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Studying Microbial Adaptation in the Laboratory: Sensor & Control Upgrades for an Experimental Evolution Biofluidics System

Experimental evolution (EE) involves iteratively exposing a microbial community to specific stressors to study its response to changes in environment over time. EE work is commonly done manually in the laboratory, but, when there are many environmental variables to measure and adjust, it is highly labor intensive, prone to human error, and challenging to scale. Single-purpose automated continuous culturing chambers exist, but implement only limited stressor types. A more general-purpose design is desirable. The BeING Lab at Ames Research Center created the prototype Automated Adaptive Directed Evolution Chamber (AADEC) to address these problems, beginning with Escherichia coli tolerance of short-wave ultraviolet (UV-C) radiation and of temperature. In newer versions, AADEC monitors microbial activity and can adjust the UV-C and temperature levels automatically. An optical density measurement is used to determine how many cells are present in the growth medium—over time, this corresponds to how many survive and reproduce. Oxidation-reduction potential provides information on consumed metabolic energy, and pH and electrical conductivity on metabolic products. Dissolved oxygen content is used to determine aerobic vs anaerobic growth. A Raspberry Pi computer processes all this data to set the UV-C stressor level. AADEC’s auxiliary systems include peristaltic pumps to change media and agitation to counteract cell settling. These actuators can also act as additional stressors. With the Raspberry Pi monitoring sensors and adjusting actuators in real time, AADEC takes measurements and controls the environment much more accurately than can be done with a manual EE implementation. The third and latest AADEC iteration is the first to simplify design and usage with circuits on PCBs and the ability to pre-program experimental protocols. Still planned is expansion to a multi-well design for the study of varying cell cultures in parallel, which will enable researchers to retain and re-inoculate cultures exhibiting the desired trait most strongly while flushing out others. AADEC’s special capabilities make it a valuable tool for studying life under multiple stressors, enabling scientists to replicate changes in climate on microbes for study in a lab setting.

Microbial Adaptation↗

DOE OSTI2020

Two novel fish paralogs provide insights into the Rid family of imine deaminases active in pre-empting enamine/imine metabolic damage

Reactive Intermediate Deaminase (Rid) protein superfamily includes eight families among which the RidA is conserved in all domains of life. RidA proteins accelerate the deamination of the reactive 2-aminoacrylate (2AA), an enamine produced by some pyridoxal phosphate (PLP)-dependent enzymes. 2AA accumulation inhibits target enzymes with a detrimental impact on fitness. As a consequence of whole genome duplication, teleost fish have two ridA paralogs, while other extant vertebrates contain a single-copy gene. We investigated the biochemical properties of the products of two paralogs, identified in Salmo salar. Ss RidA-1 and Ss RidA-2 complemented the growth defect of a Salmonella enterica ridA mutant, an in vivo model of 2AA stress. In vitro, both proteins hydrolyzed 2-imino acids (IA) to keto-acids and ammonia. Ss RidA-1 was active on IA derived from nonpolar amino acids and poorly active or inactive on IA derived from other amino acids tested. In contrast, SsRidA-2 had a generally low catalytic efficiency, but showed a relatively higher activity with IA derived from L-Glu and aromatic amino acids. The crystal structures of Ss RidA-1 and Ss RidA-2 provided hints of the remarkably different conformational stability and substrate specificity. Overall, Ss RidA-1 is similar to the mammalian orthologs whereas SsRidA-2 displays unique properties likely generated by functional specialization of a duplicated ancestral gene.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

