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Li Chen,1,2 Xi-Le Peng,1,2 Zhi-Xuan Chen,1,2 Lu-Ming Qi,1,2 Ting-Ting Deng,2,3 Li-Na Xia1,2 1School of Health Preservation and Rehabilitation, Chengdu University of TCM, Chengdu, Sichuan, People’s Republic of China; 2Key Laboratory of Traditional Chinese Medicine Regimen and Health Industry Development, State Administration of TCM, Chengdu, Sichuan, People’s Republic of China; 3School of Nursing, Chengdu University of TCM, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Li-Na Xia, School of Health Preservation and Rehabilitation, Chengdu University of TCM, Chengdu, Sichuan, People’s Republic of China, Email xialina@cdutcm.edu.cnBackground: Excessive salt consumption has been associated with detrimental health consequences, including hypertension, colitis, and autoimmune disorders. However, recent studies have proposed that high salt diet (HSD) can both stimulate the immune system, affecting the differentiation of immune cells, promoting or inhibiting cytokine secretion to fight cancer or elicit a more potent autoimmune response, and exerting an immunosuppressive effect to influence disease development, providing mechanistic insights into the direction of immune regulation in which HSD affects disease.Objective: This paper reviews the immunomodulatory effects of HSD on various innate immune and adaptive cells, especially macrophages, dendritic cells, and T cells, in relation to disease development.Methods: We identified papers by electronically searching the Web of Science (WOS) database from inception through March 2023.Results: A growing number of animal experiments and in vitro cell culture studies have shown that HSD can regulate the differentiation and activation of a variety of immune cells, and promote or inhibit different cytokines to mediate the development of a variety of diseases, including nephropathy, hypertension, cancer, inflammatory bowel disease, and a number of autoimmune diseases. These findings provide a new mechanism for pathological changes in the direction of immune regulation and suggest that HSD is a predisposing factor for a variety of diseases, providing new mechanistic insights into dietary health modification.Conclusion: HSD mediates the development of multiple diseases by regulating the differentiation and activation of a variety of immune cells, and the underlying mechanisms may be related to gut microbes and their metabolites.Keywords: HSD, immune dysregulation, disease pathogenesis, mechanistic insights, review

Abstract Background Peste des Petits Ruminants (PPR) is a highly contagious viral disease primarily affecting goats and sheep, with clinical manifestations ranging from peracute disease to subclinical infection, particularly in atypical hosts such as cattle. The role of atypical hosts such as cattle to the spread of PPR remains controversial, with conflicting reports in the literature. Despite its worldwide significance, considerable knowledge gaps exist regarding the pathogenesis and clinical progression in both primary and atypical hosts. This study aimed to elucidate the tissue tropism, pathogenesis, virus shedding, clinical progression, and pathology associated with experimental PPR virus infection in indigenous goats and cattle. To this end, 32 animals—16 goats and 16 cattle—were intranasally inoculated with the Ethiopia/Habru/2014 Lineage-IV strain of the PPR virus followed by detailed clinical evaluations and systematic sampling at pre-established intervals to assess serological conversion, viral shedding, and the pathogenesis of the infection across both species. Results The results show that goats exhibited typical clinical signs 4 days post-inoculation, with seroconversion by day 6 and early detection of viral RNA in swabs and tissues by day 3 and virus isolation starting day 4. In contrast, cattle exhibited minimal clinical signs, with seroconversion occurring at day 8 with viral RNA detected in tissue samples at day 4 and virus isolation starting day 6 in tissues and in a single nasal swab at day 8. Clinical scores and tissue positivity rates significantly differed between goats and cattle (P = 0.007 and P

The discovery of non-coding RNAs (ncRNAs) has unveiled a wide range of transcripts that do not encode proteins but play key roles in several cellular and molecular processes. Long noncoding RNAs (lncRNAs) are specific class of ncRNAs that are longer than 200 nucleotides and have gained significant attention due to their diverse mechanisms of action and potential involvement in various pathological conditions. In the current review, the authors focus on the role of lncRNAs, specifically highlighting the Myocardial Infarction Associated Transcript (MIAT), in non-oncological context. MIAT is a nuclear lncRNA that has been directly linked to myocardial infarction and is reported to control post-transcriptional processes as a competitive endogenous RNA (ceRNA) molecule. It interacts with microRNAs (miRNAs), thereby limiting the translation and expression of their respective target messenger RNA (mRNA) and regulating protein expression. Yet, MIAT has been implicated in other numerous pathological conditions such as other cardiovascular diseases, autoimmune disease, neurodegenerative diseases, metabolic diseases, and many others. In this review, the authors emphasize that MIAT exhibits distinct expression patterns and functions across different pathological conditions and is emerging as potential diagnostic, prognostic, and therapeutic agent. Additionally, the authors highlight the regulatory role of MIAT and shed light on the involvement of lncRNAs and specifically MIAT in various non-oncological pathological conditions.

Abstract The innate immune system serves as the body's first line of defense, utilizing pattern recognition receptors like Toll‐like receptors to detect pathogens and initiate rapid response mechanisms. Following this initial response, adaptive immunity provides highly specific and sustained killing of pathogens via B cells, T cells, and antibodies. Traditionally, it has been assumed that innate immunity activates adaptive immunity; however, recent studies have revealed more complex interactions. This review provides a detailed dissection of the composition and function of the innate and adaptive immune systems, emphasizing their synergistic roles in physiological and pathological contexts, providing new insights into the link between these two forms of immunity. Precise regulation of both immune systems at the same time is more beneficial in the fight against immune‐related diseases, for example, the cGAS–STING pathway has been found to play an important role in infections and cancers. In addition, this paper summarizes the challenges and future directions in the field of immunity, including the latest single‐cell sequencing technologies, CAR‐T cell therapy, and immune checkpoint inhibitors. By summarizing these developments, this review aims to enhance our understanding of the complexity interactions between innate and adaptive immunity and provides new perspectives in understanding the immune system.

