Recent Publications

Lancet. 2026 May 16;407(10542):1941-1952. doi: 10.1016/S0140-6736(26)00555-6.

ABSTRACT

BACKGROUND: Estimates of vaccine impact have typically been used to quantify the effects of, and inform, immunisation strategies. Given the growing resource constraints on health systems worldwide, robust estimates of vaccine impact that allow comparison across different vaccines are now more crucial for decision making than ever. Building on previous modelling studies, we aimed to estimate vaccine impact ratios for an expanded portfolio of Gavi, the Vaccine Alliance-supported vaccination programmes against 14 vaccine-preventable diseases across 117 low-income and middle-income countries using multiple models.

METHODS: In this modelling study, we have presented Vaccine Impact Modelling Consortium estimates of vaccine impact ratios, defined as deaths or disability-adjusted life-years averted per 1000 vaccinations, for the Gavi portfolio of vaccines. Modelling groups used standardised inputs for demographic data and vaccination coverage assumptions, including a no-vaccination counterfactual, and accounted for structural, parameter, and stochastic uncertainty to produce burden estimates. These estimates were then compared to calculate vaccine impact ratios, disaggregated by immunisation activity type and geographical subregions for vaccinations given between 2000 and 2030 (or 2000 and 2040 for cholera).

FINDINGS: Overall, we observed human papillomavirus (11·24 [95% uncertainty interval 10·88-11·64]) and measles (6·09 [4·90-7·07])vaccines averting a higher number of deaths per 1000 vaccinations than others. For other vaccines, the impact ratios varied across subregions and activity types. Due to parameter, structural, and stochastic uncertainty, the ranges of these ratios often overlap.

INTERPRETATION: Decisions around which vaccines to use are increasingly important in the context of Gavi's country vaccine budgets. Robust metrics that allow comparison between vaccines are thus essential to inform discussions. The vaccine impact ratios presented in this study can be used to complement other evidence to support effective planning and prioritisation in national immunisation programmes.

FUNDING: Gavi, the Vaccine Alliance, Gates Foundation, and Wellcome Trust.

PMID:42134355 | DOI:10.1016/S0140-6736(26)00555-6

J Med Chem. 2026 May 14. doi: 10.1021/acs.jmedchem.5c03818. Online ahead of print.

ABSTRACT

Bruton's Tyrosine Kinase (BTK) is a validated target for hematological malignancies, with numerous FDA-approved inhibitors on the market. Current therapies target the highly conserved ATP binding site and hence limit the therapeutic index given the site's highly conserved nature across the kinome. We explore a novel approach for BTK inhibition by targeting the PH domain-mediated membrane recruitment and activation of BTK. We have identified a fragment which covalently modifies a lysine in the inositol phosphate (PIP3) binding site and inhibits the binding of a soluble PIP3 headgroup analog to the PH domain. Fragment growth and an extensive structure-binding relationship study uncovered 27 crystal structures and a best-in-class analog, 24. Evaluation of pKa values of the targeted lysine in BTK and other PH domains suggests this as a more general approach to PH domain inhibition.

PMID:42130460 | DOI:10.1021/acs.jmedchem.5c03818

Beilstein J Org Chem. 2026 Apr 22;22:611-619. doi: 10.3762/bjoc.22.47. eCollection 2026.

ABSTRACT

Human protein kinase CK2 is a constitutively active serine/threonine kinase implicated in numerous cancers. Although ATP-competitive inhibitors such as CX-4945 show therapeutic potential, they are limited by off-target effects and incomplete or transient CK2 suppression. PROTACs offer an alternative strategy by inducing proteasome-mediated degradation, with potential advantages in potency, selectivity, and duration of action. Herein, a series of CK2-targeting PROTACs has been designed and synthesised. By conjugating a CAM4066-derived warhead to CRBN or VHL ligands, four VHL-recruiting PROTACs, were prepared using PEG and alkyl linkers, alongside two CRBN-recruiting analogues featuring constrained linkers. A ligand-linker analogue in which a linker is projected from the solvent-exposed region of CK2α retained binding affinity comparable to CAM4066, confirming that linker installation is tolerated and preserves key interactions in the αD and ATP sites.

