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605 records · Page 34

Chromatin structure predicts survival in glioma patients

The pathological changes in epigenetics and gene regulation that accompany the progression of low-grade to high-grade gliomas are under-studied. The authors use a large set of paired atac-seq and RNA-seq data from surgically resected glioma specimens to infer gene regulatory relationships in glioma. Thirty-eight glioma patient samples underwent atac-seq sequencing and 16 samples underwent additional RNA-seq analysis. Using an atac-seq/RNA-seq correlation matrix, atac-seq peaks were paired with genes based on high correlation values (|r 2 | > 0.6). Samples clustered by IDH1 status but not by grade. Surprisingly there was a trend for IDH1 mutant samples to have more peaks. The majority of peaks are positively correlated with survival and positively correlated with gene expression. Constructing a model of the top six atac-seq peaks created a highly accurate survival prediction model (r 2 = 0.68). Four of these peaks were still significant after controlling for age, grade, pathology, IDH1 status and gender. Grade II, III, and IV (primary) samples have similar transcription factors and gene modules. However, grade IV (recurrent) samples have strikingly few peaks. Patient-derived glioma cultures showed decreased peak counts following radiation indicating that this may be radiation-induced. This study supports the notion that IDH1 mutant and IDH1 wildtype gliomas have different epigenetic landscapes and that accessible chromatin sites mapped by atac-seq peaks tend to be positively correlated with expression. The data in this study leads to a new model of treatment response wherein glioma cells respond to radiation therapy by closing open regions of DNA.

59 BASIC BIOLOGICAL SCIENCES↗

Engineering custom morpho- and chemotypes of Populus for sustainable production of biofuels, bioproducts, and biomaterials

Humans have been modifying plant traits for thousands of years, first through selection (i.e., domestication) then modern breeding, and in the last 30 years, through biotechnology. These modifications have resulted in increased yield, more efficient agronomic practices, and enhanced quality traits. Precision knowledge of gene regulation and function through high-resolution single-cell omics technologies, coupled with the ability to engineer plant genomes at the DNA sequence, chromatin accessibility, and gene expression levels, can enable engineering of complex and complementary traits at the biosystem level. Populus spp., the primary genetic model system for woody perennials, are among the fastest growing trees in temperate zones and are important for both carbon sequestration and global carbon cycling. Ample genomic and transcriptomic resources for poplar are available including emerging single-cell omics datasets. To expand use of poplar outside of valorization of woody biomass, chassis with novel morphotypes in which stem branching and tree height are modified can be fabricated thereby leading to trees with altered leaf to wood ratios. These morphotypes can then be engineered into customized chemotypes that produce high value biofuels, bioproducts, and biomaterials not only in specific organs but also in a cell-type-specific manner. For example, the recent discovery of triterpene production in poplar leaf trichomes can be exploited using cell-type specific regulatory sequences to synthesize high value terpenes such as the jet fuel precursor bisabolene specifically in the trichomes. By spatially and temporally controlling expression, not only can pools of abundant precursors be exploited but engineered molecules can be sequestered in discrete cell structures in the leaf. The structural diversity of the hemicellulose xylan is a barrier to fully utilizing lignocellulose in biomaterial production and by leveraging cell-type-specific omics data, cell wall composition can be modified in a tailored and targeted specific manner to generate poplar wood with novel chemical features that are amenable for processing or advanced manufacturing. Precision engineering poplar as a multi-purpose sustainable feedstock highlights how genome engineering can be used to re-imagine a crop species.

