Publications by authors named "Yoram Cohen"

251 Publications

Corrigendum to 'Desupersaturation of RO concentrate and gypsum removal via seeded precipitation in a fluidized bed crystallizer' [Water Research 190 (2021) 116766].

Water Res 2021 Apr;193:116943

Water Technology Research Center, Chemical and Biomolecular Engineering Department, Henry Samueli school of Engineering and Applied Science, 5531 Boelter Hall, University of California, Los Angeles, CA 90095-1592, USA; Institute of the Environment and Sustainability, 300 LaKretz Hall, University of California, Los Angeles, Los Angeles, CA 90095-1496. Electronic address:

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http://dx.doi.org/10.1016/j.watres.2021.116943DOI Listing
April 2021

Design Guidelines for Cationic Pillar[n]arenes that Prevent Biofilm Formation by Gram-Positive Pathogens.

ACS Infect Dis 2021 03 3;7(3):579-585. Epub 2021 Mar 3.

School of Chemistry, Sackler Faculty of Exact Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel.

Bacterial biofilms are a major threat to human health, causing persistent infections that lead to millions of fatalities worldwide every year. Biofilms also cause billions of dollars of damage annually by interfering with industrial processes. Recently, cationic pillararenes were found to be potent inhibitors of biofilm formation in Gram-positive bacteria. To identify the structural features of pillararenes that result in antibiofilm activity, we evaluated the activity of 16 cationic pillar[5]arene derivatives including that of the first cationic water-soluble pillar[5]arene-based rotaxane. Twelve of the derivatives were potent inhibitors of biofilm formation by Gram-positive pathogens. Structure activity analyses of our pillararene derivatives indicated that positively charged head groups are critical for the observed antibiofilm activity. Although certain changes in the lipophilicity of the substituents on the positively charged head groups are tolerated, dramatic elevation in the hydrophobicity of the substituents or an increase in steric bulk on these positive charges abolishes the antibiofilm activity. An increase in the overall positive charge from 10 to 20 did not affect the activity significantly, but pillararenes with 5 positive charges and 5 long alkyl chains had reduced activity. Surprisingly, the cavity of the pillar[n]arene is not essential for the observed activity, although the macrocyclic structure of the pillar[n]arene core, which facilitates the clustering of the positive charges, appears important. Interestingly, the compounds found to be efficient inhibitors of biofilm formation were nonhemolytic at concentrations that are ∼100-fold of their MBIC (the minimal concentration of a compound at which at least 50% inhibition of biofilm formation was observed compared to untreated cells). The structure-activity relationship guidelines established here pave the way for a rational design of potent cationic pillar[n]arene-based antibiofilm agents.
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http://dx.doi.org/10.1021/acsinfecdis.0c00662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041275PMC
March 2021

Ethnicity has a multiplex impact upon the risk of a full mutation expansion among female heterozygotes for FMR1 premutation.

Genet Med 2021 Jan 20. Epub 2021 Jan 20.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Purpose: To evaluate whether ethnicity affects the risk of full mutation expansion among females heterozygous for FMR1 premutation.

Methods: Women who carry the FMR1 premutation alelle of Jewish origin who underwent fragile X prenatal diagnosis between 2011 and 2018 in two medical centers in Israel were included. The heterozygote women and fetuses were analyzed for the number of CGG repeats and AGG interruptions.

Results: Seven hundred sixty-six subjects were included. Parental ethnicity was fully concordant in 592 cases (Jewish, Ashkenazi, and non-Ashkenazi). Ashkenazi compared with non-Ashkenazi heterozygotes have a significantly higher mean number of CGG repeats (68 ± 8.7, 64 ± 6.4 respectively, P = 0.03) and a lower mean number of AGG interruptions (0.89 ± 0.83, 1.60 ± 1.18 respectively, p = 0.0001). Overall, 56/198 (28.2%) fetuses of Ashkenazi heterozygotes had an expansion to a full mutation compared with 6/98 among the non-Ashkenazi (6.1%) (p = 0.001). Multivariate analysis demonstrated that, in addition to CGG repeats and AGG interruptions (which contributed 68.3% of variance), ethnicity is an independent risk factor for a full mutation expansion (odds ratio [OR] = 2.04, p < 0.001) and accounted for 9% of the variation of a full mutation expansion.

Conclusion: Apart from significant differences regarding the number of CGG repeats and AGG interruptions between Ashkenazi and non-Ashkenazi heterozygotes, ethnicity independently affects the risk of a full mutation.
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http://dx.doi.org/10.1038/s41436-020-01089-3DOI Listing
January 2021

Desupersaturation of RO concentrate and gypsum removal via seeded precipitation in a fluidized bed crystallizer.

Water Res 2021 Feb 22;190:116766. Epub 2020 Dec 22.

