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DOE OSTI2020

A brief note on the properties of linear pathways

Linear metabolic pathways are the simplest network architecture we find in metabolism and are a good starting point to gain insight into the operating principles of metabolic control. Linear pathways possess some well-known properties, such as a bias of flux control towards the first few steps of the pathway as well as the lack of flux control at reactions close to equilibrium. In both cases, a rationale for these behaviors is given in terms of how elasticities transmit changes through a pathway. A discussion is given on the fundamental role that two reaction step sections play in a linear pathway when transmitting changes. For a pathway with irreversible steps, the deconstruction is straight forward and includes a product of local response coefficients that cascade along the pathway. When reversibility is included, the picture became more complex but a relationship in terms of the local response coefficients if derived that includes the reverse response coefficients and highlights the interplay between the forward and backward transmission of changes during a perturbation.

Biochemistry & Molecular Biology↗

DOE OSTI2016

Assignment of function to a domain of unknown function: DUF1537 is a new kinase family in catabolic pathways for acid sugars

Using a large-scale “genomic enzymology” approach, we ( i ) assigned novel ATP-dependent four-carbon acid sugar kinase functions to members of the DUF1537 protein family (domain of unknown function; Pfam families PF07005 and PF17042) and ( ii ) discovered novel catabolic pathways for d -threonate, l -threonate, and d -erythronate. The experimentally determined ligand specificities of several solute binding proteins (SBPs) for TRAP (tripartite ATP-independent permease) transporters for four-carbon acids, including d -erythronate and l -erythronate, were used to constrain the substrates for the catabolic pathways that degrade the SBP ligands to intermediates in central carbon metabolism. Sequence similarity networks and genome neighborhood networks were used to identify the enzyme components of the pathways. Conserved genome neighborhoods encoded SBPs as well as permease components of the TRAP transporters, members of the DUF1537 family, and a member of the 4-hydroxy- l -threonine 4-phosphate dehydrogenase (PdxA) oxidative decarboxylase, class II aldolase, or ribulose 1,5-bisphosphate carboxylase/oxygenase, large subunit (RuBisCO) superfamily. Because the characterized substrates of members of the PdxA, class II aldolase, and RuBisCO superfamilies are phosphorylated, we postulated that the members of the DUF1537 family are novel ATP-dependent kinases that participate in catabolic pathways for four-carbon acid sugars. We determined that ( i ) the DUF1537/PdxA pair participates in a pathway for the conversion of d -threonate to dihydroxyacetone phosphate and CO 2 and ( ii ) the DUF1537/class II aldolase pair participates in pathways for the conversion of d -erythronate and l -threonate (epimers at carbon-3) to dihydroxyacetone phosphate and CO 2 . As a result, the physiological importance of these pathways was demonstrated in vivo by phenotypic and genetic analyses.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Reverse β-oxidation pathways for efficient chemical production

Abstract Microbial production of fuels, chemicals, and materials has the potential to reduce greenhouse gas emissions and contribute to a sustainable bioeconomy. While synthetic biology allows readjusting of native metabolic pathways for the synthesis of desired products, often these native pathways do not support maximum efficiency and are affected by complex regulatory mechanisms. A synthetic or engineered pathway that allows modular synthesis of versatile bioproducts with minimal enzyme requirement and regulation while achieving high carbon and energy efficiency could be an alternative solution to address these issues. The reverse β-oxidation (rBOX) pathways enable iterative non-decarboxylative elongation of carbon molecules of varying chain lengths and functional groups with only four core enzymes and no ATP requirement. Here, we describe recent developments in rBOX pathway engineering to produce alcohols and carboxylic acids with diverse functional groups, along with other commercially important molecules such as polyketides. We discuss the application of rBOX beyond the pathway itself by its interfacing with various carbon-utilization pathways and deployment in different organisms, which allows feedstock diversification from sugars to glycerol, carbon dioxide, methane, and other substrates.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

Transcriptomic Analysis Reveals Novel Regulators of the Scots Pine Stilbene Pathway

