Hereditary spastic paraplegia: clues from a rare disorder for a common problem?

Hereditary spastic paraplegia is a rare disorder with gait disturbance due to a degeneration of the corticospinal tract, sometimes accompanied by involvement of other systems. Out of the 20 loci known so far, eight genes have now been identified, allowing the first molecular and cell studies in the pathophysiology of the disorder. These should also help to understand the function of the corticospinal tract at the molecular level and design strategies to prevent and treat spasticity due to more common causes. The proteins encoded by these genes play a role in development, in signal transduction between axons and myelinating cells, in cellular, particularly axonal trafficking or in energy metabolism. Some of them have actions in several areas of cellular function. Here we review the present knowledge about the genes involved in hereditary spastic paraplegia, a field presently undergoing rapid change.     

Disease transmission by cannibalism: rare event or common occurrence?

Cannibalism has been documented as a possible disease transmission route in several species, including humans. However, the dynamics resulting from this type of disease transmission are not well understood. Using a theoretical model, we explore how cannibalism (i.e. killing and consumption of dead conspecifics) and intraspecific necrophagy (i.e. consumption of dead conspecifics) affect host-pathogen dynamics. We show that group cannibalism, i.e. shared consumption of victims, is a necessary condition for disease spread by cannibalism in the absence of alternative transmission modes. Thus, endemic diseases transmitted predominantly by cannibalism are likely to be rare, except in social organisms that share conspecific prey. These results are consistent with a review of the literature showing that diseases transmitted by cannibalism are infrequent in animals, even though both cannibalism and trophic transmission are very common.     

Tenascins in fibrotic disorders—from bench to bedside

Although fibrosis is becoming increasingly recognized as a major cause of morbidity and mortality in chronic inflammatory diseases, available treatment strategies are limited. Tenascins constitute a family of matricellular proteins, primarily modulating interactions of cells with other matrix components and growth factors. Data obtained from tenascin C deficient mice show important roles of this molecule in several models of fibrosis. Moreover there is growing evidence that tenascin C has a strong impact on chronic inflammation, myofibroblast differentiation and recruitment. Tenascin C as well as tenascin X has furthermore been shown to affect TGF-β activation and signaling. Taken together these data suggest that these proteins might be important factors in fibrosis development and make them attractive both as biological markers and as targets for therapeutical intervention. So far most clinical research in fibrosis has been focused on tenascin C. This review aims at summarizing our up-to-date knowledge on the involvement of tenascin C in the pathogenesis of fibrotic disorders.     

Can Clues from Evolution Unlock the Molecular Development of the Cerebellum?

The cerebellum sits at the rostral end of the vertebrate hindbrain and is responsible for sensory and motor integration. Owing to its relatively simple architecture, it is one of the most powerful model systems for studying brain evolution and development. Over the last decade, the combination of molecular fate mapping techniques in the mouse and experimental studies, both in vitro and in vivo, in mouse and chick have significantly advanced our understanding of cerebellar neurogenesis in space and time. In amniotes, the most numerous cell type in the cerebellum, and indeed the brain, is the cerebellar granule neurons, and these are born from a transient secondary proliferative zone, the external granule layer (EGL), where proliferation is driven by sonic hedgehog signalling and causes cerebellar foliation. Recent studies in zebrafish and sharks have shown that while the molecular mechanisms of neurogenesis appear conserved across vertebrates, the EGL as a site of shh-driven transit amplification is not, and is therefore implicated as a key amniote innovation that facilitated the evolution of the elaborate foliated cerebella found in birds and mammals. Ellucidating the molecular mechanisms underlying the origin of the EGL in evolution could have significant impacts on our understanding of the molecular details of cerebellar development.     

Do persistent rare species experience stronger negative frequency dependence than common species?

Understanding why so many species are rare yet persistent remains a significant challenge for both theoretical and empirical ecologists. Yenni et al. (2012, Ecology, 93, 456–461) proposed that strong negative frequency dependence causes species to be rare while simultaneously buffering them against extinction. This hypothesis predicts that, on average, rare species should experience stronger negative frequency dependence than common species. However, it is unknown if ecological communities generally show this theoretical pattern. We discuss the implications of this phenomenon for community dynamics, and develop a method to test for a non‐random relationship between negative frequency dependence and relative abundance using species abundance data from 90 communities across a broad range of environments and taxonomic groups. To account for biases introduced by measurement error, we compared the observed correlation between species relative abundance and the strength of frequency dependence against expectations from a randomization procedure. In approximately half of the analysed communities, we found increasingly strong negative frequency dependence with decreasing relative abundance: rare species experienced stronger frequency dependence than common species. The randomization test never detected stronger negative frequency dependence in more common species. Our results suggest that strong negative frequency dependence is a signature of persistent, rare species in many communities.     

