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Triple negative breast cancer (TNBC) accounts for about a fifth of all breast cancers and includes a diverse group of cancers. The heterogeneity of TNBC and the lack of target receptors on the cell surface make it difficult to develop specific therapeutic treatments. These aspects cause the high negative prognosis of patients with this type of tumor. The analysis of the molecular profiles of TNBC samples has allowed a better characterization of this tumor, supporting the search for new reliable diagnostic markers. To this end, we have developed a bioinformatic approach to integrate networks of genes differentially expressed in basal breast cancer compared to healthy tissues, with miRNAs able to regulate their expression. We studied the role of these miRNAs in TNBC subtype cell lines. We therefore identified two miRNAs, namely miR-135b and miR-365, with a central role in regulating the altered functional pathways in basal breast cancer. These two miRNAs are differentially expressed in human TNBC immunohistochemistry-selected tissues, and their modulation has been shown to play a role in the proliferation of tumor control and its migratory and invasive capacity in TNBC subtype cell lines. From the perspective of personalized medicine, we managed to modulate the expression of the two miRNAs in organotypic cultures, suggesting their possible use as diagnostic and therapeutic molecules. miR-135b and miR-365 have a key role in TNBC, controlling proliferation and invasion. Their detection could be helpful in TNBC diagnosis, while their modulation could become a new therapeutic tool for TNBC.

Recent advances in Quantum Machine Learning (QML) have provided benefits to several computational processes, drastically reducing the time complexity. Another approach of combining quantum information theory with machine learning—without involving quantum computers—is known as Quantum-inspired Machine Learning (QiML), which exploits the expressive power of the quantum language to increase the accuracy of the process (rather than reducing the time complexity). In this work, we propose a large-scale experiment based on the application of a binary classifier inspired by quantum information theory to the biomedical imaging context in clonogenic assay evaluation to identify the most discriminative feature, allowing us to enhance cell colony segmentation. This innovative approach offers a two-fold result: (1) among the extracted and analyzed image features, homogeneity is shown to be a relevant feature in detecting challenging cell colonies; and (2) the proposed quantum-inspired classifier is a novel and outstanding methodology, compared to conventional machine learning classifiers, for the evaluation of clonogenic assays.

The human brain is characterized by highly dynamic patterns of functional connectivity. However, it is unknown whether this time-variant ‘connectome’ is related to the individual differences in the behavioural and cognitive traits described in the five-factor model of personality. To answer this question, inter-network time-variant connectivity was computed in n = 818 healthy people via a dynamical conditional correlation model. Next, network dynamicity was quantified throughout an ad-hoc measure (T-index) and the generalizability of the multi-variate associations between personality traits and network dynamicity was assessed using a train/test split approach. Conscientiousness, reflecting enhanced cognitive and emotional control, was the sole trait linked to stationary connectivity across several circuits such as the default mode and prefronto-parietal network. The stationarity in the ‘communication’ across large-scale networks offers a mechanistic description of the capacity of conscientious people to ‘protect’ non-immediate goals against interference over-time. This study informs future research aiming at developing more realistic models of the brain dynamics mediating personality differences.

Magmas in volcanic arcs have geochemical and isotopic signatures that can be related to mantle metasomatism due to fluids and melts released by the down-going oceanic crust and overlying sediments, which modify the chemistry and mineralogy of the mantle wedge. However, the effectiveness of subduction-related metasomatic processes is difficult to evaluate because the composition of arc magmas is often overprinted by interactions with crustal lithologies occurring during magma ascent and emplacement. Here, we show unequivocal evidence for recycling of continental crust components into the mantle. Veined peridotite xenoliths sampled from Tallante monogenetic volcanoes in the Betic Cordillera (southern Spain) provide insights for mantle domains that reacted with Si-rich melts derived by partial melting of subducted crustal material. Felsic veins crosscutting peridotite and the surrounding orthopyroxene-rich metasomatic aureoles show the highest 18O/16O ratios measured to date in upper mantle assemblages worldwide. The anomalously high oxygen isotope compositions, coupled with very high 87Sr/86Sr values, imply the continental crust origin of the injected melts. Isotopic anomalies are progressively attenuated in peridotite away from the veins, showing 18O isotope variations well correlated with the amount of newly formed orthopyroxene. Diffusion may also affect the isotope ratios of mantle rocks undergoing crustal metasomatism due to the relaxation of 18O isotope anomalies to normal mantle values through time. Overall, the data define an O isotope “benchmark” allowing discrimination between mantle sources that attained re-equilibration after metasomatism (>5 Myr) and those affected by more recent subduction-derived enrichment processes.

A 3800 year-long radiocarbon-dated and highly-resolved palaeoecological record from Lake Fimon (N-Italy) served to investigate the effects of potential teleconnections between North Atlantic and mid-to-low latitudes at the transition from Marine Isotope Stage (MIS) 3 to 2. Boreal ecosystems documented in the Fimon record reacted in a sensitive way to millennial and sub-millennial scale Northern Hemisphere atmospheric circulation patterns. The high median time-resolution of 58 years allows the identification of five abrupt event-boundaries (i.e., main forest expansion and decline excursions) synchronous with the sharp stadial/interstadial (GS/GI) transitions within dating uncertainties. During Heinrich Stadial 3 (HS 3) we reconstruct more open and dry conditions, compared to the other GS, with a dominant regional scale fire signal. Linkages between local fires and climate-driven fuel changes resulted in high-magnitude fire peaks close to GI/GS boundaries, even exacerbated by local peatland conditions. Finally, palaeoecological data from the HS 3 interval unveiled an internal variability suggesting a peak between 30,425 and 29,772 cal BP (2σ error) which matches more depleted δ18O values in alpine speleothems. We hypothesise that this signal, broadly resembling that of other mid-latitudes proxies, may be attributed to the southward shift of the Northern Hemisphere storm tracks and the associated delayed iceberg discharge events as documented during other HS.

The northern and northwestern margins of the Arabian Plate are a locus of a diffuse and long-lasting (early Miocene to Pleistocene) Na-alkali basaltic volcanism, sourced in the asthenosphere mantle. The upwelling asthenosphere at the Africa–Arabia margin produces very limited magma volumes in the axial zone. Therefore, portions of hot, fertile mantle continue their eastward migration and are stored at shallower depths under the 100-km thick Arabian lithosphere, which is much thinner than the African one (≈175 km): this causes the occurrence and 20-Ma persistence of magma supply under the study area. Erupted basalts sampled a continuous variation of the mantle source, with a striking correlation among temperature, pressure and isotopic composition shifting between two end members: a 100 km-deep, more depleted source, and a 60 km-deep, more enriched one. In particular, we observed an unusual variation in boron isotopes, which in the oceanic domain does not vary between more depleted and more enriched mantle sources. This study shows that, at least in the considered region, subcontinental mantle is more heterogeneous than the suboceanic one, and able to record for very long times recycling of shallow material.

Harmonic tremors consist in the release of infrasonic energy associated with volcanic activity. The typical frequency range of harmonic tremors is 0.1–12 Hz. We suppose that the harmonic tremors are due to the formation of bubbles entrapped in cavities that oscillate converting thermal energy into mechanic energy. Reproducing the natural phenomenon through an experimental apparatus, we propose here a mathematical model to describe the oscillatory mechanism and to detect the frequency as a function of the main physical parameters. We show that the frequency obtained through the model is in agreement with the one obtained through experimental measurements and with the data available from the literature, proving the consistency of the proposed model.

