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Surface Li⁺ /H⁺ exchange engineering for enhancing structural stability and electrochemical performance of lithium-rich manganese-based layered oxides
No full textLithium-rich manganese-based layered oxides (LRO) are promising ultra-high-capacity cathode materials for next-generation lithium-ion batteries but suffer from structural instability, capacity/voltage decay, and poor rate capability. Herein, a novel surface spinel coating strategy is proposed to address these challenges through a citric acid solution treatment followed by thermal annealing. A Li4Mn5O12 spinel coating layer is formed on the cathode material surface via Li+/H+ exchange and structural rearrangement, while preserving the bulk-layered structure. The spinel phase not only suppresses interfacial side reactions and lattice oxygen loss but also establishes 3D Li+ diffusion channels, enhancing kinetics and surface stability. The modified cathode material exhibits remarkable electrochemical improvements with a high-rate capacity of 205.29 mAh g−1 at 5 C, and 86.3% capacity retention after 150 cycles at 1 C, outperforming the untreated LRO. This work provides a scalable surface engineering approach to reconcile the trade-off between high energy density and long-cycle stability in the LRO, advancing their practical viability for high-energy-density batteries
Large-scale genome-wide association analyses identify novel genetic loci and mechanisms in hypertrophic cardiomyopathy
No full textHypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality with both monogenic and polygenic components. Here, we report results from a large genome-wide association study and multitrait analysis including 5,900 HCM cases, 68,359 controls and 36,083 UK Biobank participants with cardiac magnetic resonance imaging. We identified 70 loci (50 novel) associated with HCM and 62 loci (20 novel) associated with relevant left ventricular traits. Among the prioritized genes in the HCM loci, we identify a novel HCM disease gene, SVIL, which encodes the actin-binding protein supervillin, showing that rare truncating SVIL variants confer a roughly tenfold increased risk of HCM. Mendelian randomization analyses support a causal role of increased left ventricular contractility in both obstructive and nonobstructive forms of HCM, suggesting common disease mechanisms and anticipating shared response to therapy. Taken together, these findings increase our understanding of the genetic basis of HCM, with potential implications for disease management
A new double reporter strategy reveals a subset of non-migratory hematopoietic stem cells localized in a dynamic bone marrow niche
No full textPreprint versio
Myeloid cells in chronic liver inflammation
No full textChronic liver disease represents a significant global health burden. Regardless of etiology, its pathogenesis is driven by persistent liver inflammation, which can lead to fibrosis, cirrhosis, and an increased risk of cancer development. Myeloid cells, including neutrophils, eosinophils, monocytes, macrophages, and dendritic cells, play diverse and critical roles in hepatic immunity and the maintenance of tissue homeostasis but are also involved in liver injury, disease progression, and resolution. With the emergence of high-resolution omics technologies and in vivo fate-mapping models, our understanding of myeloid cell ontogeny and functional heterogeneity has been significantly refined. In this review, we discuss current insights into the myeloid cell landscape in nonviral chronic liver inflammatory conditions and summarize the roles of myeloid cell subsets in disease pathogenesis
The association between systemic inflammation, lung function and respiratory symptoms in the BOLD study in Northern Europe
No full textThe role of systemic inflammation in the pathogenesis of respiratory diseases is increasingly recognized, but the relationship between individual inflammatory markers, lung function and respiratory symptoms is not well established. We studied 1,238 adults participating in the first follow-up of the Burden of Obstructive Lung Disease (BOLD) cohort study in Sweden, Norway, Iceland, and Estonia in 2019–2021. Systemic inflammation was assessed using total white blood cell (WBC) count and WBC sub-populations (neutrophils, lymphocytes, monocytes, eosinophils, basophils and neutrophil-to-lymphocyte ratio (NLR)). In regression models adjusted for gender, age, smoking status, body mass index and study site, all WBC sub-populations, except for lymphocytes, were associated with chronic airflow obstruction (CAO) and wheeze. In never smokers, increased neutrophils were associated with reduced lung volumes (FEV1 β coef. with 95%CI -1.95 (-3.33, -0.57) p = 0.006; FVC − 1.94 (-3.18, -0.69) p = 0.002), but not CAO. Only increased basophils were associated with CAO in never smokers (OR with 95%CI 2.70 (1.28, 5.72) p = 0.009). In former smokers, increased neutrophils, monocytes and eosinophils were significantly associated with reduced FEV1, reduced FVC, CAO and wheeze. In current smokers, inflammatory markers were associated with cough (neutrophils OR with 95%CI 1.49 (1.10, 2.01) p = 0.010; monocytes 1.24 (0.99, 1.55) p = 0.058; basophils 2.56 (1.12, 5.86) p = 0.026). Systemic inflammation may be related to both obstructive and restrictive respiratory impairment in the general population, with associations that vary by smoking status
The stereochemistry of substitution at S(VI)
No full textSince the re-birth of sulfur-fluoride exchange (SuFEx) chemistry, coined by Sharpless in 2014 as a ‘click’ reaction, the prevalence of sulfur(VI) moieties in medicinal, polymer and materials chemistry has increased significantly. SuFEx and analogous substitution reactions at electrophilic S(VI) reagents are often performed on symmetrical, achiral S(VI) centres. However, when these substitution reactions are applied to chiral S(VI) substrates, often enantioenriched chiral-at-sulfur aza-S(VI) analogues, the stereochemical outcome of the reaction must be considered to obtain the appropriate 3D configuration. In this review, we aim to draw together the stereochemical outcomes and mechanistic understanding of substitution reactions occurring at electrophilic chiral S(VI) reagents to provide support, and potential word of caution, to the growing field. In addition, we review the significant developments in stereocontrolled reactions at S(VI) centres
