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Human Phenotype (human + phenotype)
Selected AbstractsEvolutionary archeology: Current status and future prospectsEVOLUTIONARY ANTHROPOLOGY, Issue 1 2002Michael J. O'Brien Abstract Darwinian evolution can be defined minimally as "any net directional change or any cumulative change in the characteristics of , populations over many generations,in other words, descent with modification"1 (p. 5). In archeology the population comprises artifacts, which are conceived of as phenotypic.2,4 Extension of the human phenotype to include ceramic vessels, projectile points, and the like is based on the notion that artifacts are material expressions of behavior, which itself is phenotypic. Archeology's unique claim within the natural sciences is its access to past phenotypic characters. Thus, historical questions are the most obvious ones archeologists can ask, although admittedly this is hardly a strong warrant for asking them. But if the issue is evolution, then historical questions must be asked. Posing and answering historical questions is the goal of evolutionary archeology.5. [source] Mouse models in non-alcoholic fatty liver disease and steatohepatitis researchINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 1 2006Quentin M. Anstee Summary Non-alcoholic fatty liver disease (NAFLD) represents a histological spectrum of liver disease associated with obesity, diabetes and insulin resistance that extends from isolated steatosis to steatohepatitis and cirrhosis. As well as being a potential cause of progressive liver disease in its own right, steatosis has been shown to be an important cofactor in the pathogenesis of many other liver diseases. Animal models of NAFLD may be divided into two broad categories: those caused by genetic mutation and those with an acquired phenotype produced by dietary or pharmacological manipulation. The literature contains numerous different mouse models that exhibit histological evidence of hepatic steatosis or, more variably, steatohepatitis; however, few replicate the entire human phenotype. The genetic leptin-deficient (ob/ob) or leptin-resistant (db/db) mouse and the dietary methionine/choline-deficient model are used in the majority of published research. More recently, targeted gene disruption and the use of supra-nutritional diets to induce NAFLD have gained greater prominence as researchers have attempted to bridge the phenotype gap between the available models and the human disease. Using the physiological processes that underlie the pathogenesis and progression of NAFLD as a framework, we review the literature describing currently available mouse models of NAFLD, highlight the strengths and weaknesses of established models and describe the key findings that have furthered the understanding of disease pathogenesis. [source] Mutations in the Insulin-Like Factor 3 Receptor Are Associated With Osteoporosis,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 5 2008Alberto Ferlin Abstract Introduction: Insulin-like factor 3 (INSL3) is produced primarily by testicular Leydig cells. It acts by binding to its specific G protein,coupled receptor RXFP2 (relaxin family peptide 2) and is involved in testicular descent during fetal development. The physiological role of INSL3 in adults is not known, although substantial INSL3 circulating levels are present. The aim of this study was to verify whether reduced INSL3 activity could cause or contribute to some signs of hypogonadism, such as reduced BMD, currently attributed to testosterone deficiency. Materials and Methods: Extensive clinical, biochemical, and hormonal study, including bone densitometry by DXA, was performed on 25 young men (age, 27,41 yr) with the well-characterized T222P mutation in the RXFP2 gene. Expression analysis of INSL3 and RXFP2 on human bone biopsy and human and mouse osteoblast cell cultures was performed by RT-PCR, quantitative RT-PCR, and immunohistochemistry. Real-time cAMP imaging analysis and proliferation assay under the stimulus of INSL3 was performed on these cells. Lumbar spine and femoral bone of Rxfp2- deficient mice were studied by static and dynamic histomorphometry and ,CT, respectively. Results: Sixteen of 25 (64%) young men with RXFP2 mutations had significantly reduced BMD. No other apparent cause of osteoporosis was evident in these subjects, whose testosterone levels and gonadal function were normal. Expression analyses showed the presence of RXFP2 in human and mouse osteoblasts. Stimulation of these cells with INSL3 produced a dose- and time-dependent increase in cAMP and cell proliferation, confirming the functionality of the RXFP2/INSL3 receptor,ligand complex. Consistent with the human phenotype, bone histomorphometric and ,CT analyses of Rxfp2,/, mice showed decreased bone mass, mineralizing surface, bone formation, and osteoclast surface compared with wildtype littermates. Conclusions: This study suggests for the first time a role for INSL3/RXFP2 signaling in bone metabolism and links RXFP2 gene mutations with human osteoporosis. [source] From congenital hyperinsulinism to diabetes mellitus: the role of pancreatic ,-cell KATP channelsPEDIATRIC DIABETES, Issue 2 2005Khalid Hussain Abstract:, Pancreatic ,-cell adenosine triphosphate (ATP)-sensitive potassium (KATP) channels play a pivotal role in linking glucose metabolism to regulated insulin secretion. KATP channels are hetero- octameric complexes comprising two subunits Kir6.2 and sulfonylurea receptor 1 (SUR1). Changes in the intracellular concentration of nucleotides (ATP) cause alterations in the resting and opening state of the KATP channels. Loss-of-function mutations in the genes encoding the two subunits of KATP channels lead to the most common form of congenital hyperinsulinism (CHI). This causes persistent and severe hypoglycemia in the neonatal and infancy period. CHI can cause mental retardation and epilepsy if not treated properly. On the other hand, now there is evidence of an association between polymorphisms in the Kir6.2 gene and type 2 diabetes mellitus, mutations in the Kir6.2 gene and neonatal diabetes mellitus, and mutations in the SUR1 gene and diabetes mellitus. Interestingly, for reasons that are unclear at present, mice knockout models of KATP channels are different from the human phenotype of CHI. This article is a review focusing on how abnormalities in the pancreatic ,-cell KATP channels can lead to severe hypoglycemia on the one hand and diabetes mellitus on the other. [source] Life, information, entropy, and time: Vehicles for semantic inheritanceCOMPLEXITY, Issue 1 2007Antony R. Crofts Abstract Attempts to understand how information content can be included in an accounting of the energy flux of the biosphere have led to the conclusion that, in information transmission, one component, the semantic content, or "the meaning of the message," adds no thermodynamic burden over and above costs