Publications by authors named "Ron Unger"

82 Publications

Blood Pressure Regulation Evolved from Basic Homeostatic Components.

Biomedicines 2021 Apr 25;9(5). Epub 2021 Apr 25.

The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 5290002, Israel.

Blood pressure (BP) is determined by several physiological factors that are regulated by a range of complex neural, endocrine, and paracrine mechanisms. This study examined a collection of 198 human genes related to BP regulation, in the biological processes and functional prisms, as well as gene expression in organs and tissues. This was made in conjunction with an orthology analysis performed in 19 target organisms along the phylogenetic tree. We have demonstrated that transport and signaling, as well as homeostasis in general, are the most prevalent biological processes associated with BP gene orthologs across the examined species. We showed that these genes and their orthologs are expressed primarily in the kidney and adrenals of complex organisms (e.g., high order vertebrates) and in the nervous system of low complexity organisms (e.g., flies, nematodes). Furthermore, we have determined that basic functions such as ion transport are ancient and appear in all organisms, while more complex regulatory functions, such as control of extracellular volume emerged in high order organisms. Thus, we conclude that the complex system of BP regulation evolved from simpler components that were utilized to maintain specific homeostatic functions that play key roles in existence and survival of organisms.
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http://dx.doi.org/10.3390/biomedicines9050469DOI Listing
April 2021

Prediction model for obstetric anal sphincter injury using machine learning.

Int Urogynecol J 2021 Mar 12. Epub 2021 Mar 12.

Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Introduction And Hypothesis: Obstetric anal sphincter injury (OASI) is a complication with substantial maternal morbidity. The aim of this study was to develop a machine learning model that would allow a personalized prediction algorithm for OASI, based on maternal and fetal variables collected at admission to labor.

Materials And Methods: We performed a retrospective cohort study at a tertiary university hospital. Included were term deliveries (live, singleton, vertex). A comparison was made between women diagnosed with OASI and those without such injury. For formation of a machine learning-based model, a gradient boosting machine learning algorithm was implemented. Evaluation of the performance model was achieved using the area under the receiver-operating characteristic curve (AUC).

Results: Our cohort comprised 98,463 deliveries, of which 323 (0.3%) were diagnosed with OASI. Applying a machine learning model to data recorded during admission to labor allowed for individualized risk assessment with an AUC of 0.756 (95% CI 0.732-0.780). According to this model, a lower number of previous births, fewer pregnancies, decreased maternal weight and advanced gestational week elevated the risk for OASI. With regard to parity, women with one previous delivery had approximately 1/3 of the risk for OASI compared to nulliparous women (OR = 0.3 (0.23-0.39), p < 0.001), and women with two previous deliveries had 1/3 of the risk compared to women with one previous delivery (OR = 0.35 (0.21-0.60), p < 0.001).

Conclusion: Our machine learning-based model stratified births to high or low risk for OASI, making it an applicable tool for personalized decision-making upon admission to labor.
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http://dx.doi.org/10.1007/s00192-021-04752-8DOI Listing
March 2021

Developmentally Regulated Novel Non-coding Anti-sense Regulators of mRNA Translation in .

iScience 2020 Dec 5;23(12):101780. Epub 2020 Nov 5.

The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 52900, Israel.

The parasite is the causative agent of sleeping sickness and cycles between insect and mammalian hosts. The parasite appears to lack conventional transcriptional regulation of protein coding genes, and mRNAs are processed from polycistronic transcripts by the concerted action of splicing and polyadenylation. Regulation of mRNA function is mediated mainly by RNA binding proteins affecting mRNA stability and translation. In this study, we describe the identification of 62 non-coding (nc) RNAs that are developmentally regulated and/or respond to stress. We characterized two novel anti-sense RNA regulators (TBsRNA-33 and 37) that originate from the rRNA loci, associate with ribosomes and polyribosomes, and interact with distinct mRNA species to regulate translation. Thus, this study suggests for the first-time anti-sense RNA regulators as an additional layer for controlling gene expression in these parasites.
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http://dx.doi.org/10.1016/j.isci.2020.101780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683347PMC
December 2020

Quantitative Analysis of Differential Expression of HOX Genes in Multiple Cancers.

Cancers (Basel) 2020 Jun 14;12(6). Epub 2020 Jun 14.

The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.