Ionic Liquids are a promising alternative to water electrolytes for the electrodeposition of metals. These solvents have a much larger electrochemical window than water that expands the potential of electrodeposition. However, mass transport in Ionic Liquids is slow. The slow mass transport dramatically affects the rate of reactions at the solid–liquid interface, hampering the exploitation of Ionic Liquids in high-throughput electrodeposition processes. In this paper, we clarify the origin of such poor mass transport in the diffusion–advection (convection) regime. To determine the extent and the dynamics of the convection boundary layers, we performed Rotating Disk Electrode (RDE) experiments on model reactions along with the finite element simulation. Both the experiments and the finite element modelling showed the occurrence of peaks in the RDE curves even at relatively high rotation rates (up to 2000 rpm). The peak in the RDE is the fingerprint of partial diffusion control that happens for the relative extent of the diffusion and convection boundary layers. In looking for a close match between the experiments and the simulations, we found that the ohmic drop plays a critical role and must be considered in the calculation to find the best match with the experimental data. In the end, we have shown that the combined approach consisting of RDE experiments and finite elements modelling providing a tool to unravel of the structure of the diffusion and convection boundary layers both in dynamic and stationary conditions.

Due to the great development of light sources for several applications from displays to lighting, great efforts are devoted to find stable and efficient visible emitting materials. Moreover, the requirement of Si compatibility could enlarge the range of applications inside microelectronic chips. In this scenario, we have studied the emission properties of bismuth doped yttrium oxide thin films grown on crystalline silicon. Under optical pumping at room temperature a stable and strong visible luminescence has been observed. In particular, by the involvement of Bi ions in the two available lattice sites, the emission can be tuned from violet to green by changing the excitation wavelength. Moreover, under electron beam at low accelerating voltages (3 keV) a blue emission with high efficiency and excellent stability has been recorded. The color is generated by the involvement of Bi ions in both the lattice sites. These peculiarities make this material interesting as a luminescent medium for applications in light emitting devices and field emission displays by opening new perspectives for the realization of silicon-technology compatible light sources operating at room temperature.

In mammals, hypoxic stress management is under the control of the Hypoxia Inducible Factors, whose activity depends on the stabilization of their labile α subunit. In particular, the skeletal muscle appears to be able to react to changes in substrates and O2 delivery by tuning its metabolism. The present study provides a comprehensive overview of skeletal muscle metabolic adaptation to hypoxia in mice and in human subjects exposed for 7/9 and 19 days to high altitude levels. The investigation was carried out combining proteomics, qRT-PCR mRNA transcripts analysis, and enzyme activities assessment in rodents, and protein detection by antigen antibody reactions in humans and rodents. Results indicate that the skeletal muscle react to a decreased O2 delivery by rewiring the TCA cycle. The first TCA rewiring occurs in mice in 2-day hypoxia and is mediated by cytosolic malate whereas in 10-day hypoxia the rewiring is mediated by Idh1 and Fasn, supported by glutamine and HIF-2α increments. The combination of these specific anaplerotic steps can support energy demand despite HIFs degradation. These results were confirmed in human subjects, demonstrating that the TCA double rewiring represents an essential factor for the maintenance of muscle homeostasis during adaptation to hypoxia.

The underlying mechanism driving the structural amorphous-to-crystalline transition in Group VI chalcogenides is still a matter of debate even in the simplest GeTe system. We exploit the extreme sensitivity of 57Fe emission Mössbauer spectroscopy, following dilute implantation of 57Mn (T½ = 1.5 min) at ISOLDE/CERN, to study the electronic charge distribution in the immediate vicinity of the 57Fe probe substituting Ge (FeGe), and to interrogate the local environment of FeGe over the amorphous-crystalline phase transition in GeTe thin films. Our results show that the local structure of as-sputtered amorphous GeTe is a combination of tetrahedral and defect-octahedral sites. The main effect of the crystallization is the conversion from tetrahedral to defect-free octahedral sites. We discover that only the tetrahedral fraction in amorphous GeTe participates to the change of the FeGe-Te chemical bonds, with a net electronic charge density transfer of ~ 1.6 e/a0 between FeGe and neighboring Te atoms. This charge transfer accounts for a lowering of the covalent character during crystallization. The results are corroborated by theoretical calculations within the framework of density functional theory. The observed atomic-scale chemical-structural changes are directly connected to the macroscopic phase transition and resistivity switch of GeTe thin films., This work was supported by the European Union Seventh Framework through ENSAR (Contract No. 262010). R. Fallica, C. Wiemer, and M. Longo acknowledge the SYNAPSE project (“SYnthesis and functionality of chalcogenide NAnostructures for PhaSE change memories”), which received funding from the European Union Seventh Framework Programme (FP7/2007–2013), under grant agreement n° 310339. H. P. Gunnlaugsson acknowledges support from the Fund for Scientific Research-Flanders and the KU Leuven BOF (SF/14/013, CREA/14/13, and STRT/14/002). K. Bharuth-Ram, H. Masenda, D. Naidoo, and M. Ncube acknowledge support from the South African National Research Foundation and the Department of Science and Technology. T. E. Mølholt, H. P. Gislason, and S. Ólafsson acknowledge support from the Icelandic Research Fund (Grant No. 110017021-23). The authors acknowledge Numonyx for the GeTe samples and Dr. Enrico Varesi (now at Micron), Dr. Davide Erbetta (now at STMicroelectronics) and Dr. Roberto Bez (now at LFoundry) for scientific discussion.

imbalance p paper contact with: Marc Estiarte, m.estiarte@creaf.uab.cat Above- and belowground carbon (C) stores of terrestrial ecosystems are vulnerable to environmental change. Ecosystem C balances in response to environmental changes have been quantified at individual sites, but the magnitudes and directions of these responses along environmental gradients remain uncertain. Here we show the responses of ecosystem C to 8-12 years of experimental drought and night-time warming across an aridity gradient spanning seven European shrublands using indices of C assimilation (aboveground net primary production: aNPP) and soil C efflux (soil respiration: Rs). The changes of aNPP and Rs in response to drought indicated that wet systems had an overall risk of increased loss of C but drier systems did not. Warming had no consistent effect on aNPP across the climate gradient, but suppressed Rs more at the drier sites. Our findings suggest that above- and belowground C fluxes can decouple, and provide no evidence of acclimation to environmental change at a decadal timescale. aNPP and Rs especially differed in their sensitivity to drought and warming, with belowground processes being more sensitive to environmental change.

Due to their altered metabolism cancer cells are more sensitive to proteasome inhibition or changes of copper levels than normal cells. Thus, the development of copper complexes endowed with proteasome inhibition features has emerged as a promising anticancer strategy. However, limited information is available about the exact mechanism by which copper inhibits proteasome. Here we show that Cu(II) ions simultaneously inhibit the three peptidase activities of isolated 20S proteasomes with potencies (IC50) in the micromolar range. Cu(II) ions, in cell-free conditions, neither catalyze red-ox reactions nor disrupt the assembly of the 20S proteasome but, rather, promote conformational changes associated to impaired channel gating. Notably, HeLa cells grown in a Cu(II)-supplemented medium exhibit decreased proteasome activity. This effect, however, was attenuated in the presence of an antioxidant. Our results suggest that if, on one hand, Cu(II)-inhibited 20S activities may be associated to conformational changes that favor the closed state of the core particle, on the other hand the complex effect induced by Cu(II) ions in cancer cells is the result of several concurring events including ROS-mediated proteasome flooding, and disassembly of the 26S proteasome into its 20S and 19S components.

Cancer metabolism is characterized by an accelerated glycolytic rate facing reduced activity of oxidative phosphorylation. This “Warburg effect” represents a standard to diagnose and monitor tumor aggressiveness with 18F-fluorodeoxyglucose whose uptake is currently regarded as an accurate index of total glucose consumption. Studying cancer metabolic response to respiratory chain inhibition by metformin, we repeatedly observed a reduction of tracer uptake facing a marked increase in glucose consumption. This puzzling discordance brought us to discover that 18F-fluorodeoxyglucose preferentially accumulates within endoplasmic reticulum by exploiting the catalytic function of hexose-6-phosphate-dehydrogenase. Silencing enzyme expression and activity decreased both tracer uptake and glucose consumption, caused severe energy depletion and decreased NADPH content without altering mitochondrial function. These data document the existence of an unknown glucose metabolism triggered by hexose-6-phosphate-dehydrogenase within endoplasmic reticulum of cancer cells. Besides its basic relevance, this finding can improve clinical cancer diagnosis and might represent potential target for therapy.