Phylometagenomics of cycad coralloid roots reveals shared symbiotic signals

Cycads are known to host symbiotic cyanobacteria, includingNostocalesspecies, as well as other sympatric bacterial taxa within their specialized coralloid roots. Yet, it is unknown if these bacteria share a phylogenetic origin and/or common genomic functions that allow them to engage in facultative symbiosis with cycad roots. To address this, we obtained metagenomic sequences from 39 coralloid roots sampled from diverse cycad species and origins in Australia and Mexico. Culture-independent shotgun metagenomic sequencing was used to validate sub-community co-cultures as an efficient approach for functional and taxonomic analysis. Our metanalysis shows a host-independent microbiome core consisting of seven bacterial orders with high species diversity within the identified taxa. Moreover, we recovered 43 cyanobacterial metagenome-assembled genomes, and in addition toNostocspp., symbiotic cyanobacteria of the genusAulosirawere identified for the first time. Using this robust dataset, we used phylometagenomic analysis to reveal three monophyletic cyanobiont clades, two host-generalist and one cycad-specific that includesAulosiraspp. Although the symbiotic clades have independently arisen, they are enriched in certain functional genes, such as those related to secondary metabolism. Furthermore, the taxonomic composition of associated sympatric bacterial taxa remained constant. Our research quadruples the number of cycad cyanobiont genomes and provides a robust framework to decipher cyanobacterial symbioses, with the potential of improving our understanding of symbiotic communities. This study lays a solid foundation to harness cyanobionts for agriculture and bioprospection, and assist in conservation of critically endangered cycads.

Genetics & Heredity↗

DOE OSTI2024

Lipid droplet-associated proteins in alcohol-associated fatty liver disease: A proteomic approach

The earliest manifestation of alcohol-associated liver disease (ALD) is steatosis characterized by deposition of fat in specialized organelles called lipid droplets (LDs). While alcohol administration causes a rise in LD numbers in the hepatocytes, little is known regarding their characteristics that allow their accumulation and size to increase. The aim of the present study is to gain insights into underlying pathophysiological mechanisms by investigating the ethanol-induced changes in hepatic LD proteome as a function of LD size. Adult male Wistar rats (180–200 g BW) were fed with ethanol liquid diet for 6 weeks. At sacrifice, large-, medium-, and small-sized hepatic LD subpopulations (LD1, LD2, and LD3, respectively) were isolated and subjected to morphological and proteomic analyses. Morphological analysis of LD1-LD3 fractions of ethanol-fed rats clearly demonstrated that LD1 contained larger LDs compared with LD2 and LD3 fractions. Our preliminary results from principal component analysis showed that the proteome of different-sized hepatic LD fractions was distinctly different. Proteomic data analysis identified over 2000 proteins in each LD fraction with significant alterations in protein abundance among the three LD fractions. Among the altered proteins, several were related to fat metabolism, including synthesis, incorporation of fatty acid, and lipolysis. Ingenuity pathway analysis revealed increased fatty acid synthesis, fatty acid incorporation, LD fusion, and reduced lipolysis in LD1 compared to LD3. Overall, the proteomic findings indicate that the increased level of protein that facilitates fusion of LDs combined with an increased association of negative regulators of lipolysis dictates the generation of large-sized LDs during the development of alcohol-associated hepatic steatosis. Several significantly altered proteins were identified in different-sized LDs isolated from livers of ethanol-fed rats. Ethanol-induced increases in specific proteins that hinder LD lipid metabolism led to the accumulation and persistence of large-sized LDs in the liver.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2025

An Innovative High Throughput Genome Releaser for Rapid and Efficient PCR Screening

High-throughput PCR screening is vital in synthetic biology and metabolic engineering as it allows researchers to rapidly analyze and detect numerous targeted genetic mutation in the genome. Current challenges for high-throughput PCR screening in synthetic biology include efficiently preparing genomic DNA, optimizing protocols for diverse sample types, managing contamination risks, and effectively analyzing the large volumes of data generated while ensuring consistent and accurate results. In this study, we present the development of a High Throughput Genome Releaser (HTGR), an innovative device addressing common challenges in screening PCR. This genome DNA releaser is designed based on a squash method for rapid, cost-effective, and efficient DNA release, optimized for subsequent PCR reactions. After experimenting with various synthetic materials, we selected a plastic that closely replicates the smooth surface and compression properties of microscope slides, ensuring reliable performance. We engineered a device featuring a 96-Well Plate and a shear applicator, operable both manually and automatically, and compatible with standard liquid-handling robot platform. This compatibility enhances ease of use in high-throughput PCR workflows. Additionally, we developed software to support its automatic functions. Our results demonstrated that the specially engineered 96-Well Plate and HTGR can effectively squash fungal spores , which release enough genome DNA for PCR screening. The genome releaser facilitates the preparation of PCR-amplifiable genomic DNA substrate from 96 samples within minutes, eliminates the need for extraction buffers, and is adaptable to a wide range of microorganisms and cells, which could significantly advance biomanufacturing processes.