Water Technology Research Center, Chemical and Biomolecular Engineering Department, Henry Samueli school of Engineering and Applied Science, 5531 Boelter Hall, University of California, Los Angeles, CA 90095-1592, USA; Institute of the Environment and Sustainability, 300 LaKretz Hall, University of California, Los Angeles, Los Angeles, CA 90095-1496. Electronic address:

The feasibility of a continuous chemically-enhanced seeded precipitation (CCESP) process was evaluated for desupersaturation of primary reverse osmosis (PRO) concentrate generated from RO desalting of inland agricultural drainage (AD) water with high gypsum scaling potential. The CCESP approach, comprised of partial lime treatment (PLT) followed by gypsum seeded precipitation (GSP), was assessed via laboratory and field tests, along with model simulations. PLT effectiveness was confirmed for residual antiscalant removal from the PRO concentrate, which otherwise would suppress gypsum crystallization. GSP was carried out in a fluidized bed crystallizer (FBC) demonstrating the feasibility of continuous PRO concentrate desupersaturation with suitable solids management. FBC operation was stable, with respect to desupersaturation performance, when operating over a sequence of periodic solids purge-only mode with intermittent seeds replenishment. The study suggests that CCESP integration with primary and secondary RO desalting (i.e., PRO-CCESP-SRO) can provide for significant enhancement of product water recovery for inland water of high gypsum scaling propensity. For example, source water of high salinity (14,347 mg/L total dissolved solid) AD water, nearly saturated with respect to gypsum, could be desalted up to a recovery of 88-96% (relative to merely 66% recovery feasible via PRO desalting. Moreover, net salt harvesting of 2.6-3.6 kg per m RO concentrate (with concentrate recycle) can be obtained from high recovery desalting of the above PRO concentrate.
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http://dx.doi.org/10.1016/j.watres.2020.116766DOI Listing
February 2021

Reading Akkadian cuneiform using natural language processing.

PLoS One 2020 28;15(10):e0240511. Epub 2020 Oct 28.

Jacob M. Alkow Department of Archaeology and Ancient Near Eastern Civilizations, Tel Aviv University, Tel Aviv, Israel.

In this paper we present a new method for automatic transliteration and segmentation of Unicode cuneiform glyphs using Natural Language Processing (NLP) techniques. Cuneiform is one of the earliest known writing system in the world, which documents millennia of human civilizations in the ancient Near East. Hundreds of thousands of cuneiform texts were found in the nineteenth and twentieth centuries CE, most of which are written in Akkadian. However, there are still tens of thousands of texts to be published. We use models based on machine learning algorithms such as recurrent neural networks (RNN) with an accuracy reaching up to 97% for automatically transliterating and segmenting standard Unicode cuneiform glyphs into words. Therefore, our method and results form a major step towards creating a human-machine interface for creating digitized editions. Our code, Akkademia, is made publicly available for use via a web application, a python package, and a github repository.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240511PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592802PMC
December 2020

Correction: QSAR without borders.

Chem Soc Rev 2020 06;49(11):3716

UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.

Correction for 'QSAR without borders' by Eugene N. Muratov et al., Chem. Soc. Rev., 2020, DOI: 10.1039/d0cs00098a.
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http://dx.doi.org/10.1039/d0cs90041aDOI Listing
June 2020

QSAR without borders.

Chem Soc Rev 2020 06 1;49(11):3525-3564. Epub 2020 May 1.

UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.

Prediction of chemical bioactivity and physical properties has been one of the most important applications of statistical and more recently, machine learning and artificial intelligence methods in chemical sciences. This field of research, broadly known as quantitative structure-activity relationships (QSAR) modeling, has developed many important algorithms and has found a broad range of applications in physical organic and medicinal chemistry in the past 55+ years. This Perspective summarizes recent technological advances in QSAR modeling but it also highlights the applicability of algorithms, modeling methods, and validation practices developed in QSAR to a wide range of research areas outside of traditional QSAR boundaries including synthesis planning, nanotechnology, materials science, biomaterials, and clinical informatics. As modern research methods generate rapidly increasing amounts of data, the knowledge of robust data-driven modelling methods professed within the QSAR field can become essential for scientists working both within and outside of chemical research. We hope that this contribution highlighting the generalizable components of QSAR modeling will serve to address this challenge.
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http://dx.doi.org/10.1039/d0cs00098aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008490PMC
June 2020

Temperature-Dependent and pH-Responsive Pillar[5]arene-Based Complexes and Hydrogen-Bond-Based Supramolecular Pentagonal Boxes in Water.

Chemistry 2020 Sep 10;26(49):11250-11255. Epub 2020 Aug 10.

School of Chemistry, Sackler Faculty of Exact Sciences, Tel Aviv University, Ramat Aviv, 69978, Tel Aviv, Israel.

Supramolecular systems in water are of paramount importance and those based on hydrogen bonds are both intriguing and scarce. Here, after studying the peculiar host-guest complexes formed between per-dimethylamino-pillar[5]arene (1) and the bis-sulfonates 2 a-c, we describe the formation of the first hydrogen-bond-based supramolecular pentagonal boxes (SPBs), which are stable in water. These pH-responsive SPBs are constructed from 1 as a body, benzene polycarboxylic acids 3 a,b as lid compounds, and 2 a-c as guests. We demonstrate that encapsulation of 2 a-c in pillar[5]arene 1 and in the highly stable water-soluble SPBs, that is, 1(3 a) and 1(3 b) , is both temperature and pH dependent and, quite interestingly, depends, on the nature of the lid compounds used for capping the boxes even at high pH. We also highlight the difference in the H NMR characteristics of 2 b and 2 c in the cavity of 1 and the SPBs.
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http://dx.doi.org/10.1002/chem.202000972DOI Listing
September 2020

NanoSolveIT Project: Driving nanoinformatics research to develop innovative and integrated tools for nanosafety assessment.

