REVIEW | doi:10.20944/preprints202305.0748.v1
Online: 10 May 2023 (11:20:49 CEST)
Virus infection is one of the most common etiologies of hearing loss. Hearing loss associated with viral infection can be unilateral or bilateral, mild or severe, sudden or progressive, and permanent or recoverable. Many viruses cause hearing loss in adults and children; however, the pathogenesis of hearing loss caused by viral infection is not fully understood. This review describes cytomegalovirus, the most common virus causing hearing loss, and other reported hearing loss-related viruses, along with their pathogenic characteristics and research progress on their pathology, hearing phenotypes, possible associated mechanisms, treatment and prevention measures, aiming to provide diagnostic and treatment assistance to clinical workers.
REVIEW | doi:10.20944/preprints201809.0533.v1
Subject: Medicine And Pharmacology, Pathology And Pathobiology Keywords: mycoplasma; virulence effectors; pathogenesis
Online: 27 September 2018 (05:54:04 CEST)
Members of the genus Mycoplasma and related organisms impose a substantial burden of infectious diseases on humans and animals, but the last comprehensive review of mycoplasmal pathogenicity was published 20 years ago. Post-genomic analyses have now begun to support the discovery and detailed molecular biological characterization of a number of specific mycoplasmal virulence factors. This review covers three categories of defined mycoplasmal virulence effectors: 1) specific macromolecules including the superantigen MAM, the ADP-ribosylating CARDS toxin, sialidase, cytotoxic nucleases, cell-activating diacylated lipopeptides, and phosphocholine-containing glycoglycerolipids; 2) the small molecule effectors hydrogen peroxide, hydrogen sulfide, and ammonia; and 3) several putative mycoplasmal orthologs of virulence effectors documented in other bacteria. Understanding such effectors and their mechanisms of action at the molecular level connects the biology of the bacteria to direct effects on the host and host responses they elicit, and is expected to translate into new interventions for human and veterinary mycoplasmosis.
REVIEW | doi:10.20944/preprints202105.0427.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Cellular senescence; Lung fibrosis; Pathogenesis
Online: 19 May 2021 (07:35:10 CEST)
:Pulmonary fibrosis is a chronic and fatal lung disease that significantly impacts the aging population globally. To date, anti-fibrotic, immunosuppressive, and other adjunct therapy demonstrate a limited efficacy. Advancing our understanding of pathogenic mechanisms of lung fibrosis provides a future path for the cure. Cellular senescence has gained substantial interest in the past decades due to the increased incidence of fibroproliferative lung diseases in the older age group. Furthermore, the pathologic state of cellular senescence that includes maladaptive tissue repair, decreased regeneration, and chronic inflammation resembles key features of progressive lung fibrosis. This review describes regulatory pathways of cellular senescence and discusses the current knowledge on the senescence of critical cellular players of lung fibrosis, including epithelial cells (alveolar type 2 cells, basal cells, etc.), fibroblasts, and immune cells, their phenotypic changes, and the cellular and molecular mechanisms by which these cells contribute to the pathogenesis of pulmonary fibrosis. A few challenges in the field include establishing appropriate in vivo experimental models and identifying senescence targeted signaling molecules and specific therapy to target senescent cells, known collectively as "senolytic" or “senotherapeutic” agents.
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: actin cytoskeleton; chlamydia; bacterial pathogenesis
Online: 9 December 2019 (03:53:26 CET)
The actin cytoskeleton is crucially important to maintenance of cellular structure, cell motility and endocytosis. Accordingly, bacterial pathogens often co-opt the actin-restructuring machinery of host cells to access or create a favorable environment for their own replication. The obligate intracellular organism Chlamydia trachomatis and related species exemplify this dynamic: by inducing actin polymerization at the site of pathogen-host attachment, Chlamydiae induce their own uptake by the typically non-phagocytic epithelium they infect. The interaction of chlamydial adhesins with host surface receptors has been implicated in this effect, as has the activity of the chlamydial effector TarP (translocated actin recruitment protein). Following invasion, C. trachomatis dynamically assembles and maintains an actin-rich cage around the pathogen’s membrane-bound replicative niche, the chlamydial inclusion. Through further induction of actin polymerization and modulation of the actin-crosslinking protein myosin II, C. trachomatis promotes egress from the host via extrusion of the inclusion. In this review, we present the experimental findings that inform our understanding of actin-dependent chlamydial pathogenesis, discuss lingering questions, and identify potential avenues of future study.
REVIEW | doi:10.20944/preprints202311.0147.v1
Subject: Biology And Life Sciences, Virology Keywords: Herpesviruses; Tegument proteins; Structure; Viral pathogenesis
Online: 2 November 2023 (10:13:22 CET)
Herpesviridae is a family of enveloped double-stranded DNA viruses that cause a wide range of diseases in hosts. Among the various components of herpesvirus particles, tegument proteins residing between the envelop and nucleocapsid play crucial roles in viral replication, immune evasion, and modulation of host cellular pathways. Understanding the three-dimensional structure of herpesvirus tegument proteins help to reveal the molecular mechanism underlying the crosstalk with other viral and cellular components, and thus is crucial for the investigation of their biological and pathological functions. In this review, we summarize the current knowledge of the structural features of herpesvirus tegument proteins, highlighting the structure-based functional implications, including the potential as targets for antiviral drug development.
REVIEW | doi:10.20944/preprints202309.0235.v1
Subject: Medicine And Pharmacology, Pulmonary And Respiratory Medicine Keywords: Rheumatoid arthritis; interstitial lung disease; pathogenesis
Online: 5 September 2023 (05:28:49 CEST)
Interstitial lung disease (ILD) is one of the most serious extra-articular complications of rheu-matoid arthritis (RA), which increases the mortality of RA. Because the pathogenesis of RA-ILD remains poorly understood, appropriate therapeutic strategies and biomarkers have not yet been identified. Thus, the goal of this review was to summarize and analyze the reported data on the etiology and pathogenesis of RA-ILD. The incidence of RA-ILD increases with age, and is also generally higher in men than in women and in patients with specific genetic variations and eth-nicity. Lifestyle factors associated with an increased risk of RA-ILD include smoking and exposure to pollutants. The presence of an anti-cyclic citrullinated peptide antibody, high RA disease activity, and rheumatoid factor positivity also increase the risk of RA-ILD. We also explored the roles of biological processes (e.g., fibroblast–myofibroblast transition, epithelial–mesenchymal transition, and immunological processes), signaling pathways (e.g., JAK/STAT and PI3K/Akt), and the his-topathology of RA involved in RA-ILD pathogenesis based on published preclinical and clinical models of RA-ILD in animal and human studies.
REVIEW | doi:10.20944/preprints202111.0350.v1
Subject: Biology And Life Sciences, Virology Keywords: arbovirus; evolution; genome; host; pathogenesis; Phenuiviridae
Online: 19 November 2021 (12:33:53 CET)
The newly established virus family Phenuiviridae in Bunyavirales harbors viruses infecting three kingdoms of host organisms (animals, plants, and fungi), which is rare in known virus families. Many phenuiviruses are arboviruses and replicate in two distinct hosts (e.g., insects and humans or rice). Multiple phenuiviruses, such as Dabie bandavirus, Rift Valley fever phlebovirus, and Rice stripe tenuivirus, are highly pathogenic to humans, animals, or plants. They impose heavy global burdens on human health, livestock industry, and agriculture and are research hotspots. In recent years the taxonomy of Phenuiviridae has been expanded greatly, and researches on phenuiviruses have made significant progress. With these advances, this review drew a novel panorama regarding the biomedical significance, distribution, morphology, genomics, taxonomy, evolution, replication, transmission, pathogenesis, and control of phenuiviruses, to aid researchers in various fields to recognize this highly adaptive and very important virus family.
REVIEW | doi:10.20944/preprints202105.0362.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Alphavirus; Virulence; Viral Pathogenesis; Viral RNA
Online: 16 May 2021 (22:27:20 CEST)
Alphaviruses are positive-sense RNA arboviruses that are capable of causing severe disease in otherwise healthy individuals. There are many aspects of viral infection that determine pathogenesis and major efforts regarding the identification and characterization of virulence determinants have largely focused on the roles of the nonstructural and structural proteins. Nonetheless, the viral RNAs of the alphaviruses themselves play important roles in regard to virulence and pathogenesis. In particular, many sequences and secondary structures within the viral RNAs play an important part in the development of disease and may be considered important determinants of virulence. In this review article, we summarize the known RNA-based virulence traits and host:RNA interactions that influence alphaviral pathogenesis for each of the viral RNA species produced during infection. Overall, the viral RNAs produced during infection are important contributors to alphaviral pathogenesis and more research is needed to fully understand how each RNA species impacts the host response to infection as well as the development of disease.
Subject: Medicine And Pharmacology, Medicine And Pharmacology Keywords: Epigenetic; Methylation; Rheumatoid Arthritis; Pathogenesis; Regulation
Online: 18 August 2020 (16:16:27 CEST)
Rheumatoid arthritis (RA) is a complex disease triggered by the interaction between genetics and environment, especially through the shared epitope (SE) and cell surface calreticulin (CSC) theory. However, the available evidence shows that genetic diversity and environmental exposure cannot explain all the clinical characteristics and heterogeneity of RA. In contrast, recent studies demonstrate that epigenetics play important roles in the pathogenesis of RA, especially DNA methylation and histone modification. DNA methylation and histone methylation are involved in innate and adaptive immune cell differentiation, and migration, proliferation, apoptosis, and mesenchymal characteristics of fibroblast-like synoviocytes (FLS). Epigenetic-mediated regulation of immune-related genes and inflammation pathways explains the dynamic expression network of RA. In this review, we summarized the comprehensive evidence to show that methylation of DNA and histones is significantly involved in the pathogenesis of RA and could be applied as a promising biomarker in the disease progression and drug response prediction. We also explained the advantages and challenges of the current epigenetics research in RA. In summary, epigenetic modules provide a possible interface, through which genetic and environmental risk factors connect to contribute to the susceptibility and pathogenesis of RA. Additionally, epigenetic regulators provide promising drug targets to develop novel therapeutic drugs for RA. Finally, DNA methylation and histone modifications could be important features for providing a better RA subtype identification, to accelerate personalized treatment and precision medicine.
REVIEW | doi:10.20944/preprints202004.0241.v2
Subject: Medicine And Pharmacology, Orthopedics And Sports Medicine Keywords: rheumatoid arthritis; miRNA; susceptibility; pathogenesis; epigenetics
Online: 22 April 2020 (05:52:20 CEST)
MicroRNAs (miRNAs) play crucial roles in the regulation of the transcriptome and development of diseases including cancer and autoimmune diseases, such as rheumatoid arthritis (RA). Currently, a comprehensive map, illustrating how miRNAs regulate transcripts, pathways, immune system differentiation, and their interaction with terminal cells, such as T cells, fibroblast-like synoviocytes (FLS), osteoblasts, and osteoclasts, is still missing. In this review, we provide a thorough summary of the roles of miRNAs in the susceptibility to pathogenesis, diagnosis, therapeutic intervention, and prognosis of RA. Numerous miRNAs are abnormally expressed in cells involved in RA, and regulate target genes and pathways including the NF-κB, Fas-FasL, JAK-STAT, IRE1-RIDD, and mTOR pathways. By regulating gene expression, miRNAs affect T cell differentiation to diverse cell types, including Th17 and T-reg cells, and thus constitute promising gene therapy targets to modulate the immune system in RA. We summarize the diagnostic and prognostic potential of blood-circulating and cell-free miRNAs, highlighting the novel opportunities to combine these with rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) to provide accurate diagnosis and prognosis, especially for seronegative patients. Furthermore, we outline how functional genetic variants of miR-499 and miR-146a partly explain the unmet susceptibility to RA. Additionally, we review the evidence implicating miRNAs as promising biomarkers of efficiency, response, and resistance to disease-modifying anti-rheumatic drugs (DMRDs) and immunotherapy. Finally, we discuss the autotherapeutic effect of miRNA intervention as a step toward the development of miRNA-based anti-RA drugs. Collectively, the current evidence supports miRNAs as interesting targets to better understand the pathogenetic mechanisms of RA and design more efficient therapeutic interventions.
