Reconstruction of the yeast Snf1 kinase regulatory network reveals its role as a global energy regulator

Highly conserved among eukaryotic cells, the AMP-activated kinase (AMPK) is a central regulator of carbon metabolism. To map the complete network of interactions around AMPK in yeast (Snf1) and to evaluate the role of its regulatory subunit Snf4, we measured global mRNA, protein and metabolite levels in wild type, Δsnf1, Δsnf4, and Δsnf1Δsnf4 knockout strains. Using four newly developed computational tools, including novel DOGMA sub-network analysis, we showed the benefits of three-level ome-data integration to uncover the global Snf1 kinase role in yeast. We for the first time identified Snf1's global regulation on gene and protein expression levels, and showed that yeast Snf1 has a far more extensive function in controlling energy metabolism than reported earlier. Additionally, we identified complementary roles of Snf1 and Snf4. Similar to the function of AMPK in humans, our findings showed that Snf1 is a low-energy checkpoint and that yeast can be used more extensively as a model system for studying the molecular mechanisms underlying the global regulation of AMPK in mammals, failure of which leads to metabolic diseases

Gamma-ray bursts: Restarting the Engine

Recent gamma-ray burst observations have revealed late-time, highly energetic events which deviate from the simplest expectations of the standard fireball picture. Instead they may indicate that the central engine is active or restarted at late times. We suggest that fragmentation and subsequent accretion during the collapse of a rapidly rotating stellar core offers a natural mechanism for this.Comment: 8 pages, 1 figure; accepted by ApJ Letter

Search for Magnetic Monopoles Trapped in Matter

There have been many searches for magnetic monopoles in flight, but few for monopoles in matter. We have searched for magnetic monopoles in meteorites, schists, ferromanganese nodules, iron ores and other materials. The detector was a superconducting induction coil connected to a SQUID (Superconducting Quantum Interference Device) with a room temperature bore 15 cm in diameter. We tested a total of more than 331 kg of material including 112 kg of meteorites. We found no monopole and conclude the overall monopole/nucleon ratio in the samples is $<1.2 \times 10^{-29}$ with a 90\% confidence level.Comment: 6 pages, rev tex, no figure

Colour Peak:An analogue environment for the waters of late Noachian Mars

The surface of Mars cannot sustain liquid water today, but there is evidence water was present during the Noachian era. The transition of the martian climate from the wet Noachian to the dry Hesperian would have resulted in saline and sulfur rich surface waters . Terrestrial analogue environments that possess a chemistry like these proposed waters can be used to develop an understanding of organisms that could have persisted under such conditions. Here we present the chemistry and microbiome of the analogue environment Colour Peak, a sulfidic and saline spring system located within the Canadian High Arctic. In this study, molecular and geochemical techniques were used to investigate the sediment of the Colour Peak springs. Nucleic acids were extracted from the microbes in the sediments and the microbiome was characterised by the amplification and sequencing of 16S rRNA gene amplicons. The elemental composition of the fluids and sediment was determined by ICP-OES and compared with brines determined from the chemistry of the “Rocknest” sand sample at Yellowknife Bay, Gale Crater (Mars) by thermochemical modelling. Gibbs energy values were calculated from this fluid chemistry to identify potentially viable metabolisms. Analysis of the chemistries of the Colour Peak fluids confirmed a chemical composition like the thermochemically modelled fluid, with this justifying the classification of Colour Peak as an appropriate analogue environment to investigate the habitability of former martian aqueous environments. 16S rRNA gene profiling of the Colour Peak microbial community revealed it was dominated by bacteria associated with oxidation of reduced sulfur species and carbon dioxide fixation. Gibbs energy values calculated using the chemistry of the modelled martian fluid demonstrated that the oxidation of reduced sulfur species was also viable in this chemical environment under aerobic and anaerobic conditions. These results demonstrate that microbial sulfide oxidation is thermodynamically viable using both modelled and environmental proxies for former martian aqueous environments. This study highlights that metabolisms utilising the oxidation of reduced sulfur species could have been thermodynamically viable in ancient martian aqueous environments. Further work is needed to assess this proposed viability and the potential for unambiguous biosignature formation