Abstract We describe a multidisciplinary teamwork approach known as “Operation IDD Gene Team” developed by the Rose F. Kennedy Intellectual and Developmental Disabilities Research Center (RFK IDDRC) at the Albert Einstein College of Medicine. This initiative brings families affected by rare genetic diseases that cause intellectual and developmental disability together with physicians, basic scientists, and their trainees. At team meetings, family members share their child’s medical and personal history, physicians describe the broader clinical consequences of the condition, and scientists provide accessible tutorials focused on the fundamental biology of relevant genes. When appropriate, possible treatment approaches are also discussed. The outcomes of team meetings have been overwhelmingly positive, with families not only expressing deep gratitude, but also becoming empowered to establish foundations dedicated to their child’s specific condition. Physicians, and in particular the scientists and their trainees, have gained a deeper understanding of challenges faced by affected families, broadening their perspective on how their research can extend beyond the laboratory. Remarkably, research by the scientists following the Gene Team meetings have often included focus on the actual gene variants exhibited by the participating children. As these investigations progress and newly created foundations expand their efforts, national as well as international collaborations are forged. These developments emphasize the importance of rare diseases as windows into previously unexplored molecular and cellular processes, which can offer fresh insights into both normal function as well as more common diseases. Elucidating the mechanisms of and treatments for rare and ultra-rare diseases thus has benefits for all involved—families, physicians, and scientists and their trainees, as well as the broader medical community. While the RFK IDDRC’s Operation IDD Gene Team program has focused on intellectual disabilities affecting children, we believe it has the potential to be applied to rare genetic diseases impacting individuals of any age and encompassing a wide variety of developmental disorders affecting multiple organ systems.

5-methylcytosine (m5C) is among the most common epigenetic modification in DNA and RNA molecules, and plays an important role in the animal development and disease pathogenesis. Interestingly, unlike other m5C DNA methyltransferases (DNMTs), DNMT2/TRDMT1 has the double-substrate specificity and adopts a DNMT-similar catalytic mechanism to methylate RNA. Moreover, it is widely involved in a variety of physiological regulatory processes, such as the gene expression, precise protein synthesis, immune response, and disease occurrence. Thus, comprehending the epigenetic mechanism and function of DNMT2/TRDMT1 will probably provide new strategies to treat some refractory diseases. Here, we discuss recent studies on the spatiotemporal expression pattern and post-translational modifications of DNMT2/TRDMT1, and summarize the research advances in substrate characteristics, catalytic recognition mechanism, DNMT2/TRDMT1-related genes or proteins, pharmacological application, and inhibitor development. This review will shed light on the pharmacological design by targeting DNMT2/TRDMT1 to treat parasitic, viral and oncologic diseases.

Abstract Friedreich ataxia (FRDA) is a rare genetic multisystem disorder caused by a pathological GAA trinucleotide repeat expansion in the FXN gene. The numerous drawbacks of historical cellular and rodent models of FRDA have caused difficulty in performing effective mechanistic and translational studies to investigate the disease. The recent discovery and subsequent development of induced pluripotent stem cell (iPSC) technology provides an exciting platform to enable enhanced disease modelling for studies of rare genetic diseases. Utilising iPSCs, researchers have created phenotypically relevant and previously inaccessible cellular models of FRDA. These models enable studies of the molecular mechanisms underlying GAA-induced pathology, as well as providing an exciting tool for the screening and testing of novel disease-modifying therapies. This review explores how the use of iPSCs to study FRDA has developed over the past decade, as well as discussing the enormous therapeutic potentials of iPSC-derived models, their current limitations and their future direction within the field of FRDA research. Graphical abstract

Klebsiella pneumoniae is among the most relevant pathogens worldwide, causing high morbidity and mortality, which is worsened by the increasing rates of antibiotic resistance. It is a constituent of the host microbiota of different mucosa, that can invade and cause infections in many different sites. The development of new treatments and prophylaxis against this pathogen rely on animal models to identify potential targets and evaluate the efficacy and possible side effects of therapeutic agents or vaccines. However, the validity of data generated is highly dependable on choosing models that can adequately reproduce the hallmarks of human diseases. The present review summarizes the current knowledge on animal models used to investigate K. pneumoniae infections, with a focus on mucosal sites. The advantages and limitations of each model are discussed and compared; the applications, extrapolations to human subjects and future modifications that can improve the current techniques are also presented. While mice are the most widely used species in K. pneumoniae animal studies, they present limitations such as the natural resistance to the pathogen and difficulties in reproducing the main steps of human mucosal infections. Other models, such as Drosophila melanogaster (fruit fly), Caenorhabditis elegans, Galleria mellonella and Danio rerio (zebrafish), contribute to understanding specific aspects of the infection process, such as bacterial lethality and colonization and innate immune system response, however, they but do not present the immunological complexity of mammals. In conclusion, the choice of the animal model of K. pneumoniae infection will depend mainly on the questions being addressed by the study, while a better understanding of the interplay between bacterial virulence factors and animal host responses will provide a deeper comprehension of the disease process and aid in the development of effective preventive/therapeutic strategies.

