Effect of heavy physical training on the catecholamine content of the heart and adrenals of the guinea-pig

Zusammenfassung Ein langdauerndes Training bewirkt keine Herabsetzung der Catecholamine in Herz und Nebennieren des Meerschweinchens.

---

---

This work has been supported by a grant from Svenska Nationalföreningen mot Hjärt- och Lungsjukdomar.     

Dynamics of fat cell turnover in humans

Obesity is increasing in an epidemic manner in most countries and constitutes a public health problem by enhancing the risk for cardiovascular disease and metabolic disorders such as type 2 diabetes. Owing to the increase in obesity, life expectancy may start to decrease in developed countries for the first time in recent history. The factors determining fat mass in adult humans are not fully understood, but increased lipid storage in already developed fat cells (adipocytes) is thought to be most important. Here we show that adipocyte number is a major determinant for the fat mass in adults. However, the number of fat cells stays constant in adulthood in lean and obese individuals, even after marked weight loss, indicating that the number of adipocytes is set during childhood and adolescence. To establish the dynamics within the stable population of adipocytes in adults, we have measured adipocyte turnover by analysing the integration of 14C derived from nuclear bomb tests in genomic DNA. Approximately 10% of fat cells are renewed annually at all adult ages and levels of body mass index. Neither adipocyte death nor generation rate is altered in early onset obesity, suggesting a tight regulation of fat cell number in this condition during adulthood. The high turnover of adipocytes establishes a new therapeutic target for pharmacological intervention in obesity.     

High-level similarity of dentitions in carnivorans and rodents

The study of mammalian evolution depends greatly on understanding the evolution of teeth and the relationship of tooth shape to diet. Links between gross tooth shape, function and diet have been proposed since antiquity, stretching from Aristotle to Cuvier, Owen and Osborn. So far, however, the possibilities for exhaustive, quantitative comparisons between greatly different tooth shapes have been limited. Cat teeth and mouse teeth, for example, are fundamentally distinct in shape and structure as a result of independent evolutionary change over tens of millions of years. There is difficulty in establishing homology between their tooth components or in summarizing their tooth shapes, yet both carnivorans and rodents possess a comparable spectrum of dietary specializations from animals to plants. Here we introduce homology-free techniques to measure the phenotypic complexity of the three-dimensional shape of tooth crowns. In our geographic information systems (GIS) analysis of 441 teeth from 81 species of carnivorans and rodents, we show that the surface complexity of tooth crowns directly reflects the foods they consume. Moreover, the absolute values of dental complexity for individual dietary classes correspond between carnivorans and rodents, illustrating a high-level similarity between overall tooth shapes despite a lack of low-level similarity of specific tooth components. These results suggest that scale-independent forces have determined the high-level dental shape in lineages that are widely divergent in size, ecology and life history. This link between diet and phenotype will be useful for inferring the ecology of extinct species and illustrates the potential of fast-throughput, high-level analysis of the phenotype.     

Susceptibility loci for intracranial aneurysm in European and Japanese populations

Stroke is the world's third leading cause of death. One cause of stroke, intracranial aneurysm, affects approximately 2% of the population and accounts for 500,000 hemorrhagic strokes annually in mid-life (median age 50), most often resulting in death or severe neurological impairment. The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24-1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm. Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells, suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role. These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.     

Nephrin in human lymphoid tissues

When nephrin, the protein product of NPHS1, was cloned, it was proposed to be specific for the kidney glomerular podocytes. Recently, however, new reports have emerged verifying additional nephrin expression sites, particularly the insulin-producing β cells of the pancreas, as well as the central nervous system. In this study, we demonstrate nephrin expression in lymphoid tissues, specifically the tonsil, adenoid and lymph node. Nephrin mRNA expression levels were 4-fold higher in tonsils and adenoids than in thymus or B lymphocytes, and 20-fold higher than in T lymphocytes or monocytes, as shown by quantitative RT-PCR analysis. Anti-nephrin antibodies recognised a specific 165-kDa band in lysates of tonsil and adenoid. In immunofluorescence and immunohistochemichal stainings of adenoid and lymph node sections, nephrin-positive cells were detected in the germinal centres of the lymphoid follicles in a staining pattern typical for interdigitating cells. These results indicate a definite and additional presence of nephrin in lymphoid tissue. Received 17 October 2005; received after revision 22 November 2005; accepted 20 December 2005     

