Deletion of individual Ku subunits in mice causes an NHEJ-independent phenotype potentially by altering apurinic/apyrimidinic site repair

Ku70 and Ku80 form a heterodimer called Ku that forms a holoenzyme with DNA dependent-protein kinase catalytic subunit (DNA-PKCS) to repair DNA double strand breaks (DSBs) through the nonhomologous end joining (NHEJ) pathway. As expected mutating these genes in mice caused a similar DSB repair-defective phenotype. However, ku70-/- cells and ku80 -/- cells also appeared to have a defect in base excision repair (BER). BER corrects base lesions, apurinic/apyrimidinic (AP) sites and single stand breaks (SSBs) utilizing a variety of proteins including glycosylases, AP endonuclease 1 (APE1) and DNA Polymerase β (Pol β). In addition, deleting Ku70 was not equivalent to deleting Ku80 in cells and mice. Therefore, we hypothesized that free Ku70 (not bound to Ku80) and/or free Ku80 (not bound to Ku70) possessed activity that influenced BER. To further test this hypothesis we performed two general sets of experiments. The first set showed that deleting either Ku70 or Ku80 caused an NHEJ-independent defect. We found ku80-/- mice had a shorter life span than dna-pkcs-/- mice demonstrating a phenotype that was greater than deleting the holoenzyme. We also found Ku70-deletion induced a p53 response that reduced the level of small mutations in the brain suggesting defective BER. We further confirmed that Ku80-deletion impaired BER via a mechanism that was not epistatic to Pol β. The second set of experiments showed that free Ku70 and free Ku80 could influence BER. We observed that deletion of either Ku70 or Ku80, but not both, increased sensitivity of cells to CRT0044876 (CRT), an agent that interferes with APE1. In addition, free Ku70 and free Ku80 bound to AP sites and in the case of Ku70 inhibited APE1 activity. These observations support a novel role for free Ku70 and free Ku80 in altering BER. © 2014 Choi et al

MicroMotility: State of the art, recent accomplishments and perspectives on the mathematical modeling of bio-motility at microscopic scales

Mathematical modeling and quantitative study of biological motility (in particular, of motility at microscopic scales) is producing new biophysical insight and is offering opportunities for new discoveries at the level of both fundamental science and technology. These range from the explanation of how complex behavior at the level of a single organism emerges from body architecture, to the understanding of collective phenomena in groups of organisms and tissues, and of how these forms of swarm intelligence can be controlled and harnessed in engineering applications, to the elucidation of processes of fundamental biological relevance at the cellular and sub-cellular level. In this paper, some of the most exciting new developments in the fields of locomotion of unicellular organisms, of soft adhesive locomotion across scales, of the study of pore translocation properties of knotted DNA, of the development of synthetic active solid sheets, of the mechanics of the unjamming transition in dense cell collectives, of the mechanics of cell sheet folding in volvocalean algae, and of the self-propulsion of topological defects in active matter are discussed. For each of these topics, we provide a brief state of the art, an example of recent achievements, and some directions for future research

Quantification of Dissolved Iron Sources to the North Atlantic Ocean

Dissolved iron is an essential micronutrient for marine phytoplankton, and its availability controls patterns of primary productivity and carbon cycling throughout the oceans1,2. The relative importance of different sources of iron to the oceans is not well known, however, and flux estimates from atmospheric dust, hydrothermal vents and oceanic sediments vary by orders of magnitude. Here we present a high-resolution transect of dissolved stable iron isotope ratios (δ56Fe) and iron concentrations ([Fe]) along a section of the North Atlantic Ocean. The different iron sources can be identified by their unique δ56Fe signatures, which persist throughout the water column. This allows us to calculate the relative contribution from dust, hydrothermal venting and reductive and non-reductive sedimentary release to the dissolved phase. We find that Saharan dust aerosol is the dominant source of dissolved iron along the section, contributing 71–87 per cent of dissolved iron. Additional sources of iron are non-reductive release from oxygenated sediments on the North American margin (10–19 per cent), reductive sedimentary dissolution on the African margin (1–4 per cent) and hydrothermal venting at the Mid-Atlantic Ridge (2–6 per cent). Our data also indicate that hydrothermal vents in the North Atlantic are a source of isotopically light iron, which travels thousands of kilometres from vent sites, potentially influencing surface productivity. Changes in the relative importance of the different iron sources through time may affect interactions between the carbon cycle and climate

Human development, nature and nurture: working beyond the divide

In this essay, I explore what social science might contribute to building a better understanding of relations between nature and nurture in human development. I first outline changing scientific perspectives on the role of the environment in the developmental and behavioural sciences, beginning with a general historical view of the developmental science of human potentials in the twentieth century, and then reflecting on a call to arms against toxic stress issued in 2012 by the American Academy of Pediatrics. I suggest that such post-genomic programmes of early intervention, which draw on emerging scientific theories of organismic plasticity and developmental malleability, raise significant social and ethical concerns. At the same time, such programmes challenge social scientists to move beyond critique and to contribute to new developmental models that deconstruct the old divide between nature and nurture. I conclude by describing efforts that posit new terms of reference and, simultaneously, new kinds of research interests and questions that are not founded upon, and are not efforts to resolve, the nature-nurture debate

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity.Peer reviewe