Books on the topic 'Mutational mechanisms'
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1
Elduque, Alberto. Mutations of Alternative Algebras. Dordrecht: Springer Netherlands, 1994.
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2
Gershenson, S. M. Molecular mechanisms of mutagenicity of DNA and other natural and synthetic polynucleotides. Kiev: National Academy of Science of Ukraine, Institute of Plant Physiology and Genetics, 1997.
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3
Hughes, Alis, and Lesley Jones. Pathogenic Mechanisms. Oxford University Press, 2014. http://dx.doi.org/10.1093/med/9780199929146.003.0013.
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Huntington’s disease (HD) pathogenesis is complex. In the two decades since the gene and its mutation were discovered, there has been extensive exploration of how the expanded CAG repeat in HTT leads to neurodegeneration in HD. This chapter focuses on the mechanisms that potentially contribute to the dysfunction and death of cells in HD. These include repeat instability and RNA toxicity and the production, processing, modification, and degradation of mutant huntingtin. The effects of mutant HTT on cellular processes such as transcription, transport, neurotransmission, and protein clearance are also described. The interdependence and individual importance of these mechanisms in disease etiology remains to be clarified; however, consideration of each could be important for the development of therapeutic interventions in HD.
4
Mendelsohn, Mortimer L. Mutation & The Environment Pt.a: BASIC MECHANISMS (DISCONTINUED (Progress in Clinical and Biological Research)). Edited by Mortimer Mendelsohn. John Wiley & Sons, 1990.
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5
Grant, Seth G. N. Synaptic Mechanisms of Psychotic Disorders. Edited by Dennis S. Charney, Eric J. Nestler, Pamela Sklar, and Joseph D. Buxbaum. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190681425.003.0017.
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Synapses are the hallmark of the neuroanatomy of the brain. The million billion synapses of the human brain connect the nerve cells into the networks that underpin all behavior. The molecular anatomy of synapses is also remarkably complicated with ~2000 proteins in the synapse proteome. The proteins are physically organized into a hierarchy of molecular machines that control synapse biology. These proteins integrate and compute the information in patterns of nerve cell activity. Mutations in hundreds of genes that encode synaptic proteins contribute to over one hundred brain diseases, including common mental disorders. The synapse proteome is of fundamental importance to mental illness.
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Cazeneuve, Cécile, and Alexandra Durr. Genetic and Molecular Studies. Oxford University Press, 2014. http://dx.doi.org/10.1093/med/9780199929146.003.0006.
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Huntington’s disease (HD) is a rare inherited neurologic disorder due to a single mutational mechanism in a large gene (HTT). The mutation is an abnormal CAG repeat expansion, which is translated to a polyglutamine stretch in the huntingtin protein. The growing field of repeat expansion disorders benefits greatly from the lessons learned from the role of the CAG repeat expansion in HD and its resulting phenotype–genotype correlations. The molecular diagnosis can be difficult, and there are some pitfalls for accurate sizing of the CAG repeat, especially in juvenile HD and for intermediate alleles. Correlation between CAG length and age of onset accounts for up to 72% of the variance in different populations, but the search for genes modifying age of onset or progression of HD is still ongoing.
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Sun, Warren Da-Ren. Structural, mutational and kinetic analyses of Aquifex aeolicus prephenate dehydrogenase: Elucidation of the catalytic mechanism. 2006.
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8
Pocheville, Arnaud, and Étienne Danchin. Genetic Assimilation and the Paradox of Blind Variation. Oxford University Press, 2017. http://dx.doi.org/10.1093/oso/9780199377176.003.0003.
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This chapter confronts the neo-Darwinian core tenet of blind variation, or random mutation, with classical and recent models of genetic assimilation. We first argue that all the mechanisms proposed so far rely on blind genetic variation fueling natural selection. Then, we examine a new hypothetical mechanism of genetic assimilation, relying on nonblind genetic variation. Yet, we show that such a model still relies on blind variation of some sort to explain adaptation. Last, we discuss the very meaning of the tenet of blind variation. We propose a formal characterization of the tenet and argue that it should not be understood solely as an empirical claim, but also as a core explanatory principle.
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Mechanisms in B-cell neoplasia 1994. Berlin: Springer-Verlag, 1995.
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10
Potter, M., and Michael Potter. Mechanisms in B-Cell Neoplasia 1994. SPRINGER-VERLAG, 1995.
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11
Lawrence, Christopher W. Induced Mutagenesis: Molecular Mechanisms and Their Implications for Environmental Protection. Springer, 2013.
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12
Lawrence, Christopher W. Induced Mutagenesis: Molecular Mechanisms and Their Implications for Environmental Protection. Springer, 2013.
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13
Singh, Bhagat, Alban Latremoliere, and Michael Costigan. Congenital insensitivity to pain. Edited by Paul Farquhar-Smith, Pierre Beaulieu, and Sian Jagger. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780198834359.003.0078.
