A nuclear lamina‐chromatin‐Ran GTPase axis modulates nuclear import and DNA damage signaling

The Ran GTPase regulates nuclear import and export by controlling the assembly state of transport complexes. This involves the direct action of RanGTP, which is generated in the nucleus by the chromatin‐associated nucleotide exchange factor, RCC1. Ran interactions with RCC1 contribute to formation of a nuclear:cytoplasmic (N:C) Ran protein gradient in interphase cells. In previous work, we showed that the Ran protein gradient is disrupted in fibroblasts from Hutchinson–Gilford progeria syndrome (HGPS) patients. The Ran gradient disruption in these cells is caused by nuclear membrane association of a mutant form of Lamin A, which induces a global reduction in heterochromatin marked with Histone H3K9me3 and Histone H3K27me3. Here, we have tested the hypothesis that heterochromatin controls the Ran gradient. Chemical inhibition and depletion of the histone methyltransferases (HMTs) G9a and GLP in normal human fibroblasts reduced heterochromatin levels and caused disruption of the Ran gradient, comparable to that observed previously in HGPS fibroblasts. HMT inhibition caused a defect in nuclear localization of TPR, a high molecular weight protein that, owing to its large size, displays a Ran‐dependent import defect in HGPS. We reasoned that pathways dependent on nuclear import of large proteins might be compromised in HGPS. We found that nuclear import of ATM requires the Ran gradient, and disruption of the Ran gradient in HGPS causes a defect in generating nuclear γ‐H2AX in response to ionizing radiation. Our data suggest a lamina–chromatin–Ran axis is important for nuclear transport regulation and contributes to the DNA damage response.     

Quantitative Analysis of the Whole-Body Metabolic Fate of Branched-Chain Amino Acids

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Delayed herbivory by migratory geese increases summer‐long CO2 uptake in coastal western Alaska

The advancement of spring and the differential ability of organisms to respond to changes in plant phenology may lead to “phenological mismatches” as a result of climate change. One potential for considerable mismatch is between migratory birds and food availability in northern breeding ranges, and these mismatches may have consequences for ecosystem function. We conducted a three‐year experiment to examine the consequences for CO₂ exchange of advanced spring green‐up and altered timing of grazing by migratory Pacific black brant in a coastal wetland in western Alaska. Experimental treatments represent the variation in green‐up and timing of peak grazing intensity that currently exists in the system. Delayed grazing resulted in greater net ecosystem exchange (NEE) and gross primary productivity (GPP), while early grazing reduced CO₂ uptake with the potential of causing net ecosystem carbon (C) loss in late spring and early summer. Conversely, advancing the growing season only influenced ecosystem respiration (ER), resulting in a small increase in ER with no concomitant impact on GPP or NEE. The experimental treatment that represents the most likely future, with green‐up advancing more rapidly than arrival of migratory geese, results in NEE changing by 1.2 µmol m^?2 s^?1 toward a greater CO₂ sink in spring and summer. Increased sink strength, however, may be mitigated by early arrival of migratory geese, which would reduce CO₂ uptake. Importantly, while the direct effect of climate warming on phenology of green‐up has a minimal influence on NEE, the indirect effect of climate warming manifest through changes in the timing of peak grazing can have a significant impact on C balance in northern coastal wetlands. Furthermore, processes influencing the timing of goose migration in the winter range can significantly influence ecosystem function in summer habitats.     

Selective estrogen receptor degraders with novel structural motifs induce regression in a tamoxifen-resistant breast cancer xenograft

Potent estrogen receptor ligands typically contain a phenolic hydrogen-bond donor. The indazole of the selective estrogen receptor degrader (SERD) ARN-810 is believed to mimic this. Disclosed herein is the discovery of ARN-810 analogs which lack this hydrogen-bond donor. These SERDs induced tumor regression in a tamoxifen-resistant breast cancer xenograft, demonstrating that the indazole NH is not necessary for robust ER-modulation and anti-tumor activity.     

Dual inhibition of Kif15 by oxindole and quinazolinedione chemical probes

The mitotic spindle is a microtubule-based machine that segregates a replicated set of chromosomes during cell division. Many cancer drugs alter or disrupt the microtubules that form the mitotic spindle. Microtubule-dependent molecular motors that function during mitosis are logical alternative mitotic targets for drug development. Eg5 (Kinesin-5) and Kif15 (Kinesin-12), in particular, are an attractive pair of motor proteins, as they work in concert to drive centrosome separation and promote spindle bipolarity. Furthermore, we hypothesize that the clinical failure of Eg5 inhibitors may be (in part) due to compensation by Kif15. In order to test this idea, we screened a small library of kinase inhibitors and identified GW108X, an oxindole that inhibits Kif15 in vitro. We show that GW108X has a distinct mechanism of action compared with a commercially available Kif15 inhibitor, Kif15-IN-1 and may serve as a lead with which to further develop Kif15 inhibitors as clinically relevant agents.     