Glycosylation is a crucial post-translational modification process where sugar molecules (glycans) are covalently linked to proteins, lipids, or other biomolecules. In this highly regulated and complex process, a series of enzymes are involved in adding, modifying, or removing sugar residues. This process plays a pivotal role in various biological functions, influencing the structure, stability, and functionality of the modified molecules. Glycosylation is essential in numerous biological processes, including cell adhesion, signal transduction, immune response, and biomolecular recognition. Dysregulation of glycosylation is associated with various diseases. Glycation, a post-translational modification characterized by the non-enzymatic attachment of sugar molecules to proteins, has also emerged as a crucial factor in various diseases. This review comprehensively explores the multifaceted role of glycation in disease pathogenesis, with a specific focus on its implications in osteoarthritis (OA). Glycosylation and glycation alterations wield a profound influence on OA pathogenesis, intertwining with disease onset and progression. Diverse studies underscore the multifaceted role of aberrant glycosylation in OA, particularly emphasizing its intricate relationship with joint tissue degradation and inflammatory cascades. Distinct glycosylation patterns, including N-glycans and O-glycans, showcase correlations with inflammatory cytokines, matrix metalloproteinases, and cellular senescence pathways, amplifying the degenerative processes within cartilage. Furthermore, the impact of advanced glycation end-products (AGEs) formation in OA pathophysiology unveils critical insights into glycosylation-driven chondrocyte behavior and extracellular matrix remodeling. These findings illuminate potential therapeutic targets and diagnostic markers, signaling a promising avenue for targeted interventions in OA management. In this comprehensive review, we aim to thoroughly examine the significant impact of glycosylation or AGEs in OA and explore its varied effects on other related conditions, such as liver-related diseases, immune system disorders, and cancers, among others. By emphasizing glycosylation's role beyond OA and its implications in other diseases, we uncover insights that extend beyond the immediate focus on OA, potentially revealing novel perspectives for diagnosing and treating OA.

Consumption of boiled crayfish may lead to Haff disease (HD), which is considered to result from an unidentified toxin, although the etiology is still obscure. Profiling of the N-glycome in HD would assist in deciphering the underlying molecular mechanism of the disease, whereas HD-associated glycosylation has never been explored. Herein, we enrolled 90 serum samples with HD patients and healthy controls from the Wuhan Center for Disease Control & Prevention between 2019 and 2020. N-glycome profiles of both serum and serum-derived immunoglobulin G (IgG) in HD were characterized by means of high-throughput-based orthogonal mass spectrometry. It was observed that HD is associated with an increase in the core fucosylation and mono-galactosylation of total serum glycoproteins. The serum level of IgG was found to serve as a good indicator for HD patients. In addition, differential galactosylation and sialylation of IgG were strongly correlated with HD. It was notable that the changes in the galactosylation and sialylation of IgG1 and IgG2 were subclass specific. Interestingly, altered sialylation and galactosylation of IgG2 or IgG3/4 strongly correlated with clinical markers for HD. Our study reveals the association of differential IgG N-glycosylation with HD, providing new insight into the etiology of this rare disease.

Graves' orbitopathy (GO) is an autoimmune disease that involves complex immune systems. The mainstays of clinical management for this disease are surgery, targeted drugs therapy, and no-targeted drugs drug therapy. targeted drugs can improve therapeutic efficacy and enhance the quality of life for GO patients. However, as a second-line treatment for GO, targeted drugs such as tocilizumab and rituximab have very limited therapeutic effects and may be accompanied by side effects. The introduction of Teprotumumab, which targets IGF-IR, has made significant progress in the clinical management of GO. The pathophysiology of GO still remains uncertain as it involves a variety of immune cells and fibroblast interactions as well as immune responses to relevant disease targets of action. Therfore, learning more about immune response feedback pathways and potential targets of action will assist in the treatment of GO. In this discussion, we explore the pathogenesis of GO and relevant work, and highlight four potential targets for GO: Interleukin-23 receptor (IL-23 R), Leptin receptor (LepR), Orbital fibroblast activating factors, and Plasminogen activator inhibitor-1 (PAI-1). A deeper understanding of the pathogenesis of GO and the role of potential target signaling pathways is crucial for effective treatment of this disease.

BackgroundNon-alcoholic steatohepatitis (NASH) has become a leading indication for liver transplantation. However, it often recurs in the graft and can also arise de novo in individuals transplanted for other indications. Post-transplant NASH (PT-NASH) is more aggressive and leads to accelerated fibrosis. The mechanistic basis of PT-NASH has not yet been defined and no specific therapeutic strategies are currently available.MethodsHere, we profiled the transcriptomes of livers with PT-NASH from liver transplant recipients to identify dysregulated genes, pathways, and molecular interaction networks.ResultsTranscriptomic changes in the PI3K-Akt pathway were observed in association with metabolic alterations in PT-NASH. Other significant changes in gene expression were associated with DNA replication, cell cycle, extracellular matrix organization, and wound healing. A systematic comparison with non-transplant NASH (NT-NASH) liver transcriptomes indicated an increased activation of wound healing and angiogenesis pathways in the post-transplant condition.ConclusionBeyond altered lipid metabolism, dysregulation of wound healing and tissue repair mechanisms may contribute to the accelerated development of fibrosis associated with PT-NASH. This presents an attractive therapeutic avenue to explore for PT-NASH to optimize the benefit and survival of the graft.

