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This study investigates thermal circulations on Reunion Island (21°07'S 55°32'E), focusing on the complex terrain of the region. Observations from the BIO‐MAÏDO campaign, along with 2 days of high‐resolution simulation using the MesoNH model, were analyzed to understand the thermally‐driven mechanisms. This simulation was conducted with a horizontal resolution of 100 m and employed a vertically stretched grid, achieving a resolution of 1 m at the lowest levels. Two distinct wind regimes were identified, characterized by katabatic flows prevailing within a 30 m thick layer during nighttime, and an anabatic flow manifesting within a layer spanning from 150 to 200 m during the daytime. The simulation was confirmed through validation with surface measurements, and thus enabling a detailed study of thermal breeze circulations. Results reveal that the intensity of trade winds significantly influences the development of thermal circulations. Complex layered structures in the atmosphere were also identified. At an intensity of 7 m s−1, trade winds impede the development of thermal circulations atop the slope, and result in the emergence of a convergence zone between local and regional circulations. The analysis of the breeze establishment period indicates that the katabatic flow stabilizes in 35 min, quicker than the anabatic flow, which takes 110 min. Momentum and heat budget analysis provide insights into the primary drivers of thermal circulations: buoyancy acceleration, influenced by local surface heating during anabatic flow onset, and local surface cooling during katabatic flow onset. Plain Language Summary: This research explores thermal circulation in the northwestern region of Reunion Island, an area significantly influenced by the return flow of the trade winds, the trade winds themselves, and breezes. Data from the BIOMAÏDO campaign and simulation using the MesoNH model were employed to analyze the heat‐driven air movements in this specific region. The study identified two distinct wind patterns: a downward katabatic flow within a 30 m layer and a diurnal anabatic flow occurring between elevetions of 150–200 m. Validation through surface measurements corroborated the model simulation, facilitating a detailed analysis of thermal breeze circulations. The results indicate that strong directional winds significantly influence air movement patterns. At a speed of 7 m s−1, these winds inhibit upward air movement along the slopes, creating a convergence zone between local and larger‐scale wind patterns. Analysis of the breeze establishment periods indicated a faster stabilization of katabatic flow at 35 min compared to 110 min of anabatic flow. Momentum and heat budget analysis revealed the primary drivers: buoyancy acceleration, influenced by local surface heating during anabatic flow and by local surface cooling during katabatic flow. Key Points: Trade winds strongly impact thermal circulations on Reunion Island, creating complex atmospheric structuresKatabatic flow stabilizes faster (35 min) than anabatic flow (110 min), affecting the island's thermal breeze patternsBuoyancy acceleration, local surface heating, and cooling play significant roles in driving thermal circulations [ABSTRACT FROM AUTHOR]

SUMMARY: Chloroplast ATP synthase contains subunits of plastid and nuclear genetic origin. To investigate the coordinated biogenesis of this complex, we isolated novel ATP synthase mutants in the green alga Chlamydomonas reinhardtii by screening for high light sensitivity. We report here the characterization of mutants affecting the two peripheral stalk subunits b and b′, encoded respectively by the atpF and ATPG genes, and of three independent mutants which identify the nuclear factor MDE1, required to stabilize the chloroplast‐encoded atpE mRNA. Whole‐genome sequencing revealed a transposon insertion in the 3′UTR of ATPG while mass spectrometry shows a small accumulation of functional ATP synthase in this knock‐down ATPG mutant. In contrast, knock‐out ATPG mutants, obtained by CRISPR‐Cas9 gene editing, fully prevent ATP synthase function and accumulation, as also observed in an atpF frame‐shift mutant. Crossing ATP synthase mutants with the ftsh1‐1 mutant of the major thylakoid protease identifies AtpH as an FTSH substrate, and shows that FTSH significantly contributes to the concerted accumulation of ATP synthase subunits. In mde1 mutants, the absence of atpE transcript fully prevents ATP synthase biogenesis and photosynthesis. Using chimeric atpE genes to rescue atpE transcript accumulation, we demonstrate that MDE1, a novel octotricopeptide repeat (OPR) protein, genetically targets the atpE 5′UTR. In the perspective of the primary endosymbiosis (~1.5 Gy), the recruitment of MDE1 to its atpE target exemplifies a nucleus/chloroplast interplay that evolved rather recently, in the ancestor of the CS clade of Chlorophyceae, ~300 My ago. [ABSTRACT FROM AUTHOR]

Background: Oestrogen receptor alpha (ER) is involved in cell growth and proliferation and functions as a transcription factor, a transcriptional coregulator, and in cytoplasmic signalling. It affects, for example, bone, endometrium, ovaries and mammary epithelium. It is a key biomarker in clinical management of breast cancer, where it is used as a prognostic and treatment‐predictive factor, and a therapeutical target. Several ER isoforms have been described, but transcript annotation in public databases is incomplete and inconsistent, and functional differences are not well understood. Methods: We have analysed short‐ and long‐read RNA sequencing data from breast tumours, breast cancer cell lines, and normal tissues to create a comprehensive annotation of ER transcripts and combined it with experimental studies of full‐length protein and six alternative isoforms. Results: The isoforms have varying transcription factor activity, subcellular localisation, and response to the ER‐targeting drugs tamoxifen and fulvestrant. Antibodies differ in ability to detect alternative isoforms, which raises concerns for the interpretation of ER‐status in routine pathology. Conclusions: Future work should investigate the effects of alternative isoforms on patient survival and therapy response. An accurate annotation of ER isoforms will aid in interpretation of clinical data and inform functional studies to improve our understanding of the ER in health and disease. [ABSTRACT FROM AUTHOR]

Jet streams are important sources of non‐orographic internal gravity waves and clear air turbulence (CAT). We analyze non‐orographic gravity waves and CAT during a merger of the polar front jet stream (PFJ) with the subtropical jet stream (STJ) above the southern Atlantic. Thereby, we use a novel combination of airborne observations covering the meso‐scale and turbulent scale in combination with high‐resolution deterministic short‐term forecasts. Coherent phase lines of temperature perturbations by gravity waves stretching along a highly sheared tropopause fold are simulated by the ECMWF IFS (integrated forecast system) forecasts. During the merging event, the PFJ reverses its direction from approximately antiparallel to parallel with respect to the STJ, going along with strong wind shear and horizontal deformation. Temperature perturbations in limb‐imaging and lidar observations onboard the research aircraft HALO during the SouthTRAC campaign show remarkable agreement with the IFS data. Ten hours earlier, the IFS data show an "X‐shaped" pattern in the temperature perturbations emanating from the sheared tropopause fold. Tendencies of the IFS wind components show that these gravity waves are excited by spontaneous emission adjusting the strongly divergent flow when the PFJ impinges the STJ. In situ observations of temperature and wind components at 100 Hz confirm upward propagation of the probed portion of the gravity waves. They furthermore reveal embedded episodes of light‐to‐moderate CAT, Kelvin Helmholtz waves, and indications for partial wave reflection. Patches of low Richardson numbers in the IFS data coincide with the CAT observations, suggesting that this event was accessible to turbulence forecasting. Plain Language Summary: Gravity waves play an in important role in vertical and horizontal energy transport in the atmosphere and are significant factors in wheather forecasting and climate projections. Among other processes, tropospheric jet streams are known to be sources of gravity waves. They furthermore can be accompanied by tropopause folds (i.e., local tropopause depressions, where stratospheric air can reach deeply into the troposphere) and turbulence, which is relevant for aviation safety. Using a novel combination of airborne observations and data by a state‐of‐the‐art forecasting system, we analyze gravity waves and turbulence during a merger of tropospheric jet streams above the southern Atlantic. The observations show a high degree of agreement with the forecast data from the troposphere to the stratosphere. Ten hours earlier, the forcast data show an "X‐shaped" gravity wave structure that emerges from a highly sheared tropopause fold between the merging jet streams. Fast in situ observations at the flight level provide information on the characteristics of the observed waves and show light‐to‐moderate turbulence, small‐scale waves and indications for partial wave reflection. The observed turbulence events are consistently located in regions where the forecast data suggest potential for turbulence. Key Points: Non‐orographic internal gravity waves and clear air turbulence are observed in merging jet streamsState‐of‐the art high resolution forecast agrees with novel combination of airborne sensors"X‐shaped" gravity wave feature resulting from merging jet streams at a highly sheared tropopause fold [ABSTRACT FROM AUTHOR]

