Key Drivers Research Articles

Identification and functional validation of miR-190b-5p and miR-296-3p as novel therapeutic attenuators of liver fibrosis.

Liver fibrosis and its end-stage form known as cirrhosis contributes to millions of deaths annually. The lack of robust anti-fibrotic molecules is in part attributed to absence of any functional screens to identify molecular regulators using patient-derived primary human hepatic myofibroblasts, which are key drivers of fibrosis. Here, to identify robust regulators of fibrosis, we performed functional microRNA screenings in primary human hepatic myofibroblasts followed by in vivo validation in three independent mouse models of fibrosis (toxin, cholestasis and MASH). We identified miR-190b-5p and miR-296-3p as robust anti-fibrotic miRNAs that suppress liver fibrosis. Notably, the expression of miR-190b-5p and miR-296-3p was found significantly reduced in human livers with fibrosis. Mechanistically, we discovered hyaluronan synthase 2 (HAS2) and integrin alpha-6 (ITGA6) as novel targets of miR-190b-5p and miR-296-3p, respectively. Furthermore, we demonstrated that the anti-fibrotic properties of miR-190b-5p and miR-296-3p are, at least in part, dependent on HAS2 and ITGA6. Finally, we showed the anti-fibrotic function of both miRNAs in a human liver bud model, which mimics multiple features of human liver. Collectively, in our study we discovered miR-190b-5p and miR-296-3p as two novel anti-fibrotic miRNAs, and that HAS2 and ITGA6 contribute to miR-190b-5p- and miR-296-3p-mediated inhibition of liver fibrosis. These results provide a foundation for future research to explore the clinical utility of miR-190b-5p and miR-296-3p in liver injuries with fibrosis. Liver fibrosis and cirrhosis contribute to millions of deaths world-wide and, till date, remain as unmet medical needs. In this study, we discovered two microRNAs, miR-190b-5p and miR-296-3p, which suppress liver fibrosis in preclinical mouse models and a human liver bud model. Our promising results encourage further studies that aim to develop both miRNAs for the treatment of liver fibrosis in patients.

The timeline of overseas imported cases acts as a strong indicator of dengue outbreak in mainland China.

The emergence of dengue viruses in new, susceptible human populations worldwide is increasingly influenced by a combination of local and global human movements and favorable environmental conditions. While various mathematical models have explored the impact of environmental factors on dengue outbreaks, the significant role of human mobility both internationally and domestically in transmitting the disease has been less frequently addressed. In this context, we introduce a modeling framework that integrates the effects of international travel-induced imported cases, climatic conditions, and local human movements to assess the spatiotemporal dynamics of dengue transmission. Utilizing the generation matrix method, we calculate the basic reproduction number and its sensitivity to various model parameters. Through numerical simulations using data on climate, human mobility, and reported dengue cases in mainland China, our model demonstrates a good agreement with observed data upon validation. Our findings reveal that while climatic conditions are a key driver for the rapid dengue transmission, human mobility plays a crucial role in its local spread. Importantly, the model highlights the significant impact of imported cases from overseas on the initiation of dengue outbreaks and their contribution to increasing the disease incidence rate by 34.6%. Furthermore, the analysis identifies that dengue cases originating from regions, such as Cambodia and Myanmar internationally, and Guangzhou and Xishuangbanna domestically, have the potential to significantly increase the disease burden in mainland China. These insights emphasize the critical need to include data on imported cases and domestic travel patterns in disease outbreak models to improve the precision of predictions, thereby enhancing dengue prevention, surveillance, and response strategies.

Analyzing Key Drivers of Digital Transformation: A Review and Framework

Analyzing Key Drivers of Digital Transformation: A Review and Framework

Cost-effectiveness analysis and return on investment of SunSmart Western Australia to prevent skin cancer.

Each year, malignant melanoma accounts for 57 000 deaths globally. If current rates continue, there will be an estimated 510 000 new cases annually and 96 000 deaths by 2040. Melanoma and keratinocyte cancers (KCs) incur a large societal burden. Using a mathematical population model, we performed an economic evaluation of the SunSmart program in the state of Western Australia (WA), a primary prevention program to reduce the incidence of skin cancer, versus no program. A societal perspective was taken combining costs to the health system, patients and lost productivity. The model combined data from pragmatic trial evidence of sun protection, epidemiological studies and national cost reports. The main outcomes modelled were societal and government costs, skin cancer counts, melanoma deaths, life years and quality-adjusted life years. Over the next 20 years, the model predicted that implementing the WA SunSmart program would prevent 13 728 KCs, 636 melanomas and 46 melanoma deaths per 100 000 population. Furthermore, 251 life years would be saved, 358 quality-adjusted life years gained and AU$2.95 million in cost savings to society per 100 000 population would be achieved. Key drivers of the model were the rate reduction of benign lesions from sunscreen use, the costs of purchasing sunscreen and the effectiveness of reducing KCs in sunscreen users. The likelihood of WA SunSmart being cost-effective was 90.1%. For the WA Government, the estimated return on investment was $8.70 gained for every $1 invested. Primary prevention of skin cancer is a cost-effective strategy for preventing skin cancers.

