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

Organ-level physiology is recapitulated in vitro by culturing cells in perfused, microfluidic devices.

Microfluidic organs-on-chips

The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by inhibiting let-7 biogenesis. We have uncovered unexpected roles for the Lin28/let-7 pathway in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promote an insulin-sensitized state that resists high-fat-diet induced diabetes. Conversely, muscle-specific loss of Lin28a or overexpression of let-7 results in insulin resistance and impaired glucose tolerance. These phenomena occur, in part, through the let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. In addition, the mTOR inhibitor, rapamycin, abrogates Lin28a-mediated insulin sensitivity and enhanced glucose uptake. Moreover, let-7 targets are enriched for genes containing SNPs associated with type 2 diabetes and control of fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism.

The Lin28/let-7 Axis Regulates Glucose Metabolism

This article summarizes the clinical definition of ankylosing spondylitis and axial spondyloarthritis, discusses the pathogenesis of these conditions, and reviews approaches to management.

https://www.nejm.org/doi/pdf/10.1056/NEJMra1406182

Ankylosing Spondylitis and Axial Spondyloarthritis

Increasing evidence suggests functional compartmentalization of interphase nuclei. This includes preferential interior localization of gene-rich and early replicating chromosome regions versus peripheral localization of gene-poor and late replicating chromosome regions , association of some active genes with nuclear speckles or transcription "factories", and association of transcriptionally repressed genes with heterochromatic regions. Dynamic changes in chromosome compartmentalization imply mechanisms for long-range interphase chromatin movements. However, live cell imaging in mammalian cells has revealed limited chromatin mobility, described as "constrained diffusion". None of these studies, though, have examined a chromosome locus undergoing an inducible repositioning between two different nuclear compartments. Here we demonstrate migration of an interphase chromosome site from the nuclear periphery to the interior 1-2 hr after targeting a transcriptional activator to this site. Spot redistribution is perturbed by specific actin or nuclear myosin I mutants. Extended periods of chromosome immobility are interspersed with several minute periods in which chromosomes move unidirectionally along curvilinear paths oriented roughly perpendicular to the nuclear envelope at velocities of 0.1-0.9 microm/min over distances of 1-5 microm. Our results suggest an active mechanism for fast and directed long-range interphase chromosome movements dependent directly or indirectly on actin/myosin.

Long-Range Directional Movement of an Interphase Chromosome Site Dependent on Actin and Nuclear Myosin

Fetal hematopoiesis occurs in multiple embryonic niches during development: after their emergence in the aorta/gonad/mesonephros (AGM) region, hematopoietic stem cells (HSC) migrate to the fetal liver (FL) where they actively proliferate and expand, before fetal bone marrow (BM) colonization. In contrast, adult hematopoiesis takes place primarily in BM, and adult HSC are quiescent. At the moment, very little is known about the changes in cell surface markers and regulators of HSC amplification and self-renewal occurring during human FL development: we described a transient CD34CD45CD144 HSC population in the first trimester (T1) FL, and CD90/GPI-80 and CD143 were shown to allow HSC enrichment in the second trimester (T2) FL. However, no surface marker allowing HSC enrichment of CD34CD38 population both in T1 and T2 FL has been described so far. Deciphering regulatory mechanisms that control HSC expansion and self-renewal during FL development could provide important clues to expand HSC for clinical use, and to highlight new fetal signatures which persist abnormally during childhood, leading to pediatric leukemias. We focused on CD117 (c-KIT), widely used in the mouse to isolate HSC-enriched populations in the AGM, FL and placenta during development, and in adult bone marrow. In humans, CD117 also marks the first HSC in the AGM, and the SCF/KIT signaling pathway regulates self-renewal properties of fetal HSC and maintenance of quiescent adult HSC, with many downstream effectors identified as important regulators of the change of HSC proliferative and self-renewal behavior during development. Using CD34CD38as the referent HSC-enriched population, we sorted CD34CD38CD45CD117 cells from T1 and T2 FL, and showed that CD117 expression allows isolation of an HSC-enriched population with high proliferation and self-renewal potential during hepatic hematopoiesis in human development. We first looked for CD117 expression in the CD34CD38 fraction of T1 FL. Since CD34 also marks endothelial cells, we added CD45 to ensure to be looking at the hematopoietic population. As shown in Figure 1, a CD34CD38CD45CD117 (hereafter called CD117) population could be detected as early as 6 weeks of gestation (WG) in T1 FL. It represents 0.35±0.07% of mononuclear cells between 6 and 9 WG and 0.21±0.05% between 9 and 12 WG. This CD117 population is still present in the T2 FL (0.15±0.07%) (Figure 1). Fluorescence-activated cell sorting (FACS) analysis showed that the CD117 population from T1 or T2 FL are CD45RA and did not overlap with the described populations enriched in HSC during FL development or in the umbilical cord blood, such as the CD144CD45, the CD90GPI80, and the CD34CD143 populations,

/pdf/cd117hi-expression-identifies-a-human-fetal-hematopoietic-4w0am71zxt.pdf

Franck Letourneur

Papers

CD117hi expression identifies a human fetal hematopoietic stem cell population with high proliferation and self-renewal potential.