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PubMed2006

Portrait of multifaceted transporter, the multidrug resistance-associated protein 1 (MRP1/ABCC1).

MRP1 (ABCC1) is a peculiar member of the ABC transporter superfamily for several aspects. This protein has an unusually broad substrate specificity and is capable of transporting not only a wide variety of neutral hydrophobic compounds, like the MDR1/P-glycoprotein, but also facilitating the extrusion of numerous glutathione, glucuronate, and sulfate conjugates. The transport mechanism of MRP1 is also complex; a composite substrate-binding site permits both cooperativity and competition between various substrates. This versatility and the ubiquitous tissue distribution make this transporter suitable for contributing to various physiological functions, including defense against xenobiotics and endogenous toxic metabolites, leukotriene-mediated inflammatory responses, as well as protection from the toxic effect of oxidative stress. In this paper, we give an overview of the considerable amount of knowledge which has accumulated since the discovery of MRP1 in 1992. We place special emphasis on the structural features essential for function, our recent understanding of the transport mechanism, and the numerous assignments of this transporter.

Adenosine Triphosphate↗
PubMed2003

Mitochondrial portraits of the Madeira and Açores archipelagos witness different genetic pools of its settlers.

We have studied the matrilineal genetic composition of the Madeira and Açores north Atlantic archipelagos, which were settled by the Portuguese in the 15th century. Both archipelagos, and particularly Madeira, were involved in a complex commercial network established by the Portuguese, which included the trading of slaves across the Atlantic. One hundred and fifty-five mtDNAs sampled from the Madeira and 179 from the Açores archipelagos were analysed for the hypervariable segment I (HVS-I), and for haplogroup-diagnostic coding-region RFLPs. The different settlement histories of both groups of islands are well reflected in their present day mtDNA pool. Although both archipelagos show identical diversity values, they are clearly different in their haplogroup content. Madeira displays a stronger sub-Saharan imprint, with haplogroups L1-L3 constituting about 13% of the lineages. Also, the relative frequencies of L sub-clusters in Madeira and mainland Portugal suggests that, at least in part, African presence in Madeira can be attributed to a direct gene flow from West Africa and not via Portugal. A comparison of the genetic composition of these two archipelagos with the Canary Islands, specially taking into account that their European source population was essentially from the Iberian Peninsula, testifies the stronger impact of the North African U6 cluster in the Canaries. This group is present in Madeira at a moderate frequency, but very reduced in the Açores. Nevertheless the recorded introduction of Canary native Guanches, who are characterized by the presence of particular sub-clade U6b1, has left no detectable imprints in the present day population of Madeira.

DNA↗
PubMed1990

Immunoproliferative small intestinal disease: portrait of a potentially preventable cancer from the Third World.

PURPOSE: To review the recent progress in the understanding of clinical and laboratory characterization as well as management of immunoproliferative small intestinal disease (IPSID). DATA IDENTIFICATION: A literature search was conducted using Index Medicus, MEDLINE (1962 to 1989), and bibliographies of identified relevant articles. STUDY SELECTION: All international comprehensive reviews, reported epidemiologic or immunologic studies, and prospective clinical trials published or abstracted in English were selected. RESULTS OF DATA SYNTHESIS: A high incidence of lymphoma primarily in the gastro-intestinal tract in Third World countries has stimulated enormous epidemiologic and pathogenetic interests globally. IPSID, with a distinctive biologic marker (alpha heavy chain para-protein), affects the young underprivileged population of those countries. The initially benign-appearing antibiotic-responsive immunoproliferative lesions often evolve to fatal high-grade lymphomas. Roles of environmental and host factors in this evolutionary course are emerging. Recently demonstrated malignant potentials form the early onset of pathogenesis have given a new dimension to the traditional management strategy of IPSID. CONCLUSIONS: Epidemiologic, immunologic, and pathogenetic data that have emerged over the last 25-year study of IPSID have improved our understanding about the complexity of infection-immunity-cancer interrelationships, comparable to those that have arisen from the study of the acquired immunodeficiency syndrome. Early detection and institution of antimicrobial-based treatment regimens with judicious and consistent follow-up can save the lives of many young patients whose manpower is badly needed in Third World countries.

Humans↗
PubMed1990

Poxviruses: an emerging portrait of biological strategy.

The meeting offered ample evidence that the field of poxvirology has truly come of age. Many investigators were attracted to the field by its experimental feasibility; indeed, the virions are "in vitro transcription systems" and the genome is a "cDNA library." The viral life cycle is synchronous and rapid and can be studied genetically and biochemically in a wide range of cell types. What has become clear is that the virus also offers a unique opportunity to dissect a range of biological problems. The enzymes involved in nucleic acid metabolism are numerous and easily accessible to study; vaccinia is fast evolving into a model system of choice for structure-function studies. The cascade of gene expression offers a chance to investigate in detail the mechanism of trans-acting factors that determine transcriptional specificity, as well as a system to probe the role of genome "chromatin" in dictating the accessibility of transcriptional units. But perhaps the most lasting impression of vaccinia is as a virus that encodes a unique repertoire of proteins governing its survival within the host. Among these are proteins that may activate the next round of cells to be infected, reduce the activation of cells responsible for the inflammatory response, and sabotage the biochemical cascades of host defenses. Never before has a virus held up a mirror so intriguing and so informative.

Congresses as Topic↗
PubMed1992

Aggregation of chymotrypsinogen: portrait by infrared spectroscopy.

