Biology subjects

Nagy, A.

Publications and source records attributed to Nagy, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Two epidemics, one genotype, different outcomes: evolutionary changes of Avian Influenza H5N1, genotype EA-2024-DI

Since 2020, high pathogenicity avian influenza H5Nx viruses of clade 2.3.4.4b have become enzootic in Europe, causing recurrent epidemic waves characterized by extensive reassortment events. Here, we describe the emergence of a single high-fitness genotype (EA-2024-DI) that has driven two consecutive waves, evolving into distinct sub-lineages. While its circulation is ongoing, during the 2025-2026 wave it caused an unprecedented number of cases in wild birds. Using phylodynamic analyses of a large dataset of genomic sequences, we compared the spatial diffusion and host transmission pattern of the EA-2024-DI sub-lineages across the three most recent epidemic waves (2023-2024, 2024-2025 and 2025-2026). We show that the genotype has persisted over time and has spread primarily through wild Anseriformes, but with a marked change in the transmission patterns between the different waves and a shift in the epicenter from Eastern to Central Europe, the latter having emerged as an important hub for virus diffusion throughout Europe. Our results reveal a recent increase in the frequency of viruses from wild and domestic mammals carrying mutations enhancing virus replication in mammalian hosts, highlighting the importance of proactive monitoring of this group of hosts to better understand its role in the virus ecology and evolution.

evolutionary biology↗

bioRxiv2026

The Uvrag-containing PI3K complex promotes Hsc70-4 dependent endosomal clathrin removal and lysosomal maturation in Drosophila nephrocytes

The class III phosphatidylinositol 3-kinase complex (PI3K(III)) generates phosphatidylinositol-3-phosphate (PI(3)P), a lipid that defines endosomal membrane identity. Two PI3K(III) complexes share core subunits but differ in their fourth component: the Atg14-containing complex I functions in autophagy, whereas the Uvrag-containing complex II is required for endosomal maturation. Despite this, the mechanism by which complex II promotes lysosomal function remains unclear. Using Drosophila nephrocytes, we show that PI(3)P is enriched on Rab7-positive late endosomes and that the Hsp70 chaperone Hsc70-4 binds phosphoinositides. Loss of PI3K complex II disrupts endolysosomal organization and phenocopies Hsc70-4 inhibition. In both cases, clathrin accumulates on intracellular, often endosomal membranes, Rab7 compartments are disorganized, and abnormal endolysosomal structures form. These defects are accompanied by impaired HOPS recruitment, lysosomal dysfunction, and secretion of endolysosomal content. Importantly, clathrin depletion partially rescues these defects. Together, our findings identify a role for PI3K complex II in promoting clathrin removal from endosomal membranes and link PI(3)P and Hsc70-4 activity to lysosomal maturation.

cell biology↗

bioRxiv2026

Multiple overlapping SNARE complexes drive endosome maturation in Drosophila nephrocytes

Endosomal maturation determines whether internalized cargo is recycled or degraded, yet the molecular logic governing early endosomal fusion remains poorly defined. This process is often depicted as a linear Rab5-to-Rab7 transition mediated by a single, ordered SNARE pathway, but extensive redundancy in mammalian systems has obscured pathway architecture. Here, using Drosophila nephrocytes as a genetically tractable in vivo model with minimal SNARE redundancy, we show that early endosome maturation is driven by multiple parallel, non-interchangeable SNARE-dependent pathways. We first resolve a long-standing discrepancy in Syntaxin 7 family orthology, demonstrating that the Drosophila protein previously termed Syx7/Avl is functionally analogous to mammalian STX12 rather than STX7, while late endosomal and lysosomal fusion is mediated by a distinct Syntaxin 7 homolog (Syx13). Based on this reclassification, we define a Syx12L-Snap29-Ykt6 complex that drives canonical homotypic early endosomal fusion. In addition, we identify two related SNARE assemblies - Syx7L-Snap29-Ykt6 and Syx7L-Snap29-Vamp7-that promote later stages of endosomal and lysosomal fusion with distinct Rab GTPase requirements. These partially compensatory complexes remain active when the canonical pathway is disrupted, producing divergent morphological outcomes, including the formation of aberrant endolysosomal swirls. We establish Snap29 as a central Qbc-SNARE integrating all endosomal fusion routes and uncover a dual role for Ykt6 in promoting maturation while also participating in endosomal recycling. Together, our findings revise the prevailing model of endosome maturation, revealing a network of parallel, regulated fusion pathways that confer robustness and plasticity to the endolysosomal system.