Stilbenes accumulate in Scots pine heartwood where they have important roles in protecting wood from decaying fungi. They are also part of active defense responses, and their production is induced by different (a)biotic stressors. The specific transcriptional regulators as well as the enzyme responsible for activating the stilbene precursor cinnamate in the pathway are still unknown. UV-C radiation was the first discovered artificial stress activator of the pathway. Here, we describe a large-scale transcriptomic analysis of pine needles in response to UV-C and treatment with translational inhibitors, both activating the transcription of stilbene pathway genes. We used the data to identify putative candidates for the missing CoA ligase and for pathway regulators. We further showed that the pathway is transcriptionally activated by phosphatase inhibitor, ethylene and jasmonate treatments, as in grapevine, and that the stilbene synthase promoter retains its inducibility in some of the tested conditions in Arabidopsis, a species that normally does not synthesize stilbenes. Shared features between gymnosperm and angiosperm regulation and partially retained inducibility in Arabidopsis suggest that pathway regulation occurs not only via ancient stress-response pathway(s) but also via species-specific regulators. Understanding which genes control the biosynthesis of stilbenes in Scots pine aids breeding of more resistant trees.

4-Coumarate-CoA ligase↗

DOE OSTI2017

Causal Pathways for Temperature Predictability from Snow Depth

Dynamical subseasonal-to-seasonal (S2S) weather forecasting has made strides in recent years, thanks partly to better initialization and representation of physical variables in models. For instance, realistic initializations of snow and soil moisture in models yield enhanced temperature predictability on S2S time scales. Snow depth and soil moisture also mediate month-to-month persistence of near-surface air temperature. Here the role of snow depth as predictor of temperature one month ahead in the Northern Hemisphere is examined via two causal pathways. Through the first pathway, snow depth anomalies in month 1 persist into month 2 and are then linked to temperature anomalies through snow–temperature feedback mechanisms. The first pathway is active from fall to summer, and its effect peaks before the melting season: in winter in the low latitudes, in spring in the midlatitudes, and in early summer in the high latitudes. The second pathway, where snow depth anomalies in month 1 lead to soil moisture anomalies in month 2 (through melting), which are then linked to temperature anomalies in month 2 through soil moisture–temperature feedbacks, is most active in spring and summer. The effect of the second pathway peaks during the melting season, namely, later in the year than the first pathway. The latitudes of the highest mediated effect through both pathways follow a seasonal cycle, shifting northward along with the seasonal insolation cycle. Finally, in keeping with this seasonal cycle, the highest snow depth mediation occurs to the north and the highest soil moisture mediation to the south of the latitudes with the highest overall temperature predictability from snow depth.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2018

CBF-dependent and CBF-independent regulatory pathways contribute to the differences in freezing tolerance and cold-regulated gene expression of two Arabidopsis ecotypes locally adapted to sites in Sweden and Italy

Arabidopsis thaliana (Arabidopsis) increases in freezing tolerance in response to low nonfreezing temperatures, a phenomenon known as cold acclimation. The CBF regulatory pathway, which contributes to cold acclimation, includes three genes—CBF1, CBF2 and CBF3—encoding closely-related transcription factors that regulate the expression of more than 100 genes—the CBF regulon—that impart freezing tolerance. Here we compare the CBF pathways of two Arabidopsis ecotypes collected from sites in Sweden (SW) and Italy (IT). Previous studies showed that the SW ecotype was more freezing tolerant than the IT ecotype and that the IT ecotype had a nonfunctional CBF2 gene. Here we present results establishing that the difference in CBF2 alleles contributes to the difference in freezing tolerance between the two ecotypes. However, other differences in the CBF pathway as well as CBF-independent pathways contribute the large majority of the difference in freezing tolerance between the two ecotypes. The results also provided evidence that most cold-induced CBF regulon genes in both the SW and IT ecotypes are coregulated by CBF-independent pathways. Additional analysis comparing our results with those published by others examining the Col-0 accession resulted in the identification of 44 CBF regulon genes that were conserved among the three accessions suggesting that they likely have important functions in life at low temperature. The comparison further supported the conclusion that the CBF pathway can account for a large portion of the increase in freezing tolerance that occurs with cold acclimation in a given accession, but that CBF-independent pathways can also make a major contribution.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

Systems Biology Model of Interactions Between Tissue Growth Factors and DNA Damage Pathways: Low Dose Response and Cross-Talk in TGFbeta and ATM Signaling

