145 research outputs found
New mini-osteotomy of the infraorbital nerve in bony decompression for endocrine orbitopathy
No full textEndocrine orbitopathy is a systemic complex disease that involves the orbital contents. The symptoms are exophthalmos and correlated. The surgical techniques used to correct this condition can be fat decompression by the Olivari technique, 3-wall bony decompression, or the combination of these 2 surgical strategies, the ancillary procedure. Fat decompression is indicated when the intraconal and extraconal fat tissue is increased, whereas bony decompression is used in the presence of extraocular muscle involvement, associated with a normal quantity of intraconal-extraconal fat. Surgical techniques include the transconjunctival approach and ostectomy of the medial wall (when possible through endoscopy), orbital floor, and lateral wall of the orbit.Complications of this type of intervention are often represented by sensitivity disorders of the second branch of the trigeminal nerve, compressed by the intraorbital contents when they prolapse into the sinus. Possible sensitivity disorders are paresthesia, anesthesia, hypoaesthesia, dysesthesia, and hyperesthesia.The innovation introduced by the first author in 2007 consists of a mini ostectomy around the infraorbital foramen with removal of bone fragment. This determines relaxation of the nerve and makes easier the descent toward the sinus, allowing a larger expansion of the orbit contents. The absence of compression significantly reduces the sensitive complications. After treatment of the basic disease, surgical indications should be given according to the Werner classification. Fat decompression with the coronal approach is almost entirely abandoned for the transconjunctival approach, which allows adequate exposure of the lower orbit.The use of mini ostectomy of the infraorbital foramen combined with a 3-wall bony expansion showed a significant reduction of sensitive complications that often cause patient discomfort
Laying the foundation for building a Quantum Networking Benchmark suite using Quantum Network Applications: Evaluating the inclusion of the Clauser-Horne-Shimony-Holt game quantum network application
No full textThe rapid advancement of Quantum Network architectures necessitates a comprehensive and quantitative comparison to assess their effectiveness and performance. Unfortunately, there does not exist an implemented quantum network benchmark suite capable of determining the superior architecture. Hence, our study aims to establish the foundation for developing a benchmark suite by leveraging existing quantum network applications. However, the specific inclusion of quantum network applications in the suite remains to be determined. Therefore, to address this gap, our study will explore the potential inclusion of the Clauser-Horne-Shimony-Holt (CHSH) game based on its effectiveness in identifying errors within various properties of the quantum networking system. We use an exploratory research methodology involving experiments performed on simulated quantum networks utilizing SquidASM. Each experiment simulates multiple quantum networks, with a single property as the independent variable. For each value of the independent variable, we calculate both the success probability of the game and the number of successes per second. Subsequently, we employ the one-way ANOVA test to examine if there are significant variations in these performance metrics. Our results demonstrate that the CHSH game exhibits sensitivity to all properties affecting the quality of entanglement between nodes, execution time, and the error probability of both single-qubit gates and measure operations. Additionally, we compare the success probabilities based on different input combinations using the Root Mean Squared metric to uncover any underlying patterns within the data. As a result, we discovered a procedure for quantifying the difference between the error probabilities of measurements of zero and one. Based on the outcomes of our study, we consider the CHSH game to be a suitable addition to the benchmark suite if the testing requirements of the suite align with the qualities offered by the application. We anticipate that these results will aid the development of the benchmark suite and advance the understanding of quantum network architectures and their evaluationhttps://gitlab.com/tmaliappis28/research-project Repository link Public repository containing all code used in the project ShowEdit https://surfdrive.surf.nl/files/index.php/s/w7qq3pQXYgUkr8T?path=%2FResults%2FCHSH%20game%20-%20Thomas%20Maliappis Surfdrive that contains also all code used in the projectCSE3000 Research ProjectComputer Science and Engineerin
The Matrisome: In Silico Definition and In Vivo Characterization by Proteomics of Normal and Tumor Extracellular Matrices
