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At least 1,657 records · Page 92

Spirometric traits show quantile-dependent heritability, which may contribute to their gene-environment interactions with smoking and pollution

Background: “Quantile-dependent expressivity” refers to a genetic effect that is dependent upon whether the phenotype (e.g., spirometric data) is high or low relative to its population distribution. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV 1 ), and the FEV 1 /FVC ratio are moderately heritable spirometric traits. The aim of the analyses is to test whether their heritability (h 2 ) is constant over all quantiles of their distribution. Methods: Quantile regression was applied to the mean age, sex, height and smoking-adjusted spirometric data over multiple visits in 9,993 offspring-parent pairs and 1,930 sibships from the Framingham Heart Study to obtain robust estimates of offspring-parent (β OP ), offspring-midparent (β OM ), and full-sib regression slopes (β FS ). Nonparametric significance levels were obtained from 1,000 bootstrap samples. β OP s were used as simple indicators of quantile-specific heritability (i.e.,h 2 = 2β OP /(1+r spouse ), where r spouse was the correlation between spouses). Results: β OP ± standard error (SE) decreased by 0.0009 ± 0.0003 (P = 0.003) with every one-percent increment in the population distribution of FEV 1 /FVC, i.e., β OP ± SE were: 0.182 ± 0.031, 0.152 ± 0.015; 0.136 ± 0.011; 0.121 ± 0.013; and 0.099 ± 0.013 at the 10th, 25th, 50th, 75th, and 90th percentiles of the FEV 1 /FVC distribution, respectively. These correspond to h 2 ± SEs of 0.350 ± 0.060 at the 10th, 0.292 ± 0.029 at the 25th, 0.262 ± 0.020 at the 50th, 0.234 ± 0.025 at the 75th, and 0.191 ± 0.025 at the 90th percentiles of the FEV 1 /FVC ratio. Maximum mid-expiratory flow (MMEF) h 2 ± SEs increased 0.0025 ± 0.0007 (P = 0.0004) with every one-percent increment in its distribution, i.e.: 0.467 ± 0.046, 0.467 ± 0.033, 0.554 ± 0.038, 0.615 ± 0.042, and 0.675 ± 0.060 at the 10th, 25th, 50th, 75th, and 90th percentiles of its distribution. This was due to forced expiratory flow at 75% of FVC (FEF75%), whose quantile-specific h 2 increased an average of 0.0042 ± 0.0008 for every one-percent increment in its distribution. It is speculated that previously reported gene-environment interactions may be partially attributable to quantile-specific h 2 , i.e., greater heritability in individuals with lower FEV 1 /FVC due to smoking or airborne particles exposure vs. nonsmoking, unexposed individuals. Conclusion: Heritabilities of FEV 1 /FVC, MMEF, and FEF75% from quantile-regression of offspring-parent and sibling spirometric data suggest their quantile-dependent expressivity.

59 BASIC BIOLOGICAL SCIENCES↗

Stimulation of Insect Herbivory by Elevated Temperature Outweighs Protection by the Jasmonate Pathway

Rising global temperatures are associated with increases in the geographic range, population size, and feeding voracity of insect herbivores. Although it is well established that the plant hormone jasmonate (JA) promotes durable resistance to many ectothermic herbivores, little is known about how JA-mediated defense is influenced by rising temperatures. Here, we used the Arabidopsis-Trichoplusia ni (cabbage looper) interaction to investigate the relative contribution of JA and elevated temperature to host resistance. Video monitoring of T. ni larval behavior showed that elevated temperature greatly enhanced defoliation by increasing the bite rate and total time spent feeding, whereas loss of resistance in a JA-deficient mutant did not strongly affect these behaviors. The acceleration of insect feeding at elevated temperature was not attributed to decreases in wound-induced JA biosynthesis, expression of JA-responsive genes, or the accumulation of defensive glucosinolates prior to insect challenge. Quantitative proteomic analysis of insect frass, however, provided evidence for a temperature-dependent increase in the production of T. ni digestive enzymes. Our results demonstrate that temperature-driven stimulation of T. ni feeding outweighs the protective effects of JA-mediated resistance in Arabidopsis, thus highlighting a potential threat to plant resilience in a warming world.

