Insider information: what viruses tell us about endocytosis

Viruses have long served as tools in molecular and cellular biology to study a variety of complex cellular processes. Currently, there is a revived interest in virus entry into animal cells because it is evident that incoming viruses make use of numerous endocytic pathways that are otherwise difficult to study. Besides the classical clathrin-mediated uptake route, viruses use caveolae-mediated endocytosis, lipid-raft-mediated endocytic pathways, and macropinocytosis. Some of these are subject to regulation, involve novel endocytic organelles, and some of them connect organelles that were previously not known to communicate by membrane traffic.     

Animals models of MCH function and what they can tell us about its role in energy balance

Melanin-concentrating hormone (MCH) has attracted considerable attention because of its effects on food intake and body weight and the MCH receptor (MCHR1) remains one of the viable targets for obesity therapy. This review summarizes the literature examining the effects of MCH on body weight, food intake and energy expenditure in rodent models, and the central sites where MCH acts in regulating energy homeostasis. Emphasis is given on the discrepancies between the genetic and pharmacologic models of MCHR1 inactivation. We propose some solutions to resolve these discrepancies and discuss some future directions in MCH research.     

Segmentation in behavior and what it can tell us about brain function

Natural human behavior is segmented into action units, functionally related groups of movements with durations of a few seconds. This phenomenon can also be found in nonhuman primates and other mammals. In humans, a similar segmentation can be found in planning, preparatory behavior, perception, and speech. Temporal segmentation may be related to the functioning of short-term memory. Segmentation may thus be a central feature of neuronal integration. Segment length was hitherto thought to be determined by either capacity constraints or temporal factors. Instead we show that segment length depends on the interplay between capacity and temporal factors.     

Small is beautiful: what flies tell us about ERM protein function in development

Actin dynamics is recognized as being a determinant in many developmental processes and pathologies, such as cell polarity, morphogenesis and tumour metastasis. However, how actin interacts with the plasma membrane is poorly understood. Although numerous studies in cell culture point to the crucial role of Ezrin, Radixin and Moesin (ERM) proteins in the actin-membrane link, genetic approaches in mice have not yet revealed their activity during development. Drosophila has recently become an alternative and promising system for the genetic study of ERM protein function. This article focuses on advances made in flies, providing evidence for the evolutionary conservation of functional properties of ERM proteins, in addition to shedding new light on their importance for development.     

Double impact: what sibling data can tell us about the long-term negative effects of parental divorce

Most prior research on the adverse consequences of parental divorce has analyzed only one child per family. As a result, it is not known whether the same divorce affects siblings differently. We address this issue by analyzing paired sibling data from the 1994 General Social Survey (GSS) and 1994 Survey of American Families (SAF). Both seemingly unrelated regressions and random effects models are used to study the effect of family background on offspring's educational attainment and marital stability. Parental divorce adversely affects the educational attainment and the probability of divorce of both children within a sibship; in other words, siblings tend to experience the same divorce the same way. However, family structure of origin only accounts for a trivial portion of the shared variance in offspring's educational attainment and marital stability, so parental divorce is only one of many factors determining how offspring fare. These findings were unchanged when controlling for a number of differences both between and within sibships. Also, the negative effects of parental divorce largely do not vary according to respondent characteristics.     

The settlement of Madagascar: what dialects and languages can tell us

The dialects of Madagascar belong to the Greater Barito East group of the Austronesian family and it is widely accepted that the Island was colonized by Indonesian sailors after a maritime trek that probably took place around 650 CE. The language most closely related to Malagasy dialects is Maanyan, but Malay is also strongly related especially for navigation terms. Since the Maanyan Dayaks live along the Barito river in Kalimantan (Borneo) and they do not possess the necessary skill for long maritime navigation, they were probably brought as subordinates by Malay sailors. In a recent paper we compared 23 different Malagasy dialects in order to determine the time and the landing area of the first colonization. In this research we use new data and new methods to confirm that the landing took place on the south-east coast of the Island. Furthermore, we are able to state here that colonization probably consisted of a single founding event rather than multiple settlements. To reach our goal we find out the internal kinship relations among all the 23 Malagasy dialects and we also find out the relations of the 23 dialects to Malay and Maanyan. The method used is an automated version of the lexicostatistic approach. The data from Madagascar were collected by the author at the beginning of 2010 and consist of Swadesh lists of 200 items for 23 dialects covering all areas of the Island. The lists for Maanyan and Malay were obtained from a published dataset integrated with the author's interviews.     

