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Journal articleWang Z, Dunican C, Dayananda P, et al., 2026,
Comparative cross-species transcriptomics during RSV infection identifies targets to treat RSV disease
, Journal of Infection, Vol: 92, ISSN: 0163-4453Respiratory syncytial virus (RSV) remains a health threat to young children worldwide. The host immune response plays a key role in disease following infection. Infection models advance our understanding of respiratory viruses, but individual models have gaps, which overlapping complementary systems can fill. We compared disease signatures in mice, adults and children; combining transcriptomic data collected from blood, nasal mucosa and lung biopsy following RSV infection. We identified both shared and species-specific pathways triggered by RSV. While systemic responses in children’s blood were more similar to those in RSV-challenged adults, mucosal responses during primary infection in mice more closely resembled those in children. We identified an association between IL-17 pathways and RSV pathogenesis and with over-expression of the downstream effectors S100A8 and S100A9. Inhibiting these with the anti-inflammatory drug Paquinimod reduced disease. Here we demonstrate that integrating mouse and human transcriptomic data can identify novel targets to treat RSV disease.
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Journal articleTam KMM, Brown NC, Bronstein M, et al., 2026,
Learning constrained static equilibrium for thrust network inverse form-finding via physics-informed geometric deep learning on CW complexes
, Advanced Engineering Informatics, Vol: 70, ISSN: 1474-0346This work integrates Geometric Deep Learning (GDL) with physics-informed modelling to approximate solutions to a constrained, ill-conditioned, and nonlinear inverse shell form-finding problem across diverse geometries and patterns. Given a target geometry and pattern design as meshes, the proposed neural framework predicts a funicular shell—defined by edge forces and vertex positions—that satisfies static equilibrium and closely matches the target form. Three main contributions are introduced: (1) a relaxed, numerically stable physics objective using efficient differentiable graph operators to mitigate the ill-conditioning of the nonlinear problem; (2) a stochastic augmentation strategy that enriches training with geometries of varying funicular feasibility, enhancing generalisation to infeasible inputs; and (3) a hierarchical GDL architecture that learns directly from irregular n -gon surface meshes, modelled as cell complexes to incorporate vertex, edge, and face features in both inputs and outputs. This approach eliminates the need for simplification of graph datastructures common in existing methods, improving mesh modelling versatility. Extensive studies examine the numerical stability of physics formulations, robustness for out-of-distribution designs, and the expressivity of the GDL architecture. While focused on a specific inverse form-finding task, this work offers general insights into addressing ill-posed inverse problems, showing how physics-based learning can support optimisation of mesh-based architectural structures under variable connectivity and design constraints.
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Journal articleCelsa C, Pressiani T, Nishida N, et al., 2026,
Reproducible safety and efficacy of durvalumab with or without tremelimumab for hepatocellular carcinoma in clinical practice: Results of the DT-real study.
, JHEP Rep, Vol: 8BACKGROUND & AIMS: Durvalumab plus tremelimumab (STRIDE) has emerged as a first-line systemic treatment option for unresectable hepatocellular carcinoma (HCC). This international multicentre study aimed to evaluate the efficacy and tolerability of STRIDE or durvalumab monotherapy in routine clinical practice, comparing outcomes between patients within and outside key eligibility criteria for the HIMALAYA trial. METHODS: From a database of 1,423 patients with advanced/unresectable HCC treated with immunotherapy across 35 centres, we analysed 233 patients receiving STRIDE or durvalumab monotherapy. Patients were categorized as HIMALAYA-IN or HIMALAYA-OUT based on key trial eligibility criteria (no prior systemic therapy, ECOG-PS 0-1, Child-Pugh class A, no Vp4 thrombosis). Baseline characteristics were assessed for overall survival (OS) and hepatic decompensation using a multivariable Cox model and competing-risk analysis, respectively. Objective response rates and treatment-related adverse events were recorded. RESULTS: Of the 233 patients, 123 (53%) were HIMALAYA-IN and 110 (47%) were HIMALAYA-OUT. STRIDE was given in 95% of HIMALAYA-IN