Broad-spectrum stress tolerance conferred by suppressing jasmonate signaling attenuation in Arabidopsis JASMONIC ACID OXIDASE mutants.

Jasmonate signaling for adaptative or developmental responses generally relies on an increased synthesis of the bioactive hormone jasmonoyl-isoleucine (JA-Ile), triggered by environmental or internal cues. JA-Ile is embedded in a complex metabolic network whose upstream and downstream components strongly contribute to hormone homeostasis and activity. We previously showed that JAO2, an isoform of four Arabidopsis JASMONIC ACID OXIDASES, diverts the precursor jasmonic acid (JA) to its hydroxylated form HO-JA to attenuate JA-Ile formation and signaling. Consequently, JAO2-deficient lines have elevated defenses and display improved tolerance to biotic stress. Here we further explored the organization and regulatory functions of the JAO pathway. Suppression of JAO2 enhances the basal expression of nearly 400 JA-regulated genes in unstimulated leaves, many of which being related to biotic and abiotic stress responses. Consistently, non-targeted metabolomic analysis revealed the constitutive accumulation of several classes of defensive compounds in jao2-1 mutant, including indole glucosinolates and breakdown products. The most differential compounds were agmatine phenolamides, but their genetic suppression did not alleviate the strong resistance of jao2-1 to Botrytis infection. Furthermore, jao2 alleles and a triple jao mutant exhibit elevated survival capacity upon severe drought stress. This latter phenotype occurs without recruiting stronger abscisic acid responses, but relies on enhanced JA-Ile signaling directing a distinct survival pathway with MYB47 transcription factor as a candidate mediator. Our findings reveal the selected spectrum of JA responses controlled by the JAO2 regulatory node and highlight the potential of modulating basal JA turnover to pre-activate mild transcriptional programs for multiple stress resilience.

Mechanistic insights into sulfur source-driven physiological responses and metabolic reorganization in the fuel-biodesulfurizing Rhodococcus qingshengii IGTS8.

Comparative proteomics and untargeted metabolomics were combined to study the physiological and metabolic adaptations of Rhodococcus qingshengii IGTS8 under biodesulfurization conditions. After growth in a chemically defined medium with either dibenzothiophene (DBT) or MgSO4 as the sulfur source, many differentially produced proteins and metabolites associated with several metabolic and physiological processes were detected including the metabolism of carbohydrates, amino acids, lipids, nucleotides, vitamins, protein synthesis, transcriptional regulation, cell envelope biogenesis, and cell division. Increased production of the redox cofactor mycofactocin and associated proteins was one of the most striking adaptations under biodesulfurization conditions. While most central metabolic enzymes were less abundant in the presence of DBT, a key enzyme of the glyoxylate shunt, isocitrate lyase, was up to 26-fold more abundant. Several C1 metabolism and oligotrophy-related enzymes were significantly more abundant in the biodesulfurizing culture. R. qingshengii IGTS8 exhibited oligotrophic growth in liquid and solid media under carbon starvation. Moreover, the oligotrophic growth was faster on the solid medium in the presence of DBT compared to MgSO4 cultures. In the DBT culture, the cell envelope and phospholipids were remodeled, with lower levels of phosphatidylethanolamine and unsaturated and short-chain fatty acids being the most prominent changes. Biodesulfurization increased the biosynthesis of osmoprotectants (ectoine and mannosylglycerate) as well as glutamate and induced the stringent response. Our findings reveal highly diverse and overlapping stress responses that could protect the biodesulfurizing culture not only from the associated sulfate limitation but also from chemical, oxidative, and osmotic stress, allowing efficient resource management. IMPORTANCE Despite decades of research, a commercially viable bioprocess for fuel desulfurization has not been developed yet. This is mainly due to lack of knowledge of the physiology and metabolism of fuel-biodesulfurizing bacteria. Being a stressful condition, biodesulfurization could provoke several stress responses that are not understood. This is particularly important because a thorough understanding of the microbial stress response is essential for the development of environmentally friendly and industrially efficient microbial biocatalysts. Our comparative systems biology studies provide a mechanistic understanding of the biology of biodesulfurization, which is crucial for informed developments through the rational design of recombinant biodesulfurizers and optimization of the bioprocess conditions. Our findings enhance the understanding of the physiology, metabolism, and stress response not only in biodesulfurizing bacteria but also in rhodococci, a precious group of biotechnologically important bacteria.