Transcription factors encoded by () genes play numerous key functions during early embryonic development and differentiation. Multiple reports have shown that mis-regulation of gene expression plays key roles in the development of cancers. Their expression levels in cancers tend to differ based on tissue and tumor type. Here, we performed a comprehensive analysis comparing gene expression in different cancer types, obtained from The Cancer Genome Atlas (TCGA), with matched healthy tissues, obtained from Genotype-Tissue Expression (GTEx). We identified and quantified differential expression patterns that confirmed previously identified expression changes and highlighted new differential expression signatures. We discovered differential expression patterns that are in line with patient survival data. This comprehensive and quantitative analysis provides a global picture of genes' differential expression patterns in different cancer types.
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http://dx.doi.org/10.3390/cancers12061572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352544PMC
June 2020

Real-time data analysis using a machine learning model significantly improves prediction of successful vaginal deliveries.

Am J Obstet Gynecol 2020 09 17;223(3):437.e1-437.e15. Epub 2020 May 17.

Division of Obstetrics and Gynecology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.

Background: The process of childbirth is one of the most crucial events in the future health and development of the offspring. The vulnerability of parturients and fetuses during the delivery process led to the development of intrapartum monitoring methods and to the emergence of alternative methods of delivery. However, current monitoring methods fail to accurately discriminate between cases in which intervention is unnecessary, partly contributing to the high rates of cesarean deliveries worldwide. Machine learning methods are applied in various medical fields to create personalized prediction models. These methods are used to analyze abundant, complex data with intricate associations to aid in decision making. Initial attempts to predict vaginal delivery vs cesarean deliveries using machine learning tools did not utilize the vast amount of data recorded during labor. The data recorded during labor represent the dynamic process of labor and therefore may be invaluable for dynamic prediction of vaginal delivery.

Objective: We aimed to create a personalized machine learning-based prediction model to predict successful vaginal deliveries using real-time data acquired during the first stage of labor.

Study Design: Electronic medical records of labor occurring during a 12-year period in a tertiary referral center were explored and labeled. Four different models were created using input from multiple maternal and fetal parameters. Initial risk assessments for vaginal delivery were calculated using data available at the time of admission to the delivery unit, followed by models incorporating cervical examination data and fetal heart rate data, and finally, a model that integrates additional data available during the first stage of labor was created.

Results: A total of 94,480 cases in which a trial of labor was attempted were identified. Based on approximately 180 million data points from the first stage of labor, machine learning models were developed to predict successful vaginal deliveries. A model using data available at the time of admission to the delivery unit yielded an area under the curve of 0.817 (95% confidence interval, 0.811-0.823). Models that used real-time data increased prediction accuracy. A model that includes real-time cervical examination data had an initial area under the curve of 0.819 (95% confidence interval, 0.813-0.825) at first examination, which increased to an area under the curve of 0.917 (95% confidence interval, 0.913-0.921) by the end of the first stage. Adding the real-time fetal heart monitor data provided an area under the curve of 0.824 (95% confidence interval, 0.818-0.830) at first examination, which increased to an area under the curve of 0.928 (95% confidence interval, 0.924-0.932) by the end of the first stage. Finally, adding additional real-time data increased the area under the curve initially to 0.833 (95% confidence interval, 0.827-0.838) at the first cervical examination and up to 0.932 (95% confidence interval, 0.928-0.935) by the end of the first stage.

Conclusion: Real-time data acquired throughout the process of labor significantly increased the prediction accuracy for vaginal delivery using machine learning models. These models enable translation and quantification of the data gathered in the delivery unit into a clinical tool that yields a reliable personalized risk score and helps avoid unnecessary interventions.
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http://dx.doi.org/10.1016/j.ajog.2020.05.025DOI Listing
September 2020

The large repertoire of 2'-O-methylation guided by C/D snoRNAs on Trypanosoma brucei rRNA.

RNA Biol 2020 07 21;17(7):1018-1039. Epub 2020 Apr 21.

The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University , Ramat-Gan, Israel.

