Recent Publications

Trends Parasitol. 2025 Apr 21:S1471-4922(25)00094-7. doi: 10.1016/j.pt.2025.03.014. Online ahead of print.

ABSTRACT

Photosynthesis has been lost independently many times in eukaryote evolutionary history. Surprisingly, the ability to synthesise chlorophyll has sometimes been retained after loss of photosynthesis. Jacko-Reynolds et al. show this phenomenon in a group of Apicomplexa parasitising corals. Possible explanations include a role in organelle-to-nucleus signalling, molecular trickery, and defence against predators.

PMID:40263028 | DOI:10.1016/j.pt.2025.03.014

Proc Natl Acad Sci U S A. 2025 May 6;122(18):e2424634122. doi: 10.1073/pnas.2424634122. Epub 2025 Apr 22.

ABSTRACT

Horizontal transfer of nuclear DNA between cells of host and cancer is a potential source of adaptive variation in cancer cells. An understanding of the frequency and significance of this process in naturally occurring tumors is, however, lacking. We screened for this phenomenon in the transmissible cancers of dogs and Tasmanian devils and found an instance in the canine transmissible venereal tumor (CTVT). This involved introduction of a 15-megabase dicentric genetic element, composed of 11 fragments of six chromosomes, to a CTVT sublineage occurring in Asia around 2,000 y ago. The element forms the short arm of a small submetacentric chromosome and derives from a dog with ancestry associated with the ancient Middle East. The introduced DNA fragment is transcriptionally active and has adopted the expression profile of CTVT. Its features suggest that it may derive from an engulfed apoptotic body. Our findings indicate that nuclear horizontal gene transfer, although likely a rare event in tumor evolution, provides a viable mechanism for the acquisition of genetic material in naturally occurring cancer genomes.

PMID:40261943 | DOI:10.1073/pnas.2424634122

Antiviral Res. 2025 Apr 18:106171. doi: 10.1016/j.antiviral.2025.106171. Online ahead of print.

ABSTRACT

Oropouche virus (OROV) has caused a new outbreak, with thousands of cases of febrile disease in South and Central America, including regions where the virus was not detected before. Oropouche fever is a neglected mosquito-borne disease that still lacks options for antiviral treatment. We developed a high-throughput screening phenotypic assay using human hepatocyte-derived HuH-7.0 cells to screen over 7,700 compounds against OROV infection. We identified 13 hit compounds that were protective against OROV-induced cytopathic effect in cell culture, of which 3 were confirmed: lysergol, amiloride hydrochloride, and pyridostatin TFA, with EC50 values below 2 μM. Orthogonal assays indicate that both lysergol and pyridostatin present antiviral activity against OROV in HuH-7.0 and T24 cell lines, but lysergol is far more potent, causing up to a 100,000-fold reduction in viral load in the low micromolar range. Mechanistic studies indicate that the antiviral effect of lysergol affects early stages of viral replication, and that lysergol is also active against a recently isolated OROV strain. In conclusion, our phenotypical screening campaign led to the identification of a first-in-class compound with potent antiviral activity against the emerging OROV in cell culture. We conclude that high-throughput screening assays can be implemented in response to the emergence of arboviruses and accelerate the discovery of candidate treatments.

PMID:40254261 | DOI:10.1016/j.antiviral.2025.106171

Vet Microbiol. 2025 Apr 11;305:110509. doi: 10.1016/j.vetmic.2025.110509. Online ahead of print.

ABSTRACT

Glaesserella parasuis is the causative agent of Glässer's disease in pigs and results in significant losses to the swine industry annually. Due to the serovar and strain specific response associated with many bacterin vaccines, there has been difficulty generating broad heterologous protection. Here, an unencapsulated G. parasuis mutant (HS069∆cap) was assessed as a bacterin vaccine and compared to a bacterin made from the encapsulated parent strain, against challenge with the homologous, parent strain (serovar 5) as well as four heterologous challenge strains (serovar 1, 4, 5, and 14). Both the HS069 and HS069∆cap bacterins generated high titers to the homologous and heterologous strains. The HS069∆cap bacterin was able to provide protection against the parent strain as well as 12939 (serovar 1), 2170B (serovar 4), and MN-H (serovar 13), but was unable to protect animals from challenge with Nagasaki (serovar 5). In contrast, the HS069 bacterin was able to provide protection against all challenge strains, showing the importance of serovar specific immunity against the challenge strain Nagasaki. This appears to be due to the production of a more abundant and well-organized capsule in Nagasaki as compared to HS069. This study indicates HS069∆cap is a good candidate strain for bacterin development; however, it may be less able to provide protection against highly encapsulated strains of G. parasuis.