PMID:42125065 | PMC:PMC13159317 | DOI:10.3762/bjoc.22.47

Microb Genom. 2026 May;12(5). doi: 10.1099/mgen.0.001701.

ABSTRACT

Streptococcus canis represents a major canine pathogen, accounting for 22.4% of streptococcal infections in dogs. However, despite its prevalence in veterinary medicine, the mechanisms underlying S. canis pathogenesis and survival remain poorly understood. Identifying targeted treatments against S. canis could help to reduce dysbiosis-related complications and minimize the selection of resistant neighbouring bacteria. In this study, we employed transposon-directed insertion-site sequencing for the first time to generate saturated mutant libraries of S. canis. By comparing three distinct strains, we defined the shared essential genome of this pathogen. We found that 90.4% of its essential genes are also present in the essential genomes of other related pyogenic streptococcal species, including Streptococcus pyogenes, Streptococcus agalactiae and Streptococcus equi subsp. equi, demonstrating the translational relevance of S. canis research to broader streptococcal biology. Notably, we identified two genes uniquely essential to S. canis at the terminal steps of glycolysis: ldh, which governs lactate metabolism, and pta, which catalyses the conversion of acetyl-CoA to acetyl phosphate in acetate metabolism. We propose that targeting these pathways may offer a novel, species-specific therapeutic strategy for treating S. canis infections.

PMID:42118567 | DOI:10.1099/mgen.0.001701

Proc Natl Acad Sci U S A. 2026 May 19;123(20):e2532064123. doi: 10.1073/pnas.2532064123. Epub 2026 May 11.

ABSTRACT

Emerging diseases can have devastating consequences for wild species, with long-term effects depending on the ability of the host to evolve resistance. Here, we show that major histocompatibility complex (MHC) genes provided standing genetic variation that enabled rabbits to mount a rapid evolutionary response to the myxoma virus pandemic that began in the 1950s. Using historical and modern specimens starting in 1865 and spanning the pandemic, we found strong parallel shifts in MHC-I allele frequencies across Australia, Britain, and France, alongside population-specific signals. These evolutionary shifts are predicted to alter the peptides presented to T cells. Our results provide evidence that MHC-I is under strong selection in natural populations during a pandemic and that the high polymorphism of MHC may have contributed to the recovery of these populations.

PMID:42113988 | DOI:10.1073/pnas.2532064123

J Chem Theory Comput. 2026 May 7. doi: 10.1021/acs.jctc.5c02081. Online ahead of print.

ABSTRACT

Molecular property prediction integrates quantum chemistry, cheminformatics, and deep learning to connect molecular structure with physicochemical and biological behavior. This survey traces four complementary paradigms, including Quantum, Descriptor Machine Learning, Geometric Deep Learning, and Foundation Models, and outlines a unified taxonomy linking molecular representations, model architectures, and interdisciplinary applications. Benchmark analyses integrate evidence from both widely used data sets and data sets reflecting industry perspectives, encompassing quantum, physicochemical, physiological, and biophysical domains. The survey examines current standards in data curation, splitting strategies, and evaluation protocols, highlighting challenges including inconsistent stereochemistry, heterogeneous assay sources, and reproducibility limitations under random or poorly defined splits. These observations motivate the modernization of benchmark design toward more transparent, time- and scaffold-aware methodologies. We further propose three forward-looking directions: (i) physics-aware learning embedding quantum consistency, (ii) uncertainty-calibrated foundation models for trustworthy inference, and (iii) realistic multimodal benchmark ecosystems integrating computational and experimental data. Repository: https://github.com/Zongru-Li/Survey-and-Benchmarks-of-DL-for-Molecular-Property-Prediction-in-the-Foundation-Model-Era.

PMID:42096352 | DOI:10.1021/acs.jctc.5c02081

J Virol. 2026 May 7:e0019526. doi: 10.1128/jvi.00195-26. Online ahead of print.