Background and Objectives: The diagnosis and 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. Materials and Methods: In this work, we analyzed a large public dataset on the IgG antibodies to 3054 EBV peptides to understand whether these immune responses could help diagnose patients and trigger pathological autoimmunity; we used healthy controls (HCs) as a comparator cohort. Subsequently, we aimed at predicting the disease status of the study participants using a super learner algorithm targeting an accuracy of 85% when splitting data into train and test datasets. Results: When we compared the data of all ME/CFS patients or the data of a subgroup of those patients with non-infectious or unknown disease triggers to the data of the HC, we could not find an antibody-based classifier that would meet the desired accuracy in the test dataset. However, we could identify a 26-antibody classifier that could distinguish ME/CFS patients with an infectious disease trigger from the HCs with 100% and 90% accuracies in 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. Conclusions: In conclusion, these 26 antibodies against EBV have an effective potential for disease diagnosis in a subset of patients. However, the peptides associated with these antibodies are less likely to induce autoimmune B-cell responses that could explain the pathogenesis of ME/CFS.

The nucleotide-binding domain leucine-rich repeat-containing receptor (NLR) family is a group of intracellular sensors activated in response to harmful stimuli, such as invading pathogens. Some NLR family members form large multiprotein complexes known as inflammasomes, acting as a platform for activating the caspase-1-induced canonical inflammatory pathway. The canonical inflammasome pathway triggers the secretion of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 by the rapid rupture of the plasma cell membrane, subsequently causing an inflammatory cell death program known as pyroptosis, thereby halting viral replication and removing infected cells. Recent studies have highlighted the importance of inflammasome activation in the response against respiratory viral infections, such as influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While inflammasome activity can contribute to the resolution of respiratory virus infections, dysregulated inflammasome activity can also exacerbate immunopathology, leading to tissue damage and hyperinflammation. In this review, we summarize how different respiratory viruses trigger inflammasome pathways and what harmful effects the inflammasome exerts along with its antiviral immune response during viral infection in the lungs. By understanding the crosstalk between invading pathogens and inflammasome regulation, new therapeutic strategies can be exploited to improve the outcomes of respiratory viral infections.

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’s 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 aggregates formed exclusively by proteins or peptides. However, since the last decade, it has been discovered that other metabolites, like single amino acids, nucleobases, lipids, glucose derivatives, etc., have a 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 that suggests amyloid-like structure formation as a common phenomenon for disease progression and pathogenesis in multiple syndromes. The review is devoted to providing readers with a broad knowledge of the structure, mode of formation, propagation, and transmission of different extracellular amyloids and their implications in the pathogenesis of diseases. We strongly believe a review on this topic is urgently required to create awareness about the understanding of the 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.

The virome constitutes the viral component of the microbiome and it consists of the genomes of all the viruses that inhabit a particular region of the human body, including those that cause acute, persistent or latent infection, and retroviral elements integrated to host chromosomes. The human virome is composed by eukaryotic viruses, bacteriophages and archaeal viruses. The understanding of the virome composition and role on human health has been delayed by the absence of specific tools and techniques to accurately characterize viruses. However, more recently, advanced methods for viral diagnostics, such as deep sequencing and metagenomics, have allowed a better understanding of the diverse viral species present in the human body. Previous studies have shown that the respiratory virome modulates the host immunity and that, since childhood, the human lung is populated by viruses for whom there is no disease association. Whether these viruses are potentially pathogenic and the reason for their persistence remain elusive. Increased respiratory viral load can cause exacerbation of chronic pulmonary diseases, including COPD, cystic fibrosis, and asthma. Moreover, the presence of resident viral populations may contribute to the pathogenesis of community-acquired respiratory virus infections. In this mini review, I will discuss the recent progress on our understanding of the human lung virome and summarize the up-to-date knowledge on the relationships among community-acquired respiratory viruses, the lung virome and the immune response to better understand disease pathophysiology and the factors that may lead to viral persistence.

Despite their small size, the membrane-bound particles named extracellular vesicles (EVs) seem to play an enormous role in the pathogenesis of acute leukemia. From oncogenic hematopoietic stem cells (HSCs) to become leukemic cells to alter the architecture of bone marrow (BM) microenvironment, EVs are critical components of leukemia development. As a carrier of essential molecules, especially a group of small non-coding RNAs known as miRNA, recently, EVs have attracted tremendous attention as a prognostic factor. Given the importance of miRNAs in the early stages of leukemogenesis and also their critical parts in the development of drug-resistant phenotype, it seems that the importance of EVs in the development of leukemia is more than what is expected. To be familiar with the clinical value of leukemia-derived EVs, this review aimed to briefly shed light on the biology of EVs and to discuss the role of EV-derived miRNAs in the development of acute myeloid leukemia and acute lymphoblastic leukemia. By elaborating the advances and challenges concerning the isolation of EVs, we discuss whether EVs could have a prognostic value in the clinical setting for leukemia.

Stony coral tissue loss disease (SCTLD) is affecting corals across the Western Atlantic and displays species-specific and regional differences in prevalence, incidence, degree of mortality, and lesion morphology. We examined two Florida sites with different temporal histories of disease emergence; Fort Lauderdale where SCTLD is endemic and the Lower Florida Keys where SCTLD has recently emerged. Our objectives were to (1) assess the potential impact of SCTLD on overall reef condition by surveying reefs in each region, (2) in a single common species, Montastraea cavernosa, examine differences in SCTLD prevalence, colony mortality, and lesion morphology in each region, and (3) look for differences in contagion by conducting transmission experiments using lesions from each region. Reef surveys found sites in both regions had low coral cover, high algae cover, and similar coral species composition. SCTLD prevalence was higher in the Lower Keys than at Fort Lauderdale and two of the common species, M. cavernosa and S. siderea at Fort Lauderdale were dominated by smaller colonies (

Abstract Single nucleotide variants (SNVs) in intronic regions have yet to be systematically investigated for their disease-causing potential. Using known pathogenic and neutral intronic SNVs (iSNVs) as training data, we develop the RegSNPs-intron algorithm based on a random forest classifier that integrates RNA splicing, protein structure, and evolutionary conservation features. RegSNPs-intron showed excellent performance in evaluating the pathogenic impacts of iSNVs. Using a high-throughput functional reporter assay called ASSET-seq (ASsay for Splicing using ExonTrap and sequencing), we evaluate the impact of RegSNPs-intron predictions on splicing outcome. Together, RegSNPs-intron and ASSET-seq enable effective prioritization of iSNVs for disease pathogenesis.