ARTICLE | doi:10.20944/preprints202307.1836.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: Sclerotinia sclerotiorum; SsCak1; sclerotia; appressoria; pathogenesis; HIGS
Online: 27 July 2023 (08:46:08 CEST)
Sclerotinia sclerotiorum is a devastating fungal pathogen that causes severe crop losses worldwide. It is of vital importance to understand its pathogenic mechanism for disease control. Through a forward genetic screen combined with next-generation sequencing, a putative protein kinase, SsCak1, was found to be involved in growth and pathogenicity of S. sclerotiorum. Knockout and complementation experiments confirmed that deletions in SsCAK1 caused defects in mycelium and sclerotia development, as well as appressoria formation and host penetration, leading to complete loss of virulence. These findings suggest that SsCak1 is essential for growth, development and pathogenicity of S. sclerotiorum. Therefore, SsCak1 could serve as a potential target for the control of S. sclerotiorum infection through host-induced gene silencing (HIGS), which could increase crop resistance to the pathogen.
REVIEW | doi:10.20944/preprints202305.0519.v1
Subject: Biology And Life Sciences, Animal Science, Veterinary Science And Zoology Keywords: FIP; FCoV; genotype; pathogenesis; diagnosis; treatment; vaccine
Online: 8 May 2023 (10:32:09 CEST)
Feline infectious peritonitis (FIP), caused by the feline coronavirus (FCoV), is a devastating dis-ease in cats. Based on its antigenicity, FCoV can be divided into two serotypes: FCoV-I and FCoV-II. Furthermore, according to its pathogenicity, FCoV can be divided into feline enteric coronavirus (FECV) and feline infectious peritonitis virus (FIPV). There are numerous factors that affect the pathogenesis of FIP, among which host immunity and viral genetics can play an es-sential role in the development of FIP. Owing to the lack of specific symptoms, existing individual diagnostic methods can only support the suspicion of FIP, and multiple diagnostic methods and test data need to be combined to make a diagnosis. Although there are still no effective FIPV vaccines or commercial drugs available in the market, various studies have shown that some compounds can be used for treatment. Therefore, FIP is no longer incurable in cats
REVIEW | doi:10.20944/preprints202304.0228.v1
Subject: Medicine And Pharmacology, Epidemiology And Infectious Diseases Keywords: Lassa fever; epidemic; epidemiological analysis; pathogenesis; prevention
Online: 12 April 2023 (02:52:58 CEST)
Lassa fever, commonly known as Lassa hemorrhagic fever (LHF), is one of the progressive illnesses invading a large population of two to three million individuals in West Africa. The infection transmitted through the rodents severely impacts the local population and the medical professionals in surrounding areas, which were also the primary target of LHF. In epidemic areas, Lassa fever causes a public health threat since it poses a significant morbidity and fatality Case rate (CFR) ≥ 50%). The disease is widespread in West Africa and has developed into one of the most common and life-threatening viral hemorrhagic fevers. Monitoring and preventing persistent disease outbreaks has been challenging in affected regions due to insufficient healthcare facilities, diagnostics labs, care centers, and low socioeconomic conditions. An absence of public awareness and the emergence of an ecological niche is advantageous for the survival and multiplication of the mouse (Mastomys natalensis) inhabiting the Lassa virus serving as the disease's natural host and reservoir. The current review focuses on early diagnosis and appropriate treatment, highlighting the immediate requirement of clinically approved vaccines for LHF, causing preventative and control actions more difficult in the present era.
REVIEW | doi:10.20944/preprints202208.0457.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: mNGS; Metabarcoding; ITS; Biyoinformatic Analysis; Fungal Pathogenesis
Online: 26 August 2022 (09:50:28 CEST)
Crop output is directly impacted by plant infections (with fungi as the major pathogen), making accurate diagnosis of these threats crucial. Developing technology and multidisciplinary approaches are turning to genomic analyses in addition to traditional culture methods in diagnosing fungal plant diseases. The metagenomic next-generation sequencing (mNGS) method is preferred for genotyping identification of organisms, identification at the species level, illumination of metabolic pathways, and determination of microbiota. Moreover, the data obtained so far show that this new approach shows promise as an emerging new trend in fungal disease detection. Another approach covered by mNGS technologies, known as metabarcoding, enables use of specific markers specific to a genetic region and allows for genotypic identification by facilitating the sequencing of certain regions. Although the core concept of mNGS remains constant across applications, the specific sequencing methods and bioinformatics tools used to analyze the data do differ. In this review, we focus on how mNGS technology, including metabarcoding, is applied in fungal pathogenesis and its promising developments for the future.
REVIEW | doi:10.20944/preprints202109.0495.v1
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: NUTM1 gene; NUT protein; Neoplasms; Pathogenesis; Therapy
Online: 29 September 2021 (12:17:31 CEST)
Nuclear protein of testis (NUT), a protein product of the NUTM1 gene (located on the long arm of chromosome 15) with highly restricted physiologic expression in post-meiotic spermatids, is the oncogenic driver of a group of emerging neoplasms when fused with genes involved in transcription regulation. Although initially identified in a group of lethal midline carcinomas in which NUT forms fusion proteins with bromodomain proteins, NUTM1-rearrangement has since been identified in tumors at non-midline locations, with non-bromodomain partners and with varied morphology. The histologic features of these tumors have also expanded to include sarcoma, skin adnexal tumors, and hematologic malignancies that harbor various fusion partners and are associated with markedly different clinical courses varying from benign to malignant. Most of these tumors have nondescript primitive morphology and therefore should be routinely considered in any undifferentiated neoplasm. The diagnosis is facilitated by the immunohistochemical use of the monoclonal C52 antibody, fluorescence in situ hybridization (FISH), and, recently, RNA-Sequencing. The pathogenesis is believed to be altered expression of oncogenes or tumor suppressor genes by NUT-mediated genome-wide histone modification. NUTM1-rearranged neoplasms respond poorly to classical chemotherapy and radiation therapy. Targeted therapies such as bromodomain and extraterminal domain inhibitor (BETi) therapy are being developed. This current review provides an update of NUTM1-rearranged neoplasms, focusing on the correlation between basic sciences and clinical aspects.
REVIEW | doi:10.20944/preprints202004.0372.v1
Subject: Biology And Life Sciences, Virology Keywords: COVID-19; Diagnosis; Pathogenesis; Treatment; SARS-CoV-2
Online: 21 April 2020 (04:44:40 CEST)
The recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread so rapidly and severely affected the people of almost every country in the world. The highly contagious nature of this virus makes it difficult to take control of the present pandemic situation. With no specific treatment available, the coronavirus disease 2019 (COVID-19) presents a threat to people of all ages including the elderly people and people with other medical complications as a vulnerable group to this disease. Better understanding of viral pathogenesis, appropriate preventive measures, early diagnosis and supportive treatments of the infected patients are now the general solutions to fight against this viral transmission. But, as an emerging disease, most about it remains still poorly understood. This article holds an overview on the origin and structure, pathogenesis, diagnosis and possible therapeutic options for the causative agent, SARS-CoV-2 and disease, COVID-19. However, few therapeutic options, laboratory experiments and other strategies proposed here need to be further clinically tested.
Subject: Medicine And Pharmacology, Oncology And Oncogenics Keywords: gene prioritization; osteosarcoma; communality analysis; pathogenesis; early recognition
Online: 12 December 2019 (05:45:18 CET)
Osteosarcoma is the most common subtype of primary bone cancers, affecting mostly adolescents. In recent years, several studies have focused on elucidating the molecular mechanisms of this sarcoma; however, its molecular etiology has still not been determined with precision. Therefore, we applied a consensus strategy with the use of several bioinformatics tools to prioritize genes involved in its pathogenesis. Subsequently, we assessed the physical interactions of the previously selected genes and applied a communality analysis to this protein-protein interaction network. The consensus strategy prioritized a total list of 553 genes. Our enrichment analysis validates several studies that describe the signaling pathways PI3K/AKT and MAPK/ERK as pathogenic. The gene ontology described TP53 as a principal signal transducer that chiefly mediates processes associated with cell cycle and DNA damage response It is interesting to note that the communality analysis clusters several members involved in metastasis events such as MMP2 and MMP9 and genes associated with DNA repair complexes, like ATM, ATR, CHEK1, and RAD51. In this study, we could identify well-known pathogenic genes for osteosarcoma and prioritized genes that need to be further explored.
REVIEW | doi:10.20944/preprints201808.0410.v1
Subject: Chemistry And Materials Science, Analytical Chemistry Keywords: metabolomics; direct mass spectrometry; Alzheimer’s disease; pathogenesis; biomarkers
Online: 23 August 2018 (10:10:47 CEST)
Direct mass spectrometry-based metabolomics has been widely employed in the last years to characterize metabolic alterations underlying to Alzheimer’s disease development and progression. This high-throughput approach presents a great potential for fast and simultaneous fingerprinting of a vast number of metabolites, which can be applied to multiple biological samples such as serum/plasma, urine, cerebrospinal fluid and tissues. In this review article we present the main advantages and drawbacks of metabolomics based on direct mass spectrometry compared with conventional analytical techniques, and provide a comprehensive revision of the literature on the application of these tools in Alzheimer’s disease research.
ARTICLE | doi:10.20944/preprints202311.1523.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Biomarker discovery; disease pathogenesis; autoimmunity; antigenic mimicry; machine learning
Online: 23 November 2023 (11:10:59 CET)
The diagnosis and the pathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) remain under debate. However, there is a growing body of evidence for an autoimmune component in ME/CFS caused by the Epstein-Barr virus (EBV) and other viral infections. In this work, we took advantage of a large public dataset on the IgG antibodies to 3,054 EBV peptides to understand whether these immune responses could be used as putative biomarkers for disease diagnosis and triggers of pathological autoimmunity in ME/CFS patients using healthy controls (HCs) as a comparator cohort. We then aimed at predicting disease status of study participants using a Super Learner algorithm targeting an accuracy of 85% when splitting data into train and test datasets. When we compared data of all ME/CFS patients or data of a subgroup of these patients with non-infectious or unknown disease trigger to the dataset of HC, we could not find an antibody-based classifier that would meet the desired accuracy in the test dataset. In contrast, we could identify a 26-antibody classifier that could distinguish ME/CFS patients with an infectious disease trigger from HCs with 100% and 90% accuracies on the train and test sets, respectively. We finally performed a bioinformatic analysis of the EBV peptides associated with these 26 antibodies. We found no correlation between the importance metric of the selected antibodies in the classifier and the maximal sequence homology between human proteins and each EBV peptide recognized by these antibodies. In conclusion, these 26 antibodies against EBV have an effective potential for disease diagnosis of a subset of patients, but they are less likely to trigger pathological autoimmune responses that could explain the pathogenesis of ME/CFS.
REVIEW | doi:10.20944/preprints202306.1042.v1
Subject: Biology And Life Sciences, Agricultural Science And Agronomy Keywords: Crop improvement; Omics, Pathogenesis; Plant-microbe interactions (PPI); Resistance
Online: 14 June 2023 (10:09:32 CEST)
The concept of omics-based technological approaches has promoted translational research by integrating knowledge from diverse areas to understand their dynamics by exploring the molecular mechanisms underlying various processes paving the way for further improvements in the crops quality by providing sound knowledge on controlling plant diseases. This area is not profoundly investigated a decade back and hence this knowledge has become exceedingly important in modern times as it has got potential for being utilized in crop improvement programs. In this review, the contributions of different omics technologies including genomics, transcriptomics, proteomics, and metabolomics in understanding and materializing the ways involved in the plant pathogen interaction (PPI) is discussed. Furthermore, opportunities, challenges, and perspectives of omics linked to signaling mechanisms have also been highlighted that are significantly linked to plant-microbe interactions.