patients. After median follow-up of 6.0 months, median OS was 20.4 months (95% CI 11.7-NR) in the overall population. HIMALAYA-IN patients achieved significantly longer OS than HIMALAYA-OUT patients (23.0 vs. 12.2 months; hazard ratio 0.61; 95% CI 0.39-0.96; p = 0.03). Macrovascular invasion and hepatic decompensation were independent negative prognostic factors in the whole cohort. Hepatic decompensation occurred in 10.5% of patients within 12 months from treatment start. Objective response rate was 23.7% and 17.8% of HIMALAYA-IN and -OUT patients, respectively. Patients achieving disease control (whole cohort: 59.4%) demonstrated 24-month OS of 58.2% in HIMALAYA-IN and 44.8% in HIMALAYA-OUT groups. Grade 3-4 treatment-related adverse events occurred in 16.3% of patients. CONCLUSIONS: STRIDE shows reproducible effectiveness and
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Journal articleTregoning JS, 2026,
Science funding needs fixing — but not through chaotic reforms
, Nature, Vol: 650, Pages: 525-525, ISSN: 0028-0836 -
Journal articlePinato D, 2026,
Reproducible safety and efficacy of durvalumab with or without tremelimumab for hepatocellular carcinoma in clinical practice: Results of the DT-real study
, JHEP Reports, ISSN: 2589-5559 -
Journal articleHo V, Baker J, Fenwick P, et al., 2026,
Single cell microfluidic quantification of miRNA-21 and miRNA-34a reveals miRNA interactions in small airway epithelial cells and fibroblasts from COPD patients
, American Journal of Physiology - Lung Cellular and Molecular Physiology, ISSN: 1040-0605Rationale: MicroRNA-21 and microRNA-34a are implicated in chronic obstructive pulmonary disease (COPD) pathogenesis, but their cell-specific expression patterns and interactions within individual airway cells remain unexplored.Objective: To develop a single cell microfluidic platform for dual, amplification-free detection of miR-21-5p and miR-34a-5p in primary small airway cells from COPD patients.Methods: Small airway epithelial cells (SAEC) and fibroblasts (SAF) were isolated from COPD patients and non-smokers (n = 6–8 per group). A microfluidic chip with dual miRNA sandwich hybridisation assays was used to quantify miR-21-5p and miR-34a-5p in single cells. Expression of miRNAs and their target genes was evaluated under oxidative stress using qPCR and Western blotting.Main Results: Single cell analysis revealed significantly higher miR-21-5p and miR-34a-5p expression in COPD-derived cells compared to controls. MiR-21 exhibited greater variability than miR-34a, and their positive correlation in control cells was disrupted in COPD. Oxidative stress elevated miR-21 and miR-34a while reducing expression of miR-21 targets and increasing senescence markers (p21Cip1/Waf1, p16INK4a). MiR-21 antagomir restored expression of suppressed targets in both cell types.Conclusions: Our novel single cell microfluidic platform enables precise, simultaneous detection of miR-21 and miR-34a in single small airway cells. This allows the interrelationship between the miRNAs to be assessed within the same cell. MiR-21 and miR-34a represent promising therapeutic targets for restoring gene regulatory balance in COPD.
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Journal articleNapolitano L, Vadukul D, Bigi A, et al., 2026,
Engineering a dimeric single-domain antibody for improved detection and neutralization of amyloid-β oligomers
, Communications Biology, ISSN: 2399-3642Soluble Aβ oligomers are regarded as major neurotoxic agents in Alzheimer’s disease. Several monoclonal antibodies have been developed to target Aβ oligomers, but most of them show limited specificity binding also to monomers and fibrils. To generate an antibody with high specificity for the oligomers, we aimed to increase the efficiency and sensitivity of a humanized Aβ-oligomer specific single domain antibody, called DesAb-O. We engineered a dimeric DesAb-O variant, DiDesAb-O, which showed significantly higher binding affinity for Aβ oligomers as compared to the monomeric sdAb. DiDesAb-O selectively detected Aβ42 oligomers not only in vitro and in cultured cells using synthetic preparations, but also in the cerebrospinal fluid from Alzheimer's patients. Moreover, it inhibited the binding of these toxic species to cellular membranes and neutralized their neurotoxicity both in cells and in patient-derived cerebrospinal fluid at lower concentrations compared to DesAb-O. These results indicate that rational dimerization of single domain antibodies can substantially enhance target engagement and functional efficacy, providing a promising strategy for the development of improved diagnostic and therapeutic molecules for Alzheimer’s disease.