arising from coding, transmission and translation. In biology, semantic content has two major roles. For all life forms, the message of the genotype encoded in DNA specifies the phenotype, and hence the organism that is tested against the real world through the mechanisms of Darwinian evolution. For human beings, communication through language and similar abstractions provides an additional supra-phenotypic vehicle for semantic inheritance, which supports the cultural heritages around which civilizations revolve. The following three postulates provide the basis for discussion of a number of themes that demonstrate some important consequences. (i) Information transmission through either pathway has thermodynamic components associated with data storage and transmission. (ii) The semantic content adds no additional thermodynamic cost. (iii) For all semantic exchange, meaning is accessible only through translation and interpretation, and has a value only in context. (1) For both pathways of semantic inheritance, translational and copying machineries are imperfect. As a consequence both pathways are subject to mutation and to evolutionary pressure by selection. Recognition of semantic content as a common component allows an understanding of the relationship between genes and memes, and a reformulation of Universal Darwinism. (2) The emergent properties of life are dependent on a processing of semantic content. The translational steps allow amplification in complexity through combinatorial possibilities in space and time. Amplification depends on the increased potential for complexity opened by 3D interaction specificity of proteins, and on the selection of useful variants by evolution. The initial interpretational steps include protein synthesis, molecular recognition, and catalytic potential that facilitate structural and functional roles. Combinatorial possibilities are extended through interactions of increasing complexity in the temporal dimension. (3) All living things show a behavior that indicates awareness of time, or chronognosis. The ,4 billion years of biological evolution have given rise to forms with increasing sophistication in sensory adaptation. This has been linked to the development of an increasing chronognostic range, and an associated increase in combinatorial complexity. (4) Development of a modern human phenotype and the ability to communicate through language, led to the development of archival storage, and invention of the basic skills, institutions and mechanisms that allowed the evolution of modern civilizations. Combinatorial amplification at the supra-phenotypical level arose from the invention of syntax, grammar, numbers, and the subsequent developments of abstraction in writing, algorithms, etc. The translational machineries of the human mind, the "mutation" of ideas therein, and the "conversations" of our social intercourse, have allowed a limited set of symbolic descriptors to evolve into an exponentially expanding semantic heritage. (5) The three postulates above open interesting epistemological questions. An understanding of topics such dualism, the élan vital, the status of hypothesis in science, memetics, the nature of consciousness, the role of semantic processing in the survival of societies, and Popper's three worlds, require recognition of an insubstantial component. By recognizing a necessary linkage between semantic content and a physical machinery, we can bring these perennial problems into the framework of a realistic philosophy. It is suggested, following Popper, that the ,4 billion years of evolution of the biosphere represents an exploration of the nature of reality at the physicochemical level, which, together with the conscious extension of this exploration through science and culture, provides a firm epistemological underpinning for such a philosophy. © 2007 Wiley Periodicals, Inc. Complexity, 2007 [source] Prognosis for splicing factor PRPF8 retinitis pigmentosa, novel mutations and correlation between human and yeast phenotypes,HUMAN MUTATION, Issue 5 2010Katherine V. Towns Abstract PRPF8 -retinitis pigmentosa is said to be severe but there has been no overview of phenotype across different mutations. We screened RP patients for PRPF8 mutations and identified three new missense mutations, including the first documented mutation outside exon 42 and the first de novo mutation. This brings the known RP-causing mutations in PRPF8 to nineteen. We then collated clinical data from new and published cases to determine an accurate prognosis for PRPF8 -RP. Clinical data for 75 PRPF8 -RP patients were compared, revealing that while the effect on peripheral retinal function is severe, patients generally retain good visual acuity in at least one eye until the fifth or sixth decade. We also noted that prognosis for PRPF8 -RP differs with different mutations, with p.H2309P or p.H2309R having a worse prognosis than p.R2310K. This correlates with the observed difference in growth defect severity in yeast lines carrying the equivalent mutations, though such correlation remains tentative given the limited number of mutations for which information is available. The yeast phenotype is caused by lack of mature spliceosomes in the nucleus, leading to reduced RNA splicing function. Correlation between yeast and human phenotypes suggests that splicing factor RP may also result from an underlying splicing deficit. © 2010 Wiley-Liss, Inc. [source] Approaches to identify genes for complex human diseases: Lessons from Mendelian disorders,,HUMAN MUTATION, Issue 4 2003Michael Dean Abstract The focus of most molecular genetics research is the identification of genes involved in human disease. In the 20th century, genetics progressed from the rediscovery of Mendel's Laws to the identification of nearly every Mendelian genetic disease. At this pace, the genetic component of all complex human diseases could be identified by the end of the 21st century, and rational therapies could be developed. However, it is clear that no one approach will identify the genes for all diseases with a genetic component, because multiple mechanisms are involved in altering human phenotypes, including common alleles with small to moderate effects, rare alleles with moderate to large effects, complex gene,gene and gene,environment interactions, genomic alterations, and noninherited genetic effects. The knowledge gained from the study of Mendelian diseases may be applied to future research that combines linkage-based, association-based, and sequence-based approaches to detect most disease alleles. The technology to complete these studies is at hand and requires that modest improvements be applied on a wide scale. Improved analytical tools, phenotypic characterizations, and functional analyses will enable complete understanding of the genetic basis of complex diseases. Hum Mutat 22:261,274, 2003. Published © 2003 Wiley-Liss, Inc. [source] | |||||||||||||