Exercise training in normobaric hypoxia in endurance runners. III. Muscular adjustments of selected gene transcripts

We hypothesized that specific muscular transcript level adaptations participate in the improvement of endurance performances following intermittent hypoxia training in endurance-trained subjects. Fifteen male high-level, long-distance runners integrated a modified living low-training high program comprising two weekly controlled training sessions performed at the second ventilatory threshold for 6 wk into their normal training schedule. The athletes were randomly assigned to either a normoxic (Nor) (inspired O2 fraction = 20.9%, n = 6) or a hypoxic group exercising under normobaric hypoxia (Hyp) (inspired O2 fraction = 14.5%, n = 9). Oxygen uptake and speed at second ventilatory threshold, maximal oxygen uptake (VO2 max), and time to exhaustion (Tlim) at constant load at VO2 max velocity in normoxia and muscular levels of selected mRNAs in biopsies were determined before and after training. VO2 max (+5%) and Tlim (+35%) increased specifically in the Hyp group. At the molecular level, mRNA concentrations of the hypoxia-inducible factor 1alpha (+104%), glucose transporter-4 (+32%), phosphofructokinase (+32%), peroxisome proliferator-activated receptor gamma coactivator 1alpha (+60%), citrate synthase (+28%), cytochrome oxidase 1 (+74%) and 4 (+36%), carbonic anhydrase-3 (+74%), and manganese superoxide dismutase (+44%) were significantly augmented in muscle after exercise training in Hyp only. Significant correlations were noted between muscular mRNA levels of monocarboxylate transporter-1, carbonic anhydrase-3, glucose transporter-4, and Tlim only in the group of athletes who trained in hypoxia (P < 0.05). Accordingly, the addition of short hypoxic stress to the regular endurance training protocol induces transcriptional adaptations in skeletal muscle of athletic subjects. Expressional adaptations involving redox regulation and glucose uptake are being recognized as a potential molecular pathway, resulting in improved endurance performance in hypoxia-trained subjects.

Clutch-size adjustments and skew models: effects on reproductive partitioning and group stability

Reproductive skew theory seeks to integrate social and ecological factors thought to influence the division of reproduction among group-living animals. However, most reproductive skew models only examine interactions between individuals of the same sex. Here, we suggest that females can influence group stability and conflict among males by modifying their clutch size and may do so if they benefit from the presence of subordinate male helpers or from reduced conflict. We develop 3 models, based on concessions-based, restraint, and tug-of-war models, in which female clutch size is variable and ask when females will increase their clutch size above that which would be optimal in the absence of male-male conflict. In concessions-based and restraint models, females should increase clutch size above their optima if the benefits of staying for subordinate males are relatively low. Relatedness between males has no effect on clutch size. When females do increase clutch size, the division of reproduction between males is not influenced by relatedness and does not differ between restraint and concessions-based models. Both of these predictions are in sharp contrast to previous models. In tug-of-war models, clutch size is strongly influenced by relatedness between males, with the largest clutches, but the fewest surviving offspring, produced when males are unrelated. These 3 models demonstrate the importance of considering third-party interests in the decisions of group-living organisms.

Multivariable adjustments counteract spectrum and test review bias in accuracy studies

OBJECTIVES: The STAndards for Reporting studies of Diagnostic accuracy (STARD) for investigators and editors and the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) for reviewers and readers offer guidelines for the quality and reporting of test accuracy studies. These guidelines address and propose some solutions to two major threats to validity: spectrum bias and test review bias. STUDY DESIGN AND SETTING: Using a clinical example, we demonstrate that these solutions fail and propose an alternative solution that concomitantly addresses both sources of bias. We also derive formulas that prove the generality of our arguments. RESULTS: A logical extension of our ideas is to extend STARD item 23 by adding a requirement for multivariable statistical adjustment using information collected in QUADAS items 1, 2, and 12 and STARD items 3-5, 11, 15, and 18. CONCLUSION: We recommend reporting not only variation of diagnostic accuracy across subgroups (STARD item 23) but also the effects of the multivariable adjustments on test performance. We also suggest that the QUADAS be supplemented by an item addressing the appropriateness of statistical methods, in particular whether multivariable adjustments have been included in the analysis.