Predicting secondary organic aerosol (SOA) formation relies either on extremely detailed, numerically expensive models accounting for the condensation of individual species or on extremely simplified, numerically affordable models parameterizing SOA formation for large‐scale simulations. In this work, we explore the possibility of creating a random forest to reproduce the behavior of a detailed atmospheric organic chemistry model at a fraction of the numerical cost. A comprehensive data set was created based on thousands of individual detailed simulations, randomly initialized to account for the variety of atmospheric chemical environments. Recurrent random forests were trained to predict organic matter formation from dodecane and toluene precursors, and the partitioning between gas and particle phases. Validation tests show that the random forests perform well without any divergence over 10 days of simulations. The distribution of errors shows that the sampling of initial conditions for the training simulations needs to focus on chemical regimes where SOA production is the most sensitive. Sensitivity tests show that specializing multiple random forests for a specific chemical regime is not more efficient than training a single general random forest for the entire data set. The most important predictors are those providing information about the chemical regime, oxidants levels, and existing organic mass. The choice of predictors is crucial as using too many unimportant predictors reduces the performances of the random forests. Plain Language Summary: Organic compounds constitute a significant fraction of atmospheric particles and thus have an impact on health and climate. Predicting the contribution of organic compounds to atmospheric particles is extremely complex because of the very large number of different chemical species potentially condensing into the aerosol phase. Air quality and climate models usually rely on simplified, empirical approaches to predict organic aerosol mass concentrations, based on laboratory experiments. In this work, we apply a machine learning approach to construct a tool that behaves like the most detailed organic chemistry model, for a numerical cost affordable by air quality and climate models. Building upon this method, it will be possible to bring the complexities of organic chemistry to large‐scale models. Key Points: Random forests were trained to reproduce toluene and dodecane secondary organic aerosol formation calculated by an explicit organic chemistry mechanismThe random forests performances are highly sensitive to the chemical regimeThere is an optimal number of predictors and their selection depends on the precursor [ABSTRACT FROM AUTHOR]

In this report the design, fabrication, and testing of inkjet‐printed electrochromic pixels (ECPs) incorporating the biochrome, xanthommatin (Xa) as programmable display units is described. As a redox sensitive chromophore, Xa is present in some species as a physiological indicator with red (reduced) or yellow (oxidized) colors associated with different behavioral or developmental stages. These features have been recently leveraged in some materials applications, illustrating a bio‐inspired design solution to color‐changing sensors and displays. This paper describes an extension of these applications to print individually addressable ECPs that can be processed in a mild annealing step to introduce localized conductivity on initially nonconductive substrates. When formulated together with a poly(3,4‐ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) carrier ink, an addition of 0.19 wt% Xa is enough to generate dynamic ECPs which can be batch printed as lateral electrodes on any substrate to serve as both conductors and display units across electrically isolated boundaries. Application of low potentials triggers reversible color changes that span the red/yellow color space and can cycle for days. These results represent an important step towards the incorporation of alternative active materials like Xa to manufacture and scale low‐power, color‐changing pixels and patterns. [ABSTRACT FROM AUTHOR]

Advances in technology have provided fresh generations of stiff polypropylene block copolymers for gravity sewerage applications. The aim of this study is to further enhance the stiffness of these materials through the incorporation of inorganic fillers. In this study, three talc filled PP and one glass fiber filled PP composites were characterized in order to be used as a middle layer in a three‐layer sewage pipe. The obtained results showed an increase of approximately more than 100% and 250% in tensile and flexural moduli by the use of 30%–50 wt% talc‐filled PP and 30 wt.% glass fiber‐filled PP, respectively. This high increase in the rigidity of the material would allow manufacturing pipes with improving ring stiffness. Composites filled with 30 wt% talc or glass fiber showed good filler‐matrix interaction and good filler distribution and dispersion. However, reduced filler‐matrix interaction was observed in the case of the composite filled with 50 wt% talc. In addition, the use of Differential Scanning Calorimetry analysis revealed that the addition of fillers enhanced the crystallization temperature of the polypropylene matrix. Furthermore, Thermogravimetric Analysis showed that the high modulus PP grade retained its thermal stability in the various composites. [ABSTRACT FROM AUTHOR]

SGLT2 inhibitors appear to protect the kidneys through pleiotropic effects.[2] SGLT2 inhibitors preserve kidney function in part by reducing the physical stress on glomerular capillaries. Sodium-glucose co-transporter-2 (SGLT2) inhibitors are anti-hyperglycemic agents that eliminate excess glucose by lowering proximal tubule glucose reabsorption and inducing a glucosuric effect. As such, SGLT2 inhibitors preserve renal oxygenation again with a three-pronged approach: by direct SGLT2 inhibition in the early proximal tubule, by lowering GFR, and via the functional coupling of SGLT2 to other transporters in the proximal tubule. [Extracted from the article]