ARTICLE | doi:10.20944/preprints202101.0023.v1
Subject: Medicine And Pharmacology, Immunology And Allergy Keywords: Familial Adenomatous Polyposis; APC; Splicing; Exon Skipping; FAP Pathogenesis
Online: 4 January 2021 (11:59:26 CET)
Familial adenomatous polyposis (FAP) is caused by germline mutations in the tumor suppressor gene APC. To date, nearly 2000 APC mutations have been described in FAP, most of which are predicted to result in truncated protein products. Mutations leading to aberrant APC splicing have rarely been reported. Here, we characterized a novel germline heterozygous splice donor site mutation in APC exon 12 (NM_000038.5: c.1621_1626+7del) leading to exon 12 skipping in an Italian family with the attenuated FAP (AFAP) phenotype. Moreover, we performed a literature me-ta-analysis of APC splicing mutations. We found that 123 unique APC splice site mutations, in-cluding the one described here, have been reported in FAP patients, 69 of which have been char-acterized at the mRNA level. Among these, only a small proportion (9/69) results in an in-frame protein, with 4 mutations causing skipping of exon 12 and/or 13 with loss of armadillo repeat 2 (ARM2) and 3 (ARM3), and 5 mutations leading to skipping of exon 5, 7, 8, and (partially) 9 with loss of regions not encompassing known functional domains. The APC splicing mutations considered in this study cluster with the AFAP phenotype and delineate a novel molecular mechanism of pathogenesis in FAP disease.
REVIEW | doi:10.20944/preprints202009.0696.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Beauveria bassiana; cuticle degrading enzymes; entomopathogenic fungi; pathogenesis; virulence
Online: 29 September 2020 (08:57:33 CEST)
Intensive crop production and extensive use of harmful synthetic chemical pesticides create numerous socio-economic problems worldwide. Therefore, sustainable solutions are needed for insect pest control, such as biological control agents. The fungal insect pathogen Beauveria bassiana has shown considerable potential as a biological control agent against a broad range of insects. The insights into virulence mechanism of B. bassiana is essential to show the robustness of its use. B. bassiana has several determinants of virulence, including the production of cuticle-degrading enzymes (CDEs), such as proteases, chitinases, and lipases. CDEs are essential in the infection process as they hydrolyze the significant components of the insect's cuticle. Moreover, B. bassiana has evolved effective antioxidant mechanisms that include enzyme families that act as ROS scavengers, e.g., superoxide dismutases, catalases, peroxidases, and thioredoxins. In B. bassiana, the number of CDEs and antioxidant enzymes characterized in recent years. The enzymatic activities are crucial for the biological control potential and significantly advanced our understanding of the infection mechanism of B. bassiana. This review focuses on the progress detailed in the studies of these enzymes and provides an overview of enzymatic activities and their contributions to virulence.
REVIEW | doi:10.20944/preprints202003.0348.v1
Subject: Medicine And Pharmacology, Epidemiology And Infectious Diseases Keywords: SARS-COV-2; COVID-19; clinical pathology; pathogenesis; immunopathology
Online: 23 March 2020 (07:51:17 CET)
Coronavirus Disease 2019 (COVID-19), caused by a novel coronavirus named Severe Acute Respiratory Syndrome - Coronavirus-2 (SARS-CoV-2), emerged in early December 2019 in China and attained a pandemic situation worldwide by its rapid spread to nearly 167 countries with 287.239 confirmed cases and 11.921 human deaths with a case fatality rate (CFR) of around 4 per cent. Bats were considered as the reservoir host, and the search of a probable intermediate host is still going on. Animals have anticipated culprit of SARS-CoV-2 as of now. The disease is mainly manifested by pneumonia and related respiratory signs and symptoms, but the involvement of the gastrointestinal system and nervous system is also suggested. The severe form of the disease associated with death is mainly reported in older and immune-compromised patients with pre-existing disease history. Death in severe cases is attributed to respiratory failure associated with hyperinflammation. Cytokine storm syndrome associated with rampant inflammation in response to SARS-CoV-2 infection is considered as the leading killer of COVID-19 patients. COVID-19 patients were reported with higher levels of many pro-inflammatory cytokines and chemokines like IFN-g, IL-1b, IP-10, and MCP-1. Furthermore, severe cases of COVID-19 revealed higher levels of TNF-α, G-CSF, and MIP-1A. Blood profile of the COVID-19 patients exhibits lymphopenia, leucopenia, thrombocytopenia and RNAaemia along with increased levels of aspartate aminotransferase. SARS-CoV-2 infection in pregnant women does not lead to fetus mortalities unlike other zoonotic coronaviruses like SARS-CoV and MERS-CoV, with no evidence of intrauterine transmission to neonates. Rapid and confirmatory diagnostics have been developed, and high efforts are being made to develop effective vaccines and therapeutics. In the absence of any virus-specific therapeutic, internationally health care authorities are recommending adoption of effective prevention and control measures to counter and contain this pandemic virus. This paper is an overview of this virus and the disease with a particular focus on SARS-COV-2 / COVID-19 clinical pathology, pathogenesis and immunopathology along with a few recent research developments.
REVIEW | doi:10.20944/preprints202310.0701.v1
Subject: Medicine And Pharmacology, Cardiac And Cardiovascular Systems Keywords: Cardiovascular diseases; COVID-19; pathophysiology; molecular pathogenesis; personalized cardiovascular medicine.
Online: 11 October 2023 (08:25:12 CEST)
Background: COVID-19 was initially identified as a respiratory system disorder, but it has been discovered to interact with and influence the cardiovascular system. COVID-19-associated cardiovascular (CV) complications are common, resulting in high acute phase mortality and a large number of morbidities in the chronic phase, thus severely impacting patients' quality of life and health outcomes. Nevertheless, clinical, cellular, and molecular biological factors underlying the pathophysiology of cardiovascular complications associated with COVID-19 are poorly understood. Objective: This review investigates putative underlying clinical factors as well as cellular and molecular biological mechanisms by which COVID-19 leads to acute CV complications, including state-of-the-art genomic sequencing-based findings, assessing the long-term CV consequences of COVID-19, and aiming to shed light on developing strategies for differential diagnosis, risk prognostic stratification, prevention, and clinical management of CV sequlea in COVID-19 patients. Methods: For this purpose, a through review of literature and published data was carried out from first report of COVID-19 till October 2023 to find out a comprehensive account of clinical, cellular and molecular genetic factors underlying COVID-19-associated cardiovascular diseases. Results: We found that the relationship between COVID-19 and CV risk is complex and multifaceted. In addition to acute COVID-19 detertriuos effects, COVID-19 survivors may experience long-term CV effects. We provide a detailed account of the involvement of a large number of genomic alterations, microRNAs, and novel viral as well as host proteins in CVDs associated with COVID-19, which has helped identify some novel drug targets to treat COVID-19-related cardiovascular complications. Conclusions: The relationship between COVID-19 and CV risk is complex and multifaceted. While COVID-19 primarily affects the respiratory system, it can also significantly affect CV health. as compared to classical cardiovascular diseases, there are new clinical, cellular and molecular biological factors in CVDs related to COVID-19, that need specific diagnostic assays, prognostic stratification and treatment modules. Therefore, specail care is must taken to treat cardiovascular diseases associated with COVID-19.
REVIEW | doi:10.20944/preprints202310.0472.v1
Subject: Medicine And Pharmacology, Dermatology Keywords: acne; apoptosis; FoxO1; FoxO3; isotretinoin; mTORC1; p53; pathogenesis; therapy; transcriptomics
Online: 9 October 2023 (07:48:02 CEST)
This review provides information on acne transcriptomics allowing deeper insights into acne pathogenesis and isotretinoin´s mode of action. Puberty-induced insulin-like growth factor 1 (IGF-1), insulin and androgen signaling activate the kinase AKT and mechanistic target of rapamycin complex 1 (mTORC1). Western diet (hyperglycemic carbohydrates, milk/dairy products) as well co-stimulate AKT/mTORC1 signaling. AKT-mediated phosphorylation of nuclear FoxO1 and FoxO3 results in their extrusion into the cytoplasm, a critical switch, which enhances the transactivation of lipogenic and proinflammatory transcription factors including androgen receptor (AR), sterol regulatory element-binding transcription factor 1 (SREBF1), peroxisome proliferator-activated receptor γ (PPARγ), and signal transducer and activator of transcription 3 (STAT3) but reduces FoxO1-dependent expression of GATA binding protein 6 (GATA6), the key transcription factor of infundibular keratinocyte homeostasis. AKT-mediated phosphorylation of the p53-binding protein MDM2 promotes the degradation of p53. In contrast, isotretinoin enhances the expression of p53, FoxO1 and FoxO3 in sebaceous glands of acne patients. Overexpression of these proapoptotic transcription factors explains isotretinoin´s desired sebum-suppressive effect via induction of sebocyte apoptosis but also its adverse effects including teratogenicity (neural crest cell apoptosis), reduced ovarian reserve (granulosa cell apoptosis), risk of depression (apoptosis of hypothalamic neurons), VLDL hyperlipidemia, intracranial hypertension and dry skin.
REVIEW | doi:10.20944/preprints202308.2059.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: M.tb pathogenesis; MDR-TB; XDR-TB; drug tolerance; new approaches
Online: 30 August 2023 (11:20:12 CEST)
Antibiotics have played a crucial role in the reduction of TB incidence globally as evidenced by the fact that before the mid-20th century, the mortality rate within five years of the onset of the disease was 50%. The use of antibiotics has eliminated TB as a devastating disease, but the challenge of resistance to anti-TB drugs, which had already been described at the time of the introduction of streptomycin, has become a major global issue in disease management. Mismanagement of multidrug-resistant tuberculosis (MDR-TB) cases, resulting from intermittent drug use, prescription errors and non-compliance of patients, has been identified as a critical risk factor for the development of extensively drug-resistant tuberculosis (XDR-TB). Antimicrobial resistance (AMR) in TB is a multi-factorial, complex problem of microbes evolving to escape antibiotics, the gradual decline of antibiotic development, and different economic and social conditions. In this review, we summarise recent advances in our understanding of how Mycobacterium tuberculosis evolves drug resistance. We also highlight the importance of developing shorter regimens that rapidly reach bacteria in diverse host environments, eradicating all mycobacterial populations and preventing the evolution of drug resistance. Lastly, we also emphasise that the current burden of this ancient disease is driven by a combination of complex interactions between mycobacterial and host factors, and that only a holistic approach that effectively addresses all the critical issues associated with drug resistance will limit the further spread of drug-resistant strains throught the community.
REVIEW | doi:10.20944/preprints202307.0397.v1
Subject: Medicine And Pharmacology, Dermatology Keywords: Rosacea; inflammation; inflammatory skin disease; pathogenesis; therapeutic strategies; treatment options
Online: 6 July 2023 (09:02:30 CEST)
Rosacea is a chronic inflammatory skin disease characterized by recurrent erythema, flushing, telangiectasia, papules, pustules, and phymatous changes in the central area of the face. Patients with this condition often experience a significant negative impact on their quality of life, self-esteem, and overall well-being. Despite its prevalence, the pathogenesis of rosacea is not yet fully understood. Recent research advances are reshaping our understanding of the underlying mechanisms of rosacea, and treatment options based on the pathophysiological perspective hold promise to improve patient outcomes and reduce incidence. In this comprehensive review, we investigate the pathogenesis of rosacea in-depth, with a focus on emerging and novel mechanisms, and provide an up-to-date overview of therapeutic strategies that target the diverse pathogenic mechanisms of rosacea. Lastly, we discuss potential future research directions aimed at enhancing our understanding of the condition and developing effective treatments.