To understand the dynamics of a pathogen in an animal population, one must assess how the infection status of individuals changes over time. With wild animals, this can be very challenging because individuals can be difficult to trap and sample, even more so since they are tested with imperfect diagnostic techniques. Multi-event capture-recapture models allow analysing longitudinal capture data of individuals whose infection status is assessed using imperfect tests. In this study, we used a two-year dataset from a longitudinal field study of peridomestic wild bird populations in the United Arab Emirates during which thousands of birds from various species were captured, sampled and tested for Newcastle disease virus exposure using a serological test. We developed a multi-event capture-recapture model to estimate important demographic and epidemiological parameters of the disease. The modelling outputs provided important insights into the understanding of Newcastle disease dynamics in peridomestics birds, which varies according to ecological and epidemiological parameters, and useful information in terms of surveillance strategies. To our knowledge, this study is the first attempt to model the dynamics of Newcastle disease in wild bird populations by combining longitudinal capture data and serological test results. Overall, it showcased that multi-event capture-recapture models represent a suitable method to analyse imperfect capture data and make reliable inferences on infectious disease dynamics in wild populations.

Reporter gene assays are widely used to study cellular signaling and transcriptional activity. Few studies describe the use of reporter genes for studying cellular responses on complex body fluids, such as urine and blood. Selection of the optimal reporter gene is crucial for study outcome. Here, we compared the characteristics of five reporter genes (Firefly luciferase, stable- and unstable Nano luciferase, secretable Gaussia luciferase and Red Fluorescent Protein) to study complex body fluids. For this comparison, the NFκB Response Element (NFκB-RE) and Smad Binding Element (SBE) were identically cloned into the five different reporter vectors. Reporter characteristics were evaluated by kinetic and concentration–response measurements in SW1353 and HeLa cell lines. Finally, reporter compatibility with complex body fluids (fetal calf serum, knee joint synovial fluid and human serum) and inter-donor variation were evaluated. Red Fluorescent Protein demonstrated poor inducibility as a reporter gene and slow kinetics compared to luciferases. Intracellularly measured luciferases, such as Firefly luciferase and Nano luciferase, revealed good compatibility with complex body fluids. Secreted Gaussia luciferase appeared to be incompatible with complex body fluids, due to variability in inter-donor signal interference. Unstable Nano luciferase demonstrated clear inducibility, high sensitivity and compatibility with complex body fluids and therefore can be recommended for cellular signaling studies using complex body fluids.

Mortality in type 2 diabetes, is determined not only by classical complications, but also by comorbidities, and is linked to hyperglycaemia and apparent even in prediabetes. We aimed to comprehensively investigate, in a population-based cohort, health burden defined as the presence of comorbidities in addition to classical complications and cardiometabolic risk factors, in not only type 2 diabetes but also prediabetes. Such population-based study has not been performed previously. Extensive phenotyping was performed in 3,410 participants of the population-based Maastricht Study (15.0% prediabetes and 28.6% type 2 diabetes) to assess presence of 17 comorbidities, six classical complications, and ten cardiometabolic risk factors. These were added up into individual and combined sum scores and categorized. Group differences were studied with multinomial regression analyses adjusted for age and sex. Individuals with type 2 diabetes and prediabetes, as compared to normal glucose metabolism (NGM), had greater comorbidities, classical complications, cardiometabolic risk factors and combined sum scores (comorbidities sum score ≥ 3: frequencies (95% CI) 61.5% (57.6;65.4) and 41.2% (36.5;45.9) vs. 25.4% (23.5;27.4), p-trend P P = 0.065 vs NGM) vs. 8.0% (6.9;9.3)); cardiometabolic risk factors ≥ 6 (39.7% (35.9;43.4) and 28.5% (24.5;32.6) vs. 14.0% (12.5;15.6); p-trend

Retinopathy and neuropathy in type 2 diabetes are preceded by retinal nerve fibre layer (RNFL) thinning, an index of neurodegeneration. We investigated whether glucose metabolism status (GMS), measures of glycaemia, and daily glucose variability (GV) are associated with RNFL thickness over the entire range of glucose tolerance. We used cross-sectional data from The Maastricht Study (up to 5455 participants, 48.9% men, mean age 59.5 years and 22.7% with type 2 diabetes) to investigate the associations of GMS, measures of glycaemia (fasting plasma glucose [FPG], 2-h post-load glucose [2-h PG], HbA1c, advanced glycation endproducts [AGEs] assessed as skin autofluorescence [SAF]) and indices of daily GV (incremental glucose peak [IGP] and continuous glucose monitoring [CGM]-assessed standard deviation [SD]) with mean RNFL thickness. We used linear regression analyses and, for GMS, P for trend analyses. We adjusted associations for demographic, cardiovascular risk and lifestyle factors, and, only for measures of GV, for indices of mean glycaemia. After full adjustment, type 2 diabetes and prediabetes (versus normal glucose metabolism) were associated with lower RNFL thickness (standardized beta [95% CI], respectively − 0.16 [− 0.25; − 0.08]; − 0.05 [− 0.13; 0.03]; Ptrend = 0.001). Greater FPG, 2-h PG, HbA1c, SAF, IGP, but not CGM-assessed SD, were also associated with lower RNFL thickness (per SD, respectively − 0.05 [− 0.08; − 0.01]; − 0.06 [− 0.09; − 0.02]; − 0.05 [− 0.08; − 0.02]; − 0.04 [− 0.07; − 0.01]; − 0.06 [− 0.12; − 0.01]; and − 0.07 [− 0.21; 0.07]). In this population-based study, a more adverse GMS and, over the entire range of glucose tolerance, greater glycaemia and daily GV were associated with lower RNFL thickness. Hence, early identification of individuals with hyperglycaemia, early glucose-lowering treatment, and early monitoring of daily GV may contribute to the prevention of RNFL thinning, an index of neurodegeneration and precursor of retinopathy and neuropathy.

Although mitochondrial DNA has been widely used in phylogeography, evidence has emerged that factors such as climate, food availability, and environmental pressures that produce high levels of stress can exert a strong influence on mitochondrial genomes, to the point of promoting the persistence of certain genotypes in order to compensate for the metabolic requirements of the local environment. As recently discovered, the gentoo penguins (Pygoscelis papua) comprise four highly divergent lineages across their distribution spanning the Antarctic and sub-Antarctic regions. Gentoo penguins therefore represent a suitable animal model to study adaptive processes across divergent environments. Based on 62 mitogenomes that we obtained from nine locations spanning all four gentoo penguin lineages, we demonstrated lineage-specific nucleotide substitutions for various genes, but only lineage-specific amino acid replacements for the ND1 and ND5 protein-coding genes. Purifying selection (dN/dS 1) was mostly present in codons of the Complex I (NADH genes), supported by two different codon-based methods at the ND1 and ND4 in the most divergent lineages, the eastern gentoo penguin from Crozet and Marion Islands and the southern gentoo penguin from Antarctica respectively. Additionally, ND5 and ATP6 were under selection in the branches of the phylogeny involving all gentoo penguins except the eastern lineage. Our study suggests that local adaptation of gentoo penguins has emerged as a response to environmental variability promoting the fixation of mitochondrial haplotypes in a non-random manner. Mitogenome adaptation is thus likely to have been associated with gentoo penguin diversification across the Southern Ocean and to have promoted their survival in extreme environments such as Antarctica. Such selective processes on the mitochondrial genome may also be responsible for the discordance detected between nuclear- and mitochondrial-based phylogenies of gentoo penguin lineages., Financial support for this study was provided by Beca ANID Doctorado Nacional (Folio: 21171214), Millennium Institute Biodiversity of Antarctic and Subantarctic Ecosystems (BASE) ANID—Millennium Science Initiative Program—ICN2021_002, Inach RT_12-14, Fondecyt 1150517, PIA ACT172065 GAB, Center of genome regulation (CRG) ANID/FONDAP/15200002, the CNPq (431463/2016-6) and the PROANTAR, IPEV programs 137 ANTAVIA-ECOPHY and 354 ETHOTAAF and by the Spanish Research Agency (CGL2004-01348, CGL2007-60369, POL2006-06635 and CTM2015-64720-R).

