In vivo characterization of a novel norepinephrine transporter PET tracer [18F]NS12137 in adult and immature Sprague-Dawley rats

Norepinephrine modulates cognitive processes such as working and episodic memory. Pathological changes in norepinephrine and norepinephrine transporter (NET) function and degeneration of the locus coeruleus produce irreversible impairments within the whole norepinephrine system, disrupting cognitive processes. Monitoring these changes could enhance diagnostic accuracy and support development of novel therapeutic components for several neurodegenerative diseases. Thus, we aimed to develop a straightforward nucleophilic fluorination method with high molar activity for the novel NET radiotracer [18F]NS12137 and to demonstrate the ability of [18F]NS12137 to quantify changes in NET expression.Methods: We applied an 18F-radiolabeling method in which a brominated precursor was debrominated by nucleophilic 18F-fluorination in dimethyl sulfoxide. Radiolabeling was followed by a deprotection step, purification, and formulation of the radiotracer. The [18F]NS12137 brain uptake and distribution were studied with in vivo PET/CT and ex vivoautoradiography using both adult and immature Sprague-Dawley rats because postnatal NET expression peaks at 10-20 days post birth. The NET specificity for the tracer was demonstrated by pretreatment of the animals with nisoxetine, which is well-known to have a high affinity for NET.Results: [18F]NS12137 was successfully synthesized with radiochemical yields of 18.6±5.6%, radiochemical purity of >99%, and molar activity of >500 GBq/μmol at the end of synthesis. The in vivo [18F]NS12137 uptake showed peak standard uptake values (SUV) of over 1.5 (adult) and 2.2 (immature) in the different brain regions. Peak SUV/30 min and peak SUV/60 min ratios were calculated for the different brain regions of the adult and immature rats, with a peak SUV/60 min ratio of more than 4.5 in the striatum of adult rats. As expected, in vivo studies demonstrated uptake of the tracer in brain areas rich in NET, particularly thalamus, neocortex, and striatum, and remarkably also in the locus coeruleus, a quite small volume for imaging with PET. The uptake was significantly higher in immature rats compared to the adult animals. Ex vivo studies using autoradiography showed very strong specific binding in NET-rich areas such as the locus coeruleus and the bed nucleus of the stria terminalis, and high binding in larger grey matter areas such as the neocortex and striatum. The uptake of [18F]NS12137 was dramatically reduced both in vivo and ex vivo by pretreatment with nisoxetine, demonstrating the specificity of binding.Conclusions: [18F]NS12137 was synthesized in good yield and high molar activity and demonstrated the characteristics of a good radiotracer, such as good brain penetration, fast washout, and high specific binding to NET.Keywords: [18F]NS12137, norepinephrine transporter, NET, locus coeruleus, PET, nucleophilic fluorination</p

Radiosynthesis and Preclinical Evaluation of an α2A-Adrenoceptor Tracer Candidate, 6-[18F]Fluoro-marsanidine

Purpose: The α2-adrenoceptors mediate many effects of norepinephrine and epinephrine, and participate in the regulation of neuronal, endocrine, cardiovascular, vegetative, and metabolic functions. Of the three receptor subtypes, only α2A and α2C are found in the brain in significant amounts. Subtype-selective positron emission tomography (PET) imaging of α2-adrenoceptors has been limited to the α2C subtype. Here, we report the synthesis of 6-[18F]fluoro-marsanidine, a subtype-selective PET tracer candidate for α2A-adrenoceptors, and its preclinical evaluation in rats and mice.Procedures: 6-[18F]Fluoro-marsanidine was synthesized using electrophilic F-18 fluorination with [18F]Selectfluor bis(triflate). The tracer was evaluated in Sprague Dawley rats and in α2A-knockout (KO) and wild-type (WT) mice for subtype selectivity. In vivo PET imaging and ex vivo brain autoradiography were performed to determine the tracer distribution in the brain. The specificity of the tracer for the target was determined by pretreatment with the subtype-non-selective α2-agonist medetomidine. The peripheral biodistribution and extent of metabolism of 6-[18F]fluoro-marsanidine were also analyzed.Results: 6-[18F]Fluoro-marsanidine was synthesized with [18F]Selectfluor bis(triflate) in a radiochemical yield of 6.4 ± 1.7 %. The molar activity was 3.1 to 26.6 GBq/μmol, and the radiochemical purity was > 99 %. In vivo studies in mice revealed lower uptake in the brains of α2A-KO mice compared to WT mice. The results for selectivity were confirmed by ex vivo brain autoradiography. Blocking studies revealed reduced uptake in α2A-adrenoceptor-rich brain regions in pretreated animals, demonstrating the specificity of the tracer. Metabolite analyses revealed very rapid metabolism of 6-[18F]fluoro-marsanidine with blood-brain barrier-permeable metabolites in both rats and mice.Conclusion: 6-[18F]Fluoro-marsanidine was synthesized and evaluated as a PET tracer candidate for brain α2A-adrenoceptors. However, rapid metabolism, extensive presence of labeled metabolites in the brain, and high non-specific uptake in mouse and rat brain make 6-[18F]fluoro-marsanidine unsuitable for α2A-adrenoceptor targeting in rodents in vivo.</p

