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At least 667 records · Page 37Linked to original sources
PubMed2006

Positive and negative regulation of Natural Killer cells: therapeutic implications.

Natural Killer (NK) cells can mediate numerous anti-tumor and anti-viral effector functions as well as play important immunoregulatory roles in various disease states. Promoting the ability of NK cells to respond in an immunotherapeutic setting has often been sought by the addition of NK cell-stimulating factors. However, such therapies are often found to be insufficient, which may in part be due to the presence of inhibitory influences on the NK cell. NK cells can respond to a plethora of cytokines which are generated by numerous cell types and these interactions can markedly affect NK cell survival and activity. NK cells also possess multiple activating and inhibiting receptors which can alter their function. Whether the NK cell will become activated or not can depend on a complex balance of activating and inhibitory signals received by the cell and modulation of these signals may shift the balance on NK activation. This review discusses the various activating and inhibitory stimuli which can act on NK cells, and suggests that future NK cell-based therapies consider not only activating stimuli but also removal of possible inhibitory elements which could prevent optimal NK cell function and/or survival.

Animals↗
PubMed2006

Autoimmunity in systemic lupus erythematosus: integrating genes and biology.

Susceptibility to the autoimmune phenotype of systemic lupus erythematosus (SLE) is heritable. Linkage analysis and recent advances in the field of single nucleotide polymorphisms (SNPs) have resulted in the identification of several genetic loci and functional allelic variants of signaling proteins which have become the mainstay of understanding disease susceptibility and exploring the basis of autoimmunity in SLE. However, genetic heterogeneity and possible epistatic interactions among genetic elements have precluded replication of these findings in multiple population groups and thus complicated their interpretation. In this regard, the discovery that a plethora of normal signaling proteins are expressed in abnormal amounts in immune cells from patients with SLE has gained significance. Thus, the key to precise elucidation of the pathologic basis of autoimmunity in SLE lies in tying genetics and disease biology. This review highlights recent discoveries of important functional genetic variants and altered expression of normal signaling proteins that network together to disrupt peripheral tolerance and initiate the autoimmune process in SLE.

Animals↗
PubMed2006

Common variable immunodeficiency: The power of co-stimulation.

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immune deficiency in adults. CVID is characterized by the sequelae of an antibody deficiency syndrome: an impaired terminal B cell differentiation results in hypogammaglobulinemia and susceptibility to recurrent infections by encapsulated bacteria. The clinical course of CVID is complicated by a plethora of systemic immunopathology, including autoimmunity, lymphoproliferation, malignancy and sarcoid-like granulomas. Phenotypic and functional studies in CVID patients revealed multiple abnormalities within the innate and adaptive immune system. The recent description of monogenic defects in ICOS, TACI and CD19 focussed our interest to an impaired T cell-B cell collaboration within the germinal center and intrinsic B cell defects as possible explanations for the etiology of CVID.

Animals↗
PubMed2006

The "hospital superbug": social representations of MRSA.

The so-called 'hospital superbug' methcillin-resistant Staphylococcus aureus (MRSA) became a topic of media and political concern in Britain from the middle of the 1990s. It was increasingly politicised in the period leading up to the British General Election of 2005. This study examines the meanings of MRSA that circulate in Britain by analysing newspaper coverage of the disease over the 10-year period 1995-2005. It utilises social representations theory and contextualises MRSA within existing research on representations of emerging infectious diseases (EIDs). A key pattern in the representation of EIDs is to externalise the threat they pose by linking the origin, risk and blame to 'the other' of those who represent them. It is in this light that this study investigates who and what MRSA is associated with and the impact that these associations have on levels of alarm and blame. Key findings are that MRSA is represented as a potentially lethal 'superbug', marking the end of a 'golden age of medicine' in which the story of the discovery of antibiotics has played such a key role. Furthermore, MRSA is constructed around an "it could be you/me" set of assumptions by way of the plethora of human interest stories that dominate the coverage. Finally, the blame for MRSA focuses not on its genesis, but rather on why it spreads. This is attributed to poor hygiene in hospitals, which is ultimately caused by mismanagement of the National Health Service and erosion of the authority and morality symbolised by the 'matron' role. This constellation of meanings informs a somewhat different pattern of response to MRSA when compared to many past EIDs.

Bibliometrics↗
PubMed2004

Human spermatozoa as a model for studying membrane receptors mediating rapid nongenomic effects of progesterone and estrogens.

