Viruses. 2025 Feb 28;17(3):355. doi: 10.3390/v17030355.

ABSTRACT

Viruses are ubiquitous across all kingdoms of cellular life, posing a significant threat to human health, and analyzing viral communities is challenging due to their genetic diversity and lack of a single, universally conserved marker gene. To address this challenge, we developed the AliMarko pipeline, a tool designed to streamline virus identification in metagenomic data. Our pipeline uses a dual approach, combining mapping reads with reference genomes and a de novo assembly-based approach involving an HMM-based homology search and phylogenetic analysis, to enable comprehensive detection of viral sequences, including low-coverage and divergent sequences. We applied our pipeline to total RNA sequencing of bat feces and identified a range of viruses, quickly validating viral sequences and assessing their phylogenetic relationships. We hope that the AliMarko pipeline will be a useful resource for the scientific community, facilitating the interpretation of viral communities and advancing our understanding of viral diversity and its impact on human health.

PMID:40143285 | DOI:10.3390/v17030355

Pharmaceutics. 2025 Feb 24;17(3):296. doi: 10.3390/pharmaceutics17030296.

ABSTRACT

Melanoma, a highly aggressive form of skin cancer, poses a major therapeutic challenge due to its metastatic potential, resistance to conventional therapies, and the complexity of the tumor microenvironment (TME). Materials science and nanotechnology advances have led to using nanocarriers such as liposomes, dendrimers, polymeric nanoparticles, and metallic nanoparticles as transformative solutions for precision melanoma therapy. This review summarizes findings from Web of Science, PubMed, EMBASE, Scopus, and Google Scholar and highlights the role of nanotechnology in overcoming melanoma treatment barriers. Nanoparticles facilitate passive and active targeting through mechanisms such as the enhanced permeability and retention (EPR) effect and functionalization with tumor-specific ligands, thereby improving the accuracy of drug delivery and reducing systemic toxicity. Stimuli-responsive systems and multi-stage targeting further improve therapeutic precision and overcome challenges such as poor tumor penetration and drug resistance. Emerging therapeutic platforms combine diagnostic imaging with therapeutic delivery, paving the way for personalized medicine. However, there are still issues with scalability, biocompatibility, and regulatory compliance. This comprehensive review highlights the potential of integrating nanotechnology with advances in genetics and proteomics, scalable, and patient-specific therapies. These interdisciplinary innovations promise to redefine the treatment of melanoma and provide safer, more effective, and more accessible treatments. Continued research is essential to bridge the gap between evidence-based scientific advances and clinical applications.

PMID:40142960 | DOI:10.3390/pharmaceutics17030296

J Clin Med. 2025 Mar 17;14(6):2040. doi: 10.3390/jcm14062040.

ABSTRACT

Oncologists increasingly recognize the microbiome as an important facilitator of health as well as a contributor to disease, including, specifically, cancer. Our knowledge of the etiologies, mechanisms, and modulation of microbiome states that ameliorate or promote cancer continues to evolve. The progressive refinement and adoption of "omic" technologies (genomics, transcriptomics, proteomics, and metabolomics) and utilization of advanced computational methods accelerate this evolution. The academic cancer center network, with its immediate access to extensive, multidisciplinary expertise and scientific resources, has the potential to catalyze microbiome research. Here, we review our current understanding of the role of the gut microbiome in cancer prevention, predisposition, and response to therapy. We underscore the promise of operationalizing the academic cancer center network to uncover the structure and function of the gut microbiome; we highlight the unique microbiome-related expert resources available at the City of Hope of Comprehensive Cancer Center as an example of the potential of team science to achieve novel scientific and clinical discovery.

PMID:40142848 | DOI:10.3390/jcm14062040

Int J Mol Sci. 2025 Mar 20;26(6):2823. doi: 10.3390/ijms26062823.