cell biology↗

bioRxiv2025

First occurrence of parasitic isopod (Braga nasuta, Schioedte & Meinert, 1881) on ornamental fish in Europe

Parasitic crustaceans represent a significant threat to both freshwater and marine aquaculture, with several families capable of inducing severe diseases with high mortality rates and therefore significant economic losses. Among them, isopods of the genus Braga (Cymothoidae) are haematophagous parasites of neotropical fish, causing anaemia, tissue damage, and mortality. Braga nasuta, endemic to Brazil, has been reported from various hosts, including ornamental species exported worldwide. During routine examination of imported cardinal tetra (Paracheirodon axelrodi, Schultz, 1956), the authors detected that one of the fish harbored an adult male isopod ([~]6.21 mm long, 2.66 mm wide) attached anterior to the dorsal fin. Based on morphological identification, the parasite was identified as Braga nasuta. No secondary pathogens were observed in affected fish. Given the global trade in ornamental species, the introduction of B. nasuta into non-native regions underscores the importance of quarantine and parasite monitoring. While the potential ability of this parasite to establish populations in Europe requires further studies, vigilance is warranted to prevent potential spread and ecological impact. In this study, the authors document the first occurrence of B. nasuta in Europe, detected on a cardinal tetra (P. axelrodi) imported to a Hungarian public aquarium.

zoology↗

bioRxiv2025

Conserved transcriptional co-regulation of pyrophosphatehomeostasis genes governs systemic mineralization factorsin mice and humans

Inorganic pyrophosphate (PPi) is a critical inhibitor of ectopic calcification, yet transcriptional regulation of genes controlling its systemic production and degradation (ABCC6, ALPL, ANKH, ENPP1) remains elusive. We hypothesized that PPi homeostasis is governed by evolutionarily conserved transcription factor (TF) network. Promoter-motif analysis of PPi genes revealed conserved enrichment of nuclear receptor TFs (ESR1, NR4A1, RXRA, NR1H3/LXR) and metabolic regulators (SREBF1, CEBPB, HNF4A) across mouse and human orthologues. Supporting this, analysis of public RNA-seq datasets and RT-qPCR in wild-type and Abcc6-/- mice demonstrated tight co-expression of these genes in the liver and the kidney, as central transcriptional hub of systemic PPi regulation. Functionally, analyses in mice revealed age-dependent inverse coupling between plasma PPi concentration and serum alkaline phosphatase (AP) activity, with strongest impact during early life. Abcc6-/- mice exhibited persistently reduced although gradually increasing PPi and altered Pi/PPi ratios during aging. Translating these findings to humans, plasma PPi correlated inversely with AP activity and positively with Pi, though associations were weaker in ABCC6-deficient pseudoxanthoma elasticum patients. These results establish a conserved TF-driven program coordinating hepatic and renal expression of PPi homeostatic genes, highlight early-life sensitivity of PPi balance, and link gene-regulation to circulating mineralization factors, highlighting species-specific and pathology-driven differences.

physiology↗

bioRxiv2025

Transposon insertion causes ctnnb2 transcript instability that results in the maternal effect zebrafish ichabod (ich) mutation

The maternal-effect mutation ichabod (ich) results in ventralized zebrafish embryos due to impaired induction of the dorsal canonical Wnt-signaling pathway. While previous studies linked the phenotype to reduced ctnnb2 transcript levels, the causative mutation remained unidentified. Using long-read sequencing, we discovered that the ich phenotype stems from the insertion of a non-autonomous CMC-Enhancer/Suppressor-mutator (CMC-EnSpm) transposon in the 3UTR of the gene. Through reporter assays, we demonstrate that while wild type ctnnb2 mRNAs exhibit remarkably high stability throughout the early stages of development, the insertion of the transposon dramatically reduces transcript stability. Genome-wide mapping of the CMC-EnSpm transposons across multiple zebrafish strains also indicated ongoing transposition activity in the zebrafish genome. Our findings not only resolve the molecular basis of the ich mutation but also highlight the continuing mutagenic potential of endogenous transposons and reveal unexpected aspects of maternal transcript regulation during early zebrafish development.

