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PubMed2025

HERV Modulation in Colorectal Carcinoma Patients: A Snapshot of Endogenous Retroviral Transcriptome.

Human endogenous retroviruses (HERVs) are proviral relics of infections that affected primates' germ line. Many HERV elements retain a residual capacity to encode transcripts and proteins that have been occasionally domesticated for the host physiology. In addition, HERV transcriptional modulation is of great interest to clarify the etiology of complex disorders such as cancer, even if a few studies assessed the specific HERV loci modulated in tumor tissues. In the present work, we used a transcriptomic approach to investigate the specific expression of ~3300 HERV loci in paired tumor and normal tissues of 7 colorectal cancer (CRC) patients. A total of 102 HERVs were significantly modulated in CRC, with a general tendency towards downregulation. Of note, among the 42 upregulated HERVs 23 belonged to the HERV-H group, that is the most investigated in CRC. De novo transcriptome reconstruction and qPCR validation allowed to identify a transcript from a HERV-H locus on chromosome Xp22.3 with high specific expression in CRC samples, potentially encoding for a partial Pol protein. These results provide a detailed description of HERV transcriptional variations in CRC and its interindividual variability, identifying a HERV-H transcript that deserves further investigation for its possible impact on tumor progression.

Endogenous Retroviruses↗

PubMed2024

Acute strength exercise training impacts differently the HERV-W expression and inflammatory biomarkers in resistance exercise training individuals.

BACKGROUND: Human Endogenous Retroviruses (HERVs) are fossil viruses that composes 8% of the human genome and plays several important roles in human physiology, including muscle repair/myogenesis. It is believed that inflammation may also regulate HERV expression, and therefore may contribute in the muscle repair, especially after training exercise. Hence, this study aimed to assess the level of HERVs expression and inflammation profile in practitioners' resistance exercises after an acute strength training session. METHODS: Healthy volunteers were separated in regular practitioners of resistance exercise training group (REG, n = 27) and non-trained individuals (Control Group, n = 20). All individuals performed a strength exercise section. Blood samples were collected before the exercise (T0) and 45 minutes after the training session (T1). HERV-K (HML1-10) and W were relatively quantified, cytokine concentration and circulating microparticles were assessed. RESULTS: REG presented higher level of HERV-W expression (~2.5 fold change) than CG at T1 (p<0.01). No difference was observed in the levels of HERV-K expression between the groups as well as the time points. Higher serum TNF-α and IL-10 levels were verified post-training session in REG and CG (p<0.01), and in REG was found a positive correlation between the levels of TNF-α at T1 and IL-10 at T0 (p = 0.01). Finally, a lower endothelial microparticle percentage was observed in REG at T1 than in T0 (p = 0.04). CONCLUSION: REG individuals exhibited a significant upregulation of HERV-W and modulation of inflammatory markers when compared to CG. This combined effect could potentially support the process of skeletal muscle repair in the exercised individuals.

Humans↗

PubMed2025

HERV-K Envelope Induce a Humoral Response in Non-Hodgkin Lymphoma Patients.

Haematological malignancies represent a heterogenous group of diseases, encompassing lymphomas, leukaemia, and multiple myeloma. Among these, the involvement of human endogenous retroviruses (HERVs) has been most consistently reported in lymphoma, while their role in leukaemia and multiple myeloma remains limited. This study investigated the humoral response to the envelope proteins of HERV-K and HERV-H in the peripheral blood of patients with multiple myeloma and non-Hodgkin lymphoma and assessed HERV-K envelope gene expression through an approach combining indirect ELISA and quantitative PCR. The study revealed an increased humoral response against the HERV-K envelope epitope in patients with non-Hodgkin lymphoma compared to matched healthy controls. However, no differences were observed in patients with multiple myeloma. Although limited to the humoral level, these findings support the relevance of HERV-K specific immune responses in non-Hodgkin lymphoma and provide a rationale for further investigation.

Humans↗

PubMed2025

Human endogenous retrovirus K (HERV-K) envelope structures in pre- and postfusion by cryo-EM.