The parasite cycles between insect and mammalian hosts, and is the causative agent of sleeping sickness. Here, we performed genome-wide mapping of 2'--methylations (Nms) on trypanosome rRNA using three high-throughput sequencing methods; RibOxi-seq, RiboMeth-seq and 2'-Me-seq. This is the first study using three genome-wide mapping approaches on rRNA from the same species showing the discrepancy among the methods. RibOxi-seq detects all the sites, but RiboMeth-seq is the only method to evaluate the level of a single Nm site. The sequencing revealed at least ninety-nine Nms guided by eighty-five snoRNAs among these thirty-eight Nms are trypanosome specific sites. We present the sequence and target of the C/D snoRNAs guiding on rRNA. This is the highest number of Nms detected to date on rRNA of a single cell parasite. Based on RiboMeth-seq, several Nm sites were found to be differentially regulated at the two stages of the parasite life cycle, the insect procyclic form (PCF) versus the bloodstream form (BSF) in the mammalian host.
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http://dx.doi.org/10.1080/15476286.2020.1750842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549662PMC
July 2020

Visualizing the structure and motion of the long noncoding RNA HOTAIR.

RNA 2020 05 27;26(5):629-636. Epub 2020 Feb 27.

Augmanity, Rehovot 7670308, Israel.

Long noncoding RNA molecules (lncRNAs) are estimated to account for the majority of eukaryotic genomic transcripts, and have been associated with multiple diseases in humans. However, our understanding of their structure-function relationships is scarce, with structural evidence coming mostly from indirect biochemical approaches or computational predictions. Here we describe direct visualization of the lncRNA HOTAIR (HOx Transcript AntIsense RNA) using atomic force microscopy (AFM) in nucleus-like conditions at 37°. Our observations reveal that HOTAIR has a discernible, although flexible, shape. Fast AFM scanning enabled the quantification of the motion of HOTAIR, and provided visual evidence of physical interactions with genomic DNA segments. Our report provides a biologically plausible description of the anatomy and intrinsic properties of HOTAIR, and presents a framework for studying the structural biology of lncRNAs.
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http://dx.doi.org/10.1261/rna.074633.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161352PMC
May 2020

Cervical dilation at the time of epidural catheter insertion is not associated with the degree of prolongation of the first or second stages of labor, or the rate of instrumental vaginal delivery.

Acta Obstet Gynecol Scand 2020 08 21;99(8):1039-1049. Epub 2020 Feb 21.

Division of Obstetrics & Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Introduction: Epidural analgesia (EA) is an established option for efficient intrapartum analgesia. Meta-analyses have shown that EA differentially affects the first stage of labor but prolongs the second. The question of EA timing remains open. We aimed to investigate whether EA prolongs delivery in total and whether the EA administration timing vis-à-vis cervical dilation at catheter insertion is associated with a modulation of its effects on the duration of the first and second stages, as well as the rate of instrumental vaginal delivery in primiparas and multiparas.

Material And Methods: A retrospective electronic medical records-based study of 18 870 singleton term deliveries occurring in our institution from 2003 to 2015. Cervical dilation was determined within a half-hour of EA administration. We examined whether cervical dilation at EA administration correlated with the duration of the first and/or second stage, with the rate of prolonged second stage, and with the rate of interventional delivery. The study group was stratified to 10 subgroups defined by 1-cm intervals of cervical dilation at EA administration. Logistic regression modeling was applied to analyze the association between EA timing and rate of instrumental delivery while controlling for possible confounders.

Results: In primiparas, receiving EA correlated with longer medians of active first stage (+51 minutes; P < .001) and second stage (+55 minutes; P < .001). In multiparas, median increases in active first stage (+43 minutes; P < .001) and second stage (+8 minutes; P < .001) were noted. The timing of EA, vis-à-vis cervical dilation (1-10 cm) was not associated with a substantial modulation of these effects. Logistic regression showed that cervical dilation at EA was not associated with a higher instrumental vaginal delivery rate.

Conclusions: Epidural analgesia prolonged the first and second stages of labor vs no epidural. Having EA was associated with a higher instrumental delivery rate but not with higher rates of maternal or neonatal complications, in primi- and multiparas. Importantly, the timing of EA, vis-à-vis cervical dilation, was not associated with substantial changes in the duration of labor stages or the instrumental delivery rate. Thus, EA may be offered early in the first stage of labor.
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http://dx.doi.org/10.1111/aogs.13822DOI Listing
August 2020

Prediction of vaginal birth after cesarean deliveries using machine learning.

Am J Obstet Gynecol 2020 06 30;222(6):613.e1-613.e12. Epub 2020 Jan 30.

