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At least 217 records · Page 12

Parallels between immune driven-hematopoiesis and T cell activation: 3 signals that relay inflammatory stress to the bone marrow

Quiescence, self-renewal, lineage commitment and differentiation of hematopoietic stem cells (HSCs) towards fully mature blood cells are a complex process that involves both intrinsic and extrinsic signals. During steady-state conditions, most hematopoietic signals are provided by various resident cells inside the bone marrow (BM), which establish the HSC micro-environment. However, upon infection, the hematopoietic process is also affected by pathogens and activated immune cells, which illustrates an effective feedback mechanism to hematopoietic stem and progenitor cells (HSPCs) via immune-mediated signals. Here, we review the impact of pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), costimulatory molecules and pro-inflammatory cytokines on the quiescence, proliferation and differentiation of HSCs and more committed progenitors. As modulation of HSPC function via these immune-mediated signals holds an interesting parallel with the “three-signal-model” described for the activation and differentiation of naïve T-cells, we propose a novel “three-signal” concept for immune-driven hematopoiesis. In this model, the recognition of PAMPs and DAMPs will activate HSCs and induce proliferation, while costimulatory molecules and pro-inflammatory cytokines confer a second and third signal, respectively, which further regulate expansion, lineage commitment and differentiation of HSPCs. We review the impact of inflammatory stress on hematopoiesis along these three signals and we discuss whether they act independently from each other or that concurrence of these signals is important for an adequate response of HSPCs upon infection. - Highlights: • Inflammation and infection have a direct impact on hematopoiesis in the bone marrow. • We draw a striking parallel between immune-driven hematopoiesis and T cell activation. • We review how PAMPs and DAMPs, costimulation and cytokines influence HSPC function.

60 APPLIED LIFE SCIENCES↗

A Bright, Photostable, and Far-Red Dye That Enables Multicolor, Time-Lapse, and Super-Resolution Imaging of Acidic Organelles

Lysosomes have long been known for their acidic lumens and efficient degradation of cellular byproducts. In recent years, it has become clear that their function is far more sophisticated, involving multiple cell signaling pathways and interactions with other organelles. Unfortunately, their acidic interior, fast dynamics, and small size make lysosomes difficult to image with fluorescence microscopy. Here we report a far-red small molecule, HMSiR 680 -Me, that fluoresces only under acidic conditions, causing selective labeling of acidic organelles in live cells. HMSiR 680 -Me can be used alongside other far-red dyes in multicolor imaging experiments and is superior to existing lysosome probes in terms of photostability and maintaining cell health and lysosome motility. We demonstrate that HMSiR 680 -Me is compatible with overnight time-lapse experiments as well as time-lapse super-resolution microscopy with a frame rate of 1.5 fps for at least 1000 frames. HMSiR 680 -Me can also be used alongside silicon rhodamine dyes in a multiplexed super-resolution microscopy experiment to visualize interactions between mitochondria and lysosomes with only a single excitation laser and simultaneous depletion. We envision this dye permitting a more detailed study of the role of lysosomes in dynamic cellular processes and disease.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Lipid binding promotes the open conformation and tumor-suppressive activity of neurofibromin 2

Neurofibromatosis type 2 (NF2) is a tumor-forming disease of the nervous system caused by deletion or by loss-of-function mutations in NF2, encoding the tumor suppressing protein neurofibromin 2 (also known as schwannomin or merlin). Neurofibromin 2 is a member of the ezrin, radixin, moesin (ERM) family of proteins regulating the cytoskeleton and cell signaling. The correlation of the tumor-suppressive function and conformation (open or closed) of neurofibromin 2 has been subject to much speculation, often based on extrapolation from other ERM proteins, and controversy. Here we show that lipid binding results in the open conformation of neurofibromin 2 and that lipid binding is necessary for inhibiting cell proliferation. Collectively, our results provide a mechanism in which the open conformation is unambiguously correlated with lipid binding and localization to the membrane, which are critical for the tumor-suppressive function of neurofibromin 2, thus finally reconciling the long-standing conformation and function debate.

