Julie Chow, Jensen, Matthew , Amini, Hajar , Hormozdiari, Farhad , Penn, Osnat , Shifman, Sagiv , Girirajan, Santhosh , ו Hormozdiari, Fereydoun . 2019.
“Dissecting The Genetic Basis Of Comorbid Epilepsy Phenotypes In Neurodevelopmental Disorders”. Genome Med, 11, 1, Pp. 65. doi:10.1186/s13073-019-0678-y.
תקציר BACKGROUND: Neurodevelopmental disorders (NDDs) such as autism spectrum disorder, intellectual disability, developmental disability, and epilepsy are characterized by abnormal brain development that may affect cognition, learning, behavior, and motor skills. High co-occurrence (comorbidity) of NDDs indicates a shared, underlying biological mechanism. The genetic heterogeneity and overlap observed in NDDs make it difficult to identify the genetic causes of specific clinical symptoms, such as seizures.
METHODS: We present a computational method, MAGI-S, to discover modules or groups of highly connected genes that together potentially perform a similar biological function. MAGI-S integrates protein-protein interaction and co-expression networks to form modules centered around the selection of a single "seed" gene, yielding modules consisting of genes that are highly co-expressed with the seed gene. We aim to dissect the epilepsy phenotype from a general NDD phenotype by providing MAGI-S with high confidence NDD seed genes with varying degrees of association with epilepsy, and we assess the enrichment of de novo mutation, NDD-associated genes, and relevant biological function of constructed modules.
RESULTS: The newly identified modules account for the increased rate of de novo non-synonymous mutations in autism, intellectual disability, developmental disability, and epilepsy, and enrichment of copy number variations (CNVs) in developmental disability. We also observed that modules seeded with genes strongly associated with epilepsy tend to have a higher association with epilepsy phenotypes than modules seeded at other neurodevelopmental disorder genes. Modules seeded with genes strongly associated with epilepsy (e.g., SCN1A, GABRA1, and KCNB1) are significantly associated with synaptic transmission, long-term potentiation, and calcium signaling pathways. On the other hand, modules found with seed genes that are not associated or weakly associated with epilepsy are mostly involved with RNA regulation and chromatin remodeling.
CONCLUSIONS: In summary, our method identifies modules enriched with de novo non-synonymous mutations and can capture specific networks that underlie the epilepsy phenotype and display distinct enrichment in relevant biological processes. MAGI-S is available at
https://github.com/jchow32/magi-s .
Daniel Mayer, Damberger, Fred F. , Samarasimhareddy, Mamidi , Feldmueller, Miki , Vuckovic, Ziva , Flock, Tilman , Bauer, Brian , Mutt, Eshita , Zosel, Franziska , Allain, Frederic H. T. , Standfuss, Jorg , Schertler, Gebhard F. X. , Deupi, Xavier , Sommer, Martha E. , Hurevich, Mattan , Friedler, Assaf , ו Veprintsev, Dmitry B.. 2019.
“Distinct G Protein-Coupled Receptor Phosphorylation Motifs Modulate Arrestin Affinity And Activation And Global Conformation”. Nature Communications, 10. doi:10.1038/s41467-019-09204-y.
תקציר
Cellular functions of arrestins are determined in part by the pattern of phosphorylation on the G protein-coupled receptors (GPCRs) to which arrestins bind. Despite high-resolution structural data of arrestins bound to phosphorylated receptor C-termini, the functional role of each phosphorylation site remains obscure. Here, we employ a library of synthetic phosphopeptide analogues of the GPCR rhodopsin C-terminus and determine the ability of these peptides to bind and activate arrestins using a variety of biochemical and biophysical methods. We further characterize how these peptides modulate the conformation of arrestin 1 by nuclear magnetic resonance (NMR). Our results indicate different functional classes of phosphorylation sites: `key sites' required for arrestin binding and activation, an `inhibitory site' that abrogates arrestin binding, and `modulator sites' that influence the global conformation of arrestin. These functional motifs allow a better understanding of how different GPCR phosphorylation patterns might control how arrestin functions in the cell.
