final destination. However, the mechanisms underlying changes in axonal projection direction without well-defined landmarks remain elusive. Here, we present evidence showcasing the dynamic nature of axonal projections in Drosophila's small ventral lateral clock neurons (s-LNvs). Our findings reveal that these axons undergo an initial vertical projection in the early larval stage, followed by a subsequent transition to a horizontal projection in the early-to-mid third instar larvae. The vertical projection of s-LNv axons correlates with mushroom body calyx expansion, while the s-LNv-expressed Down syndrome cell adhesion molecule (Dscam1) interacts with Netrins to regulate the horizontal projection. During a specific temporal window, locally newborn dorsal clock neurons secrete Netrins, facilitating the transition of axonal projection direction in s-LNvs. Our study establishes a compelling in vivo model to probe the mechanisms of axonal projection direction switching in the absence of clear landmarks. These findings underscore the significance of dynamic local microenvironments in the complementary regulation of axonal projection direction transitions.

Reduced inhibitory synaptic transmission onto striatopallidal neurons may underlie aging-related motor skill deficits.

Human beings are living longer than ever before and aging is accompanied by an increased incidence of motor deficits, including those associated with the neurodegenerative conditions, Parkinson's disease (PD) and Huntington's disease (HD). However, the biological correlates underlying this epidemiological finding, especially the functional basis at the synapse level, have been elusive. This study reveals that motor skill performance examined via rotarod, beam walking and pole tests is impaired in aged mice. This study, via electrophysiology recordings, further identifies an aging-related reduction in the efficacy of inhibitory synaptic transmission onto dorsolateral striatum (DLS) indirect-pathway medium spiny neurons (iMSNs), i.e., a disinhibition effect on DLS iMSNs. In addition, pharmacologically enhancing the activity of DLS iMSNs by infusing an adenosine A2A receptor (A2AR) agonist, which presumably mimics the disinhibition effect, impairs motor skill performance in young mice, simulating the behavior in aged naïve mice. Conversely, pharmacologically suppressing the activity of DLS iMSNs by infusing an A2AR antagonist, in order to offset the disinhibition effect, restores motor skill performance in aged mice, mimicking the behavior in young naïve mice. In conclusion, this study identifies a functional inhibitory synaptic plasticity in DLS iMSNs that likely contributes to the aging-related motor skill deficits, which would potentially serve as a striatal synaptic basis underlying age being a prominent risk factor for neurodegenerative motor deficits.

Energy-saving hydrogen production from sulfion oxidation-hybrid seawater splitting enabled by superwettable corrosion-resistant NiFe layered double hydroxide/FeNi2S4 heterostructured nanoarrays.

Electrochemical seawater splitting is a sustainable pathway towards hydrogen production independent of scarce freshwater resources. However, the high energy consumption and harmful chlorine-chemistry interference still pose major technological challenges. Herein, thermodynamically more favorable sulfion oxidation reaction (SOR) is explored to replace energy-intensive oxygen evolution reaction (OER), enabling the dramatically reduced energy consumption and the avoidance of corrosive chlorine species in electrocatalytic systems of NiFe layered double hydroxide (LDH)/FeNi2S4 grown on iron foam (IF) substrate. The resulting NiFe-LDH/FeNi2S4/IF with superwettable surfaces and favorable heterointerfaces can effectively catalyze SOR and hydrogen evolution reaction (HER), which greatly reduces the operational voltage by 1.05 V at 50 mA cm-2 compared to pure seawater splitting and achieves impressively low electricity consumption of 2.33 kW h per cubic meter of H2 at 100 mA cm-2. Significantly, benefitting from the repulsive effect of surface sulfate anions to Cl-, the NiFe-LDH/FeNi2S4/IF exhibits outstanding long-term stability for SOR-coupled chlorine-free hydrogen production with sulfion upcycling into elemental sulfur. The present study uncovers the "killing two birds with one stone" effect of SOR for energy-efficient hydrogen generation and value-added elemental sulfur recovery in seawater electrolysis without detrimental chlorine chemistry.

Change in Patient Enrollment After Site Principal Investigator Turnover in Surgical Clinical Trials.

This cohort study examines the association of principal investigator (PI) turnover with patient enrollment in surgical clinical trials.

Enhanced UV Nonlinear Optical Properties in Layered Germanous Phosphites through Functional Group Sequential Construction.

This study pioneers a novel strategy for synthesizing solar-blind ultraviolet (UV) nonlinear optical (NLO) crystals through functional groups sequential construction, effectively addressing the inherent trade-offs among broad transmittance, enhanced second-harmonic generation (SHG), and optimal birefringence. We have developed two innovative van der Waals layered germanous phosphites: GeHPO3, the first Ge(II)-based oxide NLO crystal which exhibits a black phosphorus-like structure, and K(GeHPO3)2Br, distinguished by its exceptional birefringence and graphene-like structure. Significantly, GeHPO3 exhibits a remarkable array of NLO properties, including the highest SHG coefficient recorded among all NLO crystals for phase-matching and generating 266 nm coherent light via quadruple frequency conversion. It delivers a potent SHG intensity, surpassing KH2PO4 (KDP) by 10.3 times at 1064 nm and ß-BaB2O4 by 1.3 times at 532 nm, complemented by a distinct UV absorption edge at 211 nm and moderate birefringence of 0.062 at 546 nm. Comprehensive theoretical analysis links these exceptional characteristics to the unique NLO-active GeO3 4- units and the distinctive, highly ordered layered structures. Our findings deliver essential experimental insights into the development of Ge(II)-based optoelectronic materials and present a strategic blueprint for engineering structure-driven functional materials with customized properties.

Difluoroester solvent toward fast-rate anion-intercalation lithium metal batteries under extreme conditions.

Anion-intercalation lithium metal batteries (AILMBs) are appealing due to their low cost and fast intercalation/de-intercalation kinetics of graphite cathodes. However, the safety and cycliability of existing AILMBs are constrained by the scarcity of compatible electrolytes. Herein, we showcase that a difluoroester can be applied as electrolyte solvent to realize high-performance AILMBs, which not only endows high oxidation resistance, but also efficiently tunes the solvation shell to enable highly reversible and kinetically fast cathode reaction beyond the trifluoro counterpart. The difluoroester-based electrolyte demonstrates nonflammability, high ionic conductivity, and electrochemical stability, along with excellent electrode compatibility. The Li| |graphite AILMBs reach a high durability of 10000 cycles with only a 0.00128% capacity loss per cycle under fast-cycling of 1 A g-1, and retain ~63% of room-temperature capacity when discharging at -65 °C, meanwhile supply stable power output under deformation and overcharge conditions. The electrolyte design paves a promising path toward fast-rate, low-temperature, durable, and safe AILMBs.