Junctional adhesion molecule-A: functional diversity through molecular promiscuity

Cell adhesion molecules (CAMs) of the immunoglobulin superfamily (IgSF) regulate important processes such as cell proliferation, differentiation and morphogenesis. This activity is primarily due to their ability to initiate intracellular signaling cascades at cell–cell contact sites. Junctional adhesion molecule-A (JAM-A) is an IgSF-CAM with a short cytoplasmic tail that has no catalytic activity. Nevertheless, JAM-A is involved in a variety of biological processes. The functional diversity of JAM-A resides to a large part in a C-terminal PDZ domain binding motif which directly interacts with nine different PDZ domain-containing proteins. The molecular promiscuity of its PDZ domain motif allows JAM-A to recruit protein scaffolds to specific sites of cell–cell adhesion and to assemble signaling complexes at those sites. Here, we review the molecular characteristics of JAM-A, including its dimerization, its interaction with scaffolding proteins, and the phosphorylation of its cytoplasmic domain, and we describe how these characteristics translate into diverse biological activities.     

An unwelcome discovery: The pole effect in the electric arc, a threat to early 20th century precision spectrometry

In late 1912, Fritz Goos at the Hamburg Physikalisches Staatslaboratorium discovered a systematic dependency of arc-spectra wavelengths on the length of the electric arc used and on its electric parameters, such as, for instance, the current employed. In early 1913, at Heinrich Kayser's better-equipped physical laboratory in Bonn, Goos was able to confirm these effects using a large concave Rowland grating. He was able to establish that variations of between 3 mm and 10 mm in the length of the arc produced wavelength differences of up to 0.02 Å violet shift and -0.007 Å redshift respectively. Further inquiry also revealed a dependency of the wavelength on the region of the arc selected for spectrometric observation. All these surprising effects were soon collectively named pole effect.As is shown in this paper, the pole effect threatened the validity of the results of the entire research tradition of high-precision spectroscopy which, around 1910, had excelled in establishing several internally coherent systems of wavelength assignments. These wavelength catalogues had been established by spectroscopists such as Heinrich Kayser, Paul Eversheim and their co-workers in Bonn, by August Herman Pfund in Baltimore, and by Charles Fabry and Henri Buisson in Marseille under the aegis of the International Union for Co-Operation in Solar Research. They had all produced locally consistent, homogeneous systems of wavelengths with estimated errors sometimes smaller than 0.001 Å. However, long before 1913, strange non-local inconsistencies had emerged between these systems that were of much greater magnitude than the estimated error. The discovery of the pole effect opened up the possibility that variations in the arc parameters used in the measurements, which the different teams had hitherto not specified, were responsible for the systematic differences, in their respective sets of measurements, coming to up to 0.025 Å.This paper explores the interrelations between local knowledge production, the strategies for the establishment of local coherence, and the ways in which the community of physicists and spectroscopists handled a possible threat to this coherence after 1913. Around 1930, a general agreement was reached about the physical cause of the pole effect, namely Stark effects, caused in turn by intermolecular electric fields of ions in the arc. Much before 1930, however, the community had already succeeded in standardizing the instrumentation used in high-precision spectrometry and had conformed its research practice to such an extent that from 1917 on the pole effect could be routinely circumvented in high-precision spectrometry and interferometry. Thus, experimentation along with its instrumentation, indeed had a life of its own, independent of the many unsuccessful efforts to explain the pole effect theoretically.     

Optimization of Multi-Criteria Experiments with Fuzzy Results

Introduction To reach a best quality product, experiments and an op- timized design of experiments are required in an inte- grated quality management system. The best quality level of a manufacturing process or product is defined not only by one, but by m…     

Oxysterols direct immune cell migration via EBI2

Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response.     

In-situ cosmogenic 36Cl denudation rates of carbonates in Guizhou karst area

This study quantifies surface denudation of carbonate rocks by the first application of in-situ cosmogenic36Cl in China. Concentrations of natural Cl and in-situ cosmogenic36Cl in bare carbonates from Guizhou karst areas were measured with isotope dilution by accelerator mass spectrometer. The Cl concentration varied from 16 to 206 ppm. The 36Cl concentrations were in range of (0.8-2.4)106 atom g-1 , resulting in total denudation rates of 20-50 mm ka-1 that averaged over a 104-105 a timescale. The 36Cl-denudation rates showed roughly a negative correlation with the local mean temperature. This preliminary observation may suggest the variations of proportions of chemical weathering and physical erosion in denudation process, depending upon local climatic conditions.     