Introduction and aim. HAVCR1 protein is the cellular receptor for hepatitis A virus (HAV). Genetic polymorphism in this gene may alter the outcome of HAV infection. In a previous study, a 6-amino acid insertion (157insMTTTVP) in HAVCR1 gene was associated with more severe disease. We decided to investigate this association further.Material and methods. We sequenced exon 4 of the HAVCR1 gene in patients with clinical hepatitis A attending our institution, and a group of healthy controls in a disease-endemic setting in India. Frequencies of different haplotypes of a genomic region with two overlapping insertion-deletion polymorphisms (indels; rs141023871 and rs139041445) were compared between patients and controls, as well as between patients with and without a severe form of disease (liver failure).Results. The gene had three haplotypes in the region of interest - a short form, an intermediate-form with a 5-amino acid 157insMTTVP insertion and a long-form with a 6-amino acid 157insMTTTVP insertion. The allele frequency (29/150 [19%] vs. 43/146 [29%]; p = ns) and haplotype frequency (29/75 [39%] vs. 39/73 [53%]; p = ns) of the 157insMTTTVP variant were similar in hepatitis A patients and healthy controls (30%). Further, the allele frequency (12/58 [21%] vs. 17/92 [18%]; p = ns) and haplotype frequency (12/29 [41%] vs.17/46 [37%]; p = ns) of the longest variant were also similar in patients with severe and mild disease.Discussion. In the study population, the 157insMTTTVP variant of HAVCR1 gene was not associated with more severe outcome of HAV infection. Further studies in other populations around the world are needed to assess the relation of this genetic variation with disease outcome.

The immunobullous condition Pemphigus Vulgaris (PV) is caused by autoantibodies targeting the adhesion proteins of desmosomes, leading to blistering in the skin and mucosal membrane. There is still no cure to the disease apart from the use of corticosteroids and immunosuppressive agents. Despite numerous investigations, the pathological mechanisms of PV are still incompletely understood, though the etiology is thought to be multifactorial. Thus, further understanding of the molecular basis underlying this disease process is vital to develop targeted therapies. Ample studies have highlighted the role of Desmoglein-3 (DSG3) in the initiation of disease as DSG3 serves as a primary target of PV autoantibodies. DSG3 is a pivotal player in mediating outside-in signaling involved in cell junction remodeling, cell proliferation, differentiation, migration or apoptosis, thus validating its biological function in tissue integrity and homeostasis beyond desmosome adhesion. Recent studies have uncovered new activities of DSG3 in regulating p53 and the yes-associated protein (YAP), with the evidence of dysregulation of these pathways demonstrated in PV. The purpose of this review is to summarize the earlier and recent advances highlighting our recent findings related to PV pathogenesis that may pave the way for future research to develop novel specific therapies in curing this disease.

Acute corneal hydrops is a condition characterized by stromal edema due to leakage of aqueous through a tear in descemet membrane. The patient presents with sudden onset decrease in vision, photophobia, and pain. Corneal thinning and ectasias combined with trivial trauma to the eye mostly by eye rubbing is considered as the underlying cause. With conservative approach self-resolution takes around 2 to 3 months. Surgical intervention is required in cases of non-resolution of corneal edema to avoid complications and for early visual rehabilitation. Intracameral injection of air or gas such as perflouropropane is the most common surgical procedure done. Recent investigative modality such as anterior segment optical coherence tomography is an extremely useful tool for diagnosis, surgical planning, and postoperative follow up. Resolution of hydrops may improve the contact lens tolerance and visual acuity but most cases require keratoplasty for visual rehabilitation.

Before the discovery of corneal cross-linking (CXL), patients with keratoconus would have had to undergo corneal transplantation, or wear rigid gas permeable lenses (RGPs) that would temporarily flatten the cone, thereby improving the vision. The RGP contact lens (CL) would not however alter the corneal stability and if the keratoconus was progressive, the continued steepening of the cone would occur under the RGP CL. To date, the Siena Eye has been the largest study to investigate long term effects of standard CXL. Three hundred and sixty-three eyes were treated and monitored over 4 years, producing reliable long-term results proving long-term stability of the cornea by halting the progression of keratoconus, and proving the safety of the procedure. Traditionally, CXL requires epithelial removal prior to corneal soakage of a dextran-based 0.1% riboflavin solution, followed by exposure of ultraviolet-A (UV-A) light for 30 min with an intensity of 3 mW/cm2. A series of in vitro investigations on human and porcine corneas examined the best treatment parameters for standard CXL, such as riboflavin concentration, intensity, wavelength of UV-A light, and duration of treatment. Photochemically, CXL is achieved by the generation of chemical bonds within the corneal stroma through localized photopolymerization, strengthening the cornea whilst minimizing exposure to the surrounding structures of the eye. In vitro studies have shown that CXL has an effect on the biomechanical properties of the cornea, with an increased corneal rigidity of approximately 70%. This is a result of the creation of new chemical bonds within the stroma.

