Role of MyD88-adaptor-like gene polymorphism rs8177374 in modulation of malaria severity in the Pakistani population

Abstract Introduction: The present study was designed to investigate the association between rs8177374 polymorphism and malaria symptoms due to exposure of Plasmodium vivax and Plasmodium falciparum. Materials and methods: A total of 454 samples were included in the study (228 malaria patients and 226 healthy individuals). Malaria patients, divided into P. vivax and P. falciparum groups on the basis of the causative species of Plasmodium, were categorized into mild and severe on the basis of clinical outcomes according to WHO criteria. Healthy individuals were used as controls. Allele specific PCR based strategy was used for the identification of rs8177374 SNP. Results: MyD88-adaptor-like gene polymorphism was associated with susceptibility to malaria (p < 0.001). C allele frequency (0.74) was higher in the population compared to T allele frequency (0.26). CT genotype increased the susceptibility of malaria (OR: 2.661; 95% CI: 1.722-4.113) and was positively associated with mild malaria (OR: 5.609; 95% CI: 3.479-9.044, p = 0.00). On the other hand, CC genotype was associated with severe malaria (OR: 3.116; 95% CI: 1.560-6.224, p = 0.00). P. vivax infection rate was higher in CT genotype carriers compared to other genotypes (OR: 3.616; 95% CI: 2.219-5.894, p < 0.001). Conclusion: MyD88-adaptor-like/TIR domain containing adaptor protein polymorphism for single nucleotide polymorphism rs8177374 is related with the susceptibility of malaria.

Cysteine-Rich Secretory Proteins (CRISP) and their role in mammalian fertilization

Epididymal protein CRISPI is a member of the CRISP (Cysteine-RIch Secretory proteins) family and is involved in sperm-egg fusion through its interaction with complementary sites on the egg surface. Results from our laboratory have shown that this binding ability resides in a 12-amino-acid region corresponding to a highly conserved motif of the CRISP family, named Signature 2 (S2). In addition to this, our results revealed that CRISP1 could also be involved in the previous step of sperm binding to the zona pellucida, identifying a novel role for this protein in fertilization. As another approach to elucidate the participation of CRISP1 in fertilization, a mouse line containing a targeted disruption of CRISP1 was generated. Although CRISP1-deficient mice exhibited normal fertility, CRISP1-defficient sperm presented a decreased level of protein tyrosine phosphorylation during capacitation, and an impaired ability to fertilize both zona-intact and zona-free eggs in vitro, confirming the proposed roles for the protein in fertilization. Evidence obtained in our laboratory indicated that testicular CRISP2 would also be involved in sperm-egg fusion. Competition assays between CRISP1 and CRISP2, as well as the comparison of their corresponding S2 regions, suggest that both proteins bind to common complementary sites in the egg. Together, these results suggest a functional cooperation between CRISP1 and CRISP2 to ensure the success of fertilization.

Nidogen Plays a Role in the Regenerative Axon Growth of Adult Sensory Neurons Through Schwann Cells

We previously reported that nidogen is an extracellular matrix protein regulating Schwann cell proliferation and migration. Since Schwann cells play a critical role in peripheral nerve regeneration, nidogen may play a role in it via regulation of Schwann cells. Here, we demonstrate direct evidence that nidogen induces elongation of regenerative axon growth of adult sensory neurons, and that the effect is Schwann cell dependent. Continuous infusion of recombinant ectodomain of tumor endothelial marker 7, which specifically blocks nidogen function in Schwann cells, suppressed regenerative neurite growth in a sciatic nerve axotomy model. Taken together, it is likely that nidogen is required for proper regeneration of peripheral nerves after injury.

