Glycated Hemoglobin and the Risk of Kidney Disease and Retinopathy in Adults With and Without Diabetes

10.2337/db10-1198Diabetes601298-305DIAE

Peptide Signatures for Prognostic Markers of Pancreatic Cancer by MALDI Mass Spectrometry Imaging

Simple Summary: Pancreatic cancer remains one of the most lethal tumor entities worldwide given its overall 5-year survival after diagnosis of 9%. Thus, further understanding of molecular changes to improve individual prognostic assessment as well as diagnostic and therapeutic advancement is crucial. The aim of this study was to investigate the feasibility of Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to identify specific peptide signatures linked to established prognostic parameters of pancreatic cancer. In a patient cohort of 18 patients with exocrine pancreatic cancer after tumor resection, MALDI imaging analysis additional to histopathological assessment was performed. Applying this method to tissue sections of the tumors, we were able to identify discriminative peptide signatures corresponding to nine proteins for the prognostic histopathological features lymphatic vessel invasion, lymph node metastasis and angioinvasion. This demonstrates the technical feasibility of MALDI-MSI to identify peptide signatures with prognostic value through the workflows used in this study. Abstract: Despite the overall poor prognosis of pancreatic cancer there is heterogeneity in clinical courses of tumors not assessed by conventional risk stratification. This yields the need of additional markers for proper assessment of prognosis and multimodal clinical management. We provide a proof of concept study evaluating the feasibility of Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to identify specific peptide signatures linked to prognostic parameters of pancreatic cancer. On 18 patients with exocrine pancreatic cancer after tumor resection, MALDI imaging analysis was performed additional to histopathological assessment. Principal component analysis (PCA) was used to explore discrimination of peptide signatures of prognostic histopathological features and receiver operator characteristic (ROC) to identify which specific m/z values are the most discriminative between the prognostic subgroups of patients. Out of 557 aligned m/z values discriminate peptide signatures for the prognostic histopathological features lymphatic vessel invasion (pL, 16 m/z values, eight proteins), nodal metastasis (pN, two m/z values, one protein) and angioinvasion (pV, 4 m/z values, two proteins) were identified. These results yield proof of concept that MALDI-MSI of pancreatic cancer tissue is feasible to identify peptide signatures of prognostic relevance and can augment risk assessment

The medical student

The Medical Student was published from 1888-1921 by the students of Boston University School of Medicine

The transcription factor 7-like 2 (TCF7L2) polymorphism may be associated with focal arteriolar narrowing in Caucasians with hypertension or without diabetes: the ARIC Study

<p>Abstract</p> <p>Background</p> <p>Transcription factor 7-like 2 (<it>TCF7L2</it>) has emerged as a consistently replicated susceptibility gene for type 2 diabetes, however, whether the <it>TCF7L2 </it>gene also has similar effects on the retinal microvasculature is less clear. We therefore aimed to investigate the association between the transcription factor 7-like 2 (<it>TCF7L2</it>) rs7903146 polymorphism and retinal microvascular phenotypes in the Atherosclerosis Risk in Communities (ARIC) Study (1993-1995).</p> <p>Methods</p> <p>This was a population-based, cross-sectional study of 10,320 middle-aged African American (n = 2,199) and Caucasian (n = 8,121) men and women selected from four United States communities to examine the association between <it>TCF7L2 </it>rs7903146 polymorphism and retinal microvascular signs (retinopathy, focal arteriolar narrowing, arteriovenous nicking, arteriolar and venular calibers). Photographs on one randomly selected eye were graded for presence of retinal microvascular signs and used to measure retinal vessel calibres.</p> <p>Results</p> <p>After adjusting for age, sex, study center, mean arterial blood pressure, total serum cholesterol, triglycerides, and other covariates, few associations of <it>TCF7L2 </it>rs7903146 and retinal microvascular signs were noted. <it>TCF7L2 </it>rs7903146 T risk allele was significantly associated with focal arteriolar narrowing in Caucasians with hypertension [odds ratio (OR)_{CT vs. CC}(95% CI) = 1.25 (1.09-1.44); OR_{TT vs. CC}= 1.56 (1.18-2.06); <it>P </it>= 0.002] and in Caucasians without diabetes [OR _{CT vs. CC}= 1.18 (1.06-1.32); OR _{TT vs. CC}= 1.40 (1.12, 1.75); <it>P </it>= 0.003]. No significant association of the <it>TCF7L2 </it>rs7903146 polymorphism and retinal vascular signs was noted among African American individuals.</p> <p>Conclusions</p> <p><it>TCF7L2 </it>rs7903146 is not consistently associated with retinal microvascular signs. However, we report an association between the <it>TCF7L2 </it>rs7903146 polymorphism and focal arteriolar narrowing in Caucasians with hypertension or without diabetes. Further research in other large, population-based studies is needed to replicate these findings.</p

The GLY2019SER Mutation in LRRK2 is Not Fully Penetrant in Familial Parkinson\u27s Disease: the GenePD Study

