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Functional Insights (functional + insight)
Selected AbstractsPLAC1 (Placenta-specific 1): a novel, X-linked gene with roles in reproductive and cancer biologyPRENATAL DIAGNOSIS, Issue 6 2010Michael Fant Abstract Placenta-specific 1 (PLAC1) is a recently described X-linked gene with expression restricted primarily to cells derived from trophoblast lineage during embryonic development. PLAC1 localizes to a region of the X chromosome thought to be important in placental development although its role in this process has not been defined. This review summarizes our current understanding of its expression, regulation, and function. PLAC1 is expressed throughout human pregnancy by the differentiated trophoblast and localizes to membranous structures in the syncytiotrophoblast, including the microvillous plasma membrane surface. Recent studies have demonstrated that PLAC1 is also expressed by a wide variety of human cancers. Studies of the PLAC1 promoter regions indicate that its expression in both normal placenta and cancer cells is driven by specific interactions involving a combination of transcription factors. Although functional insight into PLAC1 in the normal trophoblast is lacking, preliminary studies suggest that cancer-derived PLAC1 has the potential to promote tumor growth and function. In addition, it also appears to elicit a specific immunologic response that may influence survival in some cancer patients, suggesting that it may provide a therapeutic target for the treatment of some cancers. We also discuss a potential role for PLAC1 as a biomarker predictive of specific pregnancy complications, such as preeclampsia. Copyright © 2010 John Wiley & Sons, Ltd. [source] Prezygapophyseal articular facet shape in the catarrhine thoracolumbar vertebral column,AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY, Issue 4 2010Gabrielle A. Russo Abstract Two contrasting patterns of lumbar vertebral morphology generally characterize anthropoids. "Long-backed" monkeys are distinguished from "short-backed" apes [Benton: The baboon in medical research, Vol. 2 (1967:201)] with respect to several vertebral features thought to afford greater spinal flexibility in the former and spinal rigidity in the latter. Yet, discussions of spinal mobility are lacking important functional insight that can be gained by analysis of the zygapophyses, the spine's synovial joints responsible for allowing and resisting intervertebral movements. Here, prezygapophyseal articular facet (PAF) shape in the thoracolumbar spine of Papio, Hylobates, Pongo, Gorilla, and Pan is evaluated in the context of the "long-backed" versus "short-backed" model. A three-dimensional geometric morphometric approach is used to examine how PAF shape changes along the thoracolumbar vertebral column of each taxon and how PAF shape varies across taxa at corresponding vertebral levels. The thoracolumbar transition in PAF shape differs between Papio and the hominoids, between Hylobates and the great apes, and to a lesser extent, among great apes. At the level of the first lumbar vertebra, the PAF shape of Papio is distinguished from that of hominoids. At the level of the second lumbar vertebra, there is variation to some extent among all taxa. These findings suggest that morphological and functional distinctions in primate vertebral anatomy may be more complex than suggested by a "long-backed" versus "short-backed" dichotomy. Am J Phys Anthropol 142:600,612, 2010. © 2010 Wiley-Liss, Inc. [source] Structural and functional insights into Erwinia carotovora l -asparaginaseFEBS JOURNAL, Issue 17 2008Anastassios C. Papageorgiou Bacterial l -asparaginases are enzymes that catalyze the hydrolysis of l -asparagine to aspartic acid. For the past 30 years, these enzymes have been used as therapeutic agents in the treatment of acute childhood lymphoblastic leukemia. Their intrinsic low-rate glutaminase activity, however, causes serious side-effects, including neurotoxicity, hepatitis, coagulopathy, and other dysfunctions. Erwinia carotovora asparaginase shows decreased glutaminase activity, so it is believed to have fewer side-effects in leukemia therapy. To gain detailed insights into the properties of E. carotovora asparaginase, combined crystallographic, thermal stability and cytotoxic experiments were performed. The crystal structure of E. carotovoral -asparaginase in the presence of l -Asp was determined at 2.5 Å resolution and refined to an Rcryst of 19.2 (Rfree = 26.6%) with good stereochemistry. Cytotoxicity measurements revealed that E. carotovora asparaginase is 30 times less toxic than the Escherichia coli enzyme against human leukemia cell lines. Moreover, denaturing experiments showed that E. carotovora asparaginase has decreased thermodynamic stability as compared to the E. coli enzyme and is rapidly inactivated in the presence of urea. On the basis of these results, we propose that E. carotovora asparaginase has limited potential as an antileukemic drug, despite its promising low glutaminase activity. Our analysis may be applicable to the therapeutic evaluation of other asparaginases as well. [source] Detection of a homotetrameric structure and protein,protein interactions of Paracoccidioides brasiliensis formamidase lead to new functional insightsFEMS YEAST RESEARCH, Issue 1 2010Clayton Luiz Borges Abstract Paracoccidioides brasiliensis causes paracoccidioidomycosis, a systemic mycosis in Latin America. Formamidases hydrolyze formamide, putatively plays a role in fungal nitrogen metabolism. An abundant 45-kDa protein was identified as the P. brasiliensis formamidase. In this study, recombinant formamidase was overexpressed in bacteria and a polyclonal antibody to this protein was produced. We identified a 180-kDa protein species reactive to the antibody produced in mice against the P. brasiliensis recombinant purified formamidase of 45 kDa. The 180-kDa purified protein yielded a heat-denatured species of 45 kDa. Both protein species of 180 and 45 kDa were identified as formamidase by peptide mass fingerprinting using MS. The identical mass spectra generated by the 180 and the 45-kDa protein species indicated that the fungal formamidase is most likely homotetrameric in its native