Books on the topic 'Genomic HLA'

The regulation of the HPA axis has been categorized as the classical mechanism of slow-acting genomic regulation of gene products, but this has given way to both slow and fast regulation of the HPA axis. We do not know how cortisol restrains the production of CRF in the paraventricular nucleus, thereby directly decreasing ACTH and, subsequently, cortisol; we know the classical negative-feedback regulatory system, which provides a mechanism, but how it works, well, that is another thing. Glucocorticoids restrain the HPA axis, but not other regions of the brain, such as the central nucleus of the amygdala and bed nucleus of the amygdala. But we now know that both chemically and electrically, these regions are not the same (equal).

Family and twin studies have long suggested a large genetic component in ankylosing spondylitis (AS). The genetic association with HLA-B27 remains one of the strongest single gene variant associations reported in any complex polygenic disease. The exact mechanism by which HLA-B27 contributes to AS remains unknown, with three main theories proposed: the arthritogenic peptide, endoplasmic reticulum stress with unfolded protein response, and homodimerization theories. Genome-wide association studies have identified a number of other important susceptibility genes for AS, several of which overlap with other spondyloarthritis conditions. Of these, ERAP1 and IL-23R, are covered in more detail, highlighting their functional importance.

In addition to sharing clinical, histopathological, and immunological features, spondyloarthritis (SpA) encompasses a group of diseases that are genetically linked through shared associations with HLA-B27, as well as other genes of the IL-23R and aminopeptidase groups. Great progress has been made since the development of the genome-wide association study approach, with better dissection of the HLA associations of this group of diseases, as well as the discovery of multiple genetic loci found outside of the major histocompatibility complex, in ankylosing spondylitis (AS) in particular. These genetic data shed light on the related pathogenesis of AS and psoriatic arthritis (PsA), inflammatory bowel disease (IBD)-related arthritis, and reactive arthritis (ReA). Genetic associations also strengthen the suggestive data that Behçet’s disease (BD) and Familial Mediterranean Fever (FMF) are related to the more classical forms of SpA.

The history of ankylosing spondylitis (AS) dates back to the discovery of skeletons with characteristic spinal changes. The disease was further defined by correlating pathological and clinical features, and the development of clinical radiology. Subsequent epidemiology and familial studies highlighted the association with other related conditions as part of the spondyloarthritides. The discovery of HLA-B27 confirmed this association. Over the past two decades, genome-wide association studies, and advances in imaging and immunology have yielded dramatic insights into the disease and the development of highly effective therapies.

Juvenile rheumatic diseases are heterogeneous, complex genetic diseases; to date only juvenile idiopathic arthritis (JIA) has been extensively studied in terms of identifying genetic risk factors. The MHC region is a well-established risk factor but in the last few years candidate gene and large-scale genome-wide association studies have been utilized in the search for non-HLA risk factors. There are now 17 JIA susceptibility loci which reach the genome-wide significance threshold for association and a further 7 regions with evidence for association in more than one study. In addition, some subtype-specific associations are emerging. These risk loci now need to be investigated further using fine-mapping strategies and then appropriate functional studies to show how the variant alters the gene function. This knowledge will not only lead to a better understanding of disease pathogenesis for juvenile rheumatic diseases but may also aid in the classification of these heterogeneous diseases. It may identify new pathways for potential therapeutic targets and help in the prediction of disease outcome and response to treatment.

Juvenile rheumatic diseases are heterogeneous, complex genetic diseases; to date only juvenile idiopathic arthritis (JIA) has been extensively studied in terms of identifying genetic risk factors. The MHC region is a well-established risk factor but in the last few years candidate gene and large-scale genome-wide association studies have been utilized in the search for non-HLA risk factors. There are now 17 JIA susceptibility loci which reach the genome-wide significance threshold for association and a further 7 regions with evidence for association in more than one study. In addition, some subtype-specific associations are emerging. These risk loci now need to be investigated further using fine-mapping strategies and then appropriate functional studies to show how the variant alters the gene function. This knowledge will not only lead to a better understanding of disease pathogenesis for juvenile rheumatic diseases but may also aid in the classification of these heterogeneous diseases. It may identify new pathways for potential therapeutic targets and help in the prediction of disease outcome and response to treatment.

