Understanding the role of argininosuccinate lyase transcript variants in the clinical and biochemical variability of the urea cycle disorder argininosuccinic aciduria

Argininosuccinic aciduria (ASA) is an autosomal recessive urea cycle disorder caused by deficiency of argininosuccinate lyase (ASL) with a wide clinical spectrum from asymptomatic to severe hyperammonemic neonatal onset life-threatening courses. We investigated the role of ASL transcript variants in the clinical and biochemical variability of ASA. Recombinant proteins for ASL wild type, mutant p.E189G, and the frequently occurring transcript variants with exon 2 or 7 deletions were (co-)expressed in human embryonic kidney 293T cells. We found that exon 2-deleted ASL forms a stable truncated protein with no relevant activity but a dose-dependent dominant negative effect on enzymatic activity after co-expression with wild type or mutant ASL, whereas exon 7-deleted ASL is unstable but seems to have, nevertheless, a dominant negative effect on mutant ASL. These findings were supported by structural modeling predictions for ASL heterotetramer/homotetramer formation. Illustrating the physiological relevance, the predominant occurrence of exon 7-deleted ASL was found in two patients who were both heterozygous for the ASL mutant p.E189G. Our results suggest that ASL transcripts can contribute to the highly variable phenotype in ASA patients if expressed at high levels. Especially, the exon 2-deleted ASL variant may form a heterotetramer with wild type or mutant ASL, causing markedly reduced ASL activity.

Topographic variability of the esophageal left atrial relation influencing ablation lines in patients with atrial fibrillation.

UNLABELLED Topography of the esophagus in atrial fibrillation ablation. INTRODUCTION The close anatomic relationship of the posterior wall of the left atrium (LA) and the thermosensitive esophagus creates a potential hazard in catheter ablation procedures. METHODS AND RESULTS In 30 patients (pts) with atrial fibrillation (AF) undergoing catheter ablation, we prospectively studied the course and contact of the esophagus in relation to LA and the topographic proximity to ablation lines encircling the right-sided and left-sided pulmonary veins (PV) as well as to the posterior line connecting the encircling lines using the electromagnetic mapping system for reconstruction of LA and for tagging of the esophagus. This new technique of anatomic tagging of the esophagus was validated against the CT scan as a standard imaging procedure. The esophageal course was highly variable, extending from courses in direct vicinity to the left- or right-sided PV as well as in the midportion of the posterior LA. In order to avoid energy application in direct proximity to the esophagus, adjustments of the left and right PV encircling lines were necessary in 14/30 pts (47%) and 3/30 (10%). In 30 pts (100%), the mid- to inferior areas of the posterior LA revealed contact with the esophagus. Therefore, posterior and inferior linear ablation lines were abandoned and shifted to superior in 29 pts (97%). CONCLUSIONS Anatomic tagging of esophagus revealed a highly variable proximity to different areas of the posterior LA suggesting individual adjustment of encircling and linear ablation lines in AF ablation procedures to avoid the life threatening complication of esophagus perforation.

Estimated strength of the Atlantic overturning circulation during the last deglaciation

The Atlantic meridional overturning circulation affects the latitudinal distribution of heat, and is a key component of the climate system. Proxy reconstructions, based on sedimentary Pa-231/Th-230 ratios and the difference between surface-and deep-water radiocarbon ages, indicate that during the last glacial period, the overturning circulation was reduced during millennial-scale periods of cooling(1-5). However, much debate exists over the robustness of these proxies(6-8). Here e combine proxy reconstructions of sea surface and air temperatures and a global climate model to quantitatively estimate changes in the strength of the Atlantic meridional overturning circulation during the last glacial period. We find that, relative to the Last Glacial Maximum, the overturning circulation was reduced by approximately 14 Sv during the cold Heinrich event 1. During the Younger Dryas cold event, the overturning circulation was reduced by approximately 12 Sv, relative to the preceding warm interval. These changes are consistent with qualitative estimates of the overturning circulation from sedimentary Pa-231/Th-230 ratios. In addition, we find that the strength of the overturning circulation during the Last Glacial Maximum and the Holocene epoch are indistinguishable within the uncertainty of the reconstruction.

