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Frankenstein Ziv,Naohiro Uraoka,Umut Aypar,Ruth Aryeequaye,Mamta Rao,Meera Hameed,Yanming Zhang,Yukako Yagi 한국현미경학회 2021 Applied microscopy Vol.51 No.1
Fluorescence in situ hybridization (FISH) is a technique to visualize specific DNA/RNA sequences within the cell nuclei and provide the presence, location and structural integrity of genes on chromosomes. A confocal Whole Slide Imaging (WSI) scanner technology has superior depth resolution compared to wide-field fluorescence imaging. Confocal WSI has the ability to perform serial optical sections with specimen imaging, which is critical for 3D tissue reconstruction for volumetric spatial analysis. The standard clinical manual scoring for FISH is labor-intensive, time-consuming and subjective. Application of multi-gene FISH analysis alongside 3D imaging, significantly increase the level of complexity required for an accurate 3D analysis. Therefore, the purpose of this study is to establish automated 3D FISH scoring for z-stack images from confocal WSI scanner. The algorithm and the application we developed, SHIMARIS PAFQ, successfully employs 3D calculations for clear individual cell nuclei segmentation, gene signals detection and distribution of break-apart probes signal patterns, including standard break-apart, and variant patterns due to truncation, and deletion, etc. The analysis was accurate and precise when compared with ground truth clinical manual counting and scoring reported in ten lymphoma and solid tumors cases. The algorithm and the application we developed, SHIMARIS PAFQ, is objective and more efficient than the conventional procedure. It enables the automated counting of more nuclei, precisely detecting additional abnormal signal variations in nuclei patterns and analyzes gigabyte multi-layer stacking imaging data of tissue samples from patients. Currently, we are developing a deep learning algorithm for automated tumor area detection to be integrated with SHIMARIS PAFQ.
Braten, Ori,Livneh, Ido,Ziv, Tamar,Admon, Arie,Kehat, Izhak,Caspi, Lilac H.,Gonen, Hedva,Bercovich, Beatrice,Godzik, Adam,Jahandideh, Samad,Jaroszewski, Lukasz,Sommer, Thomas,Kwon, Yong Tae,Guharoy, M National Academy of Sciences 2016 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.113 No.32
<P>The 'canonical' proteasomal degradation signal is a substrate-anchored polyubiquitin chain. However, a handful of proteins were shown to be targeted following monoubiquitination. In this study, we established-in both human and yeast cells-a systematic approach for the identification of monoubiquitination-dependent proteasomal substrates. The cellular wild-type polymerizable ubiquitin was replaced with ubiquitin that cannot form chains. Using proteomic analysis, we screened for substrates that are nevertheless degraded under these conditions compared with those that are stabilized, and therefore require polyubiquitination for their degradation. For randomly sampled representative substrates, we confirmed that their cellular stability is in agreement with our screening prediction. Importantly, the two groups display unique features: monoubiquitinated substrates are smaller than the polyubiquitinated ones, are enriched in specific pathways, and, in humans, are structurally less disordered. We suggest that monoubiquitination-dependent degradation is more widespread than assumed previously, and plays key roles in various cellular processes.</P>
Two-dimensional flow of driven particles: a microfluidic pathway to the non-equilibrium frontier
Beatus, Tsevi,Shani, Itamar,Bar-Ziv, Roy H.,Tlusty, Tsvi The Royal Society of Chemistry 2017 Chemical Society reviews Vol.46 No.18
<P>We discuss the basic physics of the flow of micron-scale droplets in 2D geometry. Our focus is on the use of droplet ensembles to look into fundamental questions of non-equilibrium systems, such as the emergence of dynamic patterns and irreversibility. We review recent research in these directions, which demonstrate that 2D microfluidics is uniquely set to study complex out-of-equilibrium phenomena thanks to the simplicity of the underlying Stokes flow and the accessibility of lab-on-chip technology.</P>
Single Phase Medium Entropy U-Based Alloys: Thermodynamics, Synthesis, and Mechanical Behavior
Michael Aizenshtein,Eli Brosh,Shai Silhov,Shlomo Levi,Ziv Ungarish,Eyal Grinberg,Shmuel Hayun 대한금속·재료학회 2023 METALS AND MATERIALS International Vol.29 No.12
High and medium entropy alloys (HEAs and MEAs) exhibit superior resistance to irradiation damage: there is thus greatincentive to study uranium-based HEAs and MEAs. These materials could potentially be suitable candidates for use asnuclear fuels where severe irradiation regimes prevail. In the present study, the ability to predict single phase regions in thequaternary system, Mo–Nb–U–Zr, using thermodynamic calculations was demonstrated and proven experimentally. Similarlyto other known bcc HEAs systems, the bcc phase in the present MEA system was shown to exhibit high yield strengthbut also brittleness. It was also shown that a single phase in the MEA system, Mo–Nb–U–Zr, could be obtained only forcompositions containing no more than 10 at% of Mo.