Yuan, Guoliang [BATTELLE (PACIFIC NW LAB)]↗

NASA NTRS2007

Biomedical Support of U.S. Extravehicular Activity

The world's first extravehicular activity (EVA) was performed by A. A. Leonov on March 18, 1965 during the Russian Voskhod-2 mission. The first US EVA was executed by Gemini IV astronaut Ed White on June 3, 1965, with an umbilical tether that included communications and an oxygen supply. A hand-held maneuvering unit (HHMU) also was used to test maneuverability during the brief EVA; however the somewhat stiff umbilical limited controlled movement. That constraint, plus difficulty returning through the vehicle hatch, highlighted the need for increased thermal control and improved EVA ergonomics. Clearly, requirements for a useful EVA were interrelated with the vehicle design. The early Gemini EVAs generated requirements for suits providing micro-meteor protection, adequate visual field and eye protection from solar visual and infrared radiation, gloves optimized for dexterity while pressurized, and thermal systems capable of protecting the astronaut while rejecting metabolic heat during high workloads. Subsequent Gemini EVAs built upon this early experience and included development of a portable environmental control and life support systems (ECLSS) and an astronaut maneuvering unit. The ECLSS provided a pressure vessel and controller with functional control over suit pressure, oxygen flow, carbon dioxide removal, humidity, and temperature control. Gemini EVA experience also identified the usefulness of underwater neutral buoyancy and altitude chamber task training, and the importance of developing reliable task timelines. Improved thermal management and carbon dioxide control also were required for high workload tasks. With the Apollo project, EVA activity was primarily on the lunar surface; and suit durability, integrated liquid cooling garments, and low suit operating pressures (3.75 pounds per square inch absolute [psia] or 25.8 kilopascal [kPa],) were required to facilitate longer EVAs with ambulation and significant physical workloads with average metabolic rates of 1000 BTU/hr and peaks of up to 2200 BTU/hr. Mobility was further augmented with the Lunar Roving Vehicle. The Apollo extravehicular mobility unit (EMU) was made up of over 15 components, ranging from a biomedical belt for capturing and transmitting biomedical data, urine and fecal containment systems, a liquid cooling garment, communications cap, a modular portable life support system (PLSS), a boot system, thermal overgloves, and a bubble helmet with eye protection. Apollo lunar astronauts performed successful EVAs on the lunar surface from a 5 psia (34.4 kPa) 100% oxygen environment in the Lunar Lander. A maximum of three EVAs were performed on any mission. For Skylab a modified A7LB suit, used for Apollo 15, was selected. The Skylab astronaut life support assembly (ALSA) provided umbilical support through the life support umbilical (LSU) and used open loop oxygen flow, rather than closed-loop as in Apollo missions. Thermal control was provided by liquid water circulated by spacecraft pumps and electrical power also was provided from the spacecraft via the umbilical. The cabin atmosphere of 5 psia (34.4 kPa), 70% oxygen, provided a normoxic atmosphere and because of the very low nitrogen partial pressures, no special protocols were required to protect against decompression sickness (DCS) as was the case with the Apollo spacecraft with a 5 psi, 100% oxygen environment.

Gernhardt, Michael L.↗

DOE OSTI2022

Characterizing the gene–environment interaction underlying natural morphological variation in Neurospora crassa conidiophores using high-throughput phenomics and transcriptomics

