Specific Metabolic Pathways Research Articles

Targeting Energy Metabolism in Cancer Treatment

Cancer is the second most common cause of death worldwide after cardiovascular diseases. The development of molecular and biochemical techniques has expanded the knowledge of changes occurring in specific metabolic pathways of cancer cells. Increased aerobic glycolysis, the promotion of anaplerotic responses, and especially the dependence of cells on glutamine and fatty acid metabolism have become subjects of study. Despite many cancer treatment strategies, many patients with neoplastic diseases cannot be completely cured due to the development of resistance in cancer cells to currently used therapeutic approaches. It is now becoming a priority to develop new treatment strategies that are highly effective and have few side effects. In this review, we present the current knowledge of the enzymes involved in the different steps of glycolysis, the Krebs cycle, and the pentose phosphate pathway, and possible targeted therapies. The review also focuses on presenting the differences between cancer cells and normal cells in terms of metabolic phenotype. Knowledge of cancer cell metabolism is constantly evolving, and further research is needed to develop new strategies for anti-cancer therapies.

Light Intensity and Temperature Effect on Salvia yangii (B. T. Drew) Metabolic Profile in vitro.

Plant in vitro culture is a feasible system for the testing influence of an environmental factor on the accumulation and chemodiversity of specialized metabolites, especially in medicinal plants. Light and temperature are among the most important factors affecting the physiology of plant organisms but their influence on specific metabolic pathways is not completely understood. Here, we examined the morphogenetic response, photosynthetic pigments content, lipid peroxidation level, DPPH radical scavenging activity, and the production of volatile and non-volatile constituents in Salvia yangii B. T. Drew (syn. Perovskia atriplicifolia Benth.) in vitro cultures kept under different light intensities (70, 130, and 220 μmol m−2 s−1) and at two selected temperatures (25 and 30°C). The experiment was continued for 7 months to monitor the changes in the treatment response in time. Phytochemical analysis was performed using chromatographic (GC-MS and UHLPC) and spectrophotometric techniques. The light intensity significantly influenced metabolic response in a non-linear manner, whereas temperature-induced adaptive modifications varied within the long cultivation. Significant differences were noted in the content of carnosic and rosmarinic acid, as well as in several sesquiterpenes (alloaromadendrene, β-caryophyllene, α-humulene). At elevated (30°C) temperature, a trend of differently modulated content of two major antioxidants—rosmarinic acid (RA, a phenylpropanoid pathway derived phenolic acid) and carnosic acid (CA, an abietane diterpenoid) was observed, where RA, but not CA, was depending on the light intensity. At 25°C, both compounds depended on light but in various ways. Among the volatile terpenoid compounds, the influence of light was pronounced, leading to modulation of proportions between individual mono- and sesquiterpenes as well as between hydrocarbon and oxygenated compounds. The study provided new information on the metabolic profile plasticity in S. yangii and added to the existing knowledge on the chemical adaptations in plant species from severe habitats.

Probing the Central Role of Phosphatidylinositol Synthesis in Lipid Metabolism of Eukaryotic Cells

Phosphatidylinositol (PI) is the precursor of all phosphoinositides (PPIns), a class of regulatory phospholipids that play key roles in cellular physiology. PI is synthesized in the ER by a single enzyme, phosphatidylinositol synthase (PIS). PI may have important roles of its own in membranes where PPIns are not produced such as in the ER and mitochondria. Disruption of PIS in yeast and zebrafish is lethal and PIS has been postulated to be an essential gene in studies of haploid cells. Therefore, it is difficult to evaluate the processes where this enzyme, or its lipid product, PI plays a critical role. To overcome this problem, we generated stable HEK293 cell lines in which a doxycycline (Dox)‐inducible PIS‐GFP transgene was stably integrated in a safe‐harbor site of the genome and the endogenous PIS locus was inactivated via CRISPR/Cas9 genome editing. We verified the knock‐out of the endogenous PIS and the inducible expression of PIS‐GFP by western blot analysis and sequencing of genomic DNA. Using these cells, we found that PIS enzymatic activity assayed in ER membranes prepared from cells after Dox deprivation was indistinguishable from the assay blank. Dox treatment of cells elevated PIS activity in the isolated ER membrane although it was still lower than that found in the membranes prepared from parental HEK293. Surprisingly, in spite of the undetectable low PIS activity, Dox‐deprived cells still contained about 50% of PI as assessed by equilibrium labeling with 3H‐inositol and retained their PPIns distribution as shown by confocal microscopy using GFP‐tagged PPIns binding modules. This disparity between PIS activity and PI availability was observed even under culture conditions that deprived cells of any external PI source. Such cells were subjected to lipidomic analysis to assess the overall lipid changes associated with the reduction of PI synthesis and to identify processes that require PI. This analysis confirmed the ~50% PI loss and also revealed reprogramming of specific lipid metabolic pathways. Current work focuses on the possibility that alternate source(s) of PI exist and on the question of what lipid synthetic pathways show adaptation to the greatly reduced or missing PIS activity. These experiments have the promise of a better understanding of how PI lipids determine the overall lipid landscape and homeostasis of eukaryotic cells and may unravel new molecular targets that can be exploited for therapeutic interventions in human metabolic and lipid disorders.