Keratoconus (KC; Mendelian Inheritance in Man (OMIM) 14830) is a bilateral, progressive corneal defect affecting all ethnic groups around the world. It is the leading cause of corneal transplantation. The age of onset is at puberty, and the disorder is progressive until the 3 rd -4 th decade of life when it usually arrests. It is one of the major ocular problems with significant social and economic impacts as the disease affects young generation. Although genetic and environmental factors are associated with KC, but the precise etiology is still elusive. Results from complex segregation analysis suggests that genetic abnormalities may play an essential role in the susceptibility to KC. Due to genetic heterogeneity, a recent study revealed 17 different genomic loci identified in KC families by linkage mapping in various populations. The focus of this review is to provide a concise update on the current knowledge of the genetic basis of KC and genomic approaches to understand the disease pathogenesis.

Purpose : To assess the efficacy and advantages of femtosecond laser enabled keratoplasty (FLEK) over conventional penetrating keratoplasty (PKP) in advanced keratoconus. Materials and Methods: Detailed review of literature of published randomized controlled trials of operative techniques in PKP and FLEK. Results: Fifteen studies were identified, analyzed, and compared with our outcome. FLEK was found to have better outcome in view of better and earlier stabilization uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), and better refractive outcomes with low astigmatism as compared with conventional PKP. Wound healing also was noticed to be earlier, enabling early suture removal in FLEK. Conclusions: Studies relating to FLEK have shown better results than conventional PKP, however further studies are needed to assess the safety and intraoperative complications of the procedure.

Contact lenses are required for the visual improvement in patients with keratoconus. Various contact lens options, such as rigid gas permeable (RGP) lenses, soft and soft toric lenses, piggy back contact lenses (PBCL), hybrid lenses and scleral lenses are availble. This article discusses about selection of a lens depending on the type of keratoconus and the fitting philosophies of various contact lenses including the starting trial lens. A Medline search was carried out for articles in the English language with the keywords keratoconus and various contact lenses such as Rose k lens, RGP lens, hybrid lens, scleral lens and PBCL.

Keratoconus is a progressive ectatic disorder of the cornea which often presents with fluctuating refraction and high irregular astigmatism. Correcting the vision of these patients is often a challenge because glasses are unable to correct the irregular astigmatism and regular contact lenses may not fit them very well. Topography-guided custom ablation treatment (T-CAT) is a procedure of limited ablation of the cornea using excimer laser with the aim of regularizing the cornea, improving the quality of vision and possibly contact lens fit. The aim of the procedure is not to give a complete refractive correction. It has been tried with a lot of success by various groups of refractive surgeons around the world but a meticulous and methodical planning of the procedure is essential to ensure optimum results. In this paper, we attempt to elucidate the planning for a T-CAT procedure for various types of cones and asphericities.

Diagnosis of keratoconus has greatly improved from simple clinical diagnosis with the advent of better diagnostic devices like corneal topographers based on placido disc, elevation based topographers and lately optical coherence tomography (OCT). These instruments are quite sensitive to pick up early keratoconus, which could help refractive surgeons to avoid serious complications like ectasia following keratorefractive surgeries. Each of these instruments has their advantages and disadvantages; in spite of that each one of them has its own place in the clinical practice. Currently, placido disc based topographers are the most commonly used topographers all over the world. There are many different companies making such devices, which follow the different techniques and color for the display. Due to these differences they are not directly comparable to each other. Various quantitative indices based on these topographers have been suggested and validated by different authors to aid in the diagnosis and quantification of keratoconus. OCT with its higher resolution and deeper penetration has created its place in the diagnostic armamentarium for keratoconus.

Advanced cases of keratoconus often require surgical intervention to restore corneal anatomy and improve eyesight. Penetrating keratoplasty (PK) although commonly performed has potential risk of immunological rejection and is now no longer automatically the first choice of surgery. DALK procedures have evolved, which allows surgical replacement of recipient′s corneal stroma, leaving behind healthy descemet membrane (DM) and endothelium. This reduces the risk of allograft endothelial rejection and late graft failure. In recent times, DALK techniques have led to significant improvements in visual outcome and current results are comparable to PK. Big bubble technique of DALK has become the most popular among the various surgical techniques described. Manual near DM DALK also gives good outcome although the visual recovery is often delayed. Future integration of femtosecond laser technology along with diagnostic imaging technology is likely to further improve outcomes of DALK in keratoconus.

The success of collagen cross-linking as a clinical modality to modify the clinical course in keratoconus seems to have fueled the search for alternative applications for this treatment. Current clinical data on its efficacy is limited and laboratory data seems to indicate that it performs poorly against resistant strains of bacteria and against slow growing organisms. However, the biological plausibility of crosslinking and the lack of effective strategies in managing infections with these organisms continue to focus attention on this potential treatment. Well-conducted experimental and clinical studies with controls are required to answer the questions of its efficacy in future.

Keratoconus is a progressive non-inflammatory thinning of the cornea that induces myopia and irregular astigmatism and decreases the quality of vision due to monocular diplopia, halos, or ghost images. Keratoconus patients unfit for corneal procedures and intolerant to refractive correction by spectacles or contact lenses have been implanted toric posterior chamber phakic intraocular lenses (PC pIOLs) alone or combined with other surgical procedures to correct the refractive errors associated with keratoconus as an off label procedure with special informed consent from the patients. Several reports attest to the safety and efficacy of the procedure, though the associated corneal higher order aberrations would have an impact on the final visual quality.