Comput Struct Biotechnol J 2020 7;18:583-602. Epub 2020 Mar 7.

School of Geography, Earth and Environmental Sciences, University of Birmingham, B15 2TT Birmingham, UK.

Nanotechnology has enabled the discovery of a multitude of novel materials exhibiting unique physicochemical (PChem) properties compared to their bulk analogues. These properties have led to a rapidly increasing range of commercial applications; this, however, may come at a cost, if an association to long-term health and environmental risks is discovered or even just perceived. Many nanomaterials (NMs) have not yet had their potential adverse biological effects fully assessed, due to costs and time constraints associated with the experimental assessment, frequently involving animals. Here, the available NM libraries are analyzed for their suitability for integration with novel nanoinformatics approaches and for the development of NM specific Integrated Approaches to Testing and Assessment (IATA) for human and environmental risk assessment, all within the NanoSolveIT cloud-platform. These established and well-characterized NM libraries (e.g. NanoMILE, NanoSolutions, NANoREG, NanoFASE, caLIBRAte, NanoTEST and the Nanomaterial Registry (>2000 NMs)) contain physicochemical characterization data as well as data for several relevant biological endpoints, assessed in part using harmonized Organisation for Economic Co-operation and Development (OECD) methods and test guidelines. Integration of such extensive NM information sources with the latest nanoinformatics methods will allow NanoSolveIT to model the relationships between NM structure (morphology), properties and their adverse effects and to predict the effects of other NMs for which less data is available. The project specifically addresses the needs of regulatory agencies and industry to effectively and rapidly evaluate the exposure, NM hazard and risk from nanomaterials and nano-enabled products, enabling implementation of computational 'safe-by-design' approaches to facilitate NM commercialization.
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http://dx.doi.org/10.1016/j.csbj.2020.02.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090366PMC
March 2020

Kinetic Stabilities and Exchange Dynamics of Water-Soluble Bis-Formamide Caviplexes Studied Using Diffusion-Ordered NMR Spectroscopy (DOSY).

Chemistry 2020 Jul 9;26(37):8220-8225. Epub 2020 Jun 9.

Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology (BIST), Av. Països Catalans 16, 43007, Tarragona, Spain.

A deep cavitand binds long-chain trans,trans- and trans,cis-bis-formamide isomers in water solution giving a pair of caviplexes in a ca. 60:40 ratio. Both caviplexes display in/out guest exchange dynamics that are slow on the H NMR chemical shift timescale, but fast on the EXSY timescale. We apply diffusion-ordered NMR spectroscopy (DOSY) to characterize the caviplexes. On the diffusion timescale, the guest in/out exchange processes feature intermediate dynamics allowing the assessment of their kinetic stabilities. We found that the trans,cis-bis-formamide isomers form kinetically more stable caviplexes than the trans,trans-counterparts. We also show that the kinetic stabilities of the bis-formamide caviplexes relate well with their relative thermodynamic stabilities. Fortunately, the tuning of the DOSY parameters allowed the observation of the exchange dynamics as slow processes on the experiment timescale.
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http://dx.doi.org/10.1002/chem.202000781DOI Listing
July 2020

Constant gradient FEXSY: A time-efficient method for measuring exchange.

J Magn Reson 2020 02 16;311:106667. Epub 2019 Dec 16.

School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel. Electronic address:

Filter-Exchange NMR Spectroscopy (FEXSY) is a method for measurement of apparent transmembranal water exchange rates. The experiment is comprised of two co-linear sequential pulsed-field gradient (PFG) blocks, separated by a mixing period in which exchange takes place. The first block remains constant and serves as a diffusion-based filter that removes signal coming from fast-diffusing water. The mixing time and the gradient area (q-value) of the second block are varied on repeated iterations to produce a 2D data set that is analyzed using a bi-compartmental model which assumes that intra- and extra-cellular water are slow and fast diffusing, respectively. Here we suggest a variant of the FEXSY method in which measurements for different mixing times are taken at a constant gradient. This Constant Gradient FEXSY (CG-FEXSY) allows for the determination of the exchange rate by using a smaller 1D data set, so that the same information can be gathered during a considerably shorter scan time. Furthermore, in the limit of high diffusion weighting, such that the extra-cellular water signal is removed while the intra-cellular signal is retained, CG-FEXSY also allows for determination of the intra-cellular mean residence time (MRT). The theoretical results are validated on a living yeast cells sample and on a fixed porcine optic nerve, where the values obtained from the two methods are shown to be in agreement.
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http://dx.doi.org/10.1016/j.jmr.2019.106667DOI Listing
February 2020

Single- and double-Diffusion encoding MRI for studying ex vivo apparent axon diameter distribution in spinal cord white matter.

NMR Biomed 2019 12 1;32(12):e4170. Epub 2019 Oct 1.

School of Chemistry, The Raymond and Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Tel Aviv, Israel.