Human endogenous retroviruses (HERVs) are remnants of ancient infections that comprise ~8% of the human genome. The HERV-K envelope glycoprotein (Env) is aberrantly expressed in cancers, autoimmune disorders, and neurodegenerative diseases, and is targeted by patients' own antibodies. However, a lack of structural information has limited molecular and immunological studies of the roles of HERVs in disease. Here, we present cryo-electron microscopy structures of stabilized HERV-K Env in the prefusion conformation, revealing a distinct fold and architecture compared to HIV and simian immunodeficiency virus. We also generated and characterized a panel of monoclonal antibodies with subunit and conformational specificity, serving as valuable research tools. These antibodies enabled structure determination of the postfusion conformation of HERV-K Env, including its unique "tether" helix, and antibody-bound prefusion Env. Together, these results provide a structural framework that opens the door to mechanistic studies of HERV-K Env and tools for its evaluation as a potential therapeutic target.

Cryoelectron Microscopy↗

PubMed2026

Human endogenous retroviruses leading to autoimmune diseases.

Human endogenous retroviruses (HERVs) comprise approximately 8% of the human genome and were long regarded as inert remnants of ancestral retroviral infections. Increasing evidence indicates that HERVs are active genomic elements capable of influencing transcriptional programs, modulating immune responses, and contributing to disease pathogenesis. Under physiological conditions, HERV expression is tightly controlled by epigenetic mechanisms; however, infections, chronic inflammation, aging, and diverse environmental stimuli can promote HERV reactivation. HERV-derived RNAs and proteins engage innate immune sensors and trigger antiviral-like responses through mechanisms of viral mimicry, leading to activation of type I interferon and other inflammatory pathways. HERV dysregulation has been associated with disease-relevant immune pathways. This review summarizes recent advances linking HERVs to autoimmune disease pathogenesis and discusses their potential translational relevance as biomarkers and therapeutic targets.

Humans↗

PubMed2026

Mobile elements in pituitary neuroendocrine tumors: integrative evidence and future directions.

Mobile genetic elements (MGEs), including LINE-1 retrotransposons, Alu and SVA elements, and human endogenous retroviruses (HERVs), constitute nearly half of the human genome and are increasingly understood to influence multiple dimensions of cancer evolution. Yet, pituitary neuroendocrine tumors (PitNETs) remain almost absent from mobilome research, despite exhibiting genomic and epigenetic contexts permissive to retroelement activation. In this review, we synthesize current evidence linking MGEs to PitNET biology and delineate unresolved but testable mechanisms. Structural genomic studies demonstrate that Alu-mediated non-allelic homologous recombination contributes to germline mutagenesis in MEN1 and AIP, reinforcing the notion that repetitive DNA architecture shapes PitNET predisposition. Transcriptomic analyses reveal global derepression of transposable elements and LINE-1 hypomethylation in subsets of tumors, while mechanistic connections to chromatin instability emerge from recurrent ATRX/DAXX deficiency and TP53 inactivation, both established repressors of retroelements. Furthermore, the retrocopy-derived long non-coding RNA RPSAP52 exemplifies how mobilome-origin transcripts can be co-opted as oncogenic regulators in PitNETs, acting through HMGA2-dependent proliferative networks. Preliminary data also suggest endogenous retroviral activation, with consistent upregulation of HERV envelope genes across distinct tumor subtypes. Nevertheless, no study has yet systematically mapped somatic mobile-element insertions (MEIs), quantified LINE-1 protein activity, or profiled HERV expression at locus resolution in PitNETs. Mobilome biology represents a tractable and conceptually rich frontier with diagnostic, prognostic, and therapeutic potential in pituitary tumorigenesis.

Humans↗

PubMed2026

Distinct Effects of Complement C4A and C4B Copy Numbers in Systemic Sclerosis Serological and Clinical Subtypes.