The etiology of radiation carcinogenesis has been described in terms of aberrant changes that span several levels of biological organization. Growth factors regulate many important cellular and tissue functions including apoptosis, differentiation and proliferation. A variety of genetic and epigenetic changes of growth factors have been shown to contribute to cancer initiation and progression. It is known that cellular and tissue damage to ionizing radiation is in part initiated by the production of reactive oxygen species, which can activate cytokine signaling, and the DNA damage response pathways, most notably the ATM signaling pathway. Recently the transforming growth factor β (TGFβ) pathway has been shown to regulate or directly interact with the ATM pathway in the response to radiation. The relevance of this interaction with the ATM pathway is not known although p53 becomes phosphorylated and DNA damage responses are involved. However, growth factor interactions with DNA damage responses have not been elucidated particularly at low doses and further characterization of their relationship to cancer processes is warranted. Our goal will be to use a systems biology approach to mathematically and experimentally describe the low dose responses and cross-talk between the ATM and TGFβ pathways initiated by low and high LET radiation. We will characterize ATM and TGFβ signaling in epithelial and fibroblast cells using 2D models and ultimately extending to 3D organotypic cell culture models to begin to elucidate possible differences that may occur for different cell types and/or inter-cellular communication. We will investigate the roles of the Smad and Activating transcription factor 2 (ATF2) proteins as the potential major contributors to cross- talk between the TGFβ and ATM pathways, and links to cell cycle control and/or the DNA damage response, and potential differences in their responses at low and high doses. We have developed various experimental approaches to apply to these problems using confocal microscopy and flow cytometry to detail changes at low dose/dose-rate in order to understand individual cell responses, and will establish our mathematical models based on the experimental findings resulting from changes in DNA repair, apoptosis and proliferation.

O'Neill, Peter↗

DOE OSTI2018

Plant Modernization Pathway: FY 2019 External Review Summary Report

This report describes an external review conducted by the Light Water Reactor Sustainability Program Plant Modernization Pathway (referred to as Pathway) to solicit feedback on the topics and results of the ongoing Instrumentation and Control (I&C) research program. This review was held in conjunction with the Nuclear Energy Institute (NEI) Digital I&C Working Group meeting that was held at Idaho National Laboratory on October 16–17, 2018. Members of the Nuclear Regulatory Commission (NRC) staff working on digital I&C issues through their Integrated Action Plan also attended. The NEI and NRC agreed that the meeting participants would serve as an external review panel for the purpose of obtaining expert input on the value and timing of the research projects. Five major research areas were presented, along with demonstrations of new technologies in the Human Systems Simulation Laboratory and the Computer-Assisted Virtual Environment. Following the presentations, the external review was conducted by referring to a set of summary slides of the five research areas, and allowing each participant to enter ratings and comments on a survey form as each area was addressed. Fourteen forms were returned. These feedback forms were analyzed by the Pathway who compiled and responded to the data and comments, which are documented in this report. The participants also had opportunity to provide comments on the LWRS Program as a whole and to suggest additional research topics of value. The feedback provided by the external review participants is taken to be a strong endorsement of the types of projects being conducted by the Pathway, the value they hold for the operating nuclear plants, and the general timing of need. The feedback aligns well with the priorities, levels of efforts allocated for the research projects, and project schedules of the current Pathway research program. The feedback also provides realistic observations on the practicality of some aspects of implementing these technologies. The Pathway will consider all of the feedback and address the recommended research topics that have been identified by the external review participants. Pathway research plans will be adjusted as warranted.

22 GENERAL STUDIES OF NUCLEAR REACTORS↗

DOE OSTI2025

Efficient Hamiltonian encoding algorithms for extracting quantum control mechanism as interfering pathway amplitudes in the Dyson series

Hamiltonian encoding is a methodology for revealing the mechanism behind the dynamics governing controlled quantum systems. In this paper, following Mitra and Rabitz \cite{abhra_1}, we define mechanism via pathways of eigenstates that describe the evolution of the system, where each pathway is associated with a complex-valued amplitude corresponding to a term in the Dyson series. The evolution of the system is determined by the constructive and destructive interference of these pathway amplitudes. Pathways with similar attributes can be grouped together into pathway classes. The amplitudes of pathway classes are computed by modulating the Hamiltonian matrix elements and decoding the subsequent evolution of the system rather than by direct computation of the individual terms in the Dyson series. The original implementation of Hamiltonian encoding was computationally intensive and became prohibitively expensive in large quantum systems. This paper presents two new encoding algorithms that calculate the amplitudes of pathway classes by using techniques from graph theory and algebraic topology to exploit patterns in the set of allowed transitions, greatly reducing the number of matrix elements that need to be modulated. These new algorithms provide an exponential decrease in both computation time and memory utilization with respect to the Hilbert space dimension of the system. To demonstrate the use of these techniques, they are applied to two illustrative state-to-state transition problems.