Lysine 27 of histone H3.3 is a fine modulator of developmental gene expression and stands as an epigenetic checkpoint for lignin biosynthesis in Arabidopsis.

Chromatin is a dynamic platform within which gene expression is controlled by epigenetic modifications, notably targeting amino acid residues of histone H3. Among them is lysine 27 of H3 (H3K27), the trimethylation of which by the Polycomb Repressive Complex 2 (PRC2) is instrumental in regulating spatiotemporal patterns of key developmental genes. H3K27 is also subjected to acetylation and is found at sites of active transcription. Most information on the function of histone residues and their associated modifications in plants was obtained from studies of loss-of-function mutants for the complexes that modify them. To decrypt the genuine function of H3K27, we expressed a non-modifiable variant of H3 at residue K27 (H3.3K27A ) in Arabidopsis, and developed a multi-scale approach combining in-depth phenotypical and cytological analyses, with transcriptomics and metabolomics. We uncovered that the H3.3K27A variant causes severe developmental defects, part of them are reminiscent of PRC2 mutants, part of them are new. They include early flowering, increased callus formation and short stems with thicker xylem cell layer. This latest phenotype correlates with mis-regulation of phenylpropanoid biosynthesis. Overall, our results reveal novel roles of H3K27 in plant cell fates and metabolic pathways, and highlight an epigenetic control point for elongation and lignin composition of the stem.

Comparison of nocturnal and diurnal metabolomes of rose flowers and leaves.

INTRODUCTION: Roses are one of the most essential ornamental flowers and are commonly used in perfumery, cosmetics, and food. They are rich in bioactive compounds, which are of interest for therapeutic effects. OBJECTIVES: The objective of this study was to understand the kinds of changes that occur between the nocturnal and diurnal metabolism of rose and to suggest hypotheses. METHODS: Reversed-phase ultrahigh-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry or triple quadrupole mass spectrometry (TQ MS/MS) was used for nontargeted metabolomics and hormonal profiling respectively. For metabolite annotation, accurate mass spectra were compared with those in databases. RESULTS: The hormonal profile of flowers showed an increase in jasmonate at night, while that of leaves indicated an increase in the salicylic acid pathway. Nontargeted analyses of the flower revealed a switch in the plant's defense mechanisms from glycosylated metabolites during the day to acid metabolites at night. In leaves, a significant decrease in flavonoids was observed at night in favor of acid metabolism to maintain a level of protection. Moreover, it might be possible to place back some of the annotated molecules on the shikimate pathway. CONCLUSION: The influence of day and night on the metabolome of rose flowers and leaves has been clearly demonstrated. The hormonal modulations occurring during the night and at day are consistent with the plant circadian cycle. A proposed management of the sesquiterpenoid and triterpenoid biosynthetic pathway may explain these changes in the flower. In leaves, the metabolic differences may reflect night-time regulation in favor of the salicylic acid pathway.

Comparative patterns of modified nucleotides in individual tRNA species from a mesophilic and two thermophilic archaea.