Inactivation and activity of cholesterol-dependent cytolysins: what structural studies tell us

The homologous bacterially expressed cholesterol-dependent cytolysins (CDCs) form pores via oligomerization; this must occur preferentially once the target membrane has been engaged. Conformational changes in CDCs then drive partition from an aqueous environment to a lipidic one. This review addresses how premature oligomerization is prevented, how conformational changes are triggered, and how cooperativity between subunits brings about new functionality absent from isolated protomers. Variations are found in the answers provided by the CDCs to these issues. Some toxins use pH as a trigger of activity, but recent results have shown that dimerization in solution is an alternative way of preventing premature oligomerization, in particular for the CDC from Clostridium perfringens, perfringolysin. More controversially, there is still no resolution to the debate as to whether incomplete (arciform) oligomers form pores: recent results again suggest that they do.     

Gene flow in wild chimpanzee populations: what genetic data tell us about chimpanzee movement over space and time

The isolation of phylogenetically distinct primate immunodeficiency viruses from at least seven wild-born, captive chimpanzees indicates that viruses closely related to HIV-1 may be endemic in some wild chimpanzee populations. The search for the chimpanzee population or populations harbouring these viruses is therefore on. This paper attempts to answer the question of whether or not such populations of chimpanzees are likely to exist at all, and, if so, where they are likely to be found. We summarize what is known about gene flow in wild populations of chimpanzees, both between major phylogeographical subdivisions of the species, and within these subdivisions. Our analysis indicates that hitherto undocumented reproductively isolated chimpanzee populations may in fact exist. This conclusion is based on the observation that, despite limited geographical sampling and limited numbers of genetic loci, conventional notions of the nature and extent of chimpanzee gene flow have recently been substantially revised. Molecular genetic studies using mitochondrial DNA sequences and hypervariable nuclear microsatellite markers have indicated the existence of heretofore undocumented barriers to chimpanzee gene flow. These studies have identified at least one population of chimpanzees genetically distinct enough to be classified into a new subspecies (Pan troglodytes vellerosus). At the same time, they have called into question the long-accepted genetic distinction between eastern chimpanzees (Pan troglodytes schweinfurthii) and western equatorial chimpanzees (Pan troglodytes troglodytes). The same studies have further indicated that gene flow between local populations is more extensive than was previously thought, and follows patterns sometimes inconsistent with those documented through direct behavioural observation. Given the apparently incomplete nature of the current understanding of chimpanzee gene flow in equatorial Africa, it seems reasonable to speculate that a chimpanzee population or populations may exist which both harbour the putative HIV-1 ancestor, and which have remained reproductively isolated from other chimpanzee populations over the time-scale relevant to the evolution of the SIVcpz-HIV-1 complex of viruses. Continued extensive sampling of wild chimpanzee populations, both for their genes and their viruses, should be performed quickly considering the high probability of extinction that many wild chimpanzee populations face today. The history of human-chimpanzee contacts is discussed.     

Targeted disruption of the methionine synthase gene in mice

Alterations in homocysteine, methionine, folate, and/or B12 homeostasis have been associated with neural tube defects, cardiovascular disease, and cancer. Methionine synthase, one of only two mammalian enzymes known to require vitamin B12 as a cofactor, lies at the intersection of these metabolic pathways. This enzyme catalyzes the transfer of a methyl group from 5-methyl-tetrahydrofolate to homocysteine, generating tetrahydrofolate and methionine. Human patients with methionine synthase deficiency exhibit homocysteinemia, homocysteinuria, and hypomethioninemia. They suffer from megaloblastic anemia with or without some degree of neural dysfunction and mental retardation. To better study the pathophysiology of methionine synthase deficiency, we utilized gene-targeting technology to inactivate the methionine synthase gene in mice. On average, heterozygous knockout mice from an outbred background have slightly elevated plasma homocysteine and methionine compared to wild-type mice but seem to be otherwise indistinguishable. Homozygous knockout embryos survive through implantation but die soon thereafter. Nutritional supplementation during pregnancy was unable to rescue embryos that were completely deficient in methionine synthase. Whether any human patients with methionine synthase deficiency have a complete absence of enzyme activity is unclear. These results demonstrate the importance of this enzyme for early development in mice and suggest either that methionine synthase-deficient patients have residual methionine synthase activity or that humans have a compensatory mechanism that is absent in mice.     

