Effects of glucagon-like peptide-I on glucose turnover in rats

The influences of glucagon-like peptide-I-(7-36) amide (GLP-I; 15 pmol . kg(-1). min(-1)) on glucose turnover were studied in freely moving Wistar rats. In fed rats, GLP-I reduced plasma glucose (from 7.3 +/- 0.2 to 5.6 +/- 0.3 mmol/l; P = 0.017), increased plasma insulin (from 20 +/- 3 to 89 +/- 11 mU/l; P = 0.002), and reduced plasma glucagon (from 44 +/- 1 to 35 +/- 2 pg/ml; P = 0.009) and glucose appearance rate (R(a); from 3.9 1 0.2 to 1.7 +/- 0.7 mu mol . min(-1). 100 g(-1) after 30 min; P = 0.049) without affecting glucose disappearance rate (R(d)). The glucose clearance rate (MCR) was increased (P = 0.048). In 48-h-fasted rats, GLP-I reduced plasma glucose (from 5.0 +/- 0.2 to 4.4 +/- 0.3 mmol/l; P = 0.035) and increased plasma insulin (from 4 +/- 1 to 25 +/- 10 mU/l; P = 0.042) and plasma glucagon (from 43 +/- 3 to 61 +/- 7 pg/ml; P = 0.046). R(a) and R(d) were not significantly affected, although R(a) was lower than R(d) after 15-30 min (P = 0.005) and MCR was increased (P = 0.049). Thus GLP-I reduces R(a) in fed rats and increases MCR in fed and fasted rats. The reduced R(a) seems mediated by an increased insulin-to-glucagon ratio; the increased glucose clearance seems dependent on insulin and a peripheral effect of GLP-I

The Bivariate Normal Copula

We collect well known and less known facts about the bivariate normal distribution and translate them into copula language. In addition, we prove a very general formula for the bivariate normal copula, we compute Gini's gamma, and we provide improved bounds and approximations on the diagonal.Comment: 24 page

Conformational effects on the Circular Dichroism of Human Carbonic Anhydrase II: a multilevel computational study

Circular Dichroism (CD) spectroscopy is a powerful method for investigating conformational changes in proteins and therefore has numerous applications in structural and molecular biology. Here a computational investigation of the CD spectrum of the Human Carbonic Anhydrase II (HCAII), with main focus on the near-UV CD spectra of the wild-type enzyme and it seven tryptophan mutant forms, is presented and compared to experimental studies. Multilevel computational methods (Molecular Dynamics, Semiempirical Quantum Mechanics, Time-Dependent Density Functional Theory) were applied in order to gain insight into the mechanisms of interaction between the aromatic chromophores within the protein environment and understand how the conformational flexibility of the protein influences these mechanisms. The analysis suggests that combining CD semi empirical calculations, crystal structures and molecular dynamics (MD) could help in achieving a better agreement between the computed and experimental protein spectra and provide some unique insight into the dynamic nature of the mechanisms of chromophore interactions

Fixation and Spread of Somatic Mutations in Adult Human Colonic Epithelium

We investigated the means and timing by which mutations become fixed in the human colonic epithelium by visualizing somatic clones and mathematical inference. Fixation requires two sequential steps. First, one of approximately seven active stem cells residing within each colonic crypt has to be mutated. Second, the mutated stem cell has to replace neighbors to populate the entire crypt in a process that takes several years. Subsequent clonal expansion due to crypt fission is infrequent for neutral mutations (around 0.7% of all crypts undergo fission in a single year). Pro-oncogenic mutations subvert both stem cell replacement to accelerate fixation and clonal expansion by crypt fission to achieve high mutant allele frequencies with age. The benchmarking of these behaviors allows the advantage associated with different gene-specific mutations to be compared irrespective of the cellular mechanisms by which they are conferred

A new framework for cortico-striatal plasticity: behavioural theory meets In vitro data at the reinforcement-action interface