PMID:40250105 | DOI:10.1016/j.vetmic.2025.110509

Nat Commun. 2025 Apr 17;16(1):3689. doi: 10.1038/s41467-025-58977-y.

ABSTRACT

B cells have important functions in gut homeostasis, and dysregulated B cell populations are frequently observed in patients with inflammatory bowel diseases, including both ulcerative colitis (UC) and Crohn's disease (CD). How these B cell perturbations contribute to disease remains largely unknown. Here, we perform deep sequencing of the B cell receptor (BCR) repertoire in four cohorts of patients with CD, together with healthy controls and patients with UC. We identify BCR clones that are shared between patients with CD but not found in healthy individuals nor in patients with UC, indicating CD-associated B cell immune responses. Shared clones are present in the inflamed gut mucosa, draining intestinal lymph nodes and blood, suggesting the presence of common CD-associated antigens that drive B cell responses in CD patients.

PMID:40246842 | PMC:PMC12006383 | DOI:10.1038/s41467-025-58977-y

Pharmacogenomics J. 2025 Apr 17;25(3):9. doi: 10.1038/s41397-025-00367-0.

ABSTRACT

Similarity between candidate drug targets and human proteins is commonly assessed to minimize the occurrence of side effects. Although numerous drugs have been found to disrupt the health of the human microbiome, no comprehensive comparison between established drug targets and the human microbiome metaproteome has yet been conducted. Therefore, herein, sequence and structure alignments between human and pathogen drug targets and representative human gut, oral, and vaginal microbiome metaproteomes were performed. Both human and pathogen drug targets were found to be similar in sequence, function, structure, and drug binding capacity to proteins in diverse pathogenic and non-pathogenic bacteria from all three microbiomes. The gut metaproteome was identified as particularly susceptible overall to off-target effects. Certain symptoms, such as infections and immune disorders, may be more common among drugs that non-selectively target host microbiota. These findings suggest that similarities between human microbiome metaproteomes and drug target candidates should be routinely checked.

PMID:40246834 | PMC:PMC12006021 | DOI:10.1038/s41397-025-00367-0

Clin Microbiol Infect. 2025 Apr 11:S1198-743X(25)00169-7. doi: 10.1016/j.cmi.2025.04.007. Online ahead of print.

ABSTRACT

BACKGROUND: The gap between early diagnostic assumptions and final diagnoses in disease outbreaks represents a persistent challenge in global health despite advancements in diagnostic and response capabilities.

OBJECTIVES: To analyze the unfolding 2025 outbreak in the Democratic Republic of Congo (DRC) through the lens of historical cases where initial misattributions contributed to delayed recognition of novel or unexpected threats with varying public health consequences; identifying patterns from past outbreaks that can inform current diagnostic approaches and response strategies.

SOURCES: We selected illustrative examples from peer-reviewed publications, focusing on cases with initial diagnostic uncertainties that highlight specific diagnostic patterns relevant to the current DRC outbreak. For the ongoing DRC outbreak, we analyzed official World Health Organization Africa bulletins and communications from the DRC Ministry of Health through February and early March 2025.

CONTENT: As of beginning of April 2025, health authorities continue investigating clusters of unexplained acute febrile illness in Équateur Province with clinical features that were initially being suggestive of a viral haemorrhagic fever. Primary VHF pathogens have now been excluded. From selected historical and recent outbreaks, it can be deduced that diagnostic challenges extend beyond individual cognition to include structural biases in global health systems, methodological limitations and sociocultural factors.

IMPLICATIONS: We identified five evidence-informed interventions to mitigate diagnostic delays: systematic consideration of multiple working hypotheses, development of sustainable local diagnostic capacity, enhancement of clinician-to-public-health communication networks, implementation of cognitive debiasing strategies, and strengthening of One Health surveillance platforms. Historical 'misdiagnoses' offer crucial lessons for transforming outbreak response from reactive to anticipatory, potentially averting future epidemics through earlier, more accurate recognition of emerging pathogens within their complex ecological and social contexts.