Environmental genome-wide association studies across precipitation regimens reveal that the E3 ubiquitin ligase MBR1 regulates plant adaptation to rainy environments.

In an era characterized by rapidly changing and less-predictable weather conditions fueled by the climate crisis, understanding the mechanisms underlying local adaptation in plants is of paramount importance for the conservation of species. As the frequency and intensity of extreme precipitation events increase, so are the flooding events resulting from soil water saturation. The deriving onset of hypoxic stress is one of the leading causes of crop damage and yield loss. By combining genomics and remote sensing data, today it is possible to probe natural plant populations that have evolved in different rainfall regimes and look for molecular adaptation to hypoxia. Here, using an environmental genome-wide association study (eGWAS) on 934 non-redundant georeferenced Arabidopsis ecotypes, we have identified functional variants for the gene MED25 BINDING RING-H2 PROTEIN 1 (MBR1). This is a ubiquitin-protein ligase that regulates MEDIATOR25 (MED25), part of a multiprotein complex that interacts with transcription factors which act as key drivers of the hypoxic response in Arabidopsis, namely the RELATED TO AP2 proteins, RAP2.2 and RAP2.12. Through experimental validation, we show that natural variants of MBR1 have a differential impact on the stability of MED25 and, in turn, on hypoxia tolerance. This study also highlights the pivotal role of the MBR1/MED25 module in establishing a comprehensive hypoxic response. Our findings show that molecular candidates for plant environmental adaptation can be effectively mined from large datasets. This thus supports the need for the integration of forward and reverse genetics with robust molecular physiology validation of the outcomes.

Custo-Efetividade da Oxigenação por Membrana Extracorpórea Venoarterial no Choque Cardiogênico Refratário: Um Estudo na Perspectiva Brasileira

Abstract Background Refractory cardiogenic shock (CS) is associated with high mortality rates, and the use of venoarterial extracorporeal membrane oxygenation (VA-ECMO) as a therapeutic option has generated discussions. Therefore, its cost-effectiveness, especially in low- and middle-income countries like Brazil, remains uncertain.Objectives: To conduct a cost-utility analysis from the Brazilian Unified Health System perspective to assess the cost-effectiveness of VA-ECMO combined with standard care compared to standard care alone in adult refractory CS patients. Methods We followed a cohort of refractory CS patients treated with VA-ECMO in tertiary care centers located in Southern Brazilian. We collected data on hospital outcomes and costs. We conducted a systematic review to supplement our data and utilized a Markov model to estimate incremental cost-effectiveness ratios (ICERs) per quality-adjusted life year (QALY) and per life-year gained. Results In the base-case analysis, VA-ECMO yielded an ICER of Int$ 37,491 per QALY. Sensitivity analyses identified hospitalization cost, relative risk of survival, and VA-ECMO group survival as key drivers of results. Probabilistic sensitivity analysis favored VA-ECMO, with a 78% probability of cost-effectiveness at the recommended willingness-to-pay threshold. Conclusions Our study suggests that, within the Brazilian Health System framework, VA-ECMO may be a cost-effective therapy for refractory CS. However, limited efficacy data and recent trials questioning its benefit in specific patient subsets highlight the need for further research. Rigorous clinical trials, encompassing diverse patient profiles, are essential to confirm cost-effectiveness and ensure equitable access to advanced medical interventions within healthcare systems, particularly in socio-economically diverse countries like Brazil.

The endogenous growth and asset prices nexus revisited with closed-form solution

Endogenous growth models exhibit long-run risks, which are considered a potential explanation of the equity premium puzzle. Unlike previous literature, we use a closed-form solution of a simplified model to make the following contributions. First, we derive a set of conditions for a positive and large equity premium. Second, we match a key driver of endogenous growth, the R&D spending-to-GDP ratio. Third, we include a novel discussion on the role of patent obsolescence. Given that the literature concerns the accuracy of loglinear-lognormal solutions, we solve our model numerically with third-order perturbation. We find additional risk correction due to higher-order terms.