OBJECTIVE: Complement component 4 (C4), encoded by C4A and C4B within the major histocompatibility complex (MHC) on chromosome 6, regulates the immune response and clears immune complexes. The variable copy number (CN) of C4 genes and retroviral human endogenous retrovirus K (HERV-K) element influence its function. Given the relationship of C4 CN with systemic sclerosis (SSc) risk, we assessed associations with SSc clinical and serologic subtypes. METHODS: We compared imputed C4 CNs across SSc subgroups (4,049 anticentromere positive [ACA+]; 2,200 anti-topoisomerase I [ATA+]; 577 anti-RNA polymerase [ARA+]; 1,078 triple-negative [TN] patients; 6,295 limited cutaneous SSc [lcSSc]; and 2,946 diffuse cutaneous SSc [dcSSc]) and 17,991 controls. We evaluated associations with SSc subtypes, identifying C4-independent HLA alleles. RESULTS: Lower C4 CN and higher HERV-K CN were associated with increased risk in all SSc subgroups. ATA+ patients showed the strongest association, particularly with C4A (odds ratio = 1.88), and differences in C4A CN association were more pronounced between autoantibody subgroups (ATA+ vs ACA+, P = 4 × 10-11) than between clinical subgroups (dcSSc vs lcSSc, P = 1 × 10-4). In ACA+ patients, only low C4B CN showed a significant association to SSc risk (P = 1.23 × 10-5). We also observed sex-biased associations: dcSSc, ATA+, and ARA+ male patients showed stronger effects for C4A and ACA+ and lcSSc female patients for C4B. Finally, our results suggest that the HLA alleles associated with SSc subgroups are independent of C4 CN. CONCLUSION: This study highlights distinct genetic contributions of C4A and C4B in SSc subtypes susceptibility. Our findings suggest that lower C4 CNs, particularly C4A, increase the risk of the severe dcSSc subtype, potentially through a mechanism involving immune complex clearance.

Humans↗

PubMed2026

A single-cell meta-analysis evidences transposable element dysregulation in sex-based differences in Parkinson's disease.

Transposable elements (TEs) (mobile genetic elements comprising ∼45% of the human genome) have recently emerged as potential contributors to Parkinson's disease (PD); however their role and sex-specific impact remain poorly understood. Here, we present the first integrative meta-analysis of TE expression across 4 substantia nigra single-nucleus RNA-seq datasets, comprising a total of 66 donors, generating a cell-type-resolved atlas of TE dysregulation in PD. We identified widespread TE activation across major brain cell types (i.e. neurons, astrocytes, oligodendrocytes and microglia), with marked upregulation of L1s in neurons and HERVs in oligodendrocytes. Sex-stratified analyses revealed distinct male- and female-biased TE signatures, indicating regulatory programs uniquely affected in each sex, including MIR elements in microglia and Alu subfamilies in neurons. Correlation and genomic proximity analyses also uncovered TE-gene associations linked to important PD pathways such as neuroinflammation or myelination. Collectively, our study positions TEs as potential sex-modulated contributors to PD pathology and also provides a public web resource (PATOSS) to explore PD-associated TE transcriptional deregulation.

Parkinson's disease↗

PubMed2026

Restrictive vs Liberal Transfusion Strategy in Traumatic Brain Injury: A Secondary Analysis of the TRAIN Trial.