No full textThe extracellular matrix (ECM) is a complex meshwork of cross-linked proteins providing both biophysical and biochemical cues that are important regulators of cell proliferation, survival, differentiation, and migration. We present here a proteomic strategy developed to characterize the in vivo ECM composition of normal tissues and tumors using enrichment of protein extracts for ECM components and subsequent analysis by mass spectrometry. In parallel, we have developed a bioinformatic approach to predict the in silico “matrisome” defined as the ensemble of ECM proteins and associated factors. We report the characterization of the extracellular matrices of murine lung and colon, each comprising more than 100 ECM proteins and each presenting a characteristic signature. Moreover, using human tumor xenografts in mice, we show that both tumor cells and stromal cells contribute to the production of the tumor matrix and that tumors of differing metastatic potential differ in both the tumor- and the stroma-derived ECM components. The strategy we describe and illustrate here can be broadly applied and, to facilitate application of these methods by others, we provide resources including laboratory protocols, inventories of ECM domains and proteins, and instructions for bioinformatically deriving the human and mouse matrisome.National Cancer Institute (U.S.) (U54 CA126515
An Integrative Framework Reveals Signaling-to-Transcription Events in Toll-like Receptor Signaling
No full textBuilding an integrated view of cellular responses to environmental cues remains a fundamental challenge due to the complexity of intracellular networks in mammalian cells. Here, we introduce an integrative biochemical and genetic framework to dissect signal transduction events using multiple data types and, in particular, to unify signaling and transcriptional networks. Using the Toll-like receptor (TLR) system as a model cellular response, we generate multifaceted datasets on physical, enzymatic, and functional interactions and integrate these data to reveal biochemical paths that connect TLR4 signaling to transcription. We define the roles of proximal TLR4 kinases, identify and functionally test two dozen candidate regulators, and demonstrate a role for Ap1ar (encoding the Gadkin protein) and its binding partner, Picalm, potentially linking vesicle transport with pro-inflammatory responses. Our study thus demonstrates how deciphering dynamic cellular responses by integrating datasets on various regulatory layers defines key components and higher-order logic underlying signaling-to-transcription pathways
Precision proteogenomics reveals pan-cancer impact of germline variants
No full textWe investigate the impact of germline variants on cancer patients’ proteomes, encompassing 1,064 individuals across 10 cancer types. We introduced an approach, “precision peptidomics,” mapping 337,469 coding germline variants onto peptides from patients’ mass spectrometry data, revealing their potential impact on post-translational modifications, protein stability, allele-specific expression, and protein structure by leveraging the relevant protein databases. We identified rare pathogenic and common germline variants in cancer genes potentially affecting proteomic features, including variants altering protein abundance and structure and variants in kinases (ERBB2 and MAP2K2) impacting phosphorylation. Precision peptidome analysis predicted destabilizing events in signal-regulatory protein alpha (SIRPA) and glial fibrillary acid protein (GFAP), relevant to immunomodulation and glioblastoma diagnostics, respectively. Genome-wide association studies identified quantitative trait loci for gene expression and protein levels, spanning millions of SNPs and thousands of proteins. Polygenic risk scores correlated with distal effects from risk variants. Our findings emphasize the contribution of germline genetics to cancer heterogeneity and high-throughput precision peptidomics.We would like to thank the participants and investigators from the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC). This work was supported by NCI-CPTAC under award numbers U24CA210955, U24CA210985, U24CA210986, U24CA210954, U24CA210967, U24CA210972, U24CA210979, U24CA210993, U01CA214114, U01CA214116, and U01CA214125 as well as U24CA210972 (D.F., and L.D.), U24CA210979 (G.G.), U24CA270823 (M.A.G.), and contract number GR0012005 (L.D.). This work was also supported by NCI U24CA211006 and R01HG009711 to L.D. The Spanish Ministry of Science supports E.P.-P. and K.J.I. (RYC2019-026415-I and PID2019-107043RA-I00) and U.M.M. (RYC2020-030632-I and PID2019-108244RA-I00). I.M. is supported by Fundación Cris Contra el Cáncer (PR_TPD_2020-19). This research was conducted using the UK Biobank Resource under application numbers 54343 and 74382 (to E.P.-P. and U.M.M., respectively).