Abstract Neurospora crassa propagates through dissemination of conidia, which develop through specialized structures called conidiophores. Recent work has identified striking variation in conidiophore morphology, using a wild population collection from Louisiana, United States of America to classify 3 distinct phenotypes: Wild-Type, Wrap, and Bulky. Little is known about the impact of these phenotypes on sporulation or germination later in the N. crassa life cycle, or about the genetic variation that underlies them. In this study, we show that conidiophore morphology likely affects colonization capacity of wild N. crassa isolates through both sporulation distance and germination on different carbon sources. We generated and crossed homokaryotic strains belonging to each phenotypic group to more robustly fit a model for and estimate heritability of the complex trait, conidiophore architecture. Our fitted model suggests at least 3 genes and 2 epistatic interactions contribute to conidiophore phenotype, which has an estimated heritability of 0.47. To uncover genes contributing to these phenotypes, we performed RNA-sequencing on mycelia and conidiophores of strains representing each of the 3 phenotypes. Our results show that the Bulky strain had a distinct transcriptional profile from that of Wild-Type and Wrap, exhibiting differential expression patterns in clock-controlled genes (ccgs), the conidiation-specific gene con-6, and genes implicated in metabolism and communication. Combined, these results present novel ecological impacts of and differential gene expression underlying natural conidiophore morphological variation, a complex trait that has not yet been thoroughly explored.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

Parsed synthesis of pyocyanin via co-culture enables context-dependent intercellular redox communication

Abstract Background Microbial co-cultures and consortia are of interest in cell-based molecular production and even as “smart” therapeutics in that one can take advantage of division of labor and specialization to expand both the range of available functions and mechanisms for control. The development of tools that enable coordination and modulation of consortia will be crucial for future application of multi-population cultures. In particular, these systems would benefit from an expanded toolset that enables orthogonal inter-strain communication. Results We created a co-culture for the synthesis of a redox-active phenazine signaling molecule, pyocyanin (PYO), by dividing its synthesis into the generation of its intermediate, phenazine carboxylic acid (PCA) from the first strain, followed by consumption of PCA and generation of PYO in a second strain. Interestingly, both PCA and PYO can be used to actuate gene expression in cells engineered with the soxRS oxidative stress regulon, although importantly this signaling activity was found to depend on growth media. That is, like other signaling motifs in bacterial systems, the signaling activity is context dependent. We then used this co-culture’s phenazine signals in a tri-culture to modulate gene expression and production of three model products: quorum sensing molecule autoinducer-1 and two fluorescent marker proteins, eGFP and DsRed. We also showed how these redox-based signals could be intermingled with other quorum-sensing (QS) signals which are more commonly used in synthetic biology, to control complex behaviors. To provide control over product synthesis in the tri-cultures, we also showed how a QS-induced growth control module could guide metabolic flux in one population and at the same time guide overall tri-culture function. Specifically, we showed that phenazine signal recognition, enabled through the oxidative stress response regulon soxRS, was dependent on media composition such that signal propagation within our parsed synthetic system could guide different desired outcomes based on the prevailing environment. In doing so, we expanded the range of signaling molecules available for coordination and the modes by which they can be utilized to influence overall function of a multi-population culture. Conclusions Our results show that redox-based signaling can be intermingled with other quorum sensing signaling in ways that enable user-defined control of microbial consortia yielding various outcomes defined by culture medium. Further, we demonstrated the utility of our previously designed growth control module in influencing signal propagation and metabolic activity is unimpeded by orthogonal redox-based signaling. By exploring novel multi-modal strategies for guiding communication and consortia outcome, the concepts introduced here may prove to be useful for coordination of multiple populations within complex microbial systems.

Chun, Kayla↗

DOE OSTI2020

A mass spectrometry-based high-throughput screening method for engineering fatty acid synthases with improved production of medium-chain fatty acids

Microbial cell factories have been extensively engineered to produce free fatty acids (FFAs), key components of crucial nutrients, soaps, industrial chemicals, and fuels. Yet, our ability to control the specificity of microbially synthesized FFAs is still limited for medium-chain fatty acids (MCFAs), which is mainly due to lack of high-throughput approaches for FFA analysis. Here we report a mass spectrometry (MS)-based method for rapid profiling of MCFAs in Saccharomyces cerevisiae by using membrane lipids as a proxy. Specially, matrix-assisted laser desorption/ionization time-of-flight (MALDI-ToF) MS was used to detect shorter acyl chain phosphatidylcholines from membrane lipids and the m/z peak ratio at 730 and 758 was used as an index for improved MCFA production. This yeast colony-based method can be performed at a rate of ~2 second per sample, which is much faster than the gold standard gas chromatography (GC)-MS (typically > 30 min per sample). To demonstrate the power of this method, we performed site-saturation mutagenesis of the yeast fatty acid synthase and identified 9 mutants that resulted in improved MCFA production relative to the wild-type strain. This colony-based MALDI-ToF MS screening method offers an alternative way for engineering microbial fatty acid compositions in a high-throughput manner.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2021