Secondary organic aerosols (SOA) are formed from oxidation of hundreds of volatile organic compounds (VOCs) emitted from anthropogenic and natural sources. Accurate predictions of this chemistry are key for air quality and climate studies due to the large contribution of organic aerosols to submicron aerosol mass. Currently, only explicit models, such as the Generator for Explicit Chemistry and Kinetics of Organics in the Atmosphere (GECKO‐A), can fully represent the chemical processing of thousands of organic species. However, their extreme computational cost prohibits their use in current chemistry‐climate models, which rely on simplified empirical parameterizations to predict SOA concentrations. This study demonstrates that machine learning can accurately emulate SOA formation from an explicit chemistry model with an approximate error of 2%–8%, up to five days for several precursors and for potentially up to one month for recurrent neural network models, and with 100 to 100,000 times speedup over GECKO‐A, making it computationally useable in a chemistry‐climate model. We generated the training data using thousands of GECKO‐A box simulations sampled from a broad range of initial environmental conditions, and focused on three representative SOA precursors: the oxidation by OH of two anthropogenic (toluene, dodecane), and the oxidation by O3 of one biogenic VOC (α‐pinene). We compare several neural models and quantify their underlying uncertainty and robustness. These are promising results, suggesting that neural network models could be applied to predict SOA in chemistry‐climate models, limited however to the range of environmental conditions that were considered in the training datasets. Plain Language Summary: Detailed and accurate representation of organic aerosol chemistry is needed to predict the effect of atmospheric aerosols formed from natural and anthropogenic sources on both human health and climate. Ideally, these complex representations of chemistry would be directly included within state‐of‐the‐art weather and climate models to get a fully coupled system with meteorological and climatological feedback all over the globe. However, we are many years away from having the computational power needed to run such fully coupled large‐scale simulations due to the complexity of organic chemistry, which involves hundreds of thousands of organic gaseous and particle species and chemical reactions. As a potential solution, we test an approach that uses a neural network to mimic the solution of an explicit representation of organic chemistry which would be computationally feasible to link with current air quality and climate models. Key Points: Incorporation of explicit organic chemistry into 3D chemistry‐simulations requires emulationWe developed two types of neural network emulators for the Generator for Explicit Chemistry and Kinetics of Organics in the Atmosphere chemistry modelThe emulators produced accurate and stable simulations for three precursor species [ABSTRACT FROM AUTHOR]

By lowering single nephron hyperfiltration and, thus, the tubular load, SGLT2 inhibitors reduce the oxygen-consuming transport work of the kidney cortex ( B Figure b 2). Thus, SGLT2 inhibitors can protect the kidneys (and heart), and this seems to be a class effect that is independent of kidney function and, at least in part, of T2DM. Hypoxia due to hyper-reabsorption or kidney injury limits apical hyper-reabsorption and enhances basolateral glucose uptake via GLUT1, and induces a metabolic shift to glycolysis (8). [Extracted from the article]

Genomic rearrangements in cancer cells can create gene fusions where the juxtaposition of two different genes leads to the production of chimeric proteins or altered gene expression through promoter‐swapping. We have previously shown that fusion transcripts involving microRNA (miRNA) host genes contribute to deregulation of miRNA expression regardless of the protein‐coding potential of these transcripts. Many different genes can also be used as 5′ partners by a miRNA host gene in what we named recurrent miRNA‐convergent fusions. Here, we have explored the properties of 5′ partners in fusion transcripts that involve miRNA hosts in breast tumours from The Cancer Genome Atlas (TCGA). We hypothesised that firstly, 5′ partner genes should belong to pathways and transcriptional programmes that reflect the tumour phenotype and secondly, there should be a selection for fusion events that shape miRNA expression to benefit the tumour cell through the known hallmarks of cancer. We found that the set of 5′ partners in miRNA host fusions is non‐random, with overrepresentation of highly expressed genes in pathways active in cancer including epithelial‐to‐mesenchymal transition, translational regulation and oestrogen signalling. Furthermore, many miRNAs were upregulated in samples with host gene fusions, including established oncogenic miRNAs such as mir‐21 and the mir‐106b~mir‐93~mir‐25 cluster. To the list of mechanisms for deregulation of miRNA expression, we have added fusion transcripts that change the promoter region. We propose that this adds material for genetic selection and tumour evolution in cancer cells and that miRNA host fusions can act as tumour 'drivers'. [ABSTRACT FROM AUTHOR]

Objective: To develop and scale algorithm‐enabled patient prioritization to improve population‐level management of type 1 diabetes (T1D) in a pediatric clinic with fixed resources, using telemedicine and remote monitoring of patients via continuous glucose monitor (CGM) data review. Research design and methods: We adapted consensus glucose targets for T1D patients using CGM to identify interpretable clinical criteria to prioritize patients for weekly provider review. The criteria were constructed to manage the number of patients reviewed weekly and identify patients who most needed provider contact. We developed an interactive dashboard to display CGM data relevant for the patients prioritized for review. Results: The introduction of the new criteria and interactive dashboard was associated with a 60% reduction in the mean time spent by diabetes team members who remotely and asynchronously reviewed patient data and contacted patients, from 3.2 ± 0.20 to 1.3 ± 0.24 min per patient per week. Given fixed resources for review, this corresponded to an estimated 147% increase in weekly clinic capacity. Patients who qualified for and received remote review (n = 58) have associated 8.8 percentage points (pp) (95% CI = 0.6–16.9 pp) greater time‐in‐range (70–180 mg/dl) glucoses compared to 25 control patients who did not qualify at 12 months after T1D onset. Conclusions: An algorithm‐enabled prioritization of T1D patients with CGM for asynchronous remote review reduced provider time spent per patient and was associated with improved time‐in‐range. [ABSTRACT FROM AUTHOR]

The guidance document on risk assessment for birds and mammals (GD) provides generic residue values of pesticides on potential diet items for use in wildlife risk assessments. For most diet items, these values are based on a large number of residue studies. However, the default residues per unit dose (RUD; standardized for application of 1 kg substance per hectare) values for fruits were taken from a few literature trials of unclear relevance for regulatory purposes. These trials were conducted according to neither current European Union (EU) agricultural practice nor to recommendations given in the GD about how to conduct wildlife-relevant residue studies. Therefore, field study data on fruit residue levels from applications of pesticides in fruiting crops were compiled and evaluated. Corresponding studies had been conducted during the last 26 y in the EU. In the final data set, 291 studies provided 1002 residue values in different fruits, including grapes, berries (currants, raspberries, gooseberries), fruits from orchards (apple, peach, pear, lemon, mandarin, orange, apricot, cherry, plum), gourds (pumpkins, cucumbers, squash, melons), and strawberries. This data set provides a basis for revising registration-relevant RUD values for fruits as potential diet items for birds and mammals in environmental wildlife risk assessments. The objective of this study was to estimate the resulting residue levels in different fruits determined under field conditions following the application of pesticides across their growing areas within the EU in diverse climatic areas that can be used directly in wildlife risk assessments. The large data set of usually about more than 100 residue values per "fruit group," all evaluated at EU member state level, revealed significantly lower RUDs compared to the current default RUDs presented in the GD. These new RUD values for fruits should be considered for use as default values in future bird and mammal risk assessments and in respective guidance documents. Integr Environ Assess Manag 2021;17:552-561. © 2020 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology Chemistry (SETAC). [ABSTRACT FROM AUTHOR]