In the past few years, besides the classical genomic effects of steroid hormones, a plethora of so called rapid non genomic effects have been described in different cell types, which are too rapid to be due to activation of gene expression. Although some of these effects might involve the same nuclear steroid receptors acting on different cellular signalling, others have been ascribed to poorly characterized membrane receptors. Several rapid nongenomic effects of progesterone (P) and estrogens (E) have been recently demonstrated in human spermatozoa. They seem to be mediated by the steroid binding to specific receptors on plasma membrane different from the classical ones. In particular, P has been demonstrated to stimulate calcium influx, tyrosine phosphorylation of sperm proteins, including extracellular signaling regulated kinases, chloride efflux and cAMP increase, finally resulting in activation of spermatozoa through induction of capacitation, hyperactivated motility and acrosome reaction. Conversely, E, by acting rapidly on calcium influx and on protein tyrosine phosphorylation, seem to modulate sperm responsiveness to P. Several attempts have been used to characterize the putative membrane receptors for P (mPR) and E (mER) in spermatozoa, however their isolation still remains elusive. However, in the past few years our laboratory has obtained several evidences supporting the existence and functional activity of mPR and mER in human spermatozoa. To characterize these membrane receptors, we used two antibodies directed against the ligand binding domains of the classical receptors, namely c262 and H222 antibodies for PR and ER respectively, hypothesizing that these regions should be conserved between nongenomic and genomic receptors. In western blot analysis of sperm lysates the antibodies detected a band of about 57 kDa for PR and of 29 kDa for ER, excluding the presence of the classical receptors. On live human spermatozoa, both antibodies were able to block the calcium and AR response to P and E respectively, whereas, antibodies directed against different domains of the classical PR and ER were ineffective. Moreover, c262 antibody also blocks in vitro human sperm penetration of hamster oocytes. Taken together all these data strongly support the existence of mPR and mER different from the classical ones, mediating rapid effects of these steroid hormones in human spermatozoa.

Animals↗
PubMed2006

Xenoestrogens are potent activators of nongenomic estrogenic responses.

Studies of the nuclear transcriptional regulatory activities of non-physiological estrogens have not explained their actions in mediating endocrine disruption in animals and humans at the low concentrations widespread in the environment. However, xenoestrogens have rarely been tested for their ability to participate in the plethora of nongenomic steroid signaling pathways elucidated over the last several years. Here we review what is known about such responses in comparison to our recent evidence that xenoestrogens can rapidly and potently elicit signaling through nongenomic pathways culminating in functional endpoints. Both estradiol (E(2)) and compounds representing various classes of xenoestrogens (diethylstilbestrol, coumestrol, bisphenol A, DDE, nonylphenol, endosulfan, and dieldrin) act via a membrane version of the estrogen receptor-alpha on pituitary cells, and can provoke Ca(2+) influx via L-type channels, leading to prolactin (PRL) secretion. These hormones and mimetics can also cause the oscillating activation of extracellular regulated kinases (ERKs). However, individual estrogen mimetics differ in their potency and temporal phasing of these activations compared to each other and to E(2). It is perhaps in these ways that they disrupt some endocrine functions when acting in combination with physiological estrogens. Our quantitative assays allow comparison of these outcomes for each mimetic, and let us build a detailed picture of alternative signaling pathway usage. Such an understanding should allow us to determine the estrogenic or antiestrogenic potential of different types of xenoestrogens, and help us to develop strategies for preventing xenoestrogenic disruption of estrogen action in many tissues.

Animals↗
PubMed2006

Multipurpose MRG domain involved in cell senescence and proliferation exhibits structural homology to a DNA-interacting domain.

The ubiquitous MRG/MORF family of proteins is involved in cell senescence, or the terminal loss of proliferative potential, a model for aging and tumor suppression at the cellular level. These proteins are defined by the approximately 20 kDa MRG domain that binds a plethora of transcriptional regulators and chromatin-remodeling factors, including the histone deacetylase transcriptional corepressor mSin3A and the novel nuclear protein PAM14, and they are also known components of the Tip60/NuA4 complex via interactions with the MRG binding protein (MRGBP). We present here the crystal structure of a prototypic MRG domain from human MRG15 whose core consists of two orthogonal helix hairpins. Despite the lack of sequence similarity, the core structure has surprisingly striking homology to a DNA-interacting domain of the tyrosine site-specific recombinases XerD, lambda integrase, and Cre. Site-directed mutagenesis studies based on the X-ray structure and bioinformatics identified key residues involved in the binding of PAM14 and MRGBP.

Amino Acid Sequence↗
PubMed2006

Purification and 3D structural analysis of oligomeric human multidrug transporter ABCG2.