developmental biology↗

bioRxiv2025

Genetic data and meteorological conditions: unravelling the windborne transmission of H5N1 high-pathogenicity avian influenza between commercial poultry outbreaks

Understanding the transmission routes of high-pathogenicity avian influenza (HPAI) is crucial for developing effective control measures to prevent its spread. In this context, windborne transmission, the idea that the virus can travel through the air over considerable distances, is a contentious concept and, documented cases are rare. Here, though, we provide genetic evidence supporting the feasibility of windborne transmission. During the 2023-24 HPAI season, molecular surveillance identified identical H5N1 strains among a cluster of unrelated commercial farms about 8 km apart in the Czech Republic. The episode started with the abrupt mortality of fattening ducks on one farm and was followed by disease outbreaks at two nearby high-biosecurity chicken farms. Using genetic, epizootiological, meteorological and geographical data, we reconstructed a mosaic of events strongly suggesting wind was the mechanism of infection transmission between poultry in at least two independent cases. By aligning the genetic and meteorological data with critical outbreak events, we determined the most likely time window during which the transmission occurred and inferred the sequence of infected houses at the recipient sites. Our results suggest that the contaminated plume emitted from the infected fattening duck farm was the critical medium of HPAI transmission, rather than the dust generated during depopulation. Furthermore, they also strongly implicate the role of confined mechanically-ventilated buildings with high population densities in facilitating windborne transmission and propagating virus concentrations below the minimum infectious dose at the recipient sites. These findings underscore the importance of considering windborne spread in future outbreak mitigation strategies.

microbiology↗

bioRxiv2025

Huntington's disease-associated ankyrin repeat palmitoyl transferases are rate-limiting factors in lysosome formation and fusion

Protein palmitoylation in the Golgi apparatus is critical for the appropriate sorting of various proteins belonging to secretory and lysosomal systems, and defective palmitoylation can lead to the onset of severe pathologies. HIP14 and HIP14L ankyrin repeat-containing palmitoyl transferases were linked to the pathogenesis of Huntingtons disease, however, how perturbation of these Golgi resident enzymes contributes to neurological disorders is yet to be understood. In this study, we investigated the function of Hip14 and Patsas - the Drosophila orthologs of HIP14 and HIP14L respectively - to uncover their role in secretory and lysosomal membrane trafficking. Using larval salivary gland, a well-established model of the regulated secretory pathway, we found that these PAT enzymes equally contribute to the proper maturation and crinophagic degradation of glue secretory granules by mediating their fusion with the endo-lysosomal compartment. We also revealed that Patsas and Hip14 are both required for lysosomal acidification and biosynthetic transport of various lysosomal hydrolases, and we demonstrated that the rate of secretory granule-lysosome fusion and subsequent acidification positively correlates with the level of Hip14. Furthermore, Hip14 is also essential for proper lysosome formation and neuronal function in adult brains. Finally, we found that the over-activation of lysosomal biosynthetic transport and lysosomal fusions by the expression of the constitutively active form of Rab2 could compensate for the lysosomal dysfunction caused by the loss of Patsas or Hip14 both in larval salivary glands and neurons. Therefore, we demonstrated that ankyrin repeat palmitoyl transferases may act as rate-limiting factors in lysosomal fusions and provide genetic evidence that defective protein palmitoylation and the subsequent lysosomal dysfunction can contribute to the onset of Huntingtons disease-like symptoms. Author SummaryGrowing body of evidence suggests that decreased activity of HIP14 and HIP14L palmitoyl transferases caused by accumulation of mutant Huntingtin and the subsequent alterations in protein palmitoylation play a critical role in the onset of Huntingtons disease (HD). However, which cellular processes are perturbed and eventually lead to the emergence of HD due to impaired palmitoylation is still poorly understood. In our study, we used a Drosophila model to uncover the role of Hip14 and Patsas (the fly ortholog of HIP14L) in secretory and lysosomal membrane trafficking. We found that silencing of these transferases in larval salivary glands equally disrupts secretory granule lysosome-fusion, their subsequent acidification and also the trafficking of lysosomal hydrolases. While overexpression of Hip14 resulted in the acceleration of these processes. We also observed that neuron-specific loss of Hip14 not only perturbs lysosome formation but also results in a progressive decline in neuromuscular functions. Importantly, both lysosomal and neuronal defects emerging in Hip14 and Patsas deficient backgrounds could be restored by hyperactivation of Rab2 GTPase mediated lysosome formation and fusion. These findings suggest that Hip14 and Patsas protect from the onset of HD like symptoms by acting as rate-limiting factors of lysosome formation and fusion.