Has increased provision of treatment reduced the prevalence of common mental disorders? Review of the evidence from four countries

Many people identified as having common mental disorders in community surveys do not receive treatment. Modelling has suggested that closing this “treatment gap” should reduce the population prevalence of those disorders. To evaluate the effects of reducing the treatment gap in industrialized countries, data from 1990 to 2015 were reviewed from four English‐speaking countries: Australia, Canada, England and the US. These data show that the prevalence of mood and anxiety disorders and symptoms has not decreased, despite substantial increases in the provision of treatment, particularly antidepressants. Several hypotheses for this lack of improvement were considered. There was no support for the hypothesis that reductions in prevalence due to treatment have been masked by increases in risk factors. However, there was little evidence relevant to the hypothesis that improvements have been masked by increased reporting of symptoms because of greater public awareness of common mental disorders or willingness to disclose. A more strongly supported hypothesis for the lack of improvement is that much of the treatment provided does not meet the minimal standards of clinical practice guidelines and is not targeted optimally to those in greatest need. Lack of attention to prevention of common mental disorders may also be a factor. Reducing the prevalence of common mental disorders remains an unsolved challenge for health systems globally, which may require greater attention to the “quality gap” and “prevention gap”. There is also a need for nations to monitor outcomes by using standardized measures of service provision and mental disorders over time.     

Why collagens best survived in fossils? Clues from amino acid thermal stability

Explaining why type I collagens are preferentially preserved in the geological time scale remains a challenge. Several pieces of evidence indicate that its rich content in the bone and its unique, stable structure played key roles in its preservation. By considering the distinct thermal stability of amino acids, we reveal that the elevated abundance of thermostable amino acid residues in type I collagens also contribute to its survival.     

Why weight?

Whether phylogenetic data should be differentially or equally weighted is currently debated. Further, if differential weighting is to be explored, there is no consensus among investigators as to which weighting scheme is most appropriate. Mitochondrial genome data offer a powerful tool in assessment of differential weighting schemes because taxa can be selected from which a highly corroborated phylogeny is available (so that accuracy can be assessed), and it can be assumed that different data partitions share the same history (so that gene-sorting issues are not so problematic). Using mitochondrial data from 17 mammalian genomes, we evaluated the most commonly used weighting schemes, such as successive weighting, transversion weighting, codon-based weighting, and amino acid coding, and compared them to more complex weighting schemes including a 6-parameter weighting, pseudoreplicate reweighting, and tri-level weighting. We found that the most commonly used weighting schemes perform the worst with these data. Some of the more complex schemes perform well, however, none of them is consistently superior. These results support ones biases; if one has a predilection to avoid differential weighting, these data support equally weighted parsimony and maximum likelihood. Others might be encouraged by these results to try weighting as a form of data exploration.     

Heterotypic amyloid interactions: Clues to polymorphic bias and selective cellular vulnerability?

The number of atomic-resolution structures of disease-associated amyloids has greatly increased in recent years. These structures have confirmed not only the polymorphic nature of amyloids but also the association of specific polymorphs to particular proteinopathies. These observations are strengthening the view that amyloid polymorphism is a marker for specific pathological subtypes (e.g. in tauopathies or synucleinopathies). The nature of this association and how it relates to the selective cellular vulnerability of amyloid nucleation, propagation and toxicity are still unclear. Here, we provide an overview of the mechanistic insights provided by recent patient-derived amyloid structures. We discuss the framework organisation of amyloid polymorphism and how heterotypic amyloid interactions with the physiological environment could modify the solubility and assembly of amyloidogenic proteins. We conclude by hypothesising how such interactions could contribute to selective cellular vulnerability.     

Are rare variants responsible for susceptibility to complex diseases?

Little is known about the nature of genetic variation underlying complex diseases in humans. One popular view proposes that mapping efforts should focus on identification of susceptibility mutations that are relatively old and at high frequency. It is generally assumed-at least for modeling purposes-that selection against complex disease mutations is so weak that it can be ignored. In this article, I propose an explicit model for the evolution of complex disease loci, incorporating mutation, random genetic drift, and the possibility of purifying selection against susceptibility mutations. I show that, for the most plausible range of mutation rates, neutral susceptibility alleles are unlikely to be at intermediate frequencies and contribute little to the overall genetic variance for the disease. Instead, it seems likely that the bulk of genetic variance underlying diseases is due to loci where susceptibility mutations are mildly deleterious and where there is a high overall mutation rate to the susceptible class. At such loci, the total frequency of susceptibility mutations may be quite high, but there is likely to be extensive allelic heterogeneity at many of these loci. I discuss some practical implications of these results for gene mapping efforts.     

Are richness patterns of common and rare species equally well explained by environmental variables?

We investigated relationships between richness patterns of rare and common grassland species and environmental factors, focussing on comparing the degree to which the richness patterns of rare and common species are determined by simple environmental variables. Using data collected in the Machair grassland of the Outer Hebrides of Scotland, we fitted spatial regression models using a suite of grazing, soil physicochemical and microtopographic covariates, to nested sub‐assemblages of vascular and non‐vascular species ranked according to rarity. As expected, we found that common species drive richness patterns, but rare vascular species had significantly stronger affinity for high richness areas. After correcting for the prevalence of individual species distributions, we found differences between common and rare species in 1) the amount of variation explained: richness patterns of common species were better summarised by simple environmental variables, 2) the associations of environmental variables with richness showed systematic trends between common and rare species with coefficient sign reversal for several factors, and 3) richness associations with rare environments: richness patterns of rare vascular species significantly matched rare environments but those of non‐vascular species did not. Richness patterns of rare species, at least in this system, may be intrinsically less predictable than those of common species.