To improve and complete our knowledge of archaeal tRNA modification patterns, we have identified and compared the modification pattern (type and location) in tRNAs of three very different archaeal species, Methanococcus maripaludis (a mesophilic methanogen), Pyrococcus furiosus (a hyperthermophile thermococcale), and Sulfolobus acidocaldarius (an acidophilic thermophilic sulfolobale). Most abundant isoacceptor tRNAs (79 in total) for each of the 20 amino acids were isolated by two-dimensional gel electrophoresis followed by in-gel RNase digestions. The resulting oligonucleotide fragments were separated by nanoLC and their nucleotide content analyzed by mass spectrometry (MS/MS). Analysis of total modified nucleosides obtained from complete digestion of bulk tRNAs was also performed. Distinct base- and/or ribose-methylations, cytidine acetylations, and thiolated pyrimidines were identified, some at new positions in tRNAs. Novel, some tentatively identified, modifications were also found. The least diversified modification landscape is observed in the mesophilic Methanococcus maripaludis and the most complex one in Sulfolobus acidocaldarius Notable observations are the frequent occurrence of ac4C nucleotides in thermophilic archaeal tRNAs, the presence of m7G at positions 1 and 10 in Pyrococcus furiosus tRNAs, and the use of wyosine derivatives at position 37 of tRNAs, especially those decoding U1- and C1-starting codons. These results complete those already obtained by others with sets of archaeal tRNAs from Methanocaldococcus jannaschii and Haloferax volcanii.

Synthesis of Non-natural Aza-Iridoids via Ynamides and Molecular Networking-Based Tracing of Their In Planta Bioconversion.

A synthesis of new-to-nature aza-iridoids via ynamides is presented. ZrCl4 proved to be the best acid to perform this transformation. Various ynamides were accommodated, and seco-iridoids could be obtained as well. Aza-iridoids were infiltrated into leaves of Scrophularia Nodosa, an iridoid-producing plant species. High-resolution mass spectrometry coupled to computational metabolomic approaches was employed for the detection of aza-iridoid bioconversion products.

Eusociality is linked to caste-specific differences in metabolism, immune system, and somatic maintenance-related processes in an ant species.

The social organization of many primate, bird and rodent species and the role of individuals within that organization are associated with specific individual physiological traits. However, this association is perhaps most pronounced in eusocial insects (e.g., termites, ants). In such species, genetically close individuals show significant differences in behavior, physiology, and life expectancy. Studies addressing the metabolic changes according to the social role are still lacking. We aimed at understanding how sociality could influence essential molecular processes in a eusocial insect, the black garden ant (Lasius niger) where queens can live up to ten times longer than workers. Using mass spectrometry-based analysis, we explored the whole metabolome of queens, nest-workers and foraging workers. A former proteomics study done in the same species allowed us to compare the findings of both approaches. Confirming the former results at the proteome level, we showed that queens had fewer metabolites related to immunity. Contrary to our predictions, we did not find any metabolite linked to reproduction in queens. Among the workers, foragers had a metabolic signature reflecting a more stressful environment and a more highly stimulated immune system. We also found that nest-workers had more digestion-related metabolites. Hence, we showed that specific metabolic signatures match specific social roles. Besides, we identified metabolites differently expressed among behavioral castes and involved in nutrient sensing and longevity pathways (e.g., sirtuins, FOXO). The links between such molecular pathways and aging being found in an increasing number of taxa, our results confirm and strengthen their potential universality.

The Arabidopsis thaliana-Streptomyces Interaction Is Controlled by the Metabolic Status of the Holobiont.

How specific interactions between plant and pathogenic, commensal, or mutualistic microorganisms are mediated and how bacteria are selected by a plant are important questions to address. Here, an Arabidopsis thaliana mutant called chs5 partially deficient in the biogenesis of isoprenoid precursors was shown to extend its metabolic remodeling to phenylpropanoids and lipids in addition to carotenoids, chlorophylls, and terpenoids. Such a metabolic profile was concomitant to increased colonization of the phyllosphere by the pathogenic strain Pseudomonas syringae pv. tomato DC3000. A thorough microbiome analysis by 16S sequencing revealed that Streptomyces had a reduced colonization potential in chs5. This study revealed that the bacteria-Arabidopsis interaction implies molecular processes impaired in the chs5 mutant. Interestingly, our results revealed that the metabolic status of A. thaliana was crucial for the specific recruitment of Streptomyces into the microbiota. More generally, this study highlights specific as well as complex molecular interactions that shape the plant microbiota.

Innate promiscuity of the CYP706 family of P450 enzymes provides a suitable context for the evolution of dinitroaniline resistance in weed.

