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Science China. Life Sciences Feb 2023Over the past two decades, numerous non-coding RNAs (ncRNAs) have been identified in different biological systems including virology, especially in large DNA viruses... (Review)
Review
Over the past two decades, numerous non-coding RNAs (ncRNAs) have been identified in different biological systems including virology, especially in large DNA viruses such as herpesviruses. As a representative oncogenic alphaherpesvirus, Marek's disease virus (MDV) causes an important immunosuppressive and rapid-onset neoplastic disease of poultry, namely Marek's disease (MD). Vaccinations can efficiently prevent the onset of MD lymphomas and other clinical disease, often heralded as the first successful example of vaccination-based control of cancer. MDV infection is also an excellent model for research into virally-induced tumorigenesis. Recently, great progress has been made in understanding the functions of ncRNAs in MD biology. Herein, we give a review of the discovery and identification of MDV-encoded viral miRNAs, focusing on the genomics, expression profiles, and emerging critical roles of MDV-1 miRNAs as oncogenic miRNAs (oncomiRs) or tumor suppressor genes involved in the induction of MD lymphomas. We also described the involvements of host cellular miRNAs, lincRNAs, and circRNAs participating in MDV life cycle, pathogenesis, and/or tumorigenesis. The prospects, strategies, and new techniques such as the CRISPR/Cas9-based gene editing applicable for further investigation into the ncRNA-mediated regulatory mechanisms in MDV pathogenesis/oncogenesis were also discussed, together with the possibilities of future studies on antiviral therapy and the development of new efficient MD vaccines.
Topics: Animals; Cell Transformation, Neoplastic; Chickens; Herpesvirus 2, Gallid; Lymphoma; Marek Disease; MicroRNAs
PubMed: 36617590
DOI: 10.1007/s11427-022-2258-4 -
Virulence Dec 2022Co-infection of Marek's disease virus (MDV) and reticuloendotheliosis virus (REV) synergistically drives disease progression, yet little is known about the mechanism of...
Co-infection of Marek's disease virus (MDV) and reticuloendotheliosis virus (REV) synergistically drives disease progression, yet little is known about the mechanism of the synergism. Here, we found that co-infection of REV and MDV increased their replication via the RIOK3-Akt pathway. Initially, we noticed that the viral titres of MDV and REV significantly increased in REV and MDV co-infected cells compared with single-infected cells. Furthermore, tandem mass tag peptide labelling coupled with LC/MS analysis showed that Akt was upregulated in REV and MDV co-infected cells. Overexpression of Akt promoted synergistic replication of MDV and REV. Conversely, inhibition of Akt suppressed synergistic replication of MDV and REV. However, PI3K inhibition did not affect synergistic replication of MDV and REV, suggesting that the PI3K/Akt pathway is not involved in the synergism of MDV and REV. In addition, we revealed that RIOK3 was recruited to regulate Akt in REV and MDV co-infected cells. Moreover, wild-type RIOK3, but not kinase-dead RIOK3, mediated Akt phosphorylation and promoted synergistic replication of MDV and REV. Our results illustrate that MDV and REV activated a novel RIOK3-Akt signalling pathway to facilitate their synergistic replication.
Topics: Animals; Chickens; Coinfection; Genetic Diseases, X-Linked; Herpesvirus 2, Gallid; Humans; Marek Disease; Phosphatidylinositol 3-Kinases; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Reticuloendotheliosis virus; Severe Combined Immunodeficiency; Virus Replication
PubMed: 35795905
DOI: 10.1080/21505594.2022.2096247 -
Current Topics in Developmental Biology 2022The Wnt family of secreted glycolipo-proteins signals through multiple signal transduction pathways and is essential for embryonic development and organ development and...
The Wnt family of secreted glycolipo-proteins signals through multiple signal transduction pathways and is essential for embryonic development and organ development and homeostasis. The Wnt-pathways are conserved and critical in all metazoans. Wnt signaling pathways comprise the canonical Wnt/β-catenin pathway and several non-canonical signaling branches, of which Wnt-Planar Cell Polarity (PCP) signaling and the Wnt/Calcium pathway have received the most attention and are best understood. nterestingly, all Wnt-pathways have a nuclear signaling branch and also can affect many cellular processes independent of its nuclear transcriptional regulation. Canonical Wnt/β-catenin signaling is the most critical for a nuclear transcriptional response, in both development and disease, yet the mechanism(s) on how the "business end" of the pathway, β-catenin, translocates to the nucleus to act as co-activator to the TCF/Lef transcription factor family still remains obscure. Here we discuss and compare the very different strategies on how the respective Wnt signaling pathways activate a nuclear transcriptional response. We also highlight some recent new insights into how β-catenin is translocated to the nucleus via an IFT-A, Kinesin-2, and microtubule dependent mechanism and how this aspect of canonical Wnt-signaling uses ciliary proteins in a cilium independent manner, conserved between Drosophila and mammalian cells.