ABSTRACT

This study investigates the proteomic dynamics in tomato cultivars with differing resistance to potato cyst nematodes (PCNs). Cyst-forming nematodes, significant agricultural pests, induce complex molecular responses in host plants, forming syncytia in roots for their nutrition. This research employs mass spectrometry to analyze the proteomes of infected and uninfected roots from susceptible (Moneymaker) and resistant (LA1792 and L10) tomato lines. Over 2800 high-confidence protein hits were identified, revealing significant differences in abundance between susceptible and resistant lines. Notably, resistant lines exhibited a higher number of newly expressed proteins compared to susceptible lines; however, the proportion of induced and suppressed proteins was strongly genotype-dependent. Gene ontology (GO) analysis highlighted that nematode infection in susceptible line significantly regulates many defense-related proteins, particularly those involved in oxidative stress, with a similar number being upregulated and downregulated. Some GO terms enriched among nematode-regulated proteins also indicate the involvement of programmed cell death (PCD)-related processes. The susceptible line exhibited a prevalence of downregulated proteins, among which defense associated GO terms were significantly overrepresented. Four proteins (APY2, NIA2, GABA-T, and AATP1) potentially crucial for nematode parasitism were identified and their Arabidopsis orthologs were studied. Mutant Arabidopsis lines showed altered nematode resistance, supporting the involvement of these proteins in plant defense. This study highlights the complexity of host-nematode interactions and emphasizes the importance of proteomic analyses in identifying key factors and understanding plant defense mechanisms.

PMID:40141466 | DOI:10.3390/ijms26062823

Int J Mol Sci. 2025 Mar 11;26(6):2483. doi: 10.3390/ijms26062483.

ABSTRACT

Clinacanthus nutans is a valuable traditional medicinal plant that contains enriched active compounds such as triterpenoids and flavonoids. Understanding the accuulation process of these secondary metabolites in C. nutans requires exploring gene expression regulation under abiotic stresses and hormonal stimuli. qRT-PCR is a powerful method for gene expression analysis, with the selection of suitable reference genes being paramount. However, reports on stably expressed reference genes in C. nutans and even across the entire family Acanthaceae are limited. In this study, we evaluated the expression stability of 12 candidate reference genes (CnUBQ, CnRPL, CnRPS, CnPTB1, CnTIP41, CnACT, CnUBC, CnGAPDH, Cn18S, CnCYP, CnEF1α, and CnTUB) in C. nutans across different tissues and under abiotic stresses and MeJA treatment using three programs (geNorm, NormFinder, and BestKeeper). The integrated ranking results indicated that CnUBC, CnRPL, and CnCYP were the most stably expressed genes across different tissues. Under abiotic stress conditions, CnUBC, CnRPL, and CnEF1α were the most stable, while under MeJA treatment, CnRPL, CnEF1α, and CnGAPDH exhibited the highest stability. Additionally, CnRPL, CnUBC, and CnEF1α were the most stable reference genes across all tested samples, whereas CnGAPDH was the least stable. CnRPL, consistently ranking among the top three most stable genes, may therefore serve as an ideal reference gene for qRT-PCR analysis in C. nutans. To further validate the selected reference genes, we assessed the expression of two key biosynthetic genes, CnPAL and CnHMGR. The results confirmed that using the most stable reference genes yielded expression patterns consistent with biological expectations, while using unstable reference genes led to significant deviations. These findings offer valuable insights for accurately quantifying target genes via qRT-PCR in C. nutans, facilitating investigations into the mechanisms underlying active compound accumulation.

PMID:40141128 | DOI:10.3390/ijms26062483

Nat Microbiol. 2025 Mar 26. doi: 10.1038/s41564-025-01959-z. Online ahead of print.

ABSTRACT

Aging is accompanied by considerable changes in the gut microbiome, yet the molecular mechanisms driving aging and the role of the microbiome remain unclear. Here we combined metagenomics, transcriptomics and metabolomics from aging mice with metabolic modelling to characterize host-microbiome interactions during aging. Reconstructing integrated metabolic models of host and 181 mouse gut microorganisms, we show a complex dependency of host metabolism on known and previously undescribed microbial interactions. We observed a pronounced reduction in metabolic activity within the aging microbiome accompanied by reduced beneficial interactions between bacterial species. These changes coincided with increased systemic inflammation and the downregulation of essential host pathways, particularly in nucleotide metabolism, predicted to rely on the microbiota and critical for preserving intestinal barrier function, cellular replication and homeostasis. Our results elucidate microbiome-host interactions that potentially influence host aging processes. These pathways could serve as future targets for the development of microbiome-based anti-aging therapies.