The Differential Metabolic Response of Oral Squamous Cell Carcinoma Cells and Normal Oral Epithelial Cells to Cisplatin Exposure.

Metabolic reprogramming is one of the hallmarks of a tumor. It not only promotes the development and progression of tumor but also contributes to the resistance of tumor cells to chemotherapeutics. The difference in the metabolism between drug-resistant and sensitive tumor cells indicates that drug-resistant tumor cells have experienced metabolic adaptation. The metabolic response induced by chemotherapy is dynamic, but the early metabolic response of tumor cells to anticancer drugs and the effect of an initial response on the development of drug resistance have not been well studied. Early metabolic intervention may prevent or slow down the development of drug resistance. The differential metabolic responses of normal cells and tumor cells to drugs are unclear. The specific metabolites or metabolic pathways of tumor cells to chemotherapeutic drugs can be used as the target of metabolic intervention in tumor therapy. In this study, we used comparative metabolomics to analyze the differential metabolic responses of oral cancer cells and normal oral epithelial cells to short-term cisplatin exposure, and to identify the marker metabolites of early response in oral cancer cells. Oral cancer cells showed a dynamic metabolic response to cisplatin. Seven and five metabolites were identified as specific response markers to cisplatin exposure in oral cancer cell SCC-9 and normal oral epithelial cell HOEC, respectively. Glyoxylate and dicarboxylate metabolism and fructose, malate, serine, alanine, sorbose and glutamate were considered as specific enriched metabolic pathways and biomarkers of SCC-9 cells in response to cisplatin, respectively. The existence of differential metabolic responses lays a foundation for tumor chemotherapy combined with metabolic intervention.

Methylomic and transcriptomic characterization of postoperative systemic inflammatory dysregulation

In this study, we define and validate a state of postoperative systemic inflammatory dysregulation (PSID) based on postoperative phenotypic extremes of plasma C-reactive protein concentration following major abdominal surgery. PSID manifested clinically with significantly higher rates of sepsis, complications, longer hospital stays and poorer short, and long-term outcomes. We hypothesized that PSID will be associated with, and potentially predicted by, altered patterns of genome-wide peripheral blood mononuclear cell differential DNA methylation and gene expression. We identified altered DNA methylation and differential gene expression in specific immune and metabolic pathways during PSID. Our findings suggest that dysregulation results in, or from, dramatic changes in differential DNA methylation and highlights potential targets for early detection and treatment. The combination of altered DNA methylation and gene expression suggests that dysregulation is mediated at multiple levels within specific gene sets and hence, nonspecific anti-inflammatory treatments such as corticosteroids alone are unlikely to represent an effective therapeutic strategy.

