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The fungal kingdom is among the most diversified kingdoms on Earth, with estimations of up to 12 million species. However, it remains poorly understood, with only 150 000 fungal species currently described. Given the major ecological role of fungi in ecosystem functioning, these numbers stress the importance of investigating fungal diversity description across different ecosystem types. Here, we explored the spatial distribution of the soil fungal diversity on a broad geographical scale, using the French Soil Quality Monitoring Network that covers the whole French territory (2171 soils sampled along a systematic grid). Fungal alpha diversity was assessed directly from soil DNA using a meta-barcoding approach by targeting the 18S rDNA gene. The total accumulated fungal diversity across France included 136 219 operational taxonomic units (OTUs), i.e., about 1 % of worldwide soil fungal diversity (based on a maximum diversity estimate of 12 million) for a territory representing only 0.3 % of the terrestrial surface on Earth. Based on this dataset, the first extensive map of fungal alpha diversity was drawn and showed a heterogeneous and spatially structured distribution in large biogeographical patterns of 231 km radius for richness (Hill diversity of order 0) and smaller patterns of 36 km radius for dominant fungi (Hill diversity of order 2). As related to other environmental parameters, the spatial distribution of fungal diversity (Hill numbers based on different orders of diversity) was mainly influenced by local filters such as soil characteristics and land management and also by global filters such as climate conditions with various relative influences. Interestingly, cropped soils exhibited the highest pool of fungal diversity relative to forest and vineyard soils. To complement this, soil fungal OTU network interactions were calculated for the different land uses across France. They varied hugely and showed a loss of 75 % of the complexity in crop systems and grasslands compared to forests and up to 83 % in vineyard systems. Overall, our study revealed that a nationwide survey with a high spatial-resolution approach is relevant for deeply investigating the spatial distribution and determinism of soil fungal diversity. Our findings provide novel insights for a better understanding of soil fungal ecology across the 18S rDNA gene and upgrade biodiversity conservation policies by supplying representative repositories dedicated to soil fungi.

Abstract Background The development of nanoscale secondary ion mass spectrometry (NanoSIMS) has revolutionized the study of biological tissues by enabling, e.g., the visualization and quantification of metabolic processes at subcellular length scales. However, the associated sample preparation methods all result in some degree of tissue morphology distortion and loss of soluble compounds. To overcome these limitations an entirely cryogenic sample preparation and imaging workflow is required. Results Here, we report the development of a CryoNanoSIMS instrument that can perform isotope imaging of both positive and negative secondary ions from flat block-face surfaces of vitrified biological tissues with a mass- and image resolution comparable to that of a conventional NanoSIMS. This capability is illustrated with nitrogen isotope as well as trace element mapping of freshwater hydrozoan Green Hydra tissue following uptake of 15N-enriched ammonium. Conclusion With a cryo-workflow that includes vitrification by high pressure freezing, cryo-planing of the sample surface, and cryo-SEM imaging, the CryoNanoSIMS enables correlative ultrastructure and isotopic or elemental imaging of biological tissues in their most pristine post-mortem state. This opens new horizons in the study of fundamental processes at the tissue- and (sub)cellular level. Teaser CryoNanoSIMS: subcellular mapping of chemical and isotopic compositions of biological tissues in their most pristine post-mortem state.

Patient-level external control data from prior clinical studies or electronic health records can be used in the design and analysis of clinical trials. Here the authors report a hybrid trial design combining the use of external control data and randomization to test experimental treatments, using small cell lung cancer and glioblastoma datasets as examples.

Abstract NCCN guidelines for first-line treatment of advanced non-squamous non-small-cell lung cancer (NSCLC) patients without targetable driver alterations includes either immunotherapy alone or in combination with chemotherapy. In this study, we investigated genomic predictors of survival after immunotherapy to guide this treatment decision. Cox proportional hazards regression was used to identify genomic correlates of survival in a cohort of EGFR/ALK-, non-squamous NSCLC patients treated with first-line pembrolizumab monotherapy (mono-IO) or pembrolizumab in combination with carboplatin/cisplatin and pemetrexed (chemo-IO) within a real-world clinico-genomic database. The effect of deletions on 9p21 was further evaluated in five additional tumor types. Among mono-IO treated non-squamous NSCLC patients, tumors with 9p21.3 gene deletions (CDKN2A, CDKN2B, MTAP) were associated with worse survival compared to the corresponding deletion-negative tumors (CDKN2A deletion HR = 1.8, P = 0.001). However, this association was not observed among chemo-IO treated patients (CDKN2A deletion HR = 1.1, P = 0.4). This finding remained after adjusting for clinical and genomic features including TMB and PD-L1. Deletions at 9p21.3 were not associated with differences in TMB, PD-L1, or tumor inflammation. Due to the high incidence of 9p21.3 deletions across tumor types, we performed a pan-cancer analysis and found CDKN2A deletion-positive tumors had worse survival following first-line immunotherapy treatment in multiple tumor types (HR = 1.4, P

Can et al. demonstrate the ability to use hyperpolarized [1-13C]pyruvate at nearphysiological concentrations to directly assess liver enzymatic activities by 13C magnetic resonance. While in the fed state, the normalized [13C]bicarbonate signal produced from hyperpolarized [1-13C]pyruvate derives from PDH activity, which is saturated at supraphysiological doses, it results from PEPCK in the fasted state and is dose-independent, allowing non-invasive in vivo detection of hepatic gluconeogenesis.”