This project is funded in part with federal funds from the NCI, National Institutes of Health, under contract no. HHSN261201500003I, Task Order no. HHSN26100064. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.Peer Reviewed"Article signat per 35 autors/es: Fernanda Martins Rodrigues, Nadezhda V. Terekhanova, Kathleen J. Imbach, Karl R. Clauser, Myvizhi Esai Selvan, Isabel Mendizaba, Yifat Geffen,Yo Akiyama, Myranda Maynard, Tomer M. Yaron, Yize Li, Song Cao, Erik P. Storrs, Olivia S. Gonda, Adrian Gaite-Reguero, Akshay Govindan, Emily A. Kawaler, Matthew A. Wyczalkowski, Robert J. Klein, Berk Turhan, Karsten Krug, D.R. Mani, Felipe da Veiga Leprevost, Alexey I. Nesvizhskii, Steven A. Carr, David Fenyö, Michael A. Gillette, Antonio Colaprico, Antonio Iavarone, Ana I. Robles, Kuan-lin Huang, Chandan Kumar-Sinha, François Aguet, Alexander J. Lazar, Urko M. Marigorta, Zeynep H. Gümüş, Matthew H. Bailey, Gad Getz, Eduard Porta-Pardo, Li Ding, Clinical Proteomic Tumor Analysis Consortium"Postprint (published version
MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins
No full textMitochondria are complex organelles that house es-sential pathways involved in energy metabolism, ion homeostasis, signalling and apoptosis. To under-stand mitochondrial pathways in health and dis-ease, it is crucial to have an accurate inventory of the organelle’s protein components. In 2008, we made substantial progress toward this goal by per-forming in-depth mass spectrometry of mitochon-dria from 14 organs, epitope tagging/microscopy and Bayesian integration to assemble MitoCarta (www.broadinstitute.org/pubs/MitoCarta): an inven-tory of genes encoding mitochondrial-localized pro-teins and their expression across 14 mouse tis-sues. Using the same strategy we have now recon-structed this inventory separately for human and for mouse based on (i) improved gene transcript models, (ii) updated literature curation, including re-sults from proteomic analyses of mitochondrial sub-compartments, (iii) improved homology mapping and (iv) updated versions of all seven original data sets. The updated human MitoCarta2.0 consists of 1158 human genes, including 918 genes in the original inventory as well as 240 additional genes. The up-dated mouse MitoCarta2.0 consists of 1158 genes, including 967 genes in the original inventory plus 191 additional genes. The improved MitoCarta 2.0 inven-tory provides a molecular framework for system-level analysis of mammalian mitochondria
Plk1 Self-Organization and Priming Phosphorylation of HsCYK-4 at the Spindle Midzone Regulate the Onset of Division in Human Cells
No full textAnimal cells initiate cytokinesis in parallel with anaphase onset, when an actomyosin ring assembles and constricts through localized activation of the small GTPase RhoA, giving rise to a cleavage furrow. Furrow formation relies on positional cues provided by anaphase spindle microtubules (MTs), but how such cues are generated remains unclear. Using chemical genetics to achieve both temporal and spatial control, we show that the self-organized delivery of Polo-like kinase 1 (Plk1) to the midzone and its local phosphorylation of a MT-bound substrate are critical for generating this furrow-inducing signal. When Plk1 was active but unable to target itself to this equatorial landmark, both cortical RhoA recruitment and furrow induction failed to occur, thus recapitulating the effects of anaphase-specific Plk1 inhibition. Using tandem mass spectrometry and phosphospecific antibodies, we found that Plk1 binds and directly phosphorylates the HsCYK-4 subunit of centralspindlin (also known as MgcRacGAP) at the midzone. At serine 157, this modification creates a major docking site for the tandem BRCT repeats of the Rho GTP exchange factor Ect2. Cells expressing only a nonphosphorylatable form of HsCYK-4 failed to localize Ect2 at the midzone and were severely impaired in cleavage furrow formation, implying that HsCYK-4 is Plk1's rate-limiting target upstream of RhoA. Conversely, tethering an inhibitor-resistant allele of Plk1 to HsCYK-4 allowed furrows to form despite global inhibition of all other Plk1 molecules in the cell. Our findings illuminate two key mechanisms governing the initiation of cytokinesis in human cells and illustrate the power of chemical genetics to probe such regulation both in time and space