REVIEW | doi:10.20944/preprints202107.0320.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Cell-cell fusion; henipavirus; pathogenesis; paramyxovirus; syncytium; within-host dynamics
Online: 14 July 2021 (11:09:08 CEST)
Syncytium formation, i.e., cell-cell fusion resulting in the formation of multinucleated cells, is a hallmark of infection by paramyxoviruses and other important viruses. This natural mechanism has historically been a diagnostic marker for paramyxovirus infection in vivo and is now widely studied for virus-induced membrane fusion in vitro. However, the role of syncytium formation in within-host dissemination and pathogenicity of viruses remains poorly understood. The diversity of henipaviruses and their wide host range and tissue tropism make them particularly appropriate models to characterize the drivers of syncytium formation and its implications for virus fitness and pathogenicity. Based on the henipavirus literature, we summarized current knowledge on the mechanisms driving syncytium formation, mostly acquired from in vitro studies, and on the in vivo distribution of syncytia. While these data suggest that syncytium formation widely occurs across henipaviruses, hosts and tissues, we identified important data gaps that undermined our understanding of the role of syncytium formation in virus pathogenesis. Based on these observations, we propose solutions of varying complexity to fill these data gaps, from better practices in data archiving and publication for in vivo studies, to experimental approaches in vitro.
COMMUNICATION | doi:10.20944/preprints202007.0159.v1
Subject: Biology And Life Sciences, Virology Keywords: COVID-19; herd immunity; pandemic; pathogenesis; SARS-CoV-2; WHO
Online: 8 July 2020 (18:33:41 CEST)
Herd immunity happens when a relatively large proportion of a population becomes infected by an agent, subsequently recovers, and attains immunity against the same agent. That proportion thus indirectly protects the naïve population by preventing the spread of the infection. Herd immunity has been suggested to interrupt and control the COVID-19 pandemic. However, relying on establishing herd immunity can be catastrophic considering the virulence and lethality of SARS-CoV-2. Meanwhile our understanding of the pathogenesis, case-fatality rate, transmission routes, and antiviral therapy for COVID-19 remains limited now. Interrupting or slowing the COVID-19 transmission seems more opportune than vaccination, antiviral therapy, or herd immunity, all of which will take some time to yield. Thus, social distancing, face-masking, and hygiene are the most appropriate immediate countermeasures. Because the social fabrics, economic implications, and local demands of various nations are unique, early relaxation of restrictions may seem hasty particularly when fatality rates are high, or when the healthcare systems could be inadequate or become inundated. Conclusively, avoiding any overwhelmingly risky approach in fighting the pandemic is prudent.
REVIEW | doi:10.20944/preprints202004.0246.v2
Subject: Medicine And Pharmacology, Epidemiology And Infectious Diseases Keywords: Dengue Hemorrhagic Fever (DHF); Aedes Aegypti; epidemic; pathogenesis; identification; vaccine
Online: 14 May 2020 (08:36:39 CEST)
Purpose: This review features a generalized overview of dengue outbreaks, dengue pathogenesis, symptoms, immune response, diagnosis methods and preventive measures which facilitates the better understanding of the global expansion and concerns relating to the disease. Recent Findings: A recent study showed that natural killer cells of the infected person become activated soon after the infection which may help in treatment and vaccine development. A research team has also produced synthetically engineered mosquitoes that can prevent the transmission and dissemination of the dengue virus by the activation of an antibody. Furthermore, a mutation in the protein envelope of the dengue virus leads to variation in shapes, developing resistance towards the vaccine. Summary: The increasing number of reported cases indicated the worldwide distribution of the mosquito vectors, which was further facilitated by the growth in the shipping and commerce industries. The immune system, through activation of the innate and adaptive immune responses, facilitates the recruitment of an array of leukocytes which help neutralize the virus. However, the 4 different viral serotypes increases the risk of a life-threatening secondary infection due to the varying serotypes. Apart from the laboratory standard PRNT method, several other dengue detection methods such as ELISA, RT-LAMP and several optical, microfluidic and electrochemical methods have been developed. Since Dengvaxia® (CYD-TDV) has its own set of drawbacks and limitations, several companies have been investing for the production of more potential vaccines that are currently in trial.
Subject: Medicine And Pharmacology, Clinical Medicine Keywords: creatine; statin; myopathy; muscle; myalgia; prevention; treatment; pathogenesis; pathophysiology; mitochondria
Online: 11 September 2019 (04:43:37 CEST)
Statins prevent cardiovascular diseases, yet their use is limited by the muscle disturbances they cause. Rarely, statin-induced myopathy is autoimmune, but more commonly it is due to direct muscle toxicity. Available evidence suggests that statin-induced creatine deficiency may be a major cause of this toxicity, and that creatine supplementation prevents it. Statins inhibit guanidinoacetate methyl transferase (GAMT), the last enzyme in the synthesis of creatine, thus they decrease its intracellular content. Such decreased content could cause mitochondrial impairment, since creatine is the final acceptor of the phosphate group of adenosine triphosphate (ATP) at the end of mitochondrial oxidative phosphorylation. Decreased cellular synthesis of adenosine triphosphate (ATP) would follow. Accordingly, ATP synthesis is decreased in statin-treated cells. In vitro, creatine supplementation prevents the opening of mitochondrial permeability transition pore caused by statins. Clinically, creatine administration prevents statin myopathy in statin-intolerant patients. Additional research is warranted to hopefully confirm these findings. However, creatine is widely used by athletes with no adverse events, and has demonstrated to be safe even in double-blind, placebo-controlled trials of elder individuals. Thus, it should be trialed, under medical supervision, in patients who cannot assume statin due to the occurrence of muscular symptoms.
REVIEW | doi:10.20944/preprints202308.1134.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: NAFLD; NASH; pathogenesis; genetic factors; dietary factors; environmental factors; therapeutic strategies
Online: 15 August 2023 (12:51:25 CEST)
This paper provides a comprehensive review of the current understanding of non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH), focusing on key factors influencing its pathogenesis and emerging therapeutic strategies. The background highlights the growing prevalence of NAFLD and NASH, emphasizing their multifactorial nature. The methods section outlines the various contributors to NAFLD development, including genetic, dietary, and environmental factors. The results highlight the intricate interplay between these factors and their impact on hepatic lipid metabolism, inflammation, and insulin resistance. Genetic predisposition, dietary fat intake, and excessive fructose consumption are discussed as significant contributors to NAFLD progression. The conclusions emphasize the lack of a single therapeutic approach and underscore the need for combination strategies. Lifestyle interventions, particularly weight loss through diet and exercise, remain crucial, while pharmacological options like GLP-1 receptor agonists, obeticholic acid, lanifibranor, and resmetirom show promise but require further validation. Bariatric surgery and emerging endoscopic procedures offer potential in eligible patients. In sum, this review underscores the complexity of NAFLD and NASH, advocating for a multifaceted approach to address this increasingly prevalent and clinically relevant condition.
REVIEW | doi:10.20944/preprints202304.1238.v1
Subject: Medicine And Pharmacology, Urology And Nephrology Keywords: Peyronie's disease; pathogenesis; risk factors; molecular mechanisms, transforming growth factor-β1
Online: 30 April 2023 (02:21:49 CEST)
Peyronie's disease (PD) is a benign condition caused by plaque formation on the tunica albuginea of the penis. It is associated with penile pain, curvature, and shortening, and contributes to erectile dysfunction, which worsens patient quality of life. In recent years, understanding of the detailed mechanisms and risk factors involved in development of PD has been increasing. In this review, the pathological mechanisms and several closely related signaling pathways, including TGF-β, WNT/β-catenin, Hedgehog, YAP/TAZ, MAPK, ROCK, and PI3K/AKT, are described. Findings regarding cross-talk among these pathways are then discussed to elucidate the complicated cascade behind tunica albuginea fibrosis. Finally, various risk factors including genetic involved in the development of PD are presented and their association with the disease summarized. The purpose of this review is to provide better understanding regarding involvement of risk factors in the molecular mechanisms associated with PD pathogenesis, as well as provide insight into disease prevention and novel therapeutic interventions.
REVIEW | doi:10.20944/preprints202009.0565.v1
Subject: Biology And Life Sciences, Virology Keywords: Coronavirus; SARS-CoV-2; COVID-19; Immunobiochemical aspects; pathogenesis; diagnosis; management
Online: 24 September 2020 (04:39:38 CEST)
Background: A new coronavirus (SARS-CoV-2) that emerged from Wuhan, Hubei Province, China, has spread throughout the world and is declared a pandemic by the World Health Organization (WHO). A lot remains to be understood of SARS-CoV-2 and the disease (COVID-19). SARS-CoV-2 has until recently been identified as responsible for both asymptomatic and serious life-threatening infections. The unavailability of specific therapeutic agents is a major hurdle in the treatment and management of COVID-19 patients. The present review attempts to evaluate the immunobiochemical aspects of the pathogenesis, diagnosis, and management of SARS-CoV-2 infection. Main Body: This review is a comprehensive evaluation of the data collected through various sources, including Google Scholar, PubMed, and Scopus. The articles were searched and selected using key words such as “Coronavirus disease (COVID-19)”, “Diagnosis of COVID-19”, Pathogenesis of Covid-19”, “management of COVID-19”, “Immunology of COVID-19”, and “Complications of COVID-19”. The study noted that the novel Coronavirus infection could result in an exaggerated immune response, causing a cytokine storm and damaging several organs of the body. The infected patients develop several complications, including immunological, hematological, and biochemical alterations. Consequently, COVID-19 patients may develop cardiovascular, liver, renal, and neurological complications, among others. Conclusion: An increased understanding of the immunobiochemical aspects of the disease may contribute to better management of SARS-CoV-2-infected persons, as evidenced from the available literature. A holistic approach to the management of COVID-19 patients taking into consideration the effect of COVID-19 infection on various organs of the body assumes increased significance in patient management.
REVIEW | doi:10.20944/preprints202004.0430.v1
Subject: Medicine And Pharmacology, Pathology And Pathobiology Keywords: atherosclerosis; sars-cov-2; covid-19; pathogenesis of sars-cov-2
Online: 24 April 2020 (08:58:13 CEST)
Sars-CoV-2 outbreak represents a public health emergency, affecting different regions of the world. Lung is the organ more damaged due to the high presence of Sars-CoV-2 binding receptor ACE2 on epithelial alveolar cells. Severity of infection vary from absence of symptomatology to be more severe, characterized by acute respiratory distress syndrome (ARDS), multiorgan failure and sepsis requiring treatment in Intensive Care Unit (ICU).It is not still clear why in a small percentage of patients immune system is not able to efficiently suppress viral replication. It has been documented as predictive factors for severity and susceptibility affections of cardiovascular system such as heart failure (HF), coronary heart disease (CHD) and risk factors for atherosclerotic progression, hypertension and diabetes among others.Atherosclerotic progression, as chronic inflammation process, is characterized by immune system dysregulation leading to pro-inflammatory pattern, including (Interleukin 6) IL-6, Tumor Necrosis Factor α (TNF-α) and IL-1β raise. Reviewing immune system and inflammation profiles in atherosclerosis and laboratory results report in severe Sars-CoV-2 infection we have supposed a pathogenetic correlation. Atherosclerosis may be a pathogenetic ideal substrate to high viral replication ability leading to adverse outcomes, how reported in patients with cardiovascular factors. Moreover, level of atherosclerotic progression may impact on a different degree of severe infection and in a vicious circle feeding itself Sars-CoV-2 may exacerbate atherosclerotic progression due to excessive and aberrant plasmatic concentration of cytokines.