Abrams, Erez [Princeton University, Massachusetts ↗

DOE OSTI2023

CPViz: Visualizing clinical pathways represented in higher-order networks

To improve clinical care practice, it is important to understand the variability of clinical pathways executed in different contexts (e.g., pathways in different geographical locations, demographics, and phenotypic groups). A common way of representing clinical pathways is through network-based representations that capture trajectories of treatment steps. However, first-order networks, which are based on the Markovian property and the de facto standard model to represent transitions between steps, often fail to capture real trajectories. This paper introduces a visual analytic tool to explore and compare pathways represented in higher-order networks. Because each higher node in the network is a subtrajectory (i.e., partial or full history of treatment steps), the tool can display true sequences of treatment steps and compute the similarity of the two networks in a space of higher-order nodes. The tool also highlights areas in which the two networks are similar and dissimilar and how a certain subtrajectory is realized differently in different pathways. The paper demonstrates the tool's usefulness by applying it to multiple antidepressant pharmacotherapy pathways for veterans diagnosed with major depressive disorder and by illustrating heterogeneity in prescription patterns across pathways.

Chae, Junghoon↗

DOE OSTI2015

Meta gene set enrichment analyses link miR-137-regulated pathways with schizophrenia risk

Background: A single nucleotide polymorphism (SNP) within MIR137, the host gene for miR-137, has been identified repeatedly as a risk factor for schizophrenia. Previous genetic pathway analyses suggest that potential targets of this microRNA (miRNA) are also highly enriched in schizophrenia-relevant biological pathways, including those involved in nervous system development and function. Methods: In this study, we evaluated the schizophrenia risk of miR-137 target genes within these pathways. Gene set enrichment analysis of pathway-specific miR-137 targets was performed using the stage 1 (21,856 subjects) schizophrenia genome wide association study data from the Psychiatric Genomics Consortium and a small independent replication cohort (244 subjects) from the Mind Clinical Imaging Consortium and Northwestern University. Results: Gene sets of potential miR-137 targets were enriched with variants associated with schizophrenia risk, including target sets involved in axonal guidance signaling, Ephrin receptor signaling, long-term potentiation, PKA signaling, and Sertoli cell junction signaling. The schizophrenia-risk association of SNPs in PKA signaling targets was replicated in the second independent cohort. Conclusions: These results suggest that these biological pathways may be involved in the mechanisms by which this MIR137 variant enhances schizophrenia risk. SNPs in targets and the miRNA host gene may collectively lead to dysregulation of target expression and aberrant functioning of such implicated pathways. Pathway-guided gene set enrichment analyses should be useful in evaluating the impact of other miRNAs and target genes in different diseases.

Genetics & Heredity↗

DOE OSTI2016

Iron transformation pathways and redox micro-environments in seafloor sulfide-mineral deposits: Spatially resolved Fe XAS and δ 57/54 Fe observations