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The landmark paper discussed in this chapter is ‘Congenital insensitivity to pain. A clinical, genetic and neurophysiological study of four children from the same family’, published by D. C. Thrush in 1973. The study of patients with congenital conditions that result in pain insensitivity has been invaluable in helping define the molecular mechanisms of sensory processing. These patients share a major defining phenotype (they feel little or no pain from birth), although they often have differing subtle symptoms which belie a host of separate conditions that we have now started to recognize with the advent of molecular genetics (e.g. loss-of-function mutations in the gene encoding Nav1.7, and mutations related to nerve growth factor (NGF)); these include congenital insensitivity to pain with anhydrosis (CIPA; thought to be due to mutations in the gene encoding the NGF receptor NTRK1) and hereditary sensory and autonomic neuropathies (HSANs) such as familial dysautonomia.
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Potter, M. Mechanisms in B-Cell Neoplasia 1994 (Current Topics in Microbiology and Immunology). Springer-Verlag, 1994.
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15
Chung, Dah-Eun Chloe, Jeannette N. Stankowski, and Leonard Petrucelli. Neurobiology of FTD. Edited by Dennis S. Charney, Eric J. Nestler, Pamela Sklar, and Joseph D. Buxbaum. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190681425.003.0056.
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Frontotemporal dementia (FTD) is the third most common form of dementia, and is one that predominantly affects the frontal and temporal lobes. Pathological heterogeneity of FTD is highlighted in various types of protein inclusions in the brain, which can include tau, TDP-43, or FUS. The discovery of novel genes and mutations associated with FTD, along with the exciting advancement of molecular technologies, led to the development of numerous animal- and human-based model systems. These valuable models allow not only for the investigation of pathogenic mechanisms underlying FTD, but also for their utilization as powerful platforms for the screening of novel therapies.
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Divan, Aysha, and Janice A. Royds. 2. DNA. Oxford University Press, 2016. http://dx.doi.org/10.1093/actrade/9780198723882.003.0002.
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Another significant milestone was the publication in 2003 of the complete sequence of the human genome—the entire DNA contained within the forty-six chromosomes located in the nucleus of each human somatic (body) cell. Once this was published, further worldwide projects were launched to work out what the functions of these genes and other regions of the genome actually were. ‘DNA’ outlines the components of the human genome and their organization; DNA replication; mutations and correction mechanisms; polymorphisms; and new DNA technologies, including gene cloning, the polymerase chain reaction, and sequencing methods. Finally, bioinformatics and the subsequent issues of privacy and how this information could be used are discussed.
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Michael, Potter, Melchers F. 1936-, National Cancer Institute (U.S.), and Workshop on Mechanisms in B-Cell Neoplasia (12th : 1994 : Bethesda, Maryland ), eds. Mechanisms in B-cell neoplasia 1994: [12th workshop, Bethesda, MD, April 18-20, 1994]. Berlin: Springer-Verlag, 1995.
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18
Money, Nicholas P. 3. Microbial genetics and molecular microbiology. Oxford University Press, 2014. http://dx.doi.org/10.1093/actrade/9780199681686.003.0003.
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Cell structures and metabolic processes are specified by genes. The genomes of bacteria, archaea, and eukaryotic microorganisms are encoded in double-stranded helices of DNA. ‘Genetics and molecular microbiology’ explains that advances in sequencing techniques and the development of automated sequencing methods have allowed scientists to sequence the genomes of 4,000 bacterial genomes, 200 archaea, and 200 eukaryotes. Genome sizes vary a great deal within each category of microorganism and the largest prokaryote genomes overlap the smallest eukaryote genomes. Natural mutations in microorganisms play a primary role in evolution. Reproduction in prokaryotes is always asexual, whereas mechanisms of sexual reproduction have been studied in eukaryotic microorganisms belonging to all of the supergroups.
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Harold, Denise, and Julie Williams. Molecular genetics and biology of dementia. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199644957.003.0008.
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Considerable progress has been made in our understanding of the genetics and molecular biology of dementia. In this chapter we focus predominantly on the most common form of dementia, Alzheimer’s disease (AD), but also discuss vascular dementia and frontotemporal dementia. Genetic mutations have been identified that cause Mendelian subtypes of each disorder, and in recent years genome-wide association studies have greatly aided the identification of risk genes for more common forms of disease. For example, 9 susceptibility genes have been identified in AD in the past 3 years as a result of genome-wide association studies, the first robust risk loci to be identified since APOE in 1993. This progress in genetic research is having a dramatic effect on our understanding of disease pathogenesis, by refining previous ideas and defining new primary disease mechanisms.
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Tandon, Teena, and Rajiv Agarwal. Hypertension as a cause of chronic kidney disease. Edited by David J. Goldsmith. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0100.
