Mutations in the translated region of the lactase gene (LCT) underlie congenital lactase deficiency

Congenital lactase deficiency (CLD) is a severe gastrointestinal disorder characterized by watery diarrhea in infants fed with breast milk or other lactose-containing formulas. We initially assigned the CLD locus by linkage and linkage disequilibrium on 2q21 in 19 Finnish families. Here we report the molecular background of CLD via characterization of five distinct mutations in the coding region of the lactase (LCT) gene. Twenty-seven patients out of 32 (84%) were homozygous for a nonsense mutation, c.4170T-->A (Y1390X), designated "Fin(major)." Four rare mutations--two that result in a predicted frameshift and early truncation at S1666fsX1722 and S218fsX224 and two point mutations that result in substitutions Q268H and G1363S of the 1,927-aa polypeptide--confirmed the lactase mutations as causative for CLD. These findings facilitate genetic testing in clinical practice and enable genetic counseling for this severe disease. Further, our data demonstrate that, in contrast to common adult-type hypolactasia (lactose intolerance) caused by a variant of the regulatory element, the severe infancy form represents the outcome of mutations affecting the structure of the protein inactivating the enzyme.     

The role of non-synonymous NPY gene polymorphism in the nitric oxide production in HUVECs

A Leu7Pro change in the signal peptide of preproNPY is a functional substitution, which changes the processing of NPY in cells and associates with several cardiovascular and metabolic conditions in humans. The current study investigates the effect of the P7 allele in endothelial cells, where decreased nitric oxide (NO) production is a promoting factor to endothelial dysfunction. The function of NO system was assessed in the human umbilical vein endothelial cells (HUVECs) with [p.L7]+[p.L7] or [p.L7]+[p.P7] genotype. NPY seems to have a significant influence on NO system in HUVECs, and the responses are time and genotype dependent. HUVECs with [p.L7]+[p.P7] genotype seem to have higher basal production of NO, but after a long term treatment with NPY these cells express less eNOS mRNA and overall eNOS protein levels are lower. These significant differences in the NO bioavailability may explain the association of the L7P polymorphism with several cardiovascular complications.     

Graph-based methods for analysing networks in cell biology

Availability of large-scale experimental data for cell biology is enabling computational methods to systematically model the behaviour of cellular networks. This review surveys the recent advances in the field of graph-driven methods for analysing complex cellular networks. The methods are outlined on three levels of increasing complexity, ranging from methods that can characterize global or local structural properties of networks to methods that can detect groups of interconnected nodes, called motifs or clusters, potentially involved in common elementary biological functions. We also briefly summarize recent approaches to data integration and network inference through graph-based formalisms. Finally, we highlight some challenges in the field and offer our personal view of the key future trends and developments in graph-based analysis of large-scale datasets.     

Folivorous larvae on flowers: do autumnal moths benefit from catkins of the mountain birch?

Immature leaves of birches and other deciduous trees and shrubs are the principal food resource for the larvae of the autumnal moth, Epirrita autumnata (Borkhausen) (Lepidoptera: Geometridae). However, the larvae of this geometrid, which displays pronounced population cycles and causes massive forest defoliations in northernmost Europe, are also frequently found on the catkins of mountain birch, Betula pubescens ssp. czerepanovii (Orlova) Hämet-Ahti (Betulaceae). To examine whether autumnal moth larvae visit birch catkins for their high nutritional value, we conducted two growth experiments in which the larval diet was supplemented with male catkins, and a single test where female catkins were used. We found that the presence of male catkins in the larval diet had a positive effect on the larvae, in relation to their pupal mass (reflecting life span fecundity), survival probability, as well as the duration of the larval period. The presence of female catkins in the diet did not affect larval performance. Our findings suggest that young autumnal moth larvae actively move to male catkins, which provide a nutritional benefit and thus lead to a better performance compared with those feeding elsewhere. Another possible benefit for young larvae choosing the catkins instead of leaves may involve predator or parasitoid avoidance.     

Transient Dimers of Allergens

Background

Allergen-mediated cross-linking of IgE antibodies bound to the FcεRI receptors on the mast cell surface is the key feature of the type I allergy. If an allergen is a homodimer, its allergenicity is enhanced because it would only need one type of antibody, instead of two, for cross-linking.

