Integrins: Structure and Signaling

Integrins are cell surface transmembrane glycoproteins that function as adhesion receptors in cell-extracellular matrix interactions and link the matrix proteins to the cytoskeleton. The family of human integrins comprises 24 members, each of which is a heterodimer consisting of 1 of 18 alpha- and 1 of 8 beta-subunits. Integrins play an important role in the cytoskeleton organization and in transduction of intracellular signals, regulating various processes such as proliferation, differentiation, apoptosis, and cell migration. This review summarizes current views on the structure of integrins, integrin associated proteins, and biochemical mechanisms underlying their signaling functions.     

Circulating tumor microemboli: Progress in molecular understanding and enrichment technologies

Circulating tumor cells (CTCs) and their clusters, also known as circulating tumor microemboli (CTM), have emerged as valuable tool that can provide mechanistic insights into the tumor heterogeneity, clonal evolution, and stochastic events within the metastatic cascade. However, recent investigations have hinted that CTM may not be mere aggregates of tumor cells but cells comprising CTM exhibit distinct phenotypic and molecular characteristics in comparison to single CTCs. Moreover, in many cases CTM demonstrated higher metastatic potential and resistance to apoptosis as compared to their single cell counterparts. Thus, their evaluation and enumeration may provide a new dimension to our understanding of cancer biology and metastatic cancer spread as well as offer novel theranostic biomarkers. Most of the existing technologies for isolation of hematogenous tumor cells largely favor single CTCs, hence there is a need to devise new approaches, or re-configure the existing ones, for specific and efficient CTM isolation. Here we review existing knowledge and insights on CTM biology. Furthermore, a critical commentary on current and emerging trends in CTM enrichment and characterization along with recently developed ex-vivo CTC expansion methodologies is presented with the aim to facilitate researchers to identify further avenues of research and development.     

一种宏观基因调控分子SATB1

自身多聚化的SATB1(special AT-rich sequences binding protein 1)围绕异染色质形成笼状结构分布在细胞核中,SATB1不仅结合染色质DNA的核基质结合区(matrix attachment regions,MARs),也结合核基质,能够使DNA锚定在核基质并形成袢环状结构(loop)。SATB1的磷酸化、乙酰化和小泛素化样修饰可调节其DNA结合能力和细胞核内亚结构的定位;SATB1与多种蛋白质相互作用,能够募集染色质重塑复合物和组蛋白修饰酶,实现对其靶基因表达的时空特异性调控。SATB1在调节细胞分化、细胞凋亡、肿瘤生长与转移和X染色体失活等方面起到重要作用,并有可能成为肿瘤转移的治疗靶点。     

Biological control of pedological and hydro-geomorphological processes in a deciduous forest ecosystem

This study describes the effect of soil fauna and vegetation on the development of landscapes and how these actually control soil formation, geomorphological development and hydrological response. The study area is located in a semi-natural deciduous forest on marl in Luxembourg, with a strong texture contrast in the soil at 15–25 cm depth (luvic planosols). The methodology applied is both based on hydrological and geomorphological field measurements on runoff, sediment yield, perched water table dynamics, geomorphological survey, pedological survey and measurements related to in situ ectorganic horizon dynamics and litter decay, soil animal activity, as well as measurements of dynamic soil properties such as soil moisture and swelling and shrinkage. The results show that there is a positive feedback between tree type, soil fauna activity and the development of pipes, partial areas, soils and geomorphology. The landscape can be divided into two main types: Areas where Stellario-Carpinetum vegetation and partial areas are common and areas with Milio-Fagetum vegetation on dry slopes, which are differentiating more and more over time as a result of ongoing geo-ecosystem processes, and which also reflected in their sediment yield. The hydrological response is highly different for both landscape compartments as they are dominated by matrix (Beech) and pipe flow (Hornbeam) respectively. Soil fauna and tree type drive both soil and geomorphological evolution and they both can be considered as important ecosystem engineers.     