The association between breast cancer risk defined by the Tyrer‐Cuzick score (TC) and disease prognosis is not well established. Here, we investigated the relationship between 5‐year TC and disease aggressiveness and then characterized underlying molecular processes. In a case‐only study (n = 2474), we studied the association of TC with molecular subtypes and tumor characteristics. In a subset of patients (n = 672), we correlated gene expression to TC and computed a low‐risk TC gene expression (TC‐Gx) profile, that is, a profile expected to be negatively associated with risk, which we used to test for association with disease aggressiveness. We performed enrichment analysis to pinpoint molecular processes likely to be altered in low‐risk tumors. A higher TC was found to be inversely associated with more aggressive surrogate molecular subtypes and tumor characteristics (P <.05) including Ki‐67 proliferation status (P < 5 × 10−07). Our low‐risk TC‐Gx, based on the weighted sum of 37 expression values of genes strongly correlated with TC, was associated with basal‐like (P < 5 × 10−13), HER2‐enriched subtype (P < 5 × 10−07) and worse 10‐year breast cancer‐specific survival (log‐rank P < 5 × 10−04). Associations between low‐risk TC‐Gx and more aggressive molecular subtypes were replicated in an independent cohort from The Cancer Genome Atlas database (n = 975). Gene expression that correlated with low TC was enriched in proliferation and oncogenic signaling pathways (FDR < 0.05). Moreover, higher proliferation was a key factor explaining the association with worse survival. Women who developed breast cancer despite having a low risk were diagnosed with more aggressive tumors and had a worse prognosis, most likely driven by increased proliferation. Our findings imply the need to establish risk factors associated with more aggressive breast cancer subtypes. What's new? The Tyrer‐Cuzick score for assessing breast cancer risk integrates information on lifestyle, reproductive, and familial factors, including BRCA mutation status. The relationship between Tyrer‐Cuzick score and specific breast cancer subtypes, however, remains unclear. In this investigation, five‐year, low‐risk Tyrer‐Cuzick gene expression profile, expected to be negatively correlated with risk, was associated with certain, more aggressive breast cancer subtypes, including basal‐like and HER2‐enriched subtypes. Analyses further indicate that genes and biological pathways involved in increased proliferation underlie this association. The findings draw attention to factors relevant to aggressive breast cancer subtypes that are not yet captured in risk assessment tools. [ABSTRACT FROM AUTHOR]

Breast cancer is a disease of genomic alterations, of which the panorama of somatic mutations and how these relate to subtypes and therapy response is incompletely understood. Within SCAN‐B (ClinicalTrials.gov: NCT02306096), a prospective study elucidating the transcriptomic profiles for thousands of breast cancers, we developed a RNA‐seq pipeline for detection of SNVs/indels and profiled a real‐world cohort of 3,217 breast tumors. We describe the mutational landscape of primary breast cancer viewed through the transcriptome of a large population‐based cohort and relate it to patient survival. We demonstrate that RNA‐seq can be used to call mutations in genes such as PIK3CA,TP53, and ERBB2, as well as the status of molecular pathways and mutational burden, and identify potentially druggable mutations in 86.8% of tumors. To make this rich dataset available for the research community, we developed an open source web application, the SCAN‐B MutationExplorer (http://oncogenomics.bmc.lu.se/MutationExplorer). These results add another dimension to the use of RNA‐seq as a clinical tool, where both gene expression‐ and mutation‐based biomarkers can be interrogated in real‐time within 1 week of tumor sampling. Synopsis: A bioinformatics pipeline was developed for detection of single nucleotide variants and small insertions/deletions from RNA sequencing (RNA‐seq) data. The mutational landscape of 3,217 primary breast cancer transcriptomes in relation to patient survival was made available through a public web portal. An optimized pipeline for detection of single nucleotide variants and short insertions and deletions from RNA‐seq data was developed and applied to 3,217 primary breast tumors.The mutational portraits identified mutations in clinically important genes, including mutations in one or more potentially druggable genes in 85.3% percent of cases.Mutational portraits revealed significant relationships to patient outcome within specific treatment groups, including treatment resistance mutations.This rich dataset was made publicly available via our open source web‐based application, the SCAN‐B MutationExplorer, accessible at http://oncogenomics.bmc.lu.se/MutationExplorer. [ABSTRACT FROM AUTHOR]

Genomic rearrangements in cancer can join the sequences of two separate genes. Studies of such gene fusion events have mainly focused on identification of fusion proteins from the chimeric transcripts. We have previously investigated how fusions instead can affect the expression of intronic microRNA (miRNA) genes that are encoded within fusion gene partners. Here, we extend our analysis to small nucleolar RNAs (snoRNAs) that also are embedded within protein‐coding or noncoding host genes. We found that snoRNA hosts are selectively enriched in fusion transcripts, like miRNA host genes, and that this enrichment is associated with all snoRNA classes. These structural changes may have functional consequences for the cell; proteins involved in the protein translation machinery are overrepresented among snoRNA host genes, a gene architecture assumed to be needed for closely coordinated expression of snoRNAs and host proteins. Our data indicate that this structure is frequently disrupted in cancer. We furthermore observed that snoRNA genes involved in fusions tend to associate with stronger promoters than the natural host, suggesting a mechanism that selects for snoRNA overexpression. In summary, we highlight a previously unexplored frequent structural change in cancer that affects important components of cellular physiology. What's new? Genomic rearrangements in cancer can join the sequences of two separate genes, but studies of such gene fusion events have mainly focused on identification of fusion proteins from the chimeric transcripts. We instead focus on intronic non‐coding RNAs and demonstrate that snoRNA host genes are enriched among fusion partners. Our analysis of fusion transcripts in breast cancer indicates that genomic rearrangements contribute to global deregulation of snoRNA expression and protein translation dynamics in breast cancer. [ABSTRACT FROM AUTHOR]

Chronic sun‐damaged (CSD) melanoma represents 10%–20% of cutaneous melanomas and is characterized by infrequent BRAF V600E mutations and high mutational load. However, the order of genetic events or the extent of intra‐tumor heterogeneity (ITH) in CSDhigh melanoma is still unknown. Ultra‐deep targeted sequencing of 40 cancer‐associated genes was performed in 72 in situ or invasive CMM, including 23 CSDhigh cases. In addition, we performed whole exome and RNA sequencing on multiple regions of primary tumor and multiple in‐transit metastases from one CSDhigh melanoma patient. We found no significant difference in mutation frequency in melanoma‐related genes or in mutational load between in situ and invasive CSDhigh lesions, while this difference was observed in CSDlow lesions. In addition, increased frequency of BRAF V600K, NF1, and TP53 mutations (p <.01, Fisher's exact test) was found in CSDhigh melanomas. Sequencing of multiple specimens from one CSDhigh patient revealed strikingly limited ITH with >95% shared mutations. Our results provide evidence that CSDhigh and CSDlow melanomas are distinct molecular entities that progress via different genetic routes. [ABSTRACT FROM AUTHOR]

Nests play a critical role for offspring development across the animal kingdom. Nest quality may contribute to the builder's extended phenotype and serve as an ornament during mate choice. We examined male and female nest choice in the common goby (Pomatoschistus microps), a benthic fish with male‐only parental care where females deposit eggs in male‐built nests. Using prebuilt nest models, we independently manipulated two candidate nest quality traits: (a) nest entrance width with a role in oxygen ventilation, and (b) extent of sand cover with a role in camouflage. In simultaneous choice trials, male gobies exhibited no preference for any nest model type. This suggests that initial characteristics of a nesting substrate have minor importance for males, which usually remodel the nest. Females were given a choice between two males occupying either entrance‐ or cover‐manipulated nests. The same pair of males was then exposed to a second female but now with alternated nest types assigned. Most females were consistent in choosing the same, typically the heavier male of the two regardless of nest properties. However, the females that chose the same nest regardless of the male preferred low over high sand coverage and narrow over wide nest entrance. Our results indicate that females base their mating decision on a combination of male phenotype and nest traits. While we found no indication that females are attracted to highly decorated nests, our study is the first in fishes to disentangle a preference for narrow (and thus more protective) nest entrances independent of nest coverage. [ABSTRACT FROM AUTHOR]