Personalised therapeutic approaches for asthma
No full textDifferences in host susceptibility and environmental exposures result in significant heterogeneity in asthma clinical expression, natural evolution and response to treatment. These differences are influenced by many factors including genomics, epigenomics, transcriptomics, proteomics and metabolomics, many of which are modified by environmental and allergic exposures. The complex and multiple characteristics that interact in asthma development and progression pose significant challenges for personalized management. This review aims to guide the clinician in its management decisions by reviewing each of the components important in developing this therapeutic paradigm and by providing several integrated goals for precision or personalized medicine for asthma. Biologic characteristics of asthma in relation to the genomics, exposome and hypersensitivity reactions (allergic responsiveness) resulting in the asthma diathesis are discussed. Further insights including the use of targeted biologics and allergen immunotherapy are provided, while discussing the importance of targeting the epithelium, mucus production, airway smooth muscle and the small airways. We examine the value of multivariate cluster analyses as a new paradigm that can inform treatment decisions and the potential of adaptive trial design to evaluate known and novel predictive biomarkers and characterize disease heterogeneity
Genome-wide interaction study with BMI identifies CYP7A1 and GIPR as genetic modulators of MASLD
No full textBackground
Metabolic dysfunction-associated steatotic liver disease (MASLD) may progress to liver inflammation, fibrosis, cirrhosis and hepatocellular carcinoma. So far, genome-wide association studies explain a small fraction of MASLD heritability.
Objective
We sought to identify novel genetic determinants of MASLD by exploring interactions between genetic variants and body mass index (BMI).
Design
First, we examined genome-wide interactions with BMI for circulating alanine aminotransferase (ALT) levels using UK Biobank data. For identified loci, we next examined associations with hepatic proton density fat fraction (PDFF) in 35,146 independent UK Biobank participants. Associations with PDFF were replicated in four independent European cohorts, followed by a phenome-wide association study. Finally, we used human liver epigenomic maps and CRISPR/Cas9 experiments in vitro and in vivo to functionally characterize the CYP7A1 locus.
Results
Thirteen loci interact with BMI for ALT (P<5E-8), including eight well-known genetic modulators of MASLD. Two loci – UBXN2B/CYP7A1 and GIPR – are additionally associated with PDFF. For the intronic rs34783010 in GIPR, the minor T allele is associated with lower BMI and higher HbA1c and liver triglyceride content in humans. The UBXN2B/CYP7A1 locus is associated with PDFF in four additional European cohorts. Epigenomic data and in vitro experiments in human liver cells prioritise rs10504255 and CYP7A1 as the functional effectors in this locus. Perturbation of CYP7A1 orthologues using CRISPR/Cas9 results in less liver fat in 10-day-old, metabolically challenged zebrafish larvae.
Conclusion
A genome-wide SNPxBMI design fuelled identification of two MASLD genes: CYP7A1 and GIPR
Developing evidence‐based cancer prevention recommendations: methodology of the World Code Against Cancer Framework to create region‐specific codes
No full textPrevention offers the greatest public health potential and the most cost-effective long-term cancer control strategy. Authoritative, clear, evidence-based, and region-specific recommendations to actively contribute to cancer prevention are extremely valuable for the public, health professionals, advocates, and policymakers worldwide. The World Code Against Cancer Framework offers a two-level hierarchy mechanism to systematically review and synthesize the latest scientific insights, while assessing the epidemiological, socioeconomic, cultural conditions, and health systems context of a given region of the world, to inform decision-making at the individual and system levels, implemented through Regional Codes Against Cancer. In this manuscript, we describe the rigorous methodology established by the International Agency for Research on Cancer, consisting of a step-by-step decision-making algorithm to develop region-specific Codes Against Cancer. These comprehensive evidence-based tools on cancer prevention aim to transfer the latest evidence from etiological research and preventive interventions into actionable information for the population and for policymakers
Quasi-optimal complexity hp-FEM for the Poisson equation on a rectangle
No full textWe show, in one dimension, that an hp-Finite Element Method (hp-FEM) discretisation can be solved in optimal complexity because the discretisation has a special sparsity structure that ensures that the reverse Cholesky factorisation—Cholesky starting from the bottom right instead of the top left—remains sparse. Moreover, computing and inverting the factorisation may parallelise
across different elements. By incorporating this approach into an Alternating Direction Implicit (ADI) method `a la Fortunato and Townsend (2020) we can solve, within a prescribed tolerance, an hp-FEM discretisation of the (screened) Poisson equation on a rectangle with quasi-optimal complexity: O(N² log N) operations where N is the maximal total degrees of freedom in each dimension. When combined with fast Legendre transforms we can also solve nonlinear time-evolution partial differential
equations in a quasi-optimal complexity of O(N²log² N) operations, which we demonstrate on the (viscid) Burgers’ equation. We also demonstrate how the solver can be used as an effective preconditioner for PDEs with variable coefficients, including coefficients that support a singularity