The fibrocartilage chondrocyte phenotype has been recognized to attribute to osteoarthritis (OA) development. These chondrocytes express genes related to unfavorable OA outcomes, emphasizing its importance in OA pathology. BMP7 is being explored as a potential disease-modifying molecule and attenuates the chondrocyte hypertrophic phenotype. On the other hand, BMP7 has been demonstrated to relieve organ fibrosis by counteracting the pro-fibrotic TGFβ-Smad3-PAI1 axis and increasing MMP2-mediated Collagen type I turnover. Whether BMP7 has anti-fibrotic properties in chondrocytes is unknown. Human OA articular chondrocytes (HACs) were isolated from end-stage OA femoral cartilage (total knee arthroplasty; n = 18 individual donors). SW1353 cells and OA HACs were exposed to 1 nM BMP7 for 24 h, after which gene expression of fibrosis-related genes and fibrosis-mediating factors was determined by RT-qPCR. In SW1353, Collagen type I protein levels were determined by immunocytochemistry and western blotting. PAI1 and MMP2 protein levels and activity were measured with an ELISA and activity assays, respectively. MMP2 activity was inhibited with the selective MMP-2 inhibitor OA-Hy. SMAD3 activity was determined by a (CAGA)12-reporter assay, and pSMAD2 levels by western blotting. Following BMP7 exposure, the expression of fibrosis-related genes was reduced in SW1353 cells and OA HACs. BMP7 reduced Collagen type I protein levels in SW1353 cells. Gene expression of MMP2 was increased in SW1353 cells following BMP7 treatment. BMP7 reduced PAI1 protein levels and -activity, while MMP2 protein levels and -activity were increased by BMP7. BMP7-dependent inhibition of Collagen type I protein levels in SW1353 cells was abrogated when MMP2 activity was inhibited. Finally, BMP7 reduced pSMAD2 levels determined by western blotting and reduced SMAD3 transcriptional activity as demonstrated by decreased (CAGA)12 luciferase reporter activity. Our data demonstrate that short-term exposure to BMP7 decreases the fibrocartilage chondrocyte phenotype. The BMP7-dependent reduction of Collagen type I protein expression seems MMP2-dependent and inhibition of Smad2/3-PAI1 activity was identified as a potential pathway via which BMP7 exerts its anti-fibrotic action. This indicates that in chondrocytes BMP7 may have a double mode-of-action by targeting both the hypertrophic as well as the fibrotic chondrocyte phenotype, potentially adding to the clinical relevance of using BMP7 as an OA disease-modifying molecule.

Understanding transmission routes of hospital-acquired infections (HAI) is key to improve their control. In this context, describing and analyzing dynamic inter-individual contact patterns in hospitals is essential. In this study, we used wearable sensors to detect Close Proximity Interactions (CPIs) among patients and hospital staff in a 200-bed long-term care facility over 4 months. First, the dynamic CPI data was described in terms of contact frequency and duration per individual status or activity and per ward. Second, we investigated the individual factors associated with high contact frequency or duration using generalized linear mixed-effect models to account for inter-ward heterogeneity. Hospital porters and physicians had the highest daily number of distinct contacts, making them more likely to disseminate HAI among individuals. Conversely, contact duration was highest between patients, with potential implications in terms of HAI acquisition risk. Contact patterns differed among hospital wards, reflecting varying care patterns depending on reason for hospitalization, with more frequent contacts in neurologic wards and fewer, longer contacts in geriatric wards. This study is the first to report proximity-sensing data informing on inter-individual contacts in long-term care settings. Our results should help better understand HAI spread, parameterize future mathematical models, and propose efficient control strategies.

International audience; Life history strategies of most organisms are constrained by resource allocation patterns that follow a 'slow-fast continuum'. It opposes slow growing and long-lived organisms with late investment in reproduction to those that grow faster, have earlier and larger reproductive effort and a short longevity. In plants, the Leaf Economics Spectrum (LES) depicts a leaf-level trade-off between the rate of carbon assimilation and leaf lifespan, as stressed in functional ecology from interspecific comparative studies. However, it is still unclear how the LES is connected to the slow-fast syndrome. Interspecific comparisons also impede a deep exploration of the linkage between Les variation and adaptation to climate. Here, we measured growth, morpho-physiological and life-history traits, at both the leaf and whole-plant levels, in 378 natural accessions of Arabidopsis thaliana. We found that the Les is tightly linked to variation in whole-plant functioning, and aligns with the slow-fast continuum. A genetic analysis further suggested that phenotypic differentiation results from the selection of different slow-fast strategies in contrasted climates. slow growing and long-lived plants were preferentially found in cold and arid habitats while fast growing and short-lived ones in more favorable habitats. Our findings shed light on the role of the slow-fast continuum for plant adaptation to climate. More broadly, they encourage future studies to bridge functional ecology, genetics and evolutionary biology to improve our understanding of plant adaptation to environmental changes. Investigations of the genetic and phenotypic differentiation of plant lineages along environmental gradients is crucial for the understanding of plant evolutionary responses to current and future climate variations. As plants cannot simultaneously optimize competing eco-physiological functions, an important question is how plant adaptation occurs under the influence of major trade-offs between traits. The slow-fast continuum is a pervasive trade-off between resource allocation to growth, reproduction and survival , spread across the tree of life 1. The slow end of this continuum is characterized by slow growing, long-lived species and low reproductive output, while species at the fast end reach reproductive maturity faster and produce more offsprings. In plants, the leaf economics spectrum (LES hereafter) 2-4 is thought to reflect the physiological basis of the slow-fast continuum 4. The LES arrays plant species along a continuum of leaf trait syndromes going from short-lived leaves with fast metabolism to the reverse syndrome 3. Core LES traits include leaf dry mass per area (LMA), leaf lifespan (LLS) and net photosynthetic rate per mass unit (A mass) 3,5-7. LES traits are widely used in comparative ecology to infer whole-plant ecological strategies 4,8-12. However, the extent to which leaf-level resource economics reflects whole-plant physiology, performance, and ultimately fitness, is still under debate 13. Many processes can lead to a mismatch between LES and whole-plant functioning 14 , including the impact of self-shading among leaves and resource allocation patterns, such as carbon investment in non-photosynthetic tissues 15,16. To gain insights into the robustness of the slow-fast continuum at different organizational levels, we need

A discrete-time Quantum Walk (QW) is an operator driving the evolution of a single particle on the lattice, through local unitaries. Some QW admit, as their continuum limit, a well-known equation of Physics. In arXiv:1803.01015 the QW is over the honeycomb and triangular lattices, and simulates the Dirac equation. We apply a spacetime coordinate transformation upon the lattice of this QW, and show that it is equivalent to introducing spacetime-dependent local unitaries --- whilst keeping the lattice fixed. By exploiting this duality between changes in geometry, and changes in local unitaries, we show that the spacetime-dependent QW simulates the Dirac equation in $(2+1)$ - dimensional curved spacetime. Interestingly, the duality crucially relies on the non linear-independence of the three preferred directions of the honeycomb and triangular lattices: The same construction would fail for the square lattice. At the practical level, this result opens the possibility to simulate field theories on curved manifolds, via the quantum walk on different kinds of lattices., Comment: 8 pages