Colour Peak: An analogue environment for late Noachian Mars

The martian surface cannot sustain liquid water today, but there is evidence water was present during the Noachian era. The transition of the martian climate into the Hesperian would have resulted in saline and sulfuric waters. Terrestrial analogue environments that possess a chemistry like these proposed waters can be used to develop an understanding of organisms that could have persisted. Here we present the chemistry and microbiome of Colour Peak, a sulfidic and saline spring system located within the Canadian High Arctic. Nucleic acids were extracted from the microbes in the sediments and the microbiome was characterised by the amplification and sequencing of 16S rRNA gene amplicons. The elemental composition of the fluids and sediment was determined by ICP-OES and compared with brines determined from the chemistry of the “Rocknest” sample at Yellowknife Bay, Gale Crater (Mars) by thermochemical modelling. Gibbs energy values were calculated from this fluid chemistry to identify potentially viable metabolisms. Analysis of the chemistries of the Colour Peak fluids confirmed a composition like the thermochemically modelled fluid, providing justification for the classification of Colour Peak as an appropriate analogue environment to investigate the habitability of former martian waters. Profiling of the Colour Peak microbial community revealed domination by bacteria associated with oxidation of reduced sulfur species and carbon dioxide fixation. Gibbs energy values calculated using the modelled martian fluid chemistry demonstrated that oxidation of reduced sulfur species was also viable in this chemical environment under aerobic and anaerobic conditions. These results demonstrate microbial sulfide oxidation is thermodynamically viable using both modelled and environmental proxies for former martian aqueous environments. This study highlights that metabolisms utilising the oxidation of reduced sulfur species could have been thermodynamically viable in ancient martian aqueous environments. Further work is needed to test this viability and the subsequent potential for biosignature formation

Habitability of hydrothermal systems at Jezero and Gusev Craters as constrained by hydrothermal alteration of a terrestrial mafic dike

NASA’s search for habitable environments has focused on alteration mineralogy of the Martian crust and the formation of hydrous minerals, because they reveal information about the fluid and environmental conditions from which they precipitated. Extensive work has focused on the formation of alteration minerals at low temperatures, with limited work investigating metamorphic or high-temperature alteration. We have investigated such a site as an analog for Mars: a mafic dike on the Colorado Plateau that was hydrothermally altered from contact with groundwater as it was emplaced in the porous and permeable Jurassic Entrada sandstone. Our results show evidence for fluid mobility removing Si and K but adding S, Fe, Ca, and possibly Mg to the system as alteration progresses. Mineralogically, all samples contain calcite, hematite, and kaolinite; with most samples containing minor anatase, barite, halite, and dolomite. The number of alteration minerals increase with alteration. The hydrothermal system that formed during interaction of the magma (heat source) and groundwater would have been a habitable environment once the system cooled below ∼120 °C. The mineral assemblage is similar to alteration minerals seen within the Martian crust from orbit, including those at Gusev and Jezero Craters. Therefore, based on our findings, and extrapolating them to the Martian crust, these sites may represent habitable environments which would call for further exploration and sample return of such hydrothermally altered igneous materials

Perennials as Future Grain Crops: Opportunities and Challenges

Perennial grain crops could make a valuable addition to sustainable agriculture, potentially even as an alternative to their annual counterparts. The ability of perennials to grow year after year significantly reduces the number of agricultural inputs required, in terms of both planting and weed control, while reduced tillage improves soil health and on-farm biodiversity. Presently, perennial grain crops are not grown at large scale, mainly due to their early stages of domestication and current low yields. Narrowing the yield gap between perennial and annual grain crops will depend on characterizing differences in their life cycles, resource allocation, and reproductive strategies and understanding the trade-offs between annualism, perennialism, and yield. The genetic and biochemical pathways controlling plant growth, physiology, and senescence should be analyzed in perennial crop plants. This information could then be used to facilitate tailored genetic improvement of selected perennial grain crops to improve agronomic traits and enhance yield, while maintaining the benefits associated with perennialism

GRFS and CRFS in alternative donor hematopoietic cell transplantation for pediatric patients with acute leukemia.