ABSTRACT

The most recently acquired and transcriptionally active family of human endogenous retroviruses (HERVs) is HERV-K. Of the approximately 100 copies of HERV-K in our genome, many retain the potential to proliferate by retrotransposition, express viral proteins, and form functional virus particles. Aberrant expression of the HERV-K envelope glycoprotein (Env) has been associated with cancer and neurodegeneration. Autoantibodies against HERV-K Env have been found in patients with various autoimmune diseases. Here, we report the crystal structure of the Env surface subunit (SU) from HERV-K HML-2, determined at 2.25-Å resolution. The overall fold is somewhat similar to Syncytin-2 SU and distantly related to HIV-1 gp120. The structure contains five disulfides, four N-linked glycans, and two sulfate ions bound to a basic surface groove. Two extended loops form a surface for potential interactions with cell-surface receptors or other cellular factors. The structure also contains three steroid molecules bound to hydrophobic surface patches. This crystal structure provides a platform for future studies to map autoantigenic epitopes, identify small molecules that interfere with HERV-K activity, and extend our mechanistic understanding of retroviruses.IMPORTANCEEight percent to 15% of the human genome consists of endogenous retroviruses and other virus-derived elements inherited from ancestral viral infections. Many endogenous retroviruses from the HERV-K family retain the ability to proliferate across the genome and produce virus-like particles. Aberrant expression of the HERV-K envelope glycoprotein is associated with cancer, neurodegeneration, and autoimmune disease. Here, we report the crystal structure of the HERV-K envelope glycoprotein surface subunit. The structure provides an atomic-level view of the molecular components in HERV-K most likely to trigger autoimmune responses and identifies potential binding sites for drug-like molecules and cell-surface polysaccharides.

PMID:42095673 | DOI:10.1128/jvi.00195-26

Brain. 2026 May 7:awag160. doi: 10.1093/brain/awag160. Online ahead of print.

ABSTRACT

Multiple system atrophy (MSA) is a neurodegenerative condition causing parkinsonism, cerebellar ataxia and/or dysautonomia. Typical survival is between 6-10 years, but some people die before five or after 15 years. This heterogeneity complicates advanced planning and clinical trial stratification. MSA prognostication studies have shown conflicting results, possibly due to diagnostic accuracy or study size. We report results from a study of survival prognostic factors in a cohort of 555 MSA patients (including the largest post-mortem confirmed cohort to date of 254 people) gathered through the Queen Square Brain Bank and the PROSPECT-M-UK multi-centre prospective cohort study. Through PROSPECT-M-UK, 318 clinically diagnosed MSA patients (17 overlapped with the QSBB cohort) were followed up annually over 5 years. The QSBB cohort clinical data was collected through retrospective review of primary and secondary care documentation. Survival analysis was performed using counting process Cox proportionate hazards modelling, Kaplan-Meier log-rank testing and landmark survival analysis to account for guarantee-time bias. Mean onset age in the combined cohort was 58.7±9.0y with median survival of 8.25y (95% CI:7.88-8.63). 28.8% were clinically diagnosed in-life with MSA-P, 23.8% MSA-C, 40.2% mixed and the rest as non-MSA diagnoses. Later disease onset was associated with shorter survival (HR=1.04, P<0.001). The commonest cause of death was respiratory infection (67%) followed by disease related decline (20%). Median survival from indoor wheelchair use, gastrostomy insertion or development of unintelligible speech was consistently <1.5 years (95% CI upper limits<2.4 years), making these reliable late-stage disease markers. Using landmark analysis, at 3 years from onset, negative prognostic factors included recurrent falls, unintelligible speech, use of catheters and of medication for orthostatic hypotension (HR = 1.57, 3.29, 1.76, 3.29;all P<0.05). At 5 years from onset, mobility milestones including walking aid use, outdoor and indoor wheelchair use (HR = 1.70, 1.93, 2.62;all P<0.01) became significant, whilst dysautonomia milestones (catheter and orthostatic support medication use) were no longer significant. Median individual Unified Multiple System Atrophy Rating Scale (UMSARS) progression rate (n=91) was 10.27 (IQR:5.31-14.30) points/year and did not correlate with symptom duration. Higher baseline UMSARS and faster UMSARS progression were negative prognostic factors of survival from baseline review (HR=1.03 and 1.07 respectively, both P<0.001). We show that in-clinic rating scales and clinical milestone assessment can aid MSA prognostication. Importantly, prognostic factors demonstrate time-dependent variability, which may contribute to previous heterogeneity observed in smaller studies. This knowledge is important for patient care and should inform future clinical trial stratification.