DNA-based analysis of protein variants reveals different genetic variability of the paralogous equine ß-lactoglobulin genes LGB1 and LGB2

The genetic variability of milk protein genes may influence the nutritive value or processing and functional properties of the milk. While numerous protein variants are known in ruminants, knowledge about milk protein variability in horses is still limited. Mare's milk is, however, produced for human consumption in many countries. Beta-lactoglobulin belonging to the protein family of lipocalins, which are known as common food- and airborne allergens, is a major whey protein. It is absent from human milk and thus a key agent in provoking cow's milk protein allergy. Mare's milk is, however, usually better tolerated by most affected people. Several functions of β-lactoglobulin have been discussed, but its ultimate physiological role remains unclear. In the current study, the open reading frames of the two equine β-lactoglobulin paralogues LGB1 and LGB2 were re-sequenced in 249 horses belonging to 14 different breeds in order to predict the existence of protein variants at the DNA-level. Thereby, only a single signal peptide variant of LGB1, but 10 different putative protein variants of LGB2 were identified. In horses, both genes are expressed and in such this is a striking previously unknown difference in genetic variability between the two genes. It can be assumed that LGB1 is the ancestral paralogue, which has an essential function causing a high selection pressure. As horses have very low milk fat content this unknown function might well be related to vitamin-uptake. Further studies are, however, needed, to elucidate the properties of the different gene products.

Genetic variability of the equine casein genes.

The casein genes are known to be highly variable in typical dairy species, such as cattle and goat, but the knowledge about equine casein genes is limited. Nevertheless, mare milk production and consumption is gaining importance because of its high nutritive value, use in naturopathy, and hypoallergenic properties with respect to cow milk protein allergies. In the current study, the open reading frames of the 4 casein genes CSN1S1 (αS1-casein), CSN2 (β-casein), CSN1S2 (αS2-casein), and CSN3 (κ-casein) were resequenced in 253 horses of 14 breeds. The analysis revealed 21 nonsynonymous nucleotide exchanges, as well as 11 synonymous nucleotide exchanges, leading to a total of 31 putative protein isoforms predicted at the DNA level, 26 of which considered novel. Although the majority of the alleles need to be confirmed at the transcript and protein level, a preliminary nomenclature was established for the equine casein alleles.

Variations of the Atlantic meridional overturning circulation in control and transient simulations of the last millennium

The variability of the Atlantic meridional overturing circulation (AMOC) strength is investigated in control experiments and in transient simulations of up to the last millennium using the low-resolution Community Climate System Model version 3. In the transient simulations the AMOC exhibits enhanced low-frequency variability that is mainly caused by infrequent transitions between two semi-stable circulation states which amount to a 10 percent change of the maximum overturning. One transition is also found in a control experiment, but the time-varying external forcing significantly increases the probability of the occurrence of such events though not having a direct, linear impact on the AMOC. The transition from a high to a low AMOC state starts with a reduction of the convection in the Labrador and Irminger Seas and goes along with a changed barotropic circulation of both gyres in the North Atlantic and a gradual strengthening of the convection in the Greenland-Iceland-Norwegian (GIN) Seas. In contrast, the transition from a weak to a strong overturning is induced by decreased mixing in the GIN Seas. As a consequence of the transition, regional sea surface temperature (SST) anomalies are found in the midlatitude North Atlantic and in the convection regions with an amplitude of up to 3 K. The atmospheric response to the SST forcing associated with the transition indicates a significant impact on the Scandinavian surface air temperature (SAT) in the order of 1 K. Thus, the changes of the ocean circulation make a major contribution to the Scandinavian SAT variability in the last millennium.

The Mediterranean climate: An overview of the main characteristics and issues

The Mediterranean Region has many morphologic, geographical, historical, and societal characteristics, which make its climate scientifically interesting. The concept of Mediterranean climate is characterized by mild wet winters and warm to hot, dry summers and occur on the west side of continents between about 30° and 40° latitude. However, the presence of a relatively large mass of water is unique to the actual Mediterranean region. The Mediterranean Sea is a marginal and semi-enclosed sea; it is located on the western side of a large continental area and is surrounded by Europe to the North, Africa to the South, and Asia to the East. The chapter discusses that the climate of the Mediterranean region is to a large extent forced by planetary scale patterns. The time and space behavior of the regional features associated with such large-scale forcing is complex. Orography and land–sea distribution play an important role establishing the climate at basin scale and its teleconnections with global patterns. Different levels of services of readiness to emergencies, technological, and economic resources are likely to result in very different adaptation capabilities to environmental changes and new problems. The different economic situations and demographic trends are likely to produce contrasts and conflicts in a condition of limited available resources and environmental stress.