Novel Pixelwise Co-Registered Hematoxylin-Eosin and Multiphoton Microscopy Image Dataset for Human Colon Lesion Diagnosis

Colorectal cancer presents one of the most elevated incidences of cancer worldwide. Colonoscopy relies on histopathology analysis of hematoxylin-eosin (H&E) images of the removed tissue. Novel techniques such as multi-photon microscopy (MPM) show promising results for performing real-time optical biopsies. However, clinicians are not used to this imaging modality and correlation between MPM and H&E information is not clear. The objective of this paper is to describe and make publicly available an extensive dataset of fully co-registered H&E and MPM images that allows the research community to analyze the relationship between MPM and H&E histopathological images and the effect of the semantic gap that prevents clinicians from correctly diagnosing MPM images. The dataset provides a fully scanned tissue images at 10x optical resolution (0.5 m/px) from 50 samples of lesions obtained by colonoscopies and colectomies. Diagnostics capabilities of TPF and H&E images were compared. Additionally, TPF tiles were virtually stained into H&E images by means of a deep-learning model. A panel of 5 expert pathologists evaluated the different modalities into three classes (healthy, adenoma/hyperplastic, and adenocarcinoma). Results showed that the performance of the pathologists over MPM images was 65% of the H&E performance while the virtual staining method achieved 90%. MPM imaging can provide appropriate information for diagnosing colorectal cancer without the need for H&E staining. However, the existing semantic gap among modalities needs to be corrected.This work was supported by the PICCOLO project. This project has received funding from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement No. 732111. The sole re- sponsibility of this publication lies with the authors. The European Union is not responsible for any use that may be made of the information contained therei

Comparison of high and low molar activity TSPO tracer [18F]F-DPA in a mouse model of Alzheimer’s disease

[18F]F-DPA, a novel translocator protein 18 kDa (TSPO)-specific radioligand for imaging neuroinflammation, has to date been synthesized with low to moderate molar activities (Am’s). In certain cases, low Am can skew the estimation of specific binding. The high proportion of the non-radioactive component can reduce the apparent-specific binding by competitively binding to receptors. We developed a nucleophilic synthesis of [18F]F-DPA resulting in high Am (990 ± 150 GBq/µmol) and performed in vivo comparison with low Am (9.0 ± 2.9 GBq/µmol) [18F]F-DPA in the same APP/PS1-21 and wild-type mice (injected masses: 0.34 ± 0.13 µg/kg and 38 ± 15 µg/kg, respectively). The high level of microgliosis in the APP/PS1-21 mouse model enables good differentiation between diseased and healthy animals and serves better to distinguish the effect of differing Am on specific binding. The differing injected masses affect the washout profile and shape of the time–activity curves. Ratios of standardized uptake values obtained with high and low Am [18F]F-DPA demonstrate that there is a 1.5-fold higher uptake of radioactivity in the brains of APP/PS1-21 animals when imaging is carried out with high Am [18F]F-DPA. The differences between APP/PS1-21 and wild-type animals showed higher significance when high Am was used.</p

Prediction of crop coefficients from fraction of ground cover and height. Background and validation using ground and remote sensing data

