Comparative Dynamics of Retrograde Actin Flow and Focal Adhesions: Formation of Nascent Adhesions Triggers Transition from Fast to Slow Flow

Dynamic actin network at the leading edge of the cell is linked to the extracellular matrix through focal adhesions (FAs), and at the same time it undergoes retrograde flow with different dynamics in two distinct zones: the lamellipodium (peripheral zone of fast flow), and the lamellum (zone of slow flow located between the lamellipodium and the cell body). Cell migration involves expansion of both the lamellipodium and the lamellum, as well as formation of new FAs, but it is largely unknown how the position of the boundary between the two flow zones is defined, and how FAs and actin flow mutually influence each other. We investigated dynamic relationship between focal adhesions and the boundary between the two flow zones in spreading cells. Nascent FAs first appeared in the lamellipodium. Within seconds after the formation of new FAs, the rate of actin flow decreased locally, and the lamellipodium/lamellum boundary advanced towards the new FAs. Blocking fast actin flow with cytochalasin D resulted in rapid dissolution of nascent FAs. In the absence of FAs (spreading on poly-L-lysine-coated surfaces) retrograde flow was uniform and the velocity transition was not observed. We conclude that formation of FAs depends on actin dynamics, and in its turn, affects the dynamics of actin flow by triggering transition from fast to slow flow. Extension of the cell edge thus proceeds through a cycle of lamellipodium protrusion, formation of new FAs, advance of the lamellum, and protrusion of the lamellipodium from the new base.     

基于7次跨膜受体的药物发现基本方法——细胞检测

随着检测技术进步,含7个跨膜α螺旋结构的受体性质已渐为人们所了解。7次跨膜（7TM）受体不仅具有开关功能,更类似于信息微处理器;特定配体只能参与特定受体介导的部分信号机制,这就为药物发现开拓了一个新领域。为进一步发现7TM受体与配体间的新行为并量化评价药物对这一复杂系统的作用效能,进而指导药物化学研究,药理学检测已成为关注焦点。本文阐述从还原重组体到整体系统测定方法的回归,讨论药物效价与评价其效应的特定检测方法间的联系,强调新的检测方法在药物发现过程中的价值。     

Expression of SDF-1/CXCR4 in injured human kidneys

The chemokine SDF-1α is involved in migration, survival, and development of multiple cells, most notably of hematopoietic stem cells (HSC) expressing its ligand CXCR4. Recently, we have shown engraftment of human HSC in the ischemically injured murine kidney, presumably mediated by SDF-1α. To further investigate a possible role of SDF-1α in the recruitment of CXCR4⁺ cells in human renal disease of varying etiologies, we immunostained human biopsies of immunoglobulin (Ig)A nephropathy, minimal-change nephrotic syndrome, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, chronic pyelonephritis, and acute tubular necrosis (ATN) for SDF-1α, CXCR4, and CD45, a pan-hematopoietic marker. Irrespective of the diagnosis, intense SDF-1α immunoreactivity was localized to distal tubules and collecting ducts, whereas CXCR4 showed intense staining in both distal and proximal tubules. In addition, whereas varying degrees of CD45⁺ cell infiltrates were observed in all biopsies, we found focal infiltrates of CXCR4⁺ cells mostly localized to the corticomedullary junction only in ischemic ATN. This correlated with more extensive staining for SDF-1α in these sites. In all investigated renopathologic conditions, CD45+ leukocyte recruitment to the kidney seems not to be driven by SDF-1α/CXCR4 interaction. A contribution of SDF-1α for influx of CXCR4⁺ cells in the vicinity of arcuate vessels is suggested only in human ATN.     

Endogenous humoral determinants of vascular endothelial dysfunction as triggers of acute poisoning complications

The vascular endothelium is not only the semipermeable membrane that separates tissue from blood but also an organ that regulates inflammation, vascular tone, blood clotting, angiogenesis and synthesis of connective tissue proteins. It is susceptible to the direct cytotoxic action of numerous xenobiotics and to the acute hypoxia that accompanies acute poisoning. This damage is superimposed on the preformed state of the vascular endothelium, which, in turn, depends on many humoral factors. The probability that an exogenous toxicant will cause life-threatening dysfunction of the vascular endothelium, thereby complicating the course of acute poisoning, increases with an increase in the content of endogenous substances in the blood that disrupt endothelial function. These include ammonia, bacterial endotoxin, indoxyl sulfate, para-cresyl sulfate, trimethylamine N-oxide, asymmetric dimethylarginine, glucose, homocysteine, low-density and very-low-density lipoproteins, free fatty acids and products of intravascular haemolysis. Some other endogenous substances (albumin, haptoglobin, haemopexin, biliverdin, bilirubin, tetrahydrobiopterin) or food-derived compounds (ascorbic acid, rutin, omega-3 polyunsaturated fatty acids, etc.) reduce the risk of lethal vascular endothelial dysfunction. The individual variability of the content of these substances in the blood contributes to the stochasticity of the complications of acute poisoning and is a promising target for the risk reduction measures. Another feasible option may be the repositioning of drugs that affect the function of the vascular endothelium while being currently used for other indications.     

Uterine artery embolization for symptomatic fibroids with imaging follow up

The aim of this study was to determine the effectiveness of uterine artery embolization (UAE) as a primary treatment method in treatment of symptomatic fibroids, whether there are any preembolization MRI characteristics of fibroid predictive of reduction in volume and assess reduction in uterine and dominant fibroid volumes using ultrasound (US) and MRI. Study was carried out in total of 32 patients aged 25–49 years (mean 40.9 years). Uterine and dominant fibroid volume were determined using US and MRI before UAE, MRI and US at 3 months and US alone at 6 and 12 months post‐UAE, supplemented by clinical evaluation at interval of 3, 6 and 12 months. Procedure was carried out through unilateral femoral puncture using poly vinyl alcohol (PVA) particles 355–500 μm in size. All 32 patients had successful procedures. Overall, 25 patients responded, giving a clinical success rate of 78.12%. Mean reduction in volume of uterus and fibroid was 33 and 59.7% and 48.9 and 75.5% on US at 3 and 12 months respectively, and 33.3 and 58.6% on MRI at 3 months. Volume reduction on US and MRI at 3 months was highly correlative. There was no statistical difference in size reduction in volume of fibroids, which were hypointense or hyperintense on T2‐weighted image (T2WI) on pre‐UAE MRI. Uterine artery embolization leads to good technical success and fibroid volume reduction. Ultrasound alone may be used for follow up of patients post‐UAE. Preprocedure signal characteristics on T2WI are not predictors of volume reduction after UAE.