Delirium is an acute change in attention and cognition occurring in ~65% of severe SARS-CoV-2 cases. It is also common following surgery and an indicator of brain vulnerability and risk for the development of dementia. In this work we analyzed the underlying role of metabolism in delirium-susceptibility in the postoperative setting using metabolomic profiling of cerebrospinal fluid and blood taken from the same patients prior to planned orthopaedic surgery. Significant concentration differences in several amino acids, acylcarnitines and polyamines were found in delirium-prone patients leading us to a hypothesis about the significance of monoamine oxidase B (MAOB) in predisposition to . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted September 8, 2020. ; https://doi.org/10.1101/2020.06.16.20128660 doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 2 delirium. Subsequent computational structural comparison between MAOB and angiotensin converting enzyme 2 as well as protein-protein docking analysis showed possibly strong binding of SARS-CoV-2 spike protein to MAOB resulting in a hypothesis that SARS-CoV-2 influences MAOB activity possibly lead to many observed neurological and platelet-based complications of SARS-CoV-2 infection. This proposition is possibly of significance for diagnosis, treatment and prevention of vulnerabilities causing delirium, dementias and severe COVID-19 response.

Rising atmospheric CO2 concentrations and associated climate changes are thought to have contributed to the steady increase of Fusarium head blight (FHB) on wheat. However, our understanding of precisely how elevated CO2 influences the defense response of wheat against Fusarium graminearum remains limited. In this study, we evaluated the metabolic profiles of susceptible (Norm) and moderately resistant (Alsen) spring wheat in response to whole-head inoculation with two deoxynivalenol (DON)-producing F. graminearum isolates (DON+), isolates 9F1 and Gz3639, and a DON-deficient (DON-) isolate (Gzt40) at ambient (400 ppm) and elevated (800 ppm) CO2 concentrations. The effects of elevated CO2 were dependent on both the Fusarium strain and the wheat variety, but metabolic differences in the host can explain the observed changes in F. graminearum biomass and DON accumulation. The complexity of abiotic and biotic stress interactions makes it difficult to determine if the observed metabolic changes in wheat are a result of CO2-induced changes in the host, the pathogen, or a combination of both. However, the effects of elevated CO2 were not dependent on DON production. Finally, we identified several metabolic biomarkers for wheat that can reliably predict FHB resistance or susceptibility, even as atmospheric CO2 levels rise.

Fusarium head blight (FHB or scab) caused by Fusarium spp. is a destructive disease of wheat. Since the most effective sources of FHB resistance are typically associated with unfavorable agronomic traits, breeding commercial cultivars that combine desired agronomic traits and a high level of FHB resistance remains a considerable challenge. A better understanding of the molecular mechanisms governing FHB resistance will help to design more efficient and precise breeding strategies. Here, multiple molecular tools and assays were deployed to compare the resistant variety Sumai3 with three regionally adapted Canadian cultivars. Macroscopic and microscopic disease evaluation established the relative level of Type II FHB resistance of the four varieties and revealed that the F. graminearum infection process displayed substantial temporal differences among organs. The rachis was found to play a critical role in preventing F. graminearum spread within spikes. Large-scale, organ-specific RNA-seq at different times after F. graminearum infection demonstrated that diverse defense mechanisms were expressed faster and more intensely in the spikelet of resistant varieties. The roles of plant hormones during the interaction of wheat with F. graminearum was inferred based on the transcriptomic data obtained and the quantification of the major plant hormones. Salicylic acid and jasmonic acid were found to play predominantly positive roles in FHB resistance, whereas auxin and ABA were associated with susceptibility, and ethylene appeared to play a dual role during the interaction with F graminearum.

Background: Chinese hamster ovary ( CHO) cells are extremely important host cells for recombinant DNA technology with their utility requiring optimization of growth. The ability to test conditions using in silico models of growing CHO cells can help advance the optimization of bioreactor conditions towards higher viable cell concentration and increased mAb production. Methods: A new kinetic model of CHO cell metabolism is presented, tested and provided in this publication. RNASeq data from CHO cells was used to guide the selection of major metabolic pathways that were included in the kinetic model. The kinetic model includes 37 completely described reactions processing 45 species (metabolites). This model is based on previously published kinetic characteristics for this system and was evaluated against metabolomics data for mAb producing CHO cells grown under two different feeding regimes. Results and Conclusion: This work provides a kinetic model for energy metabolism of CHO cells. Application of the model offers insights into possible causes of the different performance of two feeding strategies, thus suggesting possible problems and future optimization routes.

Diseases of agricultural crops caused by fungi have devastating economic and health effects. Fusarium head blight (FHB) is one of the most damaging diseases of wheat and other small grain cereals. FHB reduces agricultural yield while also affecting food supply and safety through deposition of toxins (mycotoxins/phytotoxins). Control of FHB growth and toxin accumulation in grains remain major challenges. While the ultimate goal in the battle against FHB is the development of resistant wheat varieties, the actual use of fully resistant plants that preclude any need for treatment with fungicides remains out of sight. Current antifungals being applied against FHB are generally azole-based inhibitors. However, usage of these azole-based fungicides is being complicated by the facts that these are active only during specific short-lived developmental time periods, fungi are developing increased resistance to them and they are having significant environmental impacts. As such, there is a great need for more targeted, specific and effective antifungal agents to address the significant threat of FHB. This review provides an overview of some of the more promising fungal targets that are currently being investigated for antifungal development.

