Splice Site Mutations in the ATP7A Gene

Menkes disease (MD) is caused by mutations in the ATP7A gene. We describe 33 novel splice site mutations detected in patients with MD or the milder phenotypic form, Occipital Horn Syndrome. We review these 33 mutations together with 28 previously published splice site mutations. We investigate 12 mutations for their effect on the mRNA transcript in vivo. Transcriptional data from another 16 mutations were collected from the literature. The theoretical consequences of splice site mutations, predicted with the bioinformatics tool Human Splice Finder, were investigated and evaluated in relation to in vivo results. Ninety-six percent of the mutations identified in 45 patients with classical MD were predicted to have a significant effect on splicing, which concurs with the absence of any detectable wild-type transcript in all 19 patients investigated in vivo. Sixty-seven percent of the mutations identified in 12 patients with milder phenotypes were predicted to have no significant effect on splicing, which concurs with the presence of wild-type transcript in 7 out of 9 patients investigated in vivo. Both the in silico predictions and the in vivo results support the hypothesis previously suggested by us and others, that the presence of some wild-type transcript is correlated to a milder phenotype

A companion to a quasar at redshift 4.7

There is a growing consensus that the emergence of quasars at high redshifts is related to the onset of galaxy formation, suggesting that the detection of concentrations of gas accompanying such quasars should provide clues about the early history of galaxies. Quasar companions have been recently identified at redshifts up to $z \approx 3$. Here we report observations of Lyman-$\alpha$ emission (a tracer of ionised hydrogen) from the companion to a quasar at $z$=4.702, corresponding to a time when the Universe was less than ten per cent of its present age. We argue that most of the emission arises in a gaseous nebula that has been photoionised by the quasar, but an additional component of continuum light -perhaps quasar light scattered from dust in the companion body, or emission from young stars within the nebula- appears necessary to explain the observations. These observations may be indicative of the first stages in the assembly of galaxy-sized structures.Comment: 8 pages, 4 figures, plain LaTeX. Accepted for publication in Natur

Variation in the use of chemotherapy in lung cancer

Factors influencing the use of chemotherapy for the initial (6 months) treatment of lung cancer in South East England were investigated. The variables explored as possibly influencing the use of chemotherapy were sex, age, the year of diagnosis, the type of lung cancer, the stage, the index of multiple deprivation and the cancer network of residence. χ2 analysis and multivariate logistic regression models were used to examine the effect of each of the variables on the use of chemotherapy. The results showed a highly significant trend in use of chemotherapy over time; the adjusted proportion of patients receiving chemotherapy increasing from 13.6% in 1994 to 29.3% in 2003. However, age, cancer network and type of lung cancer had the strongest influence on the use of chemotherapy. This finding is important when we consider that the NHS Cancer Plan aims at improving inequalities in cancer care in the UK

Buses, cars, bicycles and walkers the influence of the type of human transport on the flight responses of waterbirds

One way to manage disturbance to waterbirds in natural areas where humans require access is to promote the occurrence of stimuli for which birds tolerate closer approaches, and so cause fewer responses. We conducted 730 experimental approaches to 39 species of waterbird, using five stimulus types (single walker, three walkers, bicycle, car and bus) selected to mimic different human management options available for a controlled access, Ramsar-listed wetland. Across species, where differences existed (56% of 25 cases), motor vehicles always evoked shorter flight-initiation distances (FID) than humans on foot. The influence of stimulus type on FID varied across four species for which enough data were available for complete cross-stimulus analysis. All four varied FID in relation to stimuli, differing in 4 to 7 of 10 possible comparisons. Where differences occurred, the effect size was generally modest, suggesting that managing stimulus type (e.g. by requiring people to use vehicles) may have species-specific, modest benefits, at least for the waterbirds we studied. However, different stimulus types have different capacities to reduce the frequency of disturbance (i.e. by carrying more people) and vary in their capacity to travel around important habita

Bioinformatic Characterization of P-Type ATPases Encoded Within the Fully Sequenced Genomes of 26 Eukaryotes