Bioactive diterpenoids impact the composition of the root-associated microbiome in maize (Zea mays)

Abstract Plants deploy both primary and species-specific, specialized metabolites to communicate with other organisms and adapt to environmental challenges, including interactions with soil-dwelling microbial communities. However, the role of specialized metabolites in modulating plant-microbiome interactions often remains elusive. In this study, we report that maize ( Zea mays ) diterpenoid metabolites with known antifungal bioactivities also influence rhizosphere bacterial communities. Metabolite profiling showed that dolabralexins, antibiotic diterpenoids that are highly abundant in roots of some maize varieties, can be exuded from the roots. Comparative 16S rRNA gene sequencing determined the bacterial community composition of the maize mutant Zman2 ( anther ear 2 ), which is deficient in dolabralexins and closely related bioactive kauralexin diterpenoids. The Zman2 rhizosphere microbiome differed significantly from the wild-type sibling with the most significant changes observed for Alphaproteobacteria of the order Sphingomonadales. Metabolomics analyses support that these differences are attributed to the diterpenoid deficiency of the Zman2 mutant, rather than other large-scale metabolome alterations. Together, these findings support physiological functions of maize diterpenoids beyond known chemical defenses, including the assembly of the rhizosphere microbiome.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

An Abundant and Diverse New Family of Electron Bifurcating Enzymes With a Non-canonical Catalytic Mechanism

Microorganisms utilize electron bifurcating enzymes in metabolic pathways to carry out thermodynamically unfavorable reactions. Bifurcating FeFe-hydrogenases (HydABC) reversibly oxidize NADH (E′∼−280 mV, under physiological conditions) and reduce protons to H 2 gas (E°′−414 mV) by coupling this endergonic reaction to the exergonic reduction of protons by reduced ferredoxin (Fd) (E′∼−500 mV). We show here that HydABC homologs are surprisingly ubiquitous in the microbial world and are represented by 57 phylogenetically distinct clades but only about half are FeFe-hydrogenases. The others have replaced the hydrogenase domain with another oxidoreductase domain or they contain additional subunits, both of which enable various third reactions to be reversibly coupled to NAD + and Fd reduction. We hypothesize that all of these enzymes carry out electron bifurcation and that their third substrates can include hydrogen peroxide, pyruvate, carbon monoxide, aldehydes, aryl-CoA thioesters, NADP + , cofactor F 420 , formate, and quinones, as well as many yet to be discovered. Some of the enzymes are proposed to be integral membrane-bound proton-translocating complexes. These different functionalities are associated with phylogenetically distinct clades and in many cases with specific microbial phyla. We propose that this new and abundant class of electron bifurcating enzyme be referred to as the Bfu family whose defining feature is a conserved bifurcating BfuBC core. This core contains FMN and six iron sulfur clusters and it interacts directly with ferredoxin (Fd) and NAD(H). Electrons to or from the third substrate are fed into the BfuBC core via BfuA. The other three known families of electron bifurcating enzyme (abbreviated as Nfn, EtfAB, and HdrA) contain a special FAD that bifurcates electrons to high and low potential pathways. The Bfu family are proposed to use a different electron bifurcation mechanism that involves a combination of FMN and three adjacent iron sulfur clusters, including a novel [2Fe-2S] cluster with pentacoordinate and partial non-Cys coordination. The absolute conservation of the redox cofactors of BfuBC in all members of the Bfu enzyme family indicate they have the same non-canonical mechanism to bifurcate electrons. A hypothetical catalytic mechanism is proposed as a basis for future spectroscopic analyses of Bfu family members.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

Exhaled breath condensate profiles of U.S. Navy divers following prolonged hyperbaric oxygen (HBO) and nitrogen-oxygen (Nitrox) chamber exposures