Background: We report age-dependent penetrance estimates for leucine-rich repeat kinase 2 (LRRK2)-related Parkinson\u27s disease (PD) in a large sample of familial PD. The most frequently seen LRRK2 mutation, Gly2019Ser (G2019S), is associated with approximately 5 to 6% of familial PD cases and 1 to 2% of idiopathic cases, making it the most common known genetic cause of PD. Studies of the penetrance of LRRK2 mutations have produced a wide range of estimates, possibly due to differences in study design and recruitment, including in particular differences between samples of familial PD versus sporadic PD. Methods: A sample, including 903 affected and 58 unaffected members from 509 families ascertained for having two or more PD-affected members, 126 randomly ascertained PD patients and 197 controls, was screened for five different LRRK2 mutations. Penetrance was estimated in families of LRRK2 carriers with consideration of the inherent bias towards increased penetrance in a familial sample. Results: Thirty-one out of 509 families with multiple cases of PD (6.1%) were found to have 58 LRRK2 mutation carriers (6.4%). Twenty-nine of the 31 families had G2019S mutations while two had R1441C mutations. No mutations were identified among controls or unaffected relatives of PD cases. Nine PD-affected relatives of G2019S carriers did not carry the LRRK2 mutation themselves. At the maximum observed age range of 90 to 94 years, the unbiased estimated penetrance was 67% for G2019S families, compared with a baseline PD risk of 17% seen in the non-LRRK2-related PD families. Conclusion: Lifetime penetrance of LRRK2 estimated in the unascertained relatives of multiplex PD families is greater than that reported in studies of sporadically ascertained LRRK2 cases, suggesting that inherited susceptibility factors may modify the penetrance of LRRK2 mutations. In addition, the presence of nine PD phenocopies in the LRRK2 families suggests that these susceptibility factors may also increase the risk of non-LRRK2-related PD. No differences in penetrance were found between men and women, suggesting that the factors that influence penetrance for LRRK2 carriers are independent of the factors which increase PD prevalence in men

Ernst Freund as Precursor of the Rational Study of Corporate Law

Gindis, David, Ernst Freund as Precursor of the Rational Study of Corporate Law (October 27, 2017). Journal of Institutional Economics, Forthcoming. Available at SSRN: https://ssrn.com/abstract=2905547, doi: https://dx.doi.org/10.2139/ssrn.2905547The rise of large business corporations in the late 19th century compelled many American observers to admit that the nature of the corporation had yet to be understood. Published in this context, Ernst Freund's little-known The Legal Nature of Corporations (1897) was an original attempt to come to terms with a new legal and economic reality. But it can also be described, to paraphrase Oliver Wendell Holmes, as the earliest example of the rational study of corporate law. The paper shows that Freund had the intuitions of an institutional economist, and engaged in what today would be called comparative institutional analysis. Remarkably, his argument that the corporate form secures property against insider defection and against outsiders anticipated recent work on entity shielding and capital lock-in, and can be read as an early contribution to what today would be called the theory of the firm.Peer reviewe

Effects of upward and downward social comparison information on the efficacy of an appearance-based sun protection intervention: a randomized, controlled experiment

This experiment examined the impact of adding upward and/or downward social comparison information on the efficacy of an appearance-based sun protection intervention (UV photos and photoaging information). Southern California college students (N = 126) were randomly assigned to one of four conditions: control, intervention, intervention plus upward social comparison, intervention plus downward social comparison. The results demonstrated that all those who received the basic UV photo/photoaging intervention reported greater perceived susceptibility to photoaging (d = .74), less favorable tanning cognitions (d = .44), and greater intentions to sun protect (d = 1.32) relative to controls. Of more interest, while the basic intervention increased sun protective behavior during the subsequent 5 weeks relative to controls (d = .44), the addition of downward comparison information completely negated this benefit. Upward comparison information produced sun protection levels that were only slightly (and nonsignificantly) greater than in the basic intervention condition and, as such, does not appear to be a cost-effective addition. Possible mechanisms that may have reduced the benefits of upward comparison information and contributed to the undermining effects of downward comparison information are discussed

Experimental and computational studies of the production of 1,3-butadiene from 2,3-butanediol using SiO2-supported H3PO4 derivatives