Keratoconus is a progressive corneal ectasia, which can be managed both by conservative measures like glasses or contact lenses in non-progressive cases or surgical procedures like collagen crosslinking (CXL) with or without adjuvant measures like intrastromal corneal rings segments (ICRS) or topography guided ablation. Various kinds of ICRS are available to the surgeon, but it is most essential to be able to plan the implantation of the ring to optimize outcomes. Aims: The aim of this study is to evaluate the visual outcome and progression in patients of keratoconus implanted with ICRS. Materials and Methods: Two different types of ICRS-Intacs (Addition Technology) and Kerarings (Mediphacos Inc.) were implanted in 2 different cohorts of patients and were followed-up to evaluate the outcome of the procedure. All patients underwent a complete ocular examination including best spectacle corrected visual acuity, slit lamp examination fundus examination, corneal topography and pachymetry. The ICRS implantation is done with CXL to stop the progression of the disease. Improvement in uncorrected visual acuity (UCVA), best spectacle corrected visual acuity and topographic changes were analyzed. Results: A significant improvement in keratometry and vision was seen in both groups. Conclusion: ICRS have been found to reduce corneal irregularity and flatten keratometry with improvement in UCVA and best corrected visual acuity.

Scheimpflug cross-sectioning anterior segment imaging offers significant advantages over traditional placido based curvature analysis and ultrasound pachymetry. The accurate measurement of both the anterior and posterior corneal surfaces and the anterior and posterior lens allows for the creation of a three-dimensional reconstruction of the anterior segment. Changes on both the posterior cornea and/or corneal thickness map are earlier indicators of ectatic change than would otherwise be identifiable with only anterior curvature and ultrasonic pachymetry. Scheimpflug imaging also covers significantly more of the cornea than was possible with placido based devices. This added coverage is critical in the proper diagnosis of peripheral diseases such as pellucid marginal degeneration (PMD).

Pediatric keratoconus demonstrates several distinctive management issues in comparison with adult keratoconus with respect to under-diagnosis, poor compliance and modifications in treatment patterns. The major concerns comprise of the accelerated progression of the disease in the pediatric age group and management of co-morbidities such as vernal keratoconjuntivitis. Visual impairment in pediatric patients may affect social and educational development and overall negatively impact their quality of life. The treatment algorithm between adults and pediatric keratoconus has been similar; comprising mainly of visual rehabilitation with spectacles, contacts lenses (soft or rigid) and keratoplasty (lamellar or penetrating) depending on the stage of the disease. There is a paradigm shift in the management of keratoconus, a new treatment modality, corneal collagen crosslinking (CXL), has been utilized in adult keratoconic patients halting the progression of the disease. CXL has been utilized for over a 10 year period and based on the evidence of efficacy and safety in the adult population; this treatment has been recently utilized in management of pediatric keratoconus. This article will present an update about current management of pediatric keratoconus with special focus on CXL in this age group.

Collagen cross-linking (CXL) has become the standard of care for progressive keratoconus, after numerous clinical studies have established its efficacy and safety in suitably selected eyes. The standard protocol is applicable in eyes which have a minimum corneal thickness of 400 μm after epithelial debridement. This prerequisite was stipulated to protect the corneal endothelium and intraocular tissues from the deleterious effect of ultraviolet-A (UVA) radiation. However, patients with keratoconus often present with corneal thickness of less than 400 μm and could have otherwise benefited from this procedure. A few modifications of the standard procedure have been suggested to benefit these patients without a compromise in safety. Transepithelial cross-linking, pachymetry-guided epithelial debridement before cross-linking, and the use of hypoosmolar riboflavin are some of the techniques that have been attempted. Although clinical data is limited at the present time, these techniques are worth considering in patients with thin corneas. Further studies are needed to scientifically establish their efficacy and safety.

Keratoconus is the most common corneal ectatic disorder, the cause of which is largely unknown. Many factors have been implicated, and the ocular allergy is being one of them. The commonly proposed pathogenesis includes the release of inflammatory mediators due to eye rubbing which may alter the corneal collagen and lead to corneal ectasias. The onset of keratoconus is often early in cases associated with allergy and routine corneal topography may detect subtle forms of keratoconus. These cases may require early keratoplasty and are at an increased risk of having acute corneal hydrops. Surgical outcomes are similar to primary keratoconus cases. However, post-operative epithelial breakdown may be a problem in these cases. Control of allergy and eye rubbing is the best measure to prevent corneal ectasias in cases of ocular allergy.

Corneal Cross-Linking (CXL) is an established surgical procedure for the treatment of corneal disorders such as corneal ectasia and keratoconus. This method of treatment stabilises the corneal structure and increases rigidity, reducing the requirement for corneal transplantation. Since its development, many scientific studies have been conducted to investigate ways of improving the procedure. Biomechanical stability of the cornea after exposure to UV-A light, and the effect of shortening procedure time has been some of the many topics explored

In this brief review we will discuss the reasoning and evolution of our current use of combined very high-fluence collagen crosslinking and laser in situ keratomileusis. Several presentations and pertinent publications are reviewed, along with the key steps of the enhanced LASIK procedure. Long term outcome data support the safety and efficacy of LASIK Xtra in stabilizing myopic but also hyperopic LASIK results.In conclusion, we have compelling evidence that LASIK Xtra is a safe and effective adjunct.

