eIF5A Promotes Translation Elongation, Polysome Disassembly and Stress Granule Assembly

Stress granules (SGs) are cytoplasmic foci at which untranslated mRNAs accumulate in cells exposed to environmental stress. We have identified ornithine decarboxylase (ODC), an enzyme required for polyamine synthesis, and eIF5A, a polyamine (hypusine)-modified translation factor, as proteins required for arsenite-induced SG assembly. Knockdown of deoxyhypusine synthase (DHS) or treatment with a deoxyhypusine synthase inhibitor (GC7) prevents hypusine modification of eIF5A as well as arsenite-induced polysome disassembly and stress granule assembly. Time-course analysis reveals that this is due to a slowing of stress-induced ribosome run-off in cells lacking hypusine-eIF5A. Whereas eIF5A only marginally affects protein synthesis under normal conditions, it is required for the rapid onset of stress-induced translational repression. Our results reveal that hypusine-eIF5A-facilitated translation elongation promotes arsenite-induced polysome disassembly and stress granule assembly in cells subjected to adverse environmental conditions

Proliferation of Hydroelectric Dams in the Andean Amazon and Implications for Andes-Amazon Connectivity

Due to rising energy demands and abundant untapped potential, hydropower projects are rapidly increasing in the Neotropics. This is especially true in the wet and rugged Andean Amazon, where regional governments are prioritizing new hydroelectric dams as the centerpiece of long-term energy plans. However, the current planning for hydropower lacks adequate regional and basin-scale assessment of potential ecological impacts. This lack of strategic planning is particularly problematic given the intimate link between the Andes and Amazonian flood plain, together one of the most species rich zones on Earth. We examined the potential ecological impacts, in terms of river connectivity and forest loss, of the planned proliferation of hydroelectric dams across all Andean tributaries of the Amazon River. Considering data on the full portfolios of existing and planned dams, along with data on roads and transmission line systems, we developed a new conceptual framework to estimate the relative impacts of all planned dams. There are plans for 151 new dams greater than 2 MW over the next 20 years, more than a 300% increase. These dams would include five of the six major Andean tributaries of the Amazon. Our ecological impact analysis classified 47% of the potential new dams as high impact and just 19% as low impact. Sixty percent of the dams would cause the first major break in connectivity between protected Andean headwaters and the lowland Amazon. More than 80% would drive deforestation due to new roads, transmission lines, or inundation. We conclude with a discussion of three major policy implications of these findings. 1) There is a critical need for further strategic regional and basin scale evaluation of dams. 2) There is an urgent need for a strategic plan to maintain Andes-Amazon connectivity. 3) Reconsideration of hydropower as a low-impact energy source in the Neotropics

Complete Killing of Caenorhabditis elegans by Burkholderia pseudomallei Is Dependent on Prolonged Direct Association with the Viable Pathogen

Background: Burkholderia pseudomallei is the causative agent of melioidosis, a disease of significant morbidity and mortality in both human and animals in endemic areas. Much remains to be known about the contributions of genotypic variations within the bacteria and the host, and environmental factors that lead to the manifestation of the clinical symptoms of melioidosis. Methodology/Principal Findings: In this study, we showed that different isolates of B. pseudomallei have divergent ability to kill the soil nematode Caenorhabditis elegans. The rate of nematode killing was also dependent on growth media: B. pseudomallei grown on peptone-glucose media killed C. elegans more rapidly than bacteria grown on the nematode growth media. Filter and bacteria cell-free culture filtrate assays demonstrated that the extent of killing observed is significantly less than that observed in the direct killing assay. Additionally, we showed that B. pseudomallei does not persistently accumulate within the C. elegans gut as brief exposure to B. pseudomallei is not sufficient for C. elegans infection. Conclusions/Significance: A combination of genetic and environmental factors affects virulence. In addition, we have also demonstrated that a Burkholderia-specific mechanism mediating the pathogenic effect in C. elegans requires proliferating B

Osteocyte transcriptome mapping identifies a molecular landscape controlling skeletal homeostasis and susceptibility to skeletal disease.