Topics: Animals; Cell Nucleus; Drosophila; Mammals; Proto-Oncogene Proteins; Wnt Proteins; Wnt Signaling Pathway; beta Catenin
PubMed: 35606062
DOI: 10.1016/bs.ctdb.2022.02.008 -
Microbial Pathogenesis Sep 2022Marek's disease virus (MDV), a highly contagious cell associated virus, is the etiological agent of Marek's disease (MD), a lymphoproliferative and neuropathic disease...
Marek's disease virus (MDV), a highly contagious cell associated virus, is the etiological agent of Marek's disease (MD), a lymphoproliferative and neuropathic disease of domestic chickens. Clinical signs of MD include transient paralysis, bursal/thymic atrophy, and T cell lymphomas. MicroRNAs (miRNAs) are short single-stranded non-coding RNAs that regulate gene expression by transcriptional suppression or mRNA degradation. Herpesviruses, including MDV, encode for miRNAs that are known to play essential roles in viral pathogenicity, oncogenesis, and evasion of immune responses. In this study, we performed miRNA sequencing in thymuses of control and MDV-infected chickens of MD-resistant (6) and susceptible (7) lines at 21 days post infection (dpi). The thymus is a lymphoid organ that undergoes severe atrophy due to MDV-induced apoptotic mediated destruction of T cells. Sequence analysis identified 658 total chicken miRNAs in the thymuses of control and MDV-infected birds of both lines. Of these, 453 were novel and 205 were known microRNAs. All novel miRNAs mapped to chicken genome with no sequence homology to existing miRNAs in the chicken miRbase. Comparative analysis between the thymuses of control and infected birds of resistant and susceptible lines identified 78 differentially expressed microRNAs that might provide insights into mechanisms of thymus atrophy.
Topics: Animals; Atrophy; Chickens; Marek Disease; MicroRNAs; T-Lymphocytes
PubMed: 35917989
DOI: 10.1016/j.micpath.2022.105688 -
International Journal of Molecular... Apr 2020Although gene-environment interactions are known to play an important role in the inheritance of complex traits, it is still unknown how a genotype and the environmental... (Review)
Review
Although gene-environment interactions are known to play an important role in the inheritance of complex traits, it is still unknown how a genotype and the environmental factors result in an observable phenotype. Understanding this complex interaction in the pathogenesis of diabetic retinopathy (DR) remains a big challenge as DR appears to be a disease with heterogenous phenotypes with multifactorial influence. In this review, we examine the natural history and risk factors related to DR, emphasizing distinct clinical phenotypes and their natural course in retinopathy. Although there is strong evidence that duration of diabetes and metabolic factors play a key role in the pathogenesis of DR, accumulating new clinical studies reveal that this disease can develop independently of duration of diabetes and metabolic dysfunction. More recently, studies have emphasized the role of genetic factors in DR. However, linkage analyses, candidate gene studies, and genome-wide association studies (GWAS) have not produced any statistically significant results. Our recently initiated genomics study, the Diabetic Retinopathy Genomics (DRGen) Study, aims to examine the contribution of rare and common variants in the development DR, and how they can contribute to clinical phenotype, rate of progression, and response to available therapies. Our preliminary findings reveal a novel set of genetic variants associated with proangiogenic and inflammatory pathways that may contribute to DR pathogenesis. Further investigation of these variants is necessary and may lead to development of novel biomarkers and new therapeutic targets in DR.
Topics: Animals; Biological Variation, Population; Chromosome Mapping; Diabetic Nephropathies; Diabetic Retinopathy; Disease Progression; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Humans; Multifactorial Inheritance; Phenotype; Severity of Illness Index
PubMed: 32295293
DOI: 10.3390/ijms21082712 -
Veterinary World Jan 2023Marek's disease (MD) is a common lymphoproliferative disease affecting chickens and causing economic losses in commercial poultry. The MD outbreak was noticed in the...
BACKGROUND AND AIM
Marek's disease (MD) is a common lymphoproliferative disease affecting chickens and causing economic losses in commercial poultry. The MD outbreak was noticed in the southern part of Thailand in 2019. The suspected cases were found with an abnormal number of cases of layers dying with clinical signs, for example, weakness and emaciation, with evidence of MD gross lesions. This study aimed to raise awareness of the MD outbreak through value chain analysis (VCA), identifying associated possible risk factors, and estimating the associated economic impact.
