Cryptosporidium virulence determinants--are we there yet?

Exposure to Cryptosporidium parvum in healthy individuals results in transient infection that may be asymptomatic or can result in self-limited diarrhoea. In contrast, acquired immune deficiency syndrome patients with cryptosporidiosis can experience severe manifestations of disease. Volunteer studies have demonstrated that as few as 10 oocysts can cause infection in otherwise healthy adults and that isolates from geographically diverse regions differ in infectivity and, perhaps, virulence. Variability in isolate pathogenicity and infectivity has also been seen in bovine and murine models, respectively. Furthermore, isolate specific differences in protein composition and in host immunoreactivity have been observed. The molecular basis for differences in pathogenicity is not understood. Determining which factors are responsible for host selectivity and for the initiation, establishment, and perpetuation of infection with Cryptosporidium is key to rational drug design and vaccine development. To date, no specific virulence factors have been unequivocally shown to individually cause direct or indirect damage to host tissues nor have mutant strains been produced that could prove that particular deletions result in less virulent strains. Nevertheless, a number of candidate molecules have been identified by immunological and molecular methods. Here, we review the salient characteristics of some of these putative virulence determinants, including molecules that are involved in adhesion, protein degradation and the modulation of the host responses.     

Gynodioecy to dioecy: are we there yet?

Background

The ‘gynodioecy–dioecy pathway’ is considered to be one of the most important evolutionary routes from hermaphroditism to separate sexes (dioecy). Despite a large accumulation of evidence for female seed fertility advantages in gynodioecious species (females and hermaphrodites coexist) in support of the first step in the gynodioecy–dioecy pathway, we still have very little evidence for the second step, i.e. the transition from gynodioecy to dioecy.

Scope

We review the literature to evaluate whether basic predictions by theory are supported. To establish whether females'' seed fertility advantage and frequencies are sufficient to favour the invasion of males, we review these for species along the gynodioecy–dioecy pathway published in the last 5 years. We then review the empirical evidence for predictions deriving from the second step, i.e. hermaphrodites'' male fertility increases with female frequency, selection favours greater male fertility in hermaphrodites in gynodioecious species, and, where males and hermaphrodites coexist with females (subdioecy), males have greater male fertility than hermaphrodites. We review how genetic control and certain ecological features (pollen limitation, selfing, plasticity in sex expression and antagonists) influence the trajectory of a population along the gynodioecy–dioecy pathway.

Conclusions

Females tend to have greater seed fertility advantages over hermaphrodites where the two coexist, and this advantage is positively correlated with female frequency across species, as predicted by theory. A limited number of studies in subdioecious species have demonstrated that males have an advantage over hermaphrodites, as also predicted by theory. However, less evidence exists for phenotypic selection to increase male traits of hermaphrodites or for increasing male function of hermaphrodites in populations with high female frequency. A few key case studies underline the importance of examining multiple components of male fertility and the roles of pollen limitation, selfing and plasticity, when evaluating advantages. We conclude that we do not yet have a full understanding of the transition from gynodioecy to dioecy.     

Machine learned coarse-grained protein force-fields: Are we there yet?

The successful recent application of machine learning methods to scientific problems includes the learning of flexible and accurate atomic-level force-fields for materials and biomolecules from quantum chemical data. In parallel, the machine learning of force-fields at coarser resolutions is rapidly gaining relevance as an efficient way to represent the higher-body interactions needed in coarse-grained force-fields to compensate for the omitted degrees of freedom. Coarse-grained models are important for the study of systems at time and length scales exceeding those of atomistic simulations. However, the development of transferable coarse-grained models via machine learning still presents significant challenges. Here, we discuss recent developments in this field and current efforts to address the remaining challenges.     

Pharmacogenetic studies of epilepsy drugs: are we there yet?

One of the mantras of scientists working in the field of pharmacogenetics is 'the right dose for the right patient'. A recent article has gone someway towards demonstrating that this goal can be achieved using genetic approaches. It is one of the first reports to show that a specific polymorphism can predict the maximum tolerated dose of two anti-epileptic drugs. However, further studies are necessary to validate these observations.     

Devising a pathway for hyaluronan catabolism: are we there yet?

Hyaluronan is a negatively charged, high molecular weight glycosaminoglycan found predominantly in the extracellular matrix. Intracellular locations for hyaluronan have also been documented in cytoplasm, nucleus, and nucleolus. The polymer has an extraordinarily high rate of turnover in vertebrate tissues. The focus here is to formulate a metabolic pathway for hyaluronan degradation using all available data, including the recently acquired information on the hyaluronidase gene family. Such a catabolic scheme has defied explication up to now. In somatic tissues, stepwise processing occurs, from the extracellular high molecular weight space filling, antiangiogenic approximately 107-kDa polymer, to intermediate sized highly angiogenic, inflammatory, and immune-stimulating fragments, and ultimately to tetrasaccharides that are antiapoptotic and potent inducers of heat-shock proteins. It is proposed that the high molecular weight extracellular polymer is tethered to the cell surface by the combined efforts of hyaluronan receptors and hyaluronidase-2 (Hyal-2). The hyaluronan is cleaved to a 20-kDa intermediate-sized fragment, the limit product of Hyal-2 digestion. These fragments are delivered to endosomal- and ultimately lysosomal-like structures. Further catabolism occurs there by Hyal-1, coordinated with the activity of two lysosomal beta-exoglycosidases, beta-glucuronidase and beta-N-acetyl-glucosaminidase. A membrane-associated mini-organelle is postulated, the hyaluronasome, in which coordinated synthetic and catabolic enzyme reactions occur. The hyaluronasome can respond to the physiological states of the cell by a series of membrane-bound and soluble hyaluronan-associated receptors, binding proteins, and cofactors that trigger enzymatic events and signal transduction pathways. These in turn can be modulated by the amounts and sizes of the hyaluronan polysaccharides generated in the catabolic cascade. Most of these highly dynamic interactions remain to be determined. It is also proposed that malignant cells can commandeer some of these interactions for facilitating tumor growth and spread.     

En route to early diagnosis of Alzheimer's disease--are we there yet?

As therapeutics for Alzheimer's disease (AD) become available, it will become increasingly important to develop accurate and reliable tools for its early diagnosis. A recent paper by Georganopoulou et al. suggests that nanobiotechnology could help to overcome the limitations with the current diagnostic methods. The paper introduces a nanoparticle-based assay using antibodies that are specific for amyloid beta-protein (Abeta) oligomers with sub-femtomolar sensitivity. This assay appears to be more specific for AD than previous ELISA-based work and, if specificity of the assay for Abeta oligomers can be established, the method developed might provide a sensitive, reliable diagnostic tool for AD.