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At least 703 records · Page 39

FLS2-BAK1 Extracellular Domain Interaction Sites Required for Defense Signaling Activation

Signaling initiation by receptor-like kinases (RLKs) at the plasma membrane of plant cells often requires regulatory leucine-rich repeat (LRR) RLK proteins such as SERK or BIR proteins. The present work examined how the microbe-associated molecular pattern (MAMP) receptor FLS2 builds signaling complexes with BAK1 (SERK3). We first, using in vivo methods that validate separate findings by others, demonstrated that flg22 (flagellin epitope) ligand-initiated FLS2-BAK1 extracellular domain interactions can proceed independent of intracellular domain interactions. We then explored a candidate SERK protein interaction site in the extracellular domains (ectodomains; ECDs) of the significantly different receptors FLS2, EFR (MAMP receptors), PEPR1 (damage-associated molecular pattern (DAMP) receptor), and BRI1 (hormone receptor). Repeat conservation mapping revealed a cluster of conserved solvent-exposed residues near the C-terminus of models of the folded LRR domains. However, site-directed mutagenesis of this conserved site in FLS2 did not impair FLS2-BAK1 ECD interactions, and mutations in the analogous site of EFR caused receptor maturation defects. Hence this conserved LRR C-terminal region apparently has functions other than mediating interactions with BAK1. In vivo tests of the subsequently published FLS2-flg22-BAK1 ECD co-crystal structure were then performed to functionally evaluate some of the unexpected configurations predicted by that crystal structure. In support of the crystal structure data, FLS2-BAK1 ECD interactions were no longer detected in in vivo co-immunoprecipitation experiments after site-directed mutagenesis of the FLS2 BAK1-interaction residues S554, Q530, Q627 or N674. In contrast, in vivo FLS2-mediated signaling persisted and was only minimally reduced, suggesting residual FLS2-BAK1 interaction and the limited sensitivity of co-immunoprecipitation data relative to in vivo assays for signaling outputs. However, Arabidopsis plants expressing FLS2 with the Q530A+Q627A double mutation were impaired both in detectable interaction with BAK1 and in FLS2-mediated responses, lending overall support to current models of FLS2 structure and function.

59 BASIC BIOLOGICAL SCIENCES↗

Enhanced Photo-Cross-Linking of Thymines in DNA Holliday Junction-Templated Squaraine Dimers

Programmable self-assembly of dyes using DNA templates to promote exciton delocalization in dye aggregates is gaining considerable interest. New methods to improve the rigidity of the DNA scaffold and thus the stability of the molecular dye aggregates to encourage exciton delocalization are desired. In these dye–DNA constructs, one potential way to increase the stability of the aggregates is to create an additional covalent bond via photo-cross-linking reactions between thymines in the DNA scaffold. Specifically, we report an approach to increase the yield of photo-cross-linking reaction between thymines in the core of a DNA Holliday junction while limiting the damage from UV irradiation to DNA. We investigated the effect of the distance between thymines on the photo-cross-linking reaction yields by using linkers with different lengths to tether the dyes to the DNA templates. By comprehensively evaluating the photo-cross-linking reaction yields of dye–DNA aggregates using linkers with different lengths, we conclude that interstrand thymines tend to photo-cross-link more efficiently with short linkers. A higher cross-linking yield was achieved due to the shorter intermolecular distance between thymines influenced by strong dye–dye interactions. Furthermore, our method establishes the possibility of improving the stability of DNA-scaffolded dye aggregates, thereby expanding their use in exciton-based applications such as light harvesting, nanoscale computing, quantum computing, and optoelectronics.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Mineral properties, microbes, transport, and plant-input profiles control vertical distribution and age of soil carbon stocks