ReviewThe current study aims at reviewing and providing advances on methods for estimating and applying crop coefficients from observations of ground cover and vegetation height. The review first focuses on the relationships between single Kc and basal Kcb and various parameters including the fraction of ground covered by the canopy (fc), the leaf area index (LAI), the fraction of ground shaded by the canopy (fshad), the fraction of intercepted light (flight) and intercepted photosynthetic active radiation (fIPAR). These relationships were first studied in the 1970’s, for annual crops, and later, in the last decennia, for tree and vine perennials. Research has now provided a variety of methods to observe and measure fc and height (h) using both ground and remote sensing tools, which has favored the further development of Kc related functions. In the past, these relationships were not used predictively but to support the understanding of dynamics of Kc and Kcb in relation to the processes of evapotranspiration or transpiration, inclusive of the role of soil evaporation. Later, the approach proposed by Allen and Pereira (2009), the A&P approach, used fc and height (h) or LAI data to define a crop density coefficient that was used to directly estimate Kc and Kcb values for a variety of annual and perennial crops in both research and practice. It is opportune to review the A&P method in the context of a variety of studies that have derived Kc and Kcb values from field measured data with simultaneously observed ground cover fc and height. Applications used to test the approach include various tree and vine crops (olive, pear, and lemon orchards and vineyards), vegetable crops (pea, onion and tomato crops), field crops (barley, wheat, maize, sunflower, canola, cotton and soybean crops), as well as a grassland and a Bermudagrass pasture. Comparisons of Kcb values computed with the A &P method produced regression coefficients close to 1.0 and coefficients of determination≥0.90, except for orchards. Results indicate that the A&P approach can produce estimates of potential Kcb, using vegetation characteristics alone, within reasonable or acceptable error, and are useful for refining Kcb for conditions of plant spacing, size and density that differ from standard values. The comparisons provide parameters appropriate to applications for the tested crops. In addition, the A&P approach was applied with remotely sensed fc data for a variety of crops in California using the Satellite Irrigation Management Support (SIMS) framework. Daily SIMS crop ET (ETc-SIMS) produced Kcb values using the FAO56 and A&P approaches. Combination of satellite derived fc and Kcb values with ETo data from Spatial CIMIS (California Irrigation Management Information System) produced ET estimates that were compared with daily actual crop ET derived from energy balance calculations from micrometeorological instrumentation (ETc EB).Results produced coefficients of regression of 1.05 for field crops and 1.08 for woody crops, and R2 values of 0.81 and 0.91, respectively. These values suggest that daily ETc-SIMS -based ET can be accurately estimated within reasonable error and that the A&P approach is appropriate to support that estimation. It is likely that accuracy can be improved via progress in remote sensing determination of fc. Tabulated Kcb results and calculation parameters are presented in a companion paper in this Special Issueinfo:eu-repo/semantics/publishedVersio

Planck 2013 results. XXII. Constraints on inflation

We analyse the implications of the Planck data for cosmic inflation. The Planck nominal mission temperature anisotropy measurements, combined with the WMAP large-angle polarization, constrain the scalar spectral index to be ns = 0:9603 _ 0:0073, ruling out exact scale invariance at over 5_: Planck establishes an upper bound on the tensor-to-scalar ratio of r < 0:11 (95% CL). The Planck data thus shrink the space of allowed standard inflationary models, preferring potentials with V00 < 0. Exponential potential models, the simplest hybrid inflationary models, and monomial potential models of degree n _ 2 do not provide a good fit to the data. Planck does not find statistically significant running of the scalar spectral index, obtaining dns=dln k = 0:0134 _ 0:0090. We verify these conclusions through a numerical analysis, which makes no slowroll approximation, and carry out a Bayesian parameter estimation and model-selection analysis for a number of inflationary models including monomial, natural, and hilltop potentials. For each model, we present the Planck constraints on the parameters of the potential and explore several possibilities for the post-inflationary entropy generation epoch, thus obtaining nontrivial data-driven constraints. We also present a direct reconstruction of the observable range of the inflaton potential. Unless a quartic term is allowed in the potential, we find results consistent with second-order slow-roll predictions. We also investigate whether the primordial power spectrum contains any features. We find that models with a parameterized oscillatory feature improve the fit by __2 e_ _ 10; however, Bayesian evidence does not prefer these models. We constrain several single-field inflation models with generalized Lagrangians by combining power spectrum data with Planck bounds on fNL. Planck constrains with unprecedented accuracy the amplitude and possible correlation (with the adiabatic mode) of non-decaying isocurvature fluctuations. The fractional primordial contributions of cold dark matter (CDM) isocurvature modes of the types expected in the curvaton and axion scenarios have upper bounds of 0.25% and 3.9% (95% CL), respectively. In models with arbitrarily correlated CDM or neutrino isocurvature modes, an anticorrelated isocurvature component can improve the _2 e_ by approximately 4 as a result of slightly lowering the theoretical prediction for the ` <_ 40 multipoles relative to the higher multipoles. Nonetheless, the data are consistent with adiabatic initial conditions