Silica-supported phosphoric acid and metal phosphate catalyzed 1,3-butadiene (BDE) production from 2,3-butanediol (2,3-BDO) was studied using experimental and computational techniques. The catalyst was initially tested in a continuous flow reactor using commercially available 2,3-BDO, leading to maximum BDE yields of 63C%. Quantum chemical mechanistic studies revealed 1,2-epoxybutane is a kinetically viable and thermodynamically stable intermediate, supported by experimental demonstration that this epoxide can be converted to BDE under standard reaction conditions. Newly proposed E2 and SN2′ elementary steps were studied to rationalize the formation of BDE and all detected side-products. Additionally, using quantum mechanics/molecular mechanics (QM/MM) calculations, we modeled silica-supported phosphate catalysts to study the effect of the alkali metal center. Natural population analysis showed that phosphate oxygen atoms are more negatively charged in CsH2PO4/SiO2 than in H3PO4/SiO2. In combination with temperature-programmed desorption experiments using CO2, the results of this study suggest that the improved selectivity achieved when adding the metal center is related to an increase in the basicity of the catalyst.R.S.P. and J.V.A.-R. acknowledge the RMACC Summit supercomputer, supported by the NSF (ACI-1532235 and ACI1532236), and the Extreme Science and Engineering Discovery Environment (XSEDE) allocations TG-CHE180056 and TG-CHE200033. J.V.A.-R. acknowledges financial support through the Gobierno de Aragón-Fondo Social Europeo (Research Group E07_23R) and a Juan de la Cierva Incorporación contract from the Ministry of Science and Innovation (MCIN) and the State Research Agency (AEI) of Spain, and the European Union (NextGenerationEU/PRTR) under grant reference IJC2020-044217-I. S.K. acknowledges XSEDE allocation TG-CHE210034 and the National Renewable Energy Laboratory Computational Science Center. This work was authored in part by the National Renewable Energy Laboratory, managed and operated by Alliance for Sustainable Energy, LLC, for the U.S. Department of Energy (DOE) under Contract No. DE-AC36-08GO28308. Funding was provided by U.S. Department of Energy Office of Energy Efficiency and Renewable Energy Bioenergy Technologies Office and in collaboration with the Consortium for Computational Physics and Chemistry (CCPC) and the Chemical Catalysis for Bioenergy Consortium (ChemCatBio). G.R.H., X.H., F.G.B, K.A.U., B.C.K., R.E.D., and D.R.V. acknowledge funding from the Chemical Catalysis for Bioenergy consortium by the Bioenergy Technologies Office in the DOE Office of Energy Efficiency and Renewable Energy. Microscopy was performed in collaboration with the Chemical Catalysis for Bioenergy Consortium under contract no. DE-AC05-00OR22725 with Oak Ridge National Laboratory (ORNL) and through a user project supported by ORNL’s Center for Nanophase Materials Sciences (CNMS), which is sponsored by the Scientific User Facilities Division, Office of Basic Energy Sciences, U.S. Department of Energy. Part of the microscopy research was also supported by the Office of Nuclear Energy, Fuel Cycle R&D Program and the Nuclear Science User Facilities. The results and analysis presented in this paper were partially possible thanks to the access granted to computing resources at the Galicia Supercomputing Center, CESGA, including access to the FinisTerrae supercomputer, the Red Española de Supercomputación (grant number QH-2023-1-0003) and the Drago cluster facility of SGAI-CSIC.Peer reviewe

Glutathione and Adaptive Immune Responses against Mycobacterium tuberculosis Infection in Healthy and HIV Infected Individuals

Glutathione (GSH), a tripeptide antioxidant, is essential for cellular homeostasis and plays a vital role in diverse cellular functions. Individuals who are infected with Human immuno deficiency virus (HIV) are known to be susceptible to Mycobacterium tuberculosis (M. tb) infection. We report that by enhancing GSH levels, T-cells are able to inhibit the growth of M. tb inside macrophages. In addition, those GSH-replenished T cell cultures produced increased levels of Interleukin-2 (IL-2), Interleukin-12 (IL-12), and Interferon-gamma (IFN-γ), cytokines, which are known to be crucial for the control of intracellular pathogens. Our study reveals that T lymphocytes that are derived from HIV infected individuals are deficient in GSH, and that this deficiency correlates with decreased levels of Th1 cytokines and enhanced growth of M. tb inside human macrophages

A Single Peroxisomal Targeting Signal Mediates Matrix Protein Import in Diatoms

Peroxisomes are single membrane bound compartments. They are thought to be present in almost all eukaryotic cells, although the bulk of our knowledge about peroxisomes has been generated from only a handful of model organisms. Peroxisomal matrix proteins are synthesized cytosolically and posttranslationally imported into the peroxisomal matrix. The import is generally thought to be mediated by two different targeting signals. These are respectively recognized by the two import receptor proteins Pex5 and Pex7, which facilitate transport across the peroxisomal membrane. Here, we show the first in vivo localization studies of peroxisomes in a representative organism of the ecologically relevant group of diatoms using fluorescence and transmission electron microscopy. By expression of various homologous and heterologous fusion proteins we demonstrate that targeting of Phaeodactylum tricornutum peroxisomal matrix proteins is mediated only by PTS1 targeting signals, also for proteins that are in other systems imported via a PTS2 mode of action. Additional in silico analyses suggest this surprising finding may also apply to further diatoms. Our data suggest that loss of the PTS2 peroxisomal import signal is not reserved to Caenorhabditis elegans as a single exception, but has also occurred in evolutionary divergent organisms. Obviously, targeting switching from PTS2 to PTS1 across different major eukaryotic groups might have occurred for different reasons. Thus, our findings question the widespread assumption that import of peroxisomal matrix proteins is generally mediated by two different targeting signals. Our results implicate that there apparently must have been an event causing the loss of one targeting signal even in the group of diatoms. Different possibilities are discussed that indicate multiple reasons for the detected targeting switching from PTS2 to PTS1