Hydrothermal sulfide chimneys located along the global system of oceanic spreading centers are habitats for microbial life during active venting. Hydrothermally extinct, or inactive, sulfide deposits also host microbial communities at globally distributed sites. The main goal of this study is to describe Fe transformation pathways, through precipitation and oxidation-reduction (redox) reactions, and examine transformation products for signatures of biological activity using Fe mineralogy and stable isotope approaches. The study includes active and inactive sulfides from the East Pacific Rise 9°50'N vent field. First, the mineralogy of Fe(III)-bearing precipitates is investigated using microprobe X-ray absorption spectroscopy (μXAS) and X-ray diffraction (μXRD). Second, laser-ablation (LA) and micro-drilling (MD) are used to obtain spatially-resolved Fe stable isotope analysis by multicollector-inductively coupled plasma-mass spectrometry (MC-ICP-MS). Eight Fe-bearing minerals representing three mineralogical classes are present in the samples: oxyhydroxides, secondary phyllosilicates, and sulfides. For Fe oxyhydroxides within chimney walls and layers of Si-rich material, enrichments in both heavy and light Fe isotopes relative to pyrite are observed, yielding a range of δ 57 Fe values up to 6‰. Overall, several pathways for Fe transformation are observed. Pathway 1 is characterized by precipitation of primary sulfide minerals from Fe(II)aq-rich fluids in zones of mixing between vent fluids and seawater. Pathway 2 is also consistent with zones of mixing but involves precipitation of sulfide minerals from Fe(II)aq generated by Fe(III) reduction. Pathway 3 is direct oxidation of Fe(II) aq from hydrothermal fluids to form Fe(III) precipitates. Finally, Pathway 4 involves oxidative alteration of pre-existing sulfide minerals to form Fe(III). The Fe mineralogy and isotope data do not support or refute a unique biological role in sulfide alteration. The findings reveal a dynamic range of Fe transformation pathways consistent with a continuum of micro-environments having variable redox conditions. Lastly, these micro-environments likely support redox cycling of Fe and S and are consistent with culture-dependent and -independent assessments of microbial physiology and genetic diversity of hydrothermal sulfide deposits.

mineral alteration↗

DOE OSTI2021

Four Isotope-Labeled Recombination Pathways of Ozone Formation

A theoretical approach is developed for the description of all possible recombination pathways in the ozone forming reaction, without neglecting any process a priori, and without decoupling the individual pathways one from another. These pathways become physically distinct when a rare isotope of oxygen is introduced, such as 18 O, which represents a sensitive probe of the ozone forming reaction. Each isotopologue of O 3 contains two types of physically distinct entrance channels and two types of physically distinct product wells, creating four recombination pathways. Calculations are done for singly and doubly substituted isotopologues of ozone, eight rate coefficients total. Two pathways for the formation of asymmetric ozone isotopomer exhibit rather different rate coefficients, indicating large isotope effect driven by ΔZPE-difference. Rate coefficient for the formation of symmetric isotopomer of ozone (third pathway) is found to be in between of those two, while the rate of insertion pathway is smaller by two orders of magnitude. These trends are in good agreement with experiments, for both singly and doubly substituted ozone. The total formation rates for asymmetric isotopomers are found to be somewhat larger than those for symmetric isotopomers, but not as much as in the experiment. Altogether, the distribution of lifetimes is found to be very similar for the metastable states in symmetric and asymmetric ozone isotopomers.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2017

U.S. Industrial Sector Energy Productivity Improvement Pathways

Economy-wide energy systems forecasting models often propose deep emission reduction pathways as a course of action to achieve environmental goals such as de-carbonization. These pathways typically assume that industries adopt all possible energy efficiency measures and replace their remaining energy demand with low e missions resources, e.g. , renewable or nuclear energy. However, given the significant diversity of energy sources and energy-consuming processes, this over-simplifies the real-world technology, process, and co st constraints common to the industrial sector and is a weakness in existing pathways. Moreover, these pathways do not adequately consider the importance of manufacturing to economic prosperity and for producing the technologies that achieve economy-wide environmental goals. This paper reviews historical industrial energy productivity and introduces an analytic framework for developing industrial sector energy productivity pathways that are driven by the goal to transform both the business as usual trends within the industrial sector, as well as the downstream impacts attributable to manufactured products. The framework includes (1) metrics for quantifying energy productivity growth in term s of physical units, value-added, and service; and (2) concurrent approaches for decoupling energy use an d emissions from manufacturing value-added. The framework presented here highlights that emission reduction pathways need to consider the industrial sector not in the aggregate, but as comprised of diverse manufacturing and non-manufacturing industries that affect the energy productivity of other economic sectors: electric power, transportation, and commercial sectors. Such pathways are better equipped to focus on improving the energy productivity of the US economy.