59 BASIC BIOLOGICAL SCIENCES↗

Super-Resolution Imaging of Plant Receptor-Like Kinases Uncovers Their Colocalization and Coordination with Nanometer Resolution

Plant cell signaling often relies on the cellular organization of receptor-like kinases (RLKs) within membrane nanodomains to enhance signaling specificity and efficiency. Thus, nanometer-scale quantitative analysis of spatial organizations of RLKs could provide new understanding of mechanisms underlying plant responses to environmental stress. Here, we used stochastic optical reconstruction fluorescence microscopy (STORM) to quantify the colocalization of the flagellin-sensitive-2 (FLS2) receptor and the nanodomain marker, remorin, within Arabidopsis thaliana root hair cells. We found that recovery of FLS2 and remorin in the plasma membrane, following ligand-induced internalization by bacterial-flagellin-peptide (flg22), reached ~85% of their original membrane density after ~90 min. The pairs colocalized at the membrane at greater frequencies, compared with simulated randomly distributed pairs, except for directly after recovery, suggesting initial uncoordinated recovery followed by remorin and FLS2 pairing in the membrane. The purinergic receptor, P2K1, colocalized with remorin at similar frequencies as FLS2, while FLS2 and P2K1 colocalization occurred at significantly lower frequencies, suggesting that these RLKs mostly occupy distinct nanodomains. The chitin elicitor receptor, CERK1, colocalized with FLS2 and remorin at much lower frequencies, suggesting little coordination between CERK1 and FLS2. These findings emphasize STORM’s capacity to observe distinct nanodomains and degrees of coordination between plant cell receptors, and their respective immune pathways.

59 BASIC BIOLOGICAL SCIENCES↗

Zinc: From Biological Functions to Therapeutic Potential

The trace element zinc (Zn) displays a wide range of biological functions. Zn ions control intercellular communication and intracellular events that maintain normal physiological processes. These effects are achieved through the modulation of several Zn-dependent proteins, including transcription factors and enzymes of key cell signaling pathways, namely those involved in proliferation, apoptosis, and antioxidant defenses. Efficient homeostatic systems carefully regulate intracellular Zn concentrations. However, perturbed Zn homeostasis has been implicated in the pathogenesis of several chronic human diseases, such as cancer, diabetes, depression, Wilson’s disease, Alzheimer’s disease, and other age-related diseases. This review focuses on Zn’s roles in cell proliferation, survival/death, and DNA repair mechanisms, outlines some biological Zn targets, and addresses the therapeutic potential of Zn supplementation in some human diseases.

Costa, Maria Inês↗

Shh mediates PDGF-induced contractile-to-synthetic phenotypic modulation in vascular smooth muscle cells through regulation of KLF4

Platelet-derived growth factor (PDGF) is known to induce phenotypic switching of vascular smooth muscle cells (VSMCs) from contractile to a pathological synthetic state, which played an essential role in proliferation of VSMCs. Sonic hedgehog (Shh) contributes to the proliferation of VSMCs when induced by PDGF. Here, we investigated the probable role of Shh in PDGF-induced VSMC dedifferentiation and its underlying mechanisms. We found that PDGF stimulated Shh expression in VSMCs, which was mediated by activation of PDGFRβ/ERK1/2 cell signaling pathway. Further, we found PDGF-induced VSMC phenotypic modulation was accompanied by up-regulation of Shh/Gli family zinc finger 2 (Gli2) signaling and Krüppel-like factor 4 (KLF4). When inhibited Shh in the presence of PDGF, the expressions of KLF4 and VSMC dedifferentiation markers were down-regulated and the effect of PDGF in inducing VSMC dedifferentiation was blocked. In the absence of PDGF, Shh signaling activation increased the expression of KLF4 and promoted VSMC dedifferentiation. The results indicate Shh participated in the regulation of PDGF-induced VSMC dedifferentiation. Finally, we found that KLF4 was closely involved in this process. On inhibition of KLF4, PDGF induced VSMC dedifferentiation was abrogated, even in the presence of Shh. Taken together, the results provide critical insights into the newly discovered role of Shh in phenotypic modulation of VSMCs which depends on KLF4. - Highlights: • Shh as a downstream effector of PDGF participates in PDGF-induced VSMC phenotypic modulation. • Shh can promote VSMC phenotypic switching from contractile to synthetic state. • Shh mediates VSMC phenotypic modulation through regulation of KLF4.