Clinical diagnosis of metabolic disorders using untargeted metabolomic profiling and disease-specific networks learned from profiling data

Untargeted metabolomics is a global molecular profiling technology that can be used to screen for inborn errors of metabolism (IEMs). Metabolite perturbations are evaluated based on current knowledge of specific metabolic pathway deficiencies, a manual diagnostic process that is qualitative, has limited scalability, and is not equipped to learn from accumulating clinical data. Our purpose was to improve upon manual diagnosis of IEMs in the clinic by developing novel computational methods for analyzing untargeted metabolomics data. We employed CTD, an automated computational diagnostic method that “connects the dots” between metabolite perturbations observed in individual metabolomics profiling data and modules identified in disease­specific metabolite co-perturbation networks learned from prior profiling data. We also extended CTD to calculate distances between any two individuals (CTDncd) and between an individual and a disease state (CTDdm), to provide additional network-quantified predictors for use in diagnosis. We show that across 539 plasma samples, CTD-based network-quantified measures can reproduce accurate diagnosis of 16 different IEMs, including adenylosuccinase deficiency, argininemia, argininosuccinic aciduria, aromatic l-amino acid decarboxylase deficiency, cerebral creatine deficiency syndrome type 2, citrullinemia, cobalamin biosynthesis defect, GABA-transaminase deficiency, glutaric acidemia type 1, maple syrup urine disease, methylmalonic aciduria, ornithine transcarbamylase deficiency, phenylketonuria, propionic acidemia, rhizomelic chondrodysplasia punctata, and the Zellweger spectrum disorders. Our approach can be used to supplement information from biochemical pathways and has the potential to significantly enhance the interpretation of variants of uncertain significance uncovered by exome sequencing. CTD, CTDdm, and CTDncd can serve as an essential toolset for biological interpretation of untargeted metabolomics data that overcomes limitations associated with manual diagnosis to assist diagnosticians in clinical decision-making. By automating and quantifying the interpretation of perturbation patterns, CTD can improve the speed and confidence by which clinical laboratory directors make diagnostic and treatment decisions, while automatically improving performance with new case data.

Change of intestinal microbiota in mice model of bronchopulmonary dysplasia.

BackgroundGut microbiota has been proposed to be related to the pathogenesis of pulmonary diseases such as asthma and lung cancer, according to the gut-lung axis. However, little is known about the roles of gut microbiota in the pathogenesis of bronchopulmonary dysplasia (BPD). This study was designed to investigate the changes of gut microbiota in neonatal mice with BPD.MethodsBPD model was induced through exposure to high concentration of oxygen. Hematoxylin and eosin (H&E) staining was utilized to determine the modeling efficiency. Stool samples were collected from the distal colon for the sequencing of V3–V4 regions of 16S rRNA, in order to analyze the gut microbiota diversity.ResultsAlpha diversity indicated that there were no statistical differences in the richness of gut microbiota between BPD model group and control group on day 7, 14 and 21. Beta diversity analysis showed that there were statistical differences in the gut microbiota on day 14 (R = 0.368, p = 0.021). Linear discriminant analysis effect size (LEfSe) showed that there were 22 markers with statistical differences on day 14 (p < 0.05), while those on day 7 and 21 were 3 and 4, respectively. Functional prediction analysis showed that the top three metabolic pathways were signal transduction (PFDR = 0.037), glycan biosynthesis and metabolism (PFDR = 0.032), and metabolism of terpenoids and polyketides (PFDR = 0.049).ConclusionsBPD mice showed disorder of gut microbiota, which may involve specific metabolic pathways in the early stage. With the progression of neonatal maturity, the differences of the gut microbiota between the two groups would gradually disappear.

Enzyme activity and population genetic structure analysis in wheat associated with resistance to Bipolaris sorokiniana-common root rot diseases