IMPORTANCE: Anemia is a prevalent condition among patients with traumatic brain injury (TBI); however, the optimal hemoglobin (Hb) threshold to initiate red blood cell transfusion (RBCT) is not well defined. OBJECTIVE: To assess which of 2 different Hb thresholds for guiding RBCT in patients with anemia and TBI is associated with a more favorable neurological outcome. DESIGN, SETTING, AND PARTICIPANTS: This was a preplanned secondary analysis of the Transfusion Strategies in Acute Brain Injured Patients multicentric randomized clinical trial, conducted in 72 intensive care units across 22 countries between September 1, 2017, and December 31, 2022. Follow-up was completed June 30, 2023. Only patients with TBI were included in the present analysis, conducted from February to May 2025. INTERVENTIONS: Liberal (transfusion at Hb <9 g/dL [to convert to g/L, multiply by 10.0]) vs restrictive (transfusion at Hb <7 g/dL) RBCT strategy over a maximum of 28 days. MAIN OUTCOME AND MEASURES: The primary outcome was the occurrence of unfavorable neurological outcome, defined as a Glasgow Outcome Scale Extended score of 1 to 5 (overall range, 1-8, with higher scores indicating more favorable outcome) at 180 days. In addition, 14 prespecified serious adverse events, including infection and cerebral ischemia, were assessed. Data were analyzed using both the intention-to-treat and per-protocol principles. RESULTS: Of 486 patients who presented with TBI (mean [SD] age, 46.8 [17.6] years; 347 [71.4%] male), 475 were included in the primary outcome analysis: 236 were randomized to the liberal transfusion strategy group and 239 to the restrictive transfusion strategy group. Both groups had similar baseline characteristics. In total, 534 RBCTs were administered in the liberal transfusion strategy group, compared with 246 RBCTs in the restrictive group. At 180 days after randomization, 138 patients (58.5%) in the liberal group had unfavorable neurological outcome compared with 161 patients (67.4%) in the restrictive group (relative risk [RR], 0.86 [95% CI, 0.75-1.00]; P = .047; fragility index = 1). There were no significant differences in the occurrence of secondary outcomes (eg, 28-day mortality: 42 of 240 [17.5%] vs 51 of 244 [20.9%]; RR, 0.84 [95% CI, 0.58-1.21]; P = .34) or serious adverse events (eg, RR, 1.13 [95% CI, 0.88-1.43]; P = .34 for infection and RR, 0.87 [95% CI, 0.40-1.90]; P = .72 for cerebral ischemia). After adjustment for several confounders, being randomized to the liberal group was associated with a lower observed probability of unfavorable neurological outcome (odds ratio, 0.60 [95% CI, 0.38-0.94]; P = .03). CONCLUSIONS AND RELEVANCE: In this secondary analysis of a multicenter randomized clinical trial, a liberal RBCT strategy was associated with a lower risk than a restrictive RBCT strategy of unfavorable neurological outcome at 180 days among patients with TBI. These findings should be interpreted with caution in light of the inherent uncertainty of the estimate. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02968654.

Humans↗

PubMed2025

High baseline PD-1+ CD8 T Cells and TIGIT+ CD8 T Cells in circulation associated with response to PD-1 blockade in patients with non-small cell lung cancer.

Blockade of PD-1 or its ligand PD-L1 with antibodies revolutionized treatment for stage III and IV non-small cell lung cancer (NSCLC) since FDA approval in 2015. However, resistance to PD-1/PD-L1 blockade remains a challenge, highlighting the need for biomarkers. This study analyzed 36 stage III and IV NSCLC patients, classified as responders or non-responders by iRECIST criteria. Peripheral blood mononuclear cells collected at baseline and post-treatment were examined for surface and intracellular markers via flow cytometry. CITE sequencing of CD8 T cells from three patients and plasma ctDNA analysis from 13 patients was performed using an ultrasensitive barcoding and next-generation sequencing method. Phenotypic analysis of CD8 T cells revealed higher TIGIT and PD-1 expression at baseline in responders compared to non-responders. Long-term responders (> 21 months) exhibited increased TCF-1+PD-1+ CD8 T cell frequencies relative to shorter-term responders (> 15 months) and non-responders. CITE sequencing revealed intrinsic differences in immune regulation pathways between responders and non-responders. Finally, non-responders showed elevated and increasing ctDNA levels post-treatment, correlating with declining TCF-1+PD-1+ CD8 T cells. Our data suggests combining CD8 T cell analysis with ctDNA dynamics could identify promising biomarkers for monitoring clinical response and treatment efficacy to PD-1/PD-L1 blockade in NSCLC.

Humans↗

PubMed2025

Machine learning detection of heteroresistance in Escherichia coli.