60 APPLIED LIFE SCIENCES↗

Regulation of tankyrase activity by a catalytic domain dimer interface

Highlights: • The catalytic domain of tankyrases forms a head-to-head dimer. • The catalytic domain dimer promotes the catalytic activity of tankyrases. • The catalytic domain dimer forms in the context of the SAM domain-mediated oligomer of tankyrases. Tankyrases (TNKS and TNKS2) are enzymes that catalyze poly-ADP-ribosylation (PARsylation) of their target proteins. Tankyrase-mediated PARsylation plays critical regulatory roles in cell signaling, particularly in the Wnt/β-catenin pathway. The sterile alpha motif (SAM) domain in tankyrases mediates their oligomerization, which is essential for tankyrase function. The oligomerization regulates the catalytic activity of tankyrases, but the underlying mechanism is unclear. Our analyses of crystal structures of the tankyrase catalytic domain suggest that formation of a head-to-head dimer regulates the catalytic activity. Our activity assays show that residues in the catalytic domain dimer interface are important for the PARsylation activity of tankyrases both in solution and cells. The dimer is weak and may only form in the context of the SAM domain-mediated oligomers of tankyrases, consistent with the dependence of the tankyrase activity on the SAM domain.

60 APPLIED LIFE SCIENCES↗

Using mechanistic models and machine learning to design single-color multiplexed nascent chain tracking experiments

mRNA translation is the ubiquitous cellular process of reading messenger-RNA strands into functional proteins. Over the past decade, large strides in microscopy techniques have allowed observation of mRNA translation at a single-molecule resolution for self-consistent time-series measurements in live cells. Dubbed Nascent chain tracking (NCT), these methods have explored many temporal dynamics in mRNA translation uncaptured by other experimental methods such as ribosomal profiling, smFISH, pSILAC, BONCAT, or FUNCAT-PLA. However, NCT is currently restricted to the observation of one or two mRNA species at a time due to limits in the number of resolvable fluorescent tags. In this work, we propose a hybrid computational pipeline, where detailed mechanistic simulations produce realistic NCT videos, and machine learning is used to assess potential experimental designs for their ability to resolve multiple mRNA species using a single fluorescent color for all species. Our simulation results show that with careful application this hybrid design strategy could in principle be used to extend the number of mRNA species that could be watched simultaneously within the same cell. We present a simulated example NCT experiment with seven different mRNA species within the same simulated cell and use our ML labeling to identify these spots with 90% accuracy using only two distinct fluorescent tags. We conclude that the proposed extension to the NCT color palette should allow experimentalists to access a plethora of new experimental design possibilities, especially for cell Signaling applications requiring simultaneous study of multiple mRNAs.

59 BASIC BIOLOGICAL SCIENCES↗

Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related Flavonoids: A Structure–Activity Analysis

Dietary flavonoids inhibit certain protein kinases and phospholipid kinases by competing for their ATP-binding sites. These nucleotide pockets have structural elements that are well-conserved in two human small-molecule kinases, inositol hexakisphosphate kinase (IP6K) and inositol polyphosphate multikinase (IPMK), which synthesize multifunctional inositol phosphate cell signals. Herein, we demonstrate that both kinases are inhibited by quercetin and 16 related flavonoids; IP6K is the preferred target. Relative inhibitory activities were rationalized by X-ray analysis of kinase/flavonoid crystal structures; this detailed structure–activity analysis revealed hydrophobic and polar ligand/protein interactions, the degree of flexibility of key amino acid side chains, and the importance of water molecules. The seven most potent IP6K inhibitors were incubated with intact HCT116 cells at concentrations of 2.5 $μ$M; diosmetin was the most selective and effective IP6K inhibitor (>70% reduction in activity). Overall, our data can instruct on pharmacophore properties to assist the future development of inositol phosphate kinase inhibitors. Finally, we propose that dietary flavonoids may inhibit IP6K activity in cells that line the gastrointestinal tract.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Fate Decision Between Group 3 Innate Lymphoid and Conventional NK Cell Lineages by Notch Signaling in Human Circulating Hematopoietic Progenitors

