BRG1 co-localizes with DNA replication factors and is required for efficient replication fork progression

For DNA replication to occur, chromatin must be remodeled. Yet, we know very little about which proteins alter nucleosome occupancy at origins and replication forks and for what aspects of replication they are required. Here, we demonstrate that the BRG1 catalytic subunit of mammalian SWI/SNF-related complexes co-localizes with origin recognition complexes, GINS complexes, and proliferating cell nuclear antigen at sites of DNA replication on extended chromatin fibers. The specific pattern of BRG1 occupancy suggests it does not participate in origin selection but is involved in the firing of origins and the process of replication elongation. This latter function is confirmed by the fact that Brg1 mutant mouse embryos and RNAi knockdown cells exhibit a 50% reduction in replication fork progression rates, which is associated with decreased cell proliferation. This novel function of BRG1 is consistent with its requirement during embryogenesis and its role as a tumor suppressor to maintain genome stability and prevent cancer.     

A multi-trait systems approach reveals a response cascade to bleaching in corals

Background

Climate change causes the breakdown of the symbiotic relationships between reef-building corals and their photosynthetic symbionts (genus Symbiodinium), with thermal anomalies in 2015–2016 triggering the most widespread mass coral bleaching on record and unprecedented mortality on the Great Barrier Reef. Targeted studies using specific coral stress indicators have highlighted the complexity of the physiological processes occurring during thermal stress, but have been unable to provide a clear mechanistic understanding of coral bleaching.

Results

Here, we present an extensive multi-trait-based study in which we compare the thermal stress responses of two phylogenetically distinct and widely distributed coral species, Acropora millepora and Stylophora pistillata, integrating 14 individual stress indicators over time across a simulated thermal anomaly. We found that key stress responses were conserved across both taxa, with the loss of symbionts and the activation of antioxidant mechanisms occurring well before collapse of the physiological parameters, including gross oxygen production and chlorophyll a. Our study also revealed species-specific traits, including differences in the timing of antioxidant regulation, as well as drastic differences in the production of the sulfur compound dimethylsulfoniopropionate during bleaching. Indeed, the concentration of this antioxidant increased two-fold in A. millepora after the corals started to bleach, while it decreased 70% in S. pistillata.

Conclusions

We identify a well-defined cascading response to thermal stress, demarking clear pathophysiological reactions conserved across the two species, which might be central to fully understanding the mechanisms triggering thermally induced coral bleaching. These results highlight that bleaching is a conserved mechanism, but specific adaptations linked to the coral’s antioxidant capacity drive differences in the sensitivity and thus tolerance of each coral species to thermal stress.

     

Artificial vision with wirelessly powered subretinal electronic implant alpha-IMS

This study aims at substituting the essential functions of photoreceptors in patients who are blind owing to untreatable forms of hereditary retinal degenerations. A microelectronic neuroprosthetic device, powered via transdermal inductive transmission, carrying 1500 independent microphotodiode-amplifier-electrode elements on a 9 mm² chip, was subretinally implanted in nine blind patients. Light perception (8/9), light localization (7/9), motion detection (5/9, angular speed up to 35 deg s⁻¹), grating acuity measurement (6/9, up to 3.3 cycles per degree) and visual acuity measurement with Landolt C-rings (2/9) up to Snellen visual acuity of 20/546 (corresponding to decimal 0.037 or corresponding to 1.43 logMAR (minimum angle of resolution)) were restored via the subretinal implant. Additionally, the identification, localization and discrimination of objects improved significantly (n = 8; p < 0.05 for each subtest) in repeated tests over a nine-month period. Three subjects were able to read letters spontaneously and one subject was able to read letters after training in an alternative-force choice test. Five subjects reported implant-mediated visual perceptions in daily life within a field of 15° of visual angle. Control tests were performed each time with the implant''s power source switched off. These data show that subretinal implants can restore visual functions that are useful for daily life.     