MATERIALS AND METHODS
Value chain analysis, including seasonal calendar, value chain diagram, and layer movement mapping of the layer industry, was conducted. High-risk stakeholders were identified on the basis of risk practices and interactions between stakeholders. A case-control study was conducted to determine risk factors associated with the MD outbreak on layer farms, and partial budget analysis was used to estimate economic losses associated with MD.
RESULTS
The value chain diagram showed the linkages between stakeholders, including estimation of the percentage of products moved from one stakeholder group to another and the negotiated price. Fourteen out of 35 layer farms were case farms. Farm size and source of birds were significantly associated with the MD outbreak. The MD outbreak caused total economic losses of 295,823 USD. Farms that slaughtered infected birds with additional revenues incurred losses of 140,930 USD, whereas farms that culled infected birds without additional revenue returned incurred losses of 1995 USD.
CONCLUSION
The VCA provided a better understanding of the layer and egg businesses in South Thailand and guided the development of questionnaires for outbreak investigation. The potential risk factor findings suggested the need for further exploration of the source of the MD outbreak.
PubMed: 36855347
DOI: 10.14202/vetworld.2023.35-45 -
Frontiers in Aging Neuroscience 2023To test drugs with the potential to prevent the onset of Parkinson's disease (PD), it is key to identify individuals in the general population at high risk of developing...
INTRODUCTION
To test drugs with the potential to prevent the onset of Parkinson's disease (PD), it is key to identify individuals in the general population at high risk of developing PD. This is often difficult because most of the clinical markers are non-specific, common in PD but also common in older adults (e.g., sleep problems).
OBJECTIVE
We aimed to identify the clinical markers at high specificity for developing PD by comparing individuals with PD or prodromal PD to healthy controls.
METHODS
We investigated motor and non-motor symptoms (Movement Disorder Society Unified Parkinson's Disease Rating Scale Part 1 and 2 items) in 64 prodromal PD and 422 PD individuals calculating the odds ratios, adjusting for age and gender, for PD and prodromal PD versus 195 healthy controls. Symptoms at high specificity were defined as having an adjusted odds ratio ≥ 6.
RESULTS
Constipation had an adjusted odds ratio, 6.14 [95% CI: 2.94-12.80] showing high specificity for prodromal PD, and speech difficulties had an adjusted odds ratio, 9.61 [95% CI: 7.88-48.81] showing high specificity for PD. The proportion of participants showing these specific markers was moderate (e.g., prevalence of constipation was 43.75% in prodromal PD, and speech difficulties was 33.89% in PD), suggesting these symptoms may make robust predictors of prodromal PD and PD, respectively.
DISCUSSION
Clinical markers at high specificity for developing PD could be used as tools in the screening of general populations to identify individuals at higher risk of developing PD.
PubMed: 37810617
DOI: 10.3389/fnagi.2023.1232387 -
Frontiers in Veterinary Science 2024MicroRNAs (miRNAs) serve as key regulators in gene expression and play a crucial role in immune responses, holding a significant promise for diagnosing and managing... (Review)
Review
MicroRNAs (miRNAs) serve as key regulators in gene expression and play a crucial role in immune responses, holding a significant promise for diagnosing and managing diseases in farm animals. This review article summarizes current research on the role of miRNAs in various farm animal diseases and mycotoxicosis, highlighting their potential as biomarkers and using them for mitigation strategies. Through an extensive literature review, we focused on the impact of miRNAs in the pathogenesis of several farm animal diseases, including viral and bacterial infections and mycotoxicosis. They regulate gene expression by inducing mRNA deadenylation, decay, or translational inhibition, significantly impacting cellular processes and protein synthesis. The research revealed specific miRNAs associated with the diseases; for instance, gga-miR-M4 is crucial in Marek's disease, and gga-miR-375 tumor-suppressing function in Avian Leukosis. In swine disease such as Porcine Respiratory and Reproductive Syndrome (PRRS) and swine influenza, miRNAs like miR-155 and miR-21-3p emerged as key regulatory factors. Additionally, our review highlighted the interaction between miRNAs and mycotoxins, suggesting miRNAs can be used as a biomarker for mycotoxin exposure. For example, alterations in miRNA expression, such as the dysregulation observed in response to Aflatoxin B1 (AFB1) in chickens, may indicate potential mechanisms for toxin-induced changes in lipid metabolism leading to liver damage. Our findings highlight miRNAs potential for early disease detection and intervention in farm animal disease management, potentially reducing significant economic losses in agriculture. With only a fraction of miRNAs functionally characterized in farm animals, this review underlines more focused research on specific miRNAs altered in distinct diseases, using advanced technologies like CRISPR-Cas9 screening, single-cell sequencing, and integrated multi-omics approaches. Identifying specific miRNA targets offers a novel pathway for early disease detection and the development of mitigation strategies against mycotoxin exposure in farm animals.