The role of organo-mineral interactions, microbial dynamics, and vertical plant input profiles are hypothesized to be important in controlling soil organic matter (SOM) stocks and dynamics. In this paper, to test this hypothesis, we enhanced and applied a model (Biotic and Abiotic Model of SOM – BAMS1) that represents microbial dynamics and organo-mineral interactions integrated with a multiphase reactive transport solver for variably saturated porous media. The model represents aqueous chemistry, aqueous advection and diffusion, gaseous diffusion, sorption processes, bacterial and fungal activity, and archetypal monomer- and polymer-carbon substrate groups, including dead cell wall material. This model structure is fundamentally different, and produces different SOM dynamics, than the pseudo-first order relationships that are used in most site- and global-scale terrestrial SOM models. We simulated two grasslands, a seven-site chronosequence (~3.9–240 Ky) in Northern California, and a Russian Chernozem site where soils were sampled 100 years apart. We calibrated the model's vertically-resolved soil bulk specific surface area (SBSSA) using observed bulk SOM content, and then tested the model against observed Δ 14 C profiles. The modeled microbial processes, organo-mineral interactions, and vertical aqueous transport produced realistic vertically-resolved predictions of bulk SOM content, Δ 14 C values of SOM, lignin content, and fungi-to-aerobic bacteria biomass ratios. Using sensitivity analyses, we found that vertical carbon input profiles were important controls over the Δ 14 C depth distribution. Shallower carbon input profiles lead to older carbon at depth. In addition, the SBSSA was the dominant control over the magnitude and vertical distribution of SOM stocks. Finally, the findings of this study demonstrate the value of explicitly incorporating microbial activity, sorption, and vertical transport into land models to predict SOM dynamics.

54 ENVIRONMENTAL SCIENCES↗

Natural soil microbiome variation affects spring foliar phenology with consequences for plant productivity and climate-driven range shifts

Identifying the potential for natural soil microbial communities to predictably affect complex plant traits is an important frontier in climate change research. Plant phenology varies with environmental and genetic factors, but few studies have examined if the soil microbiome interacts with plant population differentiation to affect phenology and ecosystem function. We compared soil microbial variation in a widespread tree species (Populus angustifolia) with different soil inoculum treatments in a common garden environment to test how the soil microbiome affects spring foliar phenology and subsequent biomass growth. We hypothesized and show that: 1) soil bacterial and fungal communities vary with tree conditioning from different populations and elevations, 2) this soil community variation influences patterns of foliar phenology and plant growth across populations and elevation gradients, and 3) transferring lower elevation plant genotypes to higher elevation soil communities delayed foliar phenology, thereby shortening the growing season and reducing annual biomass production. Our findings show the importance of plant-soil interactions that help shape the timing of tree foliar phenology and productivity. Here, these geographic patterns in plant population x microbiome interactions also broaden our understanding of how soil communities impact plant phenotypic variation across key climate change gradients, with consequences for ecosystem functioning.

59 BASIC BIOLOGICAL SCIENCES↗

Analysis of the Isolated SecA DEAD Motor Suggests a Mechanism for Chemical-Mechanical Coupling

The preprotein cross-linking domain and C-terminal domains of Escherichia coli SecA were removed to create a minimal DEAD motor, SecA-DM. SecA-DM hydrolyzes ATP and has the same affinity for ADP as full-length SecA. The crystal structure of SecA-DM in complex with ADP was solved and shows the DEAD motor in a closed conformation. Comparison with the structure of the E. coli DEAD motor in an open conformation (Protein Data Bank ID 2FSI) indicates main-chain conformational changes in two critical sequences corresponding to Motif III and Motif V of the DEAD helicase family. The structures that the Motif III and Motif V sequences adopt in the DEAD motor open conformation are incompatible with the closed conformation. Therefore, when the DEAD motor makes the transition from open to closed, Motif III and Motif V are forced to change their conformations, which likely functions to regulate passage through the transition state for ATP hydrolysis. The transition state for ATP hydrolysis for the SecA DEAD motor was modeled based on the conformation of the Vasa helicase in complex with adenylyl imidodiphosphate and RNA (Protein Data Bank ID 2DB3). A mechanism for chemical-mechanical coupling emerges, where passage through the transition state for ATP hydrolysis is hindered by the conformational changes required in Motif III and Motif V, and may be promoted by binding interactions with the preprotein substrate and/or other translocase domains and subunits.