Mapping average axon diameter (AAD) and axon diameter distribution (ADD) in neuronal tissues non-invasively is a challenging task that may have a tremendous effect on our understanding of the normal and diseased central nervous system (CNS). Water diffusion is used to probe microstructure in neuronal tissues, however, the different water populations and barriers that are present in these tissues turn this into a complex task. Therefore, it is not surprising that recently we have witnessed a burst in the development of new approaches and models that attempt to obtain, non-invasively, detailed microstructural information in the CNS. In this work, we aim at challenging and comparing the microstructural information obtained from single diffusion encoding (SDE) with double diffusion encoding (DDE) MRI. We first applied SDE and DDE MR spectroscopy (MRS) on microcapillary phantoms and then applied SDE and DDE MRI on an ex vivo porcine spinal cord (SC), using similar experimental conditions. The obtained diffusion MRI data were fitted by the same theoretical model, assuming that the signal in every voxel can be approximated as the superposition of a Gaussian-diffusing component and a series of restricted components having infinite cylindrical geometries. The diffusion MRI results were then compared with histological findings. We found a good agreement between the fittings and the experimental data in white matter (WM) voxels of the SC in both diffusion MRI methods. The microstructural information and apparent AADs extracted from SDE MRI were found to be similar or somewhat larger than those extracted from DDE MRI especially when the diffusion time was set to 40 ms. The apparent ADDs extracted from SDE and DDE MRI show reasonable agreement but somewhat weaker correspondence was observed between the diffusion MRI results and histology. The apparent subtle differences between the microstructural information obtained from SDE and DDE MRI are briefly discussed.
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http://dx.doi.org/10.1002/nbm.4170DOI Listing
December 2019

On the feasibility of small communities wellhead RO treatment for nitrate removal and salinity reduction.

J Environ Manage 2019 Nov 26;250:109487. Epub 2019 Sep 26.

Water Technology Research Center, Chemical and Biomolecular Engineering Department, Henry Samueli School of Engineering and Applied Science, 5531 Boelter Hall, University of California, Los Angeles, CA, 90095-1592, USA; Institute of the Environment and Sustainability, 300 LaKretz Hall, University of California, Los Angeles, Los Angeles, CA, 90095-1496, USA. Electronic address:

The feasibility of wellhead water treatment in small communities for nitrate removal and salinity reduction via a flexible high recovery RO system was evaluated through analysis of treatment options, laboratory and onsite field tests. In small remote communities that rely on septic systems for residential wastewater treatment, discharge of the RO residual stream (containing nitrate) to the community septic tank is shown to be a feasible option. It is demonstrated that RO treatment with a system that employs partial concentrate recycle, integrated with a pressure intensifier, enabled the use of a relatively low-pressure feed pump while allowing high recovery operation. The approach of integrating RO treatment into existing community small water systems is demonstrated to be suitable for providing effective nitrate removal and salinity reduction over wide range of nitrate and salinity levels, while meeting community water demand and regulatory water quality requirements.
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http://dx.doi.org/10.1016/j.jenvman.2019.109487DOI Listing
November 2019

Relative hydrophilicities of and formamides.

Proc Natl Acad Sci U S A 2019 10 16;116(40):19815-19820. Epub 2019 Sep 16.

Center for Supramolecular Chemistry and Catalysis, Shanghai University, Shanghai 200444, China;

Secondary formamides are widely encountered in biology and exist as mixtures of both and isomers. Here, we assess hydrophilicity differences between isomeric formamides through direct competition experiments. Formamides bearing long aliphatic chains were sequestered in a water-soluble molecular container having a hydrophobic cavity with an end open to the aqueous medium. NMR spectroscopic experiments reveal a modest preference (<1 kcal/mol) for aqueous solvation of the formamide terminals over the isomers. With diformamides, the supramolecular approach allows staging of intramolecular competition between short-lived species with subtle differences in hydrophobic properties.
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http://dx.doi.org/10.1073/pnas.1911331116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778222PMC
October 2019

Surface characterization data for tethered polyacrylic acid layers synthesized on polysulfone surfaces.

Data Brief 2019 Apr 7;23:103747. Epub 2019 Mar 7.

Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, CA 90095, USA.

The data presented are supplementary to an article [Kim et al., 2019] on synthesis and surface characterization of tethered polyacrylic acid (PAA) layers on polysulfone (PSf) film/membrane surfaces via atmospheric pressure plasma-induced graft polymerization (APPIGP). Data on surface characterization of the synthesized tethered PAA layers includes: AFM topographic surface images and height distributions of surface features, dry layer thickness, chain rupture length distributions determined via AFM based force spectroscopy (AFM-FS), in addition to measurements of water contact angles. Fouling propensity data for ultrafiltration of alginic acid as a model foulant are also provided for native and PAA grafted PSf ultrafiltration (UF) membranes.
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http://dx.doi.org/10.1016/j.dib.2019.103747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660637PMC
April 2019

Bayesian Network Resource for Meta-Analysis: Cellular Toxicity of Quantum Dots.

Small 2019 08 17;15(34):e1900510. Epub 2019 Jun 17.

Center for Environmental Implications of Nanotechnology, University of California, Los Angeles, Los Angeles, CA, 90095-7227, USA.