PMID:40140706 | DOI:10.1038/s41564-025-01959-z

Nature. 2025 Mar 26. doi: 10.1038/s41586-025-08795-5. Online ahead of print.

ABSTRACT

Regulatory T (Treg) cells, which specifically express the master transcription factor FOXP3, have a pivotal role in maintaining immunological tolerance and homeostasis and have the potential to revolutionize cell therapies for autoimmune diseases1-3. Although stimulation of naive CD4+ T cells in the presence of TGFβ and IL-2 can induce FOXP3+ Treg cells in vitro (iTreg cells), the resulting cells are often unstable and have thus far hampered translational efforts4-6. A systematic approach towards understanding the regulatory networks that dictate Treg differentiation could lead to more effective iTreg cell-based therapies. Here we performed a genome-wide CRISPR loss-of-function screen to catalogue gene regulatory determinants of FOXP3 induction in primary human T cells and characterized their effects at single-cell resolution using Perturb-icCITE-seq. We identify the RBPJ-NCOR repressor complex as a novel, context-specific negative regulator of FOXP3 expression. RBPJ-targeted knockout enhanced iTreg differentiation and function, independent of canonical Notch signalling. Repeated cytokine and T cell receptor signalling stimulation in vitro revealed that RBPJ-deficient iTreg cells exhibit increased phenotypic stability compared with control cells through DNA demethylation of the FOXP3 enhancer CNS2, reinforcing FOXP3 expression. Conversely, overexpression of RBPJ potently suppressed FOXP3 induction through direct modulation of FOXP3 histone acetylation by HDAC3. Finally, RBPJ-ablated human iTreg cells more effectively suppressed xenogeneic graft-versus-host disease than control iTreg cells in a humanized mouse model. Together, our findings reveal novel regulators of FOXP3 and point towards new avenues to improve the efficacy of adoptive cell therapy for autoimmune disease.

PMID:40140585 | DOI:10.1038/s41586-025-08795-5

Nature. 2025 Mar 26. doi: 10.1038/s41586-025-08676-x. Online ahead of print.

ABSTRACT

Meningomyelocele (also known as spina bifida) is considered to be a genetically complex disease resulting from a failure of the neural tube to close. Individuals with meningomyelocele display neuromotor disability and frequent hydrocephalus, requiring ventricular shunting. A few genes have been proposed to contribute to disease susceptibility, but beyond that it remains unexplained1. We postulated that de novo mutations under purifying selection contribute to the risk of developing meningomyelocele2. Here we recruited a cohort of 851 meningomyelocele trios who required shunting at birth and 732 control trios, and found that de novo likely gene disruption or damaging missense mutations occurred in approximately 22.3% of subjects, with 28% of such variants estimated to contribute to disease risk. The 187 genes with damaging de novo mutations collectively define networks including actin cytoskeleton and microtubule-based processes, Netrin-1 signalling and chromatin-modifying enzymes. Gene validation demonstrated partial or complete loss of function, impaired signalling and defective closure of the neural tube in Xenopus embryos. Our results indicate that de novo mutations make key contributions to meningomyelocele risk, and highlight critical pathways required for neural tube closure in human embryogenesis.

PMID:40140573 | DOI:10.1038/s41586-025-08676-x

Cell Death Differ. 2025 Mar 27. doi: 10.1038/s41418-025-01479-7. Online ahead of print.

ABSTRACT

Lysine acetyltransferase 2 A (KAT2A) plays a pivotal role in epigenetic gene regulation across various types of cancer. In colorectal cancer (CRC), increased KAT2A expression is associated with a more aggressive phenotype. Our study aims to elucidate the molecular underpinnings of KAT2A dependency in CRC and assess the consequences of KAT2A depletion. We conducted a comprehensive analysis by integrating CRISPR-Cas9 screening data with genomics, transcriptomics, and global acetylation patterns in CRC cell lines to pinpoint molecular markers indicative of KAT2A dependency. Additionally, we characterized the phenotypic effect of a CRISPR-interference-mediated KAT2A knockdown in CRC cell lines and patient-derived 3D spheroid cultures. Moreover, we assessed the effect of KAT2A depletion within a patient-derived xenograft mouse model in vivo. Our findings reveal that KAT2A dependency is closely associated with microsatellite stability, lower mutational burden, and increased molecular differentiation signatures in CRC, independent of the KAT2A expression levels. KAT2A-dependent CRC cells display higher gene expression levels and enriched H3K27ac marks at gene loci linked to enterocytic differentiation. Furthermore, loss of KAT2A leads to decreased cell growth and viability in vitro and in vivo, downregulation of proliferation- and stem cell-associated genes, and induction of differentiation markers. Altogether, our data show that a specific subset of CRCs with a more differentiated phenotype relies on KAT2A. For these CRC cases, KAT2A might represent a promising novel therapeutic target.