Common root rot disease (CRR) caused by Bipolaris sorokiniana (Sacc.) (Pleosporaceae), is an important fungal disease of wheat, Triticum aestivum (Poaceae), causing considerable yield losses globally. Incorporating genetic resistance in cultivated crops is considered the most efficient and sustainable solution to counter root rot diseases. Moreover, resistance to CCR is quantitative in nature, and thus the mechanism is poorly understood. To this aim, we analyzed the activities of defense-related enzymes; peroxidase (POX), superoxide dismutase (SOD), polyphenol oxidase (PPO), catalase (CAT), phenylalanine ammonia-lyase (PAL), β-1,3-glucanase (GLU) and chitinase (CHI), as well as total phenol content (TPC) to CRR on the three known resistant wheat ‘Alvand’ and ‘Bam’, ‘Mehregan’ at different time points (wpi) following CRR pathogen, B. sorokiniana inoculation. Of which, were selected out of 33 wheat cultivars previously screened for resistance to CRR. We also analyzed the genetic variability of the entire germplasm, 33 wheat cultivars using seven simple sequence repeat (SSR) primer pairs. The activity of antioxidant enzymes was increased in the related resistant genotypes. Of which, ‘Bam’ had the highest increase in PPO, and GLU activities, followed by ‘Alvand’ in SOD, PAL, and CHI significantly. Whereas, ‘Mehregan’ showed the highest level of TPC, POX, and CAT activities. In addition, five out of seven used SSR primers produced a total of 20 polymorphic bands, of which the number of alleles in each gene locus varied within 3–7 bands. The polymorphism information content (PIC) value also ranged from 0.44 to 0.81, with the mean of 0.65, Shannon Information Index (I) between 0.29 and 0.63 with an average of 0.47 per locus, and Nei's gene diversity (h) value varied from 0.16 to 0.44 with an average of 0.32. The average number of effective alleles was 1.52, ranging between 1.21 and 1.8. The gene locus Xgwm 140 showed the highest diversity in the population genetic structure, which explains the ability of the primers to resolve the assayed germplasm. Thus, resistance to CRR in wheat was mainly related to the enhancement of antioxidant enzymes, although the specific metabolic pathways require further study. This study presents new insights for understanding resistance mechanisms of the selected wheat cultivars to CRR, thus improving wheat yield in the future.

Sphingolipids control dermal fibroblast heterogeneity.

Human cells produce thousands of lipids that change during cell differentiation and can vary across individual cells of the same type. However, we are only starting to characterize the function of these cell-to-cell differences in lipid composition. Here, we measured the lipidomes and transcriptomes of individual human dermal fibroblasts by coupling high-resolution mass spectrometry imaging with single-cell transcriptomics. We found that the cell-to-cell variations of specific lipid metabolic pathways contribute to the establishment of cell states involved in the organization of skin architecture. Sphingolipid composition is shown to define fibroblast subpopulations, with sphingolipid metabolic rewiring driving cell-state transitions. Therefore, cell-to-cell lipid heterogeneity affects the determination of cell states, adding a new regulatory component to the self-organization of multicellular systems.

KL1 Domain of Longevity Factor Klotho Mimics the Metabolome of Cognitive Stimulation and Enhances Cognition in Young and Aging Mice.

Cognitive deficits are a major biomedical challenge—and engagement of the brain in stimulating tasks improves cognition in aged individuals (Wilson et al., 2002; Gates et al., 2011) and rodents (Aidil-Carvalho et al., 2017), through unknown mechanisms. Whether cognitive stimulation alters specific metabolic pathways in the brain is unknown. Understanding which metabolic processes are involved in cognitive stimulation is important because it could lead to pharmacologic intervention that promotes biological effects of a beneficial behavior, toward the goal of effective medical treatments for cognitive deficits. Here we show using male mice that cognitive stimulation induced metabolic remodeling of the mouse hippocampus, and that pharmacologic treatment with the longevity hormone α-klotho (KL), mediated by its KL1 domain, partially mimicked this alteration. The shared, metabolic signature shared between cognitive stimulation and treatment with KL or KL1 closely correlated with individual mouse cognitive performance, indicating a link between metabolite levels and learning and memory. Importantly, the treatment of mice with KL1, an endogenous circulating factor that more closely mimicked cognitive stimulation than KL, acutely increased synaptic plasticity, a substrate of cognition. KL1 also improved cognition, itself, in young mice and countered deficits in old mice. Our data show that treatments or interventions mimicking the hippocampal metabolome of cognitive stimulation can enhance brain functions. Further, we identify the specific domain by which klotho promotes brain functions, through KL1, a metabolic mimic of cognitive stimulation.SIGNIFICANCE STATEMENT Cognitive deficits are a major biomedical challenge without truly effective pharmacologic treatments. Engaging the brain through cognitive tasks benefits cognition. Mimicking the effects of such beneficial behaviors through pharmacological treatment represents a highly valuable medical approach to treating cognitive deficits. We demonstrate that brain engagement through cognitive stimulation induces metabolic remodeling of the hippocampus that was acutely recapitulated by the longevity factor klotho, mediated by its KL1 domain. Treatment with KL1, a close mimic of cognitive stimulation, enhanced cognition and countered cognitive aging. Our findings shed light on how cognition metabolically alters the brain and provide a plausible therapeutic intervention for mimicking these alterations that, in turn, improves cognition in the young and aging brain.