5 pages, 2 figures, supplementary information https://doi.org/10.1038/s41598-019-46326-1.-- Data are available in a central PostgreSQL database at UvA-BiTS (http://www.uva-bits.nl/virtual-lab), Wildlife that exploit human-made habitats hosts and spreads bacterial pathogens. This shapes the epidemiology of infectious diseases and facilitates pathogen spill-over between wildlife and humans. This is a global problem, yet little is known about the dissemination potential of pathogen-infected animals. By combining molecular pathogen diagnosis with GPS tracking of pathogen-infected gulls, we show how this knowledge gap could be filled at regional scales. Specifically, we generated pathogen risk maps of Salmonella, Campylobacter and Chlamydia based on the spatial movements of pathogen-infected yellow-legged gulls (Larus michahellis) equipped with GPS recorders. Also, crossing this spatial information with habitat information, we identified critical habitats for the potential transmission of these bacteria in southern Europe. The use of human-made habitats by infected-gulls could potentially increase the potential risk of direct and indirect bidirectional transmission of pathogens between humans and wildlife. Our findings show that pathogen-infected wildlife equipped with GPS recorders can provide accurate information on the spatial spread risk for zoonotic bacteria. Integration of GPS-tracking with classical epidemiological approaches may help to improve zoonosis surveillance and control programs, Tracking devices were funded by ICTS-RBD through a demonstrative project for the ESFRI-LifeWatch (Science and Technology Infrastructure for Biodiversity Data and Observatories; Ref: SP34567) project supported by European Regional Funds. JN was partially funded by the Andalucía Talent Hub Program (Andalusian Knowledge Agency and European Union’s Seventh Framework Program; Ref: 291780) and by the Spanish National Program Ramón y Cajal (RYC-2015-17809)

Achieving radical tumor resection while preserving disease-free tissue during breast-conserving surgery (BCS) remains a challenge. Here, mass spectrometry technologies were used to discriminate stromal tissues reported to be altered surrounding breast tumors, and build tissue classifiers ex vivo. Additionally, we employed the approach for in vivo and real-time classification of breast pathology based on electrosurgical vapors. Breast-resected samples were obtained from patients undergoing surgery at MUMC+. The specimens were subsequently sampled ex vivo to generate electrosurgical vapors analyzed by rapid evaporative ionization mass spectrometry (REIMS). Tissues were processed for histopathology to assign tissue components to the mass spectral profiles. We collected a total of 689 ex vivo REIMS profiles from 72 patients which were analyzed using multivariate statistical analysis (principal component analysis-linear discriminant analysis). These profiles were classified as adipose, stromal and tumor tissues with 92.3% accuracy with a leave-one patient-out cross-validation. Tissue recognition using this ex vivo-built REIMS classification model was subsequently tested in vivo on electrosurgical vapors. Stromal and adipose tissues were classified during one BCS. Complementary ex vivo analyses were performed by REIMS and by desorption electrospray ionization mass spectrometry (DESI-MS) to study the potential of breast stroma to guide BCS. Tumor border stroma (TBS) and remote tumor stroma (RTS) were classified by REIMS and DESI-MS with 86.4% and 87.8% accuracy, respectively. We demonstrate the potential of stromal molecular alterations surrounding breast tumors to guide BCS in real-time using REIMS analysis of electrosurgical vapors.

Although pathways controlling ribosome activity have been described to regulate chondrocyte homeostasis in osteoarthritis, ribosome biogenesis in osteoarthritis is unexplored. We hypothesized that U3 snoRNA, a non-coding RNA involved in ribosomal RNA maturation, is critical for chondrocyte protein translation capacity in osteoarthritis. U3 snoRNA was one of a number of snoRNAs with decreased expression in osteoarthritic cartilage and osteoarthritic chondrocytes. OA synovial fluid impacted U3 snoRNA expression by affecting U3 snoRNA gene promoter activity, while BMP7 was able to increase its expression. Altering U3 snoRNA expression resulted in changes in chondrocyte phenotype. Interference with U3 snoRNA expression led to reduction of rRNA levels and translational capacity, whilst induced expression of U3 snoRNA was accompanied by increased 18S and 28S rRNA levels and elevated protein translation. Whole proteome analysis revealed a global impact of reduced U3 snoRNA expression on protein translational processes and inflammatory pathways. For the first time we demonstrate implications of a snoRNA in osteoarthritis chondrocyte biology and investigated its role in the chondrocyte differentiation status, rRNA levels and protein translational capacity.

Acute kidney injury (AKI) is a relevant complication following thoracoabdominal aortic aneurysm repair (TAAA). Biomarkers, such as secretory leucocyte peptidase inhibitor (SLPI), may enable a more accurate diagnosis. In this study, we tested if SLPI measured in serum is an appropriate biomarker of AKI after TAAA repair. In a prospective observational single-center study including 33 patients (51.5% women, mean age 63.0 ± 16.2 years) undergoing open and endovascular aortic aneurysm repair in 2017, SLPI was measured peri-operatively (until 72 h after surgery). After surgery, the postoperative complications AKI, as defined according to the KDIGO diagnostic criteria, sepsis, death, MACE (major cardiovascular events) and, pneumonia were assessed. In a subgroup analysis, patients with preexisting kidney disease were excluded. Of 33 patients, 51.5% (n = 17) of patients developed AKI. Twelve hours after admission to the intensive care unit (ICU), SLPI serum levels were significantly increased in patients who developed AKI. Multivariable logistic regression revealed a significant association between SLPI 12 hours after admission to ICU and AKI (P = 0.0181, OR = 1.055, 95% CI = 1.009–1.103). The sensitivity of SLPI for AKI prediction was 76.47% (95% CI = 50.1–93.2) and the specificity was 87.5% (95% CI = 61.7–98.4) with an AUC = 0.838 (95% CI = 0.7–0.976) for an optimal cut-off 70.03 ng/ml 12 hours after surgery. In patients without pre-existing impaired renal function, an improved diagnostic quality of SLPI for AKI was observed (Sensitivities of 45.45–91.67%, Specificities of 77.7–100%, AUC = 0.716–0.932). There was no association between perioperative SLPI and the incidence of sepsis, death, MACE (major cardiovascular events), pneumonia. This study suggests that SLPI might be a post-operative biomarker of AKI after TAAA repair, with a superior diagnostic accuracy for patients without preexisting impaired renal function.

International audience; Despite the large morphological and physiological changes that plants have undergone through domestication, little is known about their impact on their microbiome. Here we characterized rhizospheric bacterial and fungal communities as well as the abundance of N-cycling microbial guilds across thirty-nine accessions of tetraploid wheat, Triticum turgidum, from four domestication groups ranging from the wild subspecies to the semi dwarf elite cultivars. We identified several microbial phylotypes displaying significant variation in their relative abundance depending on the wheat domestication group with a stronger impact of domestication on fungi. The relative abundance of potential fungal plant pathogens belonging to the Sordariomycetes class decreased in domesticated compared to wild emmer while the opposite was found for members of the Glomeromycetes, which are obligate plant symbionts. The depletion of nitrifiers and of arbuscular mycorrhizal fungi in elite wheat cultivars compared to primitive domesticated forms suggests that the Green Revolution has decreased the coupling between plant and rhizosphere microbes that are potentially important for plant nutrient availability. Both plant diameter and fine root percentage exhibited the highest number of associations with microbial taxa, highlighting their putative role in shaping the rhizosphere microbiota during domestication. Aside from domestication, significant variation of bacterial and fungal community composition was found among accessions within each domestication group. In particular, the relative abundances of Ophiostomataceae and of Rhizobiales were strongly dependent on the host accession, with heritability estimates of ~ 27% and ~ 25%, indicating that there might be room for genetic improvement via introgression of ancestral plant rhizosphere-beneficial microbe associations. Crop domestication events led to spectacular modifications of plant traits increasing their suitability to human requirements. Cereals and especially wheat have been domesticated in the Middle East 1. Domestication process led to dramatic phenotypic changes in cultivated species in relation to cultivation conditions and human needs. The Domestication syndrome 2 refers to the whole set of phenotypic changes occurred during this process, including: loss of dormancy, increasing seed size, modifying seed dispersal mode and apical dominance as well photoperiod sensitivity. open

Article consultable en ligne : https://www.nature.com/articles/s41598-017-14773-3; International audience; Rapid progress in the area of humanoid robots offers tremendous possibilities for investigating and improving social competences in people with social deficits, but remains yet unexplored in schizophrenia. In this study, we examined the influence of social feedbacks elicited by a humanoid robot on motor coordination during a human-robot interaction. Twenty-two schizophrenia patients and twenty-two matched healthy controls underwent a collaborative motor synchrony task with the iCub humanoid robot. Results revealed that positive social feedback had a facilitatory effect on motor coordination in the control participants compared to non-social positive feedback. This facilitatory effect was not present in schizophrenia patients, whose social-motor coordination was similarly impaired in social and non-social feedback conditions. Furthermore, patients’ cognitive flexibility impairment and antipsychotic dosing were negatively correlated with patients’ ability to synchronize hand movements with iCub. Overall, our findings reveal that patients have marked difficulties to exploit facial social cues elicited by a humanoid robot to modulate their motor coordination during human-robot interaction, partly accounted for by cognitive deficits and medication. This study opens new perspectives for comprehension of social deficits in this mental disorder.

