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Veterinary Research Nov 2016Marek's disease (MD), caused by Marek's disease virus (MDV), is a commercially important neoplastic disease of poultry which is only controlled by mass vaccination.... (Review)
Review
Marek's disease (MD), caused by Marek's disease virus (MDV), is a commercially important neoplastic disease of poultry which is only controlled by mass vaccination. Importantly, vaccines that can provide sterile immunity and inhibit virus transmission are lacking; such that vaccines are only capable of preventing neuropathy, oncogenic disease and immunosuppression, but are unable to prevent MDV transmission or infection, leading to emergence of increasingly virulent pathotypes. Hence, to address these issues, developing more efficacious vaccines that induce sterile immunity have become one of the important research goals for avian immunologists today. MDV shares very close genomic functional and structural characteristics to most mammalian herpes viruses such as herpes simplex virus (HSV). MD also provides an excellent T cell lymphoma model for gaining insights into other herpesvirus-induced oncogenesis in mammals and birds. For these reasons, we need to develop an in-depth knowledge and understanding of the host-viral interaction and host immunity against MD. Similarly, the underlying genetic variation within different chicken lines has a major impact on the outcome of infection. In this review article, we aim to investigate the pathogenesis of MDV infection, host immunity to MD and discuss areas of research that need to be further explored.
Topics: Animals; Chickens; Herpesvirus 2, Gallid; Marek Disease; Poultry Diseases
PubMed: 27894330
DOI: 10.1186/s13567-016-0404-3 -
Frontiers in Immunology 2021Delayed wound healing can cause significant issues for immobile and ageing individuals as well as those living with co-morbid conditions such as diabetes, cardiovascular... (Review)
Review
Delayed wound healing can cause significant issues for immobile and ageing individuals as well as those living with co-morbid conditions such as diabetes, cardiovascular disease, and cancer. These delays increase a patient's risk for infection and, in severe cases, can result in the formation of chronic, non-healing ulcers (e.g., diabetic foot ulcers, surgical site infections, pressure ulcers and venous leg ulcers). Chronic wounds are very difficult and expensive to treat and there is an urgent need to develop more effective therapeutics that restore healing processes. Sustained innate immune activation and inflammation are common features observed across most chronic wound types. However, the factors driving this activation remain incompletely understood. Emerging evidence suggests that the composition and structure of the wound microbiome may play a central role in driving this dysregulated activation but the cellular and molecular mechanisms underlying these processes require further investigation. In this review, we will discuss the current literature on: 1) how bacterial populations and biofilms contribute to chronic wound formation, 2) the role of bacteria and biofilms in driving dysfunctional innate immune responses in chronic wounds, and 3) therapeutics currently available (or underdevelopment) that target bacteria-innate immune interactions to improve healing. We will also discuss potential issues in studying the complexity of immune-biofilm interactions in chronic wounds and explore future areas of investigation for the field.
Topics: Animals; Bacteria; Biofilms; Chronic Disease; Diabetic Foot; Humans; Immunity, Innate; Microbiota; Models, Immunological; Wound Healing
PubMed: 33897696
DOI: 10.3389/fimmu.2021.648554 -
Telomeres and Telomerase: Role in Marek's Disease Virus Pathogenesis, Integration and Tumorigenesis.Viruses Jul 2017Telomeres protect the ends of vertebrate chromosomes from deterioration and consist of tandem nucleotide repeats (TTAGGG) that are associated with a number of proteins.... (Review)
Review
Telomeres protect the ends of vertebrate chromosomes from deterioration and consist of tandem nucleotide repeats (TTAGGG) that are associated with a number of proteins. Shortening of the telomeres occurs during genome replication, thereby limiting the replication potential of somatic cells. To counteract this shortening, vertebrates encode the telomerase complex that maintains telomere length in certain cell types via de novo addition of telomeric repeats. Several herpesviruses, including the highly oncogenic alphaherpesvirus Marek's disease virus (MDV), harbor telomeric repeats (TMR) identical to the host telomere sequences at the ends of their linear genomes. These TMR facilitate the integration of the MDV genome into host telomeres during latency, allowing the virus to persist in the host for life. Integration into host telomeres is critical for disease and tumor induction by MDV, but also enables efficient reactivation of the integrated virus genome. In addition to the TMR, MDV also encodes a telomerase RNA subunit (vTR) that shares 88% sequence identity with the telomerase RNA in chicken (chTR). vTR is highly expressed during all stages of the virus lifecycle, enhances telomerase activity and plays an important role in MDV-induced tumor formation. This review will focus on the recent advances in understanding the role of viral TMR and vTR in MDV pathogenesis, integration and tumorigenesis.