Modeling the Amino Acid Effect on Glucagon Secretion from Pancreatic Alpha Cells.

Type 2 Diabetes Mellitus (T2DM) is a burdensome problem in modern society, and intensive research is focused on better understanding the underlying cellular mechanisms of hormone secretion for blood glucose regulation. T2DM is a bi-hormonal disease, and in addition to 100 years of increasing knowledge about the importance of insulin, the second hormone glucagon, secreted by pancreatic alpha cells, is becoming increasingly important. We have developed a mathematical model for glucagon secretion that incorporates all major metabolic processes of glucose, fatty acids, and glutamine as the most abundant postprandial amino acid in blood. In addition, we consider cAMP signaling in alpha cells. The model predictions quantitatively estimate the relative importance of specific metabolic and signaling pathways and particularly emphasize the important role of glutamine in promoting glucagon secretion, which is in good agreement with known experimental data.

Functional microbiome strategies for the bioremediation of petroleum-hydrocarbon and heavy metal contaminated soils: A review

Petroleum hydrocarbons and heavy metals are the two major soil contaminants that are released into the environment in the forms of industrial effluents. These contaminants exert serious impacts on human health and the sustainability of the environment. In this context, remediation of these pollutants via a biological approach can be effective, low-cost, and eco-friendly approach. The implementation of microorganisms and metagenomics are regarded as the advanced solution for remediating such pollutants. Further, microbiomes can overcome this issue via adopting specific structural, functional and metabolic pathways involved in the microbial community to degrade these pollutants. Genomic sequencing and library can effectively channelize the degradation of these pollutants via microbiomes. Nevertheless, more advanced technology and reliable strategies are required to develop. The present review provides insights into the role of microbiomes to effectively remediate/degrade petroleum hydrocarbons and heavy metals in contaminated soil. The possible degradation mechanisms of these pollutants have also been discussed in detail along with their existing limitations. Finally, prospects of the bioremediation strategies using microbiomes are discussed.

Insights from shotgun metagenomics into bacterial species and metabolic pathways associated with NAFLD in obese youth.

Nonalcoholic fatty liver disease (NAFLD) is the most common form of liver disease and is often the precursor for more serious liver conditions such as nonalcoholic steatohepatitis and cirrhosis. Although the gut microbiome has been implicated in the development of NAFLD, the strong association of obesity with NAFLD and its effect on microbiome structure has made interpreting study outcomes difficult. In the present study, we examined the taxonomic and functional differences between the microbiomes of youth with obesity and with and without NAFLD. Shotgun metagenome sequencing was performed to profile the microbiomes of 36 subjects, half of whom were diagnosed with NAFLD using abdominal magnetic resonance imaging. Beta diversity analysis showed community‐wide differences between the groups (p = 0.002). Specific taxonomic differences included increased relative abundances of the species Fusicatenibacter saccharivorans (p = 0.042), Romboutsia ilealis (p = 0.046), and Actinomyces sp. ICM47 (p = 0.0009), and a decrease of Bacteroides thetaiotamicron (p = 0.0002), in the NAFLD group as compared with the non‐NAFLD group. At the phylum level, Bacteroidetes (p < 0.0001) was decreased in the NAFLD group. Functionally, branched‐chain amino acid (p = 0.01343) and aromatic amino acid (p = 0.01343) synthesis pathways had increased relative abundances in the NAFLD group along with numerous energy use pathways, including pyruvate fermentation to acetate (p = 0.01318). Conclusion: Community‐wide differences were noted based on NAFLD status, and individual bacterial species along with specific metabolic pathways were identified as potential drivers of these differences. The results of the present study support the idea that the NAFLD phenotype displays a differentiated microbial and functional signature from the obesity phenotype.