09 BIOMASS FUELS↗

Hydrodynamic and frictional modulation of deformations in switchable colloidal crystallites

Displacive transformations in colloidal crystals may offer a pathway for increasing the diversity of accessible configurations without the need to engineer particle shape or interaction complexity. To date, binary crystals composed of spherically symmetric particles at specific size ratios have been formed that exhibit floppiness and facile routes for transformation into more rigid structures that are otherwise not accessible by direct nucleation and growth. There is evidence that such transformations, at least at the micrometer scale, are kinetically influenced by concomitant solvent motion that effectively induces hydrodynamic correlations between particles. Here, we study quantitatively the impact of such interactions on the transformation of binary bcc-CsCl analog crystals into close-packed configurations. We first employ principal-component analysis to stratify the explorations of a bcc-CsCl crystallite into orthogonal directions according to displacement. We then compute diffusion coefficients along the different directions using several dynamical models and find that hydrodynamic correlations, depending on their range, can either enhance or dampen collective particle motions. These two distinct effects work synergistically to bias crystallite deformations toward a subset of the available outcomes.

42 ENGINEERING↗

Quality-Control Mechanism for Telomerase RNA Folding in the Cell

Long non-coding RNAs can often fold into different conformations. Telomerase RNA, an essential component of the telomerase ribonucleoprotein (RNP) enzyme, must fold into a defined structure to fulfill its function with the protein catalytic subunit (TERT) and other accessory factors. However, the mechanism by which the correct folding of telomerase RNA is warranted in a cell is still unknown. Here we show that La-related protein Pof8 specifically recognizes the conserved pseudoknot region of telomerase RNA and instructs the binding of the Lsm2-8 complex to its mature 3' end, thus selectively protecting the correctly folded RNA from exonucleolytic degradation. In the absence of Pof8, TERT assembles with misfolded RNA and produces little telomerase activity. Therefore, Pof8 plays a key role in telomerase RNA folding quality control, ensuring that TERT only assembles with functional telomerase RNA to form active telomerase. Our finding reveals a mechanism for non-coding RNA folding quality control.

59 BASIC BIOLOGICAL SCIENCES↗

Identification of small-molecule protein–protein interaction inhibitors for NKG2D

NKG2D (natural-killer group 2, member D) is a homodimeric transmembrane receptor that plays an important role in NK, γδ + , and CD8 + T cell-mediated immune responses to environmental stressors such as viral or bacterial infections and oxidative stress. However, aberrant NKG2D signaling has also been associated with chronic inflammatory and autoimmune diseases, and as such NKG2D is thought to be an attractive target for immune intervention. Here, in this study, we describe a comprehensive small-molecule hit identification strategy and two distinct series of protein–protein interaction inhibitors of NKG2D. Although the hits are chemically distinct, they share a unique allosteric mechanism of disrupting ligand binding by accessing a cryptic pocket and causing the two monomers of the NKG2D dimer to open apart and twist relative to one another. Leveraging a suite of biochemical and cell-based assays coupled with structure-based drug design, we established tractable structure–activity relationships with one of the chemical series and successfully improved both the potency and physicochemical properties. Together, we demonstrate that it is possible, albeit challenging, to disrupt the interaction between NKG2D and multiple protein ligands with a single molecule through allosteric modulation of the NKG2D receptor dimer/ligand interface.

59 BASIC BIOLOGICAL SCIENCES↗

Outgrowth of erlotinib-resistant subpopulations recapitulated in patient-derived lung tumor spheroids and organoids

A model that recapitulates development of acquired therapeutic resistance is needed to improve oncology drug development and patient outcomes. To achieve this end, we established methods for the preparation and growth of spheroids from primary human lung adenocarcinomas, including methods to culture, passage, monitor growth, and evaluate changes in mutational profile over time. Primary lung tumor spheroids were cultured in Matrigel® with varying concentrations of erlotinib, a small molecule kinase inhibitor of epidermal growth factor receptor (EGFR) that is ineffective against KRAS mutant cells. Subtle changes in spheroid size and number were observed within the first two weeks of culture. Spheroids were cultured for up to 24 weeks, during which time interactions between different cell types, movement, and assembly into heterogeneous organoid structures were documented. Allele-specific competitive blocker PCR (ACB-PCR) was used to quantify low frequency BRAF V600E, KRAS G12D, KRAS G12V, and PIK3CA H1047R mutant subpopulations in tumor tissue residue (TR) samples and cultured spheroids. Mutant subpopulations, including multiple mutant subpopulations, were quite prevalent. Twelve examples of mutant enrichment were found in eight of the 14 tumors analyzed, based on the criteria that a statistically-significant increase in mutant fraction was observed relative to both the TR and the no-erlotinib control. Of the mutants quantified in erlotinib-treated cultures, PIK3CA H1047 mutant subpopulations increased most often (5/14 tumors), which is consistent with clinical observations. Thus, this ex vivo lung tumor spheroid model replicates the cellular and mutational tumor heterogeneity of human lung adenocarcinomas and can be used to assess the outgrowth of mutant subpopulations. Spheroid cultures with characterized mutant subpopulations could be used to investigate the efficacy of lung cancer combination therapies.