PMID:40140561 | DOI:10.1038/s41418-025-01479-7

Nat Plants. 2025 Mar 26. doi: 10.1038/s41477-025-01938-6. Online ahead of print.

ABSTRACT

During secondary growth, the vascular cambium produces conductive xylem and phloem cells, while the phellogen (cork cambium) deposits phellem (cork) as the outermost protective barrier. Although most of the secondary tissues are made up of parenchyma cells, which are also produced by both cambia, their diversity and function are poorly understood. Here we combined single-cell RNA sequencing analysis with lineage tracing to recreate developmental trajectories of the cell types in the Arabidopsis root undergoing secondary growth. By analysing 93 reporter lines, we were able to identify 20 different cell types or cell states, many of which have not been described before. We additionally observed distinct transcriptome signatures of parenchyma cells depending on their maturation state and proximity to the conductive cell types. Our data show that both xylem and phloem parenchyma tissues are required for normal formation of conductive tissue cell types. Furthermore, we show that mature phloem parenchyma gradually obtains periderm identity, and this transformation can be accelerated by jasmonate treatment or wounding. Our study thus reveals the diversity of parenchyma cells and their capacity to undergo considerable identity changes during secondary growth.

PMID:40140531 | DOI:10.1038/s41477-025-01938-6

Nat Plants. 2025 Mar 26. doi: 10.1038/s41477-025-01944-8. Online ahead of print.

ABSTRACT

Differential growth between tissues generates mechanical conflicts influencing organogenesis in plants. Here we use the anther, the male floral reproductive organ, as a model system to understand how cell dynamics and tissue-scale mechanics control 3D morphogenesis of a complex shape. Combining deep live-cell imaging, growth analysis, osmotic treatments, genetics and mechanical modelling, we show that localized expansion of internal cells actively drives anther lobe outgrowth, while the epidermis stretches in response. At later stages, mechanical load is transferred to the sub-epidermal layer (endothecium), contributing to proper organ shape. We propose the concept of 'inflation potential', encapsulating mechanical and anatomical features causing differential growth. Our data emphasize the active mechanical role of inner tissue in controlling both organ shape acquisition and cell dynamics in outer layers.

PMID:40140530 | DOI:10.1038/s41477-025-01944-8

Transl Psychiatry. 2025 Mar 26;15(1):97. doi: 10.1038/s41398-025-03321-7.

ABSTRACT

Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by early molecular events that influence disease progression. Still, the molecular mechanisms caused by different mutations of AD are not understood. We have performed a multidisciplinary study to investigate and compare the early stages of the pathology in two transgenic AD mouse models: P301S and 5xFAD. Using SNOTRAP-based mass spectrometry, we assessed changes in S-nitrosylation, a nitric oxide-mediated post-translational modification, of proteins in both models during their juvenile age. The increased levels of 3-nitrotyrosine confirmed nitrosative stress in the mutant mice. Systems biology analysis revealed shared processes between the models, particularly in the γ-aminobutyric acid (GABA)ergic and glutamatergic neurotransmission processes. In the P301S model, we identified 273 S-nitrosylated (SNOed) proteins in the cortex, with 244 proteins uniquely SNOed in the diseased mice. In the 5xFAD model, 309 SNOed proteins were identified. We have found altered proteins expression of different glutamate/GABA-related markers in the cortex and hippocampus of both AD mouse models. Additionally, the phosphorylation levels of the mTOR signaling components revealed hyperactivation of this pathway in P301S mice. Conversely, 5xFAD mice showed no significant changes in mTOR signaling except for elevated phosphorylation of the ribosomal protein S6 in the cortex. Our findings revealed key molecular mechanisms in the two AD mouse models during their early stages. These mechanisms could serve as potential biomarkers and therapeutic targets for early-stage AD.