Topics: Animals; Carcinogenesis; Chickens; Herpesvirus 2, Gallid; Host-Pathogen Interactions; Marek Disease; Telomerase; Telomere; Virus Integration
PubMed: 28677643
DOI: 10.3390/v9070173 -
BMC Endocrine Disorders Jun 2016Oxytocin (OT) emerges as a drug for the treatment of diabetes and obesity. The entire OT system is synthesized in the rat and human heart. The direct myocardial infusion... (Review)
Review
Oxytocin (OT) emerges as a drug for the treatment of diabetes and obesity. The entire OT system is synthesized in the rat and human heart. The direct myocardial infusion with OT into an ischemic or failing heart has the potential to elicit a variety of cardioprotective effects. OT treatment attenuates cardiomyocyte (CMs) death induced by ischemia-reperfusion by activating pro-survival pathways within injured CMs in vivo and in isolated cells. OT treatment reduces cardiac apoptosis, fibrosis, and hypertrophy. The OT/OT receptor (OTR) system is downregulated in the db/db mouse model of type 2 diabetes which develops genetic diabetic cardiomyopathy (DC) similar to human disease. We have shown that chronic OT treatment prevents the development of DC in the db/db mouse. In addition, OT stimulates glucose uptake in both cardiac stem cells and CMs, and increases cell resistance to diabetic conditions. OT may help replace lost CMs by stimulating the in situ differentiation of cardiac stem cells into functional mature CMs. Lastly, adult stem cells amenable for transplantation such as MSCs could be preconditioned with OT ex vivo and implanted into the injured heart to aid in tissue regeneration through direct differentiation, secretion of protective and cardiomyogenic factors and/or their fusion with injured CMs.
Topics: Animals; Cardiotonic Agents; Diabetes Mellitus; Exercise; Humans; Mice; Models, Theoretical; Myocardium; Obesity; Oxidative Stress; Oxytocin; Rats; Signal Transduction
PubMed: 27268060
DOI: 10.1186/s12902-016-0110-1 -
Viruses Nov 2019Marek's disease virus (MDV) is an alphaherpesvirus that causes Marek's disease, a malignant lymphoproliferative disease of domestic chickens. While MDV vaccines protect...
Marek's disease virus (MDV) is an alphaherpesvirus that causes Marek's disease, a malignant lymphoproliferative disease of domestic chickens. While MDV vaccines protect animals from clinical disease, they do not provide sterilizing immunity and allow field strains to circulate and evolve in vaccinated flocks. Therefore, there is a need for improved vaccines and for a better understanding of innate and adaptive immune responses against MDV infections. Interferons (IFNs) play important roles in the innate immune defenses against viruses and induce upregulation of a cellular antiviral state. In this report, we quantified the potent antiviral effect of IFNα and IFNγ against MDV infections in vitro. Moreover, we demonstrate that both cytokines can delay Marek's disease onset and progression in vivo. Additionally, blocking of endogenous IFNα using a specific monoclonal antibody, in turn, accelerated disease. In summary, our data reveal the effects of IFNα and IFNγ on MDV infection and improve our understanding of innate immune responses against this oncogenic virus.
