Rocaglates convert DEAD-box protein eIF4A into a sequence-selective translational repressor.

Rocaglamide A (RocA) typifies a class of protein synthesis inhibitors that selectively kill aneuploid tumour cells and repress translation of specific messenger RNAs. RocA targets eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase; its messenger RNA selectivity is proposed to reflect highly structured 5' untranslated regions that depend strongly on eIF4A-mediated unwinding. However, rocaglate treatment may not phenocopy the loss of eIF4A activity, as these drugs actually increase the affinity between eIF4A and RNA. Here we show that secondary structure in 5' untranslated regions is only a minor determinant for RocA selectivity and that RocA does not repress translation by reducing eIF4A availability. Rather, in vitro and in cells, RocA specifically clamps eIF4A onto polypurine sequences in an ATP-independent manner. This artificially clamped eIF4A blocks 43S scanning, leading to premature, upstream translation initiation and reducing protein expression from transcripts bearing the RocA-eIF4A target sequence. In elucidating the mechanism of selective translation repression by this lead anti-cancer compound, we provide an example of a drug stabilizing sequence-selective RNA-protein interactions

Simulated Versus Observed Cluster Eccentricity Evolution

The rate of galaxy cluster eccentricity evolution is useful in understanding large scale structure. Rapid evolution for $z <$ 0.13 has been found in two different observed cluster samples. We present an analysis of projections of 41 clusters produced in hydrodynamic simulations augmented with radiative cooling and 43 clusters from adiabatic simulations. This new, larger set of simulated clusters strengthens the claims of previous eccentricity studies. We find very slow evolution in simulated clusters, significantly different from the reported rates of observational eccentricity evolution. We estimate the rate of change of eccentricity with redshift and compare the rates between simulated and observed clusters. We also use a variable aperture radius to compute the eccentricity, r$_{200}$. This method is much more robust than the fixed aperture radius used in previous studies. Apparently radiative cooling does not change cluster morphology on scales large enough to alter eccentricity. The discrepancy between simulated and observed cluster eccentricity remains. Observational bias or incomplete physics in simulations must be present to produce halos that evolve so differently.Comment: ApJ, in press, minor revision

Eccentricity Evolution in Simulated Galaxy Clusters

Strong cluster eccentricity evolution for $z \le 0.13$ has appeared in a variety of observational data sets. We examine the evolution of eccentricity in simulated galaxy clusters using a variety of simulation methodologies, amplitude normalizations, and background cosmologies. We do not find find such evolution for $z < 0.1$ in any of our simulation ensembles. We suggest a systematic error in the form of a redshift-dependent selection effect in cluster catalogs or missing physics in cluster simulations important enough to modify the cluster morphology.Comment: Revised version to be published in ApJ. Moderate revisions, including additional N-body simulations with varying amplitude normalization and background matter density within OCDM and $\lambda$CDM scenarios reinforce our conclusion that observed clusters have recently relaxed much more rapidly than simulated one

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so

The East India Company’sFarmān, 1622‒1747

The East India Company’s presence and ongoing trade in Persia was reliant on the privileges outlined in the Farmān, granted after the capture of Hormuz in 1622. The relationship between these two powers was cemented in the rights enshrined in the Farmān, which was used by both to regulate their varying needs and expectations over the course of 125 years. This article explores the Company’s records of the Farmān and how changes to its terms were viewed from both sides. As a Persian document, the Farmān gives a clear view of the attitudes of native officials and rulers to the Company and how these terms were used as a means of control

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

JASMINE: Near-infrared astrometry and time-series photometry science

The Japan Astrometry Satellite Mission for INfrared Exploration (JASMINE) is a planned M-class science space mission by the Institute of Space and Astronautical Science, the Japan Aerospace Exploration Agency. JASMINE has two main science goals. One is Galactic archaeology with a Galactic Center survey, which aims to reveal the Milky Way’s central core structure and formation history from Gaia-level (∼25 ${\mu}$as) astrometry in the near-infrared (NIR) Hw band (1.0–1.6 ${\mu}$m). The other is an exoplanet survey, which aims to discover transiting Earth-like exoplanets in the habitable zone from NIR time-series photometry of M dwarfs when the Galactic Center is not accessible. We introduce the mission, review many science objectives, and present the instrument concept. JASMINE will be the first dedicated NIR astrometry space mission and provide precise astrometric information on the stars in the Galactic Center, taking advantage of the significantly lower extinction in the NIR. The precise astrometry is obtained by taking many short-exposure images. Hence, the JASMINE Galactic Center survey data will be valuable for studies of exoplanet transits, asteroseismology, variable stars, and microlensing studies, including discovery of (intermediate-mass) black holes. We highlight a swath of such potential science, and also describe synergies with other missions

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19

Conformational control of eukaryotic mRNA decapping by Dcp2

The lifetime of eukaryotic messenger RNA is highly regulated by elements on both the 5' and 3' ends of the message. Methylated guanine "cap" on the 5' end of a message is critical for nuclear export, protein translation, and stability of a message. The cap structure is so crucial that many viruses hijack cellular caps to direct translation towards nefarious ends. Removal of the cap structure of a mRNA is a highly regulated, irreversible step that sentences a mRNA to destruction by conserved exonucleases, and is the ultimate goal of many mRNA surveillance and degradation pathways. An enzyme known as Dcp2 executes decapping, or removal of the cap. Dcp2 from yeast to humans contains two conserved domains: one at the very N-terminus of the protein known as the regulatory domain, and a second following directly in sequence of the Nudix hydrolase family. While the catalytic domain contains the core Nudix motif necessary and sufficient for removal of mRNA caps, the regulatory domain binds the partner Dcp1 and is required for decapping in vivo. The dynamics, structure, and functional consequences of interactions between these two domains are the focus of this manuscript. In sum, regulation of decapping appears to occur by modulating the interaction between these two domains, which creates or inhibits formation of a composite active site that apposes absolutely conserved and catalytically essential regions on both domains