Nontryptase Urinary and Hematologic Biomarkers of Mast Cell Expansion and Mast Cell Activation: Status 2022

Quantitation of urinary metabolites of histamine, prostaglandin D2, and leukotriene E4 can fill the gap in our current efforts to improve diagnosis and management of symptomatic patients with systemic mastocytosis, and/or mast cell activation syndrome, In addition, patients symptomatic due to mast cell activation but who do not meetall the criteria for mast cell activation syndrome can have elevated baseline mediator metabolites. Serum tryptase levels have been the workhorse in diagnosing these disorders, but it has several drawbacks including the need to obtain acute and baseline samples, which require 2 visits to health care facilities and 2 venipunctures. Recently, increased baseline tryptase level has been reported in hereditary alpha tryptasemia, complicating diagnostic possibilities of an increased baseline tryptase level. Furthermore, no treatment can specifically be targeted at tryptase itself. In contrast, the finding of 1 or more elevated urinary levels of histamine, prostaglandin D2, and/or leukotriene E4 metabolites (1) greatly narrows diagnostic possibilities for causes of symptoms; (2) informs the practitioner what specific metabolic pathways are involved; and (3) targets the treatment in a specific, direct fashion. As a bonus, baseline spot/random urine samples can be obtained by the patients themselves and repeated at exactly the correct time when symptoms occur.

Immunometabolism of Myeloid-Derived Suppressor Cells: Implications for Mycobacterium tuberculosis Infection and Insights from Tumor Biology.

The field of immunometabolism seeks to decipher the complex interplay between the immune system and the associated metabolic pathways. The role of small molecules that can target specific metabolic pathways and subsequently alter the immune landscape provides a desirable platform for new therapeutic interventions. Immunotherapeutic targeting of suppressive cell populations, such as myeloid-derived suppressor cells (MDSC), by small molecules has shown promise in pathologies such as cancer and support testing of similar host-directed therapeutic approaches in MDSC-inducing conditions such as tuberculosis (TB). MDSC exhibit a remarkable ability to suppress T-cell responses in those with TB disease. In tumors, MDSC exhibit considerable plasticity and can undergo metabolic reprogramming from glycolysis to fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) to facilitate their immunosuppressive functions. In this review we look at the role of MDSC during M. tb infection and how their metabolic reprogramming aids in the exacerbation of active disease and highlight the possible MDSC-targeted metabolic pathways utilized during M. tb infection, suggesting ways to manipulate these cells in search of novel insights for anti-TB therapies.

Dynamic Changes in the Proteome of Early Bovine Embryos Developed In Vivo.

Early embryo development is a dynamic process involving important molecular and structural changes leading to the embryonic genome activation (EGA) and early cell lineage differentiation. Our aim was to elucidate proteomic changes in bovine embryos developed in vivo. Eleven females were used as embryo donors and pools of embryos at the 4–6 cell, 8–12 cell, morula, compact morula and blastocyst stages were analyzed by nanoliquid chromatography coupled with label free quantitative mass spectrometry. A total of 2,757 proteins were identified, of which 1,950 were quantitatively analyzed. Principal component analysis of data showed a clear separation of embryo pools according to their developmental stage. The hierarchical clustering of differentially abundant proteins evidenced a first cluster of 626 proteins that increased in abundance during development and a second cluster of 400 proteins that decreased in abundance during development, with most significant changes at the time of EGA and blastocyst formation. The main pathways and processes overrepresented among upregulated proteins were RNA metabolism, protein translation and ribosome biogenesis, whereas Golgi vesicle transport and protein processing in endoplasmic reticulum were overrepresented among downregulated proteins. The pairwise comparison between stages allowed us to identify specific protein interaction networks and metabolic pathways at the time of EGA, morula compaction and blastocyst formation. This is the first comprehensive study of proteome dynamics in non-rodent mammalian embryos developed in vivo. These data provide a number of protein candidates that will be useful for further mechanistic and functional studies.

Bonded cumomer analysis of tumor metabolism based on 13 C magnetic resonance spectroscopy.