Increased metabolism is one of the main causes for evolution of herbicide resistance in weeds, a major challenge for sustainable food production. The molecular drivers of this evolution are poorly understood. We tested here the hypothesis that a suitable context for the emergence of herbicide resistance could be provided by plant enzymes with high innate promiscuity with regard to their natural substrates. A selection of yeast-expressed plant cytochrome P450 enzymes with well documented narrow to broad promiscuity when metabolizing natural substrates was tested for herbicide metabolism competence. The positive candidate was assayed for capacity to confer herbicide tolerance in Arabidopsis thaliana. Our data demonstrate that Arabidopsis thaliana CYP706A3, with the most promiscuous activity on monoterpenes and sesquiterpenes for flower defence, can also oxidize plant microtubule assembly inhibitors, dinitroanilines. Ectopic overexpression of CYP706A3 confers dinitroaniline resistance. We show, in addition, that the capacity to metabolize dinitroanilines is shared by other members of the CYP706 family from plants as diverse as eucalyptus and cedar. Supported by three-dimensional (3D) modelling of CYP706A3, the properties of enzyme active site and substrate access channel are discussed together with the shared physicochemical properties of the natural and exogenous substrates to explain herbicide metabolism.

Acute-onset delirium in intensive care COVID patients: association of imperfect brain repair with foodborne micro-pollutants.

BACKGROUND AND PURPOSE: COVID-19 affects the brain in various ways, amongst which delirium is worrying. An assessment was made of whether a specific, long-lasting, COVID-19-related brain injury develops in acute respiratory distress syndrome patients after life-saving re-oxygenation. METHODS: Ten COVID+ patients (COVID+) with unusual delirium associated with neuroimaging suggestive of diffuse brain injury and seven controls with non-COVID encephalopathy were studied. The assessment took place when the intractable delirium started at weaning off ventilation support. Brain magnetic resonance imaging (MRI) was performed followed by standard cerebrospinal fluid (CSF) analyses and assessment of CSF erythropoietin concentrations (as a marker for the assessment of tissue repair), and of non-targeted CSF metabolomics using liquid chromatography high resolution mass spectrometry. RESULTS: Patients were similar as regards severity scores, but COVID+ were hospitalized longer (25 [11.75; 25] vs. 9 [4.5; 12.5] days, p = 0.03). On admission, but not at MRI and lumbar puncture performance, COVID+ were more hypoxic (p = 0.002). On MRI, there were leptomeningeal enhancement and diffuse white matter haemorrhages only in COVID+. In the latter, CSF erythropoietin concentration was lower (1.73 [1.6; 2.06] vs. 3.04 [2.9; 3.91] mIU/ml, p = 0.01), and CSF metabolomics indicated (a) increased compounds such as foodborne molecules (sesquiterpenes), molecules from industrialized beverages and micro-pollutants (diethanolamine); and (b) decreased molecules such as incomplete breakdown products of protein catabolism and foodborne molecules (glabridin). At 3-month discharge, fatigue, anxiety and depression as well as MRI lesions persisted in COVID+. CONCLUSIONS: Some COVID+ are at risk of a specific delirium. Imperfect brain repair after re-oxygenation and lifestyle factors might influence long-lasting brain injuries in a context of foodborne micro-pollutants.

Phase Transfer and Biodegradation of Pesticides in Water-Sediment Systems Explored by Compound-Specific Isotope Analysis and Conceptual Modeling.

Current approaches are often limited to evaluating the contribution of pesticide dissipation processes in water-sediment systems as both degradation and phase transfer, that is, sorption-desorption, contribute to the apparent decrease of pesticide concentration. Here, the dissipation of widely used herbicides acetochlor and S-metolachlor was examined in laboratory by water-sediment microcosm experiments under oxic and anoxic conditions. Compound-specific isotope analysis (CSIA) emphasized insignificant carbon isotope fractionation in the sediment, indicating prevailing pesticide degradation in the water phase. Conceptual modeling accounting for phase transfer and biodegradation indicated that biodegradation may be underestimated when phase transfer is not included. Phase transfer does not affect carbon isotope fractionation for a wide spectrum of molecules and environmental conditions, underscoring the potential of pesticide CSIA as a robust approach to evaluate degradation in water-sediment systems. CSIA coupled with the identification of transformation products by high-resolution tandem mass spectrometry suggests the degradation of acetochlor and S-metolachlor to occur via nucleophilic substitution and the predominance of oxalinic acids as transformation products under both anoxic and oxic conditions. Altogether, combining the pesticide CSIA, the identification of transformation products, and the use of conceptual phase-transfer models improves the interpretation of pesticide dissipation in water-sediment systems.