Overexpression of SUMO perturbs the growth and development of <Emphasis Type="Italic">Caenorhabditis elegans</Emphasis>

Small ubiquitin-related modifiers (SUMOs) are important regulator proteins. Caenorhabditis elegans contains a single SUMO ortholog, SMO-1, necessary for the reproduction of C. elegans. In this study, we constructed transgenic C. elegans strains expressing human SUMO-1 under the control of pan-neuronal (aex-3) or pan-muscular (myo-4) promoter and SUMO-2 under the control of myo-4 promoter. Interestingly, muscular overexpression of SUMO-1 or -2 resulted in morphological changes of the posterior part of the nematode. Movement, reproduction and aging of C. elegans were perturbed by the overexpression of SUMO-1 or -2. Genome-wide expression analyses revealed that several genes encoding components of SUMOylation pathway and ubiquitin-proteasome system were upregulated in SUMO-overexpressing nematodes. Since muscular overexpression of SMO-1 also brought up reproductive and mobility perturbations, our results imply that the phenotypes were largely due to an excess of SUMO, suggesting that a tight control of SUMO levels is important for the normal development of multicellular organisms.     

Development and characterization of small bispecific albumin-binding domains with high affinity for ErbB3

Affinity proteins based on small scaffolds are currently emerging as alternatives to antibodies for therapy. Similarly to antibodies, they can be engineered to have high affinity for specific proteins. A potential problem with small proteins and peptides is their short in vivo circulation time, which might limit the therapeutic efficacy. To circumvent this issue, we have engineered bispecificity into an albumin-binding domain (ABD) derived from streptococcal Protein G. The inherent albumin binding was preserved while the opposite side of the molecule was randomized for selection of high-affinity binders. Here we present novel ABD variants with the ability to bind to the epidermal growth factor receptor 3 (ErbB3). Isolated candidates were shown to have an extraordinary thermal stability and affinity for ErbB3 in the nanomolar range. Importantly, they were also shown to retain their affinity to albumin, hence demonstrating that the intended strategy to engineer bispecific single-domain proteins against a tumor-associated receptor was successful. Moreover, competition assays revealed that the new binders could block the natural ligand Neuregulin-1 from binding to ErbB3, indicating a potential anti-proliferative effect. These new binders thus represent promising candidates for further development into ErbB3-signaling inhibitors, where the albumin interaction could result in prolonged in vivo half-life.     

Approaching a state shift in Earth's biosphere

Localized ecological systems are known to shift abruptly and irreversibly from one state to another when they are forced across critical thresholds. Here we review evidence that the global ecosystem as a whole can react in the same way and is approaching a planetary-scale critical transition as a result of human influence. The plausibility of a planetary-scale 'tipping point' highlights the need to improve biological forecasting by detecting early warning signs of critical transitions on global as well as local scales, and by detecting feedbacks that promote such transitions. It is also necessary to address root causes of how humans are forcing biological changes.     

Different types of synaptic vesicles in axons of the retractor penis muscle of the bull.

Three types of axon profiles were observed in the smooth muscle of the retractor penis and the penile artery of the bull: 1. profiles containing small granular vesicles, presumably representing adrenergic axons; 2. profiles containing small agranular vesicles, presumably representing cholinergic axons; 3. profiles containing numerous large and small granular vesicles. The third type of profile was not found in the vas deferens or the metatarsal artery. It is therefore possible that this type of profile represents the non-adrenergic, non-cholinergic inhibitory nerves, the presence of which has previously been pharmacologically indicated in these tissues.