p53 is required for nuclear but not mitochondrial DNA damage-induced degeneration

While the consequences of nuclear DNA damage have been well studied, the exact consequences of acute and selective mitochondrial DNA (mtDNA) damage are less understood. DNA damaging chemotherapeutic drugs are known to activate p53-dependent apoptosis in response to sustained nuclear DNA damage. While it is recognized that whole-cell exposure to these drugs also damages mtDNA, the specific contribution of mtDNA damage to cellular degeneration is less clear. To examine this, we induced selective mtDNA damage in neuronal axons using microfluidic chambers that allow for the spatial and fluidic isolation of neuronal cell bodies (containing nucleus and mitochondria) from the axons (containing mitochondria). Exposure of the DNA damaging drug cisplatin selectively to only the axons induced mtDNA damage in axonal mitochondria, without nuclear damage. We found that this resulted in the selective degeneration of only the targeted axons that were exposed to DNA damage, where ROS was induced but mitochondria were not permeabilized. mtDNA damage-induced axon degeneration was not mediated by any of the three known axon degeneration pathways: apoptosis, axon pruning, and Wallerian degeneration, as Bax-deficiency, or Casp3-deficiency, or Sarm1-deficiency failed to protect the degenerating axons. Strikingly, p53, which is essential for degeneration after nuclear DNA damage, was also not required for degeneration induced with mtDNA damage. This was most evident when the p53-deficient neurons were globally exposed to cisplatin. While the cell bodies of p53-deficient neurons were protected from degeneration in this context, the axons farthest from the cell bodies still underwent degeneration. These results highlight how whole cell exposure to DNA damage activates two pathways of degeneration; a faster, p53-dependent apoptotic degeneration that is triggered in the cell bodies with nuclear DNA damage, and a slower, p53-independent degeneration that is induced with mtDNA damage.Subject terms: Cell biology, Neuroscience     

Conservation genetics of the central newt (Notophthalmus viridescens) in Iowa: the importance of a biogeographic framework

In light of global declines in amphibian populations, genetic data have become increasingly important for understanding population structure and for revealing hidden diversity. At the species level, Notophthalmus viridescens is an IUCN species of “least concern”, but the subspecies N. v. louisianensis (central newt) is listed as “threatened” in Iowa, a state on the western periphery of the species range. Genetic data were collected from 282 N. v. louisianensis from 14 sites in Iowa. Sequences from 1,054 nucleotides of mitochondrial DNA from Iowa newts revealed unexpected diversity in the form of two major haplotype groups that are not sister clades, with southern Iowa N. v. louisianensis being more closely related to N. v. piaropicola (peninsula newt) from Florida than to consubspecifics in Iowa. Sequence differentiation indicates that the two lineages of newts present in Iowa diverged near the beginning of the Pleistocene. Northern and southern Iowa haplotypes were found together at one site, indicating an opportunity for hybridization near Remington’s biogeographic suture zone 1, a hotspot for hybridization in other species. Three microsatellite loci provided additional evidence for distinctness of northern and southern Iowa newt populations. This study highlights the relevance of historical biogeography to conservation, as management strategies for N. v. louisianensis in Iowa must reflect previously unrecognized diversity in this species. Nuclear and mitochondrial data indicate genetic isolation of nearby populations on the same drainage, and field data suggest the decline of one study population, emphasizing the need for identification and protection of newt breeding sites in Iowa.     