Can edoxaban be used at extremes of bodyweight and in patients with a creatinine clearance ≥95 ml/min? – A population pharmacokinetic analysis

BackgroundClinical evidence surrounding edoxaban use in patients weighing <50 kg and >120 kg is lacking. The International Society of Thrombosis and Haemostasis Scientific and Standardisation Committee suggests avoiding edoxaban in patients >120 kg. Additionally, concerns exist regarding decreased efficacy in patients prescribed edoxaban for atrial fibrillation with a creatinine clearance (CrCl) >95 ml/min, a finding of the ENGAGE AF-TIMI 48 trial when edoxaban was compared to warfarin. ObjectiveTo derive a population pharmacokinetic (PopPK) model using clinical practice data, to understand the impact of bodyweight and renal function on edoxaban pharmacokinetics. MethodEdoxaban plasma concentrations and patient characteristics were collated from King's College Hospital anticoagulation clinics between 11/2016 and 08/2022. A PopPK model was developed using non-linear mixed effects modelling and used to simulate edoxaban concentrations at the extremes of bodyweight and with varying renal function. ResultsData from 409 patients (46 < 50 kg, 34 > 120 kg and 123 with a CrCl > 95 ml/min) provided 455 edoxaban plasma concentrations. A one-compartment model with between-subject variability on clearance with a proportional error model best described the data. The most significant covariates impacting on edoxaban exposure were CrCl and bodyweight. Our work suggests that edoxaban exposure in patients weighing up to 140 kg is comparable to those weighing 75 kg. Edoxaban exposure is reduced in patients weighing <50 kg due to the recommended dose reductions. There is also a reduction in AUCss when CrCl > 95 ml/min compared to CrCl 80 ml/min. ConclusionsOur population PK model for edoxaban suggests that renal function is a key driver for overall edoxaban exposure. Further clinical outcome data is required to understand clinical effectiveness and adverse outcomes.

Provincial equity and enhanced health are key drivers for China’s 2060 carbon neutrality

Provincial equity and enhanced health are key drivers for China’s 2060 carbon neutrality

Competing for Research Funding: Key Elements Impacting the Evaluation of Grant Proposal

As funding is one of the key pillars of research activity, identifying the factors that impact the evaluation results in research funding competitions remains challenging, due to the heterogeneity of funding instruments. In this context, our study aims to identify the elements that ensure the application's success, comparing two perspectives: one of the applicant and the other based on the evaluation grid. The empirical investigation focuses on a survey of 243 Romanian researchers. As analysis methods, we use a binary logistic regression model to correlate the success in funding competitions for research projects with a set of factors considered determinants. The results show that the researcher’s past performance influences the proposal’s future performance/success, with the quality of the project director’s previous publications, and its international visibility being the key drivers of successful research project applications.

Actin network evolution as a key driver of eukaryotic diversification.

Eukaryotic cells have been evolving for billions of years, giving rise to wildly diverse cell forms and functions. Despite their variability, all eukaryotic cells share key hallmarks, including membrane-bound organelles, heavily regulated cytoskeletal networks and complex signaling cascades. Because the actin cytoskeleton interfaces with each of these features, understanding how it evolved and diversified across eukaryotic phyla is essential to understanding the evolution and diversification of eukaryotic cells themselves. Here, we discuss what we know about the origin and diversity of actin networks in terms of their compositions, structures and regulation, and how actin evolution contributes to the diversity of eukaryotic form and function.

Chromosome-level genome assembly and annotation of the black sea urchin Arbacia lixula (Linnaeus, 1758).

The black sea urchin (Arbacia lixula) is a keystone species inhabiting the coastal shallow waters of the Mediterranean Sea, which is a key driver of littoral communities' structure. Here, we present the first genome assembly and annotation of this species, standing as the first Arbacioida genome, including both nuclear and mitochondrial genomes. To obtain a chromosome-level assembly, we used a combination of PacBio high fidelity (HiFi) reads and chromatin capture reads (Omni-C). In addition, we generated a high-quality nuclear annotation of both coding and non-coding genes, by using published RNA-Seq data from several individuals of A. lixula and gene models from closely related species. The nuclear genome assembly has a total span of 607.91 Mb, being consistent with its experimentally estimated genome size. The assembly contains 22 chromosome-scale scaffolds (96.52% of the total length), which coincides with its known karyotype. A total of 72,767 transcripts were predicted from the nuclear genome, 24,171 coding, and 48,596 non-coding that included lncRNA, snoRNA, and tRNAs. The circularized mitochondrial genome had 15,740 bp comprising 13 protein-coding genes, 2 rRNA, and 22 tRNA. This reference genome will enhance ongoing A. lixula studies and benefit the wider sea urchin scientific community.