Mayer D., F., Damberger F. , S., Mamidi , M., Feldmueller , Z., Vuckovic , T., Flock , B., Bauer , E., Mutt , F., Zosel , T., Allain F. H. , J., Standfuss , X., Schertler G. F. , X., Deupi , E., Sommer M. , M., Hurevich , A, Friedler , ו B., Veprintsev D.. 2019.
“Distinct G Protein-Coupled Receptor Phosphorylation Motifs Modulate Arrestin Affinity And Activation And Global Conformation”. Nat. Commun. .
קישור תקציר Cellular functions of arrestins are determined in part by the pattern of phosphorylation on the G protein-coupled receptors (GPCRs) to which arrestins bind. Despite high-resolution structural data of arrestins bound to phosphorylated receptor C-termini, the functional role of each phosphorylation site remains obscure. Here, we employ a library of synthetic phosphopeptide analogues of the GPCR rhodopsin C-terminus and determine the ability of these peptides to bind and activate arrestins using a variety of biochemical and biophysical methods. We further characterize how these peptides modulate the conformation of arrestin-1 by nuclear magnetic resonance (NMR). Our results indicate different functional classes of phosphorylation sites: ‘key sites’ required for arrestin binding and activation, an ‘inhibitory site’ that abrogates arrestin binding, and ‘modulator sites’ that influence the global conformation of arrestin. These functional motifs allow a better understanding of how different GPCR phosphorylation patterns might control how arrestin functions in the cell.
A. Y. Curzon, Chandrasekhar, K. , Nashef, Y. K. , Abbo, Shahal , Bonfil, D. J. , Reifen, Ram , Bar-el, S. , Avneri, A. , ו Ben-David, R.. 2019.
“Distinguishing Between Bread Wheat And Spelt Grains Using Molecular Markers And Spectroscopy”. Journal Of Agricultural And Food Chemistry, 67, 13, Pp. 3837 - 3841. .
Publisher's Version תקציר The increasing demand for spelt products requires the baking industry to develop accurate and efficient tools to differentiate between spelt and bread wheat grains. We subjected a 272-sample spelt-bread wheat set to several potential diagnostic methods. DNA markers for γ-gliadin-D (GAG56D), γ-gliadin-B (GAG56B), and the Q-gene were used, alongside phenotypic assessment of ease-of-threshing and near-infrared spectroscopy (NIRS). The GAG56B and GAG56D markers demonstrated low diagnostic power in comparison to the Q-gene genotyping, which showed full accordance with the threshing phenotype, providing a highly accurate distinction between bread wheat and spelt kernels. A highly reliable Q classification was based on a three-waveband NIR model [Kappa (0.97), R-square (0.93)], which suggested that this gene influences grain characteristics. Our data ruled out a protein concentration bias of the NIRS-based diagnosis. These findings highlight the Q gene and NIRS as important, valuable, but simple tools for distinguishing between bread wheat and spelt.The increasing demand for spelt products requires the baking industry to develop accurate and efficient tools to differentiate between spelt and bread wheat grains. We subjected a 272-sample spelt-bread wheat set to several potential diagnostic methods. DNA markers for γ-gliadin-D (GAG56D), γ-gliadin-B (GAG56B), and the Q-gene were used, alongside phenotypic assessment of ease-of-threshing and near-infrared spectroscopy (NIRS). The GAG56B and GAG56D markers demonstrated low diagnostic power in comparison to the Q-gene genotyping, which showed full accordance with the threshing phenotype, providing a highly accurate distinction between bread wheat and spelt kernels. A highly reliable Q classification was based on a three-waveband NIR model [Kappa (0.97), R-square (0.93)], which suggested that this gene influences grain characteristics. Our data ruled out a protein concentration bias of the NIRS-based diagnosis. These findings highlight the Q gene and NIRS as important, valuable, but simple tools for distinguishing between bread wheat and spelt.
AY Curzon, Chandrasekhar, K, Nashef, YK, Abbo, Shahal , Bonfil, DJ, Reifen, R, Bar-El, S, Avneri, A, ו Ben-David, R. 2019.
