EBioMedicine最新文献

Alzheimer's disease-related dementia (ADRD) is a progressive neurodegenerative condition characterised by cognitive decline and overlapping pathological features. Despite advances in diagnostic tools and therapies, challenges persist due to limited efficacy, high costs, and the complexity of ADRD pathophysiology. Evidence suggests that ADRD arises from a lifelong interplay of genetic, lifestyle, and environmental factors, with recent findings indicating potential neurodevelopmental origins. Proteins implicated in neurodegeneration, such as amyloid and tau, may play critical roles in early nervous system development, whereas disruptions during critical periods, such as adolescence, may increase later-life susceptibility to ADRD. The global prevalence of ADRD is projected to reach 153 million by 2050, emphasising the urgent need for prevention strategies in addition to therapeutic interventions. Reframing ADRD as a neurodevelopmental condition with a delayed onset may provide alternative insights into its aetiology, paving the way for alternative innovative therapeutic and preventive approaches.

Background: Accurate monitoring of antimicrobial consumption is essential for developing effective stewardship interventions. Hospitals are mandated to report antibiotic treatment duration using the CDC's Standardized Antimicrobial Administration Ratio (SAAR). We aimed to create a metric for measuring antimicrobial spectrum to complement SAAR, benchmarked against local and individual resistance.

Methods: This retrospective cohort study utilised data from nine acute care hospitals within BJC Healthcare from January 2018 to December 2023. Adult patients meeting CDC sepsis event criteria were included, focussing on infections caused by Gram-negative bacilli (GNB). Data on patient characteristics, microbiology results, treatments, and timing were collected. We defined the antibiotic effective spectrum (AES) as the ratio of susceptible GNB to all GNB cultured. Mathematical optimisation identified the optimal antibiotic as the antibiotic with the narrowest effective spectrum active against the isolated GNB. We calculated the empirical (before culture results are available) and directed Optimal Spectrum Antibiotic Ratio (OSAR) as the ratio between the AES chosen clinically to the optimal AES, reported it for each hospital yearly, and compared it to SAAR and the Antibiotic Spectrum Index (ASI). Sensitivity analyses focused on empirical undertreatment (OSAR <1, where the empirical choice did not cover the cultured GNB).

Findings: We included 10,277 GNB cultured from clinical specimens in 7997 distinct patients. The AES ranged from 0.15 for ampicillin to 0.94 for amikacin. Empirical OSAR varied between 1.08 (95% CI 1.05-1.10) and 1.89 (95% CI 1.51-2.28), with undertreatment present in 1396 (13.6%) of cases overall and wide variations across hospitals. Directed OSAR was lower, ranging between 0.74 (95% CI 0.73-0.75) and 1.45 (95% CI 1.41-1.49). OSAR, SAAR and ASI had different trends across hospitals over the six study years.

Interpretation: The OSAR yielded different conclusions about antibiotic utilisation, complementing duration-based measures like SAAR. It determines the appropriateness of antibiotic spectrum based on local and individual resistance.

Funding: The project was funded by the CDC (5U54CK000609).

Super-resolution ultrasound, with its ability to achieve sub-diffraction resolution and directly track microvascular flow velocity in vivo, offers a level of vascular information inaccessible previously. To fully realise its clinical value, quantitative vascular markers have been explored. In this review, we explore the quantitative super-resolution markers that have been reported, with a focus on occasions where markers have been applied in a clinical or pre-clinical setting, comparing healthy and diseased cases to test the validity and usefulness of these markers. We define all the used markers from structural markers such as vessel density to velocity metrics such as flow rate, we then provide a summary showing what has been attempted and what has been found successful. We hope that this review can act as a guide both as to the range of markers that currently exist as well as indications as to what markers show potential for each clinical application.

Background: Injectable peptide-based glucagon-like peptide-1 receptor (GLP1R) agonists (GLP1RAs) are effective treatments for obesity and diabetes but are limited by patient compliance and scalability challenges. In contrast, non-peptide small-molecule GLP1RAs offer the advantage of oral delivery but are relatively inactive at the rodent GLP1R, limiting their utility in preclinical pharmacodynamic studies. This study aimed to bridge the translational gap by engineering and thoroughly validating a humanised GLP-1 receptor (hGLP1R) mouse model that more accurately recapitulates human receptor pharmacology, thereby enhancing its utility for preclinical drug development.