Educational Policy and Activities of East India Company (1600-1765)

Abstract: The 19th century witnessed a profound transformation in the political landscape of many regions, characterized by the rise of nationalism and the subsequent formation of nation-states. This research work delves into the historical context, key drivers, and consequences of this significant historical phenomenon. The research offers light on a crucial time in global history by investigating the causes of nationalism and its effects on the formation of nation-states. Employing a multidisciplinary approach, the research draws from historical, political, and sociocultural perspectives to analyze the rise of nationalism. It delves at how many peoples inside established empires and territories felt a feeling of commonality due to their shared cultural, linguistic, and historical identities. The work delves into the influence of Enlightenment ideas, Romanticism, and intellectual movements that fueled the concept of self-determination and the sovereignty of distinct nations. The study also scrutinizes the role of key historical events and figures that catalyzed the nationalist fervor. From the unification of Italy led by Giuseppe Garibaldi to the German unification orchestrated by Otto von Bismarck, the work examines the strategies employed to consolidate fragmented territories into cohesive nation-states. It also considers the implications of these transformations on regional stability, diplomacy, and balance of power. Furthermore, the research investigates the potential tensions arising from the juxtaposition of national identities and existing imperial structures. It delves into instances where nationalism clashed with multiethnic empires, often leading to complex negotiations of autonomy, self-governance, or secession.

Pogonoloma macrorhizum (Basidiomycota, Agaricales) in Slovak landscape: a distinct fungus of Quercus cerris stands transitional in space and time

AbstractThe lack of precise data on the environmental requirements of the conspicuous fungus with a northern distribution limit in Slovakia, Pogonoloma macrorhizum, initiated our study. Its identity was verified by sequencing of ITS and 28 S nrDNA regions. The analysis of trophic status by stable-isotope ratio of carbon and nitrogen suggested that the species is probably ectomycorrhizal. For the seventeen sampling sites, environmental data were obtained and information on landscape development and management were retrieved from historical maps and aerial orthophotographs. All these parameters were analysed by multivariate ordination methods. In Slovakia, P. macrorhizum is found in thermophilous to mesophilous stands on acidic soils with a pH ranging from 4.1 to 6.2. These habitats are dominated by Quercus cerris, with non-frequent tree taxa of Carpinus betulus and Quercus petraea agg. The key environmental drivers shaping the habitat of P. macrorhizum were identified as time since deforestation, with the presence of old Q. cerris individuals (former solitary trees of pastures) and soil characteristics. The fungus appears to be a species of transitional habitats historically affected by grazing. These transitions occur between thermophilic and mesophilic sites, including oak forest communities, dry steppic grasslands and forest edges, as well as spontaneously overgrown pastures and forests with a closed canopy. It is regrettable that the Q. cerris stands in Slovakia are under threat, particularly because of felling and the lack of grazing in forests. Furthermore, recent silvicultural practices have resulted in the replacement of oaks (Quercus spp.) by hornbeam (Carpinus betulus) and the formation of closed stands.

Spatiotemporal evolution and interaction of water constraints and their socio-ecological drivers in the Taihu Lake Basin

To effectively manage water constraints (WCs) within a basin, it is crucial to first scientifically delineate their spatial distribution and thoroughly understand the interactions between WCs. Investigating the complex driving mechanisms at multiple scales is also essential. In this study, a basin WC evaluation framework is constructed using a conflict risk assessment model. The spatiotemporal variations of four types of WCs across three spatial scales in the Taihu Lake Basin (TLB) are thoroughly investigated. Furthermore, the study quantifies the trade-offs, synergy effects, and bundle patterns of these water constraints. The study employs the Optimal Parameters-based Geographic Detector (OPGD) and multivariate linear regression to identify the key socio-ecological drivers of WCs. Our findings indicate that between 2010 and 2020, water resource constraint (WREC), water environment constraint (WENC), water safety constraint (WSAC), water ecology constraint (WECC), and the comprehensive WC (CWC) displayed varying degrees of heterogeneity. Particularly, the mean values of WSAC, WECC, and CWC witnessed an increase over the decade. Additionally, all WCs exhibited a strong positive spatial autocorrelation. Synergistic interactions among WCs were predominantly observed in pairs such as WREC-WSAC, WREC-WECC, and WSAC-WECC, while a weaker trade-off effect was noted in the WENC-WECC pair. At multiple scales, we identified eight types of WC bundles capable of undergoing mutual transformations, especially at the basin scale. The primary drivers of WCs varied across different stages and scales, with most factors collectively exerting a more significant impact than individually. Notably, factors like secondary and tertiary industry GDP (X2), population density (X3), precipitation (X6), and elevation (X7) were identified as core drivers influencing the evolution of WCs in the TLB. Integrating these spatiotemporal characteristics and driving mechanisms of WC interactions into basin planning and management can significantly support the alleviation of multidimensional water constraints in territorial spaces.