ABCG2 is a multidrug efflux pump associated with resistance of cancer cells to a plethora of unrelated drugs. ABCG2 is a "half-transporter," and previous studies have indicated that it forms homodimers and higher oligomeric species. In this manuscript, electron microscopic structural analysis directly addressed this issue. An N-terminal hexahistidine-tagged ABCG2(R482G) isoform was expressed to high levels in insect cells. An extensive detergent screen was employed to effect extraction of ABCG2(R482G) from membranes and identified only the fos-choline detergents as efficient. Soluble protein was purified to >95% homogeneity by a three-step procedure while retaining the ability to bind substrates. Cryonegative stain electron microscopy of purified ABCG2(R482G) provided 3D structural data at a resolution of approximately 18 A. Single-particle analysis revealed that the complex forms a tetrameric complex ( approximately 180 A in diameter x approximately 140 A high) with an aqueous central region. We interpret the tetrameric structure as comprising four homodimeric ABCG2(R482G) complexes.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2004

The role of profilin complexes in cell motility and other cellular processes.

Profilins are small actin-binding proteins that are essential in all organisms that have been examined to date. In vitro, profilins regulate the dynamics of actin polymerization, which is their key role in vivo during cell motility. However, there is growing evidence that, apart from actin binding, profilins function as hubs that control a complex network of molecular interactions. Profilins interact with a plethora of proteins and the importance of this aspect of their function is just beginning to be understood. In this article, I will summarize recent findings in mammalian cells and mice, and discuss the evidence of a role for profilins in cellular processes such as membrane trafficking, small-GTPase signaling and nuclear activities, in addition to neurological diseases and tumor formation.

Animals↗
PubMed2006

Functional distinctions of protein kinase B/Akt isoforms defined by their influence on cell migration.

The three mammalian members of the protein kinase B/Akt (PKB/Akt) family have been implicated in a plethora of cellular signaling processes with key functions in control of cellular metabolism, growth, proliferation and apoptosis. As a major target of phosphatidylinositol (PI) 3-kinase signaling, the PKB/Akt isoforms also have central roles in a variety of human cancers, with effects on tumor initiation, progression and metastasis. It has been shown that isoform-specific functions of PKB/Akt family members can contribute to tumorigenesis on multiple levels. A series of recent studies documents the isoform-specific functions of PKB/Akt family members in regulation of cellular motility and migration by influencing numerous cellular targets involved in organization of the actin cytoskeleton, cellular interaction with the extracellular matrix, expression of motility genes and establishment of cellular polarity. A thorough insight into the isoform-specific roles of PKB/Akt proteins is essential for a full understanding of the complex biological outcomes elicited by PI 3-kinase and PKB/Akt signaling.

Animals↗
PubMed2006

Role of G-protein-coupled receptor kinase 2 in the heart--do regulatory mechanisms open novel therapeutic perspectives?

G-protein-coupled receptor kinase (GRK) 2 regulates a plethora of cellular processes, including cardiac expression and function of key seven-transmembrane receptors (7TM receptors) such as the beta-adrenergic and angiotensin receptors (Penela P, Murga C, Ribas C, et al.: 2006. Mechanisms of regulation of G-protein-coupled receptor kinases [GRKs] and cardiovascular disease. Cardiovasc Res 69:46-56, Rockman HA, Koch WJ, Lefkowitz RJ: 2002. Seven-transmembrane-spanning receptors and heart function. Nature 415:206-212). Interestingly, these two G-protein-coupled receptor systems are targeted by modern heart failure treatment including beta-adrenergic blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers. Although GRK2 is ubiquitously expressed, its particular importance in the heart has been demonstrated by interesting phenotypes of genetically altered mice that suggest GRK2 inhibition can ameliorate heart failure. In essence, this work suggests GRK2 could be an endogenous receptor blocker targeting both the beta-adrenergic and angiotensin receptors in the heart. This notion immediately suggests it is important to understand the molecular mechanisms that regulate GRK2 activity in the heart. In this review, we provide a detailed presentation of the tight regulation of GRK2 expression levels and protein activity, and we discuss the cardiovascular GRK2 functions and possible therapeutic perspectives.

Animals↗
PubMed2003

Genes that shape the course of ageing.

Recent discoveries have placed the insulin signalling pathways at the heart of the genetic control of longevity. An elegant new study of genes acting downstream of these signals in the nematode worm Caenorhabditis elegans reveals a plethora of information about the complex network of mechanisms that modulate the ageing process.