Changes in the secondary structure and aggregation of chymotrypsinogen were investigated by infrared difference spectroscopy in conjunction with temperature and pressure tuning IR spectroscopy; both the amide I' band and side chain bands were studied. A prominent component of the amide I' band in the difference spectrum obtained upon cooling a chymotrypsinogen solution, or increasing the hydrostatic pressure, was observed in the region between 1627 and 1622 cm-1. Under denaturing conditions a white gel was formed, which is attributed to irreversible self-association or aggregation. This process was accompanied by the appearance of two new amide I' bands in the infrared spectrum of the protein: a very strong band at 1618 cm-1 and a weak band at 1685 cm-1. These bands are assigned to peptide segments with anti-parallel aligned beta-strands.

Chymotrypsinogen↗
PubMed1995

Traditional healers in Tanzania: sociocultural profile and three short portraits.

Traditional healers are an important part of African societies, but unfortunately the knowledge of the extent and character of traditional healing and the people involved in the practice is limited and impressionistic. They are frequently ignored in studies of user/provider patterns, although they cover the health needs of a substantial proportion of the population. For future health planning it is necessary to know what the reasons are that even in big cities, where western health care services are available, traditional healers flourish, and even compete with each other for certain aspects. The aim of this study was to investigate certain aspects of the profession of traditional healing in general in different areas in Tanzania in order to get an idea about the kind of traditional medical services which are available, and about the people who provide such services. For this reason traditional healers were interviewed with a semi-structured questionnaire in different rural and urban places: in the Kilombero valley (Kilombero/Ulanga district), on the main island of Ukerewe (Ukerewe District), and in the region near Bukoba town (Bukoba District), and in the settlement of Dar es Salaam (largest city of Tanzania). The results of the study show that traditional healers are a very heterogeneous group of persons not having much in common relating to their religion, sex and level of education. The traditional practice is very often taken over from a family member, but also other reasons for becoming a healer, like initiation through ancestor spirits, are very frequently given. More than 50% of the respondents practice full time. These full time practitioners are mainly found among men and in the younger age group. Treatment of in-patients, who can stay in special patient-houses, is offered by half of the traditional healers. Divination used as a diagnostic tool was found mainly among men. Referral of patients to the hospital was mentioned by almost all respondents in cases where they failed with their own treatment or when they knew that the patient would be better treated in the hospital or dispensary.

Adult↗
PubMed1995

A portrait of the juvenile arsonist.

In this study we evaluated if juvenile arsonists (n = 34) differ from juvenile criminals of violence (n = 33) in regard to suicide and mental problems in forensic psychiatric examination. Both arsonists and violent offenders were mostly male, poorly educated, unskilled and unemployed at the times of committing their crimes; and 79% of the arsonists and 58% of the control group had used public health services for treatment of their mental symptoms before the crime. This difference was significant (p = 0.05). Suicide was more common among the arsonists than the control subjects (p = 0.02); 74% of the arsonists had suicidal thoughts and 44% had tried to commit suicide before setting a fire. In the forensic psychiatric examination the arsonists were more often relieved from responsibility than the comparison group (p = 0.02).

Adolescent↗
PubMed1990

Molecular portrait of lens gap junction protein MP70.

A 70-kDa membrane protein (MP70) is a component of the lens fiber gap junctions. Its membrane topology and its N-terminal sequence are similar to those of the connexin family of proteins. Some features of MP70 containing fiber gap junctions are, however, distinct from gap junctions in other mammalian tissues: (i) Lens connexons form crystalline arrays only after cleavage of junctional proteins in vitro. These hexagonal arrays have a periodicity of 13.6 nm which is significantly larger than the 8- 9-nm spacing of liver and heart gap junctions. (ii) Lens fiber gap junctions dissociate in low concentrations of nonionic detergent and this provides an avenue to purify MP70 directly from a membrane mixture. Isolated MP70 in the form of 17 S structures has an appearance consistent with connexon pairs. (iii) The C-terminal half of MP70 is cleaved in situ by a lens endogenous calcium-dependent protease. The processed from MP38 remains in the membrane and is abundant in the central region of the lens. A testable hypothesis for MP70 function is presented.

Connexins↗
PubMed2004

PKA: a portrait of protein kinase dynamics.

Protein kinases play a critical role in the integration of signaling networks in eukaryotic cells. cAMP-dependent protein kinase (PKA) serves as a prototype for this large and highly diverse enzyme family. The catalytic subunit of PKA provides the best example of how a protein kinase recognizes its substrates, as well as inhibitors, and also show how the enzyme moves through the steps of catalysis. Many of the relevant conformational states associated with the catalytic cycle which have been captured in a crystal lattice are summarized here. From these structures, we can begin to appreciate the molecular events of catalysis as well as the intricate orchestration of critical residues in the catalytic subunit that contribute to catalysis. The entire molecule participates. To fully understand signaling by PKA, however, requires an understanding of a large set of related proteins, not just the catalytic subunit. This includes the regulatory subunits that serve as receptors for cAMP and the A kinase anchoring proteins (AKAPs) that serve as scaffolds for PKA. The AKAPs localize PKA to specific sites in the cell by docking to the N-terminus of the regulatory subunits, thus creating microenvironments for PKA signaling. To fully appreciate the diversity and integration of these molecules, one needs not only high-resolution structures but also an appreciation of how these molecules behave in solution. Thus, in addition to obtaining high-resolution structures by X-ray crystallography and NMR, we have used fluorescent tools and also hydrogen/deuterium exchange coupled with mass spectrometry to probe the dynamic properties of these proteins and how they interact with one another. The molecular features of these molecules are described. Finally, we describe a new recombinantly expressed PKA reporter that allows us to monitor PKA activity in living cells.

Adenosine Triphosphate↗