Histone serotonylation regulates ependymoma tumorigenesis.

Bidirectional communication between tumours and neurons has emerged as a key facet of the tumour microenvironment that drives malignancy1,2. Another hallmark feature of cancer is epigenomic dysregulation, in which alterations in gene expression influence cell states and interactions with the tumour microenvironment3. Ependymoma (EPN) is a paediatric brain tumour that relies on epigenomic remodelling to engender malignancy4,5; however, how these epigenetic mechanisms intersect with extrinsic neuronal signalling during EPN tumour progression is unknown. Here we show that the activity of serotonergic neurons regulates EPN tumorigenesis, and that serotonin itself also serves as an activating modification on histones. We found that inhibiting histone serotonylation blocks EPN tumorigenesis and regulates the expression of a core set of developmental transcription factors. High-throughput, in vivo screening of these transcription factors revealed that ETV5 promotes EPN tumorigenesis and functions by enhancing repressive chromatin states. Neuropeptide Y (NPY) is one of the genes repressed by ETV5, and its overexpression suppresses EPN tumour progression and tumour-associated network hyperactivity through synaptic remodelling. Collectively, this study identifies histone serotonylation as a key driver of EPN tumorigenesis, and also reveals how neuronal signalling, neuro-epigenomics and developmental programs are intertwined to drive malignancy in brain cancer.

Exploring COVID-19 vaccine hesitancy in unvaccinated adults within a semi-urban population of South India: A qualitative investigation

BackgroundDespite broad COVID-19 vaccination coverage in India, hesitancy persists, limiting the achievement of 100 % vaccination coverage across the country to prevent the ongoing transmission of the infection. We explored the key drivers of vaccine hesitancy among unvaccinated adults in semi-urban regions of Kerala, India. Methodology: Semi-structured face-to-face interviews were conducted from April to May 2022, using purposive sampling to enroll participants with the help of Accredited Social Health Activist (ASHA) workers. Participation in the interviews was voluntary and was conducted at the participant's residence at a time convenient for the participants. Audio files of the interviews were transcribed verbatim, and the anonymized data underwent a multistage thematic analysis using the constant comparative method. ResultsIn our study with 35 unvaccinated individuals were interviewed. Identified factors for vaccine hesitancy were categorized into different themes: individual factors (35 %), vaccine-related factors (33.33 %), and social/environmental factors (31.67 %). ConclusionsTargeted communication strategies and behavioural change interventions need be employed to mitigate major drivers of vaccine hesitancy. Addressing vaccine hesitancy requires multifaceted strategies including community engagement, collaboration with alternative medical systems, healthcare worker education, prioritizing vulnerable populations, and transparent communication about vaccine safety and adverse events. Implementing these measures will help overcome barriers and enhance vaccine coverage.

Customer enrollment and participation in building demand management programs: A review of key factors

Increasing the efficiency and flexibility of electricity demand is necessary for ensuring a cost-effective and reliable transition to zero-carbon electricity systems. Such demand-side management (DSM) resources have been procured by utilities for decades via energy efficiency and demand response programs; however, the key drivers of program enrollment and customer participation levels remain poorly understood — even as governments and grid planners seek to scale up the deployment of DSM assets to meet climate targets. Here we systematically review the evidence on multiple factors that may influence customer enrollment and participation in building DSM programs, focusing primarily on residential and commercial buildings. We examine the contexts in which relationships between DSM factors and outcomes are most often explored and with which methods; we also score the strength, direction, and internal consistency of each factor's reported impact on the enrollment and participation outcomes. We find that studies most commonly assess the effects of economic incentives for load flexibility on program participation levels, often using simulation-based methods in lieu of measured data. Few studies focus on program enrollment outcomes or regulatory drivers of either enrollment or participation, and gaps are also evident in the coverage of emerging DSM opportunities like load electrification. Removal of structural barriers (e.g., the lack of controls infrastructure) and the use of third party services (e.g., load aggregators) are the factors with the largest positive impacts on DSM outcomes, but no single factor emerges as clearly most impactful. For a given factor, the range of reported impacts typically varies widely across the relevant studies reviewed. Our findings provide a snapshot of the state of knowledge about building DSM and customer decision-making, and they expose key gaps in understanding that must be filled if building DSM is to expand as a critical resource for operating clean power grids.