Prolonged exposure to hyperbaric hyperoxia can lead to pulmonary oxygen toxicity (PO 2 tox). PO 2 tox is a mission limiting factor for special operations forces divers using closed-circuit rebreathing apparatus and a potential side effect for patients undergoing hyperbaric oxygen (HBO) treatment. In this study, we aim to determine if there is a specific breath profile of compounds in exhaled breath condensate (EBC) that is indicative of the early stages of pulmonary hyperoxic stress/PO 2 tox. Using a double-blind, randomized 'sham' controlled, cross-over design 14 U.S. Navy trained diver volunteers breathed two different gas mixtures at an ambient pressure of 2 ATA (33 fsw, 10 msw) for 6.5 h. One test gas consisted of 100% O 2 (HBO) and the other was a gas mixture containing 30.6% O 2 with the balance N 2 (Nitrox). The high O 2 stress dive (HBO) and low O 2 stress dive (Nitrox) were separated by at least seven days and were conducted dry and at rest inside a hyperbaric chamber. EBC samples were taken immediately before and after each dive and subsequently underwent a targeted and untargeted metabolomics analysis using liquid chromatography coupled to mass spectrometry (LC-MS). Following the HBO dive, 10 out of 14 subjects reported symptoms of the early stages of PO 2 tox and one subject terminated the dive early due to severe symptoms of PO 2 tox. No symptoms of PO 2 tox were reported following the nitrox dive. A partial least-squares discriminant analysis of the normalized (relative to pre-dive) untargeted data gave good classification abilities between the HBO and nitrox EBC with an AUC of 0.99 (±2%) and sensitivity and specificity of 0.93 (±10%) and 0.94 (±10%), respectively. Furthermore, the resulting classifications identified specific biomarkers that included human metabolites and lipids and their derivatives from different metabolic pathways that may explain metabolomic changes resulting from prolonged HBO exposure.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRS2021

Topical: Stem Cell-Based Tissue Regenerative Health in Space

The maintenance of healthy adult tissues in mammals requires a complex homeostasis of molecular, cellular, tissue, and metabolic processes which are fundamentally different from the development and aging processes that bookend life. Cellular homeostasis in the adult requires molecular maintenance and repair of non-dividing cells such as cardiomyocytes and neurons, but also stem cell-based tissue regeneration via direct replacement of cell loss, such as in the blood, immune system, bone, skin, liver, intestine, and other tissues. Because stem cell-based tissue regenerative health requires constant proliferation and differentiation of stem cell progenitors in the bone marrow, and other adult stem cell niches, it is uniquely sensitive to the stresses of spaceflight including exposure to space radiation and mechanical unloading in microgravity. A key central hypothesis in this field is that those spaceflight stress factors can have profound negative effects on long-term tissue regenerative health mediated by adult stem cells, and that unmitigated, they may lead to premature tissue aging and functional failure. Specifically, it is thought that mechanical unloading due to lack of weight-bearing in space reduces mitogenic mechanotransduction necessary to promote adult stem cell proliferation and differentiation, and that space radiation can also lead to activation of cell cycle arrest mechanisms, further reducing adult stem cell proliferation. These hypotheses are being tested in low earth orbit(LEO)using a variety of cellular and whole organism tissue model systems, suggesting that spaceflight consistently interferes with stem cell tissue regenerative processes such as in mammalian embryoid bodies, regenerating newt tails, and mouse bone marrow hematopoietic and osteoprogenitor cells. Furthermore, potential molecular mechanisms integrating both space radiation and mechanical disuse via oxidative stress and the cell cycle inhibitor Cdkn1aare now under study using single cell (scRNAseq) expressome analysis of bone marrow osteoprogenitors, both under stretch loading, and spaceflight conditions including in various mouse transgenic null backgrounds relevant to these mechanisms. Future work in the area of tissue regenerative health in space for the coming decade should seek to understand the responses the various tissue regenerative stem cell niches in humans and relevant model organisms, and how they respond to long-term exposure to the space environment. Special emphases of future work should be on how regenerative deficits in whole-organism stem cell niches may lead to tissue degeneration and premature aging, and on the long-term proliferation and differentiation of stem cell derived tissue organoid models in the deep space environment outside of LEO.