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There is a strong association between hypertension and progressive renal disease, and it has long been assumed that a variable but often large proportion of end-stage renal disease is caused by essential hypertension damaging the kidney. While it is clear that malignant hypertension can cause renal damage, several lines of evidence cast doubt on the idea that more moderate blood pressures are commonly a primary cause of renal disease. These include (a) observational studies showing that microalbuminuria precedes hypertension; (b) morphological studies in animals and man suggest that changes traditionally described as due to hypertension correlate poorly with blood pressure; and (c) mutations in or near the APOL1 gene appear to underlie the development of renal disease in many black Americans previously labeled as suffering from hypertensive renal disease. The same mutations strongly predispose to focal segmental glomerulosclerosis. The mechanism of the association with ‘hypertensive’ renal disease is not established but it may act as a risk factor for progression of renal disease. Hypertension is associated with reduced renal mass. It is described as a consequence of renal cysts, simple as well as multiple. Obesity may be associated with accumulation of fat in the renal sinus and with hypertension.
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West-Eberhard, Mary Jane. Developmental Plasticity and Evolution. Oxford University Press, 2003. http://dx.doi.org/10.1093/oso/9780195122343.001.0001.
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The first comprehensive synthesis on development and evolution: it applies to all aspects of development, at all levels of organization and in all organisms, taking advantage of modern findings on behavior, genetics, endocrinology, molecular biology, evolutionary theory and phylogenetics to show the connections between developmental mechanisms and evolutionary change. This book solves key problems that have impeded a definitive synthesis in the past. It uses new concepts and specific examples to show how to relate environmentally sensitive development to the genetic theory of adaptive evolution and to explain major patterns of change. In this book development includes not only embryology and the ontogeny of morphology, sometimes portrayed inadequately as governed by "regulatory genes," but also behavioral development and physiological adaptation, where plasticity is mediated by genetically complex mechanisms like hormones and learning. The book shows how the universal qualities of phenotypes--modular organization and plasticity--facilitate both integration and change. Here you will learn why it is wrong to describe organisms as genetically programmed; why environmental induction is likely to be more important in evolution than random mutation; and why it is crucial to consider both selection and developmental mechanism in explanations of adaptive evolution. This book satisfies the need for a truly general book on development, plasticity and evolution that applies to living organisms in all of their life stages and environments. Using an immense compendium of examples on many kinds of organisms, from viruses and bacteria to higher plants and animals, it shows how the phenotype is reorganized during evolution to produce novelties, and how alternative phenotypes occupy a pivotal role as a phase of evolution that fosters diversification and speeds change. The arguments of this book call for a new view of the major themes of evolutionary biology, as shown in chapters on gradualism, homology, environmental induction, speciation, radiation, macroevolution, punctuation, and the maintenance of sex. No other treatment of development and evolution since Darwin's offers such a comprehensive and critical discussion of the relevant issues. Developmental Plasticity and Evolution is designed for biologists interested in the development and evolution of behavior, life-history patterns, ecology, physiology, morphology and speciation. It will also appeal to evolutionary paleontologists, anthropologists, psychologists, and teachers of general biology.
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Vigdor, Steven E. Randomness and Complexity. Oxford University Press, 2018. http://dx.doi.org/10.1093/oso/9780198814825.003.0007.
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Chapter 7 describes the fundamental role of randomness in quantum mechanics, in generating the first biomolecules, and in biological evolution. Experiments testing the Einstein–Podolsky–Rosen paradox have demonstrated, via Bell’s inequalities, that no local hidden variable theory can provide a viable alternative to quantum mechanics, with its fundamental randomness built in. Randomness presumably plays an equally important role in the chemical assembly of a wide array of polymer molecules to be sampled for their ability to store genetic information and self-replicate, fueling the sort of abiogenesis assumed in the RNA world hypothesis of life’s beginnings. Evidence for random mutations in biological evolution, microevolution of both bacteria and antibodies and macroevolution of the species, is briefly reviewed. The importance of natural selection in guiding the adaptation of species to changing environments is emphasized. A speculative role of cosmological natural selection for black-hole fecundity in the evolution of universes is discussed.
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Allen, Shelley J. Pathophysiology of Alzheimer’s disease. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780198779803.003.0002.
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We now know that the onset of the pathological processes leading to Alzheimer’s disease (AD) may be 15–20 years before symptoms appear. This focuses attention on synaptic changes and the early role of tau, and less on the hallmark amyloid plaques (Aβ) and neurofibrillary tau tangles. Sensitive biomarkers to allow early screening will be essential. Familial autosomal AD is the result of mutations in one of three genes (APP, PSEN1, or PSEN2), each directly related to increased Aβ, and informs pathological mechanisms in common sporadic cases, but are also subject to influence by many risk genes and environmental factors. The essential role of apolipoprotein E in neuronal repair and Aβ clearance provides a therapeutic target but also a challenge in carriers of the risk gene APOE4. Current treatments are symptomatic, derived from neurotransmitter deficits seen; particularly cholinergic, but emerging data suggest alternative targets which may prove more productive.
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Wagner, Carsten A., and Olivier Devuyst. Renal acid–base homeostasis. Edited by Robert Unwin. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0024.