“Distinguishing Between Bread Wheat And Spelt Grains Using Molecular Markers And Spectroscopy”. J Agric Food Chem, 67, 13, Pp. 3837-3841. doi:10.1021/acs.jafc.9b00131.
תקציר The increasing demand for spelt products requires the baking industry to develop accurate and efficient tools to differentiate between spelt and bread wheat grains. We subjected a 272-sample spelt-bread wheat set to several potential diagnostic methods. DNA markers for γ-gliadin-D ( GAG56D), γ-gliadin-B ( GAG56B), and the Q-gene were used, alongside phenotypic assessment of ease-of-threshing and near-infrared spectroscopy (NIRS). The GAG56B and GAG56D markers demonstrated low diagnostic power in comparison to the Q-gene genotyping, which showed full accordance with the threshing phenotype, providing a highly accurate distinction between bread wheat and spelt kernels. A highly reliable Q classification was based on a three-waveband NIR model [Kappa (0.97), R-square (0.93)], which suggested that this gene influences grain characteristics. Our data ruled out a protein concentration bias of the NIRS-based diagnosis. These findings highlight the Q gene and NIRS as important, valuable, but simple tools for distinguishing between bread wheat and spelt.
Lysophosphatidic acid (LPA) is a bioactive phospholipid with mitogenic and growth factor-like activities affecting cell invasion, cancer progression, and resistance. It is produced mainly by autotaxin and acts on six G-protein-coupled receptors, LPAR1-6. LPA has recently been implicated as a growth factor present in ascites of ovarian cancer patients. However, mitogenic pathways stimulated by LPA via its receptors may involve any novel, thus far uncharacterized, signaling pathway(s). Here we show that three LPA receptors are involved in tumor progression by activation of both the AKT and ERK signaling pathways. CRISPR-edited LPAR2 and LPAR3 knockouts have opposing effects on ERK activation, whereas LPAR6 is involved in the activation of AKT, affecting cell migration and invasion. Our study identifies specific molecular machinery triggered by LPA and its receptors that modulates tumor cells and can serve as therapeutic target in this malignancy.
Richard Weichelt, Ye, Jingjing , Banin, Uri , Eychmüller, Alexander , ו Seidel, Ralf . 2019.
“Dna‐Mediated Self‐Assembly And Metallization Of Semiconductor Nanorods For The Fabrication Of Nanoelectronic Interfaces”. Chemistry–A European Journal, 25, 38, Pp. 9012-9016. .
Publisher's Version תקציר 
"DNA nanostructures provide a powerful platform for the programmable assembly of nanomaterials. Here, this approach is extended to semiconductor nanorods that possess interesting electrical properties and could be utilized for the bottom‐up fabrication of nanoelectronic building blocks. The assembly scheme is based on an efficient DNA functionalization of the nanorods. A complete coverage of the rod surface with DNA ensures a high colloidal stability while maintaining the rod size and shape. It furthermore supports the assembly of the nanorods at defined docking positions of a DNA origami platform with binding efficiencies of up to 90 % as well as the formation of nanorod dimers with defined relative orientations. By incorporating orthogonal binding sites for gold nanoparticles, defined metal‐semiconductor heterostructures can be fabricated. Subsequent application of a seeded growth procedure onto the gold nanoparticles (AuNPs) allows for to establish a direct metal‐semiconductor interface as a crucial basis for the integration of semiconductors in self‐assembled nanoelectronic devices."
Daphna Shimon, van Schooten, Kipp J. , Paul, Subhradip , Peng, Zaili , Takahashi, Susumu , Köckenberger, Walter , ו Ramanathan, Chandrasekhar . 2019.
“Dnp-Nmr Of Surface Hydrogen On Silicon Microparticles”. Solid State Nuclear Magnetic Resonance, 101, May, Pp. 68–75. doi:10.1016/j.ssnmr.2019.04.008.