Balancing redox cofactor generation and ATP synthesis: Key microaerobic responses in thermophilic fermentations

Geobacillus thermoglucosidasius is a Gram‐positive, thermophilic bacterium capable of ethanologenic fermentation of both C5 and C6 sugars and may have possible use for commercial bioethanol production [Tang et al., 2009; Taylor et al. (2009) Trends Biotechnol 27(7): 398–405]. Little is known about the physiological changes that accompany a switch from aerobic (high redox) to microaerobic/fermentative (low redox) conditions in thermophilic organisms. The changes in the central metabolic pathways in response to a switch in redox potential were analyzed using quantitative real‐time PCR and proteomics. During low redox (fermentative) states, results indicated that glycolysis was uniformly up‐regulated, the Krebs (tricarboxylic acid or TCA) cycle non‐uniformly down‐regulated and that there was little to no change in the pentose phosphate pathway. Acetate accumulation was accounted for by strong down‐regulation of the acetate CoA ligase gene (acs) in addition to up‐regulation of the pta and ackA genes (involved in acetate production), thus conserving ATP while reducing flux through the TCA cycle. Substitution of an NADH dehydrogenase (down‐regulated) by an up‐regulated NADH:FAD oxidoreductase and up‐regulation of an ATP synthase subunit, alongside the observed shifts in the TCA cycle, suggested that an oxygen‐scavenging electron transport chain likely remained active during low redox conditions. Together with the observed up‐regulation of a glyoxalase and down‐regulation of superoxide dismutase, thought to provide protection against the accumulation of toxic phosphorylated glycolytic intermediates and reactive oxygen species, respectively, the changes observed in G. thermoglucosidasius NCIMB 11955 under conditions of aerobic‐to‐microaerobic switching were consistent with responses to low pO₂ stress. Biotechnol. Bioeng. 2013; 110: 1057–1065. © 2012 Wiley Periodicals, Inc.     

Mitochondrial Dysfunction—A Pharmacological Target in Alzheimer's Disease

Increasing evidences suggest that mitochondrial dysfunction plays an important role in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD). Alterations of mitochondrial efficiency and function are mainly related to alterations in mitochondrial content, amount of respiratory enzymes, or changes in enzyme activities leading to oxidative stress, mitochondrial permeability transition pore opening, and enhanced apoptosis. More recently, structural changes of the network are related to bioenergetic function, and its consequences are a matter of intensive research. Several mitochondria-targeting compounds with potential efficacy in AD including dimebon, methylene blue, piracetam, simvastatin, Ginkgo biloba, curcumin, and omega-3 polyunsaturated fatty acids have been identified. The majority of preclinical data indicate beneficial effects, whereas most controlled clinical trials did not meet the expectations. Since mitochondrial dysfunction represents an early event in disease progression, one reason for the disappointing clinical results could be that pharmacological interventions might came too late. Thus, more studies are needed that focus on therapeutic strategies starting before severe disease progress.     

The potential of seaweed as a source of drugs for use in cancer chemotherapy

This review discusses studies on marine macroalgae that have been investigated for their potential as sources of novel anti-cancer drugs. The review highlights the very large number of studies of crude, partially purified and purified seaweed extracts, collected from many locations, which have shown potential as sources of potent anti-cancer drugs when tested in vitro and/or in vivo. The activity of polysaccharides, polyphenols, proteinaceous molecules, carotenoids, alkaloids, terpenes and others is described here. In some reports, mechanistic studies have identified specific inhibitory activity on a number of key cellular processes including apoptosis pathways, telomerase and tumour angiogenesis. However, despite the potential shown by these studies, translation to clinically useful preparations is almost non-existent. It is hoped this review will serve as a source document and guide for those carrying out research into the potential use of macroalgae as a source of novel anti-cancer agents.     