59 BASIC BIOLOGICAL SCIENCES↗

DISCRIMINATING THE PROGENITOR TYPE OF SUPERNOVA REMNANTS WITH IRON K-SHELL EMISSION

Supernova remnants (SNRs) retain crucial information about both their parent explosion and circumstellar material left behind by their progenitor. However, the complexity of the interaction between supernova ejecta and ambient medium often blurs this information, and it is not uncommon for the basic progenitor type (Ia or core-collapse) of well-studied remnants to remain uncertain. Here we present a powerful new observational diagnostic to discriminate between progenitor types and constrain the ambient medium density of SNRs using solely Fe K-shell X-ray emission. We analyze all extant Suzaku observations of SNRs and detect Fe Kα emission from 23 young or middle-aged remnants, including five first detections (IC 443, G292.0+1.8, G337.2-0.7, N49, and N63A). The Fe Kα centroids clearly separate progenitor types, with the Fe-rich ejecta in Type Ia remnants being significantly less ionized than in core-collapse SNRs. Within each progenitor group, the Fe Kα luminosity and centroid are well correlated, with more luminous objects having more highly ionized Fe. Our results indicate that there is a strong connection between explosion type and ambient medium density, and suggest that Type Ia supernova progenitors do not substantially modify their surroundings at radii of up to several parsecs. We also detect a K-shell radiative recombination continuum of Fe in W49B and IC 443, implying a strong circumstellar interaction in the early evolutionary phases of these core-collapse remnants.

79 ASTRONOMY AND ASTROPHYSICS↗

Mechanisms of interfacial reactivity in near surface and extreme environments

The local water structure surrounding ions in aqueous solutions greatly affects their chemical properties such as reaction rates, ion association, and proton and electron transport. These properties result in the behavior of ions in natural aqueous environments. For example ore transport is facilitated by chloride ion pair formation and the reaction of ions in an interface is strongly dependent on the dehydration of the ion hydration shell. We are developing the use of high-­resolution XAFS observations and 1st principles based MD-­XAFS analysis (spectra simulated using 1st principle methods with no adjustable parameters, AIMD) to interpret the solution properties of strongly interacting aqueous solutes under arbitrary pressure and temperature conditions. In the 1st principle MD-­XAFS method density functional theory (DFT) based MD simulations(Car and Parrinello, 1985) are used to generate a large ensemble of structural snap shots of the hydration region. These are then used to generate scattering intensities. I emphasize three points about this novel approach to analyzing XAFS data. 1st: As illustrated in Figure 1, the level of agreement between the calculated and observed intensities is considerably higher than has been obtained by any XAFS analysis to date (note 2nd shell region, R> 2 Å). 2nd: This result was obtained from a parameter free simulation with no fitting of the interaction potentials to any data. This supports the use of these methods for more difficult environments and more complex solutes (polyions). 3rd: New information about the shell structure (Figure 1) is now available because of this more detailed agreement. We note also that both multiple scattering and second shell features are well represented in the analysis. As far as we know this is the 1st analysis of second shell structure and multiple scattering. Excellent agreement has been obtained for most of the third row metal ions: Ca 2+ , Zn 2+ , Cu 2+ , Ni 2+ , Co 2+ , Mn 2+ , Fe 3+ , Cr 3+ . Calculations on these systems are demanding because of their open electronic shells, and high ionic charge. Principal Investigator: Professor John Weare (University of California, San Diego) The prediction of the interactions of geochemical fluids with minerals, nanoparticles, and colloids under extreme near surface conditions of temperature (T) and pressure (P) is a grand challenge research need in geosciences (U.S. DOE 2007, Basic Research Needs for Geosciences: Facilitating the 21st Energy Systems.). To evaluate the impact of these processes on energy production and management strategies it is necessary to have a high level of understanding of the interaction between complex natural fluids and mineral formations. This program emphasizes 1st principle parameter free simulations of complex chemical processes in solutions, in the mineral phase, and in the interfaces between these phases The development of new computational tools (with emphasis on oxide materials and reaction dynamics) tailored to treat wide range of conditions and time scales experienced in such geochemical applications is has been developed. Because of the sensitivity of the interaction in these systems to electronic structure and local bonding environments, and of the need to describe bond breaking/formation, our simulations are based on interactions calculated at the electronic structure level (ab-initio molecular dynamics, AIMD). The progress in the computational aspects of program may be summarized in terms of the following themes (objectives); Development of efficient parameter free dynamical simulation technology based on 1st principles force and energy calculations especially adapted for geochemical applications (e.g., mineral, interfaces and aqueous solutions) (continuing program); Calculation of the dynamics of water structure of in the surface-water interface of transition metal oxides and oxihydroxides; and Development of improved (beyond DFT+GGA) electronic structure calculations for minerals and the interface region that more accurately calculate electron correlation, spin density, and localization. The focus of the program is also on the iron oxide and oxihydroxide minerals and Fe 2+ (aq)/Fe 3+ (cr) oxidation in the mineral solution interface region. These methods included the development of model Hamilitonian methods that can be solved to near convergence for single site models (DMFT) and many-body perturbation methods (MP2, GW); Development of time decomposition methods to extend time scales of molecular dynamics (MD) simulations and support the use of high complexity electronic structure calculations (MP2, CCSD(T)) of forces for use in dynamical simulations where very high chemical accuracy is required (microsolvated reactions in absorbed surface layers); and The development of a new linear scaling finite element solver for eigenvalue problem that supports solution of quantum problems with unusual potential and boundary values. Application progress of the above new simulation technology to problems of geochemical interests includes; The prediction of metal oxide surface structure and the reduction/oxidation of Fe 3+ (cr)/Fe 2+ (aq) in metal oxide (hematite, goethite)/solution interfaces. Result: water interacts strongly with the 001 Hematite surface; interaction of water with the 100 goethite is weak; The study of ion solvation and the composition of ion hydration shells under extreme conditions (focus on Fe 3+/2+ , Al 3+ and Mg 2+ and their hydroxide speciation). Result: Ion association in water solutions can be calculated from 1st principle methods. Efficient sampling of the free energy requires more development; The continued development of new high resolution analysis of XAFS scattering of disordered systems (particularly Al, Mg) and of XANES calculations for aqueous ions. Result: EXAFS spectra can be calculated to high accuracy with DFT level dynamic simulations; The exploration of electron localization and electron transport in metal oxides (highly correlated materials). Result: Proper description of electron localization requires levels of calculation beyond DFT; and Localization of electrons in DFT type Hamiltonians was studied. Result: For very Dirac high exchange new solutions (New unphysical bifrucations) to the eigenvalue problem are found. The program was highly collaborative involving faculty and students in mathematics, physics and computer science departments as well as coworkers at the Pacific Northwest National Laboratories (PNNL). The students in this program had the opportunity to develop skills in the development of methods, the implementation of method on high performance parallel computers and the application of these methods to problem in geochemical science. Much of the software that was developed was incorporated in the NWchem software package maintained by PNNL.

