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

Transforming growth factor-beta (TGF-beta) proteins regulate cell function, and have key roles in development and carcinogenesis The intracellular effectors of TGF-beta signalling, the Smad proteins, are activated by receptors and translocate into the nucleus, where they regulate transcription Although this pathway is inherently simple, combinatorial interactions in the heteromeric receptor and Smad complexes, receptor-interacting and Smad-interacting proteins, and cooperation with sequence-specific transcription factors allow substantial versatility and diversification of TGF-beta family responses Other signalling pathways further regulate Smad activation and function In addition, TGF-beta receptors activate Smad-independent pathways that not only regulate Smad signalling, but also allow Smad-independent TGF-beta responses

Smad-dependent and Smad-independent pathways in TGF-beta family signalling.

Much has been written about the functions of the E2F transcription factor and the product of the retinoblastoma tumor suppressor gene (pRB). These proteins have been described in terms that vary from ‘‘master regulators of cell cycle and differentiation’’ to ‘‘peripheral factors that lie outside the core cell cycle machinery.’’ Most often, pRB and E2F are described in short and simple terms as opposing molecules that control the G1to Sphase transition. There is an element of truth in each of these descriptions. E2Fand pRB-family proteins clearly play important roles in cell proliferation and differentiation. The extent to which they are master regulators or peripheral factors is a question of semantics, and these terms tell us more about the writer than the proteins. Perhaps the most important development in the E2F literature is the appreciation that E2F and pRB are not unique molecules with functions that can be defined in black and white terms. Instead, E2F and pRB represent families of related proteins that have diverse and occasionally contradictory activities. We now know a great deal about E2F complexes and pRB-family proteins and the emerging picture defies a one-line explanation. The fascinating variety of activities ascribed to various E2F complexes challenges us to place these into context and to find the right perspective. This review is presented into two sections. The first section summarizes the tremendous progress into the composition and properties of E2F and the many interactions that coordinately regulate E2F-dependent transcription. The rapid growth in the size of the E2F literature hides the fact that several fundamental questions have not been fully answered. Because of this, the second section of this review details five unresolved issues that have been highlighted by recent publications. It is impossible to cover all of the relevant E2F literature in a single review and readers are referred to reviews by Farnham (1995); Sardet et al. (1997); Helin (1998); and Yamasaki (1998) for a comprehensive survey.

http://genesdev.cshlp.org/content/12/15/2245.full.pdf

The regulation of E2F by pRB-family proteins

Transgenic expression of just four defined transcription factors (c-Myc, Klf4, Oct4 and Sox2) is sufficient to reprogram somatic cells to a pluripotent state. The resulting induced pluripotent stem (iPS) cells resemble embryonic stem cells in their properties and potential to differentiate into a spectrum of adult cell types. Current reprogramming strategies involve retroviral, lentiviral, adenoviral and plasmid transfection to deliver reprogramming factor transgenes. Although the latter two methods are transient and minimize the potential for insertion mutagenesis, they are currently limited by diminished reprogramming efficiencies. piggyBac (PB) transposition is host-factor independent, and has recently been demonstrated to be functional in various human and mouse cell lines. The PB transposon/transposase system requires only the inverted terminal repeats flanking a transgene and transient expression of the transposase enzyme to catalyse insertion or excision events. Here we demonstrate successful and efficient reprogramming of murine and human embryonic fibroblasts using doxycycline-inducible transcription factors delivered by PB transposition. Stable iPS cells thus generated express characteristic pluripotency markers and succeed in a series of rigorous differentiation assays. By taking advantage of the natural propensity of the PB system for seamless excision, we show that the individual PB insertions can be removed from established iPS cell lines, providing an invaluable tool for discovery. In addition, we have demonstrated the traceless removal of reprogramming factors joined with viral 2A sequences delivered by a single transposon from murine iPS lines. We anticipate that the unique properties of this virus-independent simplification of iPS cell production will accelerate this field further towards full exploration of the reprogramming process and future cell-based therapies.

/pdf/piggybac-transposition-reprograms-fibroblasts-to-induced-18kwa2iwee.pdf

piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells

Cdi1, a human G1 and S phase protein phosphatase that associates with Cdk2

A major modification to the sterile insect technique is described, in which transgenic insects homozygous for a dominant, repressible, female-specific lethal gene system are used. We demonstrate two methods that give the required genetic characteristics in an otherwise wild-type genetic background. The first system uses a sex-specific promoter or enhancer to drive the expression of a repressible transcription factor, which in turn controls the expression of a toxic gene product. The second system uses non-sex-specific expression of the repressible transcription factor to regulate a selectively lethal gene product. Both methods work efficiently in Drosophila melanogaster, and we expect these principles to be widely applicable to more economically important organisms.

https://science.sciencemag.org/content/sci/287/5462/2474.full.pdf

Insect population control using a dominant, repressible, lethal genetic system.