59 BASIC BIOLOGICAL SCIENCES↗

A Systems Biology Approach to Energy Flow in H 2 Producing Microbial Communities: Microbial Mats

This report describes the results of work conducted at NASA Ames Research Center, in collaboration with investigators at Lawrence Livermore National Laboratory, during the time period 12/15/2014 to 12/15/2017. The work was an extension of a collaboration with LLNL that began in 2008. Work this reporting period focused primarily on tasks related to microbial mats from both the Elkhorn Slough and Baja California field sites, including the analysis and publication of data produced prior to 12/15/2014. During this reporting period, in addition to the microbial mat work, we also conducted a series of experiments with a particular algal-bacterial association (C. sorokiniana and A. brasilense). A number of aspects of this well-characterized algal-bacterial association enabled us not only to further our understanding of interactions between these particular organisms, but to apply that knowledge and techniques to our collection of microorganisms isolated from microbial mats. Microbial mat experiments focused both on intact mat communities and on cultures of organisms isolated from the mats (the Microbial Mat Living Library). In a series of co-culture experiments, we documented both positive and negative interactions amongst heterotrophic and autotrophic isolates of microbial mat microorganisms. One particularly important and novel mat cyanobacterium (ESFC-1) was studied in detail. We developed techniques to pursue an investigation of functional redundancy (the idea that closely related organisms perform identical roles in a community) in cyanobacterial autotrophs in the Elkhorn Slough microbial mat. In those experiments, we documented numerous instances of increases in growth rate between co-cultures of two organisms (relative to their growth rate in isolation) performing what would seem to be identical functional roles. Simplified microbial mat communities consisting of organisms from the Microbial Mat Living Library were constructed and studied in laboratory experiments. The “constructed mats” were grown in standard laboratory glassware and plasticware, but cultures were also combined with artificial materials in an effort to re-create the three-dimensional structure of naturally occurring microbial mats. These constructed mats re-created a number of functions attributable to natural microbial mats (N-fixation, H2-production) and simplified their study using molecular ecological techniques due to the smaller number of microbial “species” present. Cyanobacteria which migrated in response to vertical variations in light intensity (irradiance) obtained characteristic positions in constructed mats that were similar to their positions in natural mats. A detailed investigation of nitrogen cycling in both the Baja California and Elkhorn Slough microbial mats was initiated during this reporting period. The nitrogen cycle in the microbial mats has not been studied in depth, despite the fact that nitrogen usually limits growth in marine environments. The organisms conducting nitrogen cycling in both microbial mats were studied using the genomes available from earlier work on these mats, as well as with a targeted approach using molecular ecological methods developed here. Quantitative measurements of rates of nitrogen transformations were made using stable isotopically labeled nitrogen. The processes quantified and examined using molecular ecological methods included: nitrogen fixation, ammonification, ammonium and nitrate assimilation, denitrification, anaerobic oxidation of ammonium, and dissimilatory nitrate reduction to ammonium. In a series of experiments designed to examine a potential application for microbial mats, we demonstrated that both Elkhorn Slough and Baja California microbial mats were very effective in removing large quantities of both nitrate and ammonium from waste streams containing these compounds at levels where they would be considered to be pollutants. Considerable effort was expended during this reporting period to analyze, and prepare for publication, metagenomes and metatranscriptomes collected from two experimental manipulations of microbial mats. The first, a diel study, was conducted in November 2011, while the second, an investigation of the effects of sulfate on community composition, was conducted during this reporting period. For the earlier study, reference-based and reference-free methods were used to assess microbial ecology and genetic partitioning in these complex microbial systems, and that work is available as a pre-print. Four metagenomes from the same experiment were published. In the second, longer (nearly 200 day) manipulation, rRNA iTag libraries for cDNA and DNA were analyzed to determine the effects of sulfate concentration on microbial mat community composition over the course of the experiment. Work on the algal-bacterial association (Chlorella sorokiniana and Azospirillum brasilense) focused initially on demonstrating the transfer of carbon and nitrogen between the partners, using stable isotopic labeling and the LLNL NanoSIMS. Subsequently, the potential role of diazotrophy (nitrogen fixation) by the bacterial partner in supporting the growth of the association was assessed in a series of experiments. It appears to be the case that, although the bacterial partner demonstrably increases the fitness of the algae under nitrogen limitation, and cells of C. sorokiniana receive nitrogen originally fixed from atmospheric nitrogen by A. brasilense, the amount of nitrogen obtained by diazotrophy is too small to explain the increase in fitness.