A web-based resource for meta-analysis of nanomaterials toxicity is developed whereby the utility of Bayesian networks (BNs) is illustrated for exploring the cellular toxicity of Cd-containing quantum dots (QDs). BN models are developed based on a dataset compiled from 517 publications comprising 3028 cell viability data samples and 837 IC values. BN QD toxicity (BN-QDTox) models are developed using both continuous (i.e., numerical) and categorical attributes. Using these models, the most relevant attributes identified for correlating IC are: QD diameter, exposure time, surface ligand, shell, assay type, surface modification, and surface charge, with the addition of QD concentration for the cell viability analysis. Data exploration via BN models further enables identification of possible association rules for QDs cellular toxicity. The BN models as web-based applications can be used for rapid intelligent query of the available body of evidence for a given nanomaterial and can be readily updated as the body of knowledge expands.
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http://dx.doi.org/10.1002/smll.201900510DOI Listing
August 2019

Do poor-responder patients undergoing IVF benefit from splitting and increasing the daily gonadotropin dose?

Gynecol Endocrinol 2019 Oct 29;35(10):890-893. Epub 2019 Apr 29.

Infertility and IVF Unit Department of Obstetrics and Gynecology, Chaim Sheba Medical Center (Tel Hashomer), Ramat Gan, Israel.

We aim to retrospectively evaluate the role of increasing the gonadotropin daily dose from 450 IU/day to 300 IU twice a day on IVF-ET outcome in poor responder patients. All consecutive women admitted to our IVF unit and underwent COH consisting of daily gonadotropin dose of 450 IU, followed by an IVF cycle using 300 IU twice a day, were included. Ovarian stimulation characteristics, number of oocytes retrieved, number of embryo transferred and pregnancy rate was assessed. Twenty-three patients undergoing both cycles were evaluated. While there was no between-group difference in the duration of COH, number of 2PN embryos, fertilization rate and number of embryos transferred, patients receiving daily gonadotropin 300 IU twice a day achieved a significantly higher peak estradiol levels (3350.39 ± 2364.26 vs. 2223.74 ± 1299.91;  < .03, respectively), and yielded significantly higher number of follicles >15 mm in diameter on day of hCG administration (3.2 ± 2.4 vs 1.8 ± 1;  < .03, respectively) and higher number of oocytes retrieved (3.48 ± 2.54 vs 1.87 ± 1.1;  < .02, respectively) with an acceptable live birth rate (5%). To conclude, in poor responders undergoing COH a daily gonadotropin dose of 450 IU, increasing the dose to 300 IU twice daily may result in higher oocyte yield, with the possible improvement in IVF outcome.
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http://dx.doi.org/10.1080/09513590.2019.1608520DOI Listing
October 2019

Pathophysiology Mechanisms in Fragile-X Primary Ovarian Insufficiency.

Methods Mol Biol 2019 ;1942:165-171

IVF unit, Department of Obstetrics and Gynecology, Chaim Sheba Medical Center (Tel Hashomer), Ramat Gan, Israel.

Women who carry the FMR1 premutation may suffer from ongoing deterioration of ovarian function. The lucidity of the molecular mechanism of FXTAS is emerging and findings from research in the field of FXTAS could elucidate the pathogenesis of FXPOI. To date there are three possible mechanisms for ovarian dysfunction in FMR1 permutation carriers. The first is the RNA toxic gain-of-function mechanism initiating loss of function of over 30 specific RNA-binding proteins. The second is associated to the formation of an abnormal polyglycine-containing protein (FMRpolyG), and the third is related to novel lncRNAs, named FMR4 and FMR6. Herein we describe our laboratory methodology, focusing on the culturing and manipulation of granulosa cells from human female premutation carriers, trying to reveal the actual possible mechanisms liable to FXPOI. Detecting the precise pathways in premutation carrier might facilitate in offering these women the opportunity to make an informed decision regarding their reproductive and family planning.
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http://dx.doi.org/10.1007/978-1-4939-9080-1_14DOI Listing
August 2019

pH-Responsive Pillar[6]arene-based Water-Soluble Supramolecular Hexagonal Boxes.

Angew Chem Int Ed Engl 2019 Apr 14;58(16):5302-5306. Epub 2019 Mar 14.

School of Chemistry, Sackler Faculty of Exact sciences, Tel Aviv University, Ramat Aviv, 69978, Tel Aviv, Israel.

We describe the preparation of the first water-soluble pH-responsive supramolecular hexagonal boxes (SHBs) based on multiple charge-assisted hydrogen bonds between peramino-pillar[6]arenes 2 with the molecular "lid" mellitic acid (1 a). The interaction between 2 and 1 a, as well as the other "lids" pyromellitic and trimesic acids (1 b and 1 c, respecively) were studied by a combination of experimental and computational methods. Interestingly, the addition of 1 a to the complexes of the protonated form of pillar[6]arene 2, that is, 3, with bis-sulfonate 4 a or 4 b, immediately led to guest escape along with the formation of closed 1 a 2 supramolecular boxes. Moreover, the process of the openning and closing of the supramolecular boxes along with threading and escaping of the guests, respectively, was found to be reversible and pH-responsive. This study paves the way for the easy and modular preparation of different SHBs that may have myriad applications.
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http://dx.doi.org/10.1002/anie.201900217DOI Listing
April 2019

Absence of AGG Interruptions Is a Risk Factor for Full Mutation Expansion Among Israeli FMR1 Premutation Carriers.