Summary: In Chlamydomonas reinhardtii, chloroplast gene expression is tightly regulated post‐transcriptionally by gene‐specific trans‐acting protein factors. Here, we report the molecular identification of an OctotricoPeptide Repeat (OPR) protein, MDA1, which governs the maturation and accumulation of the atpA transcript, encoding subunit α of the chloroplast ATP synthase. As does TDA1, another OPR protein required for the translation of the atpA mRNA, MDA1 targets the atpA 5'‐untranslated region (UTR). Unexpectedly, it binds within a region of approximately 100 nt in the middle of the atpA 5'‐UTR, at variance with the stabilization factors characterized so far, which bind to the 5'‐end of their target mRNA to protect it from 5' → 3' exonucleases. It binds the same region as TDA1, with which it forms a high‐molecular‐weight complex that also comprises the atpA mRNA. This complex dissociates upon translation, promoting degradation of the atpA mRNA. We suggest that atpA transcripts, once translated, enter the degradation pathway because they cannot reassemble with MDA1 and TDA1, which preferentially bind to de novo transcribed mRNAs. Significance Statement: Two OctotricoPeptide Repeat (OPR) proteins, MDA1 and TDA1, respectively, required for the accumulation and translation of the atpA mRNA interact with a region in the middle of the atpA 5'‐UTR, instead of the usual interaction with its 5'‐end, to form a ternary complex. This complex dissociates upon translation, which promotes the degradation of the atpA mRNA. [ABSTRACT FROM AUTHOR]

Summary: Mangroves are forest ecosystems located at the interface between land and sea where sediments presented a variety of contrasted environmental conditions (i.e. oxic/anoxic, non‐sulfidic/sulfidic, organic matter content) providing an ideal ecosystem to study microbial communities with niche differentiation and distinct community structures. In this work, prokaryotic and fungal compositions were investigated during both wet and dry seasons in New Caledonian mangrove sediments, from the surface to deeper horizons under the two most common tree species in this region (Avicennia marina and Rhizophora stylosa), using high‐throughput sequencing. Our results showed that Bacteria and Archaea communities were mainly shaped by sediment depth while the fungal community was almost evenly distributed according to sediment depth, vegetation cover and season. A detailed analysis of prokaryotic and fungal phyla showed a dominance of Ascomycota over Basidiomycota whatever the compartment, while there was a clear shift in prokaryotic composition. Some prokaryotic phyla were enriched in surface layers such as Proteobacteria, Euryarchaeota while others were mostly associated with deeper layers as Chloroflexi, Bathyarchaeota, Aminicenantes. Our results highlight the importance of considering fungal and prokaryotic counterparts for a better understanding of the microbial succession involved in plant organic matter decomposition in tropical coastal sediments. [ABSTRACT FROM AUTHOR]

ABSTRACT: An assessment of potential risks of pesticides on wildlife is required during the process of product registration within Europe because of the importance of agricultural landscapes as wildlife habitats. Despite their peculiarity and their specific role as artificial wetlands, rice paddies are to date pooled with cereals in guidance documents on how to conduct risk assessments for birds and mammals in Europe. Hence, the focal species currently considered in risk assessments for rice paddies are those known from cereal fields and can therefore be expected to differ significantly from the species actually occurring in the wet environments of rice paddies. We present results of a comprehensive review on bird and mammal species regularly occurring in rice paddies during a time of potential pesticide exposure to identify appropriate focal species candidates for ecotoxicological pesticide risk assessment according to the European Food Safety Authority (EFSA). In addition, we present data on rice cultivation areas and agricultural practices in Europe to give background information supporting the species selection process. Our literature search identified a general scarcity of relevant data, particularly for mammals, which highlights the need for crop‐specific focal species studies. However, our results clearly indicate that the relevant bird and mammal species in rice fields indeed differ strongly from the focal species used for the cereal risk assessment. They can thus be used as a baseline for more realistic wildlife risk assessments specific to rice and the development of a revised guidance document to bridge the gap for regulatory decision makers. Integr Environ Assess Manag 2018;14:537–551. © 2018 SETAC [ABSTRACT FROM AUTHOR]

An editorial is presented, in which the author discusses cardiovascular benefits of sodium-glucose cotransporter 2 (SGLT2) inhibition in diabetes and chronic kidney diseases. It mentions SGLT2 inhibitors attenuate postprandial increases in blood glucose by targeting its reabsorption along the early proximal tubule and enhancing urinary glucose excretion. It also mentions haemodynamics and tubular transport of SGLT2 inhibitors.

Inhibitors of the sodium-glucose cotransporter SGLT2 are a new class of antihyperglycemic drugs that have been approved for the treatment of type 2 diabetes mellitus (T2DM). These drugs inhibit glucose reabsorption in the proximal tubules of the kidney thereby enhancing glucosuria and lowering blood glucose levels. Additional consequences and benefits include a reduction in body weight, uric acid levels, and blood pressure. Moreover, SGLT2 inhibition can have protective effects on the kidney and cardiovascular system in patients with T2DM and high cardiovascular risk. However, a potential side effect that has been reported with SGLT2 inhibitors in patients with T2DM and particularly during off-label use in patients with type 1 diabetes is diabetic ketoacidosis. The US Food and Drug Administration recently warned that SGLT2 inhibitors may result in euglycemic ketoacidosis. Here, we review the basic metabolism of ketone bodies, the triggers of diabetic ketoacidosis, and potential mechanisms by which SGLT2 inhibitors may facilitate the development of ketosis or ketoacidosis. This provides the rationale for measures to lower the risk. We discuss the role of the kidney and potential links to renal gluconeogenesis and uric acid handling. Moreover, we outline potential beneficial effects of modestly elevated ketone body levels on organ function that may have therapeutic relevance for the observed beneficial effects of SGLT2 inhibitors on the kidney and cardiovascular system. [ABSTRACT FROM AUTHOR]