Topics: Animals; Antibodies, Monoclonal; Chickens; Disease Progression; Herpesvirus 2, Gallid; Immunity, Innate; Interferon-alpha; Interferon-gamma; Marek Disease; Marek Disease Vaccines; Poultry Diseases
PubMed: 31795203
DOI: 10.3390/v11121103 -
Neurology Aug 2022Parkinson disease (PD) is a chronic progressive neurodegenerative disease with increasing worldwide prevalence. Despite many trials of neuroprotective therapies in...
Parkinson disease (PD) is a chronic progressive neurodegenerative disease with increasing worldwide prevalence. Despite many trials of neuroprotective therapies in manifest PD, no disease-modifying therapy has been established. Over the past several decades, a series of breakthroughs have identified discrete populations at substantially increased risk of developing PD. Based on this knowledge, now is the time to design and implement PD prevention trials. This endeavor builds on experience gained from early prevention trials in Alzheimer disease and Huntington disease. This article first reviews prevention trial precedents in these other neurodegenerative diseases before focusing on the critical design elements for PD prevention trials, including whom to enroll for these trials, what therapeutics to test, and how to measure outcomes in prevention trials. Our perspective reflects progress and remaining challenges that motivated a 2021 conference, "Planning for Prevention of Parkinson: A Trial Design Symposium and Workshop."
Topics: Alzheimer Disease; Humans; Huntington Disease; Neurodegenerative Diseases; Parkinson Disease; Research Design
PubMed: 36219787
DOI: 10.1212/WNL.0000000000200789 -
PLoS Pathogens Jun 2023Efficient transmission of herpesviruses is essential for dissemination in host populations; however, little is known about the viral genes that mediate transmission,...
Efficient transmission of herpesviruses is essential for dissemination in host populations; however, little is known about the viral genes that mediate transmission, mostly due to a lack of natural virus-host model systems. Marek's disease is a devastating herpesviral disease of chickens caused by Marek's disease virus (MDV) and an excellent natural model to study skin-tropic herpesviruses and transmission. Like varicella zoster virus that causes chicken pox in humans, the only site where infectious cell-free MD virions are efficiently produced is in epithelial skin cells, a requirement for host-to-host transmission. Here, we enriched for heavily infected feather follicle epithelial skin cells of live chickens to measure both viral transcription and protein expression using combined short- and long-read RNA sequencing and LC/MS-MS bottom-up proteomics. Enrichment produced a previously unseen breadth and depth of viral peptide sequencing. We confirmed protein translation for 84 viral genes at high confidence (1% FDR) and correlated relative protein abundance with RNA expression levels. Using a proteogenomic approach, we confirmed translation of most well-characterized spliced viral transcripts and identified a novel, abundant isoform of the 14 kDa transcript family via IsoSeq transcripts, short-read intron-spanning sequencing reads, and a high-quality junction-spanning peptide identification. We identified peptides representing alternative start codon usage in several genes and putative novel microORFs at the 5' ends of two core herpesviral genes, pUL47 and ICP4, along with strong evidence of independent transcription and translation of the capsid scaffold protein pUL26.5. Using a natural animal host model system to examine viral gene expression provides a robust, efficient, and meaningful way of validating results gathered from cell culture systems.
Topics: Humans; Animals; Marek Disease; Chickens; Proteogenomics; Herpesviridae; Herpesvirus 2, Gallid
PubMed: 37289833
DOI: 10.1371/journal.ppat.1011204 -
Molecular Neurodegeneration Jun 2023Apolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer's Disease (AD). Although ApoE4 differs from its non-pathological ApoE3...
BACKGROUND
Apolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer's Disease (AD). Although ApoE4 differs from its non-pathological ApoE3 isoform only by the C112R mutation, the molecular mechanism of its proteinopathy is unknown.