REVIEW | doi:10.20944/preprints202001.0025.v1
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: duodenal ulcer; pathogenesis; gastric acid; helicobacter pylori; psychosomatic disease; psychological stress
Online: 3 January 2020 (09:00:37 CET)
Background: The pathogenesis of duodenal ulcer has never been explained although the first description of this disease in medical literature appeared in 1817. Marshall et al. concluded that Helicobacter pylori was the most important etiological factor for duodenal ulcer in 1988, but the etiology based on this bacterium is controversial and how the bacterial infection leads to ulceration is presently unknown. Objectives: This study aims to identify the cause of duodenal ulcer, address the controversial issues surrounding Helicobacter pylori, elucidate the roles of gastric acid, and describe the pathological process of duodenal ulceration. Methods: First, a comprehensive systematic review on peptic ulcers (including gastric ulcer and duodenal ulcer) was conducted and the results were summarized. Second, a recently published causal relationship was employed to identify the etiology of peptic ulcers. Third, novel concepts and methods were applied to analyze the existing data on duodenal ulcer. Results: The etiology of duodenal ulcer and the roles of Helicobacter pylori and gastric acid in this disease were identified. The controversies surrounding Helicobacter pylori were addressed, and many characteristics and phenomena/observations of duodenal ulcer were elucidated. The pathological process of duodenal ulceration was described. Conclusion: Existing data accumulated over the past 300 years was sufficient, when analyzed using novel concepts, to understand the pathogenesis of duodenal ulcer. Duodenal ulcer is not an infectious disease caused by the infection of Helicobacter pylori, but a psychosomatic disease triggered by psychological stress. Helicobacter pylori plays a secondary role in only the late phase of duodenal ulceration.
REVIEW | doi:10.20944/preprints201809.0004.v1
Subject: Biology And Life Sciences, Virology Keywords: gammaherpesviruses, long non-coding RNAs, RNA structure and function, viral pathogenesis
Online: 1 September 2018 (17:36:48 CEST)
Advances in next-generation sequencing have facilitated the discovery of a multitude of long non-coding RNAs (lncRNAs) with pleiotropic functions in cellular processes, disease and viral pathogenesis. It came as no surprise when viruses were also revealed to transcribe their own lncRNAs. Among them, gammaherpesviruses, one of the three subfamilies of the Herpesviridae, code their largest number. These structurally and functionally intricate non-coding (nc) transcripts modulate cellular and viral gene expression to maintain viral latency or prompt lytic reactivation. The lncRNAs allow the virus to escape cytosolic surveillance, sequester and re-localize essential cellular factors and modulate the cell cycle and proliferation. Some viral lncRNAs act as “messenger molecules”, transferring information about viral infection to neighboring cells. This broad range of lncRNA functions is achieved through lncRNA structure-mediated interactions with effector molecules of viral and host origin, including other RNAs, proteins and DNAs. In this review, we discuss examples of gammaherpesvirus-encoded lncRNAs, emphasize their unique structural attributes, and link them to viral life cycle, pathogenesis and disease progression. We will address their potential as novel targets for drug discovery and propose future directions to explore lncRNA structure and function relationship.
REVIEW | doi:10.20944/preprints202305.1547.v1
Subject: Biology And Life Sciences, Neuroscience And Neurology Keywords: Amyloid; Aggregation; Self-assembly; Gene mutation; Disease Pathogenesis; Inborn errors of metabolism
Online: 23 May 2023 (03:35:10 CEST)
Amyloids were conventionally referred to as extracellular and intracellular accumulation of Aβ42 peptide which causes the formation of plaques and neurofibrillary tangles inside the brain leading to the pathogenesis in Alzheimer’s disease. Subsequently, amyloid-like deposition was found in the etiology of Prion diseases, Parkinson disease, Type II Diabetes and Cancer which was attributed to the aggregation of Prion protein, α-Synuclein, Islet Amyloid Polypeptide Protein and p53 protein respectively. Hence, traditionally amyloids were considered as aggregates formed by the proteins or peptides exclusively. However, since the last decade it has been discovered that other metabolites like single amino acids, nucleobases, lipids, glucose derivatives etc. have propensity to form amyloid-like toxic assemblies. Several studies suggest direct implications of these metabolite assemblies in the patho-physiology of various Inborn errors of metabolisms like Phenylketonuria, Tyrosinemia, Cystinuria and Gaucher’s disease to name a few. In this review, we present a comprehensive literature overview which suggests amyloid-like structure formation as a common phenomenon for the disease progression and pathogenesis in multiple syndromes. The review on this topic is urgently required to create awareness about the understanding of fundamental molecular mechanism behind the origin of diseases from an amyloid perspective and possibly look for a common therapeutic strategy for the treatment of these maladies by designing generic amyloid inhibitors.
ARTICLE | doi:10.20944/preprints202111.0252.v1
Subject: Biology And Life Sciences, Virology Keywords: African swine fever; male reproductive tract; pathogenesis; virus detection; histopathology; venereal transmission
Online: 15 November 2021 (11:14:35 CET)
African swine fever (ASF) has evolved from an exotic animal disease to a threat to global pig production. An important avenue for wide-spread transmission of animal diseases is the dissemination of viruses through boar semen used for artificial insemination (AI). In this context, we investigated the role of male reproductive organs in ASF. Mature domestic boars and adolescent wild boar inoculated with different ASF virus strains were investigated by means of virological and pathological methods. Additionally, electron microscopy was employed to investigate in vitro inoculated sperm. Viral genome, antigen and infectious virus could be found in all gonadal tissues and accessory sex glands. The viral antigen and viral mRNAs were mainly found in mononuclear cells of the respective tissues. However, some other cell types, including Leydig, endothelial and stromal cells were also found positive. Using RNAScope, p72 mRNA could be found in scattered halo cells of the epididymal duct epithelium which could point to disruption of the barrier. No direct infection of spermatozoa was observed by immunohistochemistry or electron microscopy. Taken together, our results strengthen the assumption that ASFV can be transmitted via boar semen. Future studies are needed to explore excretion dynamics and transmission efficiency.
REVIEW | doi:10.20944/preprints201807.0013.v1
Subject: Biology And Life Sciences, Virology Keywords: viral dissemination; innate immune cells; cytomegalovirus; pathogenesis; chemokines; Fenner hypothesis; neutrophils; monocytes
Online: 2 July 2018 (13:14:05 CEST)
Human cytomegalovirus (HCMV) is a β-herpes virus that is a significant pathogen within immune compromised populations. HCMV morbidity is induced through viral dissemination and inflammation. Typically, viral dissemination is thought to follow Fenner’s hypothesis where virus replicates at the site of infection, followed by replication in the draining lymph nodes, and eventually replicating within blood filtering organs. Although CMVs somewhat follow Fenner’s hypothesis, they deviate from it by spreading primarily through innate immune cells as opposed to cell free virus. Also, in vivo CMVs infect new cells via cell to cell spread and disseminate directly to secondary organs through novel mechanisms. We review the historic and recent literature pointing to CMV’s direct dissemination to secondary organs and the genes that it has evolved for increasing its ability to disseminate. We also highlight aspects of CMV infection for studying viral dissemination when using in vivo animal models.
REVIEW | doi:10.20944/preprints201611.0099.v1
Subject: Medicine And Pharmacology, Pulmonary And Respiratory Medicine Keywords: pneumonia; acute respiratory distress syndrome; pathogenesis; protein-homeostasis-system; corticosteroid; intravenous immunoglobulin
Online: 18 November 2016 (10:18:58 CET)
Acute respiratory distress syndrome (ARDS) is caused by infectious insults, such as pneumonia from various pathogens or related to other noninfectious events. Clinical and histopathologic characteristics are similar across severely affected patients, suggesting that a common mode of immune reaction may be involved in the immunopathogenesis of ARDS. There may be etiologic substances that have an affinity for respiratory cells and induce lung cell injury in cases of ARDS. These substances originate not only from pathogens, but also from injured host cells. At the molecular level, these substances have various sizes and biochemical characteristics, classifying them as protein substances and non-protein substances. Immune cells and immune proteins may recognize and act on these substances, including pathogenic proteins and peptides, depending upon the size and biochemical properties of the substances (this theory is known as the protein-homeostasis-system hypothesis). The severity or chronicity of ARDS depends on the amount of etiologic substances with corresponding immune reactions, the duration of the appearance of specific immune cells, or the repertoire of specific immune cells that control the substances. Therefore, treatment with early systemic immune modulators (corticosteroids and/or intravenous immunoglobulin) as soon as possible may reduce aberrant immune responses in the potential stage of ARDS.
CONCEPT PAPER | doi:10.20944/preprints202302.0297.v2
Subject: Medicine And Pharmacology, Gastroenterology And Hepatology Keywords: peptic ulcers, pathogenesis, etiology, Helicobacter pylori, illusion, African enigma, psychosomatic disease, psychological stress
Online: 23 October 2023 (12:01:11 CEST)
Currently, peptic ulcers are widely studied as an infectious disease caused by Helicobacter pylori primarily due to 3 supporting evidences, and this etiology may explain the other 3 observations, but cannot confront the challenges of the 15 major characteristics and the other 75 observations/phenomena of peptic ulcers. To address the challenges, a recently published Complex Causal Relationship with its accompanying methodologies was applied to analyze existing data. Peptic ulcers are identified as a psychosomatic disease triggered by psychological stress, where Helicobacter pylori plays a secondary role in only the late phase of ulceration. This new etiology elucidated all the 15 major characteristics and 81 observations/phenomena of peptic ulcers in a series of 6 articles. This sixth article focuses exclusively on the controversies surrounding the role of Helicobacter pylori in peptic ulcers. In-depth analyses find that all the 3 evidences supporting “peptic ulcers are an infectious disease caused by Helicobacter pylori” are deceiving, and 2 of the 3 explainable observations may have been misinterpreted. Meanwhile, the definitions of ‘etiological factor’ and ‘causality’ do not support ‘H. pylori infection is an etiological factor of peptic ulcers’, and existing literatures have presented a controversial view on the role of Helicobacter pylori in peptic ulcers. Interestingly, if “peptic ulcers are an infectious disease caused by Helicobacter pylori” is considered an illusion, all the characteristics of the disease, along with all the clinical, epidemiological, and laboratory observations/phenomena, can be fully understood. This illusion has misguided peptic ulcer research over the past 36 years with little progress in the field, and that may represent a widespread situation in modern medical research, resulting in a direct interference with the true understanding of disease. Evidently, keeping the concept “illusion” in mind may help remove a huge obstacle that impedes medical advance, thereby facilitating the in-depth study of disease.
REVIEW | doi:10.20944/preprints202309.1485.v1
Subject: Medicine And Pharmacology, Psychiatry And Mental Health Keywords: postpartum depression, marker, biomarkers, peripartum, postpartum, cytokines, HPA, oxidative stress, genetics, nutrients, pathogenesis
Online: 22 September 2023 (05:13:21 CEST)
Postpartum depression (PPD) is a disorder that impairs the formation of the relationship between mother and child, and reduces the quality of life for affected women to a functionally significant degree. Studying markers associated with PPD can help in early detection, prevention, or monitoring treatment. The purpose of this paper is to review biomarkers linked to PPD and to present selected theories on the pathogenesis of the disease based on data from biomarker studies. The complex etiology of the disorder reduces the specificity and sensitivity of markers, but they remain a valuable source of information to help clinicians. The biggest challenge of the future will be to translate high-tech methods for detecting markers associated with postpartum depression into more readily available and less costly ones. Population-based studies are needed to test the utility of potential PPD markers.
