Metabolic origins of spatial organization in the tumor microenvironment.

The genetic and phenotypic diversity of cells within tumors is a major obstacle for cancer treatment. Because of the stochastic nature of genetic alterations, this intratumoral heterogeneity is often viewed as chaotic. Here we show that the altered metabolism of cancer cells creates predictable gradients of extracellular metabolites that orchestrate the phenotypic diversity of cells in the tumor microenvironment. Combining experiments and mathematical modeling, we show that metabolites consumed and secreted within the tumor microenvironment induce tumor-associated macrophages (TAMs) to differentiate into distinct subpopulations according to local levels of ischemia and their position relative to the vasculature. TAMs integrate levels of hypoxia and lactate into progressive activation of MAPK signaling that induce predictable spatial patterns of gene expression, such as stripes of macrophages expressing arginase 1 (ARG1) and mannose receptor, C type 1 (MRC1). These phenotypic changes are functionally relevant as ischemic macrophages triggered tube-like morphogenesis in neighboring endothelial cells that could restore blood perfusion in nutrient-deprived regions where angiogenic resources are most needed. We propose that gradients of extracellular metabolites act as tumor morphogens that impose order within the microenvironment, much like signaling molecules convey positional information to organize embryonic tissues. Unearthing embryology-like processes in tumors may allow us to control organ-like tumor features such as tissue repair and revascularization and treat intratumoral heterogeneity

The effects of long-term fertilizations on soil hydraulic properties vary with scales

Soil structural alterations instigated by cropping system conversion and fertilization change have been well documented, but how such alterations vary with scale remains elusive. We investigated this based on the Rothamsted long-term wheat experiment (since 1843) in the UK. Triplicate cores 7cm high and 10cm in diameter were taken from plots that have been under different fertilizations and returned to natural woodland for more than one century for imaging with X-ray computed tomography at resolution of 40µm. We then broke each core and sampled three aggregates from it to scan them at resolution of 1.5µm. For each core or aggregate sample, we calculated its pore size distribution, as well as permeability and tortuosity from pore-scale simulations. The results showed that the fertilization change more than 170 years ago reshaped the soil structure but differently between the core scale and aggregate scale. Macro-porosity of the pores (>40µm) in the cores unfertilized or fertilized with inorganic fertilizers were low and poorly connected in the top 10cm of soil, compared to the cores given farmyard manure or in the woodland. In all treatments, the large macropores in the cores were hydraulically anisotropic with their permeability being higher in the horizontal direction than in the vertical direction, whereas the aggregates were comparatively isotropic. The fertilization affected porosity and permeability of macropores at core scale more significantly than those at aggregate scale, and the aggregates fertilized with farmyard manure and in the woodland were more permeable than aggregates in other treatments. It is also found that, compared to no-fertilization or fertilization with complete fertilizers, fertilizing without phosphorus over the past 20 years increased the porosity and permeability of the aggregates but not of the cores. Fertilization with inorganic fertilizers increased tortuosity of the macropores in the cores but not of the intra-aggregates micropores, compared to no-fertilization. Porosity-permeability relationship for aggregates unfertilized or fertilized with inorganic fertilisers follows a power law with R2 > 0.8. In contrast, the permeability of aggregates in farmyard manure and in the woodland trended differently with the porosity. Aggregates and cores responded differently to carbon in that, with soil carbon increasing, the permeability of the aggregates increased asymptotically while the permeability of the cores increased approximately exponentially. Since soil structure is indicators of soil quality and evolves slowly, our results have important implications for understanding how agronomical practice changes reshape soil structure at different scales as well as the long-term consequence for hydrological and biochemical processes

Using a Crop Model to Benchmark Miscanthus and Switchgrass

Crop yields are important items in the economic performance and the environmental impacts of second-generation biofuels. Since they strongly depend on crop management and pedoclimatic conditions, it is important to compare candidate feedstocks to select the most appropriate crops in a given context. Agro-ecosystem models offer a prime route to benchmark crops, but have been little tested from this perspective thus far. Here, we tested whether an agro-ecosystem model (CERES-EGC) was specific enough to capture the differences between miscanthus and switchgrass in northern Europe. The model was compared to field observations obtained in seven long-term trials in France and the UK, involving different fertilizer input rates and harvesting dates. At the calibration site (Estrées-Mons), the mean deviations between simulated and observed crop biomass yields for miscanthus varied between −0.3 t DM ha−1 and 4.2 t DM ha−1. For switchgrass, simulated yields were within 1.0 t DM ha−1 of the experimental data. Observed miscanthus yields were higher than switchgrass yields in most sites and for all treatments, with one exception. Overall, the model captured the differences between both crops adequately, with a mean deviation of 0.46 t DM ha−1, and could be used to guide feedstock selections over larger biomass supply areas

Utility of pharmacogenetic testing to optimise antidepressant pharmacotherapy in youth: a narrative literature review