The role of Notch signaling in human innate lymphoid cell (ILC) differentiation is unclear, although IL-7 and IL-15 promote differentiation of natural cytotoxicity receptor (NCR) NKp44+ group 3 ILCs (NCR+ILC3s) and conventional NK (cNK) cells from CD34 + hematopoietic progenitor cells (HPCs) ex vivo. In this study, we analyzed the functions of Notch in the differentiation of NCR + ILC3s and cNK cells from human HPC subpopulations circulating in peripheral blood by limiting dilution and clonal assays using high-throughput flow cytometry. We demonstrated that Notch signaling in combination with IL-7 induced NCR + ILC3 differentiation, but conversely suppressed IL-15–dependent cNK cell generation in CD45RA+Flt-3-c-Kit low , a novel innate lymphocyte-committed HPC subpopulation. In contrast, Notch signaling induced CD45RA-Flt-3 + c-Kithigh multipotent HPCs to generate CD34 + CD7 + CD62L high , the earliest thymic progenitor–like cells, which preserved high cNK/T cell potential, but lost NCR + ILC3 potential. These findings implicate the countervailing functions of Notch signaling in the fate decision between NCR + ILC3 and cNK cell lineages at different maturational stages of human HPCs. Inhibition of Notch functions by Abs specific for either the Notch1 or Notch2 negative regulatory region suggested that both Notch1 and Notch2 signals were involved in the fate decision of innate lymphocyte-committed HPCs and in the generation of earliest thymic progenitor–like cells from multipotent HPCs. Furthermore, the synergistic interaction between Notch and IL-7 in NCR + ILC3 commitment was primarily explicable by the induction of IL-7 receptor expression in the innate lymphocyte–committed HPCs by Notch stimulation, suggesting the pivotal role of Notch in the transcriptional control required for human NCR + ILC3 commitment.

60 APPLIED LIFE SCIENCES↗

FK866-induced NAMPT inhibition activates AMPK and downregulates mTOR signaling in hepatocarcinoma cells

Background: Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme of the NAD salvage pathway starting from nicotinamide. Cancer cells have an increased demand for NAD due to their high proliferation and DNA repair rate. Consequently, NAMPT is considered as a putative target for anti-cancer therapies. There is evidence that AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) become dysregulated during the development of hepatocellular carcinoma (HCC). Here, we investigated the effects of NAMPT inhibition by its specific inhibitor FK866 on the viability of hepatocarcinoma cells and analyzed the effects of FK866 on the nutrient sensor AMPK and mTOR complex1 (mTORC1) signaling. Results: FK866 markedly decreased NAMPT activity and NAD content in hepatocarcinoma cells (Huh7 cells, Hep3B cells) and led to delayed ATP reduction which was associated with increased cell death. These effects could be abrogated by administration of nicotinamide mononucleotide (NMN), the enzyme product of NAMPT. Our results demonstrated a dysregulation of the AMPK/mTOR pathway in hepatocarcinoma cells compared to non-cancerous hepatocytes with a higher expression of mTOR and a lower AMPKα activation in hepatocarcinoma cells. We found that NAMPT inhibition by FK866 significantly activated AMPKα and inhibited the activation of mTOR and its downstream targets p70S6 kinase and 4E-BP1 in hepatocarcinoma cells. Non-cancerous hepatocytes were less sensitive to FK866 and did not show changes in AMPK/mTOR signaling after FK866 treatment. Conclusion: Taken together, these findings reveal an important role of the NAMPT-mediated NAD salvage pathway in the energy homeostasis of hepatocarcinoma cells and suggest NAMPT inhibition as a potential treatment option for HCC. - Highlights: • FK866 increases cell death in p53-deficient hepatocarcinoma cells. • AMPK/mTOR signaling is dysregulated in hepatocarcinoma cells. • FK866-induced NAMPT inhibition activates AMPKα and downregulates mTOR signaling. • NMN abrogates the effects of FK866-induced NAMPT inhibition. • Non-cancerous human hepatocytes are less sensitive to FK866.

60 APPLIED LIFE SCIENCES↗

Reconstruction and modeling protein translocation and compartmentalization in Escherichia coli at the genome-scale

Background: Membranes play a crucial role in cellular functions. Membranes provide a physical barrier, control the trafficking of substances entering and leaving the cell, and are a major determinant of cellular ultra-structure. In addition, components embedded within the membrane participate in cell signaling, energy transduction, and other critical cellular functions. All these processes must share the limited space in the membrane; thus it represents a notable constraint on cellular functions. Membrane- and location-based processes have not yet been reconstructed and explicitly integrated into genome-scale models. Results: The recent genome-scale model of metabolism and protein expression in Escherichia coli (called a ME-model) computes the complete composition of the proteome required to perform whole cell functions. Here we expand the ME-model to include (1) a reconstruction of protein translocation pathways, (2) assignment of all cellular proteins to one of four compartments (cytoplasm, inner membrane, periplasm, and outer membrane) and a translocation pathway, (3) experimentally determined translocase catalytic and porin diffusion rates, and (4) a novel membrane constraint that reflects cell morphology. Comparison of computations performed with this expanded ME-model, named iJL1678-ME, against available experimental data reveals that the model accurately describes translocation pathway expression and the functional proteome by compartmentalized mass. Conclusion: iJL1678-ME enables the computation of cellular phenotypes through an integrated computation of proteome composition, abundance, and activity in four cellular compartments (cytoplasm, periplasm, inner and outer membrane). Reconstruction and validation of the model has demonstrated that the iJL1678-ME is capable of capturing the functional content of membranes, cellular compartment-specific composition, and that it can be utilized to examine the effect of perturbing an expanded set of network components. iJL1678-ME takes a notable step towards the inclusion of cellular ultra-structure in genome-scale models.