GABARAP deficiency modulates expression of NaPi-IIa in renal brush-border membranes

Renal reabsorption of inorganic phosphate (P(i)) is mainly mediated by the Na(+)-dependent P(i)-cotransporter NaPi-IIa that is expressed in the brush-border membrane (BBM) of renal proximal tubules. Regulation and apical expression of NaPi-IIa are known to depend on a network of interacting proteins. Most of the interacting partners identified so far associate with the COOH-terminal PDZ-binding motif (TRL) of NaPi-IIa. In this study GABA(A) receptor-associated protein (GABARAP) was identified as a novel interacting partner of NaPi-IIa applying a membrane yeast-two-hybrid system (MYTH 2.0) to screen a mouse kidney library with the TRL-truncated cotransporter as bait. GABARAP mRNA and protein are present in renal tubules, and the interaction of NaPi-IIa and GABARAP was confirmed by using glutathione S-transferase pulldowns from BBM and coimmunoprecipitations from transfected HEK293 cells. Amino acids 36-68 of GABARAP were identified as the determinant for the described interaction. The in vivo effects of this interaction were studied in a murine model. GABARAP(-/-) mice have reduced urinary excretion of P(i), higher Na(+)-dependent (32)P(i) uptake in BBM vesicles, and increased expression of NaPi-IIa in renal BBM compared with GABARAP(+/+) mice. The expression of Na(+)/H(+) exchanger regulatory factor (NHERF)1, an important scaffold for the apical expression of NaPi-IIa, is also increased in GABARAP(-/-) mice. The absence of GABARAP does not interfere with the regulation of the cotransporter by either parathyroid hormone or acute changes of dietary P(i) content.

Cross-Border Banking

Der aktuelle Band der Reihe «Schweizerische Bankrechtstagung», befasst sich vertieft mit dem Thema des «Cross-Border Banking». Im Zentrum der Tagung vom Februar 2009 in Bern standen dabei weniger die Politik als vielmehr das Recht und praktische Fragen, die sich im Zusammenhang mit dem grenzüberschreitenden Bankverkehr stellen. Die Themen: Amtshilfe und Rechtshilfe – Neue Entwicklungen, Euro-Zahlungen gemäss den SEPA-Rulebooks (insbesondere die Haftung der Banken), Rechtliche Risiken im grenzüberschreitenden Verkehr, Aufsicht über international tätige Finanzgruppen – Konsequenzen für die Bank, Praktische Fragen der Vorort-Kontrolle, Die Standards zur Aufhebung des Bankgeheimnisses, Die Verletzung des Bankgeheimnisses – Individual- und Unternehmensstrafrecht.

Pastoralists at War: Violence and Security in the Kenya-Sudan-Uganda Border Region

The majority of those living in the border region of Kenya, Sudan, and Uganda are pastoralists, whose livelihoods are dictated by the upkeep and size of their herds. Harsh environmental conditions force pastoralists to migrate in search of water and pasturelands during the dry season. With limited access to water and competing rights to land, inter-tribal conflict arises when pastoralists from one tribe enter the territory of another. The increased availability of small arms in the region from past wars increasingly makes ordinary clashes fatal. Governments in the region have responded with heavy-handed coercive disarmament operations. These have led to distrust and subsequent violent clashes between communities and security providers. This report reviews the scale, consequences of, and responses to the many pastoral conflicts, utilizing methodological tools such as key informant interviews, retrospective analy¬sis, and a thorough review of available literature.

Mucosal lesions in a sheep infected with the Border Disease Virus (BDV)

A 28-week-old sheep was presented at the animal hospital because of chronic emaciation, anemia and slight diarrhea. Due to poor general condition and bad prognosis the animal was euthanized and submitted for postmortem investigation. Multiple erosions and ulcerations were found in the dorsal region of the tongue, the pharynx, the hard palate, in the esophagus and the ruminal pillars. Histologically, these lesions consisted of necrosuppurative inflammation. The animal was tested positive for pestivirus antigen both by immunohistochemical and by virological examination (cell culture, antigen capture ELISA and RT-PCR). A non-cytopathic Border Disease Virus was identified, and sequencing revealed a virus belonging to the BDV-3 cluster. Based on the macroscopical, histological, immunohistological and virological results this case was diagnosed as Border Disease with mucosal lesions. This is the first report of such a case in Switzerland.

A frameshift mutation in the cubilin gene (CUBN) in Border Collies with Imerslund-Gräsbeck syndrome (selective cobalamin malabsorption).