08 HYDROGEN↗

Integration of ultra-low coverage whole-genome sequences for reconstructing the evolutionary history of Galapagos giant tortoises

Genomic data from contemporary and historical samples often need to be coupled for evolutionary reconstructions of multitaxon complexes. However, the genetic data recovered from historical samples may result only in ultra-low coverage whole-genome sequences (ulcWGS; <0.15× depth), leading to inaccurate evolutionary inferences given a preponderance of missing data. Using the Galapagos giant tortoise radiation as a study system (Chelonoidis spp., composed of 13 extant and four extinct lineages), we assembled a novel methodological pipeline that removes potential noise introduced by the missing data and enhances the evolutionary signal from ulcWGS samples. We leveraged existing tools for phylogenomic placement (EPA-ng), population genomic structure (smartsnp) and admixture (Admixfrog, NGSadmix) to demonstrate that the evolutionary history of samples can be uncovered with sequencing depths as low as 0.008–0.139×. Importantly, these approaches do not use genotype imputation of the ulcWGS samples, which would require extensive reference datasets. Our application to two cases of extinct lineages of Galapagos giant tortoises, with and without references from the same lineage, demonstrates the general value of the approach. We confirm where the extinct lineages from San Cristóbal and Santa Fe islands fit into the Galapagos giant tortoise radiation, and that these lineages were evolutionarily distinct entities.

ancient DNA↗

Microbial Community Structure and Ecological Networks during Simulation of Diatom Sinking

Microbial-mediated utilization of particulate organic matter (POM) during its downward transport from the surface to the deep ocean constitutes a critical component of the global ocean carbon cycle. However, it remains unclear as to how high hydrostatic pressure (HHP) and low temperature (LT) with the sinking particles affects community structure and network interactions of the particle-attached microorganisms (PAM) and those free-living microorganisms (FLM) in the surrounding water. In this study, we investigated microbial succession and network interactions in experiments simulating POM sinking in the ocean. Diatom-derived 13C- and 12C-labeled POM were used to incubate surface water microbial communities from the East China Sea (ECS) under pressure (temperature) of 0.1 (25 °C), 20 (4 °C), and 40 (4 °C) MPa (megapascal). Our results show that the diversity and species richness of the PAM and FLM communities decreased significantly with HHP and LT. Microbial community analysis indicated an increase in the relative abundance of Bacteroidetes at high pressure (40 MPa), mostly at the expense of Gammaproteobacteria, Alphaproteobacteria, and Gracilibacteria at atmospheric pressure. Hydrostatic pressure and temperature affected lifestyle preferences between particle-attached (PA) and free-living (FL) microbes. Ecological network analysis showed that HHP and LT enhanced microbial network interactions and resulted in higher vulnerability to networks of the PAM communities and more resilience of those of the FLM communities. Most interestingly, the PAM communities occupied most of the module hubs of the networks, whereas the FLM communities mainly served as connectors of the modules, suggesting their different ecological roles of the two groups of microbes. These results provided novel insights into how HHP and LT affected microbial community dynamics, ecological networks during POM sinking, and the implications for carbon cycling in the ocean.