Aging↗
PubMed2005

The LDL receptor: how acid pulls the trigger.

The low-density lipoprotein receptor normally carries lipoprotein particles into cells, and releases them upon delivery to the low pH milieu of the endosome. Recent structural and functional studies of the receptor, combined with the plethora of prior knowledge about normal receptor function and the effects of disease-associated mutations that cause familial hypercholesterolemia, reveal a detailed molecular model for how the acidic environment of the endosome triggers the release of bound lipoprotein particles. Remarkably, the receptor dynamically interconverts between open (ligand-active) and closed (ligand-inactive) conformations in response to pH, relying on a specific arrangement of fixed and flexible interdomain connections to facilitate efficient binding and release of its lipoprotein ligands.

Binding Sites↗
PubMed2005

Phospholipase C-gamma: diverse roles in receptor-mediated calcium signaling.

Ca2+ is a universal signal: the dynamic changes in its release and entry trigger a plethora of cellular responses. Central to this schema are members of the phospholipase C (PLC) superfamily, which relay information from the activated receptor to downstream signal cascades by production of second-messenger molecules. Recent studies reveal that, in addition to its enzymatic activity, PLC-gamma regulates Ca2+ entry via the formation of an intermolecular lipid-binding domain with canonical transient receptor potential 3 (TRPC3) ion channels. This complex, in turn, controls TRPC3 trafficking and cell-surface expression. Thus, TRPC3 ion channels are functionally linked to both lipase-dependent and -independent activities of PLC-gamma. Understanding the underlying molecular mechanisms that regulate this complex will probably clarify the processes of receptor-activated Ca2+ entry.

Amino Acid Sequence↗
PubMed2004

Drugs against superbugs: private lessons from bacteriophages.

Bacterial genomics has provided a plethora of potential targets for antibacterial drug discovery, however, success in the hunt for new antibiotics will hinge on selecting targets with the highest potential. A recent paper by Liu and coworkers describes a new approach to target selection that uncovers strategies used by bacteriophage to disable bacteria. The method uses key phage proteins to identify and validate vulnerable targets and exploits them further in the identification of new antibacterial leads.

Anti-Bacterial Agents↗
PubMed2005

Engineering regulatory RNAs.

RNA has long been a favoured medium for in vitro evolution and engineering. Functional RNAs produced in vitro can bind small molecules (aptamers), possess catalytic activity (ribozymes) or do both (aptazymes). A plethora of recent work has shown similar strategies used naturally for gene regulation in bacteria. Interest in these natural systems has inspired an effort to engineer and evolve this activity in vivo. A recent paper by Isaacs et al. describes the engineering and in vivo activity of a small RNA that removes translation inhibition by binding the 5' untranslated region of its target mRNA and making the ribosome-binding site accessible.

Animals↗
PubMed2005

Engineering plants with increased disease resistance: what are we going to express?

To engineer plants with increased and durable disease resistance using transgenic technologies we must address two questions. First, what gene or genes do we want to express to improve disease resistance, and second, how are we going to express these genes so that crop yields are actually increased? Emerging technologies are providing us with a plethora of candidate genes that might lead to enhanced crop protection through genetic engineering. These genes can come from plants, from pathogens or from other organisms and several strategies for their manipulation show promise. Here, we discuss recent advances and consider future perspectives for producing plants with durable disease resistance.

Crops, Agricultural↗
PubMed2004

Reading the entrails of chickens: molecular timescales of evolution and the illusion of precision.

For almost a decade now, a team of molecular evolutionists has produced a plethora of seemingly precise molecular clock estimates for divergence events ranging from the speciation of cats and dogs to lineage separations that might have occurred approximately 4 billion years ago. Because the appearance of accuracy has an irresistible allure, non-specialists frequently treat these estimates as factual. In this article, we show that all of these divergence-time estimates were generated through improper methodology on the basis of a single calibration point that has been unjustly denuded of error. The illusion of precision was achieved mainly through the conversion of statistical estimates (which by definition possess standard errors, ranges and confidence intervals) into errorless numbers. By employing such techniques successively, the time estimates of even the most ancient divergence events were made to look deceptively precise. For example, on the basis of just 15 genes, the arthropod-nematode divergence event was 'calculated' to have occurred 1167+/-83 million years ago (i.e. within a 95% confidence interval of approximately 350 million years). Were calibration and derivation uncertainties taken into proper consideration, the 95% confidence interval would have turned out to be at least 40 times larger ( approximately 14.2 billion years).

Animals↗