Front Genet 2018 13;9:606. Epub 2018 Dec 13.

IVF Unit, Sheba Medical Center, Tel Hashomer, Israel.

Fragile X syndrome (FXS) is a common form of X-linked intellectual and developmental disability with a prevalence of 1/4000-5000 in males and 1/6000-8000 in females. Most cases of the syndrome result from expansion of a premutation (55-200 CGGs) to a full mutation (>200 CGGs) repeat located in the 5' untranslated region of the fragile X mental retardation () gene. The risk for full mutation expansions increases dramatically with increasing numbers of CGG repeats. Recent studies, however, revealed AGG interruptions within the repeat area function as a "protective factor" decreasing the risk of intergenerational expansion. This study was conducted to validate the relevance of AGG analysis for the ethnically diverse Israeli population. To increase the accuracy of our results, we combined results from Israel with those from the New York State Institute for Basic Research in Developmental Disabilities (IBR). To the best of our knowledge this is the largest cohort of different ethnicities to examine risks of unstable transmissions and full mutation expansions among premutation carriers. The combined data included 1471 transmissions of maternal premutation alleles: 369 (25.1%) stable and 1,102 (74.9%) unstable transmissions. Full mutation expansions were identified in 20.6% (303/1471) of transmissions. A total of 97.4% (388/397) of transmissions from alleles with no AGGs were unstable, 79.6% (513/644) in alleles with 1 AGG and 46.7% (201/430) in alleles with 2 or more AGGs. The same trend was seen with full mutation expansions where 40% (159/397) of alleles with no AGGs expanded to a full mutation, 20.2% (130/644) for alleles with 1 AGG and only 3.2% (14/430) in alleles with 2 AGGs or more. None of the alleles with 3 or more AGGs expanded to full mutations. We recommend that risk estimates for premutation carriers be based on AGG interruptions as well as repeat size in Israel and worldwide.
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http://dx.doi.org/10.3389/fgene.2018.00606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300753PMC
December 2018

Fragile X Associated Primary Ovarian Insufficiency (FXPOI): Case Report and Literature Review.

Front Genet 2018 27;9:529. Epub 2018 Nov 27.

Sheba Medical Center, Tel Hashomer and Tel Aviv University, Tel Aviv, Israel.

Abnormalities in the X-linked gene are associated with a constellation of disorders, which have broad and profound implications for the person first diagnosed, and extended family members of all ages. The rare and pleiotropic nature of the associated disorders, both common and not, place great burdens on (1) the affected families, (2) their care providers and clinicians, and (3) investigators striving to conduct research on the conditions. Fragile X syndrome, occurring more severely in males, is the leading genetic cause of intellectual disability. Fragile X associated tremor and ataxia syndrome (FXTAS) is a neurodegenerative disorder seen more often in older men. Fragile X associated primary ovarian insufficiency (FXPOI) is a chronic disorder characterized by oligo/amenorrhea and hypergonadotropic hypogonadism before age 40 years. There may be significant morbidity due to: (1) depression and anxiety related to the loss of reproductive hormones and infertility; (2) reduced bone mineral density; and (3) increased risk of cardiovascular disease related to estrogen deficiency. Here we report the case of a young woman who never established regular menses and yet experienced a 5-year diagnostic odyssey before establishing a diagnosis of FXPOI despite a known family history of fragile X syndrome and early menopause. Also, despite having clearly documented FXPOI the woman conceived spontaneously and delivered two healthy children. We review the pathophysiology and management of FXPOI. As a rare disease, the diagnosis of FXPOI presents special challenges. Connecting patients and community health providers with investigators who have the requisite knowledge and expertise about the gene and FXPOI would facilitate both patient care and research. There is a need for an international natural history study on FXPOI. The effort should be coordinated by a global virtual center, which takes full advantage of mobile device communication systems.
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http://dx.doi.org/10.3389/fgene.2018.00529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278244PMC
November 2018

Role of CB Receptor in the Recovery of Mice after Traumatic Brain Injury.

J Neurotrauma 2019 06 7;36(11):1836-1846. Epub 2019 Feb 7.

3 Department of Pharmacology, Institute for Drug Research, Hebrew University of Jerusalem, Jerusalem, Israel.

Cannabis is one of the most widely used plant drugs in the world today. In spite of the large number of scientific reports on medical marijuana, there still exists much controversy surrounding its use and the potential for abuse due to the undesirable psychotropic effects. However, recent developments in medicinal chemistry of novel non-psychoactive synthetic cannabinoids have indicated that it is possible to separate some of the therapeutic effects from the psychoactivity. We have previously shown that treatment with the endocannabinoid 2-AG, which binds to both CB and CB receptors 1 h after traumatic brain injury in mice, attenuates neurological deficits, edema formation, infarct volume, blood-brain barrier permeability, neuronal cell loss at the CA3 hippocampal region, and neuroinflammation. Recently, we synthesized a set of camphor-resorcinol derivatives, which represent a novel series of CB receptor selective ligands. Most of the novel compounds exhibited potent binding and agonistic properties at the CB receptors with very low affinity for the CB receptor, and some were highly anti-inflammatory. This selective binding correlated with their intrinsic activities. HU-910 and HU-914 were selected in the present study to evaluate their potential effect in the pathophysiology of traumatic brain injury (TBI). In mice and rats subjected to closed-head injury and treated with these novel compounds, we showed enhanced neurobehavioral recovery, inhibition of tumor necrosis factor α production, increased synaptogenesis, and partial recovery of the cortical spinal tract. We propose these CB agonists as potential drugs for development of novel therapeutic modality to TBI.
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http://dx.doi.org/10.1089/neu.2018.6063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551996PMC
June 2019

[FROM GENETICS OF FRAGILE X SYNDROME TO DEVELOPMENT OF TARGETED AND PERSONALIZED DRUG THERAPY].

