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Metabolic flux phenotyping of secondary metabolism in cyanobacteria
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A corpus of GA4GH phenopackets: Case-level phenotyping for genomic diagnostics and discovery
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Hypoxia-cultured mouse mesenchymal stromal cells from bone marrow and compact bone display different phenotypic traits
Highlights: • Mouse compact bone is richer in MSC compared to central bone marrow. • Derivation of MSC from mouse compact bone is associated with lower risk of contamination with hematopoietic cells. • MSC from compact bone display higher osteogenic differentiation capacity than bone marrow MSC. It has been suggested that the bone marrow microenvironment harbors two distinct populations of mesenchymal stromal cells (MSC), one with a perivascular location and other present in the endosteum. A better understanding of the biology of these MSC subsets has been pursued in order to refine its clinical application. However, most comparative characterizations of mouse MSC have been performed in normoxia. This can result in misleading interpretations since mouse MSC subsets with low/defective p53 activity are known to be selected during culture in normoxia. Here, we report a comprehensive in vitro characterization of mouse MSC isolated from bone marrow (BM-MSC) and compact bone (CB-MSC) expanded and assayed under hypoxia for their morphology, clonogenic efficiency and differentiation capacity. We found that, under hypoxia, compact bone is richer in absolute numbers of MSC and isolation of MSC from compact bone is associated with a reduced risk of hematopoietic cell carryover. In addition, CB-MSC have higher in vitro osteogenic capacity than BM-MSC, while adipogenic differentiation potential is similar. These findings reinforce the hypothesis of the existence of MSC in bone marrow and compact bone representing functionally distinct cell populations and highlight the compact bone as an efficient source of murine MSC under physiological oxygen concentrations.
Continuous NF-κB pathway inhibition promotes expansion of human phenotypical hematopoietic stem/progenitor cells through metabolism regulation
Highlights: • Small molecular inhibition of NF-κB pathway efficiently expands human HSPCs. • NF-κB inhibition with TPCA-1 improves the self-renewal potential and biological function maintenance of expanded CD34{sup +} cells. • NF-κB pathway inhibition reprograms metabolism and enhances glycolysis. • Continuous NF-κB inhibition is required in the culture process to facilitate primitive HSC maintenance. Hematopoietic stem/progenitor cells (HSPCs) ex vivo expansion is critical in facilitating their widespread clinical application. NF-κB pathway is implicated in the energy homeostasis and metabolic adaptation. To explore the effect of NF-κB pathway on the ex vivo HSPC expansion and metabolism, the 50 nM–1 μM inhibitor of NF-κB pathway TPCA-1 was used to expand cord blood derived CD34{sup +} cells in serum-free culture. The expansion folds, function, mitochondrial profile and metabolism of HSPCs were determined. After 10 days of culture with 100 nM TPCA-1, the expansion of total cells CD34{sup +}CD38{sup −} cells and CD34{sup +}CD38{sup −}CD45RA{sup −}CD90{sup +}CD49f{sup +} cells were significantly increased compared to the cytokine priming alone. Notably, TPCA-1 treatment generated ~ 2-fold greater percentage of CD34{sup +}EPCR{sup +} and CD34{sup +}CD38{sup −}CD45RA{sup −}CD90{sup +}CD49f{sup +} cells compared to cytokine only conditions. Moreover, TPCA-1 expanded CD34{sup +} cells displayed enhanced serial colonies forming potential and secondary expansion capability. NF-κB inhibition increased the expression of self-renewal related genes, while downregulated the expression of mitochondrial biogenesis regulator (Pgc1α) and mitochondrial chaperones and proteases (ClpP, Hsp10, Hsp60). Mitochondrial mass and membrane potential were markedly decreased with TPCA-1 treatment, leading to the reduced mitochondrial reactive oxygen species (ROS) level in HSPCs. NF-κB inhibition displayed augmented glycolysis rate with compromising mitochondrial metabolism. This study demonstrated that NF-κB pathway inhibition improved glycolysis and limited ROS production that promoted the ex vivo expansion and maintenance of functional HSPCs.
Optimized genome-wide CRISPR screening enables rapid engineering of growth-based phenotypes in Yarrowia lipolytica
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Switchgrass Metabolomics Reveals Striking Genotypic and Developmental Differences in Specialized Metabolic Phenotypes
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Association of post-COVID phenotypic manifestations with new-onset psychiatric disease
Acute COVID-19 infection can be followed by diverse clinical manifestations referred to as Post Acute Sequelae of SARS-CoV2 Infection (PASC). Studies have shown an increased risk of being diagnosed with new-onset psychiatric disease following a diagnosis of acute COVID-19. However, it was unclear whether non-psychiatric PASC-associated manifestations (PASC-AMs) are associated with an increased risk of new-onset psychiatric disease following COVID-19. A retrospective electronic health record (EHR) cohort study of 2,391,006 individuals with acute COVID-19 was performed to evaluate whether non-psychiatric PASC-AMs are associated with new-onset psychiatric disease. Data were obtained from the National COVID Cohort Collaborative (N3C), which has EHR data from 76 clinical organizations. EHR codes were mapped to 151 non-psychiatric PASC-AMs recorded 28–120 days following SARS-CoV-2 diagnosis and before diagnosis of new-onset psychiatric disease. Association of newly diagnosed psychiatric disease with age, sex, race, pre-existing comorbidities, and PASC-AMs in seven categories was assessed by logistic regression. There were significant associations between a diagnosis of any psychiatric disease and five categories of PASC-AMs with odds ratios highest for neurological, cardiovascular, and constitutional PASC-AMs with odds ratios of 1.31, 1.29, and 1.23 respectively. Secondary analysis revealed that the proportions of 50 individual clinical features significantly differed between patients diagnosed with different psychiatric diseases. Our study provides evidence for association between non-psychiatric PASC-AMs and the incidence of newly diagnosed psychiatric disease. Significant associations were found for features related to multiple organ systems. This information could prove useful in understanding risk stratification for new-onset psychiatric disease following COVID-19. Prospective studies are needed to corroborate these findings.