59 BASIC BIOLOGICAL SCIENCES↗

Impact of solvation on the electronic resonances in uracil

Interactions of low-energy electrons with the DNA and RNA nucleobases are known to form metastable states, known as electronic resonances. In this work, we study electron attachment to solvated uracil, an RNA nucleobase, using the orbital stabilization method at the Equation of Motion-Coupled Cluster for Electron Affinities with Singles and Doubles (EOM-EA-CCSD) level of theory with the Effective Fragment Potential (EFP) solvation method. We benchmarked the approach using multireference methods, as well as by comparing EFP and full quantum calculations. The impact of solvation on the first one particle (1p) shape resonance, formed by electron attachment to the π* LUMO orbital, as well as the first two particle one hole (2p1h) resonance, formed by electron attachment to neutral uracil's π–π* excited state, was investigated. We used molecular dynamics simulations for solvent configurations and applied charge stabilization technique-based biased sampling to procure configurations adequate to cover the entire range of the electron attachment energy distribution. The electron attachment energy in solution is found to be distributed over a wide range of energies, between 4.6 eV to 6.8 eV for the 2p1h resonance, and between −0.1 eV to 2 eV for the 1p resonance. The solvent effects were similar for the two resonances, indicating that the exact electron density of the state is not as important as the solvent configurations. Multireference calculations extended the findings showing that solvation effects are similar for the lowest four resonances, further indicating that the specific solute electron density is not as important, but rather the water configurations play the most important role in solvation effects. Lastly, by comparing bulk solvation to clusters of uracil with a few water molecules around it, we find that the impact of microsolvation is very different from that of bulk solvation.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Identification of potent inhibitors of JUN N-terminal kinases for treatment of endometriosis and associated pain

Endometriosis, defined as the ectopic growth of endometrial tissue outside of the uterine cavity, is an inflammatory and hormone-dependent disease that causes excruciating pelvic pain, infertility, and significantly decreases quality of life in affected patients. The JUN N-terminal kinases (JNKs) are a leading class of nonhormonal therapeutic targets that have been validated in preclinical models of endometriosis and in a Phase 1/2 clinical trial. Despite their therapeutic potential, JNK inhibitors with increased potency and specificity are needed to address the inflammatory pathology of endometriosis and to prevent disease progression. Leveraging a DNA-encoded chemical library collection of ~4 billion compounds, we identified lead inhibitor CDD-2428 and optimized derivatives, CDD-2728 and CDD-3013, with excellent binding affinity to JNK1-3 (K d = 0.12 to 3.7 nM), enhanced selectivity, metabolic stability, and cellular permeability. Crystallographic and biochemical studies confirmed that CDD-3013 exhibited superior kinase selectivity with improved efficacy compared to existing JNK inhibitors. In primary endometriosis cell models, CDD-2728 and CDD-3013 suppressed JNK-dependent inflammatory signaling, dampening pathways linked to pain, invasion, angiogenesis, and macrophage recruitment. In an endometriosis mouse model, both CDD-2728 and CDD-3013 reduced endometriotic lesion size, macrophage infiltration, and cellular proliferation, showing in vivo efficacy. When tested in a lipopolysaccharide-induced hyperalgesia model, CDD-2728 and CDD-3013 decreased markers of induced pain, as measured by changes in a dynamic weight bearing test and Grimace scores. These findings nominate CDD-2728 and CDD-3013 as potent, nonhormonal therapeutic candidates for endometriosis with broad anti-inflammatory and analgesic activity, addressing a critical unmet clinical need.

Madasu, Chandrashekhar [Department of Pathology an↗