Many animals heavily invest in parental care but still reject at least some of their offspring. Although seemingly paradoxical, selection can favor parents to neglect offspring of particularly low reproductive value, for example, because of small survival chances. We here assess whether filial cannibalism ( FC), where parents routinely eat some of their own young, is selective in response to individual offspring reproductive value. We performed two independent laboratory experiments in the common goby ( Pomatoschistus microps) to test whether caring fathers preferentially cannibalize eggs of a given infection history and paternity. While males did not discriminate kin from nonkin eggs, they consumed significantly more eggs previously exposed to water mold compared to uninfected eggs. Our findings clearly show that parents differentiate between eggs based on differences in egg condition, and thus complement the prevailing view that FC arises for energetic reasons. By preventing the spread of microbial infections, the removal of molded eggs can constitute an important component of parental care and may represent a key driver of selective FC in a wide array of parental fish. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated that repeated short-term nutrient withdrawal (i.e. fasting) has pleiotropic actions to promote organismal health and longevity. Despite this, the molecular physiological mechanisms by which fasting is protective against metabolic disease are largely unknown. Here, we show that, metabolic control, particularly systemic and liver lipid metabolism, is aberrantly regulated in the fasted state in mouse models of metabolic dysfunction. Liver transcript assays between lean/healthy and obese/diabetic mice in fasted and fed states uncovered 'growth arrest and DNA damage-inducible' GADD45β as a dysregulated gene transcript during fasting in several models of metabolic dysfunction including ageing, obesity/pre-diabetes and type 2 diabetes, in both mice and humans. Using whole-body knockout mice as well as liver/hepatocyte-specific gain- and loss-of-function strategies, we revealed a role for liver GADD45β in the coordination of liver fatty acid uptake, through cytoplasmic retention of FABP1, ultimately impacting obesity-driven hyperglycaemia. In summary, fasting stress-induced GADD45β represents a liver-specific molecular event promoting adaptive metabolic function. [ABSTRACT FROM AUTHOR]

The transformation suppressor gene RECK was isolated by cDNA expression cloning (1998), and GPR124/ TEM5 was detected as a tumor endothelial marker by differential screening (2000). The importance of Wnt7a/b and Gpr124 in brain angiogenesis was demonstrated by reverse genetics in mice (2008-2010). A series of recent studies using genetically engineered mice and zebrafish as well as luciferase reporter assays in cultured cells led to the discovery of functional interactions among Reck, Gpr124, and Wnt7a/b in triggering canonical Wnt signaling with relevance to embryonic brain angiogenesis and blood-brain barrier formation. [ABSTRACT FROM AUTHOR]

Many animal parents invest heavily to ensure offspring survival, yet some eventually consume some or all of their very own young. This so-called filial cannibalism is known from a wide range of taxa, but its adaptive benefit remains largely unclear. The extent to which parents cannibalize their broods varies substantially not only between species, but also between individuals, indicating that intrinsic behavioral differences, or animal personalities, might constitute a relevant proximate trigger for filial cannibalism. Using a marine fish with extensive paternal care, the common goby ( Pomatoschistus microps) , we investigated the influence of animal personality on filial cannibalism by assessing (1) behavioral consistency across a breeding and a nonbreeding context; (2) correlations between different breeding (egg fanning; filial cannibalism) and nonbreeding (activity) behaviors, and, in a separate experiment; (3) whether previously established personality scores affect filial cannibalism levels. We found consistent individual differences in activity across contexts. Partial filial cannibalism was independent of egg fanning but correlated strongly with activity, where active males cannibalized more eggs than less active males. This pattern was strong initially but vanished as the breeding season progressed. The incidence of whole clutch filial cannibalism increased with activity and clutch size. Our findings indicate that filial cannibalism cannot generally be adjusted independently of male personality and is thus phenotypically less plastic than typically assumed. The present work stresses the multidimensional interaction between animal personality, individual plasticity and the environment in shaping filial cannibalism. [ABSTRACT FROM AUTHOR]

To smoothen the process of n-butanol formation in Pseudomonas putida KT2440, detailed knowledge of the impact of this organic solvent on cell physiology and regulation is of outmost importance.Here,we conducted a detailed systems biology study to elucidate cellular responses at the metabolic, proteomic, and transcriptional level. Pseudomonas putida KT2440 was cultivated in multiple chemostat fermentations using n-butanol either as sole carbon source or together with glucose. Pseudomonas putida KT2440 revealed maximum growth rates (μ) of 0.3 h-1 with n-butanol as sole carbon source and of 0.4 h-1 using equal C-molar amounts of glucose and nbutanol. While C-mole specific substrate consumption and biomass/substrate yields appeared equal at these growth conditions, the cellular physiology was found to be substantially different: adenylate energy charge levels of 0.85 were found when n-butanol served as sole carbon source (similar to glucose as sole carbon source), but were reduced to 0.4 when n-butanol was coconsumed at stable growth conditions. Furthermore, characteristic maintenance parameters changed with increasing n-butanol consumption. 13C flux analysis revealed that central metabolism was split into a glucose-fueled Entner-Doudoroff/pentose-phosphate pathway and an n-butanol-fueled tricarboxylic acid cycle when both substrates were coconsumed. With the help of transcriptome and proteome analysis, the degradation pathway of n-butanol could be unraveled, thus representing an important basis for rendering P. putida KT2440 from an n-butanol consumer to a producer in future metabolic engineering studies. [ABSTRACT FROM AUTHOR]

In plants and algae, chloroplast gene expression is controlled by nucleus-encoded proteins that bind to mRNAs in a specific manner, stabilizing mRNAs or promoting their splicing, editing, or translation. Here, we present the characterization of two mRNA stabilization factors of the green alga Chlamydomonas reinhardtii, which both belong to the OctotricoPeptide Repeat (OPR) family. MCG1 is necessary to stabilize the petG mRNA, encoding a small subunit of the cytochrome b6 f complex, while MBI1 stabilizes the psbI mRNA, coding for a small subunit of photosystem II. In the mcg1 mutant, the small RNA footprint corresponding to the 5′-end of the petG transcript is reduced in abundance. In both cases, the absence of the small subunit perturbs assembly of the cognate complex. Whereas PetG is essential for formation of a functional cytochrome b6 f dimer, PsbI appears partly dispensable as a low level of PSII activity can still be measured in its absence. Thus, nuclear control of chloroplast gene expression is not only exerted on the major core subunits of the complexes, but also on small subunits with a single transmembrane helix. While OPR proteins have thus far been involved in translation or trans-splicing of plastid mRNAs, our results expand the potential roles of this repeat family to their stabilization. [ABSTRACT FROM AUTHOR]

Environmental factors, such as noise exposure and air pollution, are associated with hypertension. These environmental factors also affect sleep quality. Given the growing evidence linking sleep quality with hypertension, the purpose of this review is to investigate the role of sleep as a key mediator in the association between hypertension and environmental factors. Through this narrative review of the extant literature, we highlight that poor sleep quality mediates the relationship between environmental factors and hypertension. The conceptual model proposed in this review offers opportunities to address healthcare disparities in hypertension among African Americans by highlighting the disparate impact that the predictors (environmental factors) and mediator (sleep) have on the African-American community. Understanding the impact of these factors is crucial since the main outcome variable (hypertension) severely burdens the African-American community. [ABSTRACT FROM AUTHOR]