BACKGROUND: Heteroresistance (HR) is a significant type of antibiotic resistance observed for several bacterial species and antibiotic classes where a susceptible main population contains small subpopulations of resistant cells. Mathematical models, animal experiments and clinical studies associate HR with treatment failure. Currently used susceptibility tests do not detect heteroresistance reliably, which can result in misclassification of heteroresistant isolates as susceptible which might lead to treatment failure. Here we examined if whole genome sequence (WGS) data and machine learning (ML) can be used to detect bacterial HR. METHODS: We classified 467 Escherichia coli clinical isolates as HR or non-HR to the often used β-lactam/inhibitor combination piperacillin-tazobactam using pre-screening and Population Analysis Profiling tests. We sequenced the isolates, assembled the whole genomes and created a set of predictors based on current knowledge of HR mechanisms. Then we trained several machine learning models on 80% of this data set aiming to detect HR isolates. We compared performance of the best ML models on the remaining 20% of the data set with a baseline model based solely on the presence of β-lactamase genes. Furthermore, we sequenced the resistant sub-populations in order to analyse the genetic mechanisms underlying HR. FINDINGS: The best ML model achieved 100% sensitivity and 84.6% specificity, outperforming the baseline model. The strongest predictors of HR were the total number of β-lactamase genes, β-lactamase gene variants and presence of IS elements flanking them. Genetic analysis of HR strains confirmed that HR is caused by an increased copy number of resistance genes via gene amplification or plasmid copy number increase. This aligns with the ML model's findings, reinforcing the hypothesis that this mechanism underlies HR in Gram-negative bacteria. INTERPRETATION: We demonstrate that a combination of WGS and ML can identify HR in bacteria with perfect sensitivity and high specificity. This improved detection would allow for better-informed treatment decisions and potentially reduce the occurrence of treatment failures associated with HR. FUNDING: Funding provided to DIA from the Swedish Research Council (2021-02091) and NIH (1U19AI158080-01).

Machine Learning↗

PubMed2024

Expert opinion elicitation for assisting deep learning based Lyme disease classifier with patient data.

BACKGROUND: Diagnosing erythema migrans (EM) skin lesion, the most common early symptom of Lyme disease, using deep learning techniques can be effective to prevent long-term complications. Existing works on deep learning based EM recognition only utilizes lesion image due to the lack of a dataset of Lyme disease related images with associated patient data. Doctors rely on patient information about the background of the skin lesion to confirm their diagnosis. To assist deep learning model with a probability score calculated from patient data, this study elicited opinions from fifteen expert doctors. To the best of our knowledge, this is the first expert elicitation work to calculate Lyme disease probability from patient data. METHODS: For the elicitation process, a questionnaire with questions and possible answers related to EM was prepared. Doctors provided relative weights to different answers to the questions. We converted doctors' evaluations to probability scores using Gaussian mixture based density estimation. We exploited formal concept analysis and decision tree for elicited model validation and explanation. We also proposed an algorithm for combining independent probability estimates from multiple modalities, such as merging the EM probability score from a deep learning image classifier with the elicited score from patient data. RESULTS: We successfully elicited opinions from fifteen expert doctors to create a model for obtaining EM probability scores from patient data. CONCLUSIONS: The elicited probability score and the proposed algorithm can be utilized to make image based deep learning Lyme disease pre-scanners robust. The proposed elicitation and validation process is easy for doctors to follow and can help address related medical diagnosis problems where it is challenging to collect patient data.

Humans↗

PubMed2026

Chronic disease in a 15th-century skeleton from the first European settlement of the Canary Islands: Early evidence in the colonial Atlantic expansion (San Marcial de Rubicón, Lanzarote).

OBJECTIVE: This study seeks to evaluate morphological changes in a skeleton recovered from San Marcial de Rubicón, the earliest permanent European settlement in the Canary Islands. MATERIALS: The individual derives from a primary inhumation dated to the early fifteenth century. METHODS: Macroscopic observation was combined with conventional radiography, computed tomography, and mitochondrial DNA analysis. A systematic differential diagnosis considered metabolic, infectious, inflammatory, neoplastic, and degenerative conditions. RESULTS: The individual under investigation is an adult male with evidence of diffuse cortical thickening, periosteal new bone formation, heterogeneous radiodensity, cranial diploic expansion, long-bone bowing, severe degenerative joint disease, sacroiliac ankylosis, and elongated thoracic vertebral defects. Mitochondrial DNA analysis identified haplogroup X2c1, consistent with European maternal ancestry. CONCLUSIONS: The overall pattern is most consistent with polyostotic Paget disease of bone, although coexisting axial ankylosis and vertebral defects complicate the interpretation. These additional lesions are insufficient to support an alternative primary diagnosis. SIGNIFICANCE: This case provides an early extra-European archaeological example of Paget disease in the context of Atlantic colonial expansion. Rather than simply extending the geographic record of the disease, it shows how chronic skeletal conditions with strong European clinical and archaeological associations may be identified in frontier populations formed through mobility, settlement and colonial interaction. LIMITATIONS: The diagnosis is based on a single individual, and nuclear DNA data were insufficient to assess genetic susceptibility. SUGGESTIONS FOR FURTHER RESEARCH: Further radiological, genomic, and isotopic analyses of early colonial skeletal assemblages are needed to evaluate chronic disease, mobility, and biological diversity in Atlantic frontier populations.