In France, 110,000 patients are admitted to hospital per year for stroke. Even though the relationship between stroke and risk factors such as low socio-economic status is well known, research in the spatial distribution (SD) of stroke as a contributing risk factor is less documented. Understanding the geographic differences of the disease may improve stroke prevention. In this study, a statistical spatial analysis was performed using a French cohort (STROKE 69) to describe spatial inequalities in the occurrence of stroke. STROKE 69 was a cohort study of 3,442 patients, conducted in the Rhône department of France, from November 2015 to December 2016. The cohort included all consecutive patients aged 18 years or older, with a likelihood of acute stroke within 24 hours of symptoms onset. Patients were geolocated, and incidence standardized rates ratio were estimated. SD models were identified using global spatial autocorrelation analysis and cluster detection methods. 2,179 patients were selected for analysis with spatial autocorrelation methods, including 1,467 patients with stroke, and 712 with a transient ischemic attack (TIA). Within both cluster detection methods, spatial inequalities were clearly visible, particularly in the northern region of the department and western part of the metropolitan area where rates were higher. Geographic methods for SD analysis were suitable tools to explain the spatial occurrence of stroke and identified potential spatial inequalities. This study was a first step towards understanding SD of stroke. Further research to explain SD using socio-economic data, care provision, risk factors and climate data is needed in the future.

Cystic fibrosis (CF)-related diabetes is associated with increased mortality. We analysed the clinical and glycemic profiles of two cohorts of patients treated according to the same guidelines in France and Canada. To investigate incidence differences in phenotypic and glucose abnormalities and to explore the evolution over a 4-year follow-up period, two cohorts of 224 Canadian and 147 French adult CF patients (≥18 years) without treated CF-related diabetes (CFRD) were followed over a 4 year period. In each of these groups, we investigated the longitudinal relationship between glucose tolerance and pulmonary function. An annual 2-hour oral glucose tolerance test was performed: fasting blood glucose (G0) and 2-h blood glucose (G2) were measured. Patients were classified at inclusion according to their glucose tolerance status: Normal glucose tolerant, abnormal glucose tolerant or de novo CFRD. Age, sex ratio and proportion of F508del homozygous patients were not statistically different between both cohorts. Canadian patients had better pulmonary function (median %FEV1 (IQR): 71.0 (55.0–82.0) vs. 64.0 (40.0–78.0), p 2) (IQR) 21.1 (19.5–22.8) vs. 19.9 (18.4–21.4), p de novo CFRD diagnosis (19.2 vs. 9.8%, p = 0.003). Decline in FEV1 over time was not different between patients according to glucose tolerance groups. Despite higher glucose levels and incidence of de novo CFRD, Canadian CF patients have a better lung function and a higher BMI than French patients. In spite of these differences between the cohorts, the decline in FEV1 in patients with abnormal glucose tolerance is similar between these groups.

The pervasive and unabated nature of global amphibian declines suggests common demographic responses to a given driver, and quantification of major drivers and responses could inform broad-scale conservation actions. We explored the influence of climate on demographic parameters (i.e., changes in the probabilities of survival and recruitment) using 31 datasets from temperate zone amphibian populations (North America and Europe) with more than a decade of observations each. There was evidence for an influence of climate on population demographic rates, but the direction and magnitude of responses to climate drivers was highly variable among taxa and among populations within taxa. These results reveal that climate drivers interact with variation in life-history traits and population-specific attributes resulting in a diversity of responses. This heterogeneity complicates the identification of conservation ‘rules of thumb’ for these taxa, and supports the notion of local focus as the most effective approach to overcome global-scale conservation challenges.

The recent developments in the field of social networks shifted the focus from static to dynamical representations, calling for new methods for their analysis and modelling. Observations in real social systems identified two main mechanisms that play a primary role in networks' evolution and influence ongoing spreading processes: the strategies individuals adopt when selecting between new or old social ties, and the bursty nature of the social activity setting the pace of these choices. We introduce a time-varying network model accounting both for ties selection and burstiness and we analytically study its phase diagram. The interplay of the two effects is non trivial and, interestingly, the effects of burstiness might be suppressed in regimes where individuals exhibit a strong preference towards previously activated ties. The results are tested against numerical simulations and compared with two empirical datasets with very good agreement. Consequently, the framework provides a principled method to classify the temporal features of real networks, and thus yields new insights to elucidate the effects of social dynamics on spreading processes.

A microwave domain characterization approach is proposed to determine the properties of high quality factor optical resonators. This approach features a very high precision in frequency and aims to acquire a full knowledge of the complex transfer function (amplitude and phase) characterizing an optical resonator using a microwave vector network analyzer. It is able to discriminate between the different coupling regimes, from the under-coupling to the selective amplification, and it is used together with a model from which the main resonator parameters are extracted, i.e. coupling factor, intrinsic losses, phase slope, intrinsic and external quality factor.

International audience; Abstract Cuticle pigmentation was shown to be associated with body temperature for several relatively large species of insects, but it was questioned for small insects. Here we used a thermal camera to assess the association between drosophilid cuticle pigmentation and body temperature increase when individuals are exposed to light. We compared mutants of large effects within species ( Drosophila melanogaster ebony and yellow mutants). Then we analyzed the impact of naturally occurring pigmentation variation within species complexes ( Drosophila americana/Drosophila novamexicana and Drosophila yakuba/Drosophila santomea ). Finally we analyzed lines of D. melanogaster with moderate differences in pigmentation. We found significant differences in temperatures for each of the four pairs we analyzed. The temperature differences appeared to be proportional to the differently pigmented area: between Drosophila melanogaster ebony and yellow mutants or between Drosophila americana and Drosophila novamexicana, for which the whole body is differently pigmented, the temperature difference was around 0.6 °C ± 0.2 °C. By contrast, between D. yakuba and D. santomea or between Drosophila melanogaster Dark and Pale lines, for which only the posterior abdomen is differentially pigmented, we detected a temperature difference of about 0.14 °C ± 0.10 °C. This strongly suggests that cuticle pigmentation has ecological implications in drosophilids regarding adaptation to environmental temperature.; Il a été démontré que la pigmentation de la cuticule est associée à la température corporelle pour plusieurs espèces d'insectes relativement grandes, mais cela a été mis en doute pour les petits insectes. Ici, nous avons utilisé une caméra thermique pour évaluer l'association entre la pigmentation de la cuticule des drosophiles et l'augmentation de la température corporelle lorsque les individus sont exposés à la lumière. Nous avons comparé des mutants avec des effets importants au sein de la même espèce ( mutants ebony et yellow de Drosophila melanogaster). Puis nous avons analysé l'impact de la variation naturelle de la pigmentation au sein de complexes d'espèces ( Drosophila americana/Drosophila novamexicana et Drosophila yakuba/Drosophila santomea ). Enfin, nous avons analysé des lignées de D. melanogaster présentant des différences modérées de pigmentation. Nous avons trouvé des différences significatives de température pour chacune des quatre paires analysées. Les différences de température se révèlent être proportionnelles à la zone différemment pigmentée : entre les mutants ebony et yellow de Drosophila melanogaster ou entre Drosophila americana et Drosophila novamexicana, pour lesquels l'ensemble du corps est différemment pigmenté, la différence de température était d'environ 0,6 °C ± 0,2 °C. En revanche, entre D. yakuba et D. santomea ou entre les lignées Dark et Pale de Drosophila melanogaster, pour lesquelles seule la partie postérieure de l'abdomen est pigmentée de manière différente, nous avons détecté une différence de température d'environ 0,14 °C ± 0,10 °C. Ceci suggère fortement que la pigmentation de la cuticule a des implications écologiques chez les drosophiles concernant l'adaptation à la température environnementale.