New Findings What is the topic of this review? This review describes how hyperglycaemia and attendant increases in proximal tubular growth and sodium reclamation form the mechanistic basis for the tubular hypothesis of hyperfiltration and nephropathy in the kidneys of patients with diabetes. The review highlights how signals arising from the gastrointestinal tract may be capable of modulating this response and how pharmacological enhancement of these signals may ameliorate the progression of diabetic kidney disease., What advances does it highlight? The review highlights the potential of glucagon-like peptide 1 analogues, glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors to exercise renoprotective effects in diabetes independent of their classical effects on endocrine pancreas., The tubular hypothesis of glomerular filtration and nephropathy in diabetes is a pathophysiological concept that assigns a critical role to the tubular system, including proximal tubular hyper-reabsorption and growth, which is relevant for early glomerular hyperfiltration and later chronic kidney disease. Here we focus on how harnessing the bioactivity of hormones released from the gut may ameliorate the early effects of diabetes on the kidney in part by attenuating proximal tubular hyper-reabsorption and growth. The endogenous tone of the glucagon-like peptide 1 (GLP-1)/GLP-1 receptor (GLP-1R) system and its pharmacological activation are nephroprotective in diabetes independent of changes in blood glucose. This is associated with suppression of increases in kidney weight and glomerular hyperfiltration, which may reflect, at least in part, its inhibitory effects on tubular hyper-reabsorption and growth. Inhibition of dipeptidyl peptidase 4 (DPP-4) is also nephroprotective independent of changes in blood glucose and involves GLP-1/GLP-1R-dependent and -independent mechanisms. The GLP-1R agonist exendin-4 induces natriuresis via activation of the GLP-1R. In contrast, DPP4 inhibition increases circulating GLP-1, but drives a GLP-1R-independent natriuretic response, implying a role for other DPP-4 substrates. The extent to which the intrarenal DPP-4/GLP-1 receptor system contributes to all these changes remains to be established, as does the direct impact of the system on renal inflammation. [ABSTRACT FROM AUTHOR]

Heavy metals are pollutants which affect all organisms. Since a small number of eukaryotes have been investigated with respect to metal resistance, we hypothesize that many genes that control this phenomenon remain to be identified. This was tested by screening soil eukaryotic metatranscriptomes which encompass RNA from organisms belonging to the main eukaryotic phyla. Soil-extracted polyadenylated mRNAs were converted into cDNAs and 35 of them were selected for their ability to rescue the metal ( Cd or Zn) sensitive phenotype of yeast mutants. Few of the genes belonged to families known to confer metal resistance when overexpressed in yeast. Several of them were homologous to genes that had not been studied in the context of metal resistance. For instance, the BOLA ones, which conferred cross metal ( Zn, Co, Cd, Mn) resistance may act by interfering with Fe homeostasis. Other genes, such as those encoding 110- to 130-amino-acid-long, cysteine-rich polypeptides, had no homologues in databases. This study confirms that functional metatranscriptomics represents a powerful approach to address basic biological processes in eukaryotes. The selected genes can be used to probe new pathways involved in metal homeostasis and to manipulate the resistance level of selected organisms. [ABSTRACT FROM AUTHOR]

A two-phase biotransformation process for selective hydroxylation of n-octane to 1-octanol via Pseudomonas putida KT2440 harboring heterologously expressed P450 monooxygenase from Mycobacterium marinum is presented. Maximum cell-specific conversion rates of 12.7 mgoctanol gCDWh-1 were observed not only in shaking flasks but also in 3.7-L-bioreactor studies. The bioreactor experiments were performed avoiding explosive gas mixtures by lowering volumetric power input, aeration rates and substrate concentrations. Based on a stoichiometric network of P. putida KT2440 topological studies were carried out. As a conclusion, potential limitations of NAD(P)H and/or ATP supply at production conditions can be excluded. Hence, the great potential of the host for further increasing conversion is outlined. [ABSTRACT FROM AUTHOR]

Summary The aim was to investigate long-term efficacy of a resilient appliance in patients with pain due to temporomandibular disorders (TMD). A randomised, controlled trial was performed in 80 recruited TMD pain patients. They were randomly allocated to one of two groups: treatment with a resilient appliance or treatment with a hard, palatal, non-occluding appliance. The primary treatment outcome was judged positive when patients' characteristic pain intensity decreased by at least 30%. Additional treatment outcomes were physical functioning, emotional functioning and headache. At the 12-month follow-up 50% of the patients in the treatment group and 42% in the control group had a 30% reduction of characteristic pain intensity, when calculated in an intent-to-treat analysis. Jaw function improved in both groups at the 6- and 12-month follow-up. Emotional functioning improved in both groups at the 6-month follow-up; an improvement concerning grade of depression was found in the control group at 12 months. Headache decreased in both groups at both follow-ups. There were no statistically significant differences found regarding primary and additional outcomes between groups at the 6- and 12-months follow-up. There was no statistically significant difference between the resilient appliance and the non-occluding control appliance in reducing TMD pain, physical functioning, emotional functioning and headache in a 12 months perspective. [ABSTRACT FROM AUTHOR]

Summary Reasons for performing study: Intense physical exercise produces an excess of reactive oxygen species which can disturb the antioxidant/oxidant balance of the horse in training. Several classes of antioxidant dietary compounds have been suggested to provide health benefits and there is evidence that consumption of these products leads to a reduction in the expression of various pro-inflammatory and/or oxidative stress biomarkers. The recent development of a new galenic system allows the oral delivery of the antioxidant enzyme: superoxide dismutase (SOD). This has been developed from a specific melon variety with a particularly high SOD activity. Objectives: To study the influence of an oral supplementation with an encapsulated melon rich in SOD on muscular and antioxidant balance variables in a population of Standardbreds in training. Methods: Twenty-four Standardbreds in training were paired by age, sex and training level. They were randomly split into 2 groups: SOD group (520 iu/day) and placebo group. At the beginning of the study (T0) and after 30 days (T30) and 60 days (T60) of supplementation, physiological response during a standardised exercise test, plasma muscular enzymes at rest and post exercise (creatine kinase), oxidative stress markers (erythrocyte SOD) and blood resistance to haemolysis (KRL test) were assessed. Analysis of variance of time, treatment and interaction time x treatment was calculated. Results: Between T0 and T60, in contrast with placebo group, a significant increase in the plasma resistance to haemolysis in the SOD group was observed and it was significantly higher (P<0.05) in the SOD group than in the placebo group on T60. Between T0 and T60, resting CK remained constant in SOD group whereas a significant increase in plasma CK in the placebo group was observed. On T60, the CK level was significantly lower (P<0.05) in SOD group than in the placebo group. Conclusions: These results suggest that oral SOD supplementation might increase blood resistance to haemolysis and reduce the increase in muscular membrane permeability induced by training. [ABSTRACT FROM AUTHOR]

Apical release of ATP and UTP can activate P2Y2 receptors in the aldosterone-sensitive distal nephron (ASDN) and inhibit the open probability (Po) of the epithelial sodium channel (ENaC). Little is known, however, about the regulation and physiological relevance of this system. Patch-clamp studies in freshly isolated ASDN provide evidence that increased dietary Na+ intake in wild-type mice lowers ENaC Po, consistent with a contribution to Na+ homeostasis, and is associated with increased urinary concentrations of UTP and the ATP hydrolytic product, ADP. Genetic deletion of P2Y2 receptors in mice (P2Y2 -/-; littermates to wild-type mice) or inhibition of apical P2Yreceptor activation in wild-type mice prevents dietary Na+-induced lowering of ENaC Po. Although they lack suppression of ENaC Po by dietary NaCl, P2Y2 -/- mice do not exhibit NaCl-sensitive blood pressure, perhaps as a consequence of compensatory down-regulation of aldosterone levels. Consistent with this hypothesis, clamping mineralocorticoid activity at high levels unmasks greater ENaC activity and NaCl sensitivity of blood pressure in P2Y2-/- mice. The studies indicate a key role of the apical ATP/UTP-P2Y2-receptor system in the inhibition of ENaC Po in the ASDN in response to an increase in Na+ intake, thereby contributing to NaCl homeostasis and blood pressure regulation. [ABSTRACT FROM AUTHOR]