Operant learning requires that reinforcement signals interact with action representations at a suitable neural interface. Much evidence suggests that this occurs when phasic dopamine, acting as a reinforcement prediction error, gates plasticity at cortico-striatal synapses, and thereby changes the future likelihood of selecting the action(s) coded by striatal neurons. But this hypothesis faces serious challenges. First, cortico-striatal plasticity is inexplicably complex, depending on spike timing, dopamine level, and dopamine receptor type. Second, there is a credit assignment problem—action selection signals occur long before the consequent dopamine reinforcement signal. Third, the two types of striatal output neuron have apparently opposite effects on action selection. Whether these factors rule out the interface hypothesis and how they interact to produce reinforcement learning is unknown. We present a computational framework that addresses these challenges. We first predict the expected activity changes over an operant task for both types of action-coding striatal neuron, and show they co-operate to promote action selection in learning and compete to promote action suppression in extinction. Separately, we derive a complete model of dopamine and spike-timing dependent cortico-striatal plasticity from in vitro data. We then show this model produces the predicted activity changes necessary for learning and extinction in an operant task, a remarkable convergence of a bottom-up data-driven plasticity model with the top-down behavioural requirements of learning theory. Moreover, we show the complex dependencies of cortico-striatal plasticity are not only sufficient but necessary for learning and extinction. Validating the model, we show it can account for behavioural data describing extinction, renewal, and reacquisition, and replicate in vitro experimental data on cortico-striatal plasticity. By bridging the levels between the single synapse and behaviour, our model shows how striatum acts as the action-reinforcement interface

DeepHistoClass: A novel strategy for confident classification of immunohistochemistry images using Deep Learning

© 2021 Elsevier Ltd. All rights reserved. This is the accepted manuscript version of the article. The final version is available online from Elsevier at: https://doi.org/10.1016/j.mcpro.2021.100140A multitude of efforts worldwide aim to create a single cell reference map of the human body, for fundamental understanding of human health, molecular medicine and targeted treatment. Antibody-based proteomics using immunohistochemistry (IHC) has proven to be an excellent technology for integration with large-scale single cell transcriptomics datasets. The golden standard for evaluation of IHC staining patterns is manual annotation, which is expensive and may lead to subjective errors. Artificial intelligence holds much promise for efficient and accurate pattern recognition, but confidence in prediction needs to be addressed. Here, the aim was to present a reliable and comprehensive framework for automated annotation of IHC images. We developed a multi-label classification of 7,848 complex IHC images of human testis corresponding to 2,794 unique proteins, generated as part of the Human Protein Atlas (HPA) project. Manual annotation data for eight different cell types was generated as a basis for training and testing a proposed Hybrid Bayesian Neural Network. By combining the deep learning model with a novel uncertainty metric; DeepHistoClass (DHC) confidence score; the average diagnostic performance improved from 86.9% to 96.3%. This metric not only reveals which images are reliably classified by the model, but can also be utilized for identification of manual annotation errors. The proposed streamlined workflow can be developed further for other tissue types in health and disease, and has important implications for digital pathology initiatives or large-scale protein mapping efforts such as the HPA project.Knut and Alice Wallenberg Foundation

Post-extraction mesio-distal gap reduction assessment by confocal laser scanning microscopy - a clinical 3-month follow-up study