PMID:40140365 | DOI:10.1038/s41398-025-03321-7

Environ Sci Pollut Res Int. 2025 Mar 26. doi: 10.1007/s11356-025-36286-7. Online ahead of print.

ABSTRACT

Nanotechnology has been utilized in diverse domains, encompassing sustainable agriculture. However, the ecotoxicity and environmental safety of nanoparticles need to be evaluated before their large-scale use. This study synthesizes and characterizes magnesium (Mg) and zinc (Zn) co-doped aluminum (Al) oxide (MgZnAl2O4) NPs and elucidates its potential growth-promoting or genotoxic performance on barley (Hordeum vulgare L.). XRD, EDX, TEM, SEM, and XPS were used to characterize the MgZnAl2O4 NPs. After characterization, the seedlings were grown in a hydroponic solution containing 0, 50, 100, 200, and 400 mg L-1 NPs for 3 weeks. The germination, growth indices, photosynthetic parameters, and nutrient absorption properties were determined. Confocal microscopy, TEM, and SEM were utilized to follow the path and reveal the structural and morphological effects of NPs. The potential genotoxic effect was evaluated using the RAPD-PCR method. Elemental composition analysis of plant parts confirmed that synthesized MgZnAl2O4 NPs, sized at 21.8 nm, were up-taken by the plant roots, leading to increased Mg, Zn, and Al contents of leaves. In addition, compared with the untreated control, the abundance of Ca, K, B, Fe, Mn, and Cu were increased by the NPs treatment. In addition, physiological indices like germination rate (~ 11%), root and leaf growth (15-29%), chlorophyll, and carotenoids (~ 39%) pigments were significantly raised by the NPs inclusion. It can be concluded that low concentrations (< 200 mg L-1) of MgZnAl2O4 NPs enhance growth parameters effectively and are safe for plant growth. On the other hand, a phytotoxic and genotoxic impact was observed at high concentrations (100-400 mg L-1). However, considerable amounts of NPs were found to be adsorbed on roots, disrupting root morphology and cell membrane integrity, thus nutrient trafficking and transport. Therefore, it is recommended that MgZnAl2O4 NPs can be used in barley breeding programs at low concentrations. Adding micro- or macroelements required by plants to the NP composition is a promising way to compensate for plant nutrition. However, the negative effects of MgZnAl2O4 NPs on the environment and other living beings due to their genotoxic effects at high doses must be carefully considered.

PMID:40140202 | DOI:10.1007/s11356-025-36286-7

Pharmaceuticals (Basel). 2025 Feb 23;18(3):307. doi: 10.3390/ph18030307.

ABSTRACT

Background/Objectives: Transarterial chemoembolization (TACE) is a widely accepted and minimally invasive treatment for primary and metastatic liver cancer. Performing TACE with drug-eluting beads helps obtain a greater drug concentration in the target lesion, significantly reducing systemic drug leakage, liver toxicity, and adverse events. The aim of this study is to describe the safety and feasibility of TACE performed with BioPearlTM, the first biodegradable drug-eluting microspheres. Methods: This was a retrospective observational study on 13 consecutive patients affected by hepatocellular carcinoma (HCC) treated with doxorubicin-loaded-BioPearlTM-TACE. Data on safety, feasibility, and tumor response were collected. Results: One intra-procedural catheter blockage was registered, as well as two post-treatment bilomas that required additional treatment. No severe general drug-related side effects were detected at the follow-up. The 1-month overall disease control was 90.9%, with six complete responses. Conclusions: Data suggest that chemoembolization with BioPearlTM is feasible and safe for the treatment of HCC as indicated by good tolerability.

PMID:40143086 | DOI:10.3390/ph18030307

BJC Rep. 2025 Mar 26;3(1):17. doi: 10.1038/s44276-025-00133-6.

ABSTRACT

BACKGROUND: Single-agent MEK1/2 inhibition has been disappointing in clinical trials targeting RAS mutant (MT) cancers, probably due to upstream receptor activation, resulting in resistance. We previously found that dual c-MET/MEK1/2 inhibition attenuated RASMT colorectal cancer (CRC) xenograft growth. In this study, we assessed safety of MEK1/2 inhibitor PD-0325901 with c-MET inhibitor crizotinib and determined the optimal biological doses for subsequent clinical trials.