Obstetrics & Gynecology Division, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

Background: Efforts to reduce cesarean delivery rates to 12-15% have been undertaken worldwide. Special focus has been directed towards parturients who undergo a trial of labor after cesarean delivery to reduce the burden of repeated cesarean deliveries. Complication rates are lowest when a vaginal birth is achieved and highest when an unplanned cesarean delivery is performed, which emphasizes the need to assess, in advance, the likelihood of a successful vaginal birth after cesarean delivery. Vaginal birth after cesarean delivery calculators have been developed in different populations; however, some limitations to their implementation into clinical practice have been described. Machine-learning methods enable investigation of large-scale datasets with input combinations that traditional statistical analysis tools have difficulty processing.

Objective: The aim of this study was to evaluate the feasibility of using machine-learning methods to predict a successful vaginal birth after cesarean delivery.

Study Design: The electronic medical records of singleton, term labors during a 12-year period in a tertiary referral center were analyzed. With the use of gradient boosting, models that incorporated multiple maternal and fetal features were created to predict successful vaginal birth in parturients who undergo a trial of labor after cesarean delivery. One model was created to provide a personalized risk score for vaginal birth after cesarean delivery with the use of features that are available as early as the first antenatal visit; a second model was created that reassesses this score after features are added that are available only in proximity to delivery.

Results: A cohort of 9888 parturients with 1 previous cesarean delivery was identified, of which 75.6% of parturients (n=7473) attempted a trial of labor, with a success rate of 88%. A machine-learning-based model to predict when vaginal delivery would be successful was developed. When features that are available at the first antenatal visit are used, the model showed a receiver operating characteristic curve with area under the curve of 0.745 (95% confidence interval, 0.728-0.762) that increased to 0.793 (95% confidence interval, 0.778-0.808) when features that are available in proximity to the delivery process were added. Additionally, for the later model, a risk stratification tool was built to allocate parturients into low-, medium-, and high-risk groups for failed trial of labor after cesarean delivery. The low- and medium-risk groups (42.4% and 25.6% of parturients, respectively) showed a success rate of 97.3% and 90.9%, respectively. The high-risk group (32.1%) had a vaginal delivery success rate of 73.3%. Application of the model to a cohort of parturients who elected a repeat cesarean delivery (n=2145) demonstrated that 31% of these parturients would have been allocated to the low- and medium-risk groups had a trial of labor been attempted.

Conclusion: Trial of labor after cesarean delivery is safe for most parturients. Success rates are high, even in a population with high rates of trial of labor after cesarean delivery. Application of a machine-learning algorithm to assign a personalized risk score for a successful vaginal birth after cesarean delivery may help in decision-making and contribute to a reduction in cesarean delivery rates. Parturient allocation to risk groups may help delivery process management.
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http://dx.doi.org/10.1016/j.ajog.2019.12.267DOI Listing
June 2020

Unplanned Cesarean Delivery in the Second Stage of Labor Holds Higher Odds of Complications than in the First Stage, while Similar in Primiparas and Multiparas.

Fetal Diagn Ther 2020 24;47(7):565-571. Epub 2020 Jan 24.

The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.

Background: While endeavors to reduce cesarean delivery (CD) rates are given priority worldwide, it is important to evaluate if these efforts place parturients and neonates at risk. CD performed in the second stage of labor carries higher risks of maternal and fetal complications and is a more challenging surgical procedure than that performed in the first stage or before labor. In a population with a low CD rate, we sought to evaluate the rate of maternal and fetal complications associated with unplanned CD (UCD) performed in the second vs. the first stage of labor, in primiparas and multiparas, as well as the risk factors leading to and the complications associated with UCD in the second stage of labor in this low-CD rate setting.

Methods: This was a retrospective, electronic medical record-based study of 7,635 term and preterm singletons born via UCD in the period 2003-2015. Maternal and neonatal background and outcome parameters were compared between groups. Logistic regression modeling was applied to adjust for clinically and statistically significant risk factors.

Results: UCD was more likely to be performed in the second stage of labor in mothers delivering larger fetuses (head circumference and body weight ≥90 centile) and those with persistent occiput posterior (POP) presentation. UCD in the second stage was strongly associated with serious maternal complications (excessive hemorrhage and fever) compared to UCD performed in the first stage, in both primiparas and multiparas.