Niemann-Pick type C1 protein influences the delivery of cholesterol to the SREBP: SCAP complex

The proposed role of Niemann-Pick type C1 protein (NPC1) in the delivery of low-density lipoprotein (LDL) cholesterol to the sterol regulatory element binding protein (SREBP):SREBP cleavage activation protein (SCAP) complex in the endoplasmic reticulum has been largely based on indirect studies and remains contentious. The major aim of the present study was to assess whether NPC1 is involved in the delivery of LDL cholesterol to the SREBP:SCAP complex. A cell line stably expressing green fluorescence protein-SCAP was cultured in the presence of U18666A, which can induce a Niemann-Pick type C disease phenotype, in order to locate the SREBP:SCAP complex by fluorescence microscopy. Our major finding was that defective NPC1 caused a delay in the ability of LDL cholesterol to suppress SREBP processing. This was shown in a time-course experiment by the effect of LDL on green fluorescence protein-SCAP movement when cells were treated with pharmacological agents to induce a Niemann-Pick type C disease phenotype. We demonstrated directly by fluorescence microscopy that defective NPC1 causes a delay in LDL cholesterol delivery to the endoplasmic reticulum where SCAP senses cholesterol.

Specific structural features of syndecans and heparan sulfate chains are needed for cell signaling

The syndecans, heparan sulfate proteoglycans, are abundant molecules associated with the cell surface and extracellular matrix and consist of a protein core to which heparan sulfate chains are covalently attached. Each of the syndecan core proteins has a short cytoplasmic domain that binds cytosolic regulatory factors. The syndecans also contain highly conserved transmembrane domains and extracellular domains for which important activities are becoming known. These protein domains locate the syndecan on cell surface sites during development and tumor formation where they interact with other receptors to regulate signaling and cytoskeletal organization. The functions of cell surface heparan sulfate proteoglycan have been centered on the role of heparan sulfate chains, located on the outer side of the cell surface, in the binding of a wide array of ligands, including extracellular matrix proteins and soluble growth factors. More recently, the core proteins of the syndecan family transmembrane proteoglycans have also been shown to be involved in cell signaling through interaction with integrins and tyrosine kinase receptors.

Viral membrane fusion: is glycoprotein G of rhabdoviruses a representative of a new class of viral fusion proteins?

Enveloped viruses always gain entry into the cytoplasm by fusion of their lipid envelope with a cell membrane. Some enveloped viruses fuse directly with the host cell plasma membrane after virus binding to the cell receptor. Other enveloped viruses enter the cells by the endocytic pathway, and fusion depends on the acidification of the endosomal compartment. In both cases, virus-induced membrane fusion is triggered by conformational changes in viral envelope glycoproteins. Two different classes of viral fusion proteins have been described on the basis of their molecular architecture. Several structural data permitted the elucidation of the mechanisms of membrane fusion mediated by class I and class II fusion proteins. In this article, we review a number of results obtained by our laboratory and by others that suggest that the mechanisms involved in rhabdovirus fusion are different from those used by the two well-studied classes of viral glycoproteins. We focus our discussion on the electrostatic nature of virus binding and interaction with membranes, especially through phosphatidylserine, and on the reversibility of the conformational changes of the rhabdovirus glycoprotein involved in fusion. Taken together, these data suggest the existence of a third class of fusion proteins and support the idea that new insights should emerge from studies of membrane fusion mediated by the G protein of rhabdoviruses. In particular, the elucidation of the three-dimensional structure of the G protein or even of the fusion peptide at different pH's might provide valuable information for understanding the fusion mechanism of this new class of fusion proteins.

Anormalidades en el sistema adhesivo de neoplasias pulmonares / Abnormalities in adhesión system of pulmonary neoplasms

La progresión de una neoplasia pulmonar requiere alteraciones en la expresión de moléculas de adhesión en la célula tumoral. Un decremento en la expresión de E-cadherina y de las cateninas a y b disminuye la adhesión homotípica e incrementa el número de células neoplásicas liberadas del tumor primario. Las integrinas presentan cambios complejos en su expresión; la capacidad invasiva se ve favorecida por el aumento en la expresión de unas integrinas, como la a 2b 1 y por la disminución en la expresión de otras, como la a 3b 1. Los cambios en la expresión de ICAM-1 favorecen la evasión de la respuesta inmune. La disminución en la densidad de ICAM-1 en la superficie de células tumorales disminuye la posibilidad de contacto célula-célula. El aumento en la concentración de la isoforma soluble de ICAM-1 bloquea los contrarreceptores presentes en las células inmunológicas. También se han identificado alteraciones en moléculas que modulan la adhesión, como FAK y paxilina. Las moléculas de adhesión y los componentes regulatorios de la adhesión, pueden ser blancos farmacológicos para el desarrollo de nuevas terapias adyuvantes para el tratamiento del cáncer.