cell biology↗

bioRxiv2024

Substrate Stiffness Dictates Unique Doxorubicin-induced Senescence-associated Secretory Phenotypes and Transcriptomic Signatures in Human Pulmonary Fibroblasts

Cells are subjected to dynamic mechanical environments which impart forces and induce cellular responses. In age-related conditions like pulmonary fibrosis, there is both an increase in tissue stiffness and an accumulation of senescent cells. While senescent cells produce a senescence-associated secretory phenotype (SASP), the impact of physical stimuli on both cellular senescence and the SASP is not well understood. Here, we show that mechanical tension, modeled using cell culture substrate rigidity, influences senescent cell markers like SA-{beta}-gal and secretory phenotypes. Comparing human primary pulmonary fibroblasts (IMR-90) cultured on physiological (2 kPa), fibrotic (50 kPa), and plastic (approximately 3 GPa) substrates, followed by senescence induction using doxorubicin, we identified unique high-stiffness-driven secretory protein profiles using mass spectrometry and transcriptomic signatures, both showing an enrichment in collagen proteins. Consistently, clusters of p21+ cells are seen in fibrotic regions of bleomycin induced pulmonary fibrosis in mice. Computational meta-analysis of single-cell RNA sequencing datasets from human interstitial lung disease confirmed these stiffness SASP genes are highly expressed in disease fibroblasts and strongly correlate with mechanotransduction and senescence-related pathways. Thus, mechanical forces shape cell senescence and their secretory phenotypes.

cell biology↗

bioRxiv2024

Interactions of N- and C-terminal parts of Ana1 permitting centriole duplication but not elongation

The conserved process of centriole duplication requires establishment of a Sas6-centred cartwheel initiated by Plk4s phosphorylation of Ana1/STIL. Subsequently the centriole undergoes conversion to a centrosome requiring its radial expansion and elongation, mediated by a network requiring interactions between Cep135, Ana1/Cep295, and Asterless/Cep152. Here we show that mutant alleles encoding overlapping N- and C-terminal parts of Ana1 are capable of intragenic complementation to rescue radial expansion. This permits recruitment of Asl and thereby centriole duplication and mechanosensory cilia formation to restore the coordination defects of these mutants. This genetic combination also rescues centriole duplication in the male germ line but does not rescue the elongation of the triplet microtubule-containing centrioles of primary spermatocytes and consequently these males are coordinated but sterile. Such centriole elongation is rescued by the continuous, full-length Ana1 sequence. We define a region that when deleted within otherwise intact Ana1 does not permit primary spermatocyte centrioles to elongate but still allows recruitment of Asl. Our findings point to differing demands upon the physical organization of Ana1 for the distinct processes of radial expansion and elongation of centrioles. IMPACT STATEMENTThe centriole can undergo radial development and duplication using separated parts of the conserved Ana1 protein whereas elongation of centriolar microtubule triplets requires the continuous Ana1 primary sequence.

genetics↗

bioRxiv2024

GDF11 secreting cell transplant efficiently ameliorates age-related pulmonary fibrosis