P-type ATPases play essential roles in numerous processes, which in humans include nerve impulse propagation, relaxation of muscle fibers, secretion and absorption in the kidney, acidification of the stomach and nutrient absorption in the intestine. Published evidence suggests that uncharacterized families of P-type ATPases with novel specificities exist. In this study, the fully sequenced genomes of 26 eukaryotes, including animals, plants, fungi and unicellular eukaryotes, were analyzed for P-type ATPases. We report the organismal distributions, phylogenetic relationships, probable topologies and conserved motifs of nine functionally characterized families and 13 uncharacterized families of these enzyme transporters. We have classified these proteins according to the conventions of the functional and phylogenetic IUBMB-approved transporter classification system (www.tcdb.org, Saier et al. in Nucleic Acids Res 34:181–186, 2006; Nucleic Acids Res 37:274–278, 2009)

Haemodynamic effects of plasma-expansion with hyperoncotic albumin in cirrhotic patients with renal failure: a prospective interventional study

<p>Abstract</p> <p>Background</p> <p>Patients with advanced cirrhosis of the liver typically display circulatory disturbance. Haemodynamic management may be critical for avoiding and treating functional renal failure in such patients. This study investigated the effects of plasma expansion with hyperoncotic albumin solution and the role of static haemodynamic parameters in predicting volume responsiveness in patients with advanced cirrhosis.</p> <p>Methods</p> <p>Patients with advanced cirrhosis (Child B and C) of the liver receiving albumin substitution because of renal compromise were studied using trans-pulmonary thermodilution. Paired measurements before and after two infusions of 200 ml of 20% albumin per patient were recorded and standard haemodynamic parameters such as central venous pressure (CVP), mean arterial pressure (MAP), systemic vascular resistance index (SVRI), cardiac index (CI) and derived variables were assessed, including global end-diastolic blood volume index (GEDVI), a parameter that reflects central blood volume</p> <p>Results</p> <p>100 measurements in 50 patients (33 m/17 w; age 56 years (± 8); Child-Pugh-score 12 (± 2), serum creatinine 256 μmol (± 150) were analyzed. Baseline values suggested decreased central blood volumes GEDVI = 675 ml/m²(± 138) despite CVP within the normal range (11 mmHg (± 5). After infusion, GEDVI, CI and CVP increased (682 ml/m²(± 128) vs. 744 ml/m²(± 171), p < 0.001; 4.3 L/min/m²(± 1.1) vs. 4.7 L/min/m²(± 1.1), p < 0.001; 12 mmHg (± 6) vs. 14 mmHg (± 6), p < 0.001 respectively) and systemic vascular resistance decreased (1760 dyn s/cm⁵/m²(± 1144) vs. 1490 dyn s/cm⁵/m²(± 837); p < 0.001). Changes in GEDVI, but not CVP, correlated with changes in CI (r²= 0.51; p < 0.001). To assess the value of static haemodynamic parameters at baseline in predicting an increase in CI of 10%, receiver-operating-characteristic curves were constructed. The areas under the curve were 0.766 (p < 0.001) for SVRI, 0.723 (p < 0.001) for CI, 0.652 (p = 0.010) for CVP and 0.616 (p = 0.050) for GEDVI.</p> <p>Conclusion</p> <p>In a substantial proportion of patients with advanced cirrhosis, plasma expansion results in an increase in central blood volume. GEDVI but not CVP behaves as an indicator of cardiac preload, whereas high baseline SVRI is predictive of fluid responsiveness.</p

Cell Wall Trapping of Autocrine Peptides for Human G-Protein-Coupled Receptors on the Yeast Cell Surface