Conclusions: UCD performed in the second stage of labor, while less frequent than first-stage UCD, is more likely with larger neonates and POP presentation, and is associated with a higher rate of maternal complications in primiparas and multiparas. Complication rates in our low-CD-rate population did not exceed those reported in the literature from high-CD-rate areas.
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http://dx.doi.org/10.1159/000504573DOI Listing
January 2020

Defining the Celiac Disease Transcriptome using Clinical Pathology Specimens Reveals Biologic Pathways and Supports Diagnosis.

Sci Rep 2019 11 7;9(1):16163. Epub 2019 Nov 7.

The Pediatric Gastroenterology Unit, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.

Celiac disease is provoked by gluten exposure, but the complete pathogenic process in the duodenum and the loss of tolerance to gluten is not well understood. We aimed to define the core celiac transcriptomic signature and pathologic pathways in pre-treatment formalin-fixed paraffin-embedded (FFPE) duodenum biopsies used for clinical diagnosis. We use mRNAseq to define pre-treatment diagnostic duodenum gene expression in 54 pediatric celiac patients and non-celiac controls, and we validate our key findings in two independent cohorts of 67 adults and pediatric participants that used fresh frozen biopsies. We further define similar and divergent genes and pathways in 177 small bowel Crohn disease patients and controls. We observe a marked suppression of mature epithelial metabolic functions in celiac patients, overlapping substantially with the Crohn disease signature. A marked adaptive immune response was noted for the up-regulated signature including interferon response, alpha-beta, and gamma-delta T-cells that overlapped to some extent with the Crohn disease signature. However, we also identified a celiac disease specific signature linked to increased cell proliferation, nuclear division, and cell cycle activity that was localized primarily to the epithelia as noted by CCNB1 and Ki67 staining. Lastly, we demonstrate the utility of the transcriptomic date to correctly classify disease or healthy states in the discovery and validation cohorts. Our data supplement recently published datasets providing insights into celiac pathogenesis using clinical pathology FFPE samples, and can stimulate new approaches to address this highly prevalent condition.
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http://dx.doi.org/10.1038/s41598-019-52733-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838157PMC
November 2019

Contemporary patterns of labor in nulliparous and multiparous women.

Am J Obstet Gynecol 2020 03 28;222(3):267.e1-267.e9. Epub 2019 Sep 28.

Lis Maternity Hospital, Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Controversy surrounds the definition of "normal" and "abnormal" labor.

Objective: In this study, we used contemporary labor charts to explore labor patterns in large obstetric population (2011-2016).

Study Design: Detailed information from electronic medical records of live singleton deliveries at term (≥37 weeks of gestation) was extracted. Cases of elective cesarean deliveries, nonvertex presentation, and cesarean deliveries during the first stage of labor were excluded.

Results: Overall, 35,146 deliveries were included, of whom 15,948 deliveries (45.3%) were of nulliparous women. Median cervical dilation at admission was not significantly different between nulliparous (median, 4 cm; interquartile range, 3-5 cm) and multiparous women (median, 4 cm; interquartile range, 3-6 cm). In all, 99.3% of the women delivered vaginally. For nulliparous women, the median duration of the first stage of labor was 274 minutes (interquartile range, 145-441 minutes; 95th percentile, 747.5 minutes). Likewise, for multiparous women, the corresponding duration was 133 minutes (interquartile range, 56-244 minutes; 95th percentile, 494 minutes). During the latent phase (cervical dilation at admission, ≤4 cm), the time elapsed to the second stage of labor was 120-140 minutes longer in nulliparous women, whereas the gap between the groups decreased dramatically with advanced cervical dilation on admission. Nulliparous and multiparous women appeared to progress at a similar pace during the latent phase; however, after 5 cm, labor accelerated faster in multiparous women. Epidural anesthesia lengthens duration first and second stages of labor in all parities. Partograms according to cervical dilation at presentation are proposed.

Conclusion: Cervical dilation rate is relatively constant between nulliparous and multiparous pregnant women during the latent phase. Time interval of the first stage was far slower than previously described, which allowed labor to continue for a longer period during this stage. These findings may reduce the rate of intrapartum iatrogenic interventions.
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http://dx.doi.org/10.1016/j.ajog.2019.09.035DOI Listing
March 2020

Assessing predictions of the impact of variants on splicing in CAGI5.

Hum Mutat 2019 09 19;40(9):1215-1224. Epub 2019 Aug 19.