International audience; Mixotrophic protists are increasingly recognized for their significant contribution to carbon (C) cycling. As phototrophs they contribute to photosynthetic C fixation, whilst as predators of decomposers, they indirectly influence organic matter decomposition. Despite these direct and indirect effects on the C cycle, little is known about the responses of peatland mixotrophs to climate change and the potential consequences for the peatland C cycle. With a combination of field and microcosm experiments, we show that mixotrophs in the Sphagnum bryosphere play an important role in modulating peatland C cycle responses to experimental warming. We found that five years of consecutive summer warming with peaks of �2 to +8°C led to a 50% reduction in the biomass of the dominant mixotrophs, the mixotrophic testate amoebae (MTA). The biomass of other microbial groups (including decomposers) did not change, suggesting MTA to be particularly sensitive to temperature. In a microcosm experiment under controlled conditions, we then manipulated the abundance of MTA, and showed that the reported 50% reduction of MTA biomass in the field was linked to a significant reduction of net C uptake (-13%) of the entire Sphagnum bryosphere. Our findings suggest that reduced abundance of MTA with climate warming could lead to reduced peatland C fixation. The vast majority of the Earth's organisms meet their requirements for carbon (C) and energy either by utilising light to assimilate CO 2 through photosynthesis (autotrophy), or by the uptake of organic C compounds (heterotrophy). However, some organisms have the potential to combine auto-and heterotrophic C uptake, a strategy termed 'mixotrophy'

Scientific reports 12, 734 (2022). doi:10.1038/s41598-021-04531-x, Published by Macmillan Publishers Limited, part of Springer Nature, [London]

Tear fluid is emerging as a source of non-invasive biomarkers, both for ocular and systemic conditions. Accurate quantification of tear proteins can be improved by standardizing methods to collect and process tear fluid. The aim of this study was to determine sample handling factors that may influence the tear protein biomarker profile. Tear fluid was collected using Schirmer’s strips. Tear proteins were extracted by elution through centrifugation. Total protein content was determined using the bicinchoninic acid assay. Key concepts that apply to the entire sample processing cycle are tear sampling, tear storage, protein extraction and data normalization. Differences in wetting or migration length were observed between Schirmer’s strips from different manufacturers, and between protein-free and protein-rich solutions. One unit of migration length (mm) did not correspond to one unit of volume (µL). A positive correlation (r = 0.6671, p

In chronic obstructive pulmonary disease (COPD), comorbidities and worse functional status predict worse outcomes, but how these predictors compare with regard to different outcomes is not well studied. We thus compared the role of cardiovascular comorbidities for mortality and exacerbations. Data from baseline and up to four follow-up visits of the COSYCONET cohort were used. Cox or Poisson regression was employed to determine the relationship of predictors to mortality or mean annual exacerbation rate, respectively. Predictors comprised major comorbidities (including cardiovascular disease), lung function (forced expiratory volume in 1 s [FEV1], diffusion capacity for carbon monoxide [TLCO]) and their changes over time, baseline symptoms, exacerbations, physical activity, and cardiovascular medication. Overall, 1817 patients were included. Chronic coronary artery disease (p = 0.005), hypertension (p = 0.044) and the annual decline in TLCO (p = 0.001), but not FEV1 decline, were predictors of mortality. In contrast, the annual decline of FEV1 (p = 0.019) but not that of TLCO or cardiovascular comorbidities were linked to annual exacerbation rate. In conclusion, the presence of chronic coronary artery disease and hypertension were predictors of increased mortality in COPD, but not of increased exacerbation risk. This emphasizes the need for broad diagnostic workup in COPD, including the assessment of cardiovascular comorbidity.Clinical Trials: NCT01245933.

In most social and information systems the activity of agents generates rapidly evolving time-varying networks. The temporal variation in networks' connectivity patterns and the ongoing dynamic processes are usually coupled in ways that still challenge our mathematical or computational modelling. Here we analyse a mobile call dataset and find a simple statistical law that characterize the temporal evolution of users' egocentric networks. We encode this observation in a reinforcement process defining a time-varying network model that exhibits the emergence of strong and weak ties. We study the effect of time-varying and heterogeneous interactions on the classic rumour spreading model in both synthetic, and real-world networks. We observe that strong ties severely inhibit information diffusion by confining the spreading process among agents with recurrent communication patterns. This provides the counterintuitive evidence that strong ties may have a negative role in the spreading of information across networks., 22 pages, 15 figures

We investigated the prospective associations of body composition with cardiac structure and function and explored effect modification by sex and whether inflammation was a mediator in these associations. Total body (BF), trunk (TF) and leg fat (LF), and total lean mass (LM) were measured at baseline by a whole body DXA scan. Inflammatory biomarkers and echocardiographic measures were determined both at baseline and follow-up in the Hoorn Study (n = 321). We performed linear regression analyses with body composition measures as determinant and left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI) or left atrial volume index (LAVI) at follow-up as outcome. Additionally, we performed mediation analysis using inflammation at follow-up as mediator. The study population was 67.7 ± 5.2 years and 50% were female. After adjustment, BF, TF and LF, and LM were associated with LVMI with regression coefficients of 2.9 (0.8; 5.1)g/m2.7, 2.3 (0.6; 4.0)g/m2.7, 2.0 (0.04; 4.0)g/m2.7 and − 2.9 (− 5.1; − 0.7)g/m2.7. Body composition measures were not associated with LVEF or LAVI. These associations were not modified by sex or mediated by inflammation. Body composition could play a role in the pathophysiology of LV hypertrophy. Future research should focus on sex differences in regional adiposity in relation with diastolic dysfunction.

Peripheral artery disease (PAD) patients have an increased cardiovascular risk despite pharmacological treatment strategies. Biomarker research improving risk stratification only focused on known atherothrombotic pathways, but unexplored pathways might play more important roles. To explore the association between a broad cardiovascular biomarker set and cardiovascular risk in PAD. 120 PAD outpatients were enrolled in this observational cohort study. Patients were followed for one year in which the composite endpoint (myocardial infarction, coronary revascularization, stroke, acute limb ischemia and mortality) was assessed. Patient data and blood samples were collected upon inclusion, and citrated platelet-poor plasma was used to analyze 184 biomarkers in Olink Cardiovascular panel II and III using a proximity extension assay. Fifteen patients reached the composite endpoint. These patients had more prior strokes and higher serum creatinine levels. Multivariate analysis revealed increased plasma levels of protease-activated receptor 1 (PAR1), galectin-9 (Gal-9), tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) and interleukin 6 (IL-6) to be most predictive for cardiovascular events and mortality. Positive regulation of acute inflammatory responses and leukocyte chemotaxis were identified as involved biological processes. This study identified IL-6, PAR1, Gal-9, TNFRSF11A as potent predictors for cardiovascular events and mortality in PAD, and potential drug development targets.