Trophic Tangles through Time? Opposing Direct and Indirect Effects of an Invasive Omnivore on Stream Ecosystem Processes

Omnivores can impact ecosystems via opposing direct or indirect effects. For example, omnivores that feed on herbivores and plants could either increase plant biomass due to the removal of herbivores or decrease plant biomass due to direct consumption. Thus, empirical quantification of the relative importance of direct and indirect impacts of omnivores is needed, especially the impacts of invasive omnivores. Here we investigated how an invasive omnivore (signal crayfish, Pacifastacus leniusculus) impacts stream ecosystems. First, we performed a large-scale experiment to examine the short-term (three month) direct and indirect impacts of crayfish on a stream food web. Second, we performed a comparative study of un-invaded areas and areas invaded 90 years ago to examine whether patterns from the experiment scaled up to longer time frames. In the experiment, crayfish increased leaf litter breakdown rate, decreased the abundance and biomass of other benthic invertebrates, and increased algal production. Thus, crayfish controlled detritus via direct consumption and likely drove a trophic cascade through predation on grazers. Consistent with the experiment, the comparative study also found that benthic invertebrate biomass decreased with crayfish. However, contrary to the experiment, crayfish presence was not significantly associated with higher leaf litter breakdown in the comparative study. We posit that during invasion, generalist crayfish replace the more specialized native detritivores (caddisflies), thereby leading to little long-term change in net detrital breakdown. A feeding experiment revealed that these native detritivores and the crayfish were both effective consumers of detritus. Thus, the impacts of omnivores represent a temporally-shifting interplay between direct and indirect effects that can control basal resources.     

Weakly Circadian Cells Improve Resynchrony

The mammalian suprachiasmatic nuclei (SCN) contain thousands of neurons capable of generating near 24-h rhythms. When isolated from their network, SCN neurons exhibit a range of oscillatory phenotypes: sustained or damping oscillations, or arrhythmic patterns. The implications of this variability are unknown. Experimentally, we found that cells within SCN explants recover from pharmacologically-induced desynchrony by re-establishing rhythmicity and synchrony in waves, independent of their intrinsic circadian period We therefore hypothesized that a cell''s location within the network may also critically determine its resynchronization. To test this, we employed a deterministic, mechanistic model of circadian oscillators where we could independently control cell-intrinsic and network-connectivity parameters. We found that small changes in key parameters produced the full range of oscillatory phenotypes seen in biological cells, including similar distributions of period, amplitude and ability to cycle. The model also predicted that weaker oscillators could adjust their phase more readily than stronger oscillators. Using these model cells we explored potential biological consequences of their number and placement within the network. We found that the population synchronized to a higher degree when weak oscillators were at highly connected nodes within the network. A mathematically independent phase-amplitude model reproduced these findings. Thus, small differences in cell-intrinsic parameters contribute to large changes in the oscillatory ability of a cell, but the location of weak oscillators within the network also critically shapes the degree of synchronization for the population.     

Retinoid Binding Properties of Nucleotide Binding Domain 1 of the Stargardt Disease-associated ATP Binding Cassette (ABC) Transporter,ABCA4

The retina-specific ATP binding cassette transporter, ABCA4 protein, is associated with a broad range of inherited macular degenerations, including Stargardt disease, autosomal recessive cone rod dystrophy, and fundus flavimaculatus. In order to understand its role in retinal transport in rod out segment discs, we have investigated the interactions of the soluble domains of ABCA4 with both 11-cis- and all-trans-retinal. Using fluorescence anisotropy-based binding analysis and recombinant polypeptides derived from the amino acid sequences of the four soluble domains of ABCA4, we demonstrated that the nucleotide binding domain 1 (NBD1) specifically bound 11-cis-retinal. Its affinity for all-trans-retinal was markedly reduced. Stargardt disease-associated mutations in this domain resulted in attenuation of 11-cis-retinal binding. Significant differences in 11-cis-retinal binding affinities were observed between NBD1 and other cytoplasmic and lumenal domains of ABCA4. The results suggest a possible role of ABCA4 and, in particular, the NBD1 domain in 11-cis-retinal binding. These results also correlate well with a recent report on the in vivo role of ABCA4 in 11-cis-retinal transport.