59 BASIC BIOLOGICAL SCIENCES↗

The interactive role of subsynoptic scale jet sreak and planetary boundary layer adjustments in organizing an apparently isolated convective complex

A mesoscale atmospheric simulation system is described that is being developed in order to improve the simulation of subsynoptic and mesoscale adjustments associated with cyclogenesis, severe storm development, and significant atmospheric transport processes. Present emphasis in model development is in the parameterization of physical processes, time-dependent boundary conditions, sophisticated initialization and analysis procedures, nested grid solutions, and applications software development. Basic characteristics of the system as of March 1982 are listed. In a case study, the Grand Island tornado outbreak of 3 June 1980 is considered in substantial detail. Results of simulations with a mesoscale atmospheric simulation system indicate that over the high plains subtle interactions between existing jet streaks and deep well mixed boundary layers can lead to well organized patterns of mesoscale divergence and pressure falls. The amplitude and positioning of these mesoscale features is a function of the subtle nonlinear interaction between the pre-existing jet-streak and deep well mixed boundary layers. Model results for the case study indicate that the model has the potential for forecasting the precursor mesoscale convective environment.

Kaplan, M. L.↗

The Promise of Emergent Nanobiotechnologies for In Vivo Applications and Implications for Safety and Security

Nanotechnology, the multi-disciplinary field based on the exploitation of the unique physicochemical properties of nanoparticles (NPs) and nanoscale materials, has opened a new realm of possibilities for biological research and biomedical applications. The development and deployment of mRNA-NP vaccines for COVID-19, for example, may revolutionize vaccines and therapeutics. However, regulatory and ethical frameworks that protect the health and safety of the global community and environment are lagging, particularly for nanotechnology geared towards biological applications (i.e., bio-nanotechnology). Considering this, the following review, while not comprehensive, attempts to illustrate the breadth and promise of bionanotechnology developments, and how they may present future safety and security challenges. Specifically, we address current advancements to streamline the development of engineered NPs for in vivo applications and provide discussion on nano-bio interactions, NP in vivo delivery, nano-enhancement of human performance, nanomedicine, and the impacts of NPs on human health and the environment.

59 BASIC BIOLOGICAL SCIENCES↗

A simulator study of the interaction of pilot workload with errors, vigilance, and decisions

A full mission simulation of a civil air transport scenario that had two levels of workload was used to observe the actions of the crews and the basic aircraft parameters and to record heart rates. The results showed that the number of errors was very variable among crews but the mean increased in the higher workload case. The increase in errors was not related to rise in heart rate but was associated with vigilance times as well as the days since the last flight. The recorded data also made it possible to investigate decision time and decision order. These also varied among crews and seemed related to the ability of captains to manage the resources available to them on the flight deck.

Smith, H. P. R.↗

Four dimensional observations of clouds from geosynchronous orbit using stereo display and measurement techniques on an interactive information processing system

Simultaneous Geosynchronous Operational Environmental Satellite (GOES) 1 km resolution visible image pairs can provide quantitative three dimensional measurements of clouds. These data have great potential for severe storms research and as a basic parameter measurement source for other areas of meteorology (e.g. climate). These stereo cloud height measurements are not subject to the errors and ambiguities caused by unknown cloud emissivity and temperature profiles that are associated with infrared techniques. This effort describes the display and measurement of stereo data using digital processing techniques.

Hasler, A. F.↗

Remote sensing applied to agriculture: Basic principles, methodology, and applications

The general principles of remote sensing techniques as applied to agriculture and the methods of data analysis are described. the theoretical spectral responses of crops; reflectance, transmittance, and absorbtance of plants; interactions of plants and soils with reflectance energy; leaf morphology; and factors which affect the reflectance of vegetation cover are dicussed. The methodologies of visual and computer-aided analyses of LANDSAT data are presented. Finally, a case study wherein infrared film was used to detect crop anomalies and other data applications are described.