Bonded cumomers are sets of isotopomers of 13 C-labeled metabolites containing a particular sequence of contiguously or singly labeled carbon atoms. Only these isotopomers contribute to multiplet structure in the 13 C NMR spectrum. We discuss the application of this technique to the study of quantitative tumor metabolism, bioenergetics, and the Warburg effect. The advantages and sensitivity of bonded cumomer analysis over positional enrichment analysis are discussed. When sensitivity requirements are met, bonded cumomer analysis enables the extraction of fluxes through specific metabolic pathways with higher precision. In conjunction with isotopomer control analysis, we evaluate the sensitivity of experimentally measurable metabolite multiplets to determine the robustness of flux analysis in 13 C spectra of tumors. This review examines the role of glycolytic and tricarboxylic acid cycle metabolism with special emphasis on flux through the pentose phosphate pathway (PPP). The impact of reversibility of the nonoxidative branch of the PPP with various 13 C glucose tracers on fine-structure multiplets is analyzed.

Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy.

Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has led to unprecedented responses in patients with high-risk hematologic malignancies. However, up to 60% of patients still experience disease relapse and up to 80% of patients experience CAR-mediated toxicities, such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. We investigated the role of the intestinal microbiome on these outcomes in a multicenter study of patients with B cell lymphoma and leukemia. We found in a retrospective cohort (n = 228) that exposure to antibiotics, in particular piperacillin/tazobactam, meropenem and imipenem/cilastatin (P-I-M), in the 4 weeks before therapy was associated with worse survival and increased neurotoxicity. In stool samples from a prospective cohort of CAR T cell recipients (n = 48), the fecal microbiome was altered at baseline compared to healthy controls. Stool sample profiling by 16S ribosomal RNA and metagenomic shotgun sequencing revealed that clinical outcomes were associated with differences in specific bacterial taxa and metabolic pathways. Through both untargeted and hypothesis-driven analysis of 16S sequencing data, we identified species within the class Clostridia that were associated with day 100 complete response. We concluded that changes in the intestinal microbiome are associated with clinical outcomes after anti-CD19 CAR T cell therapy in patients with B cell malignancies.

Inborn errors of metabolism and their impact in paediatric dentistry.

The management of paediatric patients with inborn errors of metabolism (IEM) presents an unparalleled challenge for paediatric dentists owing to the multiplex of interrelated dental manifestations and metabolic management necessitating modifications to dental care. Inborn errors of metabolism describe a largely heterogenous group of genetic disorders namely attributable to a single gene defect essential for a specific metabolic pathway. Approximately 400 disorders have been described with an overall incidence of 1 in 5000 live births worldwide. Clinical presentation is classically inconspicuous and insidious in the neonatal period with pathophysiology attributable to accumulation of toxic by-products which interfere with normal function, or insufficient synthesis of essential compounds. This paper aims to discuss the primary oral and maxillofacial manifestations across the scope of inborn errors of metabolism, whilst also considering how metabolic treatment has the propensity to complicate dental management.

Modifying Anthocyanins Biosynthesis in Tomato Hairy Roots: A Test Bed for Plant Resistance to Ionizing Radiation and Antioxidant Properties in Space.

Gene expression manipulation of specific metabolic pathways can be used to obtain bioaccumulation of valuable molecules and desired quality traits in plants. A single-gene approach to impact different traits would be greatly desirable in agrospace applications, where several aspects of plant physiology can be affected, influencing growth. In this work, MicroTom hairy root cultures expressing a MYB-like transcription factor that regulates the biosynthesis of anthocyanins in Petunia hybrida (PhAN4), were considered as a testbed for bio-fortified tomato whole plants aimed at agrospace applications. Ectopic expression of PhAN4 promoted biosynthesis of anthocyanins, allowing to profile 5 major derivatives of delphinidin and petunidin together with pelargonidin and malvidin-based anthocyanins, unusual in tomato. Consistent with PhAN4 features, transcriptomic profiling indicated upregulation of genes correlated to anthocyanin biosynthesis. Interestingly, a transcriptome reprogramming oriented to positive regulation of cell response to biotic, abiotic, and redox stimuli was evidenced. PhAN4 hairy root cultures showed the significant capability to counteract reactive oxygen species (ROS) accumulation and protein misfolding upon high-dose gamma irradiation, which is among the most potent pro-oxidant stress that can be encountered in space. These results may have significance in the engineering of whole tomato plants that can benefit space agriculture.