[EN] AimThe aim of this 3-month follow-up study is to quantify the reduction in the mesio-distal gap dimension (MDGD) that occurs after tooth extraction through image analysis of three-dimensional images obtained with the confocal laser scanning microscopy (CLSM) technique. Materials and MethodsFollowing tooth extraction, impressions of 79 patients 1month and 72 patients 3months after tooth extraction were obtained. Cast models were processed by CLSM, and MDGD changes between time points were measured. ResultsThe mean mesio-distal gap reduction 1month after tooth extraction was 343.4m and 3months after tooth extraction was 672.3m. The daily mean gap reduction rate during the first term (between baseline and 1month post-extraction measurements) was 10.3m/day and during the second term (between 1 and 3months) was 5.4m/day. ConclusionsThe mesio-distal gap reduction is higher during the first month following the extraction and continues in time, but to a lesser extent. When the inter-dental contacts were absent, the mesio-distal gap reduction is lower. When a molar tooth is extracted or the distal tooth to the edentulous space does not occlude with an antagonist, the mesio-distal gap reduction is larger. The consideration of mesio-distal gap dimension changes can help improve dental treatment planning.The authors would like to express their gratitude to MEC (contract grant number AP2008-01653), to FEDER, to the Generalitat Valenciana for its help in the CLSM acquisition (MY08/ISIRM/S/100), to the Universitat Politecnica de Valencia (PAID-05-12) and to Dr. Asuncion Jaime for her translation assistance.García-Herraiz, A.; Silvestre, FJ.; Leiva García, R.; Crespo Abril, F.; Garcia-Anton, J. (2017). Post-extraction mesio-distal gap reduction assessment by confocal laser scanning microscopy - a clinical 3-month follow-up study. Journal Of Clinical Periodontology. 44(5):548-555. https://doi.org/10.1111/jcpe.12706S548555445Aguilar, M. 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Wear and morphology of infiltrated white spot lesions. Journal of Dentistry, 39(5), 376-385. doi:10.1016/j.jdent.2011.02.009Brauchli, L. M., Baumgartner, E.-M., Ball, J., & Wichelhaus, A. (2011). Roughness of enamel surfaces after different bonding and debonding procedures. Journal of Orofacial Orthopedics / Fortschritte der Kieferorthopädie, 72(1), 61-67. doi:10.1007/s00056-010-0002-3Chen, S. Y., Liang, W. M., & Chen, F. N. (2004). Factors affecting the accuracy of elastometric impression materials. Journal of Dentistry, 32(8), 603-609. doi:10.1016/j.jdent.2004.04.002Christou, P., & Kiliaridis, S. (2007). Three-dimensional changes in the position of unopposed molars in adults. The European Journal of Orthodontics, 29(6), 543-549. doi:10.1093/ejo/cjm036Craddock, H. L., Youngson, C. C., Manogue, M., & Blance, A. (2007). Occlusal Changes Following Posterior Tooth Loss in Adults. Part 2. Clinical Parameters Associated with Movement of Teeth Adjacent to the Site of Posterior Tooth Loss. 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Influence of Inflammation-Mediated Osteopenia on the Regional Acceleratory Phenomenon and the Systemic Acceleratory Phenomenon During Healing of a Bone Defect in the Rat. Calcified Tissue International, 63(2), 160-166. doi:10.1007/s002239900508Scivetti, M., Pilolli, G. P., Corsalini, M., Lucchese, A., & Favia, G. (2007). Confocal laser scanning microscopy of human cementocytes: Analysis of three-dimensional image reconstruction. Annals of Anatomy - Anatomischer Anzeiger, 189(2), 169-174. doi:10.1016/j.aanat.2006.09.009SHUGARS, D. A., BADER, J. D., PHILLIPS, S. W., WHITE, B. A., & BRANTLEY, C. F. (2000). THE CONSEQUENCES OF NOT REPLACING A MISSING POSTERIOR TOOTH. The Journal of the American Dental Association, 131(9), 1317-1323. doi:10.14219/jada.archive.2000.0385Thalmair, T., Fickl, S., Schneider, D., Hinze, M., & Wachtel, H. (2013). Dimensional alterations of extraction sites after different alveolar ridge preservation techniques - a volumetric study. 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Stability assessment of organic sulfur and organosulfate compounds in filter samples for quantification by Fourier- transform infrared spectroscopy

Organic sulfur and sulfate compounds, which are tracers for sources and atmospheric processes, are not currently measured in national monitoring networks such as the Interagency Monitoring of Protected Visual Environments (IMPROVE). The goal of this paper is to begin to assess the stability of organic sulfur and sulfate-containing compounds on polytetrafluoroethylene (PTFE) filters and the suitability of Fourier-transform infrared (FT-IR) spectroscopy to measure these compounds. Stability assessment is needed because PTFE samples collected by IMPROVE are typically stored 6–9 months prior to analysis. For this study, two organosulfur compounds, methanesulfonic acid (MSA) and hydroxymethanesulfonate ion (HMS), and two organosulfate compounds, methyl sulfate (MS) and 2-methyltetrol sulfate (2-MTS), are collected individually on PTFE filters. Gravimetric mass measurements are used to assess mass stability over time. FT-IR spectra are evaluated to assess the capability of measuring the compound from PTFE filters by assessing the compound stability or chemical changes over time. Ion chromatography (IC) and inductively coupled plasma optical emission spectroscopy (ICP-OES) are used as additional tools to assess stability or chemical changes over time. MS has the highest potential to be measured by FT-IR in IMPROVE samples. For MS, a simple organosulfate, the mass changes are within measurement uncertainty and FT-IR spectra indicate no compositional change over a 4-month period, suggesting that MS can be measured using FT-IR. IC and ICP-OES support the conclusion that MS is stable on the filter. However, for 2-MTS, the other organosulfate measured in this study, spectral changes after a month on the filter suggest that it decomposes into other organosulfates or an inorganic sulfate. MSA in IMPROVE samples can be measured, but only as a lower bound, due to volatility off the filter as indicated by FT-IR and gravimetry. FT-IR and IC both show that MSA does not chemically change over the course of the study. Measurements by all methods indicate that HMS is unstable on the PTFE filter, and IC and FT-IR indicate that it likely converts to inorganic sulfate. Future work includes the evaluation of these compounds in an ambient aerosol sample matrix to determine any differences in stability, identifying interference that could limit quantification, and developing calibrations to measure the compounds or functional groups in ambient samples.</p