Oncostatin M-driven macrophage-fibroblast circuits as a drug target in autoimmune arthritis

BackgroundRecent single-cell RNA sequencing (scRNA-seq) analysis revealed the functional heterogeneity and pathogenic cell subsets in immune cells, synovial fibroblasts and bone cells in rheumatoid arthritis (RA). JAK inhibitors which ameliorate joint inflammation and bone destruction in RA, suppress the activation of various types of cells in vitro. However, the key cellular and molecular mechanisms underlying the potent clinical effects of JAK inhibitors on RA remain to be determined. Our aim is to identify a therapeutic target for JAK inhibitors in vivo.MethodsWe performed scRNA-seq analysis of the synovium of collagen-induced arthritis (CIA) mice treated with or without a JAK inhibitor, followed by a computational analysis to identify the drug target cells and signaling pathways. We utilized integrated human RA scRNA-seq datasets and genetically modified mice administered with the JAK inhibitor for the confirmation of our findings.ResultsscRNA-seq analysis revealed that oncostatin M (OSM) driven macrophage-fibroblast interaction is highly activated under arthritic conditions. OSM derived from macrophages, acts on OSM receptor (OSMR)-expressing synovial fibroblasts, activating both inflammatory and tissue-destructive subsets. Inflammatory synovial fibroblasts stimulate macrophages, mainly through IL-6, to exacerbate inflammation. Tissue-destructive synovial fibroblasts promote osteoclast differentiation by producing RANKL to accelerate bone destruction. scRNA-seq analysis also revealed that OSM-signaling in synovial fibroblasts is the main signaling pathway targeted by JAK inhibitors in vivo. Mice specifically lacking OSMR in synovial fibroblasts (Osmr∆Fibro) displayed ameliorated inflammation and joint destruction in arthritis. The JAK inhibitor was effective on the arthritis of the control mice while it had no effect on the arthritis of Osmr∆Fibro mice.ConclusionsOSM functions as one of the key cytokines mediating pathogenic macrophage-fibroblast interaction. OSM-signaling in synovial fibroblasts is one of the main signaling pathways targeted by JAK inhibitors in vivo. The critical role of fibroblast-OSM signaling in autoimmune arthritis was shown by a combination of mice specifically deficient for OSMR in synovial fibroblasts and administration of the JAK inhibitor. Thus, the OSM-driven synovial macrophage-fibroblast circuit is proven to be a key driver of autoimmune arthritis, serving as a crucial drug target in vivo.

Ensuring China's food security in a geographical shift of its grain production: Driving factors, threats, and solutions

Grain production in China has increased over time despite limited access to natural resources. However, this has led to China's grain supply system becoming increasingly vulnerable and unsustainable due to a northward shift of its grain production. Here, we establish a framework to guide future grain policy formulation in response to previous practices and lessons learned from China's past grain production. This framework integrated the spatial gravity model, spatial mismatch index, logarithmic mean Divisia index (LMDI), and Monte Carlo simulation to identify the key drivers behind grain growth, analyze their impacts on food security, and propose countermeasures. We found that grain production increase in China is not universally attributable to increased input of farmland and water resources, but rather, socio-economic factors including agricultural technology and irrigation facilities have improved efficiency. The spatial heterogeneity in their driving effects in different major grain producing regions has led grain production to shifted to the northern regions that have few natural resources, posing new challenges for food security: without new policies, China will not be poised to meet increased grain demand projected from 2025 to 2030, especially for rice and soybeans. From a comparison across four grain policies, it is found that region-specific policies will most effectively accelerate transitions to sustainable food production systems. We urge decision-makers to reach beyond natural resource inputs and focus on socio-economic factors, particularly inputs for replanting abandoned farmland and irrigation facilities that can ensure food security in the future.