58 GEOSCIENCES↗

Interferon-Inducible Protein 16: Insight into the Interaction with Tumor Suppressor p53

IFI16 is a member of the interferon-inducible HIN-200 family of nuclear proteins. It has been implicated in transcriptional regulation by modulating protein-protein interactions with p53 tumor suppressor protein and other transcription factors. However, the mechanisms of interaction remain unknown. Here, we report the crystal structures of both HIN-A and HIN-B domains of IFI16 determined at 2.0 and 2.35 {angstrom} resolution, respectively. Each HIN domain comprises a pair of tightly packed OB-fold subdomains that appear to act as a single unit. We show that both HIN domains of IFI16 are capable of enhancing p53-DNA complex formation and transcriptional activation via distinctive means. HIN-A domain binds to the basic C terminus of p53, whereas the HIN-B domain binds to the core DNA-binding region of p53. Both interactions are compatible with the DNA-bound state of p53 and together contribute to the effect of full-length IFI16 on p53-DNA complex formation and transcriptional activation.

59 BASIC BIOLOGICAL SCIENCES↗

Crystal Structure of the Human NKX2.5 Homeodomain in Complex with DNA Target

NKX2.5 is a homeodomain containing transcription factor regulating cardiac formation and function, and its mutations are linked to congenital heart disease. Here we provide the first report of the crystal structure of the NKX2.5 homeodomain in complex with double-stranded DNA of its endogenous target, locating within the proximal promoter -242 site of the atrial natriuretic factor gene. The crystal structure, determined at 1.8 {angstrom} resolution, demonstrates that NKX2.5 homeodomains occupy both DNA binding sites separated by five nucleotides without physical interaction between themselves. The two homeodomains show identical conformation despite the differences in the DNA sequences they bind, and no significant bending of the DNA was observed. Tyr54, absolutely conserved in NK2 family proteins, mediates sequence-specific interaction with the TAAG motif. This high resolution crystal structure of NKX2.5 protein provides a detailed picture of protein and DNA interactions, which allows us to predict DNA binding of mutants identified in human patients.