Osteocytes are master regulators of the skeleton. We mapped the transcriptome of osteocytes from different skeletal sites, across age and sexes in mice to reveal genes and molecular programs that control this complex cellular-network. We define an osteocyte transcriptome signature of 1239 genes that distinguishes osteocytes from other cells. 77% have no previously known role in the skeleton and are enriched for genes regulating neuronal network formation, suggesting this programme is important in osteocyte communication. We evaluated 19 skeletal parameters in 733 knockout mouse lines and reveal 26 osteocyte transcriptome signature genes that control bone structure and function. We showed osteocyte transcriptome signature genes are enriched for human orthologs that cause monogenic skeletal disorders (P = 2.4 × 10-22) and are associated with the polygenic diseases osteoporosis (P = 1.8 × 10-13) and osteoarthritis (P = 1.6 × 10-7). Thus, we reveal the molecular landscape that regulates osteocyte network formation and function and establish the importance of osteocytes in human skeletal disease

Rare and low-frequency coding variants alter human adult height

Height is a highly heritable, classic polygenic trait with ~700 common associated variants identified so far through genome - wide association studies . Here , we report 83 height - associated coding variants with lower minor allele frequenc ies ( range of 0.1 - 4.8% ) and effects of up to 2 16 cm /allele ( e.g. in IHH , STC2 , AR and CRISPLD2 ) , >10 times the average effect of common variants . In functional follow - up studies, rare height - increasing alleles of STC2 (+1 - 2 cm/allele) compromise d proteolytic inhibition of PAPP - A and increased cleavage of IGFBP - 4 in vitro , resulting in higher bioavailability of insulin - like growth factors . The se 83 height - associated variants overlap genes mutated in monogenic growth disorders and highlight new biological candidates ( e.g. ADAMTS3, IL11RA, NOX4 ) and pathways ( e.g . proteoglycan/ glycosaminoglycan synthesis ) involved in growth . Our results demonstrate that sufficiently large sample sizes can uncover rare and low - frequency variants of moderate to large effect associated with polygenic human phenotypes , and that these variants implicate relevant genes and pathways

Multi-messenger searches via IceCube’s high-energy neutrinos and gravitational-wave detections of LIGO/Virgo

We summarize initial results for high-energy neutrino counterpart searches coinciding with gravitational-wave events in LIGO/Virgo\u27s GWTC-2 catalog using IceCube\u27s neutrino triggers. We did not find any statistically significant high-energy neutrino counterpart and derived upper limits on the time-integrated neutrino emission on Earth as well as the isotropic equivalent energy emitted in high-energy neutrinos for each event

In-situ estimation of ice crystal properties at the South Pole using LED calibration data from the IceCube Neutrino Observatory

The IceCube Neutrino Observatory instruments about 1 km3 of deep, glacial ice at the geographic South Pole using 5160 photomultipliers to detect Cherenkov light emitted by charged relativistic particles. A unexpected light propagation effect observed by the experiment is an anisotropic attenuation, which is aligned with the local flow direction of the ice. Birefringent light propagation has been examined as a possible explanation for this effect. The predictions of a first-principles birefringence model developed for this purpose, in particular curved light trajectories resulting from asymmetric diffusion, provide a qualitatively good match to the main features of the data. This in turn allows us to deduce ice crystal properties. Since the wavelength of the detected light is short compared to the crystal size, these crystal properties do not only include the crystal orientation fabric, but also the average crystal size and shape, as a function of depth. By adding small empirical corrections to this first-principles model, a quantitatively accurate description of the optical properties of the IceCube glacial ice is obtained. In this paper, we present the experimental signature of ice optical anisotropy observed in IceCube LED calibration data, the theory and parametrization of the birefringence effect, the fitting procedures of these parameterizations to experimental data as well as the inferred crystal properties.</p