Is Hysteroscopy a Good Option to Manage Severe Cesarean Scar Defect?

STUDY OBJECTIVE: To compare the outcomes of hysteroscopic management in women with a severe or nonsevere symptomatic cesarean scar defect (residual myometrium ≤3-mm vs >3-mm, respectively). DESIGN: Retrospective cohort study. SETTING: Gynecology department of a teaching hospital. PATIENTS: Seventy-one women with an operative hysteroscopy for a symptomatic defect (49 with severe defects and 22 with nonsevere ones). INTERVENTIONS: Operative hysteroscopy for cesarean scar defect in women with a severe defect (residual myometrium ≤3-mm) and with nonsevere defect (residual myometrium >3-mm). MEASUREMENTS: The main objective was to compare success rates between the 2 groups. The secondary objectives were the comparisons of (1) the number of women who required more than 1 procedure, (2) the rate of complications, (3) the number of subsequent pregnancies, and (4) the evolution of residual myometrium thickness between the groups. MAIN RESULTS: The success rates were not significantly different between the groups (73.5% in the severe group and 63.6% in the nonsevere group [p = .40]). The number of women requiring more than 1 procedure was also similar, as were the rate of complications and the mean increase of myometrium thickness. The rate of subsequent pregnancies in women who were infertile was significantly higher in women with a severe defect (p = .04). CONCLUSION: The hysteroscopic approach seems to be a good way to manage cesarean scar defects even when the residual myometrium is thin. A prospective study is, however, necessary to confirm these findings.

Environmental exposure to phthalates and dementia with Lewy bodies: contribution of metabolomics.

BACKGROUND: In neurodegenerative diseases, alongside genetic factors, the possible intervention of environmental factors in the pathogenesis is increasingly being considered. In particular, recent evidence suggests the intervention of a pesticide-like xenobiotic in the initiation of disease with Lewy bodies (DLB). OBJECTIVES: To test for the presence of pesticides or other xenobiotics in the cerebrospinal fluid (CSF) of patients with DLB. METHODS: A total of 45 patients were included in this study: 16 patients with DLB at the prodromal stage, 8 patients with DLB at the demented stage, 8 patients with Alzheimer's disease (AD) at the prodromal stage and 13 patients with AD at the demented stage. CSF was obtained by lumbar puncture and analysed by liquid chromatography-mass spectrometry. RESULTS: Among the compounds detected in greater abundance in the CSF of patients with DLB compared with patients with AD, only one had a xenobiotic profile potentially related to the pathophysiology of DLB. After normalisation and scaling, bis(2-ethylhexyl) phthalate was more abundant in the CSF of patients with DLB (whole cohort: 2.7-fold abundant in DLB, p=0.031; patients with dementia: 3.8-fold abundant in DLB, p=0.001). CONCLUSIONS: This study is the first reported presence of a phthalate in the CSF of patients with DLB. This molecule, which is widely distributed in the environment and enters the body orally, nasally and transdermally, was first introduced in the 1920s as a plasticizer. Thereafter, the first cases of DLB were described in the 1960s and 1970s. These observations suggest that phthalates may be involved in the pathophysiology of DLB.

Comparison of stimulated versus modified natural cycles for endometrial preparation prior to frozen embryo transfer: a randomized controlled trial.