Imerslund-Gräsbeck syndrome (IGS) or selective cobalamin malabsorption has been described in humans and dogs. IGS occurs in Border Collies and is inherited as a monogenic autosomal recessive trait in this breed. Using 7 IGS cases and 7 non-affected controls we mapped the causative mutation by genome-wide association and homozygosity mapping to a 3.53 Mb interval on chromosome 2. We re-sequenced the genome of one affected dog at ∼10× coverage and detected 17 non-synonymous variants in the critical interval. Two of these non-synonymous variants were in the cubilin gene (CUBN), which is known to play an essential role in cobalamin uptake from the ileum. We tested these two CUBN variants for association with IGS in larger cohorts of dogs and found that only one of them was perfectly associated with the phenotype. This variant, a single base pair deletion (c.8392delC), is predicted to cause a frameshift and premature stop codon in the CUBN gene. The resulting mutant open reading frame is 821 codons shorter than the wildtype open reading frame (p.Q2798Rfs*3). Interestingly, we observed an additional nonsense mutation in the MRC1 gene encoding the mannose receptor, C type 1, which was in perfect linkage disequilibrium with the CUBN frameshift mutation. Based on our genetic data and the known role of CUBN for cobalamin uptake we conclude that the identified CUBN frameshift mutation is most likely causative for IGS in Border Collies.

Transnational Migration and Cross-border Mobility in the Serbian-Hungarian Border Region

The study is aiming to present migrant groups in the Serbian-Hungarian border region which are playing a role in forming transnational migration, ransnational networks and transnational spaces. Transnational migrants are using material, cultural, social and symbolical capital in various forms. The everyday activities of the people as well as their mobility, emotional attachments, and economic relationships have contributed to a transnational region the cross-border contacts in the last century were always present, even in spite of political and historical changes, only their intensity, political charge and tension has been changing. The asymmetries defining the border region has been reflected in different directions, places, time and in different volume. In this specially built and constantly reorganising scope, people who were living their everyday life have tried to use the differences for their benefit, and to improve their possibilities. With their transnational lifestyles and cross-border networks, they substantially contribute to the stability and prosperity of the cross-border region.

Late Quaternary palaeoenvironmental reconstruction from Lakes Ohrid and Prespa (Macedonia/Albania border) using stable isotopes

Abstract. Here we present stable isotope data from three sediment records from lakes that lie along the Macedonian- Albanian border (Lake Prespa: 1 core, and Lake Ohrid: 2 cores). The records only overlap for the last 40 kyr, although the longest record contains the MIS 5/6 transition (Lake Ohrid). The sedimentary characteristics of both lakes differ significantly between the glacial and interglacial phases. At the end of MIS 6 Lake Ohrid’s water level was low (high �18Ocalcite) and, although productivity was increasing (high calcite content), the carbon supply was mainly from inorganic catchment rock sources (high �13Ccarb). During the last interglacial, calcite and TOC production and preservation increased, progressively lower �18Ocalcite suggest increase in humidity and lake levels until around 115 ka. During ca. 80 ka to 11 ka the lake records suggest cold conditions as indicated by negligible calcite precipitation and low organic matter content. In Lake Ohrid, �13Corg are complacent; in contrast, Lake Prespa shows consistently higher �13Corg suggesting a low oxidation of 13C-depleted organic matter in agreement with a general deterioration of climate conditions during the glacial. From 15 ka to the onset of the Holocene, calcite and TOC begin to increase, suggesting lake levels were probably low (high �18Ocalcite). In the Holocene (11 ka to present) enhanced productivity is manifested by high calcite and organic matter content. All three cores show an early Holocene characterised by low �18Ocalcite, apart from the very early Holocene phase in Prespa where the lowest �18Ocalcite occurs at ca. 7.5 ka, suggesting a phase of higher lake level only in (the more sensitive) Lake Prespa. From 6 ka, �18Ocalcite suggest progressive aridification, in agreement with many other records in the Mediterranean, although the uppermost sediments in one core records low �18Ocalcite which we interpret as a result of human activity. Overall, the isotope data present here confirm that these two big lakes have captured the large scale, low frequency palaeoclimate variation that is seen in Mediterranean lakes, although in detail there is much palaeoclimate information that could be gained, especially small scale, high frequency differences between this region and the Mediterranean.