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The kidney is central to acid–base homeostasis. Major processes are reabsorption of filtered bicarbonate, de novo synthesis of bicarbonate from ammoniagenesis, and net excretion of protons. The latter requires buffers such as ammonium, phosphate, citrate and other bases binding protons (so-called titratable acids). The proximal tubule is the major site of bicarbonate reabsorption and only site of ammoniagenesis. The thick ascending limb and the distal convoluted tubule handle ammonia/ammonium and complete bicarbonate reabsorption. The collecting duct system excretes protons and ammonium, but may switch to net bicarbonate secretion. The kidney displays a great plasticity to adapt acid or bicarbonate excretion. Angiotensin II, aldosterone and endothelin are involved in regulating these processes, and they induce morphological changes along the nephron. Inborn and acquired disorders of renal acid–base handling are caused by mutations in acid–base transport proteins or by dysregulation of adaptive mechanisms.
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Minelli, Alessandro. Evolvability and Its Evolvability. Oxford University Press, 2017. http://dx.doi.org/10.1093/oso/9780199377176.003.0007.
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No universally accepted notion of evolvability is available, focus being alternatively put onto either genetic or phenotypic change. The heuristic power of this concept is best found when considering the intricacies of the genotype→phenotype map, which is not necessarily predictable, expression of variation depending on the structure of gene networks and especially on the modularity and robustness of developmental systems. We can hardly ignore evolvability whenever studying the role of cryptic variation in evolution, the often pervious boundary between phenotypic plasticity and the expression of a genetic polymorphism, the major phenotypic leaps that the mechanisms of development can produce based on point mutations, or the morphological stasis that reveals how robust a developmental process can be in front of genetic change. Evolvability is subject itself to evolution, but it is still uncertain to what extent there is positive selection for enhanced evolvability, or for evolvability biased in a specific direction.
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Sousek, Alexandra, and Mehdi Tafti. The genetics of sleep. Edited by Sudhansu Chokroverty, Luigi Ferini-Strambi, and Christopher Kennard. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780199682003.003.0005.
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Although there is strong evidence for a genetic contribution to inter-individual variations in sleep, the underlying factors and their interaction remain largely elusive. Much effort has been expended in studying genetic variations contributing to circadian and sleep phenotypes, the individual pattern of the human sleep EEG, reactions to sleep loss, and the pathophysiology of sleep-related disorders. Certain sleep-related diseases may be caused by single genes, while the etiology of others seems to be variable and complex. This is especially the case when the immune system is involved. This chapter reports on twin and familial studies, genetic variations and mutations affecting neurotransmitters and other signaling pathways and thereby affecting sleep, and impacts of gene expression processes and the immune system on sleep. Although much knowledge has been gained, further research is needed to elucidate the all-embracing mechanisms and their interactions that regulate sleep.
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Wackerhage, Henning, Jonathon Smith, and Darren Wisniewski. Molecular exercise physiology. Edited by Neil Armstrong and Willem van Mechelen. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780198757672.003.0031.
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Molecular exercise physiology is the study of exercise physiology using molecular biology methods. The development of differentiated cell types is regulated by transcription factors like the muscle-making MyoD that specifies cell type, while others regulate the development of muscle, tendons, and bones. Maternal nutrition and exercise commonly affect embryonic development through epigenetic mechanisms. Adaptation to exercise involves sensor proteins detecting exercise-related signals, the processing of signals by signalling proteins and networks, and the regulation of the actual adaptations by effector proteins. Many sport- and exercise-related traits depend on both common and rare DNA sequence variations, including the muscle mass-increasing myostatin (GDF8) loss-of-function and the haematocrit-increasing EPOR gain-of-function mutations. Additionally, common DNA sequence variations contribute to the inherited variability of development, body height, strength, and endurance. Finally, in addition to ethical concerns, current genetic performance tests only explain a fraction of the variation of sport and exercise-related traits.
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Gaitanis, John, Phillip L. Pearl, and Howard Goodkin. The EEG in Degenerative Disorders of the Central Nervous System. Edited by Donald L. Schomer and Fernando H. Lopes da Silva. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190228484.003.0013.
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Nervous system alterations can occur at any stage of prenatal or postnatal development. Any of these derangements, whether environmental or genetic, will affect electrical transmission, causing electroencephalogram (EEG) alteration and possibly epilepsy. Genetic insults may be multisystemic (for example, neurocutaneous syndromes) or affect only the brain. Gene mutations account for inborn errors of metabolism, channelopathies, brain malformations, and impaired synaptogenesis. Inborn errors of metabolism cause seizures and EEG abnormalities through a variety of mechanisms, including disrupted energy metabolism (mitochondrial disorders, glucose transporter defect), neuronal toxicity (amino and organic acidopathies), impaired neuronal function (lysosomal and peroxisomal disorders), alteration of neurotransmitter systems (nonketotic hyperglycinemia), and vitamin and co-factor dependency (pyridoxine-dependent seizures). Environmental causes of perinatal brain injury often result in motor or intellectual impairment (cerebral palsy). Multiple proposed etiologies exist for autism, many focusing on synaptic development. This chapter reviews the EEG findings associated with this myriad of pathologies occurring in childhood.