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Journal articleHamilton MS, Derks I, Kaforou M, et al., 2026,
Identifying correlates of risk for future tuberculosis disease progression in South African children (intrepid): a protocol paper
, BMJ Open, ISSN: 2044-6055IntroductionYoung children and children living with HIV are at high risk of progressing to tuberculosis (TB) disease following Mycobacterium tuberculosis (Mtb) exposure and infection, and also of developing severe forms of disease and TB-related mortality. Identifying children who have very early (sub-clinical) TB disease, prior to progression to clinically apparent TB, would mean that TB preventive treatment (TPT) could be more efficiently targeted to this group. Identifying biomarker changes on drug therapy in children with Mtb infection or very early disease could pave the way for the development of tests that can identify which children have viable bacilli and are therefore at increased risk of disease progression. Methods and analysisThe INTREPID study will utilize already collected samples taken from well-phenotyped paediatric cohorts in three clinical studies conducted in South Africa in children <5 years, including a drug-resistant TPT trial (TB-CHAMP), an observational household contact study (IGRA studies), and a prospective diagnostic study (Umoya), all conducted in a setting with a high burden of TB and HIV. We will employ transcriptomic, proteomic, metabolomic, and serology approaches to analyse changes in host blood profiles at every stage along the TB continuum, from Mtb exposure to disease and from children treated for Mtb infection and early TB disease, as well as targeted Mtb antibody analysis. Data on viral co-infections and relevant clinical and epidemiological parameters will be integrated and evaluated to identify the optimal biosignatures that can predict future progression to clinically overt disease in children below 5 years of age, including those living with HIV. Ethics and disseminationThe study protocol received ethical approval from the Stellenbosch University Health Research Ethics Committee (N23/03/025). The study findings will be disseminated through peer-reviewed publications, scientific conferences, and formal presentations to
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Journal articleWang D, Hadad N, Moss S, et al., 2026,
Assessment of mosaic loss of chromosome Y in pulmonary fibrosis reveals limited association with susceptibility or disease severity.
, BMJ Open Respir Res, Vol: 13BACKGROUND: Pulmonary fibrosis (PF) is a rare lung disease with diverse pathogenesis and biological mechanisms. Mosaic loss of chromosome Y (mLOY) has been reported to be associated with increased risk of fibrotic diseases. However, the exact role of mLOY in the development of PF remains to be elucidated. METHODS: Copy number on chromosome Y was used to estimate mLOY comparing patients in PROFILE and gnomAD cohorts and between cases and control patients from the GE100KGP cohort. Correlation of mLOY with demographic and clinical variables was tested using patients from the PROFILE cohort. Lung single-cell transcriptomic data were analysed to assess the cell types implicated in mLOY. Mendelian randomisation was performed to examine the causal relationship between mLOY, idiopathic pulmonary fibrosis (IPF) and telomere length. RESULTS: The genetic analysis suggests that mLOY is found in PF from both case cohorts but when compared with an age matched population the effect is minimal (p=0.00316, median: 0.288 vs 0.291). mLOY is related to age (p=0.000214) and shorter telomere length (p=0.00815) rather than PF severity or progression. Single-cell analysis indicates that mLOY appears to be found primarily in immune cells. Mendelian randomisation demonstrates that mLOY is not on the causal pathway for IPF, but partial evidence supports that telomere shortening is on the causal pathway for mLOY. CONCLUSIONS: Our study confirms the existence of mLOY in PF patients, suggests that mLOY is not a major driver of IPF, and might support a triangulation model where telomere shortening leads to both IPF and mLOY.
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Journal articleHunt M, Hinrichs AS, Anderson D, et al., 2026,
Addressing pandemic-wide systematic errors in the SARS-CoV-2 phylogeny.
, Nat MethodsThe majority of SARS-CoV-2 genomes obtained during the pandemic were derived by amplifying overlapping windows of the genome ('tiled amplicons'), reconstructing their sequences and fitting them together. This leads to systematic errors in genomes unless the software is both aware of the amplicon scheme and of the error modes of amplicon sequencing. Additionally, over time, amplicon schemes need to be updated as new mutations in the virus interfere with the primer binding sites at the end of amplicons. Thus, waves of variants swept the world during the pandemic and were followed by waves of systematic errors in the genomes, which had significant impacts on the inferred phylogenetic tree.Here we reconstruct the genomes from all public data as of June 2024 using an assembly tool called Viridian ( https://github.com/iqbal-lab-org/viridian ), developed to rigorously process amplicon sequence data. With these high-quality consensus sequences we provide a global phylogenetic tree of 4,471,579 samples, viewable at https://viridian.taxonium.org . We provide simulation and empirical validation of the methodology, and quantify the improvement in the phylogeny.
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