PubMed: 38803799
DOI: 10.3389/fvets.2024.1372961 -
Viruses Feb 2023Marek's disease virus (MDV), a highly cell-associated oncogenic α-herpesvirus, is the etiological agent of T cell lymphomas and neuropathic disease in chickens known as...
Marek's disease virus (MDV), a highly cell-associated oncogenic α-herpesvirus, is the etiological agent of T cell lymphomas and neuropathic disease in chickens known as Marek's disease (MD). Clinical signs of MD include neurological disorders, immunosuppression, and lymphoproliferative lymphomas in viscera, peripheral nerves, and skin. Although vaccination has greatly reduced the economic losses from MD, the molecular mechanism of vaccine-induced protection is largely unknown. To shed light on the possible role of T cells in immunity induced by vaccination, we vaccinated birds after the depletion of circulating T cells through the IP/IV injection of anti-chicken CD4 and CD8 monoclonal antibodies, and challenged them post-vaccination after the recovery of T cell populations post-treatment. There were no clinical signs or tumor development in vaccinated/challenged birds with depleted CD4 or CD8 T cells. The vaccinated birds with a combined depletion of CD4 and CD8 T cells, however, were severely emaciated, with atrophied spleens and bursas. These birds were also tumor-free at termination, with no virus particles detected in the collected tissues. Our data indicated that CD4 and CD8 T lymphocytes did not play a critical role in vaccine-mediated protection against MDV-induced tumor development.
Topics: Animals; Marek Disease; CD8-Positive T-Lymphocytes; Chickens; Lymphoma; Herpesvirus 2, Gallid; Viral Vaccines
PubMed: 36992357
DOI: 10.3390/v15030648 -
Neurology Aug 2022There is clinical and phenotypic heterogeneity in G2019S Parkinson disease (PD), including loss of smell. Olfactory scores have defined subgroups of PD at baseline. We...
BACKGROUND AND OBJECTIVES
There is clinical and phenotypic heterogeneity in G2019S Parkinson disease (PD), including loss of smell. Olfactory scores have defined subgroups of PD at baseline. We now extend this work longitudinally to better determine features associated with olfactory classes and to gain further insight into this heterogeneity.
METHODS
Evaluation of 162 patients with PD and 198 patients with idiopathic PD (IPD) from the Ashkenazi Jewish Consortium was performed, with follow-up available for 92 patients with PD and 74 patients with IPD. Olfaction (University of Pennsylvania Smell Identification Test [UPSIT]), motor function (Unified Parkinson Disease Rating Scale), and cognition (Montreal Cognitive Assessment), as well as sleep, nonmotor, and mood, were measured. Gaussian mixture models were applied on the UPSIT percentile score to determine subgroups based on olfactory performance. Linear mixed effects models, using PD duration as the time scale, assessed the relationship between UPSIT subgroup membership and motor/cognitive change.
RESULTS
Baseline olfaction was better in PD compared with IPD (mean UPSIT ± SD: 24.2 ± 8.8 vs 18.9 ± 7.6), with higher mean percentile scores (difference: 15.3 ± 11.6) ( < 0.001) and less frequent hyposmia (55.6% vs 85.4%; < 0.001). Analysis suggested 3 classes among PD. Age at onset in PD was earlier in the worst olfaction group (group 1), compared with groups 2 and 3 (54.5 ± 11.1 vs 61.7 ± 9.3) ( = 0.012), and separately in the hyposmic group overall (55.0 ± 11.3 vs 61.7 ± 9.1) ( < 0.001). Longitudinal motor deterioration in PD was also significantly faster in the worst UPSIT group than the best UPSIT group (group 3 vs group 1: B = 0.31, SE = 0.35 vs B = 0.96, SE = 0.28) (rate difference = -0.65, SE = 0.29) ( = 0.03). However, olfactory group membership was not significantly associated with cognitive decline.
DISCUSSION
In this large cohort with longitudinal analysis, we extend prior work demonstrating subgroups defined by olfaction in G2019S PD and show that the worst olfaction group has earlier age at PD onset and more rapid motor decline. This supports a subgroup of PD that might show more rapid change in a clinical trial of -related agents and highlights the need to integrate careful phenotyping into allocation schema in clinical trials of -related agents.
CLASSIFICATION OF EVIDENCE
This study provides Class II evidence that worse olfactory scores were associated with an earlier age at symptomatic onset and a faster rate of motor deterioration in patients with PD.
Topics: Age of Onset; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Mutation; Olfaction Disorders; Parkinson Disease; Smell
PubMed: 35995594
DOI: 10.1212/WNL.0000000000200737