59 BASIC BIOLOGICAL SCIENCES↗

Structure of human adenovirus

A detailed structural analysis of the entire human adenovirus capsid has been stymied by the complexity and size of this 150 MDa macromolecular complex. Over the past 10 years, the steady improvements in viral genome manipulation concomitant with advances in crystallographic techniques and data processing software has allowed structure determination of this virus by X-ray diffraction at 3.5 {angstrom} resolution. The virus structure revealed the location, folds, and interactions of major and minor (cement proteins) on the inner and outer capsid surface. This new structural information sheds further light on the process of adenovirus capsid assembly and virus-host cell interactions.

59 BASIC BIOLOGICAL SCIENCES↗

Molecular basis for the specific recognition of the metazoan cyclic GMP-AMP by the innate immune adaptor protein STING

Cyclic GMP-AMP containing a unique combination of mixed phosphodiester linkages (2'3'-cGAMP) is an endogenous second messenger molecule that activates the type-I IFN pathway upon binding to the homodimer of the adaptor protein STING on the surface of endoplasmic reticulum membrane. However, the preferential binding of the asymmetric ligand 2'3'-cGAMP to the symmetric dimer of STING represents a physicochemical enigma. In this paper, we show that 2'3'-cGAMP, but not its linkage isomers, adopts an organized free-ligand conformation that resembles the STING-bound conformation and pays low entropy and enthalpy costs in converting into the active conformation. Finally, our results demonstrate that analyses of free-ligand conformations can be as important as analyses of protein conformations in understanding protein–ligand interactions.

59 BASIC BIOLOGICAL SCIENCES↗

Testing the light:nutrient hypothesis: Insights into biofilm structure and function using metatranscriptomics

Aquatic biofilms are hotspots of biogeochemical activity due to concentrated microbial biomass (Battin, Kaplan, Newbold, & Hansen, 2003). However, biofilms are often considered a single entity when their role in biogeochemical transformations is assessed, even though these biofilms harbour functionally diverse microbial communities (Battin, Besemer, Bengtsson, Romani, & Packmann, 2016; Veach, Stegen, Brown, Dodds, & Jumpponen, 2016). Often overlooked are the biotic interactions among biofilm components that can affect ecosystem-scale processes such as primary production and nutrient cycling. These interactions are likely to be especially important under resource limitation. Light is a primary resource mediating algal photosynthesis and both phototrophic and heterotrophic production due to bacterial reliance on C-rich algal exudates (Cole, 1982). However, current understanding of function–structure linkages in streams has yet to unravel the relative degree of these microbial feedbacks under resource availability gradients. In this issue of Molecular Ecology, Bengtsson, Wagner, Schwab, Urich, and Battin (2018) studied stream biofilm responses to light availability to understand its impact across three domains of life. By integrating biogeochemical rate estimation and metatranscriptomics within a microcosm experiment, they were able to link primary production and nutrient uptake rates to algal and bacterial metabolic processes and specify what taxa contributed to gene expression. Under low light, diatoms and cyanobacteria upregulated photosynthetic machinery and diatom-specific chloroplast rRNA suggesting heightened transcriptional activity under light limitation to maintain phototrophic energy demands. Under high light, heterotrophic bacteria upregulated mRNAs related to phosphorous (P) metabolism while biofilm P uptake increased indicating high bacterial-specific P demand when algal biomass was high. Together, these results indicate that biogeochemical function is mediated by complex microbial interactions across trophic levels.