Methods: The hGLP1R mouse was generated via CRISPR-Cas9-mediated replacement of the endogenous murine Glp1r gene with the human orthologue. The hGLP1R mouse model was pharmacologically characterised using peptide (semaglutide) and small-molecule (orforglipron) GLP1RAs in lean and diet-induced obese (DIO) hGLP1R and wild-type (WT) mice.

Findings: Immunohistochemistry confirmed expression of the human GLP1R and complete absence of the endogenous murine GLP1R in pancreatic β-cells and key appetite-regulatory brain regions of hGLP1R mice. In lean hGLP1R mice, both semaglutide and orforglipron significantly reduced body weight and food intake, improved glucose tolerance, and induced taste aversion. CNS response profiles were evaluated using high-resolution 3D whole-brain imaging, revealing overlapping c-Fos activation patterns for both agonists. In DIO hGLP1R mice, chronic administration of either compound produced robust reductions in body weight, food intake and plasma lipids. Notably, orforglipron was inactive in WT mice, which responded only to semaglutide.

Interpretation: These findings establish the hGLP1R mouse as a robust and translational platform for advancing the discovery and evaluation of novel small-molecule GLP1RAs targeting obesity and related metabolic diseases.

Funding: This research was funded by Gubra A/S and Terns Pharmaceuticals, Inc.; there was no external funding.

Background: Cholesterol is a main contributor to coronary artery disease (CAD). Although the genetic basis of blood cholesterol concentration is well studied, there is currently a lack of studies investigating the genetics of its precursors from de novo biosynthesis.

Methods: We conducted a genome-wide association meta-analysis, combining data from KORA, LIFE-Heart, LIFE-Adult, LURIC, the Sorbs study, and YFS, resulting in up to 10,519 individuals. We investigated 14 traits related to serum concentrations of lanosterol, desmosterol, and cholesterol. Direct and indirect effects of lanosterol on CAD were investigated with a Mendelian randomisation mediation analysis.

Findings: Our analysis revealed four genome-wide significant (p < 5 × 10^-8) associations not previously reported in the GWAS catalogue. These include two loci without prior connection to cholesterol, associated with lanosterol (7q21.2, CYP51A1) and free cholesterol (11q14.1), and two associations with lanosterol at loci previously reported for cholesterol (5q13.3, HMGCR; 11q23.3, APO cluster). We also replicated eight loci previously reported for associations with cholesterol-related traits. Lanosterol exhibited significant total and indirect effects on CAD, but its direct effect was not significant.

Interpretation: We demonstrate that the investigation of intermediate phenotypes can help to functionally fine map previously reported associations for cholesterol, improving our understanding of genetic regulation of cholesterol concentrations. Further, the effect of lanosterol on CAD is probably fully mediated by total cholesterol.

Funding: This investigation was primarily funded by the ministry for science and health of the Rhineland-Palatinate through the CoAGE graduate programme. A complete list of funding organisations is provided in the acknowledgements.

Background: Fibroblast behaviour is a key determinant of outcomes in interstitial lung diseases (ILDs), yet mechanisms governing the switch between reversible repair and progressive fibrosis remain unclear. How disease-specific cellular niches shape fibroblast fate across ILD phenotypes has not been compared in situ.

Methods: We profiled peripheral lung tissues from controls, organising pneumonia (OP), connective tissue disease-associated ILD (CTD-ILD), and idiopathic pulmonary fibrosis (IPF) using High-Definition Visium spatial transcriptomics. A matched single-cell RNA-seq atlas was integrated via robust cell-type deconvolution to map cellular neighbourhoods. Differential expression and pathway activity were validated by immunofluorescence. Predicted ligand-receptor mechanisms and fibroblast responses were tested in vitro under glucocorticoid (GC), TGF-β1, and B-cell/MIF perturbations with receptor blockade.

Findings: Disease-specific niches were tightly coupled to fibroblast states. OP exhibited B-cell-AT2-myofibroblast-enriched niches with high GC responsiveness and apoptosis. IPF was dominated by bronchiolised epithelium, alongside myofibroblasts exhibiting glucocorticoid resistance and strong matrix programmes. CTD-ILD exhibited macrophage-rich niches with multinucleated giant cells. In vitro, GC induced NR3C1-mediated apoptosis in fibroblasts, whereas TGF-β1 drove a senescent, GC-resistant phenotype. IgD + B-cell-derived MIF enhanced fibroblast migration via CD74, an effect blunted by TGF-β1. Thus, niche composition dictates fibroblast fate, distinguishing GC-sensitive resolution from apoptosis-resistant fibrosis.