Dejesusparada, N.↗

Two-component LDV investigation of 3-dimensional shock/turbulent boundary layer interactions

Mean-velocity and turbulence measurements obtained by two-component laser Doppler velocimetry are presented, together with numerical predictions, for the shock-related separation of a turbulent boundary layer at Mach 2.85. The basic geometry, a 30 deg half-angle flare mounted on a long cylinder, is made three-dimensional by tipping the flare at an angle of attack, alpha. The separation length and general upstream influence increase with alpha. A recirculating vortex in the separated zone becomes stronger as three-dimensionality increases. A large-scale unsteadiness of the separation shock wave and surrounding flowfields grows in amplitude with alpha, and appears to strongly influence the amplification of turbulence correlations ahead of detachment. Scaling of the streamwise coordinate by separation length causes two-dimensional and three-dimensional data profiles on the cylinder to collapse for most measured quantities.

Brown, J. D.↗

Monochromatization interaction region optics design for direct s-channel Higgs production at FCC-ee

The FCC-ee offers the potential to measure the electron Yukawa coupling via direct s-channel Higgs production, e + e − → H , at a centre-of-mass (CM) energy of ∼125 GeV. This measurement is significantly facilitated if the CM energy spread of e + e − collisions can be reduced to a level comparable to the natural width of the Higgs boson, Γ H = 4.1 MeV, without substantial loss in luminosity. Achieving this reduction in collision-energy spread is possible through the “monochromatization” concept. The basic idea is to create opposite correlations between spatial position and energy deviation within the colliding beams, which can be accomplished in beam optics by introducing a nonzero dispersion function with opposite signs for the two beams at the interaction point. Since the first proposal in 2016, the implementation of monochromatization at the FCC-ee has been continuously improved, starting from preliminary parametric studies. In this paper, we present a detailed study of the interaction region optics design for this newly proposed collision mode, exploring different potential configurations and their implementation in the FCC-ee global lattice, along with beam dynamics simulations and performance evaluations including the impact of “beamstrahlung.”

43 PARTICLE ACCELERATORS↗

Identification of Exported Plasmodium falciparum Proteins That Bind to the Erythrocyte Cytoskeleton

Plasmodium proteins are exported to the erythrocyte cytoplasm to create an environment that supports parasite replication. Although hundreds of proteins are predicted to be exported through Plasmodium export element (PEXEL)-dependent and -independent mechanisms, the functions of exported proteins are largely uncharacterized. In this study, we used a biochemical screening approach to identify putative exported P. falciparum proteins that bound to inside-out vesicles prepared from erythrocytes. Out of 69 P. falciparum PEXEL-motif proteins tested, 18 bound to inside-out vesicles (IOVs) in two or more independent assays. Using co-affinity purifications followed by mass spectrometry, pairwise co-purification experiments, and the split-luciferase assay, we identified 31 putative protein–protein interactions between erythrocyte cytoskeletal proteins and predicted exported P. falciparum proteins. We further showed that PF3D7_1401600 binds to the spectrin-binding domain of erythrocyte ankyrin via its MESA erythrocyte cytoskeleton binding (MEC) motif and to the N-terminal domains of ankyrin and 4.1R through a fragment that required an intact Plasmodium helical interspersed sub-telomeric (PHIST) domain. Introduction of PF3D7_1401600 into erythrocyte ghosts increased retention in the microsphiltration assay, consistent with previous data that reported a reduction of rigidity in red blood cells infected with PF3D7_1401600-deficient parasites.