METHODS
Here, we reveal the molecular mechanism of ApoE4 aggregation using a combination of experimental and computational techniques, including X-ray crystallography, site-directed mutagenesis, hydrogen-deuterium mass spectrometry (HDX-MS), static light scattering and molecular dynamics simulations. Treatment of ApoE ε3/ε3 and ε4/ε4 cerebral organoids with tramiprosate was used to compare the effect of tramiprosate on ApoE4 aggregation at the cellular level.
RESULTS
We found that C112R substitution in ApoE4 induces long-distance (> 15 Å) conformational changes leading to the formation of a V-shaped dimeric unit that is geometrically different and more aggregation-prone than the ApoE3 structure. AD drug candidate tramiprosate and its metabolite 3-sulfopropanoic acid induce ApoE3-like conformational behavior in ApoE4 and reduce its aggregation propensity. Analysis of ApoE ε4/ε4 cerebral organoids treated with tramiprosate revealed its effect on cholesteryl esters, the storage products of excess cholesterol.
CONCLUSIONS
Our results connect the ApoE4 structure with its aggregation propensity, providing a new druggable target for neurodegeneration and ageing.
Topics: Humans; Apolipoprotein E4; Alzheimer Disease; Apolipoprotein E3; Mutation; Apolipoproteins E
PubMed: 37280636
DOI: 10.1186/s13024-023-00620-9 -
Cancers Mar 2020Marek's disease virus (MDV) infects chickens and causes one of the most frequent cancers in animals. Over 100 years of research on this oncogenic alphaherpesvirus has... (Review)
Review
Marek's disease virus (MDV) infects chickens and causes one of the most frequent cancers in animals. Over 100 years of research on this oncogenic alphaherpesvirus has led to a profound understanding of virus-induced tumor development. Live-attenuated vaccines against MDV were the first that prevented cancer and minimized the losses in the poultry industry. Even though the current gold standard vaccine efficiently protects against clinical disease, the virus continuously evolves towards higher virulence. Emerging field strains were able to overcome the protection provided by the previous two vaccine generations. Research over the last few years revealed important insights into the virus life cycle, cellular tropism, and tumor development that are summarized in this review. In addition, we discuss recent data on the MDV transcriptome, the constant evolution of this highly oncogenic virus towards higher virulence, and future perspectives in MDV research.
PubMed: 32164311
DOI: 10.3390/cancers12030647 -
Endokrynologia Polska 2019Acromegaly is a rare, chronic condition caused by growth hormone (GH) overproduction, usually due to a benign tumour of the pituitary gland. During the disease many... (Review)
Review
Acromegaly is a rare, chronic condition caused by growth hormone (GH) overproduction, usually due to a benign tumour of the pituitary gland. During the disease many complications occur, including cardiovascular disease and changes in the musculoskeletal, respiratory, and endocrine systems. Treatment includes surgery, medical therapy, and radiation. In this paper a literature review was conducted for information related to costs of management of acromegaly and its associated comorbidities using PubMed.The majority of total costs represent pharmacological treatment, especially the most common somatostatin analogues (SSA) therapy. The average reported annual cost of SSA therapy is EUR 12,000-40,000. Surgery reduces the cost of care via the possibility of avoiding lifelong pharmacological treatment. Radiotherapy is also suggested to lower the costs of therapy because about 60% of patients eventually will not require further pharmacological treatment; however, it is connected with negative outcomes like hypopituitarism, lower quality of life, and increased mortality. Cabergoline and pegvisomant are the lowest and highest priced treatments, respectively, but the overall impact on the cost of therapy is minor due to less frequent usage of these drugs. It is hard to fully estimate the impact of comorbidities of acromegaly on financial burden because patients are treated for them many years before the diagnosis of the underlying pathology. The treatment cost of comorbidities is higher in uncontrolled patients. Life-long treatment of acromegaly and its comorbidities is very expensive. Early diagnosis and successful treatment reduce direct and indirect costs.
Topics: Acromegaly; Costs and Cost Analysis; Disease Management; Female; Humans; Male; Somatostatin
PubMed: 30843180
DOI: 10.5603/EP.a2018.0080