Neutron-state entanglement with overlapping paths
No full textThe development of direct probes of entanglement is integral to the rapidly expanding field of complex quantum materials. Here we test the robustness of entangled neutrons as a quantum probe by measuring the Clauser-Horne-Shimony-Holt contextuality witness while varying the beam properties. Specifically, we show that the mode entanglement of the spin and path subsystems of individual neutrons prepared in two different experiments using two different apparatuses persists even after varying the entanglement length, coherence length, and neutron energy difference of the paths. The two independent apparatuses acting as entangler-disentangler pairs are static-field magnetic Wollaston prisms and resonance-field radio-frequency flippers. Our results show that the spatial and energy properties of the neutron beam may be significantly altered without reducing the contextuality witness value below the Tsirelson bound, meaning that maximum entanglement is preserved. We also show that two paths may be considered distinguishable even when the path states significantly overlap. Therefore, we have shown that our experimental results are consistent with the distinguishable subsystem assumption down to a separation of less than 100 nm, proving entanglement and the contextual nature of reality on short length scales. This work is the key step in the realization of the modular, robust technique of entangled neutron scattering, which can extract entanglement information from a sample without the knowledge of the microscopic sample Hamiltonian: only semiquantitative knowledge of the correlation lengths of the relevant degrees of freedom and the timescales of the characteristic dynamics is required.RID/TS/Instrumenten groe
The production and X-ray structure determination of perdeuterated Staphylococcal nuclease
No full textEnrichment of Extracellular Matrix Proteins from Tissues and Digestion into Peptides for Mass Spectrometry Analysis
No full textThe extracellular matrix (ECM) is a complex meshwork of cross-linked proteins that provides biophysical and biochemical cues that are major regulators of cell proliferation, survival, migration, etc. The ECM plays important roles in development and in diverse pathologies including cardio-vascular and musculo-skeletal diseases, fibrosis, and cancer. Thus, characterizing the composition of ECMs of normal and diseased tissues could lead to the identification of novel prognostic and diagnostic biomarkers and potential novel therapeutic targets. However, the very nature of ECM proteins (large in size, cross-linked and covalently bound, heavily glycosylated) has rendered biochemical analyses of ECMs challenging. To overcome this challenge, we developed a method to enrich ECMs from fresh or frozen tissues and tumors that takes advantage of the insolubility of ECM proteins. We describe here in detail the decellularization procedure that consists of sequential incubations in buffers of different pH and salt and detergent concentrations and that results in 1) the extraction of intracellular (cytosolic, nuclear, membrane and cytoskeletal) proteins and 2) the enrichment of ECM proteins. We then describe how to deglycosylate and digest ECM-enriched protein preparations into peptides for subsequent analysis by mass spectrometry.United States. Department of Defense (DOD Innovator Award W81XWH-14-1-0240)National Cancer Institute (U.S.) (Grant U54 CA126515/CA163109)Broad Institute of MIT and HarvardHoward Hughes Medical InstituteNational Cancer Institute (U.S.) (David H. Koch Institute for Integrative Cancer Research at MIT. Grant P30-CA14051
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