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26 records · Page 2

Structural and functional characterization of NEMO cleavage by SARS-CoV-2 3CLpro

Abstract In addition to its essential role in viral polyprotein processing, the SARS-CoV-2 3C-like protease (3CLpro) can cleave human immune signaling proteins, like NF-κB Essential Modulator (NEMO) and deregulate the host immune response. Here, in vitro assays show that SARS-CoV-2 3CLpro cleaves NEMO with fine-tuned efficiency. Analysis of the 2.50 Å resolution crystal structure of 3CLpro C145S bound to NEMO 226–234 reveals subsites that tolerate a range of viral and host substrates through main chain hydrogen bonds while also enforcing specificity using side chain hydrogen bonds and hydrophobic contacts. Machine learning- and physics-based computational methods predict that variation in key binding residues of 3CLpro-NEMO helps explain the high fitness of SARS-CoV-2 in humans. We posit that cleavage of NEMO is an important piece of information to be accounted for, in the pathology of COVID-19.

60 APPLIED LIFE SCIENCES↗

Tomato deploys defence and growth simultaneously to resist bacterial wilt disease

Abstract Plant disease limits crop production, and host genetic resistance is a major means of control. Plant pathogenic Ralstonia causes bacterial wilt disease and is best controlled with resistant varieties. Tomato wilt resistance is multigenic, yet the mechanisms of resistance remain largely unknown. We combined metaRNAseq analysis and functional experiments to identify core Ralstonia ‐responsive genes and the corresponding biological mechanisms in wilt‐resistant and wilt‐susceptible tomatoes. While trade‐offs between growth and defence are common in plants, wilt‐resistant plants activated both defence responses and growth processes. Measurements of innate immunity and growth, including reactive oxygen species production and root system growth, respectively, validated that resistant plants executed defence‐related processes at the same time they increased root growth. In contrast, in wilt‐susceptible plants roots senesced and root surface area declined following Ralstonia inoculation. Wilt‐resistant plants repressed genes predicted to negatively regulate water stress tolerance, while susceptible plants repressed genes predicted to promote water stress tolerance. Our results suggest that wilt‐resistant plants can simultaneously promote growth and defence by investing in resources that act in both processes. Infected susceptible plants activate defences, but fail to grow and so succumb to Ralstonia , likely because they cannot tolerate the water stress induced by vascular wilt.

Meline, Valerian↗

Fecal microbiota transplantation ameliorates type 2 diabetes via metabolic remodeling of the gut microbiota in db/db mice

Gut microbiome (GM) deregulation has been implicated in major conditions such as obesity and type 2 diabetes (T2DM). Our previous prospective study indicated that fecal microbiota transplantation (FMT) successfully improved patients with T2DM. We hypothesized that FMT may be a potential therapeutic method for T2DM, but its precise mechanisms in T2DM remains to be elucidated. Eight db/m mice were FMT donors and control mice, and 16 genetically diabetic db/db mice were equally divided into two groups (db/db+phosphate-buffered saline (PBS) group, db/db+FMT group). The db/db+FMT group was administered fresh fecal suspension (0.2 mL/mice) daily for 4 weeks. Analysis of the GM and serum metabolome was carried out by 16S ribosomal RNA sequencing and liquid chromatogram-mass spectrometry, respectively. Effects of FMT on the gut barrier and pancreas were assessed using protein assays, messenger RNA, immunohistology and clinical indicators testing. Our results showed that FMT treatment of db/db mice relieves a series of clinical indicators, including fasting plasma glucose, serum insulin and oral glucose tolerance test among others. Compared with non-diabetic control mice, db/db+PBS mice exhibited decreased abundance of Ruminococaceae, Porphyromonadaceae and increased abundance of Rikenellaceae and Lactobacillaceae. FMT treatment reversed this effect on the microbiome. Eleven metabolites were changed between the db/db+PBS and db/db+FMT groups. Correlation analysis showed that the structural changes of the GM were correlated with host metabolite levels. We further showed that FMT treatment of db/db mice improved intestinal barrier function, reduced inflammation and caused an alteration in the number of circulating immune cells. FMT-mediated changes in the GM, serum metabolites, intestinal epithelial barrier, inflammation and circulating immune cells play an important role in the efficacy of FMT on T2DM disease progression.

60 APPLIED LIFE SCIENCES↗

Is the exquisite specificity of lymphocytes generated by thymic selection or due to evolution?

We have previously argued that the antigen receptors of T and B lymphocytes evolved to be sufficiently specific to avoid massive deletion of clonotypes by negative selection. Their optimal ‘specificity’ level, i.e., probability of binding any particular epitope, was shown to be inversely related to the number of self-antigens that the cells have to be tolerant to. Experiments have demonstrated that T lymphocytes also become more specific during negative selection in the thymus, because cells expressing the most crossreactive receptors have the highest likelihood of binding a self-antigen, and hence to be tolerized (i.e., deleted, anergized, or diverted into a regulatory T cell phenotype). Thus, there are two —not mutually exclusive— explanations for the exquisite specificity of T cells, one involving evolution and the other thymic selection. To better understand the impact of both, we extend a previously developed mathematical model by allowing for T cells with very different binding probabilities in the pre-selection repertoire. We confirm that negative selection tends to tolerize the most crossreactive clonotypes. As a result, the average level of specificity in the functional post-selection repertoire depends on the number of self-antigens, even if there is no evolutionary optimization of binding probabilities. However, the evolutionary optimal range of binding probabilities in the pre-selection repertoire also depends on the number of self-antigens. Species with more self antigens need more specific pre-selection repertoires to avoid excessive loss of T cells during thymic selection, and hence mount protective immune responses. We conclude that both evolution and negative selection are responsible for the high level of specificity of lymphocytes.