ARTICLE | doi:10.20944/preprints202107.0687.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Vesicular Stomatitis Virus; macrophage; microarray analysis; differential gene expression; molecular pathogenesis; immune evasion
Online: 30 July 2021 (09:27:29 CEST)
Molecular mechanisms associated with the pathogenesis of Vesicular stomatitis virus (VSV) in livestock remain poorly understood. Several studies have highlighted the relevant role of macrophages in controlling the systemic dissemination of VSV during infection in different animal models, including mice, cattle and pigs. To gain more insight on the molecular mechanisms used by VSV to impair the immune response in macrophages, we used microarrays to determine the transcriptomic changes produced by VSV infection in primary cultures of porcine macrophages. The results indicated that VSV infection induced the massive expression of multiple anorexic, pyrogenic, proinflammatory and immunosuppressive genes. Overall, the interferon (IFN) response appeared suppressed, leading to the absence of stimulation of interferon-stimulated genes (ISG). Interestingly, VSV infection promoted the expression of several genes known to downregulate the expression of IFNb. This represents an alternate mechanism for VSV control of the IFN response, beyond the recognized mechanisms mediated by the matrix protein. Although there was no significant differential gene expression in macrophages infected with a highly virulent epidemic strain compared to a less virulent endemic strain, the endemic strain consistently induced higher expression of all upregulated cytokines and chemokines. Collectively, this study provides novel insights into VSV molecular pathogenesis and immune evasion that warrants further investigation
REVIEW | doi:10.20944/preprints202007.0305.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: spondyloarthritis; HLA-B27; pathogenesis; inflammation; arthritogenic peptides; unfolded protein response; ERAP1; gut dysbiosis
Online: 14 July 2020 (11:39:13 CEST)
Spondyloarthritis comprises of a group of inflammatory diseases of the joints and spine with various clinical manifestations. The group includes ankylosing spondylitis, reactive arthritis, psoriatic arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthritis. The exact etiology and pathogenesis of spondyloarthritis are still unknown, but five hypotheses explaining the pathogenesis exist. These hypotheses suggest that spondyloarthritis is caused by arthritogenic peptides, an unfolded protein response, HLA-B27 homodimer formation, malfunctioning endoplasmic reticulum aminopeptidases, and, last but not least, gut inflammation and dysbiosis. Here we discuss the five hypotheses and the evidence supporting each. In all of these hypotheses, HLA-B27 plays a central role. It is likely that a combination of these hypotheses, with HLA-B27 taking center stage, will eventually explain the development of spondyloarthritis in predisposed individuals.
HYPOTHESIS | doi:10.20944/preprints202005.0480.v1
Subject: Biology And Life Sciences, Virology Keywords: endothelial; infection; basement membrane; fibroblast; fibrosis; nsp7; hypothesis; pathogenesis; COVID-19; SARS-CoV2
Online: 31 May 2020 (16:28:19 CEST)
Severe COVID-19 is associated with viraemia and multiple organ disease. Similar clinicopathological features have been previously seen in SARS and MERS. Clinically, the severity of SARS, MERS and COVID-19 has been associated with the presence of SARS-CoV, MERS-CoV or SARS-CoV2 viraemia in affected patients. In vitro work has looked at the pattern of viral entry and release from polarised epithelial cells infected by coronaviruses. This work has demonstrated a correlation between the severity of a coronavirus infection and the ability of the virus to reach and infect the basal surface of host cells. It has been postulated that this ability helps the virus invade the bloodstream of the host, resulting in a systemic infection with multiple organ involvement. Here we propose that basal surface release and entry of COVID-19 into and out of cells at epithelial-endothelial interface plays a key pathogenic role in severe COVID-19 disease.
REVIEW | doi:10.20944/preprints202310.0556.v1
Subject: Medicine And Pharmacology, Hematology Keywords: acute leukemia; chronic leukemia; cutis; diagnosis; pathogenesis; prolympchocytic leukemia; Richter transformation; skin lesions; treatment
Online: 10 October 2023 (05:36:42 CEST)
Leukemia cutis (LC) is defined as leukemic infiltration of the epidermis, the dermis, and the subcutaneous tissue. Leukemia cutis may follow or occur simultaneously with the diagnosis of systemic leukemia. However, cutaneous lesions are occasionally diagnosed as the primary manifestation of leukemia. Leukemic skin infiltrations demonstrate considerable variation regarding number of changes, distribution, and morphology. The highest incidence of LC is observed in chronic lymphocytic leukemia, monocytic and myelomonocytic acute myeloid leukemia, and in T-cell lineage leukemia. Although the pathogenic mechanism of the invasion of leukemic cells into the skin is not well understood, chemokine receptors and adhesion molecules as well as genetic characteristics of leukemia are thought to play a role. Leukemic skin lesions may be localized or disseminated and may occur alone or in combination on any site of the skin, most frequently in the trunk and extremities. The most common clinical presentations of leukemia cutis are papules, nodules, macules, plaques, and ulcers. In most patients, complete or partial resolution of cutaneous infiltrations occurs simultaneously with hematologic remission. However, in patients with resistant disease or recurrent skin infiltration, local radiotherapy can be used. This review presents recent data on the pathogenesis, diagnosis and treatment of leukemic skin involvement in different types of leukemia
REVIEW | doi:10.20944/preprints202305.0591.v1
Subject: Medicine And Pharmacology, Pediatrics, Perinatology And Child Health Keywords: 1. Bronchopulmonary dysplasia; 2. Sepsis; 3. Mechanical ventilation; 4. Pathogenesis; 5. Inflammation; 6. PDA
Online: 9 May 2023 (08:03:01 CEST)
Bronchopulmonary dysplasia (BPD), also known as chronic lung disease, is the most common respiratory morbidity in preterm infants. "Old" or "Classic" BPD, as per the original description, is less common now. "New BPD," which presents with distinct clinical and pathological features, is more frequently observed in the current era of advanced neonatal care, where extremely premature infants are surviving due to medical advancements. The pathogenesis of BPD is complex and multifactorial and involves both genetic and environmental factors. This review provides an overview of the pathology of BPD and discusses the influence of several prenatal and postnatal factors on its pathogenesis, such as maternal factors, genetic susceptibility, ventilator-associated lung injury, oxygen toxicity, sepsis, patent ductus arteriosus (PDA), and nutritional deficiencies. This in-depth review draws on existing literature to explore these factors and their potential contribution to the development of BPD.
REVIEW | doi:10.20944/preprints202310.2067.v1
Subject: Biology And Life Sciences, Immunology And Microbiology Keywords: anti-DNA antibodies; systemic lupus erythematosus (SLE); penetration; endocytosis; neutrophil extracellular traps (NETs); NETosis; pathogenesis
Online: 31 October 2023 (12:34:43 CET)
Anti-DNA antibodies are hallmark autoantibodies produced in systemic lupus erythematosus (SLE), but their pathogenetic roll is not fully understood. Accumulating evidence suggests that some anti-DNA antibodies enter different types of live cells and affect the pathophysiology of SLE by stimulating or impairing these cells. Circulating neutrophils in SLE are activated by type I interferon or other stimuli and primed to release neutrophil extracellular traps (NETs) on additional stimulation. Anti-DNA antibodies are also involved in this process and may induce NET release. Thereafter, they bind and protect extracellular DNA in the NETs from digestion by nucleases, resulting in increased NET immunogenicity. This review discusses the pathogenetic role of anti-DNA antibodies in SLE, mainly focusing on recent progress in the two research fields concerning antibody penetration into live cells and NETosis.
ARTICLE | doi:10.20944/preprints202304.0781.v1
Subject: Biology And Life Sciences, Animal Science, Veterinary Science And Zoology Keywords: porcine circovirus; swine influenza A virus; epithelial cells; macrophages; co-infection; viral pathogenesis; virus replication
Online: 23 April 2023 (07:22:26 CEST)
The pathogenesis of porcine circovirus type 2b (PCV2b) and swine influenza A virus (SwIV) during co-infection in swine respiratory cells is poorly understood. To elucidate the impact of PCV2b/SwIV co-infection, newborn porcine tracheal epithelial cells (NPTr) and immortalized porcine alveolar macrophages (iPAM 3D4/21) were co-infected with PCV2b and SwIV (H1N1 or H3N2 genotype). Viral replication, cell viability and cytokine mRNA expression were determined and compared between single-infected and co-infected cells. Finally, 3’mRNA sequencing was performed to identify the modulation of gene expression and cellular pathways in co-infected cells. It was found that PCV2b significantly decreased and improved SwIV replication, in co-infected NPTr and iPAM 3D4/21 cells respectively, compared to single infected cells. Interestingly, PCV2b/SwIV co-infection synergistically up-regulated IFN expression in NPTr cells whereas in iPAM 3D4/21 cells, PCV2b impaired the SwIV IFN induced response, both correlating with SwIV replication modulation. RNA-sequencing analyses revealed that the modulation of gene expression and enriched cellular pathways during PCV2b/SwIV H1N1 co-infection is regulated in a cell type-dependent-manner. This study revealed different outcomes of PCV2b/SwIV co-infection in porcine epithelial cells and macrophages and provides new insights on porcine viral co-infections pathogenesis.
ARTICLE | doi:10.20944/preprints202211.0413.v1
Subject: Biology And Life Sciences, Virology Keywords: African swine fever virus; early virus detection; artificial insemination; pathogenesis; transmission; boar semen; vertical transmission
Online: 22 November 2022 (09:13:27 CET)
Rapid spread of African swine fever virus (ASFV), causing severe disease with often high fatality rates in Eurasian suids, prevails as a threat for pig populations and dependent industries world-wide. Although advancing scientific progress continually enhances our understanding of ASFV pathogenesis, alternative transmission routes for ASFV have yet to be assessed. Here, we demonstrate that ASFV can efficiently be transferred from infected boars to naïve recipient gilts through artificial insemination (AI). In modern pig production, semen from boar studs often supplies many sow herds. Thus, the infection of a boar stud presents the risk of rapidly and widely distributing ASFV within or between countries. Daily blood and semen collection from four boars after intramuscular inoculation with ASFV strain ‘Estonia 2014’ resulted in detection of ASFV genomes in the semen as early as 2 dpi, in blood at 1 dpi while semen quality remained largely unaffected. Ultimately, after insemination with extended semen, 7 of 14 gilts were ASFV positive by 7 days post insemination, and all gilts were ASFV positive by 35 days post insemi-nation. Twelve out of 13 gilts aborted at the onset of fever. A proportion of fetuses originating from the remaining gilt showed both abnormalities and replication of ASFV in fetal tissues. Thus, we present evidence for the efficient transmission of ASFV to gilts via AI and also to im-planted embryos. These results underline the critical role that boar semen could play in ASFV transmission.
ARTICLE | doi:10.20944/preprints202111.0124.v1
Subject: Medicine And Pharmacology, Pathology And Pathobiology Keywords: tuberculosis; secretory antigens; bronchiolar epithelium; alveolar pneumocytes; M2 polarization; COX-2, FAS; Pathogenesis; early lesion
Online: 5 November 2021 (14:50:58 CET)
The characteristic lesion of primary tuberculosis is the granuloma as is widely studied in human tissues and animal models. Post-primary tuberculosis is different. It develops only in human lungs and begins as a prolonged subclinical obstructive lobular pneumonia that slowly accumulates mycobacterial antigens and host lipids in alveolar macrophages with nearby highly sensitized T cells. After several months, the lesions undergo necrosis to produce a mass of caseous pneumonia large enough to fragment and be coughed out to produce a cavity or be retained as the focus of a post-primary granuloma. Here we extend these findings with the demonstration of mycobacterial antigen, but not AFB, of M. tuberculosis in the cytoplasm of ciliated bronchiolar epithelium and alveolar pneumocytes in association with elements of the programmed death ligand 1 (PD-L1), cyclo-oxygenase (COX)-2, and fatty acid synthase (FAS) pathways in the early lesion. This suggests that M. tuberculosis uses its secreted antigens to coordinate prolonged subclinical development of the early le-sions in preparation for a necrotizing reaction sufficient to produce a cavity, post-primary granulomas and fibrocaseous disease.