Aims: Aims of this study were to assess undergraduates’ and graduates’ perceptions of their education by documenting their attitudes and investigating acquired competencies in temporomandibular disorders (TMD) and orofacial pain (OP). Methods: In 2006, 141 undergraduates (in semesters 1, 6, and 10 of a 5-year dental programme) and 60 graduates of 2000 and 2001 were invited to fill in questionnaires designed for their levels. The four questionnaires contained open-ended questions, closed-ended questions, and questions requiring a scaled response on an 11-point numerical rating scale (NRS). Questions covered personal experience of pain, attitudes toward TMD/OP, clinical competencies, and satisfaction with their education. Participants rated importance of and satisfaction with clinical competencies on a 5-point scale. Results: The importance of understanding TMD/OP patients was rated high (NRS 9—10) and attitudes to given statements about TMD/OP patients were positive. In general, perception of clinical competencies increased with level of education. Mean scores for importance of and satisfaction with clinical competencies of 10th semester undergraduates and graduates were above 4.0. Median graduate satisfaction with undergraduate education in TMD/OP patient management was high (NRS 9). All but one graduate had treated patients with TMD/OP. One-third of the responding graduates expressed a wish for additional training, such as in pharmacological treatment and evaluation of treatment outcome. Conclusion: In general, the perception of acquired clinical competencies in TMD and OP increased with level of education, and the importance of, and satisfaction with, training was highly rated. Positive attitudes toward these kinds of patients were expressed at all levels. [ABSTRACT FROM AUTHOR]

Abstract: Therapy of heart failure is more difficult when renal function is impaired. Here, we outline the effects on kidney function of the autacoid, adenosine, which forms the basis for adenosine A1 receptor (A1R) antagonists as treatment for decompensated heart failure. A1R antagonists induce a eukaliuretic natriuresis and diuresis by blocking A1R-mediated NaCl reabsorption in the proximal tubule and the collecting duct. Normally, suppressing proximal reabsorption will lower glomerular filtration rate (GFR) through the tubuloglomerular feedback mechanism (TGF). But the TGF response, itself, is mediated by A1R in the preglomerular arteriole, so blocking A1R allows natriuresis to proceed while GFR remains constant or increases. The influence of A1R over vascular resistance in the kidney is augmented by angiotensin II while A1R activation directly suppresses renin secretion. These interactions could modulate the overall impact of A1R blockade on kidney function in patients taking angiotensin II blockers. A1R blockers may increase the energy utilized for transport in the semi-hypoxic medullary thick ascending limb, an effect that could be prevented with loop diuretics. Finally, while the vasodilatory effect of A1R blockade could protect against renal ischaemia, A1R blockade may act on non-resident cells to exacerbate reperfusion injury, where ischaemia to occur. Despite these uncertainties, the available data on A1R antagonist therapy in patients with decompensated heart failure are promising and warrant confirmation in further studies. [Copyright &y& Elsevier]

Mastitis, an inflammatory response of the mammary tissue to invading pathogenic bacteria, is a common disease in breast-feeding women and dairy animals. Escherichia coli is a leading cause of mastitis in dairy animals. During the course of the disease the host mounts a strong inflammatory response, but specific bacterial virulence factors have not yet been identified. Here we report the use of a murine mastitis model to investigate the innate inflammatory reaction of the mammary gland. We show that lipopolysaccharide (LPS) infusion induces mastitis in wild-type mice (C3H/HeN), but not in mice expressing mutated Toll-like receptor 4 (TLR4) (C3H/HeJ). The wild-type phenotype was restored by adoptive transfer of TLR4-expressing macrophages into the alveolar milk space of C3H/HeJ mice. In contrast to the LPS treatment, infection with E. coli P4 (ECP4) resulted in inflammation even in the absence of LPS/TLR4 signalling, indicating that additional factors play a role in the pathogenesis of the intact bacteria. Furthermore, in the absence of functional TLR4 the infecting ECP4 invade the epithelial cells with high efficiency, forming intracellular microcolonies. However, adoptive transfer with TLR4-expressing macrophages drastically reduced the epithelial invasion. Taken together, these results indicate that ECP4 has an invasive potential, which is restricted by alveolar macrophages in response to the LPS/TLR4 signalling. [ABSTRACT FROM AUTHOR]

Extracellular nucleotides (e.g., ATP) regulate many physiological and pathophysiological processes through activation of nucleotide (P2) receptors in the plasma membrane. Here we report that gene-targeted (knockout) mice that lack P2Y2 receptors have salt-resistant arterial hypertension in association with an inverse relationship between salt intake and heart rate, indicating intact baroreceptor function. Knockout mice have multiple alterations in their handling of salt and water: these include suppressed plasma renin and aldosterone concentrations, lower renal expression of the aldosterone-induced epithelial sodium channel α-ENaC, greater medullary expression of the Na-K-2Cl-cotransporter NKCC2, and greater furosemide-sensitive Na+ reabsorption in association with greater renal medullary expression of aquaporin-2 and vasopressin-dependent renal cAMP formation and water reabsorption despite similar vasopressin levels compared with wild type. Of note, smaller increases in plasma aldosterone were required to adapt renal Na+ excretion to restricted intake ha knockout mice, suggesting a facilitation in renal Na+ retention. The results thus identify a previously unrecognized role for P2Y2 receptors in blood pressure regulation that is linked to an inhibitory influence on renal Na+ and water reabsorption. Based on these findings in knockout mice, we propose that a blunting in P2Y2 receptor expression or activity is a new mechanism for salt-resistant arterial hypertension. [ABSTRACT FROM AUTHOR]

The (C)F1 sector from H+-ATP synthases comprises five subunits: α, β, γ, δ and ɛ, assembled in a 3:3:1:1:1 stoichiometry. Here, we describe the molecular mechanism ensuring this unique stoichiometry, required for the functional assembly of the chloroplast enzyme. It relies on a translational feedback loop operating in two steps along the assembly pathway of CF1. In Chlamydomonas, production of the nucleus-encoded subunit γ is required for sustained translation of the chloroplast-encoded subunit β, which in turn stimulates the expression of the chloroplast-encoded subunit α. Translational downregulation of subunits β or α, when not assembled, is born by the 5′UTRs of their own mRNAs, pointing to a regulation of translation initiation. We show that subunit γ, by assembling with α3β3 hexamers, releases a negative feedback exerted by α/β assembly intermediates on translation of subunit β. Moreover, translation of subunit α is transactivated by subunit β, an observation unprecedented in the biogenesis of organelle proteins. [ABSTRACT FROM AUTHOR]