Here, we present a combination of cell and gene therapy that harnesses the regenerative properties of GDF11 in age-related pulmonary fibrosis. Our genome-edited FailSafeTM-GDF11 mouse ESC line provides controlled proliferation and efficient derivation to lung progenitors while inducibly expressing GDF11. When these cells were transplanted into bleomycin-injured aged mice, they acted as a source of reparative cells, restoring the damaged alveolar epithelium. Furthermore, the transplanted cells acted as an "in situ factory", enabling the production of GDF11 in response to the inducer drug. This approach attenuated age-associated senescence and led to the successful resolution of fibrosis. Our study presents a promising method for treating pulmonary fibrosis. Additionally, this approach offers a versatile tool that can be expanded to incorporate other regenerative and anti-aging factors. This helps overcome limitations such as high production costs and a short half-life of therapeutic factors. One of the strengths of our system is its ability to allow precise regulation of factor-expression when needed to address specific aging phenotypes.

developmental biology↗

bioRxiv2024

The Rab7-Epg5 and Rab39-ema modules cooperately position autophagosomes for efficient lysosomal fusions

Macroautophagy, a major self-degradation pathway in eukaryotic cells, utilizes autophagosomes to transport self-material to lysosomes for degradation. While microtubular transport is crucial for the proper function of autophagy, the exact roles of factors responsible for positioning autophagosomes remain incompletely understood. In this study, we performed a loss-of-function genetic screen targeting genes potentially involved in microtubular motility. A genetic background that blocks autophagosome-lysosome fusions was used to accurately analyze autophagosome positioning. We discovered that pre-fusion autophagosomes move towards the non-centrosomal microtubule organizing center (ncMTOC) in Drosophila fat cells, which requires a dynein-dynactin complex. This process is regulated by the small GTPases Rab7 and Rab39 together with their adaptors: Epg5 and ema, respectively. The dynein-dependent movement of vesicles toward the nucleus/ncMTOC is essential for efficient autophagosomal fusions with lysosomes and subsequent degradation. Remarkably, altering the balance of kinesin and dynein motors changes the direction of autophagosome movement, indicating a competitive relationship where normally dynein-mediated transport prevails. Since pre-fusion lysosomes were positioned similarly to autophagosomes, it indicates that pre-fusion autophagosomes and lysosomes converge at the ncMTOC, which increases the efficiency of vesicle fusions.

cell biology↗

bioRxiv2021

ELICE16INDURES (R): a plant immune-priming activator targeting jasmonate metabolism via TIFY and RHOMBOID proteins in Hordeum vulgare

Priming activity of plant-based allelochemicals is advanced research nowadays meaning a high potential in sustainable agriculture. The ELICE16INDURES(R) (RIMPH LTD, Hungary) plant conditioner of CO2 botanical extracts is rich in plant-active ingredients such as phenolic compounds, alkaloids, and flavonoids formulated in small multilamellar liposomes. This product was investigated in autumn barley (Hordeum vulgare). Field experiments of ELICE16INDURES showed augmented NDVI values interconnected with higher photosynthetic activity and yield increase. Background of the better vitality of plants was investigated by whole genomic gene expression profiling and showed an enhanced response to wounding, jasmonic acid, oxidative detoxification, and chloroplast activity. Among top50 differentially expressed genes the TIFY domain protein TIFY11B and RHOMBOID-like protein 2 related to JA signaling were up-regulated in field-collected samples. Phytotron experiments of barley were set up to validate and evaluate the transcriptomic effect of ELICE16INDURES. Well-studied priming active agents such as salicylic acid and beta-aminobutyric acid were compared with ELICE16INDURES and confirmed as priming inducer material with positive regulation of TIFY11B, TIFY3B, TIFY9, TIF10A, and RHOMBOID like protein 2 by using NGS GEx and RT-qPCR methods. One-sentence summaryELICE16INDURES(R) is a plant conditioner agent with a high amount of allelochemicals encapsulated into small multilamellar liposomes and found as an immune priming activator tested in H. vulgare field and phytotron cultures.

plant biology↗

bioRxiv2021

Reservoir host studies of Lloviu virus: first isolation, sequencing and serology in Schreiber's bats in Europe