In this chapter, the current understanding of the mechanisms of endocrine disruption on the brain and nervous system are presented. Because the overwhelming majority of mechanistic studies on EDCs have focused on the actions mediated by nuclear hormone receptors, this mechanisms is described in detail. The chapter also discusses the classic transcriptional mechanisms of steroid action and the impact of EDCs on rapid signaling (non-genomic) mechanisms. It presents an overview of the enzymes and pathways involved in the biosynthesis of steroid hormones, which are critical to proper functioning of the HPA and HPG axis, and the neuroactive steroids synthesized and active in the mammalian brain. The potential for EDCs to alter metabolic enzymes, with a focus on possible targets in the metabolic blood-brain barrier, is presented as a potential, though largely unexplored, mode of EDC action in the brain.

This chapter examines the search for a pattern of repetitive adaptive substitutions over evolutionary time. In contrast with the previous chapter, only a modest number of tests toward this aim have been proposed. The HKA and McDonald-Kreitman tests contrast the polymorphism to divergence ratio between different genomic classes (such as different genes or silent versus replacement sites within the same gene). These approaches can detect an excess of substitutions, which allows one to estimate the fraction of adaptive sites. This chapter reviews the empirical data on estimates of this fraction and discusses some of the sources of bias it its estimation. Over an even longer time scale, one can contrast the rate of change of sites in a sequence over a phylogeny. These tests require a rather special type of selection, wherein the same specific site (usually a codon) experiences multiple adaptive substitutions over a phylogeny, such as might occur in arms-race genes.

Hållbar utveckling, jämställdhet och ett barnrätts- och ungdomsperspektiv är övergripande områden som är viktiga för hela Nordiska ministerrådets arbete. Ansvaret att ta hänsyn till dessa i Nordiska ministerrådets arbete gäller alla som verkar inom eller på uppdrag av Nordiska ministerrådet oavsett politikområde. Genom att stärka detta arbete säkerställer vi att Nordiska ministerrådets arbete är hållbart, jämställt, inkluderande, representativt och tillgängligt.

A range of epidemiological studies have clearly established that susceptibility to rheumatoid arthritis (RA) is determined by both genetic and environmental factors. Studies over the last five decades have used a variety of approaches to identify the genetic variants associated with disease. HLA DRB1 was the first RA susceptibility locus to be discovered and has the largest effect size. We describe current understanding of the complexities of HLA association for RA. Linkage and small-scale association studies prior to 2007 provided convincing evidence for only one more RA susceptibility locus, PTPN22. Major breakthroughs in high-throughput genotyping and systematic discovery and mapping of hundreds of thousands of single nucleotide polymorphisms (SNPs) led to large-scale genome-wide association studies used for the first time for RA in 2007. This approach has had a dramatic impact on our knowledge of the susceptibility loci for RA, such that over 60 risk variants have now been robustly identified. We present an overview of these studies and the loci that have been identified. We consider how this knowledge is contributing to a greater understanding of the aetiology and pathology of the disease and in turn how this can influence management of patients presenting with an inflammatory arthritis. We consider some of the unanswered questions and the approaches that will need to be taken to address them.

A range of epidemiological studies have clearly established that susceptibility to rheumatoid arthritis (RA) is determined by both genetic and environmental factors. Studies over the last five decades have used a variety of approaches to identify the genetic variants associated with disease. HLA DRB1 was the first RA susceptibility locus to be discovered and has the largest effect size. We describe current understanding of the complexities of HLA association for RA. Linkage and small-scale association studies prior to 2007 provided convincing evidence for only one more RA susceptibility locus, PTPN22. Major breakthroughs in high-throughput genotyping, and systematic discovery and mapping of hundreds of thousands of single nucleotide polymorphisms (SNPs) led to large-scale genome-wide association studies used for the first time for RA in 2007. Widespread utilization of this approach has had a dramatic impact on our knowledge of the susceptibility loci for RA, such that over 100 risk variants have now been robustly identified. We present an overview of these studies and the loci that have been identified. We consider how this knowledge is contributing to a greater understanding of the aetiology and pathology of the disease, and in turn how this can influence management of patients presenting with an inflammatory arthritis. We consider some of the unanswered questions and the approaches that will need to be taken to address them.