59 BASIC BIOLOGICAL SCIENCES↗

Unraveling heterogeneous susceptibility and the evolution of breast cancer using a systems biology approach

Background: An essential question in cancer is why individuals with the same disease have different clinical outcomes. Progress toward a more personalized medicine in cancer patients requires taking into account the underlying heterogeneity at different molecular levels. Results: Here, we present a model in which there are complex interactions at different cellular and systemic levels that account for the heterogeneity of susceptibility to and evolution of ERBB2-positive breast cancers. Our model is based on our analyses of a cohort of mice that are characterized by heterogeneous susceptibility to ERBB2-positive breast cancers. Our analysis reveals that there are similarities between ERBB2 tumors in humans and those of backcross mice at clinical, genomic, expression, and signaling levels. We also show that mice that have tumors with intrinsically high levels of active AKT and ERK are more resistant to tumor metastasis. Our findings suggest for the first time that a site-specific phosphorylation at the serine 473 residue of AKT1 modifies the capacity for tumors to disseminate. Finally, we present two predictive models that can explain the heterogeneous behavior of the disease in the mouse population when we consider simultaneously certain genetic markers, liver cell signaling and serum biomarkers that are identified before the onset of the disease. Conclusions: Considering simultaneously tumor pathophenotypes and several molecular levels, we show the heterogeneous behavior of ERBB2-positive breast cancer in terms of disease progression. This and similar studies should help to better understand disease variability in patient populations.

59 BASIC BIOLOGICAL SCIENCES↗

Phenotypic and functional characterization of corneal endothelial cells during in vitro expansion

The advent of cell culture-based methods for the establishment and expansion of human corneal endothelial cells (CEnC) has provided a source of transplantable corneal endothelium, with a significant potential to challenge the one donor-one recipient paradigm. However, concerns over cell identity remain, and a comprehensive characterization of the cultured CEnC across serial passages has not been performed. To this end, we compared two established CEnC culture methods by assessing the transcriptomic changes that occur during in vitro expansion. In confluent monolayers, low mitogenic culture conditions preserved corneal endothelial cell state identity better than culture in high mitogenic conditions. Expansion by continuous passaging induced replicative cell senescence. Transcriptomic analysis of the senescent phenotype identified a cell senescence signature distinct for CEnC. We identified activation of both classic and new cell signaling pathways that may be targeted to prevent senescence, a significant barrier to realizing the potential clinical utility of in vitro expansion.

59 BASIC BIOLOGICAL SCIENCES↗

PIP4Kγ as a potential target for Huntington's disease

Phosphoinositide lipids provide spatial and temporal regulation of cell signaling and membrane traffic. The PI5P‐4‐kinase family is one of the less studied phosphoinositide lipid kinases. These enzymes catalyze the conversion of phosphatidylinositol 5‐phosphate to phosphatidylinositol 4,5‐bis phosphate. A recent study by Vicinanza et al., a suggested that depletion of the PI5P‐4‐kinase, PIP4Kγ promotes a non‐canonical autophagy pathway. Moreover, this depletion reduced the presence of huntingtin‐exon1‐polyglutamine aggregates. Expression of exon1 of huntingtin with an extended polyglutamine tract is a model for huntingtin protein aggregates. To further test the hypothesis that PIP4Kγ is a potential target to reduce huntingtin aggregates, we tested the depletion of PIP4Kγ in cell culture models that express full length mutant huntingtin (mHtt). We determined that depletion of PIP4Kγ, but not PIP4Kα or PIP4Kβ, lowers the levels of mHtt in patient fibroblasts and in immortalized Hdh Q111 mouse striatal neurons. We show that PIP4Kγ‐dependent depletion of mHtt requires lysosomal function because the depletion is blocked by the lysosomal inhibitor, bafilomycin A1. Moreover, we show that depletion of PIP4Kγ increases autophagic flux, as measured by an increase in LC3‐II levels by western blot analysis and an increase in LC3‐II puncta by microscopy. Our studies suggest that PIP4kγ should be further pursued as a target for Huntington's disease. Support or Funding Information This work was supported by AHA postdoctoral fellowship 14POST20480137 (Sai Srinivas Panapakkam Giridharan), NIH grants R01GM050403 and NS064015 (Lois S Weisman) and by HSS funding 1R03MH084839 (Juan Marugan)