RESEARCH QUESTION: To compare stimulated cycle (STC) versus modified natural cycle (MNC) for endometrial preparation prior to frozen embryo transfer (FET) in terms of convenience and efficacy. DESIGN: Prospective, open-label, randomized controlled study including 119 patients aged 20-38 years, undergoing intra-conjugal IVF/intracytoplasmic sperm injection, having regular cycles, at least two day 2 or day 3 frozen embryos, for whom it was the first or second FET performed, randomized to either MNC (n = 59) or STC (n = 60). Monitoring consisted of ultrasound and hormonal measurements. The number of monitoring visits required was compared between the two groups. RESULTS: STC required a significantly lower number of monitoring visits compared with MNC (3.6 ± 0.9 versus 4.4 ± 1.1, respectively, P < 0.0001), a lower number of blood tests (2.7 ± 0.8 versus 3.5 ± 1.0, respectively, P < 0.0001) and of ultrasounds (1.2 ± 0.4 versus 1.5 ± 0.6, respectively, P = 0.0039). FET during 'non-opening' hours (22.6% versus 27.5%, respectively, P = 0.32) and cancellation rates (11.7% versus 11.9%, respectively, P = 0.97) were comparable between the STC and MNC groups. No difference concerning HCG-positive rates (34.0% versus 23.1%, respectively, P = 0.22) nor live birth rates (24.5% for STC versus 23.1% for MNC, respectively, P = 0.86) was observed. Quality of life as defined by the FertiQol score was not different (P > 0.05 for each item). CONCLUSION: Altogether, these findings can be used for everyday clinical practice to better inform patients when deciding on the protocol to use for FET. These results suggest that MNC is a good option for patients reluctant to have injections, but requires increased monitoring. STC may offer more flexibility for patients and IVF centres.

Xenobiotics metabolization in Salix alba leaves uncovered by mass spectrometry imaging.

INTRODUCTION: Micropollutants are increasingly monitored as their presence in the environment is rising due to human activities, and they are potential threats to living organisms. OBJECTIVES: This study aimed at understanding the role of plants in xenobiotics removal from polluted environments by following xenobiotics metabolism in leaf tissues. METHODS: Different classes of micropollutants were investigated using liquid chromatography (LC) coupled to quadrupole-time of flight (Q-TOF) high resolution mass spectrometry (HRMS). The tissue localization of xenobiotics in the leaves of a spontaneous (not planted by humans) Salix alba growing near the water flux was further investigated using matrix-assisted laser desorption ionization (MALDI) mass spectrometry imaging (MSI). RESULTS: The LC-Q-TOF analysis revealed the distribution of micropollutants in three different compartments of a tertiary treatment wetland. When further investing the metabolic profile of S. alba leaves using MSI, different distribution patterns were observed in specific leaf tissues. Xenobiotic metabolites were predicted and could also be tentatively identified in S. alba leaves, shedding new light on the metabolic processes at play in leaves to manage xenobiotics uptake from a polluted environment. CONCLUSION: Using complementary metabolomics approaches, this study performed a large-scale exploration of micropollutants spreading in the environment at the exit of a tertiary treatment wetland. The use of MSI coupled with the prediction of xenobiotic metabolites yielded novel insights into plant metabolism during chronical exposure to low doses of a mixture of micropollutants.

Influence of a change in activity regime on femoral bone architecture and failure behaviour.

The incidence and morbidity of femoral fractures increases drastically with age. Femoral architecture and associated fracture risk are strongly influenced by loading during physical activities and it has been shown that the rate of loss of bone mineral density is significantly lower for active individuals than inactive. The objective of this work is to evaluate the impact of a cessation of some physical activities on elderly femoral structure and fracture behaviour. The authors previously established a biofidelic finite element model of the femur considered as a structure optimised to loading associated with daily activities. The same structural optimisation algorithm was used here to quantify the changes in bone architecture following cessation of stair climbing and sit-to-stand. Side fall fracture simulations were run on the adapted bone structures using a damage elasticity formulation. Total cortical and trabecular bone volume and failure load reduced in all cases of activity cessation. Bone loss distribution was strongly heterogeneous, with some locations even showing increased bone volume. This work suggests that maintaining the physical activities involved in the daily routine of a young healthy adult would help reduce the risk of femoral fracture in the elderly population by preventing bone loss.