Physiology: does gut hormone PYY3-36 decrease food intake in rodents?

Batterham et al. report that the gut peptide hormone PYY3-36 decreases food intake and body-weight gain in rodents, a discovery that has been heralded as potentially offering a new therapy for obesity. However, we have been unable to replicate their results. Although the reasons for this discrepancy remain undetermined, an effective anti-obesity drug ultimately must produce its effects across a range of situations. The fact that the findings of Batterham et al. cannot easily be replicated calls into question the potential value of an anti-obesity approach that is based on administration of PYY3-36.     

Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome

Distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (OMIM #182960) is a heterogeneous group of disorders characterized by an almost exclusive degeneration of motor nerve fibers, predominantly in the distal part of the limbs. Silver syndrome (OMIM #270685) is a rare form of hereditary spastic paraparesis mapped to chromosome 11q12-q14 (SPG17) in which spasticity of the legs is accompanied by amyotrophy of the hands and occasionally also the lower limbs. Silver syndrome and most forms of dHMN are autosomal dominantly inherited with incomplete penetrance and a broad variability in clinical expression. A genome-wide scan in an Austrian family with dHMN-V (ref. 4) showed linkage to the locus SPG17, which was confirmed in 16 additional families with a phenotype characteristic of dHMN or Silver syndrome. After refining the critical region to 1 Mb, we sequenced the gene Berardinelli-Seip congenital lipodystrophy (BSCL2) and identified two heterozygous missense mutations resulting in the amino acid substitutions N88S and S90L. Null mutations in BSCL2, which encodes the protein seipin, were previously shown to be associated with autosomal recessive Berardinelli-Seip congenital lipodystrophy (OMIM #269700). We show that seipin is an integral membrane protein of the endoplasmic reticulum (ER). The amino acid substitutions N88S and S90L affect glycosylation of seipin and result in aggregate formation leading to neurodegeneration.     

Bacterial growth and primary production along a north-south transect of the Atlantic Ocean

The oceanic carbon cycle is mainly determined by the combined activities of bacteria and phytoplankton, but the interdependence of climate, the carbon cycle and the microbes is not well understood. To elucidate this interdependence, we performed high-frequency sampling of sea water along a north-south transect of the Atlantic Ocean. Here we report that the interaction of bacteria and phytoplankton is closely related to the meridional profile of water temperature, a variable directly dependent on climate. Water temperature was positively correlated with the ratio of bacterial production to primary production, and, more strongly, with the ratio of bacterial carbon demand to primary production. In warm latitudes (25 degrees N to 30 degrees S), we observed alternating patches of predominantly heterotrophic and autotrophic community metabolism. The calculated regression lines (for data north and south of the Equator) between temperature and the ratio of bacterial production to primary production give a maximum value for this ratio of 40% in the oligotrophic equatorial regions. Taking into account a bacterial growth efficiency of 30%, the resulting area of net heterotrophy (where the bacterial carbon demand for growth plus respiration exceeds phytoplankton carbon fixation) expands from 8 degrees N (27 degrees C) to 20 degrees S (23 degrees C). This suggests an output of CO2 from parts of the ocean to the atmosphere.     

Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration

RNA exosomes are multi-subunit complexes conserved throughout evolution and are emerging as the major cellular machinery for processing, surveillance and turnover of a diverse spectrum of coding and noncoding RNA substrates essential for viability. By exome sequencing, we discovered recessive mutations in EXOSC3 (encoding exosome component 3) in four siblings with infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1 (PCH1; MIM 607596). We identified mutations in EXOSC3 in an additional 8 of 12 families with PCH1. Morpholino knockdown of exosc3 in zebrafish embryos caused embryonic maldevelopment, resulting in small brain size and poor motility, reminiscent of human clinical features, and these defects were largely rescued by co-injection with wild-type but not mutant exosc3 mRNA. These findings represent the first example of an RNA exosome core component gene that is responsible for a human disease and further implicate dysregulation of RNA processing in cerebellar and spinal motor neuron maldevelopment and degeneration.