59 BASIC BIOLOGICAL SCIENCES↗

Climatically driven changes in primary production propagate through trophic levels

Abstract Climate and land‐use change are the major drivers of global biodiversity loss. Their effects are particularly acute for wide‐ranging consumers, but little is known about how these factors interact to affect the abundance of large carnivores and their herbivore prey. We analyzed population densities of a primary and secondary consumer (mule deer, Odocoileus hemionus , and mountain lion, Puma concolor ) across a climatic gradient in western North America by combining satellite‐based maps of plant productivity with estimates of animal abundance and foraging area derived from Global Positioning Systems telemetry data (GPS). Mule deer density exhibited a positive, linear relationship with plant productivity ( r 2 = 0.58), varying by a factor of 18 across the climate‐vegetation gradient (range: 38–697 individuals/100 km 2 ). Mountain lion home range size decreased in response to increasing primary productivity and consequent changes in the abundance of their herbivore prey (range: 20–450 km 2 ). This pattern resulted in a strong, positive association between plant productivity and mountain lion density ( r 2 = 0.67). Despite varying densities, the ratio of prey to predator remained constant across the climatic gradient (mean ± SE = 363 ± 29 mule deer/mountain lion), suggesting that the determinacy of the effect of primary productivity on consumer density was conserved across trophic levels. As droughts and longer term climate changes reduce the suitability of marginal habitats, consumer home ranges will expand in order for individuals to meet basic nutritional requirements. These changes portend decreases in the abundance of large‐bodied, wide‐ranging wildlife through climatically driven reductions in carrying capacity, as well as increased human–wildlife interactions stemming from anthropogenic land use and habitat fragmentation.

Stoner, David C.↗

Design, Synthesis, and Biological and Structural Evaluations of Novel HIV-1 Protease Inhibitors To Combat Drug Resistance

A series of new HIV-1 protease inhibitors (PIs) were designed using a general strategy that combines computational structure-based design with substrate-envelope constraints. The PIs incorporate various alcohol-derived P2 carbamates with acyclic and cyclic heteroatomic functionalities into the (R)-hydroxyethylamine isostere. Most of the new PIs show potent binding affinities against wild-type HIV-1 protease and three multidrug resistant (MDR) variants. In particular, inhibitors containing the 2,2-dichloroacetamide, pyrrolidinone, imidazolidinone, and oxazolidinone moieties at P2 are the most potent with Ki values in the picomolar range. Several new PIs exhibit nanomolar antiviral potencies against patient-derived wild-type viruses from HIV-1 clades A, B, and C and two MDR variants. Crystal structure analyses of four potent inhibitors revealed that carbonyl groups of the new P2 moieties promote extensive hydrogen bond interactions with the invariant Asp29 residue of the protease. These structure-activity relationship findings can be utilized to design new PIs with enhanced enzyme inhibitory and antiviral potencies.

59 BASIC BIOLOGICAL SCIENCES↗

Direct visualization reveals kinetics of meiotic chromosome synapsis

The synaptonemal complex (SC) is a conserved protein complex that stabilizes interactions along homologous chromosomes (homologs) during meiosis. The SC regulates genetic exchanges between homologs, thereby enabling reductional division and the production of haploid gametes. Here, we directly observe SC assembly (synapsis) by optimizing methods for long-term fluorescence recording in C. elegans . We report that synapsis initiates independently on each chromosome pair at or near pairing centers—specialized regions required for homolog associations. Once initiated, the SC extends rapidly and mostly irreversibly to chromosome ends. Quantitation of SC initiation frequencies and extension rates reveals that initiation is a rate-limiting step in homolog interactions. Eliminating the dynein-driven chromosome movements that accompany synapsis severely retards SC extension, revealing a new role for these conserved motions. This work provides the first opportunity to directly observe and quantify key aspects of meiotic chromosome interactions and will enable future in vivo analysis of germline processes.