Bone morphogenetic protein (BMP)1-3 enhances bone repair

Members of the astacin family of metalloproteinases such as human bone morphogenetic protein 1 (BMP-1) regulate morphogenesis by processing precursors to mature functional extracellular matrix (ECM) proteins and several growth factors including TGFβ, BMP2, BMP4 and GFD8. We have recently discovered that BMP1-3 isoform of the Bmp-1 gene circulates in the human plasma and is significantly increased in patients with acute bone fracture. We hypothesized that circulating BMP1-3 might have an important role in bone repair and serve as a novel bone biomarker. When administered systemically to rats with a long bone fracture and locally to rabbits with a critical size defect of the ulna, recombinant human BMP1-3 enhanced bone healing. In contrast, neutralization of the endogenous BMP1-3 by a specific polyclonal antibody delayed the bone union. Invitro BMP1-3 increased the expression of collagen type I and osteocalcin in MC3T3-E₁ osteoblast like cells, and enhanced the formation of mineralized bone nodules from bone marrow mesenchymal stem cells. We suggest that BMP1-3 is a novel systemic regulator of bone repair.     

Matrix Metalloproteinases of Normal Human Tissues

This review considers biochemical properties of the family of matrix metalloproteinases (MMPs) of normal human tissues and the involvement of these enzymes in morphogenesis. Four main MMP subfamilies are characterized, and a group of other MMPs is described. Data on mechanisms of activation and inhibition of MMPs in certain tissues during various physiological processes (embryogenesis, angiogenesis, tissue growth and involution) are considered. Information about tissue inhibitors of MMP is presented, and the ability of these inhibitors to regulate the activity of MMPs is analyzed.     

Neurite outgrowth is enhanced by laminin-mediated down-regulation of the low affinity neurotrophin receptor, p75NTR

Laminin (LN), an extracellular matrix component, is a key factor in promoting axonal regeneration, coordinately regulating growth in conjunction with trophic signals provided by the neurotrophins, including nerve growth factor (NGF). This study investigated potential interactions between the LN and NGF-mediated signaling pathways in PC12 cells and primary neurons. Neurite outgrowth stimulated by NGF was enhanced on a LN substrate. Western blot analysis of pertinent signal transduction components revealed both enhanced phosphorylation of early signaling intermediates upon co-stimulation, and a LN-induced down-regulation of p75NTR which could be prevented by the addition of integrin inhibitory arginine-glycine-aspartate (RGD) peptides. This p75NTR down-regulation was associated with a LN-mediated up-regulation of PTEN and resulted in a decrease in Rho activity. Studies using over-expression or siRNA-mediated knock-down of PTEN demonstrate a consistent inverse relationship with p75NTR, and the over-expression of p75NTR impaired neurite outgrowth on a LN substrate, as well as resulting in sustained activation of Rho which is inhibitory to neurite outgrowth. p75NTR is documented for its role in the transduction of inhibitory myelin-derived signals, and our results point to extracellular matrix regulation of p75NTR as a potential mechanism to ameliorate inhibitory signaling leading to optimized neurite outgrowth.     

Fisher information matrix of the Dirichlet-multinomial distribution

In this paper we derive explicit expressions for the elements of the exact Fisher information matrix of the Dirichlet-multinomial distribution. We show that exact calculation is based on the beta-binomial probability function rather than that of the Dirichlet-multinomial and this makes the exact calculation quite easy. The exact results are expected to be useful for the calculation of standard errors of the maximum likelihood estimates of the beta-binomial parameters and those of the Dirichlet-multinomial parameters for data that arise in practice in toxicology and other similar fields. Standard errors of the maximum likelihood estimates of the beta-binomial parameters and those of the Dirichlet-multinomial parameters, based on the exact and the asymptotic Fisher information matrix based on the Dirichlet distribution, are obtained for a set of data from Haseman and Soares (1976), a dataset from Mosimann (1962) and a more recent dataset from Chen, Kodell, Howe and Gaylor (1991). There is substantial difference between the standard errors of the estimates based on the exact Fisher information matrix and those based on the asymptotic Fisher information matrix.