METHODS: In this dose-escalation phase I trial, patients with advanced solid tumours received PD-0325901 with crizotinib, using a rolling-6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. Blood samples for pharmacokinetics and skin biopsies were collected.

RESULTS: Twenty-five patients were recruited in 4 cohorts up to doses of crizotinib 200 mg B.D continuously with PD-0325901 8 mg B.D, days 1-21 every 28 days. One in six patients exhibited a dose-limiting toxicity at this dose level. Drug-related adverse events were in keeping with single-agent toxicity profiles. The best clinical response was stable disease in seven patients (29%).

CONCLUSIONS: PD-0325901/crizotinib can be given together at pharmacologically-active doses. The MTD for PD-0325901/crizotinib was 8 mg B.D (days 1-21) and 200 mg B.D continuously in a 28-days cycle. The combination was further explored with an alternate MEK1/2 inhibitor in RASMT CRC patients.

EUDRACT-NUMBER: 2014-000463-40.

PMID:40140597 | DOI:10.1038/s44276-025-00133-6

Sci Rep. 2025 Mar 26;15(1):10384. doi: 10.1038/s41598-025-94947-6.

ABSTRACT

OBJECTIVE: To analyze and compare the incidence of adverse events (AEs) associated with different administration routes of colistin, with the aim of providing a reference for its safe and effective clinical use.

METHODS: Adverse event (AE) reports related to colistin were retrieved from the FDA Adverse Event Reporting System (FAERS) database. The reporting trends were analyzed, and the Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) for colistin-associated AEs were calculated. A comparative analysis was conducted to examine the occurrence of AEs under different administration routes of colistin.

RESULTS: A total of 13,043 AE reports were extracted from the FAERS database. Further analysis of 176 key AEs associated with colistin indicated a significant increase in the number of reports after 2021. The year and country of the reports showed heterogeneity across different administration routes. Intravenous (IV) administration of colistin was associated with the highest proportion of AEs, and heterogeneity was also observed in the types of AEs reported for inhaled and oral (PO) administration routes.

CONCLUSION: Compared to inhaled and PO administration routes, IV administration of colistin is more likely to result in AEs such as nephrotoxicity and drug ineffectiveness. Additionally, there are significant differences in the types of AEs associated with colistin across different administration routes.

PMID:40140483 | DOI:10.1038/s41598-025-94947-6

Therapie. 2025 Mar 4:S0040-5957(25)00039-3. doi: 10.1016/j.therap.2025.02.011. Online ahead of print.

ABSTRACT

INTRODUCTION: Dentists, in their practice, bear responsibility for the benefits and the risks associated with the medications they prescribe. Their code of ethics grants them the freedom to prescribe while encouraging them to limit their interventions to what is strictly necessary for the quality and effectiveness of care. Furthermore, dentists also face ontological adverse effects resulting from medications they did not personally prescribe. A study based on the analysis of cases recorded over ten years in the national pharmacovigilance database (BNPV) is relevant for assessing the current state of pharmacovigilance reports submitted by dentists.

METHODS: We conducted a retrospective analysis of the cases recorded in the BNPV, reported by dentists between 01/01/2013 and 31/12/2023.

RESULTS: Over 10 years, 509 reports were recorded, representing 0.06% of all registered cases. These reports were divided into three main groups. Among the 509 declarations, 24.8% were cases associated with medications used in the field of dentistry, such as anti-inflammatory drugs, antibiotics, local anaesthetics, and local antiseptics. In total, 35.2% were cases of odontological adverse effects, such as jaw osteonecrosis, gingival hypertrophy, and oral ulcers. Finally, 28.3% of the cases involved reports of adverse effects related to coronavirus disease 2019 (COVID-19) vaccination, which began in late December 2020.

CONCLUSION: The low rate of pharmacovigilance reports by dentists in France over the past ten years highlights an issue of underreporting of adverse effects in dental practice. Recent literature emphasizes the importance of pharmacovigilance reporting in the field of dentistry, particularly concerning odontological effects.