PMID:40222556 | DOI:10.1016/j.cmi.2025.04.007

BJPsych Open. 2025 Apr 11;11(3):e86. doi: 10.1192/bjo.2025.32.

ABSTRACT

BACKGROUND: Rates of childhood mental health problems are increasing in the UK. Early identification of childhood mental health problems is challenging but critical to children's future psychosocial development. This is particularly important for children with social care contact because earlier identification can facilitate earlier intervention. Clinical prediction tools could improve these early intervention efforts.

AIMS: Characterise a novel cohort consisting of children in social care and develop effective machine learning models for prediction of childhood mental health problems.

METHOD: We used linked, de-identified data from the Secure Anonymised Information Linkage Databank to create a cohort of 26 820 children in Wales, UK, receiving social care services. Integrating health, social care and education data, we developed several machine learning models aimed at predicting childhood mental health problems. We assessed the performance, interpretability and fairness of these models.

RESULTS: Risk factors strongly associated with childhood mental health problems included age, substance misuse and being a looked after child. The best-performing model, a gradient boosting classifier, achieved an area under the receiver operating characteristic curve of 0.75 (95% CI 0.73-0.78). Assessments of algorithmic fairness showed potential biases within these models.

CONCLUSIONS: Machine learning performance on this prediction task was promising. Predictive performance in social care settings can be bolstered by linking diverse routinely collected data-sets, making available a range of heterogenous risk factors relating to clinical, social and environmental exposures.

PMID:40214105 | DOI:10.1192/bjo.2025.32

Eur J Cell Biol. 2025 Apr 4;104(2):151488. doi: 10.1016/j.ejcb.2025.151488. Online ahead of print.

ABSTRACT

Mitochondria adapt to the cell proliferative demands induced by growth factors through dynamic changes in morphology, distribution, and metabolic activity. Galectin-8 (Gal-8), a carbohydrate-binding protein that promotes cell proliferation by transactivating the EGFR-ERK signaling pathway, is overexpressed in several cancers. However, its impact on mitochondrial dynamics during cell proliferation remains unknown. Using MDCK and RPTEC kidney epithelial cells, we demonstrate that Gal-8 induces mitochondrial fragmentation and perinuclear redistribution. Additionally, mitochondria adopt donut-shaped morphologies, and live-cell imaging with two Keima-based reporters demonstrates Gal-8-induced mitophagy. ERK signaling inhibition abrogates all these Gal-8-induced mitochondrial changes and cell proliferation. Studies with established mutant versions of Gal-8 and CHO cells reveal that mitochondrial changes and proliferative response require interactions between the N-terminal carbohydrate recognition domain of Gal-8 and α-2,3-sialylated N-glycans at the cell surface. DRP1, a key regulator of mitochondrial fission, becomes phosphorylated in MDCK cells or overexpressed in RPTEC cells in an ERK-dependent manner, mediating mitochondrial fragmentation and perinuclear redistribution. Bafilomycin A abrogates Gal-8-induced cell proliferation, suggesting that mitophagy serves as an adaptation to cell proliferation demands. Functional analysis under Gal-8 stimulation shows that mitochondria maintain an active electron transport chain, partially uncoupled from ATP synthesis, and an increased membrane potential, indicative of healthy mitochondria. Meanwhile, the cells exhibit increased extracellular acidification rate and lactate production via aerobic glycolysis, a hallmark of an active proliferative state. Our findings integrate mitochondrial dynamics with metabolic adaptations during Gal-8-induced cell proliferation, with potential implications for physiology, disease, and therapeutic strategies.

PMID:40209344 | DOI:10.1016/j.ejcb.2025.151488

Nat Struct Mol Biol. 2025 Apr 9. doi: 10.1038/s41594-025-01530-8. Online ahead of print.