Link to Full Text תקציר Political developments since the 2008 financial crisis have sparked renewed interest in the electoral implications of economic downturns. Research describes a correlation between adverse economic conditions and support for radical parties campaigning on the populist promise to retake the country from a corrupt elite. But does the success of radical parties following economic crises rely on people who are directly affected? To answer this question, we examine whether individual-level changes in economic circumstances drive support for radical parties across the ideological divide. Analyzing eight waves of panel data collected in The Netherlands, before, during, and after the Great Recession (2007–2015), we demonstrate that people who experienced an income loss became more supportive of the radical left but not of the radical right. Looking at these parties’ core concerns, we find that income loss increased support for income redistribution championed by the radical left, but less so fo
Diabetic nephropathy (DN), a distinct manifestation of diabetic kidney disease, affects approximately 30% of patients with diabetes. While most attention has been focused on glomerular changes related to DN, there is growing evidence that tubulopathy is a key feature in the pathogenesis of this disease. The renal proximal tubule cells (RPTCs) are particularly sensitive to the deleterious effect of chronic hyperglycemia. However, the cellular changes that control the dysfunction of the RPTCs are not fully understood. Controlling glucose reabsorption in the proximal tubules via inhibition of glucose transporters (GLUT) has emerged as a promising therapeutic in ameliorating DN. Overactivation of the renal endocannabinoid (eCB) system via the cannabinoid-1 receptor (CB1R) contributes to the development of DN, and its blockade by globally acting or peripherally restricted CB1R antagonists has been shown to ameliorate renal dysfunction in different murine models for diabetes. Recently, we have utilized various pharmacological and genetic tools to show that the eCB/CB1R system contributes to the development of DN via regulating the expression, translocation, and activity of the facilitative GLUT2 located in the RPTCs. These findings have the potential to be translated into therapy, and support the rationale for the preclinical development of novel renal-specific CB1R and/or GLUT2 inhibitors for the treatment of DN. © 2019 S. Karger AG, Basel. All rights reserved.
Diabetic nephropathy (DN), a distinct manifestation of diabetic kidney disease, affects approximately 30% of patients with diabetes. While most attention has been focused on glomerular changes related to DN, there is growing evidence that tubulopathy is a key feature in the pathogenesis of this disease. The renal proximal tubule cells (RPTCs) are particularly sensitive to the deleterious effect of chronic hyperglycemia. However, the cellular changes that control the dysfunction of the RPTCs are not fully understood. Controlling glucose reabsorption in the proximal tubules via inhibition of glucose transporters (GLUT) has emerged as a promising therapeutic in ameliorating DN. Overactivation of the renal endocannabinoid (eCB) system via the cannabinoid-1 receptor (CB1R) contributes to the development of DN, and its blockade by globally acting or peripherally restricted CB1R antagonists has been shown to ameliorate renal dysfunction in different murine models for diabetes. Recently, we have utilized various pharmacological and genetic tools to show that the eCB/CB1R system contributes to the development of DN via regulating the expression, translocation, and activity of the facilitative GLUT2 located in the RPTCs. These findings have the potential to be translated into therapy, and support the rationale for the preclinical development of novel renal-specific CB1R and/or GLUT2 inhibitors for the treatment of DN.
Eyal Peer, Yuval, Feldman , Eyal, Gamliel , Limor, Sahar , Ariel, Tikotsky , Nurit, Hod , ו Schupak, Hilla . 2019.
“Do Minorities Like Nudges? The Role Of Group Norms In Attitudes Towards Behavioral Policy”. Judgment And Decision Making.
תקציר Attitudes of public groups towards behavioral policy interventions (or nudges) can be important for both the policy makers who design and deploy nudges, and to researchers who try to understand when and why some nudges are supported while others are not. Until now, research on public attitudes towards nudges has focused on either state- or country-level comparisons, or on correlations with individual-level traits, and has neglected to study how different social groups (such as minorities) might view nudges. Using a large and representative sample, we tested the attitudes of two distinct minority groups in Israel (Israeli Arabs and Ultra-Orthodox Jews), and discovered that nudges that operated against a minority group’s held social norms, promoting a more general societal goal not aligned with the group’s norms, were often less supported by minorities. Contrary to expectations, these differences could not be explained by differences in trust in the government applying these nudges. We discuss implications for public policy and for the research and applications of behavioral interventions.