Nucleotide excision repair efficiency in quiescent human fibroblasts is modulated by circadian clock

The efficiency of Nucleotide Excision Repair (NER)process is crucial for maintaining genomic integrity because in many organisms, including humans, it represents the only system able to repair a wide range of DNA damage. The aim of the work was to investigate whether the efficiency of the repair of photoproducts induced by UV-light is affected by the circadian phase at which irradiation occurred. NER activity has been analyzed in human quiescent fibroblasts (in the absence of the cell cycle effect), in which circadian rhythmicity has been synchronized with a pulse of dexamethasone. Our results demonstrate that both DNA damage induction and repair efficiency are strictly dependent on the phase of the circadian rhythm at which the cells are UV-exposed. Furthermore, the differences observed between fibroblasts irradiated at different circadian times (CTs) are abolished when the clock is obliterated. In addition, we observe that chromatin structure is regulated by circadian rhythmicity. Maximal chromatin relaxation occurred at the same CT when photoproduct formation and removal were highest. Our data suggest that the circadian clock regulates both the DNA sensitivity to UV damage and the efficiency of NER by controlling chromatin condensation mainly through histone acetylation.     

The freshwater zooplankton of Central America and the Caribbean

So far mainly sporadic studies have been made on the freshwater zooplankton of this region. We studied material from Costa Rica, Cuba, Bahamas, El Salvador, Haiti and Trinidad and listed unpublished species data from Jamaica. In all 183 species of Rotifera; 104 of Cladocera; 64 Calanoida and Cyclopoida and a few Ostracoda are known from the region which includes Central America, the Caribbean Islands from the Bahamas to Trinidad and the islands off South America and Central America. Records from individual countries are generally low except for Cuban Cladocera and Copepoda. The total number of Copepoda and Cladocera recorded for the whole regions appears to be reasonably comprehensive. Daphnia is rare or absent from the equatorial regions and it is likely that the low species diversity may be due partly to the lack of a range of habitat types.     

A transitory signaling center controls timing of primordial germ cell differentiation

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Assessment of cortical bone fracture resistance curves by fusing artificial neural networks and linear regression

Bone injures (BI) represents one of the major health problems, together with cancer and cardiovascular diseases. Assessment of the risks associated with BI is nontrivial since fragility of human cortical bone is varying with age. Due to restrictions for performing experiments on humans, only a limited number of fracture resistance curves (R-curves) for particular ages have been reported in the literature. This study proposes a novel decision support system for the assessment of bone fracture resistance by fusing various artificial intelligence algorithms. The aim was to estimate the R-curve slope, toughness threshold and stress intensity factor using the two input parameters commonly available during a routine clinical examination: patients age and crack length. Using the data from the literature, the evolutionary assembled Artificial Neural Network was developed and used for the derivation of Linear regression (LR) models of R-curves for arbitrary age. Finally, by using the patient (age)-specific LR models and diagnosed crack size one could estimate the risk of bone fracture under given physiological conditions. Compared to the literature, we demonstrated improved performances for estimating nonlinear changes of R-curve slope (R² = 0.82 vs. R² = 0.76) and Toughness threshold with ageing (R² = 0.73 vs. R² = 0.66).     

FUS contributes to mTOR-dependent inhibition of translation

The amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)–linked RNA-binding protein called FUS (fused in sarcoma) has been implicated in several aspects of RNA regulation, including mRNA translation. The mechanism by which FUS affects the translation of polyribosomes has not been established. Here we show that FUS can associate with stalled polyribosomes and that this association is sensitive to mTOR (mammalian target of rapamycin) kinase activity. Specifically, we show that FUS association with polyribosomes is increased by Torin1 treatment or when cells are cultured in nutrient-deficient media, but not when cells are treated with rapamycin, the allosteric inhibitor of mTORC1. Moreover, we report that FUS is necessary for efficient stalling of translation because deficient cells are refractory to the inhibition of mTOR-dependent signaling by Torin1. We also show that ALS-linked FUS mutants R521G and P525L associate abundantly with polyribosomes and decrease global protein synthesis. Importantly, the inhibitory effect on translation by FUS is impaired by mutations that reduce its RNA-binding affinity. These findings demonstrate that FUS is an important RNA-binding protein that mediates translational repression through mTOR-dependent signaling and that ALS-linked FUS mutants can cause a toxic gain of function in the cytoplasm by repressing the translation of mRNA at polyribosomes.