Total area of spontaneous portosystemic shunts independently predicts hepatic encephalopathy and mortality in liver cirrhosis

BACKGROUND: Spontaneous portosystemic shunts (SPSS) frequently develop in liver cirrhosis. Recent data suggested that presence of a single large SPSS is associated with complications, especially overt hepatic encephalopathy (oHE). However, presence of >1 SPSS is common. This study evaluates the impact of total cross-sectional SPSS area (TSA) on outcome of patients with liver cirrhosis. METHODS: In this retrospective international multicentric study, computed tomography (CT) scans of 908 cirrhotic patients with SPSS were evaluated for TSA. Clinical and laboratory data were recorded. Each detected SPSS radius was measured and TSA calculated. 1-year survival was primary and acute decompensation (oHE, variceal bleeding, ascites) secondary endpoint. RESULTS: 301 patients (169 male) were included in the training cohort. 30% of all patients presented >1 SPSS. TSA cut-off of 83 mm2 was determined to classify patients with small or large TSA (S-/L-TSA). L-TSA patients presented higher MELD (11 vs. 14) and more commonly history of oHE (12% vs. 21%, p83mm2 increases the risk for oHE and mortality in liver cirrhosis. Our results may have impact on clinical use of TSA/SPSS for risk stratification and clinical decision-making considering management of SPSS

El grupu neandertal de la Cueva d' El Sidrón (Borines, Piloña)

El artículo está en la lengua asturianaPeer reviewe

The interplay of landscape composition and configuration: new pathways to manage functional biodiversity and agroecosystem services across Europe

Managing agricultural landscapes to support biodiversity and ecosystem services is a key aim of a sustainable agriculture. However, how the spatial arrangement of crop fields and other habitats in landscapes impacts arthropods and their functions is poorly known. Synthesising data from 49 studies (1515 landscapes) across Europe, we examined effects of landscape composition (% habitats) and configuration (edge density) on arthropods in fields and their margins, pest control, pollination and yields. Configuration effects interacted with the proportions of crop and non‐crop habitats, and species’ dietary, dispersal and overwintering traits led to contrasting responses to landscape variables. Overall, however, in landscapes with high edge density, 70% of pollinator and 44% of natural enemy species reached highest abundances and pollination and pest control improved 1.7‐ and 1.4‐fold respectively. Arable‐dominated landscapes with high edge densities achieved high yields. This suggests that enhancing edge density in European agroecosystems can promote functional biodiversity and yield‐enhancing ecosystem services

Planck 2015 results. XX. Constraints on inflation

We present the implications for cosmic inflation of the Planck measurements of the cosmic microwave background (CMB) anisotropies in both temperature and polarization based on the full Planck survey. The Planck full mission temperature data and a first release of polarization data on large angular scales measure the spectral index of curvature perturbations to be n s = 0.968 ± 0.006 and tightly constrain its scale dependence to dn s /dlnk = −0.003 ± 0.007 when combined with the Planck lensing likelihood. When the high-ℓ polarization data is included, the results are consistent and uncertainties are reduced. The upper bound on the tensor-to-scalar ratio is r 0.002 <0.11 (95% CL), consistent with the B-mode polarization constraint r<0.12 (95% CL) obtained from a joint BICEP2/Keck Array and Planck analysis. These results imply that V(ϕ)∝ϕ 2 and natural inflation are now disfavoured compared to models predicting a smaller tensor-to-scalar ratio, such as R 2 inflation. Three independent methods reconstructing the primordial power spectrum are investigated. The Planck data are consistent with adiabatic primordial perturbations. We investigate inflationary models producing an anisotropic modulation of the primordial curvature power spectrum as well as generalized models of inflation not governed by a scalar field with a canonical kinetic term. The 2015 results are consistent with the 2013 analysis based on the nominal mission data