Interpretation: A GC-sensitive, apoptosis-prone myofibroblast niche in OP may underpin reversibility, whereas CTD-ILD and IPF follow distinct trajectories driven by immune dysregulation and epithelial-stromal maladaptation. These spatial microenvironmental signatures nominate therapeutic targets and may inform precision therapy for fibrotic lung disease.

Funding: The National Natural Science Foundation of China (82172109 to L.X., 82570001 to H.C.), the Ministry of Science and Technology of the People's Republic of China (2023YFC3502605, 2024YFA1108906) (H.C.), the Natural Science Foundation of Tianjin, China (25JCZDJC01260) (H.C.); the Key Laboratory of Medical Rescue Key Technology and Equipment, Ministry of Emergency Management (Open Fund Project No. YJBKFKT202410).

Background: Neuroblastoma and Wilms tumour (WT) are common childhood embryonal malignancies. Germline 2p24 duplication has been reported in several cases of neuroblastoma and WT, either as part of a larger 2p duplication or as a microduplication involving just 2p24.3. Although the larger duplications involve many genes, including ALK, the microduplications have been localised to a region including MYCN and DDX1.

Methods: We analysed Whole Genome Sequence data from adults and children sequenced for various indications. We utilised a workflow to extract structural and copy number variants, filtered to include duplications or gains of 2 kb-20 Mb, including these loci, followed by manual inspection in IGV. Associations were assessed using Fisher's exact test. Penetrance was estimated by Bayesian calculation of the conditional probability of disease.

Findings: Among 113,431 genomes, there were 6 participants with a microduplication that included the MYCN locus. Of these, two had a diagnosis of WT and one of neuroblastoma. The 2p24.3 microduplication was therefore identified in 3/197 with a definite history of WT/neuroblastoma and 3/113,234 without such a history (p < 0.0001). Penetrance is estimated to be 13%. Twelve participants were identified with a 2p24.3 microduplication that included the DDX1 locus but not MYCN, none of whom received a diagnosis of a childhood embryonal tumour.

Interpretation: We have shown that 2p24.3 microduplications that include MYCN predispose to childhood embryonal tumours and should be routinely assessed when WT or neuroblastoma predisposition is suspected. We have also shown that there does not appear to be any increased incidence of childhood tumours when DDX1 alone is duplicated.

Funding: UCL Great Ormond Street Institute of Child Health Child Health Research CIO PhD Studentship, Brain Tumour Charity, Children with Cancer UK, Great Ormond Street Hospital Children's Charity, Olivia Hodson Cancer Fund, Cancer Research UK and the National Institute for Health Research.

Background: Metabolomics is a valuable tool for characterising biological mechanisms involved in cancer development, but produces complex datasets with intricate interdependencies. While linear dimension reduction techniques such as principal component analysis (PCA), have proven useful to summarise informative hidden patterns, biological evidence suggests metabolic relationships extend beyond linearity. Non-linear dimension reduction techniques, such as autoencoders (AEs), may identify more meaningful components.

Methods: We applied AEs and PCA to metabolomic data available for 5828 matched case-control pairs from 8 cancer-specific case-control studies nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, and compared their performance. We evaluated the association between components identified by AEs and PCA with cancer risk, and explored the biological interpretation of components through their association with genetic factors and selected biomarkers.

Findings: PCA and AEs showed similar reconstruction performance. PCA's first component (PCA.1) captured phosphatidylcholines (PCs) as the primary source of variability and was associated with cancer risk. Conversely, AEs decomposed PC metabolism into two components, one of which exhibited a stronger association with cancer risk than PCA.1. Unlike PCA.1, this component was strongly associated with genetic variants mapping to the TMEM258 and FADS genes, key in polyunsaturated fatty acids (PUFA) biosynthesis and regulation. Consistently, the AE component demonstrated stronger associations with circulating omega-3 and omega-6 PUFA levels than PCA.1.

Interpretation: Linear methods remain adequate for general dimension reduction. However, AEs better captured specific pathways, identifying a component reflecting perturbations in PUFA metabolism associated with cancer risk.

Funding: World Cancer Research Fund (IIG_FULL_2022_013).