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

https://www.um.es/biomybiotec/web/Seminarios/2010/papers/Cano_2.pdf

Epithelial-Mesenchymal Transitions in Development and Disease

The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

/pdf/how-do-glucocorticoids-influence-stress-responses-4egr3fa2k0.pdf

How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

The clinical performance of a laboratory test can be described in terms of diagnostic accuracy, or the ability to correctly classify subjects into clinically relevant subgroups. Diagnostic accuracy refers to the quality of the information provided by the classification device and should be distinguished from the usefulness, or actual practical value, of the information. Receiver-operating characteristic (ROC) plots provide a pure index of accuracy by demonstrating the limits of a test's ability to discriminate between alternative states of health over the complete spectrum of operating conditions. Furthermore, ROC plots occupy a central or unifying position in the process of assessing and using diagnostic tools. Once the plot is generated, a user can readily go on to many other activities such as performing quantitative ROC analysis and comparisons of tests, using likelihood ratio to revise the probability of disease in individual subjects, selecting decision thresholds, using logistic-regression analysis, using discriminant-function analysis, or incorporating the tool into a clinical strategy by using decision analysis.

/pdf/receiver-operating-characteristic-roc-plots-a-fundamental-1bsmhsp7j4.pdf

Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine.

The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.

Molecular mechanisms of epithelial–mesenchymal transition

Patients with recurrent IVF failure are defined as patients who are younger than 37 years and who had at least three consecutive unsuccessful IVF/intracytoplasmic sperm injection (ICSI) cycles with good quality embryos. These patients might be predisposed to chromosome errors in their embryos and therefore might benefit from preimplantation genetic diagnosis for aneuploidy screening (PGD-AS). This technique is, however, expensive and some normal embryos might be lost due to the error rate. The aim of this retrospective study was to define those patients who would benefit most from it. One hundred and twenty-one first PGD-AS cycles for recurrent IVF failure were analysed. The aneuploidy rate, ‘no embryo transfer’ rate, live birth rate per embryo transfer and implantation rate were respectively 48.3, 22.3, 29.7 and 19.5%. A multivariate logistic regression analysis gave us a predictive model demonstrating that to have a 90% probability of having an embryo transfer after PGD-AS, the patient should have at least 10 mature oocytes, eight normally fertilized oocytes and six embryos for biopsy. This study suggests that most patients with recurrent IVF failure may benefit from PGD-AS. Future studies, however, should more strictly define this heterogeneous group of patients, so that comparison is easier.

https://www.rbmojournal.com/article/S1472-6483(10)61006-1/pdf

Which patients with recurrent implantation failure after IVF benefit from PGD for aneuploidy screening

Charcot-Marie-Tooth (CMT) disease is the 'common' name for a range of hereditary peripheral neuropathies. CMT1 is the most common form and is transmitted in an autosomal dominant manner. CMT1A maps to chromosome 17p11.2 and is caused, in the majority of cases, by a 1.5 Mb DNA duplication, that includes the peripheral myelin protein 22 (PMP) gene. This paper reports on preimplantation genetic diagnosis (PGD) for CMT1A in five couples. The CMT1A duplication was detected by fluorescent PCR analysis using polymorphic (CA)n markers localized within the duplication. Single-cell PCR on blastomeres allowed genetic analysis of embryos obtained after ICSI. Only healthy unaffected embryos were transferred to the uterus. PCR experiments with single EBV-transformed lymphoblasts or with research blastomeres allowed the evaluation of amplification efficiencies, as well as contamination and allele drop-out (ADO) rates for each PCR protocol. Three simplex PCR protocols (using one primer pair) and two duplex PCR protocols (using two primer pairs) were developed for CMT1A. Additionally, a protocol using all three primer pairs in triplex was also established. Thirteen clinical ICSI-PGD cycles were performed for five couples (12 simplex PCR cycles and one duplex PCR cycle), resulting in seven embryo transfers. Three singleton pregnancies ensued in two couples and three healthy babies were delivered. This report describes different fluorescent PCR-based tests which allow efficient and accurate single-cell level detection of the CMT1A duplication. On the basis of the presence of the healthy allele of the affected parent-to-be (and/or absence of the affected one), healthy embryos can be selected for transfer. The assays are suitable for PGD for other couples who present with the same CMT1A duplication [depending on their informativity for the (CA)n markers available] as described here.

/pdf/preimplantation-genetic-diagnosis-for-charcot-marie-tooth-1cnl6ops48.pdf

Preimplantation genetic diagnosis for Charcot-Marie-Tooth disease type 1A.

Intracytoplasmic sperm injection three years after the birth of the first ICSI child.

Mature mouse oocytes were frozen ultrarapidly with a cryoprotectant solution consisting of 3.5 mol dimethylsulfoxide l-1 and 0.5 mol sucrose l-1 or exposed to the freezing solution and recovered. Freshly collected oocytes were used as controls. After ultrarapid freezing and thawing, a high mean percentage of oocytes (78%) survived. The incidence of parthenogenetic activation in frozen-thawed oocytes was not increased. After insemination in vitro, the rate of two-cell formation was decreased (59% versus 69%). Examination of the chromosome complement of first-cleavage embryos revealed that the incidence of polyploid embryos was four times that of the control group (23% versus 6%). Fewer fertilized eggs progressed to the blastocyst stage (49% versus 81%) and the mean number of cells per blastocyst was decreased. Furthermore, the capacity of transferred blastocysts to develop in vivo was reduced. Autopsy at day 17 of gestation revealed that the proportion of embryos implanting was lower in the embryos derived from ultrarapidly frozen-thawed oocytes. Furthermore, some of the living fetuses were abnormal, but our sample size is too small for the effect to be significant. In the solution control group, no differences were found compared with the control group. Although the study needs further results to draw definite conclusions, our findings question whether the applied protocol is suitable for mouse oocytes.

/pdf/association-of-ultrarapid-freezing-of-mouse-oocytes-with-xiyrnb4r8j.pdf

Association of ultrarapid freezing of mouse oocytes with increased polyploidy at the pronucleate stage, reduced cell numbers in blastocysts and impaired fetal development.

In order to examine if the transfer of more than three embryos has any beneficial effect on the outcome of intracytoplasmic sperm injection (ICSI) cycles in women aged > 40 years, a retrospective analysis was made of all the ICSI cycles which were performed in this age group from 1 October 1991 to 31 December 1995. A total of 525 cycles was performed in 321 patients. In 413 cycles, at least one normally fertilized embryo was available for transfer. In 271 cycles, one to three embryos were replaced while in the remaining 142 cycles at least four embryos were replaced. There was no difference in implantation rate (number of gestational sacs/number of embryos transferred), after the transfer of one to three embryos (5.2%), compared with the transfer of at least four embryos (5.1%). The pregnancy rate/embryo transfer and the clinical pregnancy rate/embryo transfer were, however, higher when at least four embryos were replaced than was the case with one to three embryos (27.5 versus 11.8%, P or = 40 years of age are related to the number of embryos replaced.

A. Van Steirteghem

Papers

Which patients with recurrent implantation failure after IVF benefit from PGD for aneuploidy screening

Preimplantation genetic diagnosis for Charcot-Marie-Tooth disease type 1A.

Intracytoplasmic sperm injection three years after the birth of the first ICSI child.

Association of ultrarapid freezing of mouse oocytes with increased polyploidy at the pronucleate stage, reduced cell numbers in blastocysts and impaired fetal development.

The role of the number of replaced embryos on intracytoplasmic sperm injection outcome in women over the age of 40.