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Copenhagen, Denmark

Goel S.,Pennsylvania State University | Valiyaveettil M.,Pennsylvania State University | Achur R.N.,Pennsylvania State University | Achur R.N.,Kuvempu University | And 6 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) family members mediate the adherence of parasite-infected red blood cells (IRBCs) to various host receptors. A previous study has shown that the parasite protein, cytoadherence-linked asexual gene 9 (CLAG9), is also essential for IRBC adherence. However, how CLAG9 influences this process remains unknown. In this study, we show that CLAG9 interacts with VAR2CSA, a PfEMP1 that mediates IRBC adherence to chondroitin 4-sulfate in the placenta. Importantly, our results show that the adherent parasites synthesize CLAG9 at two stages - the early ring and late trophozoite stages. Localization studies revealed that a substantial level of CLAG9 is located mainly at or in close proximity of the IRBC membrane in association with VAR2CSA. Upon treatment of IRBCs with trypsin, a significant amount of CLAG9 (≈150 kDa) was converted into ≈142-kDa polypeptide. Together these data demonstrate that a considerable amount of CLAG9 is embedded in the IRBC membrane such that at least a portion of the polypeptide at either N or C terminus is exposed on the cell surface. In parasites lacking CLAG9, VAR2CSA failed to express on the IRBC surface andwas located within the parasite. Based on these findings, we propose that CLAG9 plays a critical role in the trafficking of PfEMP1s onto the IRBC surface. These results have important implications for the development of therapeutics for cerebral, placental, and other cytoadherence-associated malaria illnesses. Source

Better understanding of the complex factors leading to human diseases will be necessary for both long term prevention and for managing short and long-term health problems. The underlying causes, leading to a global health crisis in both acute and chronic diseases, include finite global health care resources for sustained healthy human survival, the population explosion, increased environmental pollution, decreased clean air, water, food distribution, diminishing opportunities for human self-esteem, increased median life span, and the interconnection of infectious and chronic diseases. The transition of our pre-human nutritional requirements for survival to our current culturally- shaped diet has created a biologically-mismatched human dietary experience. While individual genetic, gender, and developmental stage factors contribute to human diseases, various environmental and culturally-determined factors are now contributing to both acute and chronic diseases. The transition from the hunter-gatherer to an agricultural- dependent human being has brought about a global crisis in human health. Initially, early humans ate seasonally- dependent and calorically-restricted foods, during the day, in a "feast or famine" manner. Today, modern humans eat diets of caloric abundance, at all times of the day, with foods of all seasons and from all parts of the world, that have been processed and which have been contaminated by all kinds of factors. No longer can one view, as distinct, infectious agent-related human acute diseases from chronic diseases. Moreover, while dietary and environmental chemicals could, in principle, cause disease pathogenesis by mutagenic and cytotoxic mechanisms, the primary cause is via "epigenetic", or altered gene expression, modifications in the three types of cells (e.g., adult stem; progenitor and terminally-differentiated cells of each organ) during all stages of human development. Even more significantly, alteration in the quantity of adult stem cells during early development by epigenetic chemicals could either increase or decrease the risk to various stem cell-based diseases, such as cancer, later in life. A new concept, the Barker hypothesis, has emerged that indicates pre-natal maternal dietary exposures can now affect diseases later in life. Examples from the studies of the atomic bomb survivors should illustrate this insight. copyright © 2007 KFN. Source

Tetteh K.K.A.,London School of Hygiene and Tropical Medicine | Osier F.H.A.,Center for Geographical Medicine Research | Salanti A.,Institute of International Health | Kamuyu G.,Center for Geographical Medicine Research | And 5 more authors.
Infection and Immunity | Year: 2013