Abstract Glioblastoma (GBM) is the most aggressive brain tumor type in adults. GBM is heterogeneous, with a compact core lesion surrounded by an invasive tumor front. This front is highly relevant for tumor recurrence but is generally non-detectable using standard imaging techniques. Recent studies demonstrated distinct metabolic profiles of the invasive phenotype in GBM. Magnetic resonance (MR) of hyperpolarized 13C-labeled probes is a rapidly advancing field that provides real-time metabolic information. Here, we applied hyperpolarized 13C-glucose MR to mouse GBM models. Compared to controls, the amount of lactate produced from hyperpolarized glucose was higher in the compact GBM model, consistent with the accepted “Warburg effect”. However, the opposite response was observed in models reflecting the invasive zone, with less lactate produced than in controls, implying a reduction in aerobic glycolysis. These striking differences could be used to map the metabolic heterogeneity in GBM and to visualize the infiltrative front of GBM.

Background: Counseling patients on medication adherence could be ameliorated in pharmacy practice. There is a lack of simple and practical strategies to address medication adherence with patients in daily practice. The goal was to develop and test a framework that allows pharmacy teams to define and apply a strategy to address medication adherence in community pharmacies. Methods: A framework based on the principles of social marketing was developed. It consisted of 3 items: the target patient (“Who”), the target plan (“How”), and the target goal (“How many”). To test the framework, each participating pharmacy team developed their strategy by defining the 3 items and applied them during one pilot day. A master student observed the encounters between patients and pharmacy team members and used a structured checklist to document the patient's characteristics, counseling content, and strategy use. Pharmacy teams answered a feedback questionnaire at the end of the pilot day. Results: Ten pharmacy teams were included. During a brainstorming session that lasted on average 31 ± 8 min, unique strategies comprised 18 different target patients and 20 different target plans. The planned target goal was a mean of 31 patients (range: 1 to “all”). A total of 325 encounters were observed, of which 208 patients (64%) corresponded to the predefined target patients. Medication adherence was addressed with 73 patients (22.5%), and adherence counseling was performed with 50 patients (15%). The pharmacy teams accepted the framework and judged it feasible and adaptable to their needs. Conclusion: The proposed framework represents a simple tool that enables pharmacy teams to develop a strategy for addressing medication adherence in community pharmacies. Its adoption by pharmacy teams occurred without additional training and its integration into daily practice without difficulties. A further study is now needed to investigate if pharmacy teams can successfully engage patients in discussion on medication adherence and ultimately propose targeted adherence interventions.

As both a consumer and producer of glucose, the kidney plays a significant role in glucose homeostasis. Measuring renal gluconeogenesis requires invasive techniques, and less invasive methods would allow renal gluconeogenesis to be measured more routinely. Magnetic resonance spectroscopy and imaging of infused substrates bearing hyperpolarized carbon-13 spin labels allows metabolism to be detected within the body with excellent sensitivity. Conversion of hyperpolarized 1-13C pyruvate in the fasted rat liver is associated with gluconeogenic flux through phosphoenolpyruvate carboxykinase (PEPCK) rather than pyruvate dehydrogenase (PDH), and this study tested whether this was also the case in the kidney. The left kidney was scanned in fed and overnight-fasted rats either with or without prior treatment by the PEPCK inhibitor 3-mercaptopicolinic acid (3-MPA) following infusion of hyperpolarized 1-13C pyruvate. The 13C-bicarbonate signal normalized to the total metabolite signal was 3.2-fold lower in fasted rats (p = 0.00073) and was not significantly affected by 3-MPA treatment in either nutritional state. By contrast, the normalized [1-13C]aspartate signal was on average 2.2-fold higher in the fasted state (p = 0.038), and following 3-MPA treatment it was 2.8-fold lower in fed rats and 15-fold lower in fasted rats (p = 0.001). These results confirm that, unlike in the liver, most of the pyruvate-to-bicarbonate conversion in the fasted kidney results from PDH flux. The higher conversion to aspartate in fasted kidney and the marked drop following PEPCK inhibition demonstrate the potential of this metabolite as a marker of renal gluconeogenesis.