ABSTRACT

Pathogens have evolved diverse strategies to counteract host immunity. Ubiquitylation of lipopolysaccharide (LPS) on cytosol-invading bacteria by the E3 ligase RNF213 creates 'eat me' signals for antibacterial autophagy, but whether and how cytosol-adapted bacteria avoid LPS ubiquitylation remains poorly understood. Here, we show that the enterobacterium Shigella flexneri actively antagonizes LPS ubiquitylation through IpaH1.4, a secreted effector protein with ubiquitin E3 ligase activity. IpaH1.4 binds to RNF213, ubiquitylates it and targets it for proteasomal degradation, thus counteracting host-protective LPS ubiquitylation. To understand how IpaH1.4 recognizes RNF213, we determined the cryogenic electron microscopy structure of the IpaH1.4-RNF213 complex. The specificity of the interaction is achieved through the leucine-rich repeat of IpaH1.4, which binds the RING domain of RNF213 by hijacking the conserved RING interface required for binding to ubiquitin-charged E2 enzymes. IpaH1.4 also targets other E3 ligases involved in inflammation and immunity through binding to the E2-interacting face of their RING domains, including the E3 ligase LUBAC that is required for the synthesis of M1-linked ubiquitin chains on cytosol-invading bacteria downstream of RNF213. We conclude that IpaH1.4 has evolved to antagonize multiple antibacterial and proinflammatory host E3 ligases.

PMID:40205224 | DOI:10.1038/s41594-025-01530-8

Nat Microbiol. 2025 Apr 9. doi: 10.1038/s41564-025-02003-w. Online ahead of print.

NO ABSTRACT

PMID:40204877 | DOI:10.1038/s41564-025-02003-w

Proc Mach Learn Res. 2024 Jul;235:39529-39555.

ABSTRACT

Topological deep learning (TDL) is a rapidly evolving field that uses topological features to understand and design deep learning models. This paper posits that TDL is the new frontier for relational learning. TDL may complement graph representation learning and geometric deep learning by incorporating topological concepts, and can thus provide a natural choice for various machine learning settings. To this end, this paper discusses open problems in TDL, ranging from practical benefits to theoretical foundations. For each problem, it outlines potential solutions and future research opportunities. At the same time, this paper serves as an invitation to the scientific community to actively participate in TDL research to unlock the potential of this emerging field.

PMID:40196046 | PMC:PMC11973457

Sci Rep. 2025 Apr 7;15(1):11907. doi: 10.1038/s41598-025-95644-0.

ABSTRACT

The TMPRSS2 cell surface protease is used by a broad range of respiratory viruses to facilitate entry into target cells. Together with ACE2, TMPRSS2 represents a key factor for SARS-CoV-2 infection, as TMPRSS2 mediates cleavage of viral spike protein, enabling direct fusion of the viral envelope with the host cell membrane. Since the start of the COVID-19 pandemic, TMPRSS2 has gained attention as a therapeutic target for protease inhibitors which would inhibit SARS-CoV-2 infection, but little is known about TMPRSS2 regulation, particularly in cell types physiologically relevant for SARS-CoV-2 infection. Here, we performed an unbiased genome-wide CRISPR-Cas9 library screen, together with a library targeted at epigenetic modifiers and transcriptional regulators, to identify cellular factors that modulate cell surface expression of TMPRSS2 in human colon epithelial cells. We find that endogenous TMPRSS2 is regulated by the Elongin BC-VHL complex and HIF transcription factors. Depletion of Elongin B or treatment of cells with PHD inhibitors resulted in downregulation of TMPRSS2 and inhibition of SARS-CoV-2 infection. We show that TMPRSS2 is still utilised by SARS-CoV-2 Omicron variants for entry into colonic epithelial cells. Our study enhances our understanding of the regulation of endogenous surface TMPRSS2 in cells physiologically relevant to SARS-CoV-2 infection.

PMID:40195420 | PMC:PMC11976923 | DOI:10.1038/s41598-025-95644-0

J Virol. 2025 Apr 7:e0216724. doi: 10.1128/jvi.02167-24. Online ahead of print.