Proteoglycans in skeletal muscle

1. Proteoglycans are macromolecules composed of a protein and one or mor chains of sulfated carbohydrates, the glycosaminoglycans. Proteoglycans are found on the cell surface and in the extracellular matrix participating in the cell-cell-extracellular matrizx interaction. In this review I present the information accumulated in the past years regarding the presence, characteristics, localization, control of expression and alteration in some pathological states of skeletal muscle proteoglycans. 2. This review presents and discusses current information in this area and some projections for the future in four sections: first, the proteoglycans present in embryonic cells and cell lines from skeletal muscle. Second, the presence of proteoglycans in adult skeletal muscles. Third, the regulation of the expression of skeletal muscle proteoglycans, and fourth, skeletal muscle proteoglycans in pathological conditions

Thrombospondin: relationship to protease and growth factor/cytokine activity

1. The finding in the last two years of different proteins presenting structural homology with platelet thrombospondin (TSP-1) has permitted to establish the existence of a set of related genes referred to as thrombospondin family. While much work remains to be done concerning the characterization of the newly described members of the family, careful studies carried out on TSP-1 have been implicating this high molecular weight molecule (420-450 KDa) in a variety of aspects of celular physiology. 2. The present text discusses the implications of the matrix-bound and fluid TSP-1 forms for cell adhesion and protease activity generation. Their relationships with growth factors in matrices are also discussed

Herpesvírus humanos: consideraçöes estruturais e imunopatogênicas / Human herpesvirus: structural and immunopathogenic considerations

A família herpesviridae contém mais de 120 vírus patogênicos para uma grande variedade de organismos eucarióticos. Diferem de maneira significativa quanto à seqüência de DNA mas apresentam várias propriedades comuns, incluindo a habilidade em estabelecer latência e reativaçäo periódica no hospedeiro. Glicoproteínas de membranas, codificadas pelos herpesvírus humanos, säo importantes determinantes da patogenicidade viral, além de importantes estimuladores da resposta imune, tornandos-se os melhores candidatos para futuras vacinas.

Thy-1 functions as a recognition/signaling molecule during mouse T lymphocyte development

Thy-1 is a prototype of mammalian glycosilphosphatidylinositol(GPI)-anchored molecules and belongs to the Ig sperfamily. This cell surface glycoprotein is expressed on mouse T lymphocytes, neurons and hematopoietic stem cells. Despite detailed structural studies, little is known about the physiological role(s) of Thy-1. We discuss here our results on the of Thy-1 in immature T lymphocytes during intrathymic maturation. It was observed that Thy-1-mediated adhesion of mouse thymocytes to thymic stromal cells occurs through interaction with an unknown ligand. The interaction occurs by a Ca²+ -independent mechanism and does not require TCR/CD3 surface expression. To evaluate the signal transduction upon Thy-1 ligation in immature thymocytes, we cultured mouse thymocytes with monoclonal antibodies specific for Thy-1, immobilized onto the tissue culture plates. Monoclonal antibodies directed at determinants located in a defined epitope domain, but not others, triggered marked physiological cell death (apoptosis) of immature thymocytes, as evidenced by morphological and biochemical data. This apoptosis is independent of the cell surface expression of TCR/CD3. It is a developmentally regulated process since the period in which thymocytes are sensitive to Thy-1-dependent apoptosis corresponds to the developmental "window" during which massive death of immature thymocytes takes place within the thymus. Therefore, we propose that Thy-1 could function as a cell survival/death regulator in mouse T lymphocyte development

Resistencia múltiple a drogas: un problema en la quimioterapia de cáncer / Multidrug resistance: a problem in cancer treatment