ARTICLE | doi:10.20944/preprints202107.0404.v2
Subject: Medicine And Pharmacology, Pathology And Pathobiology Keywords: tuberculosis; secretory antigens; bronchiolar epithelium; alveolar pneumocytes; M2 polarization; COX-2, FAS; Pathogenesis; early lesion
Online: 29 September 2021 (09:56:22 CEST)
The characteristic lesion of primary tuberculosis is the granuloma as is widely studied in human tissues and animal models. Post-primary tuberculosis is different. It develops only in human lungs and begins as a prolonged subclinical obstructive lobular pneumonia that slowly accumulates mycobacterial antigens and host lipids in alveolar macrophages with nearby highly sensitized T cells. After several months, the lesions under necrosis to produce a mass of caseous pneumonia large enough to fragment and be coughed out to produce a cavity or be retained as the focus of a post-primary granuloma. Here we extend these findings with the demonstration of mycobacterial antigen, but not AFB, of M. tuberculosis in the cytoplasm of ciliated bronchiolar epithelium and alveolar pneumocytes in association with elements of the programmed death ligand 1 (PD-L1), cyclo-oxygenase (COX)-2, and fatty acid synthase (FAS) pathways in the early lesion. This suggests that M. tuberculosis use its secreted antigens to coordinate prolonged subclinical development of the early lesions in preparation for a necrotizing reaction sufficient to produce a cavity, post-primary granulomas and fibrocaseous disease
REVIEW | doi:10.20944/preprints202002.0048.v1
Subject: Medicine And Pharmacology, Psychiatry And Mental Health Keywords: NO; NOS; genetics; nitric oxide; nitric oxide synthase; oxidative stress; pathogenesis; mental disorders, neurological diseases
Online: 4 February 2020 (11:06:10 CET)
According to the recent data, nitric oxide (NO) is a chemical messenger that mediates functions such as vasodilation and neurotransmission, it also possesses antimicrobial and antitumoral activities. Nitric oxide has been implicated in neurotoxicity associated with stroke and neurodegenerative diseases, neural regulation of smooth muscle, including peristalsis, and penile erection. We searched for full-text English publications in Pubmed and SNPedia databases using keywords and combined word searches (nitric oxide, single nucleotide variants, single nucleotide polymorphisms, genes) over the past 15 years. In addition, earlier publications of historical interest were included in the review. In our review, we have sum up all NOS1, NOS2, NOS3, and NOS1AP single nucleotide variants (SNVs) involved in the development of mental disorders and neurological diseases/conditions. The results of studies we have discussed in this review are contradictory, that might be due to different designs of the studies, small sample sizes in some of them, as well as different social and geographical characteristics. However, the contribution of genetic and environmental factors has been understudied, that makes this issue increasing for researchers as the understanding of these mechanisms can support a search for new approaches to pathogenetic and disease-modifying treatment.
REVIEW | doi:10.20944/preprints201804.0009.v1
Subject: Biology And Life Sciences, Animal Science, Veterinary Science And Zoology Keywords: feline immunodeficiency virus; FIV; human immunodeficiency virus; HIV; animal models, opportunistic disease, lentiviral pathogenesis; molecular biology
Online: 2 April 2018 (07:54:28 CEST)
Feline immunodeficiency virus (FIV) is a naturally-occurring retrovirus that infects domestic and non-domestic feline species, producing progressive immune depletion that results in an acquired immunodeficiency syndrome (AIDS). Much has been learned about FIV since it was first described in 1987, particularly in regard to its application as a model to study the closely related lentivirus, human immunodeficiency virus (HIV). In particular, FIV and HIV share remarkable structure and sequence organization, utilize parallel modes of receptor-mediated entry, and result in a similar spectrum of immunodeficiency-related diseases due to analogous modes of immune dysfunction. This review summarizes current knowledge of FIV infection kinetics and mechanisms of immune dysfunction in relation to opportunistic disease, specifically in regard to studying HIV pathogenesis. Furthermore, we present data which highlight changes in the oral microbiota and oral immune system during FIV infection, and outline the potential for the feline model of oral AIDS manifestations to elucidate pathogenic mechanisms of HIV-induced oral disease. Finally, we discuss advances in molecular biology, vaccine development, neurologic dysfunction, and the ability to apply pharmacologic interventions and sophisticated imaging technologies to study experimental and naturally occurring FIV, which provide an excellent, but often overlooked resource for advancing therapies and management of HIV/AIDS.
REVIEW | doi:10.20944/preprints202104.0543.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Pathogenic relationship; Symbiotic relationship; LUCA; Horizontal gene transfer; Recombination; Transposition; Disease pathogenesis; CRISPR-Cas & Anti-CRISPR system
Online: 20 April 2021 (12:56:45 CEST)
Mutual survival among different species of living organisms is quite common in our living world. That mutual survival can produce symbiotic or parasitic relationship among different living organisms. But at the same time, some relationships are harmful to the living organisms creating pathogenic relationships. Why some mutual survivals are beneficial, whereas some relationships are harmful creating different diseases in the living world? That harmful or pathological relationship producing different diseases in both the animal and plant kingdom has been extensively studied by the scientific community several times under the heading of ‘Host-pathogen interaction’ and ‘Disease pathogenesis’. But it is still not clear why some mutual survivals are beneficial or non-harmful, whereas some co-survivals are harmful producing different disease conditions in the living world mainly due to different immune mediated reactions or direct toxic effect of substances produced by an organism. To find the answer to this question, we have to search retrospectively to the evolutionary pattern of our diverse living world. If it is assumed that we have originated from Last Universal Common Ancestor (LUCA) by different cumulative mutations, horizontal gene transfer, mobile genetic elements (MGE), transposition and natural selection, then it would be quite pragmatic to consider that two things were moving side by side in our ancient living world. On one hand it’s purpose was to create the diversification of both unicellular and multi-cellular living world and on the other hand it’s another purpose was to maintain the specific identity of the living organisms. It is the second purpose or the maintenance of specific identity that ultimately led to the development of Immune system.
REVIEW | doi:10.20944/preprints201909.0212.v1
Subject: Biology And Life Sciences, Virology Keywords: positive-sense single-stranded rna viruses; innate immune evasion; type 1 interferon; viral pathogenesis; type 3 interferon
Online: 18 September 2019 (17:12:01 CEST)
Positive-sense single-stranded RNA (+ssRNA) viruses comprise many (re-)emerging human pathogens that pose a public health problem. Our innate immune system and in particular the interferon response form the important first line of defense against these viruses. Given their genetic flexibility, these viruses have therefore developed multiple strategies to evade the innate immune response in order to optimize their replication capacity. Already many molecular mechanisms of innate immune evasion by +ssRNA viruses have been identified. However, research addressing the effect of host innate immune evasion on the pathology caused by the viral infection is less prevalent in literature, though very relevant and interesting. Since interferons have been implicated in inflammatory diseases and immunopathology in addition to their protective role in infection, the influence of antagonizing the immune response may have an ambiguous effect on the clinical outcome of the viral disease. Therefore, this review discusses what is currently known about the role of interferons and host immune evasion in the pathogenesis of emerging viruses belonging to the coronaviruses, alphaviruses and flaviviruses.
ARTICLE | doi:10.20944/preprints202205.0395.v1
Subject: Biology And Life Sciences, Virology Keywords: African swine fever; pathogenesis; biomarkers; serum; saliva; virus inactivation; detergent treatment; heat treatment; impact of treatment on biomarkers
Online: 30 May 2022 (11:22:19 CEST)
African swine fever (ASF) is a notifiable viral disease of domestic and wild suids. Despite intensive re-search efforts, the pathogenesis of the disease is still far from being understood. Analysis of biomarkers in different body fluids may supplement traditional pathogenesis studies. As reliable protocols are often es-tablished in laboratories with lower biosafety, reliable inactivation of samples is crucial. The objective of this study was to find a procedure that inactivates the virus while preserving the biomarkers for down-stream analyses. To this means, three different inactivation protocols were employed, namely Tergitol-type NP-40 (NP-40) and polyoxyethylene-p-t-octylphenol (Triton X-100), respectively, and one with 95 °C heating. It could be demonstrated that all samples treated with 0.5% (v/v) concentration of both deter-gents showed absence of virus infectivity. The same was true for heated samples. However, heated serum was not suitable for analyses. Next, the treatment impact on biomarker readouts was assessed. While all protocols had an impact on the detection of biomarkers, correlation was retained. Especially NP-40 could be the desired detergent for more accurate measurements while achieving efficient virus inactivation. Based on these studies, samples can be reliably inactivated for most biomarker analyses and thus broader interdisciplinary cooperation is possible.
ARTICLE | doi:10.20944/preprints202310.1192.v1
Subject: Medicine And Pharmacology, Endocrinology And Metabolism Keywords: Diabetes; Pro and anti-inflammatory cytokines; T2DM in Saudi Arabia; Pathogenesis; IL-10; IL-19; and IL 22; Obesity
Online: 18 October 2023 (13:47:02 CEST)
Background. Type 2 diabetes mellitus (T2DM) is becoming a major global health concern, especially in poorer nations. The high prevalence of obesity and the ensuing diabetes I attributed to rapid economic progress, physical inactivity, consumption of high-calorie foods, and changing lifestyles. Objectives. We investigated the role of interleukins-10 , 19 and 22 with varying levels of obesity in T2DM in the Asir region of Saudi Arabia. Materials and methods. 170 confirmed T2DM patients and a control group were enrolled. The demographic data, serum levels of IL-10, IL-19, and IL-22, and biochemical indices were assessed in patients and control groups by standard procedures. Results. T2DM patients were divided into four groups: A (normal body weight), B (Overweight), C (obese), and D (highly obese). Both male and female T2DM subjects in Group A showed significant decreases in IL-10 levels as compared to controls; however, there were insignificant changes in IL-10 levels in Groups C and D. T2DM patients in groups C and D, in both males and females, depicted very significant (p 0.001) increases in IL-19 levels as compared to controls and group A. Patient groups A to D displayed a progressive elevation of Il-22 levels irrespective of gender, although significant alterations were seen only in groups B to D, with p 0.05 for group B and p 0.01 for groups C and D respectively, as compared to healthy controls. Conclusions. IL-10 showed a strong relationship with T2DM in males with varying degrees of obesity, but females depicted relatively higher IL-10 levels in obese and highly obese groups, pointing to a protective phenomenon. IL-19 levels showed significant increases in all four groups, irrespective of gender. IL-22 appears to be unrelated to T2DM per se but shows an association with varying degrees of obesity.
ARTICLE | doi:10.20944/preprints202207.0426.v1
Subject: Computer Science And Mathematics, Applied Mathematics Keywords: SARS-CoV-2 infection; innate immune response; antigen-specific immune response; kinetic coordination; mathematical model; pathogenesis, long COVID-19
Online: 27 July 2022 (15:11:44 CEST)
A calibrated mathematical model of antiviral immune response to SARS-CoV-2 infection is developed. The model considers the innate and antigen-specific responses to SARS-CoV-2 infection. Recently published data sets from human challenge studies with SARS-CoV-2 were used for parameter estimation. Understanding the regulation of multiple intertwined reaction components of the immune system is necessary for linking the clinical phenotypes of COVID-19 with the kinetics of immune responses. Consideration of multiple immune reaction components in a single calibrated mathematical model allowed us to address some fundamental issues related to pathogenesis of COVID-19, i.e. sensitivity of the peak viral load to parameters characterizing the specific response components, the kinetic coordination of the individual responses, and the factors favoring a prolonged viral persistence. The model provides a tool for predicting the infectivity of patients, i.e. the amount of virus which is transmitted via droplets from the person infected with SARS-CoV-2, depending on the time of infection. The thresholds in the relative unbalance between innate and adaptive response parameters which lead to a prolonged persistence of SARS-CoV-2 due to the loss of a kinetic response synchrony/coordination were identified.