59 BASIC BIOLOGICAL SCIENCES↗

Ecosystems and Networks Integrated with Genes and Molecular Assemblies (Final Scientific/Technical Report)

The ENIGMA science focus area (SFA) is a multi-disciplinary, multi-institutional research effort focused on addressing foundational knowledge gaps in environmental microbial communities by studying groundwater and sediment microbiomes in the shallow subsurface at the contaminated Oak Ridge Field Research Site (FRC). We seek to discover and characterize the reciprocal interactions between the microbial communities and the geochemical and geophysical parameters of the shallow subsurface within the contamination plume. The goal of the Fields lab is to help manage and conduct laboratory experiments informed by field observations using ecological and physiological approaches to study microbial populations in situ as well as ex situ (in the laboratory). In particular, we aim to study and characterize the impact of hydrological constraints on free-living and biofilm biomass and activity with increasing spatial and temporal resolution under static and flow conditions. We also aim to help characterize novel microbial groups that are present and active under relevant field conditions, including the development of molecular techniques for in situ detection as well as metabolic interactions that underlie pertinent physiology and ecology.

59 BASIC BIOLOGICAL SCIENCES↗

Bioimaging Science Program: 2022 Principal Investigator Meetings Proceedings

The mission of the U.S. Department of Energy’s (DOE) Biological and Environmental Research (BER) program’s Bioimaging Science Program (BSP) is to understand the translation of genomic information into the mechanisms that power living cells, communities of cells, and whole organisms. The goal of BSP is to develop new imaging and measurement technologies to visualize the spatial and temporal relationships of key metabolic processes governing phenotypic expression in plants and microbes. The extended goal of dynamic imaging is to functionally connect cellular components and interdependent organisms. Information about the time and place of chemical reactions in situ can identify causal relationships between biological activators and downstream effectors. BSP held its annual PI meeting virtually February 28–March 1. Contributing investigators are convened to review progress and current state-of-the-art bioimaging research. Holding the 2022 BSP meeting as part of the broader Genomic Science Program (GSP) PI meeting allowed researchers to interact with the extended GSP community. This convergence provided a platform for networking and exchange of ideas with experts in other technologies and in target BSP application areas, helping to forge new multidisciplinary collaborations among investigators from the sister programmatic areas within BER’s Biological Systems Science Division. An important highlight of the BSP meeting was the keynote presentation by Nobel Laureate Dr. Joachim Frank on Time-Resolved Macromolecular Imaging using Cryo-EM. He discussed microfluidic mixing and fast freezing to capture nonequilibrium intermediate states during molecular binding and conformational changes. The action of molecular machines can be captured at nanometer resolution and millisecond discrimination. BSP PIs made presentations describing their research focus and progress in plenary sessions on bioimaging science and on quantum-enabled bioimaging science research projects. BSP research at universities and DOE laboratories is presented in this report. A final discussion of the BSP was organized by meeting plenary session chairs, who prepared the following Executive Summary of current BSP research, research challenges, future opportunities, and potential ideas for expanding the BSP’s impact and interactions.

59 BASIC BIOLOGICAL SCIENCES↗

Molecular Mechanisms of Nanomaterial-Bacterial Interactions Revealed by Omics—The Role of Nanomaterial Effect Level

Nanotechnology is employed across a wide range of antibacterial applications in clinical settings, food, pharmaceutical and textile industries, water treatment and consumer goods. Depending on type and concentration, engineered nanomaterials (ENMs) can also benefit bacteria in myriad contexts including within the human body, in biotechnology, environmental bioremediation, wastewater treatment, and agriculture. However, to realize the full potential of nanotechnology across broad applications, it is necessary to understand conditions and mechanisms of detrimental or beneficial effects of ENMs to bacteria. To study ENM effects, bacterial population growth or viability are commonly assessed. However, such endpoints alone may be insufficiently sensitive to fully probe ENM effects on bacterial physiology. To reveal more thoroughly how bacteria respond to ENMs, molecular-level omics methods such as transcriptomics, proteomics, and metabolomics are required. Because omics methods are increasingly utilized, a body of literature exists from which to synthesize state-of-the-art knowledge. Here we review relevant literature regarding ENM impacts on bacterial cellular pathways obtained by transcriptomic, proteomic, and metabolomic analyses across three growth and viability effect levels: inhibitory, sub-inhibitory or stimulatory. As indicated by our analysis, a wider range of pathways are affected in bacteria at sub-inhibitory vs. inhibitory ENM effect levels, underscoring the importance of ENM exposure concentration in elucidating ENM mechanisms of action and interpreting omics results. In addition, challenges and future research directions of applying omics approaches in studying bacterial-ENM interactions are discussed.