We report graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) (a composite end point of survival without grade III-IV acute GVHD [aGVHD], systemic therapy-requiring chronic GVHD [cGVHD], or relapse) and cGVHD-free relapse-free survival (CRFS) among pediatric patients with acute leukemia (n = 1613) who underwent transplantation with 1 antigen-mismatched (7/8) bone marrow (BM; n = 172) or umbilical cord blood (UCB; n = 1441). Multivariate analysis was performed using Cox proportional hazards models. To account for multiple testing, P \u3c .01 for the donor/graft variable was considered statistically significant. Clinical characteristics were similar between UCB and 7/8 BM recipients, because most had acute lymphoblastic leukemia (62%), 64% received total body irradiation-based conditioning, and 60% received anti-thymocyte globulin or alemtuzumab. Methotrexate-based GVHD prophylaxis was more common with 7/8 BM (79%) than with UCB (15%), in which mycophenolate mofetil was commonly used. The univariate estimates of GRFS and CRFS were 22% (95% confidence interval [CI], 16-29) and 27% (95% CI, 20-34), respectively, with 7/8 BM and 33% (95% CI, 31-36) and 38% (95% CI, 35-40), respectively, with UCB (P \u3c .001). In multivariate analysis, 7/8 BM vs UCB had similar GRFS (hazard ratio [HR], 1.12; 95% CI, 0.87-1.45; P = .39), CRFS (HR, 1.06; 95% CI, 0.82-1.38; P = .66), overall survival (HR, 1.07; 95% CI, 0.80-1.44; P = .66), and relapse (HR, 1.44; 95% CI, 1.03-2.02; P = .03). However, the 7/8 BM group had a significantly higher risk for grade III-IV aGVHD (HR, 1.70; 95% CI, 1.16-2.48; P = .006) compared with the UCB group. UCB and 7/8 BM groups had similar outcomes, as measured by GRFS and CRFS. However, given the higher risk for grade III-IV aGVHD, UCB might be preferred for patients lacking matched donors. © 2019 American Society of Hematology. All rights reserved

Rare variant contribution to human disease in 281,104 UK Biobank exomes.

Genome-wide association studies have uncovered thousands of common variants associated with human disease, but the contribution of rare variants to common disease remains relatively unexplored. The UK Biobank contains detailed phenotypic data linked to medical records for approximately 500,000 participants, offering an unprecedented opportunity to evaluate the effect of rare variation on a broad collection of traits1,2. Here we study the relationships between rare protein-coding variants and 17,361 binary and 1,419 quantitative phenotypes using exome sequencing data from 269,171 UK Biobank participants of European ancestry. Gene-based collapsing analyses revealed 1,703 statistically significant gene-phenotype associations for binary traits, with a median odds ratio of 12.4. Furthermore, 83% of these associations were undetectable via single-variant association tests, emphasizing the power of gene-based collapsing analysis in the setting of high allelic heterogeneity. Gene-phenotype associations were also significantly enriched for loss-of-function-mediated traits and approved drug targets. Finally, we performed ancestry-specific and pan-ancestry collapsing analyses using exome sequencing data from 11,933 UK Biobank participants of African, East Asian or South Asian ancestry. Our results highlight a significant contribution of rare variants to common disease. Summary statistics are publicly available through an interactive portal ( http://azphewas.com/ )

High-speed, sub-pull-in voltage MEMS switching.

We have proposed and demonstrated MEMS switching devices that take advantage of the dynamic behavior of the MEMS devices to provide lower voltage actuation and higher switching speeds. We have explored the theory behind these switching techniques and have demonstrated these techniques in a range of devices including MEMS micromirror devices and in-plane parallel plate MEMS switches. In both devices we have demonstrated switching speeds under one microsecond which has essentially been a firm limit in MEMS switching. We also developed low-loss silicon waveguide technology and the ability to incorporate high-permittivity dielectric materials with MEMS. The successful development of these technologies have generated a number of new projects and have increased both the MEMS switching and optics capabilities of Sandia National Laboratories