REVIEW | doi:10.20944/preprints202308.0520.v1
Subject: Medicine And Pharmacology, Epidemiology And Infectious Diseases Keywords: SARS-CoV-2; spike protein; mutations; viral infectivity; pathogenesis; vaccine efficacy; immune evasion; antibody neutralization; T-cell response; therapeutic targeting
Online: 7 August 2023 (10:12:28 CEST)
The SARS-CoV-2 virus, which is responsible for the COVID-19 pandemic which emerged and spread, has sparked intense research on its spike protein, which is essential for viral entrance into host cells. Viral reproduction and transmission, host immune response regulation, receptor recognition and host cell entrance mechanisms, as well as structural and functional effects have all been linked to mutations in the spike protein. Spike protein mutations can also result in immune evasion mechanisms that impair vaccine effectiveness and escape, and they are linked to illness severity and clinical consequences. Numerous studies have been conducted to determine the effects of these mutations on the spike protein structure and how it interacts with host factors. These results have important implications for the design and development of medicines and vaccines based on spike proteins as well as for the assessment of those products' efficiency against newly discovered spike protein mutations. The paper gives a general overview of how spike protein mutations are categorized and named, as well as the genomic and phylogenetic techniques that have been used to track their genesis and dissemination. Additionally, it looks at the links between spike protein mutations and clinical outcomes, illness severity, unanswered problems, and future research prospects. Additionally, explored are the effects of these mutations on vaccine effectiveness as well as the possible therapeutic targeting of spike protein mutations.
ARTICLE | doi:10.20944/preprints202206.0201.v1
Subject: Biology And Life Sciences, Virology Keywords: human coronaviruses; envelope protein; PDZ-binding motif (PBM), homology-based modelling; docking; HADDOCK; protein-protein interaction; PALS1; pathogenesis; SARS-CoV-2
Online: 14 June 2022 (09:52:47 CEST)
The less virulent human (h) coronaviruses (CoVs) 229E, NL63, OC43, and HKU1 cause mild, self-limiting respiratory tract infections, while the more virulent SARS-CoV-1, MERS-CoV, and SARS-CoV-2 have caused severe outbreaks. The CoV envelope (E) protein, an important contributor to the pathogenesis of severe hCoVs infections, may provide insight into this disparate severity of the disease. We, therefore, generated full-length E protein models for SARS-CoV-1, -2, MERS-CoV, HCoV-229E, and HCoV-NL63 and docked C-terminal peptides of each model to the PDZ domain of the human PALS1 protein. The PDZ-binding motif (PBM) of the SARS-CoV-1, -2, and MERS-CoV models adopted a more flexible, extended coil while the HCoV-229E and HCoV-NL63 models adopted a less flexible alpha helix. All the E peptides docked to PALS1 occupied the same binding site and the more virulent hCoV E peptides generally interacted more stably with PALS1 than the less virulent ones. We propose that the increased flexibility of the PBM in more virulent hCoVs may permit more stable binding to various host proteins, thereby possibly contributing to more severe disease. This is the first paper to model full-length 3D structures for both more virulent and less virulent hCoVs E proteins, providing novel insights for possible drug and/or vaccine development.
REVIEW | doi:10.20944/preprints201804.0063.v1
Subject: Biology And Life Sciences, Virology Keywords: Zika virus; ZIKV-host interactions; viral pathogenesis; cell surface receptors; antiviral responses; viral counteraction; cytopathic effects; microcephaly; ZIKV-associated neurologic disorders
Online: 5 April 2018 (05:34:07 CEST)
The recent Zika virus (ZIKV) outbreak in Americas surprised all of us because of its rapid spread and association with neurologic disorders including fetal microcephaly, brain and ocular anomalies and Guillain-Barré syndrome. In responding to this global health outcry, unprecedented and world-wide efforts are taking place to study the ZIKV etiology. Much have been learned about this virus in the areas of epidemiology, clinical manifestation, viral sequences and protein structures, as well as effects of ZIKV infection on fetal brain development and microcephaly. However, the molecular mechanism underlying ZIKV-mediated neurologic disorders remains elusive. Some critical questions include: 1) what type of virologic changes has taken place that increased the viral virulence? 2) which ZIKV protein(s) is responsible for the enhanced viral pathogenicity? And 3) how the newly adapted and pathogenic ZIKV strains alter their interactions with host cells leading to neurologic disorders? The goal of this review is to explore the molecular insights into the ZIKV-host interactions with special focuses on host cell receptor usage for viral entry, host cellular and immune antiviral responses, ZIKV counteraction and ZIKV-induced cytopathic effects. Our hope with this literature review is to inspire additional studies focusing on molecular studies of ZIKV-host Interactions.
REVIEW | doi:10.20944/preprints202309.0407.v1
Subject: Biology And Life Sciences, Life Sciences Keywords: human T-cell leukemia virus type 1; adult T-cell leukemia/lymphoma; viral genes; genetic alterations; immune response; host–pathogen interaction; pathogenesis; treatment
Online: 6 September 2023 (09:32:44 CEST)
Human T-cell leukemia virus type-1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATL). HTLV-1 carriers have a life-long asymptomatic balance between infected cells and host antiviral immunity, but 5–10% of carriers lose this balance and develop ATL. Coinfection with Strongyloides also promotes ATL development, suggesting that the immunological status of infected individuals is a determinant of viral pathogenicity. As CD4+ T cells play a central role in host immunity, deregulation of their function and differentiation by HTLV-1 promotes the immune evasion of infected T cells. During ATL development, the accumulation of genetic and epigenetic alterations in key host immunity-related genes further disturbs immunological conditions. Various therapeutic approaches have been developed to treat these abnormalities. Allogeneic hematopoietic stem cell transplantation is currently the only treatment with the potential to cure ATL; however, the patient's immune state may also contribute to its outcome. Additionally, the activity of the anti-CC chemokine receptor 4 antibody, mogamulizumab, also depends on immune functions, such as antibody-dependent cytotoxicity. In this review, we comprehensively summarize the immunological pathogenesis of HTLV-1 infection in ATL and integrate clinical findings to determine the factors to be considered for developing treatment strategies for ATL.
REVIEW | doi:10.20944/preprints202305.1487.v1
Subject: Medicine And Pharmacology, Clinical Medicine Keywords: biomarkers; COVID-19; epidemiology; laboratory; long COVID; pathogenesis; post-acute sequelae of SARS-CoV-19 infection (PASC); post COVID; post-COVID syndrome (PCS)
Online: 22 May 2023 (09:41:11 CEST)
Long COVID (LC) encompasses a constellation of long-term symptoms experienced by at least 10% of people after the initial SARS-CoV-2 infection, and so far has affected about 65 million people. The etiology of LC remains unclear; however, many pathophysiological pathways may be involved, including viral persistence; chronic, low grade inflammatory response; immune dysregulation and defective immune response; reactivation of latent viruses; autoimmunity; persistent endothelial dysfunction and coagulopathy; gut dysbiosis; hormonal dysregulation, mitochondrial dysfunction; and autonomic nervous system dysfunction. There are no specific tests for the diagnosis of LC, and clinical features including laboratory findings and biomarkers may not specifically relate to LC. Therefore, it is of paramount importance to develop and validate biomarkers that can be employed for the prediction, diagnosis and prognosis of LC and its therapeutic response. Promising candidate biomarkers that are found in some patients are markers of systemic inflammation including acute phase proteins, cytokines and chemokines; biomarkers reflecting SARS-CoV-2 persistence, reactivation of herpesviruses and immune dysregulation; biomarkers of endotheliopathy, coagulation and fibrinolysis; microbiota alterations; diverse proteins and metabolites; hormonal and metabolic biomarkers; as well as cerebrospinal fluid biomarkers. At present, there are only two reviews summarizing relevant biomarkers; however, they do not cover the entire umbrella of current biomarkers or their link to etiopathogenetic mechanisms, and the diagnostic work-up in a comprehensive manner. Herein, we aim to appraise and synopsize the available evidence on the typical laboratory manifestations and candidate biomarkers of LC, their classification based on main LC symptomatology in the frame of the epidemiological and pathogenetic aspects of the syndrome, and furthermore assess limitations and challenges as well as potential implications in candidate therapeutic interventions.
REVIEW | doi:10.20944/preprints202006.0120.v1
Subject: Medicine And Pharmacology, Epidemiology And Infectious Diseases Keywords: SARS-CoV-2; COVID-19; pathogenesis; children; neonates; immune response; secondary hemophagocytic lymphohistiocytosis; renin-angiotensin system; genetic polymorphisms; ACE2; AGTR2; AGTR1; NOS; lung injury
Online: 9 June 2020 (08:07:40 CEST)
The spread of the infection caused by the new coronavirus SARS-CoV-2 (COVID-19) became pandemic on March 11, 2020. From the time of the first cases (in November 2019, Wuhan, China), to date, a large number of COVID-19 observations have been accumulated in different age groups of patients both in China and abroad. Published scientific data allows us to conclude that children suffer from COVID-19 much less often than adults and tolerate the disease in a milder form, often appear to be asymptomatic. There is currently no final answer why children are less susceptible to this virus; however, scientists are increasingly inclined to consider a complex effect of the immune response and components of the renin-angiotensin system (RAS), which according to recent studies affects not only the cardiovascular system, but is also responsible for the activation of inflammatory reactions. A hypothesis of genetic predisposition to the development of severe forms of COVID-19 has recently been made. We conducted a search for publications in the databases and showed current scientific ideas about COVID-19 pathogenesis and factors influencing the disease development in childhood. Childhood immunity may have several protective features against SARS-CoV-2: immaturity of particular elements of the innate immune response, constitutional lymphocytosis with a shift towards anti-inflammatory Th2-response, as well as "trained" immunity. The influence of renin-angiotensin system reactions in this review is shown from two perspectives: expression of ACE2 receptors and polymorphisms of certain genes of this system. It was established that ACE2 transmembrane protein is not only the entry point for the virus but also plays a regulatory role, turning the pro-inflammatory vasoconstrictor angiotensin II into anti-inflammatory angiotensin (1-7), which has vasodilating properties. Higher ACE2 content in children compared with adults helps maintain balance in the renin-angiotensin system and prevents the development of complications. It was also shown that the presence of certain genetic polymorphisms (AGTR1, AGTR2, ACE2, ACE) could determine the imbalance inside the RAS, leading to more pronounced reactions of alveolocytes, vascular endothelium and smooth muscle fibers in response to SARS-CoV-2 infection due to a shift towards vasoconstrictor, proliferative and profibrotic mechanisms.
REVIEW | doi:10.20944/preprints202301.0460.v1
Subject: Medicine And Pharmacology, Cardiac And Cardiovascular Systems Keywords: COVID-19 mRNA vaccines; Myo-pericarditis and COVID-19 mRNA vaccines; Multisystem-Inflammatory-Syndrome and COVID-19 mRNA vaccines; arrhythmias and COVID-19 mRNA vaccines; Pathogenesis of myocarditis following COVID-19 mRNA vaccines; MIS-A; MIS-C; MIS-V; Myocarditis; COVID-19 mRNA vaccine Adverse Events.
Online: 26 January 2023 (02:50:29 CET)
Each injection of any known vaccine results in a strong expression of pro-inflammatory cytokines. This is the result of the innate immune system activation, without which no adaptive response to the injection of vaccines is possible. COVID-19 mRNA vaccines would not escape this rule. Unfortunately, the degree of inflammation produced by these vaccines is variable, probably depending on the genetic background and previous immune experiences, which through epigenetic modifications, could have made the innate immune system of each individual tolerant or reactive to subsequent immune stimulations.We hypothesize that we can move from a limited pro-inflammatory condition to conditions of increasing expression of pro-inflammatory cytokines that can culminate in multisystem hyperinflammatory syndromes following COVID-19 mRNA vaccines (MIS-V). We have graphically represented this idea in a hypothetical inflammatory pyramid (IP) and we have correlated the time factor to the degree of inflammation produced after the injection of vaccines. Furthermore, we have placed the clinical manifestations within this hypothetical IP, correlating them to the degree of inflammation produced. Surprisingly, excluding the possible presence of an early MIS-V, the time factor and the complexity of clinical manifestations are correlated to the increasing degree of inflammation: symptoms, heart disease and syndromes (MIS-V).