Giridharan, Sai Srinivas Panapakkam↗

Cell Science and Cell Biology Research at MSFC: Summary

The common theme of these research programs is that they investigate regulation of gene expression in cells, and ultimately gene expression is controlled by the macromolecular interactions between regulatory proteins and DNA. The NASA Critical Path Roadmap identifies Muscle Alterations and Atrophy and Radiation Effects as Very Serious Risks and Severe Risks, respectively, in long term space flights. The specific problem addressed by Dr. Young's research ("Skeletal Muscle Atrophy and Muscle Cell Signaling") is that skeletal muscle loss in space cannot be prevented by vigorous exercise. Aerobic skeletal muscles (i.e., red muscles) undergo the most extensive atrophy during long-term space flight. Of the many different potential avenues for preventing muscle atrophy, Dr. Young has chosen to study the beta-adrenergic receptor (betaAR) pathway. The reason for this choice is that a family of compounds called betaAR agonists will preferentially cause an increase in muscle mass of aerobic muscles (i.e., red muscle) in animals, potentially providing a specific pharmacological solution to muscle loss in microgravity. In addition, muscle atrophy is a widespread medical problem in neuromuscular diseases, spinal cord injury, lack of exercise, aging, and any disease requiring prolonged bedridden status. Skeletal muscle cells in cell culture are utilized as a model system to study this problem. Dr. Richmond's research ("Radiation & Cancer Biology of Mammary Cells in Culture") is directed toward developing a laboratory model for use in risk assessment of cancer caused by space radiation. This research is unique because a human model will be developed utilizing human mammary cells that are highly susceptible to tumor development. This approach is preferential over using animal cells because of problems in comparing radiation-induced cancers between humans and animals.

Source record↗

High-Throughput Directed Evolution of Marine Microalgae and Phototrophic Consortia for Improved Biomass Yields (Final Report)