Our objective was to assess the incidence of drug bioaccumulation in critically ill COVID-19 patients with AKI receiving intermediate dose nadroparin for thrombosis prophylaxis. We conducted a Prospective cohort study of critically ill COVID-19 patients. In patients on intermediate dose nadroparin (5700 IU once daily) we assessed the incidence of bioaccumulation (trough anti-Xa level > 0.2 IU/mL) stratified according to presence of AKI. We quantified this association using multilevel analyses. To assess robustness of our observations, we explored the association between AKI and anti-Xa activity in patients receiving high dose nadroparin (> 5700 IU). 108 patients received intermediate dose nadroparin, of whom 24 had AKI during 36 anti-Xa measurements. One patient with AKI (4.2% [95%CI 0.1–21%]) and 1 without (1.2% [95%CI 0.03–6.5%]) developed bioaccumulation (p = 0.39). Development of AKI was associated with a mean increase of 0.04 (95%CI 0.02–0.05) IU/ml anti-Xa activity. There was no statistically significant association between anti-Xa activity and AKI in 51 patients on high dose nadroparin. There were four major bleeding events, all in patients on high dose nadroparin. In conclusion, Bioaccumulation of an intermediate dose nadroparin did not occur to a significant extent in critically ill patients with COVID-19 complicated by AKI. Dose adjustment in AKI may be unnecessary.

International audience; The black truffle Tuber melanosporum was disseminated all over the world, propelled by the development of a wide variety of empirical practices. A widespread practice, called ‘truffle trap’, consists of placing pieces of truffles into excavations dug under host trees, and of collecting truffle in these traps in the next years. This research aims at (1) evaluating the effect of this practice on fruitbody production based on the analysis of 9924 truffle traps installed in 11 orchards across T. melanosporum native area in France and (2) exploring the mechanisms involved in fruitbody emergence using traps where the genotypes of introduced truffles were compared with those of fruitbodies collected in the same traps. We confirmed that truffle traps provide a major and highly variable part of truffle ground production, representing up to 89% of the collected fruitbodies. We evidenced a genetic link between introduced spores and collected fruitbodies, and then demonstrated that truffle growers provide paternal partners for mating with local maternal mycelia. We also highlighted that soil disturbance stimulate the vegetative development of established maternal mycelia. This research supports that a widely used traditional practice enhances fruitbody production by shaping favorable conditions and providing sexual partners required for fruiting.The black truffle Tuber melanosporum was disseminated all over the world, propelled by the development of a wide variety of empirical practices. A widespread practice, called ‘truffle trap’, consists of placing pieces of truffles into excavations dug under host trees, and of collecting truffle in these traps in the next years. This research aims at (1) evaluating the effect of this practice on fruitbody production based on the analysis of 9924 truffle traps installed in 11 orchards across T. melanosporum native area in France and (2) exploring the mechanisms involved in fruitbody emergence using traps where the genotypes of introduced truffles were compared with those of fruitbodies collected in the same traps. We confirmed that truffle traps provide a major and highly variable part of truffle ground production, representing up to 89% of the collected fruitbodies. We evidenced a genetic link between introduced spores and collected fruitbodies, and then demonstrated that truffle growers provide paternal partners for mating with local maternal mycelia. We also highlighted that soil disturbance stimulate the vegetative development of established maternal mycelia. This research supports that a widely used traditional practice enhances fruitbody production by shaping favorable conditions and providing sexual partners required for fruiting.

Patients with SARS-CoV-2 infection present with different lung compliance and progression of disease differs. Measures of lung mechanics in SARS-CoV-2 patients may unravel different pathophysiologic mechanisms during mechanical ventilation. The objective of this prospective observational study is to describe whether Electrical Impedance Tomography (EIT) guided positive end-expiratory pressure (PEEP) levels unravel changes in EIT-derived parameters over time and whether the changes differ between survivors and non-survivors. Serial EIT-measurements of alveolar overdistension, collapse, and compliance change in ventilated SARS-CoV-2 patients were analysed. In 80 out of 94 patients, we took 283 EIT measurements (93 from day 1–3 after intubation, 66 from day 4–6, and 124 from day 7 and beyond). Fifty-one patients (64%) survived the ICU. At admission mean PaO2/FiO2-ratio was 184.3 (SD 61.4) vs. 151.3 (SD 54.4) mmHg, (p = 0.017) and PEEP was 11.8 (SD 2.8) cmH2O vs. 11.3 (SD 3.4) cmH2O, (p = 0.475), for ICU survivors and non-survivors. At day 1–3, compliance was ~ 55 mL/cmH2O vs. ~ 45 mL/cmH2O in survivors vs. non-survivors. The intersection of overdistension and collapse curves appeared similar at a PEEP of ~ 12–13 cmH2O. At day 4–6 compliance changed to ~ 50 mL/cmH2O vs. ~ 38 mL/cmH2O. At day 7 and beyond, compliance was ~ 38 mL/cmH2O with the intersection at a PEEP of ~ 9 cmH2O vs. ~ 25 mL/cmH2O with overdistension intersecting at collapse curves at a PEEP of ~ 7 cmH2O. Surviving SARS-CoV-2 patients show more favourable EIT-derived parameters and a higher compliance compared to non-survivors over time. This knowledge is valuable for discovering the different groups.

Scientific reports 12(1), 14011 (2022). doi:10.1038/s41598-022-18294-6, Published by Macmillan Publishers Limited, part of Springer Nature, [London]

IDH1-mutated cholangiocarcinomas (CCAs) are an interesting group of neoplasia with particular behavior and therapeutic implications. The aim of the present work is to highlight the differences characterizing IDH1m and IDH1wt CCAs in terms of genomic landscape. 284 patients with iCCA treated for resectable, locally advanced or metastatic disease were selected and studied with the FOUNDATION Cdx technology. A comparative genomic analysis and survival analyses for the most relevant altered genes were performed between IDH1m and IDH1wt patients. Overall, 125 patients were IDH1m and 122 IDH1wt. IDH1m patients showed higher mutation rates compared to IDH1wt in CDKN2B and lower mutation rates in several genes including TP53, FGFR2, BRCA2, ATM, MAP3K1, NOTCH2, ZNF703, CCND1, NBN, NF1, MAP3KI3, and RAD21. At the survival analysis, IDH1m and IDH1wt patients showed no statistically differences in terms of survival outcomes, but a trend in favor of IDH1wt patients was observed. Differences in prognostic values of the most common altered genes were reported. In surgical setting, in IDH1m group the presence of CDKN2A and CDKN2B mutations negatively impact DFS, whereas the presence of CDKN2A, CDKN2B, and PBRM1 mutations negatively impact OS. In advanced setting, in the IDH1m group, the presence of KRAS/NRAS and TP53 mutations negatively impact PFS, whereas the presence of TP53 and PIK3CA mutations negatively impact OS; in the IDH1wt group, only the presence of MTAP mutation negatively impact PFS, whereas the presence of TP53 mutation negatively impact OS. We highlighted several molecular differences with distinct prognostic implications between IDH1m and IDH1wt patients.

N-acetylaspartate (NAA) is the second most abundant metabolite in the human brain; although it is assumed to be a proxy for a neuronal marker, its function is not fully elucidated. NAA is also detectable in plasma, but its relation to cerebral NAA levels, cognitive performance, or features of cerebral disease has not been investigated. To study whether circulating NAA tracks cerebral NAA levels, and whether circulating NAA correlates with cognitive function and features of cerebral small vessel disease (SVD). Two datasets were analyzed. In dataset 1, structural MRI was acquired in 533 subjects to assess four features of cerebral SVD. Cognitive function was evaluated with standardized test scores (N = 824). In dataset 2, brain 1H-MRS from the occipital region was acquired (N = 49). In all subjects, fasting circulating NAA was measured with mass spectrometry. Dataset 1: in univariate and adjusted for confounders models, we found no correlation between circulating NAA and the examined features of cerebral SVD. In univariate analysis, circulating NAA levels were associated inversely with the speed in information processing and the executive function score, however these associations were lost after accounting for confounders. In line with the negative findings of dataset 1, in dataset 2 there was no correlation between circulating and central NAA or total NAA levels. This study indicates that circulating NAA levels do not reflect central (occipital) NAA levels, cognitive function, or cerebral small vessel disease in man.

International audience; No abstract available