抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

BIOE 402. Medical Technology Assessment. 2 or 3 hours. Bioentrepreneur course. Assessment of medical technology in the context of commercialization. Objectives, competition, market share, funding, pricing, manufacturing, growth, and intellectual property; many issues unique to biomedical products. Course Information: 2 undergraduate hours. 3 graduate hours. Prerequisite(s): Junior standing or above and consent of the instructor.

“Bioinformatics” 특집을 내면서

Is human life expectancy approaching its limit? Many--including individuals planning their retirement and officials responsible for health and social policy--believe it is, but the evidence presented in the
 Policy Forum
 suggests otherwise. For 160 years, best-performance life expectancy has steadily increased by a quarter of a year per year, an extraordinary constancy of human achievement. Mortality experts have repeatedly asserted that life expectancy is close to an ultimate ceiling; these experts have repeatedly been proven wrong. The apparent leveling off of life expectancy in various countries is an artifact of laggards catching up and leaders falling behind.

/pdf/broken-limits-to-life-expectancy-3fna6yf8to.pdf

Broken Limits to Life Expectancy

The nematode Caenorhabditis elegans ages and dies in a few weeks, but humans can live for 100 years or more. Assuming that the ancestor we share with nematodes aged rapidly, this means that over evolutionary time mutations have increased lifespan more than 2,000-fold. Which genes can extend lifespan? Can we augment their activities and live even longer? After centuries of wistful poetry and wild imagination, we are now getting answers, often unexpected ones, to these fundamental questions.

The genetics of ageing

Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, from which the family derives its name, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologues also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiology, since they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. In this review we describe our current understanding of the biological function of the seven mammalian sirtuins, SIRT1-7, and we will also discuss their potential as mediators of caloric restriction and as pharmacological targets to delay and treat human age-related diseases.

/pdf/sirtuins-in-mammals-insights-into-their-biological-function-4n0wwh14ol.pdf

Sirtuins in mammals: insights into their biological function

Dietary restriction (DR) increases life-span in organisms from yeast to mammals, presumably by slowing the accumulation of aging-related damage. Here we show that in Drosophila, DR extends life-span entirely by reducing the short-term risk of death. Two days after the application of DR at any age for the first time, previously fully fed flies are no more likely to die than flies of the same age that have been subjected to long-term DR. DR of mammals may also reduce short-term risk of death, and hence DR instigated at any age could generate a full reversal of mortality.

https://science.sciencemag.org/content/sci/301/5640/1731.full.pdf

Demography of dietary restriction and death in Drosophila.

Several members of the two-component signal transduction family have been implicated in the control of polar development in Caulobacter crescentus: PleC and DivJ, two polarly localized histidine sensor kinases; and the response regulators DivK and PleD. The PleD protein was shown previously to be required during the swarmer-to-stalked cell transition for flagellar ejection and efficient stalk biogenesis. Here, we present data indicating that PleD also controls the onset of motility and a cell density switch immediately preceding cell division. Constitutively active alleles of pleD or wspR, an orthologue from Pseudomonas fluorescens, almost completely suppressed C. crescentus motility and inhibited the increase in swarmer cell density during cell differentiation. The observation that these alleles also had a dominant-negative effect on motility in a pleC divJ and a pleC divK mutant background indicated that PleD is located downstream of the other components in the signal transduction cascade, which controls the activity of the flagellar motor. In addition, the presence of a constitutive pleD or wspR allele resulted in a doubling of the average stalk length. Together, this is consistent with a model in which the active form of PleD, PleD approximately P, negatively controls aspects of differentiation in the late predivisional cell, whereas it acts positively on polar development during the swarmer-to-stalked cell transition. In agreement with such a model, we found that DivJ, which localizes to the stalked pole during cell differentiation, positively controlled the in vivo phosphorylation status of PleD, and the swarmer pole-specific PleC kinase modulated this status in a negative manner. Furthermore, domain switch experiments demonstrated that the WspR GGDEF output domain from P. fluorescens is active in C. crescentus, favouring a more general function for this novel signalling domain over a specific role such as DNA or protein interaction. Possible roles for PleD and its C-terminal output domain in modulating the polar cell surface of C. crescentus are discussed.

Role of the GGDEF regulator PleD in polar development of Caulobacter crescentus.

The degeneracy of the genetic code means that many mutations in coding sequences, especially at the third base of codons, do not affect protein sequence and are therefore considered silent. However, there is increasing evidence that they could still have effects on transcription, splicing, mRNA transport or translation, any of which could alter the phenotype. New research shows that a synonymous polymorphism that is part of a common haplotype in humans affects the function of the encoded protein by altering its structure. Kimchi-Sarfaty et al. looked for phenotypic effects of a synonymous polymorphism in a common haplotype in the multidrug resistance 1 (MDR1) gene, which encodes P-glycoprotein, by expressing it in cell lines. The synonymous variant altered the effectiveness of inhibitors of P-glycoprotein. The mRNA levels were not altered by the mutation, implying that its effect was not at the level of transcription. On the other hand, the effect was enhanced by increasing the concentration of the transgene, implying that an increase in the amount of mRNA that is available to the translation machinery might be causative. The authors therefore reasoned that differences in tRNA abundance underlie the variation. This is consistent with the fact that the variant uses a codon that is rarer than the wild type. As further evidence for this, the authors created a variant that uses an even rarer codon, and found an even greater phenotypic effect. The authors suggest that the need for rare tRNAs to translate rare codons slows down translation and causes the protein to fold into a different structure. In support of this theory, the conformation-sensitive antibody binding and trypsin susceptibility of the variant were found to be different from the wild-type protein. These results show that a common human polymorphism, that might be assumed to be silent, has phenotypic effects in a clinically important protein. The phenomenon of non-silent synonymous mutations is therefore of interest not only to evolutionary biologists. Many of the synonymous polymorphisms in the accumulating body of SNP data might turn out to have important phenotypic consequences. Patrick Goymer

Synonymous mutations break their silence

Cancer cells vary; they compete; the fittest survive. Patrick Goymer reports on how evolutionary biology can be applied to cancer — and what good it might do.

/pdf/natural-selection-the-evolution-of-cancer-30v01q5ac0.pdf

Natural selection: The evolution of cancer

For Patrick Goymer, the story behind the scientists who first described the phenomenon known as hydrogen bonding is a familiar one.

100 years of the hydrogen bond

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