Harefuah 2018 Aug;157(8):529-533

IVF Unit, Sheba Medical Center, Tel Hashomer.

Introduction: At the end of the last century Fragile X syndrome was identified, and the main syndrome characteristics were discovered. The syndrome is caused from a flaw in the number of nucleotide repeats that encodes for a regulatory protein which is critical for neural connectivity and normal brain development. The syndrome is characterized by neurodevelopmental and intellectual disabilities, autism spectrum features and other clinical features associated with the same gene aberration. The number of trinucleotide repeats have a direct effect on the outcome and the need for genetic counseling. We advocate performing genetic tests for every child with developmental delay, learning disabilities, autism spectrum disorders and especially, intellectual impairment. It is also advisable to check the number of nucleotide repeats of the gene, in every woman suffering from infertility or early menopause. In addition, genetic testing should be performed on older adults manifesting early symptoms of Parkinson's disease, balance instability, tremor or cognitive dysfunction with unknown etiology. Due to the tremendous progress in understanding the biological mechanisms of the syndrome, new molecules/drugs have been proposed and are tested, in order to find a way to bypass the defect mechanism underlying the disorder. We will review the most commonly used drugs in the treatment of Fragile X syndrome and many medications that are currently under investigation as a more targeted treatment.
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August 2018

Preimplantation genetic diagnosis versus prenatal diagnosis-decision-making among pregnant FMR1 premutation carriers.

J Assist Reprod Genet 2018 Nov 22;35(11):2071-2075. Epub 2018 Aug 22.

IVF Unit, Sheba Medical Center, Tel Hashomer, Israel.

Purpose: To detect which factors influence decision-making among pregnant FMR1 premutation carriers regarding the preferred mode of genetic diagnosis: IVF-PGT-M (in vitro fertilization with preimplantation genetic testing for monogenic gene diseases), or CVS (chorionic villus sampling), or AC (amniocentesis) after spontaneous conception.

Methods: In Israel FMR1 premutation preconception genetic screening is offered, free of charge, to every woman in her reproductive years. FMR1 premutation carriers with ≥ 70 CGG repeats, or a history of FXS offspring, are offered IVF-PGT-M. This is a historical cohort study including all pregnant FMR1 premutation carriers who underwent prenatal diagnosis between the years 2011 and 2016 at a tertiary medical center. Data were collected from electronic charts and through phone interviews.

Results: One hundred seventy-five women with high-risk pregnancies who were offered IVF-PGT-M were evaluated. In 37 pregnancies (21%), the women decided to undergo IVF-PGT-M. Using the generalized estimating equations (GEE) statistical method including seven parameters, we found that previous termination of pregnancy due to FXS and advanced woman's age were significantly associated with making the decision to undergo IVF-PGT-M. Previously failed IVF was the most significant parameter in a woman's decision not to undergo IVF-PGT-M.

Conclusion: The most dominant factor affecting the decision of FMR1 premutation carriers to choose spontaneous conception with prenatal diagnosis versus IVF-PGT-M is a previous experience of failed IVF treatments. Women whose IVF treatments failed in the past tended to try to conceive naturally and later, during the course of the pregnancy, perform CVS or AC. Conversely, women who previously experienced a termination of pregnancy (TOP) due to an affected fetus, and older women, preferred to undergo IVF-PGT-M procedures.
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http://dx.doi.org/10.1007/s10815-018-1293-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240542PMC
November 2018

High Exchange Rate Complexes of Xe with Water-Soluble Pillar[5]arenes for Adjustable Magnetization Transfer MRI.

Chemphyschem 2019 01 21;20(2):246-251. Epub 2018 Aug 21.

Molecular Imaging, Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Robert-Rössle-Str. 10, 13125, Berlin, Germany.

Macrocyclic host structures for generating transiently bound Xe have been used in various ultra-sensitive NMR and MRI applications for molecular sensing of biochemical analytes. They are based on hyperpolarized nuclei chemical exchange saturation transfer (Hyper-CEST). Here, we tested a set of water-soluble pillar[5]arenes with different counterions in order to compare their potential contrast agent abilities with that of cryptophane-A (CrA), the most widely used host for such purposes. The exchange of Xe with such compounds was found to be sensitive to the type of ions present in solution and can be used for switchable magnetization transfer (MT) contrast that arises from off-resonant pre-saturation. We demonstrate that the adjustable MT magnitude depends on the interplay of saturation parameters and found that the optimum MT contrast surpasses the CrA CEST performance at moderate saturation power. Since modification of such water-soluble pillar[5]arenes is straightforward, these compounds can be considered a promising platform for designing various sensors that may complement the field of Xe HyperCEST-based biosensing MRI.
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http://dx.doi.org/10.1002/cphc.201800618DOI Listing
January 2019

Bis-resorcin[4]arene Selectively Forms Hexameric Capsules in Apolar Solvents: Evidence from Diffusion NMR.