p62- and ubiquitin-dependent stress-induced autophagy of the mammalian 26S proteasome
Cohen-Kaplan, Victoria,Livneh, Ido,Avni, Noa,Fabre, Bertrand,Ziv, Tamar,Kwon, Yong Tae,Ciechanover, Aaron National Academy of Sciences 2016 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.113 No.47
<P>The ubiquitin-proteasome system and autophagy are the two main proteolytic systems involved in, among other functions, the maintenance of cell integrity by eliminating misfolded and damaged proteins and organelles. Both systems remove their targets after their conjugation with ubiquitin. An interesting, yet incompletely understood problem relates to the fate of the components of the two systems. Here we provide evidence that amino acid starvation enhances polyubiquitination on specific sites of the proteasome, a modification essential for its targeting to the autophagic machinery. The uptake of the ubiquitinated proteasome is mediated by its interaction with the ubiquitin-associated domain of p62/SQSTM1, a process that also requires interaction with LC3. Importantly, deletion of the PB1 domain of p62, which is important for the targeting of ubiquitinated substrates to the proteasome, has no effect on stress-induced autophagy of this proteolytic machinery, suggesting that the domain of p62 that binds to the proteasome determines the function of p62 in either targeting substrates to the proteasome or targeting the proteasome to autophagy.</P>
KPC1-Mediated Ubiquitination and Proteasomal Processing of NF-κB1 p105 to p50 Restricts Tumor Growth
Kravtsova-Ivantsiv, Y.,Shomer, I.,Cohen-Kaplan, V.,Snijder, B.,Superti-Furga, G.,Gonen, H.,Sommer, T.,Ziv, T.,Admon, A.,Naroditsky, I.,Jbara, M.,Brik, A.,Pikarsky, E.,Kwon, Y.,Doweck, I.,Ciechanover, Cell Press ; MIT Press 2015 Cell Vol.161 No.2
NF-κB is a key transcriptional regulator involved in inflammation and cell proliferation, survival, and transformation. Several key steps in its activation are mediated by the ubiquitin (Ub) system. One uncharacterized step is limited proteasomal processing of the NF-κB1 precursor p105 to the p50 active subunit. Here, we identify KPC1 as the Ub ligase (E3) that binds to the ankyrin repeats domain of p105, ubiquitinates it, and mediates its processing both under basal conditions and following signaling. Overexpression of KPC1 inhibits tumor growth likely mediated via excessive generation of p50. Also, overabundance of p50 downregulates p65, suggesting that a p50-p50 homodimer may modulate transcription in place of the tumorigenic p50-p65. Transcript analysis reveals increased expression of genes associated with tumor-suppressive signals. Overall, KPC1 regulation of NF-κB1 processing appears to constitute an important balancing step among the stimulatory and inhibitory activities of the transcription factor in cell growth control.
Pnina Scherzer,Shachaf Katalan,Gay Got,Galina Pizov,Irene Londono,Anca Gal-Moscovici,Mordecai M,Popovtzer,Ehud Ziv,Moise Bendayan 대한해부학회 2011 Anatomy & Cell Biology Vol.44 No.3
The Psammomys obesus lives in natural desert habitat on low energy (LE) diet, however when maintained in laboratory conditions with high energy (HE) diet it exhibits pathological metabolic changes resembling those of type 2 diabetes. We have evaluated and correlated the histopathology, metabolic and functional renal alterations occurring in the diabetic Psammomys. Renal function determined by measuring glomerular filtration rate (GFR), protein excretion, protein/creatinine ratio and morpho-immunocytochemical evaluations were performed on HE diet diabetic animals and compared to LE diet control animals. The diabetic animals present a 54% increase in GFR after one month of hyperglycemic condition and a decrease of 47% from baseline values after 4 months. Protein excretion in diabetic animals was 5 folds increased after 4 months. Light microscopy showed an increase in glomeruli size in the diabetic Psammomys, and electron microscopy and immunocytochemical quantitative evaluations revealed accumulation of basement membrane material as well as frequent splitting of the glomerular basement membrane. In addition, glycogen-filled Armanni-Ebstein clear cells were found in the distal tubules including the thick ascending limbs of the diabetic animals. These renal complications in the Psammomys, including changes in GFR with massive proteinuria sustained by physiological and histopathological changes, are very similar to the diabetic nephropathy in human. The Psamommys obesus represents therefore a reliable animal model of diabetic nephropathy.
The Immune Landscape of Cancer
Thorsson, Vé,steinn,Gibbs, David L.,Brown, Scott D.,Wolf, Denise,Bortone, Dante S.,Ou Yang, Tai-Hsien,Porta-Pardo, Eduard,Gao, Galen F.,Plaisier, Christopher L.,Eddy, James A.,Ziv, Elad,Culhane, Elsevier 2018 Immunity Vol.48 No.4
<P><B>Summary</B></P> <P>We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes—wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-β dominant—characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (<I>CTNNB1</I>, <I>NRAS</I>, or <I>IDH1</I>) or higher (<I>BRAF</I>, <I>TP53</I>, or <I>CASP8</I>) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Six identified immune subtypes span cancer tissue types and molecular subtypes </LI> <LI> Immune subtypes differ by somatic aberrations, microenvironment, and survival </LI> <LI> Multiple control modalities of molecular networks affect tumor-immune interactions </LI> <LI> These analyses serve as a resource for exploring immunogenicity across cancer types </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>