Targeted disruption of the mouse cis-retinol dehydrogenase gene: visual and nonvisual functions

It has been proposed that cis-retinol dehydrogenase (cRDH) acts within the body to catalyze the oxidation of 9-cis-retinol, an oxidative step needed for 9-cis-retinoic acid synthesis, the oxidation of 11-cis-retinol [an oxidative step needed for 11-cis-retinal (visual chromophore) synthesis], and 3 alpha-hydroxysteroid transformations. To assess in vivo the physiological importance of each of these proposed actions of cRDH, we generated cRDH-deficient (cRDH-/-) mice. The cRDH-/- mice reproduce normally and appear to be normal. However, the mutant mice do have a mild visual phenotype of impaired dark adaptation. This phenotype is evidenced by electroretinagram analysis of the mice and by biochemical measures of eye levels of retinoid intermediates during recovery from an intense photobleach. Although it is thought that cRDH is expressed in the eye almost solely in retinal pigment epithelial cells, we detected cRDH expression in other retinal cells, including ganglion cells, amacrine cells, horizontal cells, and the inner segments of the rod photoreceptor cells. Aside from the eye, there are no marked differences in retinoid levels in other tissues throughout the body for cRDH-/- compared with cRDH+/+ mice. Moreover, we did not detect any non-visual phenotypic changes for cRDH-/- mice, suggesting that these mice do not have problems in metabolizing 3 alpha-hydroxysteroids.Thus, cRDH may act essentially in the visual cycle but is redundant for catalyzing 9-cis-retinoic acid formation and 3 alpha-hydroxysteroid metabolism.     

WhatEntamoeba histolytica andGiardia lamblia tell us about the evolution of eukaryotic diversity

Entamoeba histolytica andGiardia lamblia are microaerophilic protists, which have long been considered models of ancient pre-mitochondriate eukaryotes. As transitional eukaryotes, amoebae and giardia appeared to lack organelles of higher eukaryotes and to depend upon energy metabolism appropriate for anaerobic conditions early in the history of the planet. However, our studies have shown that amoebae and giardia contain splicoeosomal introns, ras-family signal-transduction proteins, ATP-binding casettes (ABC)-family drug transporters, Golgi, and a mitochondrion-derived organelle (amoebae only). These results suggest that most of the organelles of higher eukaryotes were present in the common ancestor of all eukaryotes, and so dispute the notion of transitional eukaryotic forms. In addition, phylogenetic studies suggest many of the genes encoding the fermentation enzymes of amoebae and giardia derive from prokaryotes by lateral gene transfer (LGT). While LGT has recently been shown to be an important determinant of prokaryotic evolution, this is the first time that LGT has been shown to be an important determinant of eukaryotic evolution. Further, amoebae contain cyst wall-associated lectins, which resemble, but are distinct from lectins in the walls of insects (convergent evolution). Giardia have a novel microtubule-associated structure which tethers together pairs of nuclei during cell division. It appears then that amoebae and giardia tell us less about the origins of eukaryotes and more about the origins of eukaryotic diversity.     

Systemic lupus erythematosus and the brain: what mice are telling us

Neuropsychiatric symptoms occur in systemic lupus erythematosus (SLE), a complex, autoimmune disease of unknown origin. Although several pathogenic mechanisms have been suggested to play a significant role in the etiology of the disease, the exact underlying mechanisms still remain elusive. Several inbred strains of mice are used as models to study SLE, which exhibit a diversity of central nervous system (CNS) manifestations similar to that observed in patients. This review will attempt to give a brief overview of the CNS alterations observed in these models, including biochemical, structural and behavioral changes.