conformation. Furthermore, the purified formamidase migrated as a protein of 191 kDa in native polyacrylamide gel electrophoresis, thus revealing that the enzyme forms a homotetrameric structure in its native state. This enzyme is present in the fungus cytoplasm and the cell wall. Use of a yeast two-hybrid system revealed cell wall membrane proteins, in addition to cytosolic proteins interacting with formamidase. These data provide new insights into formamidase structure as well as potential roles for formamidase and its interaction partners in nitrogen metabolism. [source] Molecular regulation of cognitive functions and developmental plasticity: impact of GABAA receptorsJOURNAL OF NEUROCHEMISTRY, Issue 1 2007Hanns Möhler Abstract By controlling spike timing and sculpting neuronal rhythms, inhibitory interneurons play a key role in regulating neuronal circuits and behavior. The pronounced diversity of GABAergic (,-aminobutyric acid) interneurons is paralleled by an extensive diversity of GABAA receptor subtypes. The region- and domain-specific location of these receptor subtypes offers the opportunity to gain functional insights into the role of defined neuronal circuits. These developments are reviewed with regard to the regulation of sleep, anxiety, memory, sensorimotor processing and post-natal developmental plasticity. [source] INVITED REVIEW: Using genome scans of DNA polymorphism to infer adaptive population divergenceMOLECULAR ECOLOGY, Issue 3 2005JAY F. STORZ Abstract Elucidating the genetic basis of adaptive population divergence is a goal of central importance in evolutionary biology. In principle, it should be possible to identify chromosomal regions involved in adaptive divergence by screening genome-wide patterns of DNA polymorphism to detect the locus-specific signature of positive directional selection. In the case of spatially separated populations that inhabit different environments or sympatric populations that exploit different ecological niches, it is possible to identify loci that underlie divergently selected traits by comparing relative levels of differentiation among large numbers of unlinked markers. In this review I first address the question of whether diversifying selection on polygenic traits can be expected to produce predictable patterns of allelic variation at the underlying quantitative trait loci (QTL), and whether the locus-specific effects of selection can be reliably detected against the genome-wide backdrop of stochastic variability. I then review different approaches that have been developed to identify loci involved in adaptive population divergence and I discuss the relative merits of model-based approaches that rely on assumptions about population structure vs. model-free approaches that are based on empirical distributions of summary statistics. Finally, I consider the evolutionary and functional insights that might be gained by conducting genome scans for loci involved in adaptive population divergence. [source] The structural and functional diversity of Hsp70 proteins from Plasmodium falciparumPROTEIN SCIENCE, Issue 9 2007Addmore Shonhai Abstract It is becoming increasingly apparent that heat shock proteins play an important role in the survival of Plasmodium falciparum against temperature changes associated with its passage from the cold-blooded mosquito vector to the warm-blooded human host. Interest in understanding the possible role of P. falciparum Hsp70s in the life cycle of the parasite has led to the identification of six HSP70 genes. Although most research attention has focused primarily on one of the cytosolic Hsp70s (PfHsp70-1) and its endoplasmic reticulum homolog (PfHsp70-2), further functional insights could be inferred from the structural motifs exhibited by the rest of the Hsp70 family members of P. falciparum. There is increasing evidence that suggests that PfHsp70-1 could play an important role in the life cycle of P. falciparum both as a chaperone and immunogen. In addition, P. falciparum Hsp70s and Hsp40 partners are implicated in the intracellular and extracellular trafficking of proteins. This review summarizes data emerging from studies on the chaperone role of P. falciparum Hsp70s, taking advantage of inferences gleaned from their structures and information on their cellular localization. The possible associations between P. falciparum Hsp70s with their cochaperone partners as well as other chaperones and proteins are discussed. [source] Extracellular and intracellular mechanisms that mediate the metastatic activity of exogenous osteopontinCANCER, Issue 8 2009Jami Mandelin PhD Abstract BACKGROUND: Osteopontin affects several steps of the metastatic cascade. Despite direct correlation with metastasis in experimental systems and in patient studies, the extracellular and intracellular basis for these observations remains unsolved. In this study, the authors used human melanoma and sarcoma cell lines to evaluate the effects of soluble osteopontin on metastasis. METHODS: Exogenous osteopontin or negative controls, including a site-directed mutant osteopontin, were used in functional assays in vitro, ex vivo, and in vivo that were designed to test the extracellular and intracellular mechanisms involved in experimental metastasis. RESULTS: In the extracellular environment, the results confirmed that soluble osteopontin is required for its prometastatic effects; this phenomenon is specific, arginine-glycine-aspartic acid (RGD)-dependent, and evident in experimental models of metastasis. In the intracellular environment, osteopontin initially induced rapid tyrosine 418 (Tyr-418) dephosphorylation of the cellular homolog of the Rous sarcoma virus (c-Src), with decreases in actin stress fibers and increased binding to the vascular endothelium. This heretofore undescribed Tyr dephosphorylation was followed by a tandem c-Src phosphorylation after tumor cell attachment to the metastatic site. CONCLUSIONS: The results of this study revealed a complex molecular interaction as well as a dual role for osteopontin in metastasis that depends on whether tumor cells are in circulation or attached. Such context-dependent functional insights may contribute to antimetastasis strategies. Cancer 2009. © 2009 American Cancer Society. [source] | |||||||||||||