Primary project achievements include using selective pressures (O 2 , light, temperature) and developing culturing regimes for the diatom Nitzschia inconspicua str. hildebrandi to attain enrichments with an ~90% increase in areal biomass productivity relative to the parental strain under pond-mimicking conditions with high O 2 stress in laboratory bioreactors. The resulting strain (GAI-337) was tested further for dilution time, culture density, CO 2 supplementation, pH, temperature, and dissolved O 2 concentration under outdoor pond-mimicking conditions to improve areal productivities. These experiments yielded an optimum harvest and dilution time just after sunset, ~0.45 g AFDW L -1 initial culture density for maximal productivities, no requirement for CO 2 supplementation or pH control, maximal performance under a diel temperature curve going from 24 °C at night to 36 °C during the day, and benefits from some O 2 removal from the culture by bubbling with air. Using pond-mimicking laboratory bioreactors, N. inconspicua GAI-337 achieved ~42 g AFDW m -2 d -1 . Nutrient limitation experiments resulted in a biomass composition that equated to ~160 Gallons of Gasoline Equivalent energy per ton AFDW, highlighting the potential of GAI-337 as a promising renewable fuel feedstock strain. Genome resequencing has revealed genome alterations potentially contributing to the improved growth of GAI-337 in the laboratory. Based on the comparative analyses of the GAI-337 and GAI-229 (reference) strains, we identified 144 single nucleotide substitutions that resulted in amino acid change, 7 single nucleotide substitutions that resulted in protein truncation; 5 deletions; and 1 frameshift mutation. From the mutations that potentially affect expression of functionally annotated genes, particular interest was noted for an interferon-induced 6-16 family protein that may be involved in the host immune response against microbe invasion; the chaperone protein DnaK, which may function to protect the folding of proteins within the cell; and SPRY domain protein that is found in many eukaryotic proteins important in cell signaling pathways. Transcriptome analysis revealed over 1000 genes with increased transcript levels. Many of these and many of the genes with mutations are not yet functionally annotated and an increased bioinformatics effort is necessary to more completely analyze the Nitzschia inconspicua genome. Adaptive laboratory evolution (ALE) was performed for over 300 days using consecutive 0.5°C temperature increases in a constant temperature incubator to attain greater thermal tolerance in Nitzschia inconspicua. The adapted strain was able to grow at a constant temperature of 37.5°C; whereas this constant temperature was lethal to the parental control, which had an upper temperature boundary of 35.5°C prior to adaptive evolution. Several high-temperature clonal isolates were obtained from the evolved population following ALE, and increased temperature tolerance was observed in clonal adapted cultures. The final temperature adaptation was maintained through cryopreservation and was observed in multiple clonal isolates, including multiple clonal isolates with significantly increased cell size, indicating the potential occurrence of a sexual cycle during the clonal isolation process. A survey of Nannochloropsis strains was conducted for tolerances to high pH and high bicarbonate media. Nannochloropsis granulata showed promising growth in diel bioreactors and was successfully grown at the GAI Kauai farm site in long-term growth campaigns. Co-culturing using Nitzschia inconspicua, Nannochloropsis and a cyanobacterium were assembled in the laboratory to determine if productivity synergies could be attained. Although all strains grew well in the laboratory high-bicarbonate media individually, the cyanobacterium quickly outgrew the other strains in the laboratory consortium pushing the co-culture away from a diverse (and potentially synergistic assemblage) phototroph culture towards a monoculture dominated by the cyanobacterium. Several outdoor growth campaigns were conducted, with productivities ranging between 10-20 g/m 2 /d of biomass. The best performing strain in the laboratory (GAI-337) did not outperform reference strains at the Kauai farm under the conditions used. Addition growth campaigns are necessary under conditions that result in higher biomass (>20 g/m 2 /d) and that attain higher O 2 levels are likely necessary. Initial data indicate that the thermally adapted strain did slightly better than the control strain at higher temperatures; however, additional campaigns are necessary to establish statistical significance. In summary, Nitzschia inconspicua is able to attain exemplary biomass and lipid yields in the laboratory bioreactors. Strain evolution to both O 2 and temperature resulted in targeted strain improvements. Additional outdoor campaigns are necessary to determine if laboratory improvements translate to the field.

09 BIOMASS FUELS↗

Discovery and characterization of an iminocoumarin scaffold as an inhibitor of MEKK2 (MAP3K2)

Highlights: • Two novel small molecule inhibitors of MEKK2 discovered from screening. • Structures validated and activities confirmed in multiple MEKK2 biochemical assays. • Synthesis of analogs for iminocoumarin scaffold led to ≥20-fold more potent analogs. • Kinase profiling indicated that scaffold modifications could increase selectivity. • One analog inhibited ERK5 pathway activation in cells and cell migration. The kinase MEKK2 (MAP3K2) activates the MEK5/ERK5 cell signaling pathway and may play an important role in tumor growth and metastasis. Thus, MEKK2 may represent a novel kinase target for cancer. In order to identify inhibitors of MEKK2, we screened a library of compounds using a high throughput MEKK2 intrinsic ATPase enzyme assay. We identified two hits with validated structures and confirmed activity in the primary assay (IC{sub 50} values = 322 nM and 7.7 μM) and two orthogonal MEKK2 biochemical assays. Compound 1, the more potent hit, was the subject of further investigation. Limited structure-activity relationship (SAR) studies were performed on this iminocoumarin hit which resulted in ≥20-fold more potent analogs (e.g. 8 and 16 nM IC{sub 50}). Two analogs had improved selectivity in a 50-member kinase profiling panel compared to the hit. These studies suggested that substitutions around the phenoxy ring of this scaffold can impart improved potency and selectivity for MEKK2. Analog Compound 1s (16 nM IC{sub 50}) was further verified by external testing to inhibit MEKK2 and MEKK3 with similar potencies. Compound 1s displayed activity in cell-based assays in which it inhibited ERK5 pathway activation in cells and inhibited cell migration in a scratch assay. Thus, we have identified a scaffold that has promising potential to be developed into a highly selective and potent inhibitor of MEKK2. Information from these SAR studies provides specific guidance for the future design of MEKK2 inhibitor probes.

60 APPLIED LIFE SCIENCES↗