ABSTRACT

Synthesis of subgenomic RNAs is a strategy commonly used by polycistronic positive-sense single-stranded RNA viruses to express 3'-proximal genes. Members of the order Nidovirales, including coronaviruses and arteriviruses, use a unique discontinuous transcription strategy to synthesize subgenomic RNAs. In this study, in silico synonymous site conservation analysis and RNA structure folding predicted the existence of intra-family conserved high-order RNA structure within the M ORF of arteriviral genomes, which was further confirmed by RNA secondary structure probing. This RNA structure was determined to be important for the transcription/accumulation of subgenomic RNAs and the production of infectious viral particles. Mutations disrupting the stability of the RNA structures significantly decreased the accumulation of multiple subgenomic RNAs. In contrast, the impact of mutagenesis on full-length genomic RNA accumulation was limited. The degree to which wild-type levels of subgenomic RNA accumulation were maintained was found to correlate with the efficiency of infectious virus production. Moreover, the thermo-stability of stems within the high-order RNA structure is also well correlated with viral replication capacity and the maintenance of subgenomic RNA accumulation. This study is the first to report an intra-Arteriviridae conserved high-order RNA structure that is located in a protein-coding region and functions as an important cis-acting element to control the accumulation/transcription of arteriviral subgenomic RNAs. This work suggests a complex regulation mechanism between genome replication and discontinuous transcription in nidoviruses.IMPORTANCEArteriviruses are a group of RNA viruses that infect different animal species. They can cause diseases associated with respiratory/reproductive syndromes, abortion, or hemorrhagic fever. Among arteriviruses, porcine reproductive and respiratory syndrome virus (PRRSV) and equine arteritis virus (EAV) are economically important veterinary pathogens. The challenge in control of arterivirus infection reflects our limited knowledge of viral biology. In this study, we conducted a comprehensive analysis of arteriviral genomes and discovered intra-family conserved regions in the M ORF with a high-order RNA structure. The thermo-stability of the RNA structure influences sgRNA transcription/accumulation and correlates with the level of infectious virus production. Our studies provide new insight into arterivirus replication mechanisms, which may have implications for developing disease control and prevention strategies.

PMID:40192289 | DOI:10.1128/jvi.02167-24

Front Vet Sci. 2025 Mar 19;12:1551065. doi: 10.3389/fvets.2025.1551065. eCollection 2025.

ABSTRACT

Bovine tuberculosis (bTB) severely impacts Ethiopia's growing dairy sector, where test-and-cull control methods are economically unfeasible, and test-and-segregation is impractical in herds with very high prevalence. We assessed the feasibility of establishing bTB-free replacement stock through early segregation of calves born to bTB-positive cows. In a two-year longitudinal study on a high-prevalence (98% tuberculin skin test positive) dairy farm, 26 newborn calves were separated from their bTB-positive dams on day five after birth and screened for bTB at 2 to 5 month intervals across eight rounds, with test-positive calves immediately removed from the negative herd. The majority of segregated calves (19 out of 25; 76%; 95% CI: 58-94) remained bTB-test negative through the testing period, with nine uninfected female calves and two males reaching 18 months of age, demonstrating potential for establishing bTB-free breeding stock. However, six calves (24%; 95% CI: 6-42) turned to test positive during the study period. The extended dam-calf contact during the first five days likely contributed to some infections, suggesting that immediate separation and alternative colostrum sources could improve success rates. The addition of interferon gamma release assays in later testing rounds enabled detection of infected animals potentially missed by skin testing alone, highlighting the value of complementary diagnostic approaches for surveillance. These findings provide preliminary evidence that early calf segregation can generate bTB-negative replacement stock from infected herds, and provide a framework for larger-scale studies across different farm settings.

PMID:40177672 | PMC:PMC11963379 | DOI:10.3389/fvets.2025.1551065

Nat Methods. 2025 Apr;22(4):641-645. doi: 10.1038/s41592-025-02635-0.

NO ABSTRACT

PMID:40175561 | DOI:10.1038/s41592-025-02635-0

Am J Infect Control. 2025 Apr 2:S0196-6553(25)00127-0. doi: 10.1016/j.ajic.2025.03.014. Online ahead of print.

NO ABSTRACT

PMID:40172504 | DOI:10.1016/j.ajic.2025.03.014

Biomed Pharmacother. 2025 Mar 31;186:117957. doi: 10.1016/j.biopha.2025.117957. Online ahead of print.

