Evolution of the multi-domain structures of virulence genes in the human malaria parasite, Plasmodium falciparum

The var gene family of Plasmodium falciparum encodes the immunodominant variant surface antigens PfEMP1. These highly polymorphic proteins are important virulence factors that mediate cytoadhesion to a variety of host tissues, causing sequestration of parasitized red blood cells in vital organs, including the brain or placenta. Acquisition of variant-specific antibodies correlates with protection against severe malarial infections; however, understanding the relationship between gene expression and infection outcome is complicated by the modular genetic architectures of var genes that encode varying numbers of antigenic domains with differential binding specificities. By analyzing the domain architectures of fully sequenced var gene repertoires we reveal a significant, non-random association between the number of domains comprising a var gene and their sequence conservation. As such, var genes can be grouped into those that are short and diverse and genes that are long and conserved, suggesting gene length as an important characteristic in the classification of var genes. We then use an evolutionary framework to demonstrate how the same evolutionary forces acting on the level of an individual gene may have also shaped the parasite's gene repertoire. The observed associations between sequence conservation, gene architecture and repertoire structure can thus be explained by a trade-off between optimizing within-host fitness and minimizing between-host immune selection pressure. Our results demonstrate how simple evolutionary mechanisms can explain var gene structuring on multiple levels and have important implications for understanding the multifaceted epidemiology of P. falciparum malaria.     

A Genome-Scale RNA–Interference Screen Identifies RRAS Signaling as a Pathologic Feature of Huntington's Disease

A genome-scale RNAi screen was performed in a mammalian cell-based assay to identify modifiers of mutant huntingtin toxicity. Ontology analysis of suppressor data identified processes previously implicated in Huntington''s disease, including proteolysis, glutamate excitotoxicity, and mitochondrial dysfunction. In addition to established mechanisms, the screen identified multiple components of the RRAS signaling pathway as loss-of-function suppressors of mutant huntingtin toxicity in human and mouse cell models. Loss-of-function in orthologous RRAS pathway members also suppressed motor dysfunction in a Drosophila model of Huntington''s disease. Abnormal activation of RRAS and a down-stream effector, RAF1, was observed in cellular models and a mouse model of Huntington''s disease. We also observe co-localization of RRAS and mutant huntingtin in cells and in mouse striatum, suggesting that activation of R-Ras may occur through protein interaction. These data indicate that mutant huntingtin exerts a pathogenic effect on this pathway that can be corrected at multiple intervention points including RRAS, FNTA/B, PIN1, and PLK1. Consistent with these results, chemical inhibition of farnesyltransferase can also suppress mutant huntingtin toxicity. These data suggest that pharmacological inhibition of RRAS signaling may confer therapeutic benefit in Huntington''s disease.     

The Polyfunctionality of Human Memory CD8+ T Cells Elicited by Acute and Chronic Virus Infections Is Not Influenced by Age

As humans age, they experience a progressive loss of thymic function and a corresponding shift in the makeup of the circulating CD8+ T cell population from naïve to memory phenotype. These alterations are believed to result in impaired CD8+ T cell responses in older individuals; however, evidence that these global changes impact virus-specific CD8+ T cell immunity in the elderly is lacking. To gain further insight into the functionality of virus-specific CD8+ T cells in older individuals, we interrogated a cohort of individuals who were acutely infected with West Nile virus (WNV) and chronically infected with Epstein Barr virus (EBV) and Cytomegalovirus (CMV). The cohort was stratified into young (<40 yrs), middle-aged (41–59 yrs) and aged (>60 yrs) groups. In the aged cohort, the CD8+ T cell compartment displayed a marked reduction in the frequency of naïve CD8+ T cells and increased frequencies of CD8+ T cells that expressed CD57 and lacked CD28, as previously described. However, we did not observe an influence of age on either the frequency of virus-specific CD8+ T cells within the circulating pool nor their functionality (based on the production of IFNγ, TNFα, IL2, Granzyme B, Perforin and mobilization of CD107a). We did note that CD8+ T cells specific for WNV, CMV or EBV displayed distinct functional profiles, but these differences were unrelated to age. Collectively, these data fail to support the hypothesis that immunosenescence leads to defective CD8+ T cell immunity and suggest that it should be possible to develop CD8+ T cell vaccines to protect aged individuals from infections with novel emerging viruses.     

Effects of Acidification, Sodium Chloride, and Moisture Levels on Wheat Dough: II. Modeling of Bread Texture and Staling Kinetics

The effect of three experimental factors pH (addition of lactic acid and sodium hydroxide), water, and sodium chloride (NaCl) addition on wheat bread making performance (volume, baking loss, crumb firmness, crumb grain features) and the crumb staling during storage was studied. The staling behavior was modeled with the Avrami equation and with linear regressions. All bread quality parameters were reliably modeled using response surface methodology (up to R ² ?=?0.97). The crumb staling behavior was better described by a linear regression than by the rate constant k of the Avrami equation (R ² ?=?0.87 / R ² ?=?0.36). The highest volume can be achieved with the experimental values pH 5.39, 0.41?g NaCl 100?g^?1 flour and 68.7?g water 100?g^?1 flour. Correlation analysis revealed significant linear dependency of dough rheology (complex shear modulus) on the firmness of the bread crumb (r?=?0.73) and staling attributes (r????0.73). Dough microstructural properties showed significant but low correlation with bread making performance attributes.     

Effects of Acidification, Sodium Chloride, and Moisture Levels on Wheat Dough: I. Modeling of Rheological and Microstructural Properties

The rheological attributes of polymers as wheat dough are strongly related to its microstructure. To quantify dough protein microstructure confocal laser scanning microscopy combined with image analysis was used. The effect of three experimental factors pH (addition of lactic acid and sodium hydroxide), water addition, and sodium chloride (NaCl) addition on empirical and fundamental rheological properties as well as microstructural protein properties were studied and modeled by applying a response surface methodology. The obtained models revealed high correlations between the experimental factors and the complex shear modulus (R ²?=?0.97), dough resistance (R_max ^k; R ²?=?0.91) and stickiness (R ²?=?0.93). Furthermore it was possible to determine microstructural attributes as the area fraction (R ²?=?0.88) and Feret??s diameter (R ²?=?0.86) as a function of pH, water and NaCl addition. Especially measures of R^k _max revealed highly significant correlations with the protein microstructure as the branching index (r?=?0.79).     

New retinoid derivatives as back-ups of Adarotene

Adarotene belongs to the so-called class of atypical retinoids. The presence of the phenolic hydroxyl group on Adarotene structure allows a rapid O-glucuronidation as a major mechanism of elimination of the drug, favoring a fast excretion of its glucuronide metabolite in the urines. A series of ether, carbamate and ester derivatives was synthesized. All of them were studied and evaluated for their stability at different pH. The cytotoxic activity in vitro on NCI-H460 non-small cell lung carcinoma and A2780 ovarian tumor cell lines was also tested. A potential back-up of Adarotene has been selected to be evaluated in tumor models.     

Global tuberculosis control: lessons learnt and future prospects

Tuberculosis (TB) is an ancient disease, but not a disease of the past. After disappearing from the world public health agenda in the 1960s and 1970s, TB returned in the early 1990s for several reasons, including the emergence of the HIV/AIDS pandemic and increases in drug resistance. More than 100 years after the discovery of the tubercle bacillus by Robert Koch, what is the status of TB control worldwide? Here, we review the evolution of global TB control policies, including DOTS (directly observed therapy, short course) and the Stop TB Strategy, and assess whether the challenges and obstacles faced by the public health community worldwide in developing and implementing this strategy can aid future action towards the elimination of TB.