Juvenile rheumatic diseases are heterogeneous, complex genetic diseases; to date only juvenile idiopathic arthritis (JIA) has been extensively studied in terms of identifying genetic risk factors. The MHC region is a well-established risk factor but in the last few years candidate gene and genome-wide association studies have been utilized in the search for non-HLA risk factors. There are now an additional 12 JIA susceptibility loci with evidence for association in more than one study. In addition, some subtype-specific associations are emerging. These risk loci now need to be investigated further using fine-mapping strategies and then appropriate functional studies to show how the variant alters the gene function. This knowledge will not only lead to a better understanding of disease pathogenesis for juvenile rheumatic diseases but may also aid in the classification of these heterogeneous diseases. It may identify new pathways for potential therapeutic targets and help in the prediction of disease outcome and response to treatment.

El siglo XXI se ha caracterizado desde sus inicios por una problemática de salud que ha afectado al mundo, que va desde un incremento de la resistencia microbiana, aumento de las enfermedades oncológicas hasta la aparición de nuevas enfermedades infecciosas emergentes y reemergentes, como ha sido la aparición de la COVID-19 a finales del pasado año. Los coronavirus son una extensa familia de virus que pueden causar enfermedades tanto en animales como en humanos. En los humanos, se sabe que varios coronavirus causan infecciones respiratorias que pueden ir desde el resfriado común hasta enfermedades más graves como el síndrome respiratorio de Oriente Medio (MERS) y el síndrome respiratorio agudo severo (SRAS). La COVID-19 (coronavirus disease 2019) también conocida como enfermedad por nuevo coronavirus es causada por el coronavirus del síndrome respiratorio agudo severo (SARS-CoV-2), su forma es redonda u ovalada y a menudo polimórfica, tiene un diámetro de 60 a 140 nm, la proteína espiga que se encuentra en la superficie del virus y forma una estructura en forma de barra, es la estructura principal utilizada para la tipificación, la proteína de la nucleocápside encapsula el genoma viral y puede usarse como antígeno de diagnóstico. Produce síntomas similares a los de la gripe, entre los que se incluyen fiebre, tos, disnea, mialgia y fatiga. También se ha observado la pérdida súbita del olfato y el gusto (sin que la mucosidad fuese la causa). En casos graves se caracteriza por producir neumonía, síndrome de dificultad respiratoria aguda, sepsis y choque séptico que conduce a alrededor del 3 % de los infectados a la muerte, aunque la tasa de mortalidad se encuentra en 4,48 % y sigue ascendiendo.