ABSTRACT

BACKGROUND: Overactive neutrophilic inflammation causes damage to the airways and death in people with cystic fibrosis (CF), a genetic disorder resulting from mutations in the CFTR gene. Reducing the impact of inflammation is therefore a major concern in CF. Evidence indicates that dysfunctional NRF2 signaling in CF individuals may impair their ability to regulate their oxidative and inflammatory responses, although the role of NRF2 in neutrophil-dominated inflammation and tissue damage associated with CF has not been determined. Therefore, we examined whether curcumin, an activator of NRF2, might provide a beneficial effect in the context of CF.

METHODS: Combining Cftr-depleted zebrafish as an innovative biomedical model with CF patient-derived airway organoids (AOs), we aimed to understand how NRF2 dysfunction leads to abnormal inflammatory status and tissue remodeling and determine the effects of curcumin in reducing inflammation and tissue damage in CF.

RESULTS: We demonstrate that NFR2 is instrumental in regulating neutrophilic inflammation and repair processes in vivo, thereby preventing inflammatory damage. Importantly, curcumin treatment restores NRF2 activity in both CF zebrafish and AOs. Curcumin reduces neutrophilic inflammation in CF context, by rebalancing the production of epithelial ROS and pro-inflammatory cytokines. Furthermore, curcumin improves tissue repair by reducing CF-associated fibrosis. Our findings demonstrate that curcumin prevents CF-mediated inflammation via activating the NRF2 pathway.

CONCLUSIONS: This work highlights the protective role of NRF2 in limiting inflammation and injury and show that therapeutic strategies to normalize NRF2 activity, using curcumin or others NRF2 activators, might simultaneously reduce airway inflammation and damage in CF.

PMID:40168724 | DOI:10.1016/j.biopha.2025.117957

Microb Genom. 2025 Mar;11(3). doi: 10.1099/mgen.0.001366.

ABSTRACT

Streptococcus equi subsp. equi causes the equine respiratory disease 'strangles', which is highly contagious, debilitating and costly to the equine industry. S. equi emerged from the ancestral Streptococcus equi subsp. zooepidemicus and continues to evolve and disseminate globally. Previous work has shown that there was a global population replacement around the beginning of the twentieth century, obscuring the early genetic events in this emergence. Here, we have used large-scale genomic analysis of S. equi and its ancestor S. zooepidemicus to identify evolutionary events, leading to the successful expansion of S. equi. One thousand two hundred one whole-genome sequences of S. equi were recovered from clinical samples or from data available in public databases. Seventy-four whole-genome sequences representative of the diversity of S. zooepidemicus were used to compare the gene content and examine the evolutionary emergence of S. equi. A dated Bayesian phylogeny was constructed, and ancestral state reconstruction was used to determine the order and timing of gene gain and loss events between the different species and between different S. equi lineages. Additionally, a newly developed framework was used to investigate the fitness of different S. equi lineages. We identified a novel S. equi lineage, comprising isolates from donkeys in Chinese farms, which diverged nearly 300 years ago, after the emergence of S. equi from S. zooepidemicus, but before the global sweep. Ancestral state reconstruction demonstrated that phage-encoded virulence factors slaA, seeL and seeM were acquired by the global S. equi after the divergence of the basal donkey lineage. We identified the equibactin locus in both S. equi populations, but not S. zooepidemicus, reinforcing its role as a key S. equi virulence mechanism involved in its initial emergence. Evidence of a further population sweep beginning in the early 2000s was detected in the UK. This clade now accounts for more than 80% of identified UK cases since 2016. Several sub-lineages demonstrated increased fitness, within which we identified the acquisition of a new, fifth prophage containing additional toxin genes. We definitively show that acquisition of the equibactin locus was a major determinant in S. equi becoming an equid-exclusive pathogen, but that other virulence factors were fixed by the population sweep at the beginning of the twentieth century. Evidence of a secondary population sweep in the UK and acquisition of further advantageous genes implies that S. equi is continuing to adapt, and therefore, continued investigations are required to determine further risks to the equine industry.

PMID:40152912 | DOI:10.1099/mgen.0.001366

Nat Microbiol. 2025 Apr;10(4):813-816. doi: 10.1038/s41564-025-01969-x.

NO ABSTRACT

PMID:40140704 | DOI:10.1038/s41564-025-01969-x