G-protein-coupled receptors (GPCRs) regulate a wide variety of physiological processes and are important pharmaceutical targets for drug discovery. Here, we describe a unique concept based on yeast cell-surface display technology to selectively track eligible peptides with agonistic activity for human GPCRs (Cell Wall Trapping of Autocrine Peptides (CWTrAP) strategy). In our strategy, individual recombinant yeast cells are able to report autocrine-positive activity for human GPCRs by expressing a candidate peptide fused to an anchoring motif. Following expression and activation, yeast cells trap autocrine peptides onto their cell walls. Because captured peptides are incapable of diffusion, they have no impact on surrounding yeast cells that express the target human GPCR and non-signaling peptides. Therefore, individual yeast cells can assemble the autonomous signaling complex and allow single-cell screening of a yeast population. Our strategy may be applied to identify eligible peptides with agonistic activity for target human GPCRs

The Etiology of Multiple Sclerosis: Genetic Evidence for the Involvement of the Human Endogenous Retrovirus HERV-Fc1

We have investigated the role of human endogenous retroviruses in multiple sclerosis by analyzing the DNA of patients and controls in 4 cohorts for associations between multiple sclerosis and polymorphisms near viral restriction genes or near endogenous retroviral loci with one or more intact or almost-intact genes. We found that SNPs in the gene TRIM5 were inversely correlated with disease. Conversely, SNPs around one retroviral locus, HERV-Fc1, showed a highly significant association with disease. The latter association was limited to a narrow region that contains no other known genes. We conclude that HERV-Fc1 and TRIM5 play a role in the etiology of multiple sclerosis. If these results are confirmed, they point to new modes of treatment for multiple sclerosis

Hypersensitive to Red and Blue 1 and Its Modification by Protein Phosphatase 7 Are Implicated in the Control of Arabidopsis Stomatal Aperture

The stomatal pores are located on the plant leaf epidermis and regulate CO2 uptake for photosynthesis and the loss of water by transpiration. Their stomatal aperture therefore affects photosynthesis, water use efficiency, and agricultural crop yields. Blue light, one of the environmental signals that regulates the plant stomatal aperture, is perceived by the blue/UV-A light-absorbing cryptochromes and phototropins. The signal transduction cascades that link the perception of light to the stomatal opening response are still largely unknown. Here, we report two new players, Hypersensitive to Red and Blue 1 (HRB1) and Protein Phosphatase 7 (PP7), and their genetic and biochemical interactions in the control of stomatal aperture. Mutations in either HRB1 or PP7 lead to the misregulation of the stomatal aperture and reduce water loss under blue light. Both HRB1 and PP7 are expressed in the guard cells in response to a light-to-dark or dark-to-light transition. HRB1 interacts with PP7 through its N-terminal ZZ-type zinc finger motif and requires a functional PP7 for its stomatal opening response. HRB1 is phosphorylated in vivo, and PP7 can dephosphorylate HRB1. HRB1 is mostly dephosphorylated in a protein complex of 193 kDa in the dark, and blue light increases complex size to 285 kDa. In the pp7 mutant, this size shift is impaired, and HRB1 is predominately phosphorylated. We propose that a modification of HRB1 by PP7 under blue light is essential to acquire a proper conformation or to bring in new components for the assembly of a functional HRB1 protein complex. Guard cells control stomatal opening in response to multiple environmental or biotic stimuli. This study may furnish strategies that allow plants to enjoy the advantages of both constitutive and ABA-induced protection under water-limiting conditions

Does Genetic Diversity Predict Health in Humans?

Genetic diversity, especially at genes important for immune functioning within the Major Histocompatibility Complex (MHC), has been associated with fitness-related traits, including disease resistance, in many species. Recently, genetic diversity has been associated with mate preferences in humans. Here we asked whether these preferences are adaptive in terms of obtaining healthier mates. We investigated whether genetic diversity (heterozygosity and standardized mean d2) at MHC and nonMHC microsatellite loci, predicted health in 153 individuals. Individuals with greater allelic diversity (d2) at nonMHC loci and at one MHC locus, linked to HLA-DRB1, reported fewer symptoms over a four-month period than individuals with lower d2. In contrast, there were no associations between MHC or nonMHC heterozygosity and health. NonMHC-d2 has previously been found to predict male preferences for female faces. Thus, the current findings suggest that nonMHC diversity may play a role in both natural and sexual selection acting on human populations