Male↗

PubMed2026

Biochemical Insights Into the Conserved Interactions of NMD Factors From Budding Yeast to Humans.

Nonsense-mediated mRNA decay (NMD) is one of the most extensively studied pathways of cytoplasmic mRNA degradation. It plays a critical role in diverse cellular processes by eliminating aberrant transcripts containing premature stop codons and by regulating the stability of physiological mRNAs. NMD factors were initially identified through genetic screens in S. cerevisiae (UPF1, 2, 3) and C. elegans (SMG-1, SMG5-7). Subsequent biochemical and genetic studies revealed the composition of NMD complexes and identified additional factors. A major protein hub for NMD is Upf1, an ATP-dependent RNA helicase that is part of two mutually exclusive NMD assemblies, the Upf1-Upf2-Upf3 complex and the Upf1-decapping complex, which contains the decapping enzyme and its co-factors. Here, we discuss recent findings, primarily from budding yeast, on the protein-protein interactions driving NMD complexes dynamics and their similarities to human NMD. Together, the N-terminal cysteine and histidine rich (CH) and helicase domains (HD) of Upf1 act as a hub for binding multiple partners. Upf1 is required for binding to NMD substrates and for the initiation of RNA degradation through decapping (yeast) or endonucleolytic hydrolysis (humans). We focus on the interplay between Upf2, Dcp2 and Nmd4 (yeast SMG6), which ensures the mutually exclusive formation of Upf1-bound subcomplexes modulating Upf1's affinity for RNA. Thus, the study of NMD factors interactions in different organisms sheds new light on the remarkable conservation of NMD molecular mechanisms.

Nonsense Mediated mRNA Decay↗

PubMed2026

Clinical and Molecular Evaluation of HER2-Low and HER2-Ultralow Breast Cancer in the Penelope-B Clinical Trial Cohort.

The DestinyBreast (DB)04 and DB06 trials have shown clinical activity of trastuzumab-deruxtecan (T-DXd) in HER2-low and HER2-ultralow metastatic breast cancer. The identification of HER2-low and HER2-ultralow breast cancer is therefore essential for personalized therapy with T-DXd. We evaluated 723 residual tumors from the Penelope-B trial (NCT01864746) and correlated different levels of HER2 protein expression with prognosis and messenger RNA (mRNA) profiles, including HER2 transcripts. In Penelope-B, 57.68% (n = 417) of 723 residual tumors were HER2 low. The HER2-ultralow category was assigned to 109 (15.08%) tumors, and 197 (27.25%) tumors were completely HER2 negative (HER2 0). In Kaplan-Meier analysis, there were no survival differences among these 3 subgroups. There was no significant difference in HER2 mRNA expression between HER2-0 and HER2-ultralow tumors (P = .08). In contrast, there was a highly significant difference in HER2 mRNA expression between HER2-ultralow and HER2-low tumors (P < .0001) and between HER2-low and HER2-positive tumors (P < .0001). The extracellular protease cathepsin L, which has been suggested as a biomarker for extracellular cleavage of T-DXd, was detectable in all HER2-related subgroups and was a negative prognostic factor for invasive disease-free survival and overall survival (P = .0001) in preneoadjuvant core biopsies. In our study, we were able to characterize HER2 low as a clinically relevant and molecular defined tumor group with significantly increased HER2 expression. In contrast, for HER2 ultralow, we did not observe a defined molecular phenotype, despite the clinically relevant regulatory approval of T-DXd also in the ultralow subgroup. Additional investigations are needed to identify biomarkers beyond HER2 for T-DXd response as a basis for refined criteria for treatment eligibility.

Adult↗

PubMed2026

Mapping the causal chain from genetic risk variants to lipid dysmetabolism in Parkinson's disease.