Eduardo A C Almeida↗

NASA NTRS2000

Deconditioning and Reconditioning: Humans in Stressful Environments

Deconditioning is an integrated physiological response of the body to a reduction in metabolic rate; that is, to a reduction in energy use or in exercise level. While it may involve assumption of a horizontal body position, it certainly perturbs bodily homeostasis - at least temporarily. The reduction in physical activity that causes deconditioning is often associated with an increase in the time spent, for whatever reason, in a sitting or horizontal position. As a result, orthostatic factors may also contribute to the deconditioning mechanism. The word decondition may be defined as "1: to cause extinction of (a conditioned response) 2: to cause to lose physical fitness". This definition implies that psychological/emotional factors may accompany physical deconditioning, and it is this interpretation of the word that is used throughout this volume. It is apparent that deconditioning plays a major role in the mechanism of the general adaptive (homeostatic) response that is initiated by exposure to prolonged bed rest (BR). And the total homeostatic response to BR involves more than deconditioning per se. For example, it has been shown that the restoration of plasma volume and maximal work capacity after 4 weeks of BR deconditioning left other bodily functions (submaximal exercise oxygen uptake and cardiac output, leg proprioception and posterior leg muscle thickness and volume, head-up tilt tolerance, and sleep quality) functioning at decreased levels. The precise effect of deconditioning on BR homeostasis is difficult to determine, because the fundamental interactive neuro-endocrine-immune control networks that facilitate conditioning and deconditioning also act to maintain basic wholebody homeostasis. For example, is the mechanism of BR-induced deconditioning independent of the mechanism that provokes concomitant orthostatic intolerance; that is, fainting? Assumption of the recumbent body position for prolonged periods of time, results in a new adaptive-homeostatic state. This state occurs in response to the mutually interactive effects of the change in bodily position (hydrostatic pressure), to the virtual elimination of longitudinal pressure on the bones, to the increased confinement with possible reduction in total daily energy (exercise) expenditure, to the reorientation of stimuli within the vestibular organs, and (often) to altered socio-psychological conditions. The exercise-training (reconditioning) syndrome affects total body homeostasis by facilitating increases in work capacity and endurance, whereas deconditioning decreases physical performance. There are many interrelated factors that influence the control parameters that seek to maintain the adaptive conditioning-deconditioning syndrome. These control parameters can be better elucidated by subjecting otherwise healthy ambulatory people to various stresses, such as exercise training and prolonged spaceflight, bed rest, water immersion, hyperbaria, and isolation and confinement. Changes in control parameters will be manifested in muscle function, orthostatic tolerance, cardiorespiratory responses, musculo-skeletal systems, free-radical processes, and body thermoregulation with overarching effects on the subjects' psycho-sociological states. A discussion of these factors and the control parameters constitutes the substance of this volume. Special emphasis is placed on delineating practical applications of the findings that will be of special interest to physicians, nurses, and other health-care workers.

Greenleaf, John E.↗

DOE OSTI2024

MIBiG 4.0: advancing biosynthetic gene cluster curation through global collaboration

Specialized or secondary metabolites are small molecules of biological origin, often showing potent biological activities with applications in agriculture, engineering and medicine. Usually, the biosynthesis of these natural products is governed by sets of co-regulated and physically clustered genes known as biosynthetic gene clusters (BGCs). To share information about BGCs in a standardized and machine-readable way, the Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard and repository was initiated in 2015. Since its conception, MIBiG has been regularly updated to expand data coverage and remain up to date with innovations in natural product research. Here, we describe MIBiG version 4.0, an extensive update to the data repository and the underlying data standard. In a massive community annotation effort, 267 contributors performed 8304 edits, creating 557 new entries and modifying 590 existing entries, resulting in a new total of 3059 curated entries in MIBiG. Particular attention was paid to ensuring high data quality, with automated data validation using a newly developed custom submission portal prototype, paired with a novel peer-reviewing model. MIBiG 4.0 also takes steps towards a rolling release model and a broader involvement of the scientific community. MIBiG 4.0 is accessible online at https://mibig.secondarymetabolites.org/.

59 BASIC BIOLOGICAL SCIENCES↗