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Medjeral-Thomas, Nicholas, Anna Richards, and Matthew C. Pickering. Molecular basis of complement-mediated renal disease. Edited by Neil Turner. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199592548.003.0333.
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Abnormal regulation of complement is intimately associated with C3 glomerulopathy and atypical haemolytic uraemic syndrome. Atypical haemolytic uraemic syndrome is characterized by renal thrombotic microangiopathy due to an inability to regulate complement activation along the renal endothelium. The development of thrombosis is critically dependent on the ability to activate C5. Eculizumab, a monoclonal anti-C5 antibody, is an effective therapy for this condition. C3 glomerulopathy refers to glomerular lesions characterized by accumulation of C3 in the absence of immunoglobulin. The prototypic example is dense deposit disease. This condition is associated with impaired regulation of the alternative pathway in plasma. In other subtypes of C3 glomerulopathy, familial studies have identified mutations within the complement factor H-related protein family. Polymorphic variation within this protein family also influences susceptibility to IgA nephropathy. The mechanism underlying these associations remains unknown and is the subject of ongoing research efforts.
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Fieder, Martin, and Susanne Huber. Evolution and Human Reproduction. Edited by Rosemary L. Hopcroft. Oxford University Press, 2018. http://dx.doi.org/10.1093/oxfordhb/9780190299323.013.29.
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This chapter discusses, from an evolutionary standpoint, crucial factors influencing human reproduction. It emphasizes the importance of social status and homogamy on the level of the individual and raises the question how genetics and also epigenetics may contribute to explain human mate choice and fertility patterns. The chapter discusses the differential association of status with fertility for men and women, evolutionary reasons for the prevalence of homogamy along cultural traits and considers, on the level of genetics, the interplay of inbreeding and outbreeding. The role of mutations due to paternal age for human mate choice is debated. Finally, the chapter discusses the effects of early life conditions on later reproduction and also the role of epigenetics as a potential underlying mechanism. It is concluded that an evolutionary perspective helps explain reproductive patterns in modern humans and may thus make a valuable contribution in the assessment of urgent contemporary problems.
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Clarke, Andrew. Temperature and diversity. Oxford University Press, 2017. http://dx.doi.org/10.1093/oso/9780199551668.003.0015.
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The diversity (species richness) of plants and animals is typically highest in the tropics and the strongest environmental correlate of species richness is often climate. The energy for plant production is sunlight, but the rate is governed jointly by temperature and the availability of water (as captured by actual evapotranspiration, AET). Greater production is then linked to higher diversity because larger population size protects against stochastic extinction (the more individuals mechanism). A greater biomass and diversity of plants allows for a greater diversity of herbivores and so on through the food web, though the correlation with climate (AET) gets progressively weaker at higher trophic levels. This is the basis of the species-energy theory of diversity. The Metabolic Theory of Biodiversity posits a mechanistic explanation for higher diversity in warmer places mediated through an enhanced generation of mutations as a by-product of the faster metabolic rate associated with a higher body temperature. Evidence for this is equivocal, and this mechanism cannot explain the strong association between endotherm species richness and climate. The striking differences between the northern and southern hemispheres point to an important role for history, particularly recent glacial history, in influencing current patterns of diversity. We still lack a comprehensive theory of biological diversity, but evidence points to a complex series of factors being important, with the dominant ones being energy and time (history).
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Suman, Shankar, Shivam Priya, and Akanksha Nigam, eds. Breast Cancer: Current Trends in Molecular Research. BENTHAM SCIENCE PUBLISHERS, 2022. http://dx.doi.org/10.2174/97816810895221120101.
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Breast cancer is one of the most common cancer types worldwide, and is a leading cause of cancer related deaths in women. In this book, medical experts review our current understanding of the molecular biology and characteristics of breast cancer. The topics covered in this book provide comprehensive knowledge of mechanisms underlying breast carcinogenesis, and are intended for a wide audience including scientists, teachers, and students. 11 chapters present information about several topics on breast cancer, including the role of cell growth and proliferation pathways, androgen and cytokine signaling, germline mutations in breast cancer susceptibility genes, and molecular factors causing invasive and metastatic breast cancer. In addition, the editors discuss the recent advancements in multi-omics data analysis based on inter-and intra-tumor molecular profiles. The reference highlights how the knowledge and understanding of the biological behavior of breast neoplasms have facilitated ongoing investigations into dietary polyphenolic compounds with antioxidant properties, making them function as cancer chemopreventive agents. Along with this, the current development of treatment strategies such as targeted molecular therapy, and radiation therapy is brought to the fore to update readers.
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Thursfield, Rebecca, Chris Orchard, Rosanna Featherstone, and Jane C. Davies. Future treatments. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780198702948.003.0013.
