Emerging concepts in acute mountain sickness and high-altitude cerebral edema: from the molecular to the morphological

Acute mountain sickness (AMS) is a neurological disorder that typically affects mountaineers who ascend to high altitude. The symptoms have traditionally been ascribed to intracranial hypertension caused by extracellular vasogenic edematous brain swelling subsequent to mechanical disruption of the blood–brain barrier in hypoxia. However, recent diffusion-weighted magnetic resonance imaging studies have identified mild astrocytic swelling caused by a net redistribution of fluid from the “hypoxia-primed” extracellular space to the intracellular space without any evidence for further barrier disruption or additional increment in brain edema, swelling or pressure. These findings and the observation of minor vasogenic edema present in individuals with and without AMS suggest that the symptoms are not explained by cerebral edema. This has led to a re-evaluation of the relevant pathogenic events with a specific focus on free radicals and their interaction with the trigeminovascular system. (Part of a multi-author review.)     

Automatic arima modelling by the cartesian search algorithm

In the present study we report on the development and test results of a Cartesian ARIMA Search Algorithm, designed for automatic generation of univariate models for time series data within specified parameter intervals of the identification and estimation stages. Model retention is determined within a preselected set of statistics. By interpreting these statistics as dimensions of the constructed criterion space, we obtain a subset of non-dominated models according to the rule of maximum dispersion over the efficient set. The CARIMA algorithm allows free specification of the number of criteria used in the runs. The algorithm was tested with both simulated and real economic data. The results based on simulated data indicate that the precision of the CARIMA algorithm is lower for seasonal models and higher for non-seasonal ones, thus suggesting an inverse relationship between algorithm performance and model complexity.     

RNA molecules stimulate prion protein conversion

Much evidence supports the hypothesis that the infectious agents of prion diseases are devoid of nucleic acid, and instead are composed of a specific infectious protein. This protein, PrP(Sc), seems to be generated by template-induced conformational change of a normally expressed glycoprotein, PrP(C) (ref. 2). Although numerous studies have established the conversion of PrP(C) to PrP(Sc) as the central pathogenic event of prion disease, it is unknown whether cellular factors other than PrP(C) might be required to stimulate efficient PrP(Sc) production. We investigated the biochemical amplification of protease-resistant PrP(Sc)-like protein (PrPres) using a modified version of the protein-misfolding cyclic amplification method. Here we report that stoichiometric transformation of PrP(C) to PrPres in vitro requires specific RNA molecules. Notably, whereas mammalian RNA preparations stimulate in vitro amplification of PrPres, RNA preparations from invertebrate species do not. Our findings suggest that host-encoded stimulatory RNA molecules may have a role in the pathogenesis of prion disease. They also provide a practical approach to improve the sensitivity of diagnostic techniques based on PrPres amplification.     

Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans

Fibrogenesis or scarring of the liver is a common consequence of all chronic liver diseases. Here we refine a quantitative trait locus that confers susceptibility to hepatic fibrosis by in silico mapping and show, using congenic mice and transgenesis with recombined artificial chromosomes, that the gene Hc (encoding complement factor C5) underlies this locus. Small molecule inhibitors of the C5a receptor had antifibrotic effects in vivo, and common haplotype-tagging polymorphisms of the human gene C5 were associated with advanced fibrosis in chronic hepatitis C virus infection. Thus, the mouse quantitative trait gene led to the identification of an unknown gene underlying human susceptibility to liver fibrosis, supporting the idea that C5 has a causal role in fibrogenesis across species.     

Conservation and diversification of Wnt signaling function during the evolution of nematode vulva development

Cell-fate specification and cell-cell signaling have been well studied during vulva development in Caenorhabditis elegans and provide a paradigm in evolutionary developmental biology. Pristionchus pacificus has been developed as a 'satellite' organism with an integrated physical and genetic map that allows detailed comparisons to C. elegans. A common aspect of vulva formation in both species is the polarization of the P7.p lineage, which is responsible for vulval symmetry. In C. elegans, Wnt signaling is crucial for P7.p cell-fate patterning; nothing is known about vulval symmetry in P. pacificus. We isolated mutations that disrupt polarization of the P7.p lineage in P. pacificus and found that the corresponding gene encodes a Frizzled-like molecule. In addition, mutations in Ppa-lin-17 (encoding Frizzled) and morpholino knock-down of Ppa-lin-44 (encoding Wnt), Ppa-egl-20 (encoding Wnt), Ppa-mig-5 (encoding Dsh), Ppa-apr-1 (encoding APC) and Ppa-bar-1 (encoding beta-catenin) results in gonad-independent vulva differentiation, indicating that these genes have a role in a negative signaling process. In contrast, in C. elegans, Wnt signaling has a positive role in vulva induction, and mutations in bar-1 result in a hypoinduced phenotype. Therefore, whereas the molecular mechanisms that generate vulval symmetry are conserved, the genetic control of vulva induction diversified during evolution.     

A transcriptomic analysis of the phylum Nematoda

The phylum Nematoda occupies a huge range of ecological niches, from free-living microbivores to human parasites. We analyzed the genomic biology of the phylum using 265,494 expressed-sequence tag sequences, corresponding to 93,645 putative genes, from 30 species, including 28 parasites. From 35% to 70% of each species' genes had significant similarity to proteins from the model nematode Caenorhabditis elegans. More than half of the putative genes were unique to the phylum, and 23% were unique to the species from which they were derived. We have not yet come close to exhausting the genomic diversity of the phylum. We identified more than 2,600 different known protein domains, some of which had differential abundances between major taxonomic groups of nematodes. We also defined 4,228 nematode-specific protein families from nematode-restricted genes: this class of genes probably underpins species- and higher-level taxonomic disparity. Nematode-specific families are particularly interesting as drug and vaccine targets.     

Spermatid differentiation requires the assembly of a cell polarity complex downstream of junctional adhesion molecule-C

During spermatogenesis in the mammalian testis, stem cells (spermatogonia) differentiate into spermatocytes, which subsequently undergo two consecutive meiotic divisions to give rise to haploid spermatids. These cells are initially round but progressively elongate, condense their nuclei, acquire flagellar and acrosomal structures, and shed a significant amount of their cytoplasm to form spermatozoa (the sperm cells) in a developmental cascade termed spermiogenesis. Defects in these processes will lead to a lack of mature sperm cells (azoospermia), which is a major cause of male infertility in the human population. Here we report that a cell-surface protein of the immunoglobulin superfamily, junctional adhesion molecule-C (JAM-C), is critically required for the differentiation of round spermatids into spermatozoa in mice. We found that Jam-C is essential for the polarization of round spermatids, a function that we attribute to its role in the assembly of a cell polarity complex.