IntroductoryFiloviruses are prime examples of emerging human pathogens that are transmitted to humans by zoonotic spillover events. Since their initial discovery, filovirus outbreaks have occured with increasing frequency and intensity. There is an urgent need to better understand their enzootic ecology and pathogenic potential, given recent zoonotic virus spillover events including the 2013-2016 West African Ebola virus (EBOV) epidemic. Several novel filoviruses have been discovered with a markedly wider geographic distribution than previously described. One of these novel filoviruses, Lloviu virus (LLOV), was first identified in 2002 in Schreibers bats (Miniopterus schreibersii) in Spain, Portugal, and southern France. Subsequently, in 2016, LLOV was detected during the passive monitoring of bats in Hungary. Here we report the first isolation of infectious Lloviu virus; from the blood of an asymptomatic Schreibers bat, subsequently cultivated in the Miniopterus sp. kidney cell line SuBK12-08. We also show that LLOV is able to infect monkey and human cells, suggesting that LLOV might have spillover potential. We performed a multi-year surveillance of LLOV and detected LLOV RNA in both deceased and asymptomatic live animals as well as in coupled ectoparasites from the families Nycteribiidae and Ixodidae. We present data on the natural infection and seropositivity of Schreibers bats and provide novel LLOV genomic sequence information from a bat host and an arthropod parasite. Our data support the role of bats, specifically Miniopterus schreibersii as natural reservoirs for the LLOV filovirus in Europe. We also suggest that bat-associated parasites might play a role in the natural ecology of filoviruses in temperate climate regions compared to filoviruses in the tropics. These results raise the possibility of cross-species transmission events via bat-human interactions.

microbiology↗

bioRxiv2021

COVIDOUTCOME - Estimating COVID Severity Based on Mutation Signatures in the SARS-CoV-2 Genome

IntroductionNumerous studies demonstrate frequent mutations in the genome of SARS-CoV-2. Our goal was to statistically link mutations to severe disease outcome. MethodsWe used an automated machine learning approach where 1,594 viral genomes with available clinical follow-up data were used as the training set (797 "severe" and 797 "mild"). The best algorithm, based on random forest classification combined with the LASSO feature selection algorithm was employed to the training set to link mutation signatures and outcome. The performance of the final model was estimated by repeated, stratified, 10-fold cross validation (CV), then adjusted for multiple testing with Bootstrap Bias Corrected CV. ResultsWe identified 26 protein and UTR mutations significantly linked to severe outcome. The best classification algorithm uses a mutation signature of 22 mutations as well as the patients age as the input and shows high classification efficiency with an AUC of 0.94 (CI: [0.912, 0.962]) and a prediction accuracy of 87% (CI: [0.830, 0.903]). Finally, we established an online platform (https://covidoutcome.com/) which is capable to use a viral sequence and the patients age as the input and provides a percentage estimation of disease severity. DiscussionWe demonstrate a statistical association between mutation signatures of SARS-CoV-2 and severe outcome of COVID-19. The established analysis platform enables a real-time analysis of new viral genomes. KEY MESSAGESO_LIA statistical link between SARS-Cov-2 mutation status and severe COVID outcome was established using automated machine learning techniques based on random forest and logistic regression combined with feature selection algorithms. C_LIO_LIA mutation signature based on 3,779 protein coding and 36 UTR mutations capable to identify severe outcome cases was established. C_LIO_LIThe trained model showed high classification performance (AUC=0.94 (CI: [0.912, 0.962]), accuracy=0.87 (CI: [0.830, 0.903])). C_LIO_LIA registration-free web-server for automated classification of new samples was set up and is accessible at http://www.covidoutcome.com. C_LIO_LIThe established pipeline provides a quick assessment of future patients warranting a prospective clinical validation. C_LI

bioinformatics↗

bioRxiv2021

Signal requirement for cortical potential of transplantable human neuroepithelial stem cells