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There are only a relatively limited armoury of drugs, the majority of which are aimed at downstream symptoms of cystic fibrosis. Therapies targeting the basic defect in CF as well as continued availability of more conventional drugs are required. Progress in gene therapy has been limited by the significant barriers to gene transfer of the CF lung, but the UK is hosting a large repeated dose trial of nebulized non-viral gene therapy designed around clinically meaningful outcomes. The UK CF Gene Therapy Consortium is also seeking to develop a promising modified lentiviral approach, although this is some years off. Perhaps the exciting development of recent decades has come from small molecule CFTR modulators, driven by an understanding of basic pathophysiological mechanisms. Ivacaftor is the first drug to be licensed, having proved itself highly clinically efficacious in patients with the class-3 gating mutation G551D. The trial pipeline seeks to expand indications for this and to explore the potential of Phe508del correctors. Finally, a number of anti-inflammatory and anti-infective strategies are being pursued. The emerging global problem of antibiotic resistance is leading to exciting alternatives such as biofilm disruption and bacteriophage to be explored.
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Wordsworth, B. P. Skeletal dysplasias. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0150.
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Bone is metabolically active throughout life and metabolic disturbances may have wide-ranging consequences that are not restricted to altering its mechanics. The study of some genetic bone diseases has already provided remarkable insights into the normal regulation of bone metabolism. Skeletal dysplasias are developmental disorders of the chondro-osseous tissues commonly resulting in short stature, which is often disproportionate. The underlying mutations are often in the structural genes encoding components of the matrix but may also involve growth factors or cell signalling. In contrast, the dysostoses tend to affect single bones or groups of bones, reflecting the transient nature of the many different signalling factors to which they are responsive during development. Abnormalities of bone density (high or low) may be due to primary deficiency of bone matrix synthesis (e.g. osteogenesis imperfecta and hypophosphatasia) but may also reflect an imbalance between bone formation and resorption. This may be caused by abnormalities of bone formation (e.g. hyperostosis/sclerosteosis and osteoporosis pseudoglioma syndrome) or bone resorption (e.g. classic osteopetrosis and fibrous dysplasia).
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Holliday, Kate L., Wendy Thomson, and John McBeth. Genetics of chronic musculoskeletal pain. Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0045.
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Chronic pain disorders are prevalent and a large burden on health care resources. Around 10% of the general population report chronic widespread pain, which is the defining feature of fibromyalgia. Fibromyalgia is a poorly understood idiopathic disorder which is also characterized by widespread tenderness and commonly occurs with comorbid mood disorders, fatigue, sleep disturbance, and cognitive dysfunction. A role for genetics in chronic pain disorders has been identified by twin studies, with heritability estimates of around 50%. Susceptibility genes for chronic pain are likely to be involved in pain processing or the psychological component of these disorders. A number of genes have been implicated in influencing how pain is perceived due to mutations causing monogenic pain disorders or an insensitivity to pain from birth. The role of common variation, however, is less well known. The findings from human candidate gene studies of musculoskeletal pain to date are discussed. However, the scope of these studies has been relatively limited in comparison to other complex conditions. Identifying susceptibility loci will help to determine the biological mechanisms involved and potentially new therapeutic targets; however, this is a challenging research area due to the subjective nature of pain and heterogeneity in the phenotype. Using more quantitative phenotypes such as experimental pain measures may prove to be a more fruitful strategy to identify susceptibility loci. Findings from these studies and other potential approaches are discussed.
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Holliday, Kate L., Wendy Thomson, John McBeth, and Nisha Nair. Genetics of chronic musculoskeletal pain. Oxford University Press, 2015. http://dx.doi.org/10.1093/med/9780199642489.003.0045_update_001.
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Chronic pain disorders are prevalent and a large burden on health care resources. Around 10% of the general population report chronic widespread pain, which is the defining feature of fibromyalgia. Fibromyalgia is a poorly understood idiopathic disorder which is also characterized by widespread tenderness and commonly occurs with comorbid mood disorders, fatigue, sleep disturbance, and cognitive dysfunction. A role for genetics in chronic pain disorders has been identified by twin studies, with heritability estimates of around 50%. Susceptibility genes for chronic pain are likely to be involved in pain processing or the psychological component of these disorders. A number of genes have been implicated in influencing how pain is perceived due to mutations causing monogenic pain disorders or an insensitivity to pain from birth. The role of common variation, however, is less well known. The findings from human candidate gene studies of musculoskeletal pain to date are discussed. However, the scope of these studies has been relatively limited in comparison to other complex conditions. Identifying susceptibility loci will help to determine the biological mechanisms involved and potentially new therapeutic targets; however, this is a challenging research area due to the subjective nature of pain and heterogeneity in the phenotype. Using more quantitative phenotypes such as experimental pain measures may prove to be a more fruitful strategy to identify susceptibility loci. Findings from these studies and other potential approaches are discussed.
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Levtchenko, Elena N., and Mirian C. Janssen. Cystinosis. Edited by Neil Turner. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199592548.003.0339_update_001.