PMID:40140295 | DOI:10.1016/j.therap.2025.02.011

Genome Res. 2025 Apr 14;35(4):755-768. doi: 10.1101/gr.279414.124.

ABSTRACT

Solve-RD is a pan-European rare disease (RD) research program that aims to identify disease-causing genetic variants in previously undiagnosed RD families. We utilized 10-fold coverage HiFi long-read sequencing (LRS) for detecting causative structural variants (SVs), single-nucleotide variants (SNVs), insertion-deletions (indels), and short tandem repeat (STR) expansions in previously studied RD families without a clear molecular diagnosis. Our cohort includes 293 individuals from 114 genetically undiagnosed RD families selected by European Reference Network (ERN) experts. Of these, 21 families were affected by so-called "unsolvable" syndromes for which genetic causes remain unknown and for which prior testing was not a prerequisite. The remaining 93 families had at least one individual affected by a rare neurological, neuromuscular, or epilepsy disorder without a genetic diagnosis despite extensive prior testing. Clinical interpretation and orthogonal validation of variants in known disease genes yielded 12 novel genetic diagnoses due to de novo and rare inherited SNVs, indels, SVs, and STR expansions. In an additional five families, we identified a candidate disease-causing variant, including an MCF2/FGF13 fusion and a PSMA3 deletion. However, no common genetic cause was identified in any of the "unsolvable" syndromes. Taken together, we found (likely) disease-causing genetic variants in 11.8% of previously unsolved families and additional candidate disease-causing SVs in another 5.4% of these families. In conclusion, our results demonstrate the potential added value of HiFi long-read genome sequencing in undiagnosed rare diseases.

PMID:40138663 | DOI:10.1101/gr.279414.124

Soc Sci Med. 2025 May;372:117958. doi: 10.1016/j.socscimed.2025.117958. Epub 2025 Mar 14.

ABSTRACT

Rare disease organisations can play a crucial role in shaping the medical and scientific landscape. This article draws from interviews with sixteen founders of UK-based, rare disease organisations, all of whom were patients, parents or family members, to understand their experiences and commitment to the organisation and its community. First, we explore the work involved in creating a professional community and addressing the challenge of expert capacity-building for rare diseases. We then utilise the concept of 'translation' to emphasise the efforts of founders at an intermediate stage, for example encouraging health professionals to collaborate and realise that a project is achievable. Third, we consider the personal implications for the founders in their efforts to develop and sustain the organisation. Founders' biographies are intimately entwined with the establishment and development of their organisation, and we highlight how they are fundamentally shaped by the necessity of their hard work, skills and passion. Finally, we recognise that although some of the efforts of founders are undervalued both socially and economically, the founders themselves understand their work and role as crucial to the organisation's long-term success.

PMID:40138978 | DOI:10.1016/j.socscimed.2025.117958

Pharmacol Res. 2025 Mar 24:107710. doi: 10.1016/j.phrs.2025.107710. Online ahead of print.

ABSTRACT

Drug-target interaction prediction is critical for drug development. Through the integration of structural and transcriptional signature information, molecules both binding to the target and inducing therapeutic activities could be found out to improve targeted drug prediction. Therefore, the approaches that integrate the two types of data are worth exploring. Here, we present an integrated method named Data Integration Oriented Repurposing Strategy (DIORS) combining molecular docking and gene-signature matching to enhance the prediction of protein-targeted drugs. The StandardScaler algorithm was selected after evaluation of five algorithms and was used in DIORS. Surface Plasmon Resonance (SPR) was used to verify the molecular affinities and cell-based assays were used to verify the activities of DIORS predicted molecules. In Piezo1-targeted molecule prediction, among the top ten predicted molecules by DIORS, four of them, namely gefitinib, rifaximin, bosutinib and vandetanib, exhibited binding affinities. In the prediction of TLR4/MD2-targeted anti-inflammatory molecules, among the top ten predicted molecules, three of them, namely enoxolone, dabrafenib and ponatinib, exhibit both high binding affinities and anti-inflammatory activities. The results demonstrated that DIORS can serve as a better approach with high performance to predict and find new targeted drugs by combining structural and signature information.

PMID:40139454 | DOI:10.1016/j.phrs.2025.107710