59 BASIC BIOLOGICAL SCIENCES↗

Tuning Inner-Ear Tip-Link Affinity Through Alternatively Spliced Variants of Protocadherin-15

Human hearing relies upon the tip-to-tip interaction of two nonclassical cadherins, protocadherin-15 (PCDH15) and cadherin-23 (CDH23). Together, these proteins form a filament called the tip link that connects neighboring stereocilia of mechanosensitive hair cells. As sound waves enter the cochlea, the stereocilia deflect and tension is applied to the tip link, opening nearby transduction channels. Disruption of the tip link by loud sound or calcium chelators eliminates transduction currents and illustrates that tip-link integrity is critical for mechanosensing. Tip-link remodeling after disruption is a dynamic process, which can lead to the formation of atypical complexes that incorporate alternatively spliced variants of PCDH15. These variants are categorized into six groups (N1–N6) based upon differences in the first two extracellular cadherin (EC) repeats. Here, we characterized the two N-terminal EC repeats of all PCDH15 variants (pcdh15(N1) to pcdh15(N6)) and combined these variants to test complex formation. We solved the crystal structure of a new complex composed of CDH23 EC1-2 (cdh23) and pcdh15(N2) at 2.3 Å resolution and compared it to the canonical cdh23–pcdh15(N1) complex. While there were subtle structural differences, the binding affinity between cdh23 and pcdh15(N2) is ~6 times weaker than cdh23 and pcdh15(N1) as determined by surface plasmon resonance analysis. Steered molecular dynamics simulations predict that the unbinding force of the cdh23–pcdh15(N2) complex can be lower than the canonical tip link. Our results demonstrate that alternative heterophilic tip-link structures form stable protein–protein interactions in vitro and suggest that homophilic PCDH15–PCDH15 tip links form through the interaction of additional EC repeats.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Helical 1:1 α/Sulfono-γ-AA Heterogeneous Peptides with Antibacterial Activity

As one of the greatest threats facing in 21st century, antibiotic resistance is now a major public health concern. Host-defense peptides (HDPs) offer an alternative approach to combat emerging multidrug-resistant bacteria. It is known that helical HDPs such as magainin 2 and its analogs adopt cationic amphipathic conformations upon interaction with bacterial membranes, leading to membrane disruption and subsequent bacterial cell death. We have previously shown that amphipathic sulfono-γ-AApeptides could mimic magainin 2 and exhibit bactericidal activity. In this article, we demonstrate for the first time that amphipathic helical 1:1 α/sulfono-γ-AA heterogeneous peptides, in which regular amino acids and sulfono-γ-AApeptide building blocks are alternatively present in a 1:1 pattern, display potent antibacterial activity against both Gram-positive and Gram-negative bacterial pathogens. Small Angle X-ray Scattering (SAXS) suggests that the lead sequences adopt defined helical structures. The subsequent studies including 2 fluorescence microscopy and time-kill experiments indicate that these hybrid peptides exert antimicrobial activity by mimicking the mechanism of HDPs. Our findings may lead to the development of HDP-mimicking antimicrobial peptidomimetics that combat drug-resistant bacterial pathogens. In addition, our results also demonstrate the effective design of a new class of helical foldamer, which could be employed to interrogate other important biological targets such as protein-protein interactions in the future.

59 BASIC BIOLOGICAL SCIENCES↗

Behavior of Water Near Multimodal Chromatography Ligands and Its Consequences for Modulating Protein–Ligand Interactions

Multimodal chromatography is a powerful approach for purifying proteins that uses ligands containing multiple modes of interaction. Recent studies have shown that selectivity in multimodal chromatographic separations is a function of the ligand structure and geometry. Here, we performed molecular dynamics simulations to explore how the ligand structure and geometry affect ligand–water interactions and how these differences in solution affect the nature of protein–ligand interactions. Our investigation focused on three chromatography ligands: Capto MMC, Nuvia cPrime, and Prototype 4, a structural variant of Nuvia cPrime. First, the solvation characteristics of each ligand were quantified via three metrics: average water density, fluctuations, and residence time. We then explored how solvation was perturbed when the ligand was bound to the protein surface and found that the probability of the phenyl ring dewetting followed the order: Capto MMC > Prototype 4 > Nuvia cPrime. To explore how these differences in dewetting affect protein–ligand interactions, we calculated the probability of each ligand binding to different types of residues on the protein surface and found that the probability of binding to a hydrophobic residue followed the same order as the dewetting behavior. This study illustrates the role that wetting and dewetting play in modulating protein–ligand interactions.

59 BASIC BIOLOGICAL SCIENCES↗