Uno de los principales problemas que enfrenta la oncología es la resistencia celular a drogas, en particular, el fenómeno de resistencia múltiple (MDR del inglés multidrug resistence) que involucra tumores que desarrollan resistencia a un amplio espectro de drogas no relacionadas entre sí y a las que nunca han sido expuestas. Se han descrito varios mecanismos que podrían ser responsables de este fenómeno, entre ellos, el aumento del producto del gene MDR1, la glicoproteína gp-P de membrana plasmática. Esta glicoproteína asemeja una bomba de transporte de amplia especificidad y parece tener una función fisiológica normal; sin embargo, la expresión de este gen aumenta en algunos tumores refractarios al tratamiento quimioterapéutico. En líneas celulares, el aumento en la expresión de gp-P se relaciona directamente con una disminución en la acumulación y retención de las drogas en el interior de las células. Además de gp-P, por lo menos otros dos mecanismos de resistencia múltiple se han descrito: la disminución en la expresión o cambios en la actividad catalítica de la enzima topoisomerasa II, y la alteración en los niveles de expresión de la enzima glutatión-transferasa. A través de métodos bioquímicos y moleculares, en gran cantidad de tumores refractarios a tratamiento, se han buscado asociaciones con cambios en los mecanismos de resitencia anteriormente descritos. Los estudios sugieren que son varios los factores que participan en la resistencia celular en tumores humanos, además de que es probable que éstos interactúen entre sí. En la práctica clínica, la gran motivación por controlar el fenómeno de MDR ha repercutido por controlar el fenómeno de MDR ha repercutido en el diseño de estrategias terapéuticas alternativas

Spermatozoon maturation in vertebrates with internal fertilization

La maduración del espermatozoide de los mamíferos ocurre durante su tránsito a través del epidídimo. La maduración comprende una serie de cambios morfológicos y fisiológicos que comprenden la adquisición de la capacidad fertilizante de la gameta. Este proceso de maduración ha sido estudiado principalmente en los mamíferos, pero existen datos que revelan que los pájaros, reptiles y ciertos tipos de peces poseen características similares. El análisis anatómico e histológico del epidídimo de los mamíferos y de los conductos de Wolff de algunos pájaros y reptiles muestra el predominio de un sistema de células secretoras. Las proteínas secretadas por los conductos de los machos parece ser un factor importante en la adquisición de la motilidad del espermatozoide, así como en los cambios que ocurren en la organización molecular de la membrana plasmática. Los cambios que ocurren en la membrana plasmática de los espermatozoides de mamíferos se relacionan con la adquisición de proteínas foráneas (de origen epididimario). Algunos de estos cambios de la membrana parecen conectarse con el fenómeno de capacitación y también con la interacción de las gametas durante la fertilización. El uso de anticuerpos contra las proteínas del conducto de Wolff ha mostrado que los espermatozoides de los pájaros y reptiles también incorporan proteínas durante su pasaje a través de este conducto. Sin embargo, en los pájaros y también en los reptiles, la capacitación no es un prerequisito para fertilizar y algunos son capaces de fertilizar con espermatozoides del testículo. Por consiguiente se plantea la cuestión acerca del real significado de los cambios de maduración en estos vertebrados. Las proteínas adquiridas durante la maduración en tales especies tendrían funciones diferentes a las de los mamíferos, probablemente como apoyo para la sobrevivencia de los espermatozoides durante el transporte en el tracto reproductor femenino, donde as veces son depositados por largo tiempo. Posiblemente un rol similar podrían tener los cambios de superficie en las gametas de los mamíferos cuando están en el tracto reproductor femenino

Serologic characterization of Paracoccidioides brasiliensis E2 antigen

1. The behavior of the specific E2 antigen of paracoccidioides brasiliensis was studied by agarose gel counterimmonoelectrophoresis. When immunoelectrophoresis. When the gel was read immediately after the electrophoretic run no precipitation band was visible. Visualization of the complex was possible only after incubation of the gel at room temperature overnight. 2. At alkaline pH, the, the E2 antigen migrates in the direvtion of the cathodem as do the immunoglobulins. The higher sensitivity of counterimmunoelectrophoresis when compared to double immunodiffusion for the diagnosis of paracoccidioidomycosis is due to the presence of antibodies directed agaisnt antigens which migrate to the anode. 3. The use of specific antiserum to E2 antigen reference permits the double immunodiffusion method to be a very sensitive test for the specific serodiagnosis of paracoccidioidomycosis