Vibrio parahaemolyticus es la principal causa de gastroenteritis transmitida por mariscos en todo el mundo. La virulencia de V. parahaemolyticus se ha atribuido hasta ahora principalmente a la hemolisina directa termoestable (TDH) y la hemolisina relacionada con TDH (TRH). Recientemente el Sistema de Secreción de tipo III del cromosoma II (T3SS2), el cual codifica para varios efectores, ha sido relacionado con citotoxicidad y enterotoxicidad. Después de la aparición y posterior caída de la cepa pandémica, se han notificado casos de diarrea producidos por cepas clínicas que carecen de los genes tdh, trh y T3SS2 en muchos países, incluido Chile. Estas cepas, llamadas “no toxigénicas”, constituyen el 9-10% de los casos de diarrea a nivel mundial y aunque se han hecho avances en la descripción de los factores de virulencia de V. parahaemolyticus, la capacidad de las cepas no toxigénicas para causar enfermedad no ha sido completamente entendida. El hecho de que los genes tdh y trh se utilizan para estimar la carga de cepas patógenas en los mariscos durante el análisis de riesgo llama la atención sobre cuán fiables son estos análisis para detectar la gran variedad de cepas potencialmente patógenas presentes en las aguas y productos marinos. Por otra parte se conoce que en Vibrio, la evolución de la virulencia, parece estar estrechamente asociada a su capacidad para generar diversidad genética, en parte, a través de la modificación de la expresión génica, aunque mayoritariamente a través de transferencia genética horizontal (HGT). Con base en lo descrito anteriormente, esta propuesta hipotetiza que las cepas no toxigénicas de Vibrio parahaemolyticus han adquirido nuevos factores de virulencia mediante transferencia genética horizontal. Es por ello que el objetivo de esta tesis es: Identificar y caracterizar nuevos factores de virulencia en cepas chilenas no toxigénicas de Vibrio parahaemolyticus adquiridos mediante transferencia génica horizontal. Esta tesis está organizada en tres capítulos, el capítulo 1 comprende el marco teórico, el planteamiento del problema, la hipótesis y los objetivos. El capítulo 2, correspondiente al desarrollo del objetivo 1, en el cual se caracteriza el genoma de seis cepas no toxigénicas de V. parahaemolyticus aisladas del Sur de Chile. Uno de los principales hallazgos de este estudio fue la variabilidad genética de estas cepas al analizar su genoma accesorio. Este análisis mostró además la presencia de nuevas islas genómicas y elementos tipo profagos que codifican toxinas como zonula occludens (Zot) y repeats-in-toxin (RTX), ambas descritas en otros patógenos como V. cholerae donde se consideran factores de virulencia, aunque últimamente se ha descrito que la pérdida de RTX no afecta la virulencia de esta bacteria. En el capítulo 3 y final de esta tesis, se aborda el objetivo 2 que corresponde a la caracterización de posibles nuevos factores de virulencia, en este caso, la toxina Zonula Occludens (Zot). Aunque se sabe que Zot aumenta la permeabilidad epitelial intestinal por interacción con el receptor celular de zonulina PAR2 y esta unión desencadena una cascada de eventos intracelulares que conducen al desensamblaje de las uniones estrechas intercelulares, lo que se ha asociado con la producción de la diarrea en V. cholerae, el potencial patógeno de Zot de V. parahaemolyticus no se ha investigado aún. La cepa clínica PMC53.7, tdh/trh/T3SS2/negativa, resultó ser altamente citotóxica en cultivo celular de Caco-2 y contiene en su genoma accesorio un gen homólogo de zot. Con este antecedente, se caracterizó la toxina Zot en la cepa clínica PMC53.7 de V. parahaemolyticus y sus efectos sobre la barrera epitelial intestinal. El gen zot de PMC53.7 se clonó y se expresó en Escherichia coli BL21(DE3) y los efectos sobre la barrera epitelial intestinal se examinaron usando el modelo celular Caco-2. Se evaluó el cambio en la distribución de las proteínas de transmembrana asociadas a uniones estrechas (ZO-1 y ocludina), y en la distribución de actina en monocapas de Caco-2. Tras el tratamiento con Zot, se observó una modificación de la morfología celular. El cambio en las distribuciones de ocludina y F-actina se observó como una fragmentación de los límites brillantes de las células, con áreas de baja y alta intensidad, lo que indica una pérdida y redistribución de las proteínas asociadas a uniones estrechas. Los resultados de este trabajo sugieren que V. parahaemolyticus Zot puede contribuir a la virulencia de cepas no toxigénicas. En resumen, estos estudios han arrojado información sobre la diversidad de cepas de V. parahaemolyticus del sur del Pacífico, en especial aquellas que no poseen los principales factores de virulencia descritos para este microorganismo. Además, se caracteriza por primera vez una toxina Zot de V. parahaemolyticus en una cepa aislada de un paciente. Finalmente, los ensayos preliminares realizados en cultivo celular demostraron un posible potencial patógeno de esta toxina en la barrera epitelial intestinal.