59 BASIC BIOLOGICAL SCIENCES↗

Phosphate tolerance of nitrogen-coordinated-iron-carbon (FeNC) catalysts for oxygen reduction reaction: A size-related hindrance effect

The greatest challenges facing the large – scale commercialization of the intermediate temperature phosphoric acid fuel cell (PAFC) technology are: (i) the high cost of Pt catalyst that is required to overcome the slow kinetics of oxygen reduction reaction (ORR) on the PAFC cathode, and (ii) deactivation of the Pt catalyst by exposure to the phosphoric acid electrolyte. Inexpensive carbon-based materials, particularly iron- spectroscopy is used to explore the phenomenon of phosphate poisoning nitrogen-coordinated carbon supported catalysts (FeNC), are promising cathodes for PAFCs. The higher ORR activation energy and phosphate poisoning resistance of FeNC present a clear advantage over the Pt-based commercial catalysts that are easily susceptible to deactivation after exposure to phosphate anions. While the immunity of FeNC catalysts to phosphate anion poisoning has been reported previously, this work explores the counter-intuitive and conditional nature of this poisoning resistance based on the properties of the carbon support used in the preparation of the FeNC catalyst. Additionally, a combination of electrochemical measurements with characterization experiments performed using X-ray photoelectron spectroscopy, infrared spectroscopy and in-situ X-ray absorption on FeNC catalysts synthesized from two different carbon supports. Results from these studies reveal a “size-related hindrance effect” wherein the ORR active Fe centers in FeNC remain inaccessible to larger anions such as phosphate when the Fe sites are present deeper inside the pores of a carbon support with high porosity. However, FeNC catalyst is poisoned by phosphate anions when synthesized using a carbon support with low porosity. This work helps gain insights into the nature of active sites in FeNC catalysts that will be useful in designing precious-metal free ORR catalysts for intermediate temperature fuel cell technologies.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

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↗

Structural insights into protection against a SARS-CoV-2 spike variant by T cell receptor diversity

T cells play a crucial role in combatting SARS-CoV-2 and forming long-term memory responses to this coronavirus. The emergence of SARS-CoV-2 variants that can evade T cell immunity has raised concerns about vaccine efficacy and the risk of reinfection. Some SARS-CoV-2 T cell epitopes elicit clonally restricted CD8 + T cell responses characterized by T cell receptors (TCRs) that lack structural diversity. Mutations in such epitopes can lead to loss of recognition by most T cells specific for that epitope, facilitating viral escape. Here, we studied an HLA-A2–restricted spike protein epitope (RLQ) that elicits CD8 + T cell responses in COVID-19 convalescent patients characterized by highly diverse TCRs. We previously reported the structure of an RLQ-specific TCR (RLQ3) with greatly reduced recognition of the most common natural variant of the RLQ epitope (T1006I). Opposite to RLQ3, TCR RLQ7 recognizes T1006I with even higher functional avidity than the WT epitope. To explain the ability of RLQ7, but not RLQ3, to tolerate the T1006I mutation, we determined structures of RLQ7 bound to RLQ–HLA-A2 and T1006I–HLA-A2. These complexes show that there are multiple structural solutions to recognizing RLQ and thereby generating a clonally diverse T cell response to this epitope that assures protection against viral escape and T cell clonal loss.

60 APPLIED LIFE SCIENCES↗

Temperature modulation of CAMTA3 gene induction activity is mediated through the DNA binding domain

The calmodulin-binding transcription activator (CAMTA) proteins of Arabidopsis thaliana play a major role in cold acclimation, contributing to the rapid induction of the C-REPEAT BINDING FACTOR (CBF) genes and other genes that impart freezing tolerance in plants exposed to cold temperature (4°C). The goal of this study was to better understand how the gene induction activity of CAMTA3 is modulated by temperature. Our results indicate that a severely truncated version of CAMTA3, CAMTA3 334 , which includes the N-terminal CG-1 DNA binding domain and a newly identified transcriptional activation domain (TAD), was able to rapidly induce the expression of CBF2 and two newly identified target genes, EXPANSIN-LIKE A1 (EXPL1) and NINE-CIS-EPOXYCAROTENOID DIOXYGENASE 3 (NCED3), in response to cold temperature. Additionally, CAMTA3 334 was able to restore freezing tolerance when expressed in a camta23 double mutant. The ability of CAMTA3 and CAMTA3 334 to induce target genes at cold temperature did not involve increased levels of these proteins or increased binding of these proteins to target gene promoters in cold-treated plants. Rather, domain-swapping experiments indicated that the CAMTA3 CG-1 domain conferred temperature dependence to the ability of the CAMTA3 TAD to induce gene expression. The CG-1 domain also enabled the TAD to induce the expression of target genes at a moderate temperature (22°C) in response to cycloheximide treatment, consistent with the TAD activity not being intrinsically temperature dependent. We propose a working model in which the temperature modulation of CAMTA3 gene induction activity occurs independently from the C-terminal calmodulin-binding domains that previously have been proposed to activate CAMTA3 transcriptional activity in response to cold temperature.

59 BASIC BIOLOGICAL SCIENCES↗