Pharmacogenetics (PGx) is the study and application of how interindividual differences in our genomes can influence drug responses. By evaluating individuals’ genetic variability in genes related to drug metabolism, PGx testing has the capabilities to individualise primary care and build a safer drug prescription model than the current “one-size-fits-all” approach. In particular, the use of PGx testing in psychiatry has shown promising evidence in improving drug efficacy as well as reducing toxicity and adverse drug reactions. Despite randomised controlled trials demonstrating an evidence base for its use, there are still numerous barriers impeding its implementation. This review paper will discuss the management of mental health conditions with PGx-guided treatment with a strong focus on youth mental illness. PGx testing in clinical practice, the concerns for its implementation in youth psychiatry, and some of the barriers inhibiting its integration in clinical healthcare will also be discussed. Overall, this paper provides a comprehensive review of the current state of knowledge and application for PGx in psychiatry and summarises the capabilities of genetic information to personalising medicine for the treatment of mental ill-health in youth

Phylogeny of Lithobiidae Newport, 1844, with emphasis on the megadiverse genus Lithobius Leach, 1814 (Myriapoda, Chilopoda)

Abstract Phylogenetic analyses based on molecular and morphological data were conducted to shed light on relationships within the mostly Palaearctic/Oriental centipede family Lithobiidae, with a particular focus on the Palaearctic genus Lithobius Leach, 1814 (Lithobiidae, Lithobiomorpha), which contains >500 species and subspecies. Previous studies based on morphological data resolved Lithobius as nonmonophyletic, but molecular-based phylogenetic analyses have until now sampled few species. To elucidate species inter-relationships of the genus, test the validity of its classification into subgenera, and infer its relationships with other Lithobiidae, we obtained molecular data (nuclear markers: 18S rRNA, 28S rRNA; mitochondrial markers: 16S rRNA, COI) and 61 morphological characters for 44 species of Lithobius representing four of its eight subgenera and nine other representatives of Lithobiidae. The data were analyzed phylogenetically using maximum-likelihood, parsimony and Bayesian inference. This study suggests that (i) a close relationship between L. giganteus and the pterygotergine Disphaerobius loricatus highlighted in recent morphological analyses is also strongly supported by molecular data, and Pterygoterginae is formally synonymized with Lithobiinae; (ii) the Oriental/Australian genus Australobius is consistently resolved as sister group to all other sampled Lithobiidae by the molecular and combined data; (iii) the subfamily Ethopolyinae may be paraphyletic; (iv) the genus Lithobius is nonmonophyletic; (v) the subgenera Lithobius, Sigibius and Monotarsobius are nonmonophyletic and should not be used in future taxonomic studies; and (vi) there are instances of cryptic species and cases in which subspecies should be elevated to full species status, as identified for some European taxa within Lithobius

Significant structural evolution of a long-term fallow soil in response to agricultural management practices requires at least 10 years after conversion at the aggregate level

Agricultural practices can have significant effects on the physical and biological properties of soil. The aim of this study was to understand how the physical structure of a compromised soil, arising from long-term bare-fallow management, was modified by adopting different field management practices. We hypothesised that changing agricultural practice from bare-fallow to arable or grassland would influence the modification of pore structure via an increase in porosity, pore connectivity, and a more homogenous distribution of pore sizes; and that this change exerts a rapid development of soil structure following conversion. Soil aggregates (< 2 mm) collected in successive years from field plots subjected to three contrasting managements were studied; viz. bare-fallow, bare-fallow converted to arable, and bare-fallow converted to grassland. Soil structure was assessed by X-ray Computed Tomography on the aggregates at 1.5 µm resolution, capturing detail relevant to soil biophysical processes. The grassland system increased porosity, diversity of pore sizes, pore-connectivity and pore-surface density significantly over the decade following conversion. However, measured at this resolution, the development of most of these metrics of soil structure required approximately 10 years post-conversion to show a significant effect. The arable system did not influence soil structural development significantly. Only the pore size distribution was modified in grassland in a shorter time frame (2 years post-conversion). Hence development of the soil structural characteristics appears to require at least a decadal timescale following conversion to grassland

Effects of cropping systems upon the three-dimensional architecture of soil systems are modulated by texture

Soil delivers fundamental ecosystem functions via interactions between physical and biological processes mediated by soil structure. The structure of soil is also dynamic and modified by natural factors and management intervention. The aim of this study was to investigate the effects of different cropping systems on soil structure at contrasting spatial scales. Three systems were studied in replicated plot field experiments involving varying degrees of plant-derived inputs to the soil, viz. perennial (grassland), annual (arable), and no-plant control (bare fallow), associated with two contrasting soil textures (clayey and sandy). We hypothesized the presence of plants results in a greater range (diversity) of pore sizes and that perennial cropping systems invoke greater structural heterogeneity. Accordingly, the nature of the pore systems was visualised and quantified in 3D by X-ray Computed Tomography at the mm and μm scale. Plants did not affect the porosity of clay soil at the mm scale, but at the μm scale, annual and perennial plant cover resulted in significantly increased porosity, a wider range of pore sizes and greater connectivity compared to bare fallow soil. However, the opposite occurred in the sandy soil, where plants decreased the porosity and pore connectivity at the mm scale but had no significant structural effect at the μm scale. These data reveal profound effects of different agricultural management systems upon soil structural modification, which are strongly modulated by the extent of plant presence and also contingent on the inherent texture of the soil

Macrophage Ontogeny Underlies Differences in Tumor-Specific Education in Brain Malignancies.