Keratoconus is a progressive corneal thinning disease associated with significant tissue remodeling activities and activation of a variety of signaling networks. However, it is not understood how differential gene and protein expression direct function in keratoconus corneas to drive the underlying pathology, ectasia. Research in the field has focused on discovering differentially expressed genes and proteins and quantifying their levels and activities in keratoconus patient samples. In this study, both microarray analysis of total ribonucleic acid (RNA) and whole proteome analyses are carried out using corneal epithelium and tears from keratoconus patients and compared to healthy controls. A number of structural proteins, signaling molecules, cytokines, proteases, and enzymes have been found to be deregulated in keratoconus corneas. Together, the data provide clues to the complex process of corneal degradation which suggest novel ways to clinically diagnose and manage the disease. This review will focus on discussing these recent advances in the knowledge of keratoconus biology from a gene expression and function point-of-view.

Dengue Virus (DV) infects between 50 and 100 million people globally, with public health costs totaling in the billions. It is the causative agent of dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), vector-borne diseases that initially predominated in the tropics. Due to the expansion of its mosquito vector, Aedes spp., DV is increasingly becoming a global problem. Infected individuals may present with a wide spectrum of symptoms, spanning from a mild febrile to a life-threatening illness, which may include thrombocytopenia, leucopenia, hepatomegaly, hemorrhaging, plasma leakage and shock. Deciphering the underlining mechanisms responsible for these symptoms has been hindered by the limited availability of animal models that can induce classic human pathology. Currently, several permissive nonhuman primate (NHP) species and mouse breeds susceptible to adapted DV strains are available. Though virus replication occurs in these animals, none of them recapitulate the cardinal features of human symptomatology, with disease only occasionally observed in NHPs. Recently our group established a DV serotype 2 intravenous infection model with the Indian rhesus macaque, which reliably produced cutaneous hemorrhages after primary virus exposure. Further manipulation of experimental parameters (virus strain, immune cell expansion and depletion, etc.) can refine this model and expand its relevance to human DF. Future goals include applying this model to elucidate the role of pre-existing immunity upon secondary infection and immunopathogenesis. Of note, virus titers in primates in vivo and in vitro, even with our model, have been consistently 1000-fold lower than those found in humans. We submit that an improved model, capable of demonstrating severe pathogenesis may only be achieved with higher virus loads. Nonetheless, our DV coagulopathy disease model is valuable for the study of select pathomechanisms and testing DV drug and vaccine candidates.

Innate sensors play a critical role in the early innate immune responses to invading pathogens through sensing of diverse biochemical signatures also known as pathogen associated molecular patterns (PAMPs). These biochemical signatures primarily consist of a major family of biomolecules such as proteins, lipids, nitrogen bases, and sugar and its complexes, which are distinct from host molecules and exclusively expressed in pathogens and essential to their survival. The family of sensors known as pattern recognition receptors (PRRs) are germ-line encoded, evolutionarily conserved molecules and consist of Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), C-type lectin-like receptors (CLRs), and DNA sensors. Sensing of PAMP by PRR initiates the cascade of signaling leading to the activation of transcription factors, such as NF-κB and interferon regulatory factors (IRFs), resulting in a variety of cellular responses, including the production of interferons (IFNs) and pro-inflammatory cytokines. In this review, we discuss sensing of different types of glycosylated PAMPs such as -glucan (a polymeric sugar) or lipopolysaccharides, nucleic acid, and so on (sugar complex PAMPs) by different families of sensors, its role in pathogenesis, and its application in development of potential vaccine and vaccine adjuvants.

Corneal collagen cross-linking with riboflavin and UVA light (CXL) is the only method designed to arrest the progression of keratoconus. Visual improvement generally starts 3 months after treatment. Reduction is coma seen on aberrometry in early postoperative phase is also responsible for the improvement in visual acuity. In the light of currently available data we can thus say that CXL is a safe procedure that is successful in arresting keratoconus.

Keratoconus is a common ectatic disorder occurring in more than 1 in 1,000 individuals. The condition typically starts in adolescence and early adulthood. It is a disease with an uncertain cause and its progression is unpredictable, but in extreme cases, vision deteriorates and can require corneal transplant surgery. Corneal collagen cross-linking (CCL) with riboflavin (C3R) is a recent treatment option that can enhance the rigidity of the cornea and prevent disease progression. Since its inception, the procedure has evolved with newer instrumentation, surgical techniques, and is also now performed for expanded indications other than keratoconus. With increasing experience, newer guidelines regarding optimization of patient selection, the spectrum of complications and their management, and combination procedures are being described. This article in conjunction with the others in this issue, will try and explore the uses of collagen cross-linking (CXL) in its current form.

Corneal cross-linking with riboflavin is a technique to stabilize or reduce corneal ectasia, in diseases such as keratoconus and post-laser-assisted in situ keratomileusis (LASIK) ectasia. There is an interest by patient as well as clinicians to reduce the overall treatment time. Especially, the introduction of corneal cross-linking in combination with corneal laser surgery demands a shorter treatment time to assure a sufficient patient flow. The principles and techniques of accelerated corneal cross-linking is discussed.

Keratoconus (KC) is progressive disease of corneal thinning, steepening and collagen degradation. Biomechanics of the cornea is maintained by the intricate collagen network, which is responsible for its unique shape and function. With the disruption of this collagen network, the cornea loses its shape and function, resulting in progressive visual degradation. While KC is essentially a stromal disease, there is evidence that the epithelium undergoes significant thinning similar to the stroma. Several topographical approaches have been developed to detect KC early. However, it is now hypothesized that biomechanical destabilization of the cornea may precede topographic evidence of KC. Biomechanics of KC has been investigated only to a limited extent due to lack of in vivo measurement techniques and/or devices. In this review, we focus on recent work performed to characterize the biomechanical characteristics of KC.