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Cystinosis is a rare autosomal recessive disease caused by mutations in the lysosomal cystine transporter cystinosin encoded by the CTNS gene (17p.13.2). Cystinosis is characterized by lysosomal cystine accumulation throughout the body with renal Fanconi syndrome being the most common presenting symptom of a multisystem disorder. It must be distinguished from cystinuria in which formation of cystine stones is the core problem. When left untreated, kidney dysfunction gradually progresses towards end-stage renal failure during the first 10 years of life. The advent of renal replacement therapy allowed cystinosis patients to survive into adulthood, but revealed numerous extrarenal manifestations of the disease, affecting eyes, endocrine organs, gastrointestinal tract, muscles, and central and peripheral nervous systems. The disease mechanism of cystinosis is not fully understood. The administration of the cystine-depleting agent cysteamine slows down renal and extrarenal organ damage, pointing to the pivotal role of cystine accumulation in the disease pathogenesis. Treatment with cysteamine should be initiated as early as possible and continued lifelong, and also after kidney transplantation for protecting extrarenal organs. Cysteamine eye drops are an indispensable part of the treatment of corneal cystine accumulation. Life expectancy of cystinosis patients has substantially improved and is now above 50 years.
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Zhang, Marina, Mark Dodgson, and David Gann. Demystifying China's Innovation Machine. Oxford University Press, 2021. http://dx.doi.org/10.1093/oso/9780198861171.001.0001.
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China’s extraordinary economic development is explained in large part by the way it innovates. This book explains how it innovates, which has important implications not only for China but also for the rest of the world. Contrary to widely held views, China’s innovation machine is not created and controlled by an all-powerful government. Instead, it is a complex, interdependent system composed of hundreds of millions of elements, involving bottom-up innovation driven by innovators and entrepreneurs and highly pragmatic and adaptive top-down policy. Using case studies of leading firms and industries, statistics, and policy analysis, the book argues that China’s innovation machine is similar to a natural ecosystem. Innovations in technology, organization, and business model resemble genetic mutations which are random, self-serving and isolated initially, but the best fitting are selected by the market and their impacts are amplified by the innovation machine. This machine draws on China’s massive number of manufacturers, supply chains, innovation clusters, and digitally literate population, connected through supersized digital platforms. China’s innovation suffers from a lack of basic research and reliance upon certain critical technologies from overseas; its scale (size) and scope (diversity) possess attributes that make it self-correcting and stronger in the face of challenges. China’s innovation machine is most effective in a policy environment where the market prevails; policy intervention plays a significant role when market mechanisms are premature or fail. The book concludes that the future success of China’s innovation will depend on continuing policy pragmatism, mass entrepreneurship and innovation, and the development of the ‘new infrastructures’.
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Roddy, Edward, and Michael Doherty. Calcium pyrophosphate crystal deposition (CPPD). Oxford University Press, 2013. http://dx.doi.org/10.1093/med/9780199642489.003.0142.
Full textAbstract:
Calcium pyrophosphate crystal deposition (CPPD) in articular cartilage is a common age-related phenomenon. Recent important advances in our understanding of the pathophysiology of pyrophosphate metabolism include the identification of a mutation within the ANK gene which associates with familial CPPD, and elucidation of the interleukin-1β (IL-1β)-dependent mechanisms by which crystals invoke an inflammatory response. Risk factors for CPPD include age, prior joint damage and osteoarthritis, genetic factors, and occasionally metabolic diseases (hyperparathyroidism, haemochromatosis, hypomagnesaemia, and hypophosphatasia). CPPD is commonly asymptomatic or may present as osteoarthritis with CPPD, acute calcium pyrophosphate (CPP) crystal arthritis, or chronic CPP crystal inflammatory arthritis. Although radiographic chondrocalcinosis is often taken to be synonymous with CPPD, other calcium crystals can also have this appearance and definitive diagnosis requires identification of CPP crystals by compensated polarized light microscopy of aspirated synovial fluid. Recently, the ultrasonographic appearances of CPPD have been described. Treatment of CPPD is targeted to the clinical presentation. Acute CPP crystal arthritis is treated by aspiration and injection of glucocorticosteroid, local ice packs, non-steroidal anti-inflammatory drugs (NSAIDS), low-dose colchicine, oral or parenteral glucocorticosteroids, or adrenocorticotrophic hormone (ACTH). Treatment of osteoarthritis with CPPD is very similar to the treatment of osteoarthritis alone. There is no specific therapy for chronic CPP crystal inflammatory arthritis: options include NSAID, low-dose colchicine, low-dose glucocorticosteroid, methotrexate, and hydroxychloroquine. Recommendations for the management of CPPD are derived from a small evidence base and largely based on clinical experience and extrapolation from gout. Further research into diagnosis and management including novel treatment strategies such as IL-1β blockade is much needed.
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Keshav, Satish, and Alexandra Kent. Immunology and genetics in gastrointestinal and hepatic medicine. Edited by Patrick Davey and David Sprigings. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199568741.003.0196.