Var i Malmö träffades män för att ha sex med varandra på 1910-talet? Vad gjorde bögar och lesbiska för att skapa uppmärksamhet på Folkfesten i Pildammsparken under 1970-talet? Hur upplevdes ankomsten till Malmö för Sveriges första homosexuella anhöriginvandrare? Vilka var de hetaste queerpunkbanden på malmöscenen under det härjiga 2010-talet? Dessa och många andra frågor får sina svar i Queera historier från Malmö. Här samlas 20 berättelser om människor, organisationer och händelser som på olika sätt expanderar, utmanar och skriver om stadens historia. Det är en bok om det förflutna, sprungen ur samtiden som blandar akademiska skribenter med aktivister i dagens HBTQI-organisationer. Med avstamp i samtiden och den nära dåtiden söker sig texterna bakåt genom decennierna och århundradena, då HBTQI-liv var förbjudet, sjukdomsklassat och stigmatiserat. Fram tills nu har det saknats en historieskrivning om HBTQI-liv som geografiskt berör Malmö och södra Sverige, varför boken gör ett banbrytande arbete av synliggörande. Det här är en bok som väljer det spretiga och motstridiga framför en enhetlig och konfliktdöljande historieskrivning, i fast förvissning att sådana berättelser förmår fånga mer och kanske också ge en mer sann bild av det förgångna. Det blir en bok som fångar Malmös vibrerande aktiva och mångfacetterade HBTQI-rörelser i all dess mångfald och brokighet.

Influenza is a highly infectious, acute illness which has affected humans and animals since ancient times. Influenza viruses form the Orthomyxoviridae family and are grouped into types A, B, and C on the basis of the antigenic nature of the internal nucleocapsid or the matrix protein. Infl uenza A viruses infect a large variety of animal species, including humans, pigs, horses, sea mammals, and birds, occasionally producing devastating pandemics in humans, such as in 1918 when it has been estimated that between 50–100 million deaths occurred worldwide.There are two important viral surface glycoproteins, the haemagglutinin (HA) and neuraminidase (NA). The HA binds to sialic acid receptors on the membrane of host cells and is the primary antigen against which a host’s antibody response is targeted. The NA cleaves the sialic acid bond attaching new viral particles to the cell membrane of host cells allowing their release. The NA is also the target of the neuraminidase inhibitor class of antiviral agents that include oseltamivir and zanamivir and newer agents such as peramivir. Both these glycoproteins are important antigens for inducing protective immunity in the host and therefore show the greatest variation.Influenza A viruses are classified into 16 antigenically distinct HA (H1–16) and 9 NA subtypes (N1–9). Although viruses of relatively few subtype combinations have been isolated from mammalian species, all subtypes, in most combinations, have been isolated from birds. Each virus possesses one HA and one NA subtype.Last century, the sudden emergence of antigenically different strains in humans, termed antigenic shift, occurred on three occasions, 1918 (H1N1), 1957 (H2N2) and 1968 (H3N2), resulting in pandemics. The frequent epidemics that occur between the pandemics are as a result of gradual antigenic change in the prevalent virus, termed antigenic drift. Epidemics throughout the world occur in the human population due to infection with influenza A viruses, such as H1N1 and H3N2 subtypes, or with influenza B virus. Phylogenetic studies have led to the suggestion that aquatic birds that show no signs of disease could be the source of many influenza A viruses in other species. The 1918 H1N1 pandemic strain is thought to have arisen as a result of spontaneous mutations within an avian H1N1 virus. However, most pandemic strains, such as the 1957 H2N2, 1968 H3N2 and 2009 pandemic H1N1, are considered to have emerged by genetic re-assortment of the segmented RNA genome of the virus, with the avian and human influenza A viruses infecting the same host.Influenza viruses do not pass readily between humans and birds but transmission between humans and other animals has been demonstrated. This has led to the suggestion that the proposed reassortment of human and avian influenza viruses takes place in an intermediate animal with subsequent infection of the human population. Pigs have been considered the leading contender for the role of intermediary because they may serve as hosts for productive infections of both avian and human viruses, and there is good evidence that they have been involved in interspecies transmission of influenza viruses; particularly the spread of H1N1 viruses to humans. Apart from public health measures related to the rapid identification of cases and isolation. The main control measures for influenza virus infections in human populations involves immunization and antiviral prophylaxis or treatment.