Org Lett 2018 07 20;20(13):3958-3961. Epub 2018 Jun 20.

School of Chemistry, The Sackler Faculty of Exact Sciences, Tel Aviv University , Ramat Aviv 69978 , Tel Aviv , Israel.

Bis-resorcin[4]arene 2 connected by its lower rims was synthesized via click chemistry and found, by diffusion NMR, to self-assemble quantitatively, despite the different alternatives, into hexameric capsules reminiscent of the well-characterized hexameric capsule of resorcin[4]arene 1. The hexameric capsules of the flexible bis-resorcin[4]arene 2 prevail in apolar organic solvents and can, as expected, encapsulate quite well ammonium salts, demonstrating that spontaneous self-assembly into hexameric capsules is a general characteristic of such systems.
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http://dx.doi.org/10.1021/acs.orglett.8b01526DOI Listing
July 2018

Single-Nucleotide Polymorphisms in IL23R-IL12RB2 (rs1495965) Are Highly Prevalent in Patients with Behcet's Uveitis and Vary Between Populations.

Ocul Immunol Inflamm 2019 24;27(5):766-773. Epub 2018 May 24.

b Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv , Israel.

: To test the frequency of single-nucleotide polymorphisms in the genes in patients with Behcet's uveitis. : Blood samples were collected from 89 Israeli and Turkish patients, and from healthy control subjects of different origins. Genomic DNA was extracted from peripheral blood leukocytes and genotyped. : The risk allele, A, in rs1800871, of gene was highly prevalent in Behcet's uveitis and healthy control samples alike; highest among the Turkish groups. Prevalence of G allele, in rs1495965, in the gene was high in Behcet's uveitis patients, and among healthy Turkish and Israelis of Middle Eastern origin, while lower among the other Israeli control group (77.9%, 78.9%, 27.8%, respectively, < 0.001). : Our findings highlight the differences between populations and may account for the increased prevalence of the disease among Turkish and Israelis of Middle Eastern origin. Further studies are required to map other healthy and affected populations.
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http://dx.doi.org/10.1080/09273948.2018.1467463DOI Listing
January 2020

Pillararene-Based Two-Component Thixotropic Supramolecular Organogels: Complementarity and Multivalency as Prominent Motifs.

Chemistry 2018 Oct 16;24(59):15750-15755. Epub 2018 Jul 16.

School of Chemistry, Sackler Faculty of Exact Sciences, Tel Aviv University, Ramat Aviv, 69978, Tel Aviv, Israel.

Rationally designed two-component supramolecular organogels based on multiple chemical interactions between percarboxylato- and peramino-pillararenes are described. Mixing low concentration solutions (<1 % w/v) of decacarboxylato-pillar[5]arene (1) with decaamino-pillar[5]arenes (2 b-d) affords, rapidly and without heating, organogels displaying an exceptional combination of properties. These supramolecular organogels, the characteristics of which are tunable, were found to be thixotropic and thermally stable, with T values in some cases exceeding the boiling point of the embedded solvent. It is demonstrated that both structural complementarity and multivalency are important determinants in the gelation process of these attractive soft materials.
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http://dx.doi.org/10.1002/chem.201801418DOI Listing
October 2018

[FMR1 PREMUTATION CARRIERS - ARE THEY REALLY ASYMPTOMATIC?]

Harefuah 2018 Apr;157(4):241-244

The Child Development Center, Sheba Medical Center, Tel Hashomer.

Introduction: Fragile X Syndrome (FXS), the most common form of inherited mental retardation, is caused by a trinucleotide repeat expansion (CGG) in the 5'-untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene located at Xq27.3. Patients with fragile X -related mental retardation, carry the full mutation CGG-repeat expansions (>200 CGG repeats), which are generally accompanied by hypermethylation of the promoter region, with the consequent transcriptional silencing of the FMR1 gene and absence of the encoded FMR1 protein (FMRP). Expansion of the CGG triplet number above the normal range (n=5-54) towards the so-called premutation status (n=55-199) is associated with increased risk for Fragile X-Associated Premature Ovarian Insufficiency (FXPOI) in females and Fragile X-Associated Tremor/ Ataxia Syndrome (FXTAS) predominantly in males. In addition, premutation women carriers are at increased risk for learning disabilities, as well as psychologic, endocrine, autoimmune and metabolic disorders. The observation that premutation carriers, both males and females, have increased FMR1 transcript levels, led researchers to suggest a similar molecular pathogenesis in both FXPOI and FXTAS. Two models have been proposed as the culprits of FXTAS and FXPOI: The toxic RNA gain-of-function model and the Repeat Associated Non-AUG initiated (RAN) translation protein toxicity model. The Fragile X Multidisciplinary Center in Sheba Medical Center, at Tel Hashomer includes a team of geneticists, fertility specialists, endocrinologists, psychologists and neurologists who work together in order to provide early detection of FMR1 premutation carriers and offer FMR1 premutation carriers and their families adequate multidisciplinary medical consultation, follow-up and care.
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April 2018