Extensive transcriptional and ontogenetic diversity exists among normal tissue-resident macrophages, with unique transcriptional profiles endowing the cells with tissue-specific functions. However, it is unknown whether the origins of different macrophage populations affect their roles in malignancy. Given potential artifacts associated with irradiation-based lineage tracing, it remains unclear if bone-marrow-derived macrophages (BMDMs) are present in tumors of the brain, a tissue with no homeostatic involvement of BMDMs. Here, we employed multiple models of murine brain malignancy and genetic lineage tracing to demonstrate that BMDMs are abundant in primary and metastatic brain tumors. Our data indicate that distinct transcriptional networks in brain-resident microglia and recruited BMDMs are associated with tumor-mediated education yet are also influenced by chromatin landscapes established before tumor initiation. Furthermore, we demonstrate that microglia specifically repress Itga4 (CD49D), enabling its utility as a discriminatory marker between microglia and BMDMs in primary and metastatic disease in mouse and human

Altered gut microbiome in Parkinson\u27s disease and the influence of lipopolysaccharide in a human α-synuclein over-expressing mouse model

The interaction between the gut microbiota and alpha-synuclein (αSyn) aggregation in Parkinson’s disease (PD) is receiving increasing attention. The objective of this study was to investigate gut microbiota, and effects of an inflammatory lipopolysaccharide (LPS) trigger in a human αSyn over-expressing mouse model of PD (Thy1-αSyn). Stool samples from patients with confirmed PD and Thy1-αSyn mice were analyzed using 16S ribosomal RNA sequencing. Compared to healthy controls, the relative abundance of mucin-degrading Verrucomicrobiae and LPS-producing Gammaproteobacteria were greater in PD patients. In mice, the abundance of Gammaproteobacteria was negligible in both Thy1-αSyn and wild-type (WT) animals, while Verrucomicrobiae were reduced in Thy1-αSyn mice. The effect of LPS on intestinal barrier function was investigated in vitro using intestinal epithelial (IEC-6) cells, and in vivo via administration of LPS in drinking water to Thy1-αSyn mice. Acute exposure to LPS in vitro resulted in a reduction and altered distribution of the tight junction markers ZO-1 and e-Cadherin around the cell membrane in IEC-6 cells, as shown by immunohistochemistry. LPS administration in Thy1-αSyn mice resulted in the emergence of early motor manifestations at 10 weeks, compared to untreated mice who were still asymptomatic at this age. This study reaffirms that an altered microbiome exists in patients with PD, and supports the notion of a proinflammatory gut microbiome environment as a trigger for PD pathogenesis

Health promoting potential of herbal teas and tinctures from Artemisia campestris subsp maritima: from traditional remedies to prospective products

This work explored the biotechnological potential of the medicinal halophyte Artemisia campestris subsp. maritima (dune wormwood) as a source of health promoting commodities. For that purpose, infusions, decoctions and tinctures were prepared from roots and aerial-organs and evaluated for in vitro antioxidant, anti-diabetic and tyrosinase-inhibitory potential, and also for polyphenolic and mineral contents and toxicity. The dune wormwood extracts had high polyphenolic content and several phenolics were identified by ultra-high performance liquid chromatography-photodiode array-mass-spectrometry (UHPLC-PDA-MS). The main compounds were quinic, chlorogenic and caffeic acids, coumarin sulfates and dicaffeoylquinic acids; several of the identified phytoconstituents are here firstly reported in this A. campestris subspecies. Results obtained with this plant's extracts point to nutritional applications as mineral supplementary source, safe for human consumption, as suggested by the moderate to low toxicity of the extracts towards mammalian cell lines. The dune wormwood extracts had in general high antioxidant activity and also the capacity to inhibit a-glucosidase and tyrosinase. In summary, dune wormwood extracts are a significant source of polyphenolic and mineral constituents, antioxidants and a-glucosidase and tyrosinase inhibitors, and thus, relevant for different commercial segments like the pharmaceutical, cosmetic and/or food industries.FCT - Foundation for Science and Technology [CCMAR/Multi/04326/2013]; Portuguese National Budget; FCT [IF/00049/2012, SFRH/BD/94407/2013]; Research Foundation - Flanders (FWO) [12M8315N]info:eu-repo/semantics/publishedVersio