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗

DOE OSTI2021

A Comparative Techno-Economic Analysis of Renewable Methanol Synthesis Pathways from Biomass and CO2: Preprint

Global demand for methanol as both a chemical precursor and a fuel additive is rising. At the same time, numerous sustainable methanol production pathways are under development which, if commercialized, could present significant environmental benefits over traditional methanol synthesis pathways. There is a need to harmonize the analyses of sustainable pathways using a consistent techno-economic approach to evaluate the potential for commercialization of various pathways. This analysis considers economic and environmental factors critical to market acceptance of three sustainable pathways versus a commercial baseline. We suggest that biomass gasification to methanol represents a near-term viable pathway with high technology readiness level and commercially competitive market price. However, long-term solutions should consider CO2 electrolysis pathways which offer further improvements in sustainability metrics to support global decarbonization efforts.

biomass↗

DOE OSTI2021

Mineralogy-dependent sulfide oxidation via polysulfide and thiosulfate pathways during weathering of mixed-sulfide bearing mine waste rock

Tracking the S oxidation pathway in sulfide-bearing mine waste-rock piles is complicated by variations in water content, O 2 and Fe 3+ concentrations, microbial diversity, mineralogy, the occurrence of a variety of S species associated with incomplete oxidation, and nonlinear coupling between physicochemical processes. Synchrotron-based S K-edge X-ray absorption near edge structure (XANES) spectroscopy facilitates the identification and quantification of S species (i.e., S 2– , $S_{2}O_{2}^{2–}$, S 8 , $S_{2}O_{3}^{2–}$, and $S_{2}O_{4}^{2–}$) in a weathered mine waste-rock pile containing pyrite, sphalerite, galena, pyrrhotite, and chalcopyrite. Mineralogy-dependent polysulfide and thiosulfate pathways both affect the S oxidation within the waste-rock pile. Currently, the polysulfide pathway, with S 8 as the intermediate S species, generates high concentrations of dissolved metals (from the rapid oxidation of monosulfides including sphalerite, galena, pyrrhotite, and chalcopyrite). As these monosulfides are depleted, the thiosulfate pathway of pyrite oxidation, including intermediate oxidation products (i.e., S 8 and $S_{2}O_{3}^{2–}$), will become the dominant oxidation pathway, resulting in the potential for generation of additional acidic drainage. This information highlights the importance of identifying the sulfide-mineral oxidation reaction pathways when attempting to estimate acid generation potential, and when developing remediation strategies for the storage and management of sulfide-bearing waste rock.

58 GEOSCIENCES↗

DOE OSTI2020

Logic-based analysis of gene expression data predicts association between TNF, TGFB1 and EGF pathways in basal-like breast cancer

For breast cancer, clinically important subtypes are well characterized at the molecular level in terms of gene expression profiles. In addition, signaling pathways in breast cancer have been extensively studied as therapeutic targets due to their roles in tumor growth and metastasis. However, it is challenging to put signaling pathways and gene expression profiles together to characterize biological mechanisms of breast cancer subtypes since many signaling events result from post-translational modifications, rather than gene expression differences. We designed a logic-based computational framework to explain the differences in gene expression profiles among breast cancer subtypes using Pathway Logic and transcriptional network information. Pathway Logic is a rewriting-logic-based formal system for modeling biological pathways including post-translational modifications. Our method demonstrated its utility by constructing subtype-specific path from key receptors (TNFR, TGFBR1 and EGFR) to key transcription factor (TF) regulators (RELA, ATF2, SMAD3 and ELK1) and identifying potential association between pathways via TFs in basal-specific paths, which could provide a novel insight on aggressive breast cancer subtypes. Lastly, codes and results are available at http://epigenomics.snu.ac.kr/PL/.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2015

Screening and modular design for metabolic pathway optimization

Biological conversion of substrate sugars to a variety of products is an increasingly popular option for chemical transformation due to its high specificity and because of significant interest in the use of renewable feedstocks. Yet, pathway optimization through metabolic engineering is often needed to make such molecules economically at a relevant scale. Employing effective methods to search and narrow the immense pathway parameter space is essential to meet performance metrics such as high titer, yield and productivity with efficiency. This review focuses on two practices that increase the likelihood of finding a more advantageous pathway solution: implementing a screen to identify high producers and utilizing modular pathway design to streamline engineering efforts. While screens seek to couple product titer with a high-throughput measurement output, modular design aims to rationally construct pathways to allow parallel optimization of various units. Both of these methodologies have proven widely successful in metabolic engineering, with combinations of them resulting in synergistic enhancements to pathway optimization. This review will specifically illustrate their utility for microbially derived acid and alcohol products, which are of interest as fuels and value added products.

59 BASIC BIOLOGICAL SCIENCES↗