Transformation is an alternative to normal skeletal muscle development

The differentiation of skeletal muscle is characterized by cessation of proliferation and fusion of single myoblasts to form non-replicating multinucleate fibers (myotubes). If termination of proliferation is an obligate requirement for further differentiation, myoblasts defective in this stage of development should fail to fuse or exhibit any further characteristics of myotubes. Furthermore, myoblasts which have lost the ability to control and cease proliferation may represent a transformed, potentially tumorigenic population. Formation of the neoplastic state may therefore be viewed as an alternate path, antithetical to the normal differentiation of skeletal muscle. To test this hypothesis, we isolated 13 clones of non-fusing cells from the myogenic L₈ line of rat myoblasts. In contrast to the L₈ line, all of the non-fusing clones maintain their proliferative capacity, do not form myotubes, nor elevated creatine kinase activity nor increased myosin, but do develop into tumors when injected into athymic mice. L₈ cells do not produce tumors in these mice. Analysis of cell growth and serum requirements, plasminogen activator, hexose transport, adhesiveness, LETS protein and growth in soft agar, indicates that these non-fusing cells are transformed and clearly distinguished from the parent L₈ cells. Whereas the L₈ line maintains a near diploid complement of chromosomes, all non-fusing clones were polyploid. In addition, 12 of 13 non-fusing clones (but not the L₈ cells) express an endogenous type C virus. Although all clones defective in differentiation formed tumors, no single in vitro characteristic was found to be a constant index of this tumorigenic capacity. We conclude that cessation of proliferation is an obligate requirement for skeletal myogenesis, that transformation is an alternative to normal skeletal muscle development and that the phenotype of these transformed cells may be quite varied.     

Cytoprotective Effect of Ferritin H in Renal Ischemia Reperfusion Injury

Oxidative stress is a major contributor to kidney injury following ischemia reperfusion. Ferritin, a highly conserved iron-binding protein, is a key protein in the maintenance of cellular iron homeostasis and protection from oxidative stress. Ferritin mitigates oxidant stress by sequestering iron and preventing its participation in reactions that generate reactive oxygen species. Ferritin is composed of two subunit types, ferritin H and ferritin L. Using an in vivo model that enables conditional tissue-specific doxycycline-inducible expression of ferritin H in the mouse kidney, we tested the hypothesis that an increased level of H-rich ferritin is renoprotective in ischemic acute renal failure. Prior to induction of ischemia, doxycycline increased ferritin H in the kidneys of the transgenic mice nearly 6.5-fold. Following reperfusion for 24 hours, induction of neutrophil gelatinous-associated lipocalin (NGAL, a urine marker of renal dysfunction) was reduced in the ferritin H overexpressers compared to controls. Histopathologic examination following ischemia reperfusion revealed that ferritin H overexpression increased intact nuclei in renal tubules, reduced the frequency of tubular profiles with luminal cast materials, and reduced activated caspase-3 in the kidney. In addition, generation of 4-hydroxy 2-nonenal protein adducts, a measurement of oxidant stress, was decreased in ischemia-reperfused kidneys of ferritin H overexpressers. These studies demonstrate that ferritin H can inhibit apoptotic cell death, enhance tubular epithelial viability, and preserve renal function by limiting oxidative stress following ischemia reperfusion injury.     

Flexible Use of Patch-Leaving Mechanisms in a Parasitoid Wasp

Classical optimal-foraging theory predicts that a parasitoid is less likely to leave a patch after a host encounter when the host distribution is aggregated, whereas a parasitoid is more likely to leave after a host encounter when the host distribution is regular. Field data on host distributions in the area of origin of the whitefly parasitoid Encarsia formosa showed that whiteflies aggregate at several spatial scales. However, infested leaves most likely contained a single host. This suggests that a host encounter is not enough to decide when to leave. We therefore tested the effect of host distribution and parasitoid experience on patch-leaving behavior. Each parasitoid was observed for several consecutive days in a three-dimensional arena with leaflets containing on average one host per leaflet in an either regular or aggregated host distribution. A proportional hazards model showed that a host encounter decreased the leaving tendency on a leaflet with one host when the time since the latest host encounter was short, but increased the leaving tendency when the time since the latest host encounter was long, independent of host distribution. We conclude that a parasitoid can switch from decreasing to increasing its tendency to leave a patch after a host encounter. We propose two hypotheses that may explain the evolution of such a switching mechanism.     

Telomere length behaves as biomarker of somatic redundancy rather than biological age

Biomarkers of aging are essential to predict mortality and aging‐related diseases. Paradoxically, age itself imposes a limitation on the use of known biomarkers of aging because their associations with mortality generally diminish with age. How this pattern arises is, however, not understood. With meta‐analysis we show that human leucocyte telomere length (TL) predicts mortality, and that this mortality association diminishes with age, as found for other biomarkers of aging. Subsequently, we demonstrate with simulation models that this observation cannot be reconciled with the popular hypothesis that TL is proportional to biological age. Using the reliability theory of aging, we instead propose that TL is a biomarker of somatic redundancy, the body's capacity to absorb damage, which fits the observed pattern well. We discuss to what extent diminishing redundancy with age may also explain the observed diminishing mortality modulation with age of other biomarkers of aging. Considering diminishing somatic redundancy as the causal agent of aging may critically advance our understanding of the aging process, and improve predictions of life expectancy and vulnerability to aging‐related diseases.