De novo uridine-diphosphate-N-acetylglucosamine (UDP-GlcNAc) biosynthesis requires glucose, glutamine, acetyl-CoA and uridine, however GlcNAc salvaged from glycoconjugate turnover and dietary sources also makes a significant contribution to the intracellular pool. Herein we ask whether dietary GlcNAc regulates nutrient transport and intermediate metabolism in C57BL/6 mice by increasing UDP-GlcNAc and in turn Golgi N-glycan branching. GlcNAc added to the drinking water showed a dose-dependent increase in growth of young mice, while in mature adult mice fat and body-weight increased without affecting calorie-intake, activity, energy expenditure, or the microbiome. Oral GlcNAc increased hepatic UDP-GlcNAc and N-glycan branching on hepatic glycoproteins. Glucose homeostasis, hepatic glycogen, lipid metabolism and response to fasting were altered with GlcNAc treatment. In cultured cells GlcNAc enhanced uptake of glucose, glutamine and fatty-acids, and enhanced lipid synthesis, while inhibition of Golgi N-glycan branching blocked GlcNAc-dependent lipid accumulation. The N-acetylglucosaminyltransferase enzymes of the N-glycan branching pathway (Mgat1,2,4,5) display multistep ultrasensitivity to UDP-GlcNAc, as well as branching-dependent compensation. Indeed, oral GlcNAc rescued fat accumulation in lean Mgat5(-/-) mice and in cultured Mgat5(-/-) hepatocytes, consistent with N-glycan branching compensation. Our results suggest GlcNAc reprograms cellular metabolism by enhancing nutrient uptake and lipid storage through the UDP-GlcNAc supply to N-glycan branching pathway.

Understanding the significance of bacterial species that colonize and persist in cystic fibrosis (CF) airways requires a detailed examination of bacterial community structure across a broad range of age and disease stage. We used 16S ribosomal RNA sequencing to characterize the lung microbiota in 269 CF patients spanning a 60 year age range, including 76 pediatric samples from patients of age 4–17 and a broad cross-section of disease status to identify features of bacterial community structure and their relationship to disease stage and age. The CF lung microbiota shows significant inter-individual variability in community structure, composition and diversity. The core microbiota consists of five genera - Streptococcus, Prevotella, Rothia, Veillonella and Actinomyces. CF-associated pathogens such as Pseudomonas, Burkholderia, Stenotrophomonas and Achromobacter are less prevalent than core genera, but have a strong tendency to dominate the bacterial community when present. Community diversity and lung function are greatest in patients less than 10 years of age and lower in older age groups, plateauing at approximately age 25. Lower community diversity correlates with worse lung function in a multivariate regression model. Infection by Pseudomonas correlates with age-associated trends in community diversity and lung function.

The etiology of colorectal cancer (CRC) has been linked to deficiencies in mismatch repair and adenomatous polyposis coli (APC) proteins, diet, inflammatory processes, and gut microbiota. However, the mechanism through which the microbiota synergizes with these etiologic factors to promote CRC is not clear. We report that altering the microbiota composition reduces CRC in APC(Min/+)MSH2(-/-) mice, and that a diet reduced in carbohydrates phenocopies this effect. Gut microbes did not induce CRC in these mice through an inflammatory response or the production of DNA mutagens but rather by providing carbohydrate-derived metabolites such as butyrate that fuel hyperproliferation of MSH2(-/-) colon epithelial cells. Further, we provide evidence that the mismatch repair pathway has a role in regulating β-catenin activity and modulating the differentiation of transit-amplifying cells in the colon. These data thereby provide an explanation for the interaction between microbiota, diet, and mismatch repair deficiency in CRC induction. PAPERCLIP:

Systematic analysis of gene overexpression phenotypes provides an insight into gene function, enzyme targets, and biological pathways. Here, we describe a novel functional genomics platform that enables a highly parallel and systematic assessment of overexpression phenotypes in pooled cultures. First, we constructed a genome-level collection of ~5100 yeast barcoder strains, each of which carries a unique barcode, enabling pooled fitness assays with a barcode microarray or sequencing readout. Second, we constructed a yeast open reading frame (ORF) galactose-induced overexpression array by generating a genome-wide set of yeast transformants, each of which carries an individual plasmid-born and sequence-verified ORF derived from the Saccharomyces cerevisiae full-length EXpression-ready (FLEX) collection. We combined these collections genetically using synthetic genetic array methodology, generating ~5100 strains, each of which is barcoded and overexpresses a specific ORF, a set we termed "barFLEX." Additional synthetic genetic array allows the barFLEX collection to be moved into different genetic backgrounds. As a proof-of-principle, we describe the properties of the barFLEX overexpression collection and its application in synthetic dosage lethality studies under different environmental conditions.