An Individual-Based Diploid Model Predicts Limited Conditions Under Which Stochastic Gene Expression Becomes Advantageous

Recent studies suggest the existence of a stochasticity in gene expression (SGE) in many organisms, anditsnon-negligible effecton their phenotype and fitness. To date, however, how SGE affects the key parameters of population genetics are not well understood. SGE can increase the phenotypic variation and act as a load for individuals, if they are at the adaptive optimum in a stable environment. On the other hand, part of the phenotypic variation caused by SGE might become advantageous if individuals at the adaptive optimum become genetically less-adaptive, for example due to an environmental change. Furthermore, SGE of unimportant genes might have little or no fitness consequences. Thus, SGE can be advantageous, disadvantageous, or selectively neutral depending on its context. In addition, there might be a genetic basis that regulates magnitude of SGE, which is often referred to as “modifier genes,” but little is known about the conditions under which such an SGE-modifier gene evolves. In the present study, we conducted individual-based computer simulations to examine these conditions in a diploid model. In the simulations, we considered a single locus that determines organismal fitness for simplicity, and that SGE on the locus creates fitness variation in a stochastic manner. We also considered another locus that modifies the magnitude of SGE. Our results suggested that SGE was always deleterious in stable environments and increased the fixation probability of deleterious mutations in this model. Even under frequently changing environmental conditions, only very strong natural selection made SGE adaptive. These results suggest that the evolution of SGE-modifier genes requires strict balance among the strength of natural selection, magnitude of SGE, and frequency of environmental changes. However, the degree of dominance affected the condition under which SGE become sadvantageous, indicating a better opportunity for the evolution of SGE in different genetic models

Fine structure of OPCs observed by SBF-SEM

Oligodendrocyte precursor cells (OPC) arise from restricted regions of the central nervous system (CNS) and differentiate into myelin-forming cells after migration, but their ultrastructural characteristics have not been fully elucidated. This study examined the three-dimensional ultrastructure of OPCs in comparison with other glial cells in the early postnatal optic nerve by serial block-face scanning electron microscopy. We examined 70 putative OPCs (pOPC) that were distinct from other glial cells according to established morphological criteria. The pOPCs were unipolar in shape with relatively few processes, and their Golgi apparatus were localized in the perinuclear region with a single cisterna. Astrocytes abundant in the optic nerve were distinct from pOPCs and had a greater number of processes and more complicated Golgi apparatus morphology. All pOPCs and astrocytes contained a pair of centrioles (basal bodies). Among them, 45% of pOPCs extended a short cilium, and 20% of pOPCs had centrioles accompanied by vesicles, whereas all astrocytes with basal bodies had cilia with invaginated ciliary pockets. These results suggest that the fine structures of pOPCs during the developing and immature stages may account for their distinct behavior. Additionally, the vesicular transport of the centrioles, along with a short cilium length, suggests active ciliogenesis in pOPCs

A CASE OF HODGKIN’S DISEASE EXHIBITING ERYTHRODERMIA PROBABLY DUE TO ALLERGIC REACTION TO VINCA ALKALOIDS

症例は58歳の男性。Hodgkin病の診断確定後，MOPP療法を開始したところ紅皮症の発現および好酸球増加を認めた。しかし，VCRとVDSをetoposideに変更すると紅皮症の発現はみられなくなり，治療の継続が可能となり寛解した。本例における紅皮症は，臨床経過からvinca alkaloid剤に対するアレルギー反応によると考えられた。VCR,VDSの主な副作用は血液障害，神経障害であるが，VDSにより紅皮症を生じた例の報告はまだない。化学療法には，複数の薬剤が同時に使われる場合が多く，副作用出現時にその原因薬剤の同定はしばしば困難である。したがって，薬剤の副作用についての症例の集積が重要と考えられる。A 58 year-old man with Hodgkin’s disease exhibited erythrodermia due to allergic reaction to vincristine sulfate (VCR) and vindesine sulfate (VDS). However, chemotherapy could be continued by changing VCR and VDS to etoposide without allergic symptom. Clinical observation strongly suggested that erythrodermia was due to the use of vinca alkaloids in this patient. Hematological and neurological side effects have been well known for VDS and VCR, but erythrodermia has not yet been reported as being caused by these agents. It is often difficult to difference drugs as a cause of an allergic reaction when several drugs are used together. Therefore, it is important to collect all the cases showing the effects of drugs

A Role of Suppressor of Cytokine Signaling 3 (SOCS3/CIS3/SSI3) in CD28-mediated Interleukin 2 Production

Suppressor of cytokine signaling (SOCS)3 has been characterized as a negative feedback regulator in cytokine-mediated Janus kinase signal transducer and activator of transcription signaling. However, this study shows that T cells from transgenic mice expressing SOCS3 exhibit a significant reduction in interleukin (IL)-2 production induced by T cell receptor cross-linking when T cells are costimulated with CD28. Decreased protein expression in SOCS3+/− mice enhanced CD28-mediated IL-2 production, clearly indicating the correlation between expression level of SOCS3 and IL-2 production ability. The SOCS3 protein interacted with phosphorylated CD28 through its SH2 domain but not the kinase inhibitory region. In addition, a point mutation in the SOCS3 SH2 domain attenuated the inhibition of CD28 function in IL-2 promoter activation. Committed T helper (Th)2 cells exclusively expressed SOCS3 and production of Th2 cytokines, such as IL-4 and IL-5, was much less dependent on CD28 costimulation compared with interferon γ and IL-2 production in Th1 cells. Consistent with this notion, the expression level of SOCS3 in early T cell activation influenced the ability of IL-2 production induced by CD28 costimulation. Therefore, the SOCS3 may play an alternative role in prohibiting excessive progression of CD28-mediated IL-2 production

Promotion of rabbit ligament healing by local delivery of hepatocyte growth factor

Background: Extracapsular ligament injuries of the knee and ankle are common injuries. Ligaments heal slowly, usually over months or longer by scar formation rather than by tissue regeneration. This study was performed to evaluate the therapeutic effect of locally delivered recombinant hepatocyte growth factor (HGF) on the early healing of ligaments in a rabbit model. Methods: Japanese white rabbits were subjected to a standardized gap injury in the medial collateral ligaments (MCLs) of both knees. Each rabbit underwent bilateral transection of the midsubstance of the MCL, which was not repaired. During postoperative days 0-6, the rabbits were injected with 10 μg human recombinant HGF into the right MCL, while the left MCL was injected with saline alone. One, 3, 6, and 12 weeks after surgery, experimental rabbits were sacrificed. The structural properties of the femur-MCL-tibia complex were then assessed and the tissue was subjected to histological evaluation. To see the distribution of cells that express c-Met receptor, the tissue was subjected to immunohistochemistry. Results: Immunohistochemical evaluation revealed that c-Met expression was observed particularly at opposing ligament ends in the HGF-treated limbs 1 week after surgery. Histological evaluation revealed earlier neovascularization and more aligned collagen fibers in the MCLs of the HGF-treated group than the control group. In mechanical evaluations, similar ligament failure modes were noted in the two groups. After 3 weeks, HGF-treated limbs had significantly improved structural properties than the paired control limbs. Conclusions: Our findings indicate local administration of recombinant HGF promotes early steps in ligament healing and the repair of structural properties in a rabbit model. Local administration of HGF may represent a new therapeutic approach to accelerating healing and rehabilitation after ligament injury. © 2011 The Japanese Orthopaedic Association