Full textAbstract:
The gut has a pivotal role in immune homeostasis. It is constantly exposed to a wide array of antigens in food, and resident and consumed microorganisms. It is estimated that the number of bacterial cells in the gastrointestinal tract is tenfold greater than the number of cells in the human body. The gut needs to recognize harmful bacteria, and consequently contains the largest number of immune cells in the body. However, it must remain tolerant to commensal bacteria. Bacteria express antigens that stimulate an immunological response via the gut-associated lymphoid tissue (GALT). The GALT includes the appendix, tonsils, Peyer’s patches, and mesenteric lymph nodes. Therefore, the intestinal immune system is finely balanced between tolerance and reactivity. An example of an abnormal response that generally the individual should be tolerant to is gliadin peptides in coeliac disease. An example of excessive tolerance to an otherwise controllable infection is cryptosporidiosis, which causes diarrhoea in patients with HIV infection. The understanding of genetics in disease has progressed rapidly with the introduction of genome-wide association studies. The Welcome Trust Case Control Consortium has performed extensive research on the genetics of many illnesses, including Crohn’s disease, ulcerative colitis, Barrett’s oesophagus, oesophageal adenocarcinoma, and primary biliary cholangitis. Although these studies have increased our understanding of the molecular basis of disease, they have had little impact on clinical management. This may change as studies associate genotype and phenotype. Several gastrointestinal diseases have an etiology based on immunological or genetic aberrations, and these immunological mechanisms and genetic mutations can be utilized for diagnostic purposes. However, there is no genetic or immunological marker that is 100% specific to a disease and, consequently, the markers are used to support clinical, histological, and/or radiological findings.
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Grant, Warren, and Martin Scott-Brown. Prevention of cancer. Edited by Patrick Davey and David Sprigings. Oxford University Press, 2018. http://dx.doi.org/10.1093/med/9780199568741.003.0350.
Full textAbstract:
In the UK, the four commonest cancers—lung cancer, breast cancer, colon cancer, and prostate cancer—result in around 62 000 deaths every year. Although deaths from cancer have fallen in the UK over the last 20 years, the UK still suffers from higher cancer death rates than many other countries in Western Europe. In 1999, the UK government produced a White Paper called Saving Lives: Our Healthier Nation that outlined a national target to reduce the death rate from cancer by at least 20% in people under 75 by 2010. The subsequent NHS Cancer Plan of 2000 designed a framework by which to achieve this target through effective prevention, screening, and treatment programmes as well as restructuring and developing new diagnostic and treatment facilities. But do we know enough about the biology of the development of cancer for government health policies alone to force dramatic changes in survival? The science behind the causes of cancer tells us that its origin lies in acquired or inherited genetic abnormalities. Inherited gene mutation syndromes and exposure to environmental mutagens cause cancer, largely through abnormalities in DNA repair mechanisms, leading to uncontrolled cell proliferation. Although screening those thought to be at highest risk, and regulating exposure to environmental carcinogens such as tobacco or ionizing radiation, have reduced, and will continue to reduce, cancer deaths, there are many other environmental factors that have been shown to increase the population risk of cancer. These will be outlined in this chapter. However, the available evidence is largely from retrospective and cross-sectional population-based studies and therefore limits the ability to apply this knowledge to the risk of the individual patient who may been seen in clinic. Although we may be able to put him or her into a high-, intermediate-, or low-risk category, the question ‘will I get cancer, doc?’ is one that we cannot answer with certainty. The NHS Cancer Plan of 2000, designed to reduce cancer deaths in this country and to bring UK treatment results in line with those other countries in Europe, focuses on preventing malignancy as part of its comprehensive cancer management strategy. It highlights that the rich are less likely to develop cancer, and will survive longer if they are diagnosed than those who live in poverty. This may reflect available treatment options, but is more likely to be related to the lifestyle of those with regular work, as they may be more health aware. The Cancer Plan, however, suggests that relieving poverty may be more labour intensive and less rewarding than encouraging positive risk-reducing behaviour in all members of the population. Eating well can reduce the risk of developing many cancers, particularly of the stomach and bowel. The Cancer Plan outlines the ‘Five-a-Day’ programme which was rolled out in 2002 and encouraged people to eat at least five portions of fruit and vegetables per day. Obese people are also at higher risk of cancers, in particular endometrial cancer. A good diet and regular exercise not only reduce obesity but are also independent risk-reducing factors. Alcohol misuse is thought to be a major risk factor in around 3% of all cancers, with the highest risk for cancers of the mouth and throat. As part of the Cancer Plan, the Department of Health promotes physical activity and general health programmes, as well as alcohol and smoking programmes, particularly in deprived areas. Focusing on these healthy lifestyle points can potentially reduce an individual lifetime risk of all cancers. However, our knowledge of the biology of four cancers in particular has led to the development of specific life-saving interventions. Outlined in this chapter are details regarding ongoing prevention strategies for carcinomas of the lung, the breast, the bowel, and the cervix.