Prospective studies continue to identify malaria parasite genes with particular patterns of polymorphism which indicate they may be under immune selection, and the encoded proteins require investigation. Sixteen new recombinant protein reagents were designed to characterize three such polymorphic proteins expressed in Plasmodium falciparum schizonts and merozoites: MSPDBL1 (also termed MSP3.4) and MSPDBL2 (MSP3.8), which possess Duffy binding-like (DBL) domains, and SURFIN4.2, encoded by a member of the surface-associated interspersed (surf) multigene family. After testing the antigenicities of these reagents by murine immunization and parasite immunofluorescence, we analyzed naturally acquired antibody responses to the antigens in two cohorts in coastal Kenya in which the parasite was endemic (Chonyi [n+497] and Ngerenya [n+461]). As expected, the prevalence and levels of serum antibodies increased with age. We then investigated correlations with subsequent risk of clinical malaria among children<11 years of age during 6 months follow-up surveillance. Antibodies to the polymorphic central region of MSPDBL2 were associated with reduced risk of malaria in both cohorts, with statistical significance remaining for the 3D7 allelic type after adjustment for individuals' ages in years and antibody reactivity to whole-schizont extract (Chonyi, risk ratio, 0.51, and 95% confidence interval [CI], 0.28 to 0.93; Ngerenya, risk ratio, 0.38, and 95% CI, 0.18 to 0.82). For the MSPDBL1 Palo Alto allelic-type antigen, there was a protective association in one cohort (Ngerenya, risk ratio, 0.53, and 95% CI, 0.32 to 0.89), whereas the other antigens showed no protective associations after adjustment. These findings support the prediction that antibodies to the polymorphic region of MSPDBL2 contribute to protective immunity. ©2013, American Society for Microbiology. Source

Chaimongkol N.,Chiang Mai University | Khamrin P.,Chiang Mai University | Suantai B.,Chiang Mai University | Saikhreang W.,Chiang Mai University | And 6 more authors.
Clinical Laboratory | Year: 2012

Background: Viral gastroenteritis has been recognized as one of the most common illnesses that affects infants and young children all over the world. A wide variety of viruses associated with the disease are continually being reported. To investigate the epidemiological situation of diarrhea virus infection in Chiang Mai, Thailand, surveillance was conducted during January to December 2007. Methods: A total of 160 fecal specimens collected from pediatric patients admitted to the hospital with acute gastroenteritis were tested for the presence of group A, B, and C rotaviruses, norovirus, sapovirus, astrovirus, adenovirus, Aichi virus, enterovirus, bocavirus, and human parechovirus by RT-multiplex PCR. Results: Of 160 fecal specimens tested, 85 (53.1%) were positive for diarrhea viruses. Of these, group A rotavirus was the predominant with a prevalence of 27.5%, followed by norovirus GII (11.9%), sapovirus (3.1%), enterovirus (2.5%), human parechovirus (1.9%), and norovirus GI, astrovirus, adenovirus (each 0.6%). Mixed-infections of 2 or 3 viruses were observed in 7 (4.4%) patients. However, none of groups B and C rotaviruses and Aichi virus were detected in this study. Monthly distribution analysis revealed that all those diarrhea viruses were detected continually throughout the year at a low level of infection except for group A rotavirus and norovirus infections which appeared to peak in a cool season in January-March and December, respectively. Conclusions: This surveillance revealed a wide variety of diarrhea viruses currently circulating in pediatric patients with acute gastroenteritis in Chiang Mai, Thailand. Source

Thuring C.,Lund University | Follin E.,Lund University | Geironson L.,Lund University | Freyhult E.,Uppsala University | And 4 more authors.
British Journal of Cancer | Year: 2015

Background:Tumour cells can evade the immune system by dysregulation of human leukocyte antigens (HLA-I). Low quantity and/or altered quality of HLA-I cell surface expression is the result of either HLA-I alterations or dysregulations of proteins of the antigen-processing machinery (APM). Tapasin is an APM protein dedicated to the maturation of HLA-I and dysregulation of tapasin has been linked to higher malignancy in several different tumours.Methods:We studied the expression of APM components and HLA-I, as well as HLA-I tapasin-dependency profiles in glioblastoma tissues and corresponding cell lines.Results:Tapasin displayed the strongest correlation to HLA-I heavy chain but also clustered with β 2 -microglobulin, transporter associated with antigen processing (TAP) and LMP. Moreover, tapasin also correlated to survival of glioblastoma patients. Some APM components, for example, TAP1/TAP2 and LMP2/LMP7, showed variable but coordinated expression, whereas ERAP1/ERAP2 displayed an imbalanced expression pattern. Furthermore, analysis of HLA-I profiles revealed variable tapasin dependence of HLA-I allomorphs in glioblastoma patients.Conclusions:Expression of APM proteins is highly variable between glioblastomas. Tapasin stands out as the APM component strongest correlated to HLA-I expression and we proved that HLA-I profiles in glioblastoma patients include tapasin-dependent allomorphs. The level of tapasin was also correlated with patient survival time. Our results support the need for individualisation of immunotherapy protocols. Source

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