The molecular pathways linking genetic variants to Parkinson's disease (PD) onset and progression remain incompletely defined; however, risk alleles in multiple genes, including GBA1, strongly implicate lipid metabolism. To systematically identify causal biomarker signatures, we analysed comprehensive metabolome profiles from blood plasma in 149 PD patients and 150 controls, along with complementary genetic, RNA-sequencing and metabolic data from other available clinical and pathologic cohorts. Using colocalization and summary-data-based Mendelian randomization, we tested whether expression and metabolic quantitative trait loci mediate the association between implicated genetic variants and PD risk. We further integrated differential metabolomics and proteomics from blood and brain to reveal pertinent mechanisms. We show that common PD risk variants at the serine palmitoyltransferase small subunit B (SPTSSB) locus, a key regulator of de novo sphingolipid biosynthesis, are associated with increased SPTSSB brain expression and elevated plasma ceramides. Additional analyses strongly support our hypothesis that a common SPTSSB causal variant is responsible for PD risk as well as the expression and metabolic quantitative trait loci. Multiple sphingolipids and fatty acid derivatives were perturbed in PD, and we identified both unique and shared features with the Alzheimer's disease metabolome. A PD acylcarnitine signature was further replicated in human post-mortem brain tissue, when comparing those with or without preclinical Lewy body pathology. Integrated analysis of complementary brain proteomic profiles revealed dysregulation of mitochondrial processes dependent on acylcarnitines, including fatty acid beta-oxidation, the tricarboxylic acid cycle and oxidative phosphorylation. Our results identify promising biomarkers and reveal a causal chain linking genetic variation to altered gene/protein expression, lipid dysmetabolism, and the manifestation of PD.

Humans↗

PubMed2026

Phylotranscriptomics Allows Distinguishing Major Gene Flow Events from Incomplete Lineage Sorting in Rapidly Diversifying Mimetic Orchids (Genus Ophrys).

Ophrys orchids (or bee orchids) provide an outstanding example of a plant adaptive radiation. Over the last 5 million years, this genus has diversified into hundreds of taxa as a result of its unconventional pollination strategy, known as "sexual swindling". However, the rapid and substantial diversification of this genus, combined with its capacity for hybridization and large genome size, poses significant challenges in addressing its systematics. We used phylotranscriptomics as a genome complexity reduction technique to infer the phylogenetic relationships among Ophrys main lineages. More than seven thousand gene trees enabled us to determine the relative contributions of gene flow and incomplete lineage sorting (ILS) in Ophrys evolution. First, we propose a new phylogenetic hypothesis for the genus with an unprecedented resolution that largely confirms the relationships between the main Ophrys lineages, but also provides new insights within each subgenera. By combining phylogenetic network inference with introgression analyzes based on gene tree topologies and branch lengths, we then show that the numerous phylogenetic incongruences among gene tree topologies result from a pervasive background of ILS, over which stand out several well-supported, ancient and potentially adaptive gene flow events between lineages. These major gene flow events provide a new perspective on the evolution of the Ophrys genus and its pollination, questioning previous hypotheses inferred without considering its reticulate evolution, and providing a better understanding of discrepancies observed among previous phylogenetic studies of the genus.

Orchidaceae↗

PubMed2026

PKMYT1 is a targetable vulnerability in del(17p) high-risk multiple myeloma.

Deletion of chromosome 17p [del(17p)] is among the most adverse cytogenetic abnormalities in multiple myeloma (MM). By integrating RNA sequencing data from cells of patients with MM with genetic dependency data from MM cell lines, we identified protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1), a member of the WEE family, as a potential therapeutic target in MM cells harboring del(17p). Genetic suppression or pharmacological inhibition of PKMYT1 activity with the selective inhibitor RP-6306 triggered accumulation of DNA damage, micronucleus formation, and mitotic catastrophe, resulting in preferential cell death in del(17p) MM cells while largely sparing del(17p)- MM cells and healthy cells. RP-6306 also reduced tumor burden and extended survival in vivo in both xenograft and TP53-deficient syngeneic models. Collectively, our findings nominate PKMYT1 as an actionable target and support PKMYT1 inhibition as a biomarker-driven therapeutic strategy for patients with del(17p) or TP53-deficient MM.

Humans↗