The cerebral cortex develops from dorsal forebrain neuroepithelial progenitor cells. Initial expansion of the progenitor cell pool is followed by the generation of neurons of all the cortical layers and later, astrocytes and oligodendrocytes. However, the regulatory pathways that control the expansion and maintenance of the neuroepithelial progenitor cell pool are currently unknown. Here we define six basic pathway components that regulate proliferation of cortically specified human neuroepithelial stem cells (cNESCs) in vitro without the loss of developmental potential. We show that activation of FGF and inhibition of BMP and ACTIVIN A signalling are required for long-term cNESC proliferation. We also demonstrate that cNESCs preserve dorsal telencephalon-specific potential when GSK3, AKT and nuclear CATENIN-{beta}1 activity are low. Remarkably, regulation of these six pathway components supports the clonal expansion of cNESCs. Moreover, cNESCs differentiate to lower and upper layer cortical neurons both in vitro and in vivo. Identifying the mechanisms that drive the self-renewal and fate of cNESCs decision of neuroepithelial stem cells is key to developing new stem cell-based therapeutic approaches to treat neurological conditions.

developmental biology↗

bioRxiv2020

Pancancer survival analysis of cancer hallmark genes

Cancer hallmark genes are responsible for the most essential phenotypic characteristics of malignant transformation and progression. In this study, our aim was to estimate the prognostic effect of the established cancer hallmark genes in multiple distinct cancer types. RNA-seq HTSeq counts and survival data from 26 different tumor types were acquired from the TCGA repository. DESeq was used for normalization. Correlations between gene expression and survival were computed using the Cox proportional hazards regression and by plotting Kaplan-Meier survival plots. The false discovery rate was calculated to correct for multiple hypothesis testing. Signatures based on genes involved in genome instability and invasion reached significance in most individual cancer types. Thyroid and glioblastoma were independent of hallmark genes (61 and 54 genes significant, respectively), while renal clear cell cancer and low grade gliomas harbored the most prognostic changes (403 and 419 genes significant, respectively). The eight genes with the highest significance included BRCA1 (genome instability, HR=4.26, p<1E-16), RUNX1 (sustaining proliferative signaling, HR=2.96, p=3.1E-10) and SERPINE1 (inducing angiogenesis, HR=3.36, p=1.5E-12) in low grade glioma, CDK1 (cell death resistance, HR=5.67, p=2.1E-10) in kidney papillary carcinoma, E2F1 (tumor suppressor, HR=0.38, p=2.4E-05) and EREG (enabling replicative immortality, HR=3.23, p=2.1E-07) in cervical cancer, FBP1 (deregulation of cellular energetics, HR=0.45, p=2.8E-07) in kidney renal clear cell carcinoma and MYC (invasion and metastasis, HR=1.81, p=5.8E-05) in bladder cancer. We observed unexpected heterogeneity and tissue specificity when correlating cancer hallmark genes and survival. These results will help to prioritize future targeted therapy development in different types of solid tumors.

bioinformatics↗

bioRxiv2020

A universal RT-qPCR assay for "One Health" detection of influenza A viruses

The mutual dependence of human and animal health is central to the One Health initiative as an integrated strategy for infectious disease control and management. A crucial element of the One Health includes preparation and response to influenza A virus (IAV) threats at the human-animal interface. The IAVs are characterized by extensive genetic variability, they circulate among different hosts and establish host-specific lineages. The four main host reservoirs are: avian, swine, human and equine, with occasional transmission to other mammalian species. The host diversity is mirrored in the range of the RT-qPCR assays for IAV detection. Different assays are recommended by the responsible health authorities for generic IAV detection in birds, swine or humans. In order to unify IAV monitoring in different hosts and apply the One Health approach, we developed a single RT-qPCR assay for universal detection of all IAVs of all subtypes, species origin and global distribution. The assay design was centred on a highly conserved region of the IAV MP-segment identified by a comprehensive analysis of 99,353 sequences. The reaction parameters were effectively optimised with efficiency of 93-97% and LOD95% of approximately ten IAV templates per reaction. The assay showed high repeatability, reproducibility and robustness. The extensive in silico evaluation demonstrated high inclusivity, i.e. perfect sequence match in the primers and probe binding regions, established as 94.6% for swine, 98.2% for avian and 100% for human H3N2, pandemic H1N1, as well as other IAV strains, resulting in an overall predicted detection rate of 99% on the analysed dataset. The theoretical predictions were confirmed and extensively validated by collaboration between six veterinary or human diagnostic laboratories on a total of 1970 specimens, of which 1455 were clinical and included a diverse panel of IAV strains.

microbiology↗