Transcription factor binding divergence drives transcriptional and phenotypic variation in maize
Regulatory elements are essential components of plant genomes that have shaped the domestication and improvement of modern crops. However, their identity, function and diversity remain poorly characterized, limiting our ability to harness their full power for agricultural advances using induced or natural variation. Here, in this study, we mapped transcription factor (TF) binding for 200 TFs from 30 families in two distinct maize inbred lines historically used in maize breeding. TF binding comparison revealed widespread differences between inbreds, driven largely by structural variation, that correlated with gene expression changes and explained complex quantitative trait loci such as Vgt1, an important determinant of flowering time, and DICE, an herbivore resistance enhancer. CRISPR–Cas9 editing of TF binding regions validated the function and structure of regulatory regions at various loci controlling plant architecture and biotic resistance. Our maize TF binding catalogue identifies functional regulatory regions and enables collective and comparative analysis, highlighting its value for agricultural improvement.
Unforeseen plant phenotypic diversity in a dry and grazed world
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Connecting metabolome and phenotype: recent advances in functional metabolomics tools for the identification of bioactive natural products
In this review we discuss emerging functional metabolomics strategies and their potential use to reveal mechanistic insights in large-scale natural product discovery studies.
Accelerating strain phenotyping with desorption electrospray ionization-imaging mass spectrometry and untargeted analysis of intact microbial colonies
Significance Synthetic biology has entered an era in which reading and writing DNA sequences are no longer rate-limiting steps in microbial strain engineering. Indeed, analytical methods measuring the resulting metabolic outcomes of specific gene edits have lagged behind the ability to generate new recombinant strains. Herein, we report a mass spectrometry strategy to accelerate these analytical workflows by directly analyzing metabolites and molecules produced from engineered microorganisms in a multiplexed process. Using untargeted acquisitions and unsupervised analytics, we assess the molecular features that change across discrete strains including primary target species, secondary products, and species outside the engineered fatty acid biosynthesis pathway.
Incubation Temperature and Maternal Resource Provisioning, but Not Contaminant Exposure, Shape Hatchling Phenotypes in a Species with Temperature-Dependent Sex Determination
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Evaluation of overtime phenotypic variation of yeasts in chronic vulvovaginal candidosis cases
Abstract Chronic vulvovaginal candidosis results either from reinfection or from the ability of Candida spp. to persist in the vulva and/or vagina. Persistence is usually associated with increased antifungal (mainly azoles) resistance rates, which can explain treatment failure, and/or increased expression of virulence factors by Candida spp. The aim of this study was to assess the mechanisms leading to Candida spp persistence, by studying sequential isolates from women with chronic vulvovaginal candidosis, focusing on strains genotypes, azole resistance, and ability to form biofilms along the period of clinical evaluation. The strains were identified at species level by automated analysis of biochemical profiles and molecular typing evaluated by polymorphic DNA analysis. The capacity to form biofilm was assessed with a microtiter plate assay. Fluconazole susceptibility was determined by the microdilution broth assay at both pH 7 (following the recommended guideline) and pH 4.5 (as representative of vaginal pH). We studied samples from 17 clinically recurrent cases. In 53% of the chronic cases there were two or more isolates that had a phylogenetic relationship while the remaining (47%) were caused by different species. In those cases where related strains were involved in recurrence, we verified an increase in MIC at pH 7 and also an increased capacity to form biofilms over time. Significant correlation between these two parameters was observed only in cases caused by C. glabrata, evidencing the importance of these two factors to enhance persistence in the vaginal mucosa for this particular species.
Canalization of Phenotypes—When the Transcriptome is Constantly but Weakly Perturbed
Abstract Recent studies have increasingly pointed to microRNAs (miRNAs) as the agent of gene regulatory network (GRN) stabilization as well as developmental canalization against constant but small environmental perturbations. To analyze mild perturbations, we construct a Dicer-1 knockdown line (dcr-1 KD) in Drosophila that modestly reduces all miRNAs by, on average, ∼20%. The defining characteristic of stabilizers is that, when their capacity is compromised, GRNs do not change their short-term behaviors. Indeed, even with such broad reductions across all miRNAs, the changes in the transcriptome are very modest during development in stable environment. By comparison, broad knockdowns of other regulatory genes (esp. transcription factors) by the same method should lead to drastic changes in the GRNs. The consequence of destabilization may thus be in long-term development as postulated by the theory of canalization. Flies with modest miRNA reductions may gradually deviate from the developmental norm, resulting in late-stage failures such as shortened longevity. In the optimal culture condition, the survival to adulthood is indeed normal in the dcr-1 KD line but, importantly, adult longevity is reduced by ∼90%. When flies are stressed by high temperature, dcr-1 KD induces lethality earlier in late pupation and, as the perturbations are shifted earlier, the affected stages are shifted correspondingly. Hence, in late stages of development with deviations piling up, GRN would be increasingly in need of stabilization. In conclusion, miRNAs appear to be a solution to weak but constant environmental perturbations.
A Thermoacoustic Imaging System for Noninvasive and Nondestructive Root Phenotyping
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