PMID:42095271 | DOI:10.1093/brain/awag160

BMJ Public Health. 2026 Apr 27;4(2):e003957. doi: 10.1136/bmjph-2025-003957. eCollection 2026.

ABSTRACT

INTRODUCTION: Large out-of-home (OOH) food businesses in England have been required by law to display calorie information on menus since 6 April 2022. This study investigated whether the implementation of this policy was associated with changes in calories purchased OOH by consumers.

METHODS: Controlled interrupted time series analysis was used to estimate changes in calories purchased from all OOH outlets in England (intervention group). Secondary outcomes included purchases from large chains, non-chain outlets and five subtypes of purchases (meals, lower-calorie coffee, higher-calorie coffee, sandwiches and fish and chip meals). The control series consisted of purchases from non-chain outlets in Scotland and Wales to avoid spillover labelling in chains across Great Britain. We aggregated self-reported itemised OOH food and non-alcoholic drink purchases from a rolling consumer panel of ~7500 individuals spanning 13 weeks pre intervention and 34 weeks post intervention to population-level average weekly per-person calorie (kcal) purchase estimates. Linear regression, adjusted for season and inflation, modelled level and trend changes compared with the counterfactual of no mandatory policy. Subgroup analyses explored effects by age, sex, occupational socioeconomic status, weight status and weekday/weekend purchases.

RESULTS: Compared with the counterfactual, we found no evidence of a change in overall calories purchased OOH associated with mandatory calorie labelling (level change -95.6 kcal, 95% CI -471.2 to 280.0; trend change 5.1 kcal, 95% CI -5.5 to 15.8). There was also no robust evidence of changes in calories purchased OOH for secondary outcomes and by subgroups compared with the counterfactual of no mandatory calorie labelling. Small changes observed in these analyses were sensitive to analytical choices.

CONCLUSIONS: This study supports existing evidence that calorie labelling alone is unlikely to secure significant changes in food purchasing behaviour at population level. Possible changes to menus were not included in the study and warrant further investigation.

PMID:42094650 | PMC:PMC13141202 | DOI:10.1136/bmjph-2025-003957

Microb Genom. 2026 May;12(5). doi: 10.1099/mgen.0.001654.

ABSTRACT

Background. Rates of multidrug resistance (MDR) in Gram-negative bacteria (GNB), particularly those harbouring extended-spectrum beta-lactamases (ESBL) and/or carbapenemases, are increasing globally. Intensive care unit (ICU) patients are vulnerable to healthcare-associated infection (HCAI). Surveillance for carriage of multidrug-resistant Gram-negative bacteria (MDR GNB) is inconsistent, with differing practices amongst ICUs, hospitals and countries. Furthermore, the impact of asymptomatic carriage on HCAI rates is unclear.Methods. We conducted a 6-month prospective surveillance study of MDR GNB in a UK adult ICU. Screening samples were collected from all study participants on admission, once a week (depending on length of stay) and on discharge from the ICU. Whole-genome sequencing (WGS) was used to examine the population structure and antimicrobial resistance mechanisms of MDR GNB and to determine evidence of recent transmission between patients.Findings. Of 424 participants recruited between June and December 2016, 15% (n=64) were positive for MDR GNB during admission screening to the ICU. The most frequently identified organisms were Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae. In total, 10% (n=42) of patients acquired an ESBL-producing or carbapenem-resistant MDR GNB during their ICU admission. WGS of the bacterial populations reflected national trends. An undetected outbreak of carbapenemase-producing K. pneumoniae, which had spread to several wards, was identified and controlled. Most positive patients carried identical lineages across multiple body sites.Interpretation. Our findings suggest that prospective screening for MDR GNB in ICU patients could be beneficial and be considered in other UK critical care settings. This would not only improve early detection but also enable the prompt institution of enhanced infection control measures.

PMID:42089880 | DOI:10.1099/mgen.0.001654