59 BASIC BIOLOGICAL SCIENCES↗

From molecular manipulation of domesticated Chlamydomonas reinhardtii to survival in nature

In the mid-20th century, the unicellular and genetically tractable green alga Chlamydomonas reinhardtii was first developed as a model organism to elucidate fundamental cellular processes such as photosynthesis, light perception and the structure, function and biogenesis of cilia. Various studies of C. reinhardtii have profoundly advanced plant and cell biology, and have also impacted algal biotechnology and our understanding of human disease. However, the 'real' life of C. reinhardtii in the natural environment has largely been neglected. To extend our understanding of the biology of C. reinhardtii, it will be rewarding to explore its behavior in its natural habitats, learning more about its abundance and life cycle, its genetic and physiological diversity, and its biotic and abiotic interactions.

59 BASIC BIOLOGICAL SCIENCES↗

Quantile-dependent expressivity of plasma adiponectin concentrations may explain its sex-specific heritability, gene-environment interactions, and genotype-specific response to postprandial lipemia

“Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g. adiponectin) is high or low relative to its distribution. We have previously shown that the heritability ( h 2 ) of adiposity, lipoproteins, postprandial lipemia, pulmonary function, and coffee and alcohol consumption are quantile-specific. Whether adiponectin heritability is quantile specific remains to be determined. Plasma adiponectin concentrations from 4,182 offspring-parent pairs and 1,662 sibships from the Framingham Heart Study were analyzed. Quantile-specific heritability from offspring-parent (β OP , h 2 = 2 β OP /(1 + r spouse )) and full-sib regression slopes ( β FS , h 2 = {(1 + 8r spouse β FS ) 0.05 -1}/(2r spouse )) were robustly estimated by quantile regression with nonparametric significance assigned from 1,000 bootstrap samples. Quantile-specific h 2 (± SE) increased with increasing percentiles of the offspring’s age- and sex-adjusted adiponectin distribution when estimated from β OP ( P trend = 2.2 × 10 -6 ): 0.30 ± 0.03 at the 10th, 0.33 ± 0.04 at the 25th, 0.43 ± 0.04 at the 50th, 0.55 ± 0.05 at the 75th, and 0.57 ± 0.08 at the 90th percentile, and when estimated from β FS (P trend = 7.6 × 10 -7 ): 0.42 ± 0.03 at the 10th, 0.44 ± 0.04 at the 25th, 0.56 ± 0.05 at the 50th, 0.73 ± 0.08 at the 75th, and 0.79 ± 0.11 at the 90th percentile. Consistent with quantile-dependent expressivity, adiponectin’s: (1) heritability was greater in women in accordance with their higher adiponection concentrations; (2) relationships to ADIPOQ polymorphisms were modified by adiposity in accordance with its adiponectin-lowering effect; (3) response to rosiglitazone was predicted by the 45T> G ADIPOQ polymorphism; (4) difference by ADIPOQ haplotypes increased linearly with increasing postprandial adiponectin concentrations. Adiponectin heritability is quantile dependent, which may explain sex-specific heritability, gene-environment and gene-drug interactions, and postprandial response by haplotypes.

Postprandial↗

High-resolution crystal structure of a hepatitis B virus replication inhibitor bound to the viral core protein

The hepatitis B virus (HBV) core protein is essential for HBV replication and an important target for antiviral drug discovery. We report the first, to our knowledge, high-resolution crystal structure of an antiviral compound bound to the HBV core protein. The compound NVR-010–001-E2 can induce assembly of the HBV core wild-type and Y132A mutant proteins and thermostabilize the proteins with a T m increase of more than 10 °C. NVR-010–001-E2 binds at the dimer–dimer interface of the core proteins, forms a new interaction surface promoting protein–protein interaction, induces protein assembly, and increases stability. The impact of naturally occurring core protein mutations on antiviral activity correlates with NVR-010–001-E2 binding interactions determined by crystallography. In conclusion, the crystal structure provides understanding of a drug efficacy mechanism related to the induction and stabilization of protein–protein interactions and enables structure-guided design to improve antiviral potency and drug-like properties.

59 BASIC BIOLOGICAL SCIENCES↗