Ultrasonic elastography for the prevention of breast implant rupture: Detection of an increase with stiffness over implantation time.

Breast implants are widely used after breast cancer resection and must be changed regularly to avoid a rupture. To date, there are no quantitative criteria to help this decision. The mechanical evolution of the gels and membranes of the implants is still underinvestigated, although it can lead to early rupture. In this study, 35 breast explants having been implanted in patients for up to 17 years were characterized by ex vivo measurements of their mechanical properties. Using Acoustic Radiation Force Impulse (ARFI) ultrasound elastography, an imaging method for non-destructive mechanical characterization, an increase in the stiffness of the explants has been observed. This increase was correlated with the implantation duration, primarily after 8 years of implantation. With an increase of the shear modulus of up to a factor of nearly 3, the loss of flexibility of the implants is likely to lead to a significant increase of their risk of rupture. A complementary analysis of the gel from the explants by mass spectrometry imaging (MSI) and liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) confirms the presence of metabolites of cholesterol originating from the breast tissues, which most likely crossed the membrane of the implants and most likely degrades the gel. By observing the consequences of the physical-chemical mechanisms at work within patients, this study shows that ultrasound elastography could be used in vivoas a quantitative indicator of the risk of breast implant rupture and help diagnose their replacement.

Should personalised dosing have a role in cancer treatment?

Almost all pharmaceutical products are approved on the basis of their effect in patients representing the "average" of the population studied in registrational trials, with most drug labels allowing, at most, for empirical dose reduction in the case of toxicity. In this perspective article we explore some of the evidence that supports the use of personalised dosing in cancer treatment and show how we have been able to build on existing models linking dose, exposure and toxicity to demonstrate how dose optimisation, including increasing the dose, has the potential to significantly improve efficacy outcomes. We also explore, through the lens of our own experience of developing a personalised dosing platform, some of the hurdles that stand in the way of implementing a personalised approach to dosing in real world settings. In particular, our experience is illustrated by the application of a dosing platform for docetaxel treatment in prostate cancer.

Evolutionary metabolomics of specialized metabolism diversification in the genus Nicotiana highlights N-acylnornicotine innovations.

Specialized metabolite (SM) diversification is a core process to plants' adaptation to diverse ecological niches. Here, we implemented a computational mass spectrometry-based metabolomics approach to exploring SM diversification in tissues of 20 species covering Nicotiana phylogenetics sections. To markedly increase metabolite annotation, we created a large in silico fragmentation database, comprising >1 million structures, and scripts for connecting class prediction to consensus substructures. Together, the approach provides an unprecedented cartography of SM diversity and section-specific innovations in this genus. As a case study and in combination with nuclear magnetic resonance and mass spectrometry imaging, we explored the distribution of N-acylnornicotines, alkaloids predicted to be specific to Repandae allopolyploids, and revealed their prevalence in the genus, albeit at much lower magnitude, as well as a greater structural diversity than previously thought. Together, the data integration approaches provided here should act as a resource for future research in plant SM evolution.

Mass spectrometry imaging for biosolids characterization to assess ecological or health risks before reuse.

Biosolids are byproducts of wastewater treatment. With the increasing global population, the amounts of wastewater to be treated are expanding, along with the amounts of biosolids generated. The reuse of biosolids is now accepted for diversified applications in fields such as agriculture, engineering, agro-forestry. However, biosolids are known to be potential carriers of compounds that can be toxic to living beings or alter the environment. Therefore, biosolid reuse is subject to regulations, mandatory analyses are performed on heavy metals, persistent organic pollutants or pathogens. Conventional methods for the analysis of heavy metals and persistent organic pollutants are demanding, lengthy, and sometimes unsafe. Here, we propose mass spectrometry imaging as a faster and safer method using small amounts of material to monitor heavy metals and persistent organic pollutants in different types of biosolids, allowing for ecological and health risk assessment before reuse. Our methodology can be extended to other soil-like matrices.