Effective vector control, and more specifically mosquito control, is a complex and difficult problem, as illustrated by the continuing prevalence (and spread) of mosquito-transmitted diseases. The sterile insect technique and similar methods control certain agricultural insect pest populations in a species-specific, environmentally sound, and effective manner; there is increased interest in applying this approach to vector control. Such an approach, like all others in use and development, is not a one-size-fits-all solution, and will be more appropriate in some situations than others. In addition, the proposed release of pest insects, and more so genetically modified pest insects, is bound to raise questions in the general public and the scientific community as to such a method's efficacy, safety, and sustainability. This article attempts to address these concerns and indicate where sterile-insect methods are likely to be useful for vector control.

http://reviverestore.org/wp-content/uploads/2015/02/Alphey-Benedict-et-al-2010-VBZD-mosquito-sterile-release-review-copy.pdf

Sterile-Insect Methods for Control of Mosquito-Borne Diseases: An Analysis

The increasing burden of dengue, and the relative failure of traditional vector control programs highlight the need to develop new control methods. SIT using self-limiting genetic technology is one such promising method. A self-limiting strain of Aedes aegypti, OX513A, has already reached the stage of field evaluation. Sustained releases of OX513A Ae. aegypti males led to 80% suppression of a target wild Ae. aegypti population in the Cayman Islands in 2010. Here we describe sustained series of field releases of OX513A Ae. aegypti males in a suburb of Juazeiro, Bahia, Brazil. This study spanned over a year and reduced the local Ae. aegypti population by 95% (95% CI: 92.2%-97.5%) based on adult trap data and 81% (95% CI: 74.9-85.2%) based on ovitrap indices compared to the adjacent no-release control area. The mating competitiveness of the released males (0.031; 95% CI: 0.025-0.036) was similar to that estimated in the Cayman trials (0.059; 95% CI: 0.011 – 0.210), indicating that environmental and target-strain differences had little impact on the mating success of the OX513A males. We conclude that sustained release of OX513A males may be an effective and widely useful method for suppression of the key dengue vector Ae. aegypti. The observed level of suppression would likely be sufficient to prevent dengue epidemics in the locality tested and other areas with similar or lower transmission.

/pdf/suppression-of-a-field-population-of-aedes-aegypti-in-brazil-3ki817hg2q.pdf

Suppression of a Field Population of Aedes aegypti in Brazil by Sustained Release of Transgenic Male Mosquitoes.

Reduction or elimination of vector populations will tend to reduce or eliminate transmission of vector-borne diseases. One potential method for environmentally-friendly, species-specific population control is the Sterile Insect Technique (SIT). SIT has not been widely used against insect disease vectors such as mosquitoes, in part because of various practical difficulties in rearing, sterilization and distribution. Additionally, vector populations with strong density-dependent effects will tend to be resistant to SIT-based control as the population-reducing effect of induced sterility will tend to be offset by reduced density-dependent mortality. We investigated by mathematical modeling the effect of manipulating the stage of development at which death occurs (lethal phase) in an SIT program against a density-dependence-limited insect population. We found late-acting lethality to be considerably more effective than early-acting lethality. No such strains of a vector insect have been described, so as a proof-of-principle we constructed a strain of the principal vector of the dengue and yellow fever viruses, Aedes (Stegomyia) aegypti, with the necessary properties of dominant, repressible, highly penetrant, late-acting lethality. Conventional SIT induces early-acting (embryonic) lethality, but genetic methods potentially allow the lethal phase to be tailored to the program. For insects with strong density-dependence, we show that lethality after the density-dependent phase would be a considerable improvement over conventional methods. For density-dependent parameters estimated from field data for Aedes aegypti, the critical release ratio for population elimination is modeled to be 27% to 540% greater for early-acting rather than late-acting lethality. Our success in developing a mosquito strain with the key features that the modeling indicated were desirable demonstrates the feasibility of this approach for improved SIT for disease control.

/pdf/late-acting-dominant-lethal-genetic-systems-and-mosquito-4hs50qtqzg.pdf

Late-acting dominant lethal genetic systems and mosquito control

Genetics can potentially provide new, species-specific, environmentally friendly methods for mosquito control. Genetic control strategies aim either to suppress target populations or to introduce a harm-reducing novel trait. Different approaches differ considerably in their properties, especially between self-limiting strategies, where the modification has limited persistence, and self-sustaining strategies, which are intended to persist indefinitely in the target population and may invade other populations. Several methods with different molecular biology are under development and the first field trials have been completed successfully.

/pdf/genetic-control-of-mosquitoes-323levzu0k.pdf

Luke Alphey

Papers

Insect population control using a dominant, repressible, lethal genetic system.

Sterile-Insect Methods for Control of Mosquito-Borne Diseases: An Analysis

Suppression of a Field Population of Aedes aegypti in Brazil by Sustained Release of Transgenic Male Mosquitoes.

Late-acting dominant lethal genetic systems and mosquito control

Genetic Control of Mosquitoes