Methodology/Principal Findings

An analysis of 55 crystal structures of allergens showed that 80% of them exist in symmetric dimers or oligomers in crystals. The majority are transient dimers that are formed at high protein concentrations that are reached in cells by colocalization. Native mass spectrometric analysis showed that native allergens do indeed form transient dimers in solution, while hypoallergenic variants of them exist almost solely in the monomeric form. We created a monomeric Bos d 5 allergen and show that it has a reduced capability to induce histamine release.

Conclusions/Significance

The results suggest that dimerization would be a very common and essential feature for allergens. Thus, the preparation of purely monomeric variants of allergens could open up novel possibilities for specific immunotherapy.     

Predicting quantitative genetic interactions by means of sequential matrix approximation

Despite the emerging experimental techniques for perturbing multiple genes and measuring their quantitative phenotypic effects, genetic interactions have remained extremely difficult to predict on a large scale. Using a recent high-resolution screen of genetic interactions in yeast as a case study, we investigated whether the extraction of pertinent information encoded in the quantitative phenotypic measurements could be improved by computational means. By taking advantage of the observation that most gene pairs in the genetic interaction screens have no significant interactions with each other, we developed a sequential approximation procedure which ranks the mutation pairs in order of evidence for a genetic interaction. The sequential approximations can efficiently remove background variation in the double-mutation screens and give increasingly accurate estimates of the single-mutant fitness measurements. Interestingly, these estimates not only provide predictions for genetic interactions which are consistent with those obtained using the measured fitness, but they can even significantly improve the accuracy with which one can distinguish functionally-related gene pairs from the non-interacting pairs. The computational approach, in general, enables an efficient exploration and classification of genetic interactions in other studies and systems as well.     

Breeding habitat and lair structure of the ringed seal (Phoca hispida ladogensis) in northern Lake Ladoga in Russia

The breeding habitat and lair structures of the ringed seal (Phoca hispida ladogensis) were studied by snowmobile expeditions in northern Lake Ladoga, Russia, during 1996 to 1999. Mostly flat ice and no large pack ice existed in northern Lake Ladoga during this study. All birth lairs and 88% of haul-out lairs were located in snowdrifts in the shorelines of islands or islets and 12% of the haul-out lairs occurred in pressured ice ridges. Some large haul-out lairs had been used communally by the seals. A total of 15% of the lairs observed had been attacked or marked by red fox (Vulpes vulpes), wolf (Canis lupus) or unidentified canines. The colour of the lanugo fur of the Ladoga ringed seal pup appeared to be dark grey. We conclude that the northern part of Lake Ladoga is an active breeding area for the ringed seal, which attests conservation needs for this area. Accepted: 18 September 2000     

Spatial and seasonal variation in greenhouse gas and nutrient dynamics and their interactions in the sediments of a boreal eutrophic lake

Dynamics of greenhouse gases, CH₄, CO₂ and N₂O, and nutrients, NO ₂ ^– + NO ₃ ^– , NH ₄ ⁺ and P, were studied in the sediments of the eutrophic, boreal Lake Kevätön in Finland. Undisturbed sediment cores taken in the summer, autumn and winter from the deep and shallow profundal and from the littoral were incubated in laboratory microcosms under aerobic and anaerobic water flow conditions. An increase in the availability of oxygen in water overlying the sediments reduced the release of CH₄, NH ₄ ⁺ and P, increased the flux of N₂O and NO ₂ ^– + NO ₃ ^– , but did not affect CO₂ production. The littoral sediments produced CO₂ and CH₄ at high rates, but released only negligible amounts of nutrients. The deep profundal sediments, with highest carbon content, possessed the greatest release rates of CO₂, CH₄, NH ₄ ⁺ and P. The higher fluxes of these gases in summer and autumn than in winter were probably due to the supply of fresh organic matter from primary production. From the shallow profundal sediments fluxes of CH₄, NH₄ ⁺ and P were low, but, in contrast, production of N₂O was the highest among the different sampling sites. Due to the large areal extension, the littoral and shallow profundal zones had the greatest importance in the overall gas and nutrient budgets in the lake. Methane emissions, especially the ebullition of CH₄ (up to 84% of the total flux), were closely related to the sediment P and NH ₄ ⁺ release. The high production and ebullition of CH₄, enhances the internal loading of nutrients, lake eutrophication status and the impact of boreal lakes to trophospheric gas budgets.