Optimizing return‐on‐effort for coral nursery and outplanting practices to aid restoration of the Great Barrier Reef

Coral nursery and outplanting practices have grown in popularity worldwide for targeted restoration of degraded “high value” reef sites, and recovery of threatened taxa. Success of these practices is commonly gauged from coral propagule growth and survival, which fundamentally determines the return‐on‐effort (RRE) critical to the cost‐effectiveness and viability of restoration programs. In many cases, RRE has been optimized from past successes and failures, which therefore presents a major challenge for locations such as the Great Barrier Reef (GBR) where no local history of restoration exists to guide best practice. In establishing the first multi‐taxa coral nursery on the GBR (Opal Reef, February 2018), we constructed a novel scoring criterion from concurrent measurements of growth and survivorship to guide our relative RRE, including nursery propagule numbers (stock density). We initially retrieved RRE scores from a database of global restoration efforts to date (n = 246; 52 studies) to evaluate whether and how success commonly varied among coral taxa. We then retrieved RRE scores for Opal Reef using initial growth and survivorship data for six key coral taxa, to demonstrate that RRE scores were high for all taxa predominantly via high survivorship over winter. Repeated RRE scoring in summer is therefore needed to capture the full dynamic range of success where seasonal factors regulating growth versus survivorship differ. We discuss how RRE scoring can be easily adopted across restoration practices globally to standardize and benchmark success, but also as a tool to aid decision‐making in optimizing future propagation (and outplanting) efforts.     

Benthic ctenophore (Order Platyctenida) reproduction,recruitment, and seasonality in south Florida

Reproductive structures, modes, and seasonal patterns of size–class abundances are examined in two benthic platyctene (Family Coeloplanidae) ctenophore species present in dissimilar shallow marine environments in subtropical southeast Florida. Coeloplana waltoni, a minute (1–3 mm body length) epizoic associate of octocorals, occurs in exposed environments often under turbulent conditions, and Vallicula multiformis (2–10 mm) commonly occurs epiphytically on macroalgae in protected, calm‐water environments. Reproductive activity in C. waltoni is most active during the warm‐water summer season (June–October); gonadal development in V. multiformis occurs year‐round, and is most pronounced during sea‐warming periods in late spring (May) and late summer to early autumn (August–October), with release of cydippid larvae. Both species are hermaphroditic brooders, exhibiting paedogenesis (early gonadal development) at body lengths approximately one‐third (Coeloplana) to one‐sixth (Vallicula) of maximum adult size. Juvenile individuals (<0.6 mm) increased in abundance in C. waltoni during the summer reproductive period, and large (≥1 mm) pink‐colored individuals comprised 50% or more of samples from July through September. Seasonal abundance of gravid individuals and the timing of cydippid larval release in V. multiformis did not correspond closely with juvenile or adult population densities. Asexual fragmentation occurred in both ctenophore species, but was observed more frequently in individuals of V. multiformis. This asexual mode of reproduction probably accounted in part for the discordance between ctenophore abundances and larval recruitment events by sexual means. Morphological structures and behaviors associated with reproduction are described in this study. Uncommon images of reproductive products (gametes, embryos, larvae), spawning events, brooding, and asexual fragmentation are included, some for the first time in the published literature.     

Proximity to canopy mediates changes in the defensive chemistry and herbivore loads of an understory tropical shrub,Piper kelleyi

Phytochemical traits are a key component of plant defense theory. Chemical ecology has been biased towards studying effects of individual metabolites even though effective plant defenses are comprised of diverse mixtures of metabolites. We tested the phytochemical landscape hypothesis, positing that trophic interactions are contingent upon their spatial location across a phytochemically diverse landscape. Specifically, intraspecific phytochemical changes associated with vertical strata in forests were hypothesised to affect herbivore communities of the neotropical shrub Piper kelleyi Tepe (Piperaceae). Using a field experiment, we found that phytochemical diversity increased with canopy height, and higher levels of phytochemical diversity located near the canopy were characterised by tradeoffs between photoactive and non‐photoactive biosynthetic pathways. For understory plants closer to the ground, phytochemical diversity increased as direct light transmittance decreased, and these plants were characterised by up to 37% reductions in herbivory. Our results suggest that intraspecific phytochemical diversity structures herbivore communities across the landscape, affecting total herbivory.