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

Precision medicine and sequence-based clinical diagnostics seek to predict disease risk or to identify causative variants from sequencing data. The Critical Assessment of Genome Interpretation (CAGI) is a community experiment consisting of genotype-phenotype prediction challenges; participants build models, undergo assessment, and share key findings. In the past, few CAGI challenges have addressed the impact of sequence variants on splicing. In CAGI5, two challenges (Vex-seq and MaPSY) involved prediction of the effect of variants, primarily single-nucleotide changes, on splicing. Although there are significant differences between these two challenges, both involved prediction of results from high-throughput exon inclusion assays. Here, we discuss the methods used to predict the impact of these variants on splicing, their performance, strengths, and weaknesses, and prospects for predicting the impact of sequence variation on splicing and disease phenotypes.
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http://dx.doi.org/10.1002/humu.23869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744318PMC
September 2019

Pseudouridines on Trypanosoma brucei spliceosomal small nuclear RNAs and their implication for RNA and protein interactions.

Nucleic Acids Res 2019 08;47(14):7633-7647

The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 52900, Israel.

The parasite Trypanosoma brucei, the causative agent of sleeping sickness, cycles between an insect and a mammalian host. Here, we investigated the presence of pseudouridines (Ψs) on the spliceosomal small nuclear RNAs (snRNAs), which may enable growth at the very different temperatures characterizing the two hosts. To this end, we performed the first high-throughput mapping of spliceosomal snRNA Ψs by small RNA Ψ-seq. The analysis revealed 42 Ψs on T. brucei snRNAs, which is the highest number reported so far. We show that a trypanosome protein analogous to human protein WDR79, is essential for guiding Ψ on snRNAs but not on rRNAs. snoRNA species implicated in snRNA pseudouridylation were identified by a genome-wide approach based on ligation of RNAs following in vivo UV cross-linking. snRNA Ψs are guided by single hairpin snoRNAs, also implicated in rRNA modification. Depletion of such guiding snoRNA by RNAi compromised the guided modification on snRNA and reduced parasite growth at elevated temperatures. We further demonstrate that Ψ strengthens U4/U6 RNA-RNA and U2B"/U2A' proteins-U2 snRNA interaction at elevated temperatures. The existence of single hairpin RNAs that modify both the spliceosome and ribosome RNAs is unique for these parasites, and may be related to their ability to cycle between their two hosts that differ in temperature.
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http://dx.doi.org/10.1093/nar/gkz477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698659PMC
August 2019

Integration of multiple epigenomic marks improves prediction of variant impact in saturation mutagenesis reporter assay.

Hum Mutat 2019 09 23;40(9):1280-1291. Epub 2019 Jun 23.

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland.

The integrative analysis of high-throughput reporter assays, machine learning, and profiles of epigenomic chromatin state in a broad array of cells and tissues has the potential to significantly improve our understanding of noncoding regulatory element function and its contribution to human disease. Here, we report results from the CAGI 5 regulation saturation challenge where participants were asked to predict the impact of nucleotide substitution at every base pair within five disease-associated human enhancers and nine disease-associated promoters. A library of mutations covering all bases was generated by saturation mutagenesis and altered activity was assessed in a massively parallel reporter assay (MPRA) in relevant cell lines. Reporter expression was measured relative to plasmid DNA to determine the impact of variants. The challenge was to predict the functional effects of variants on reporter expression. Comparative analysis of the full range of submitted prediction results identifies the most successful models of transcription factor binding sites, machine learning algorithms, and ways to choose among or incorporate diverse datatypes and cell-types for training computational models. These results have the potential to improve the design of future studies on more diverse sets of regulatory elements and aid the interpretation of disease-associated genetic variation.
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http://dx.doi.org/10.1002/humu.23797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879779PMC
September 2019

Identification of evolutionarily conserved downstream core promoter elements required for the transcriptional regulation of Fushi tarazu target genes.

PLoS One 2019 18;14(4):e0215695. Epub 2019 Apr 18.

The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel.

The regulation of transcription initiation is critical for developmental and cellular processes. RNA polymerase II (Pol II) is recruited by the basal transcription machinery to the core promoter where Pol II initiates transcription. The core promoter encompasses the region from -40 to +40 bp relative to the +1 transcription start site (TSS). Core promoters may contain one or more core promoter motifs that confer specific properties to the core promoter, such as the TATA box, initiator (Inr) and motifs that are located downstream of the TSS, namely, motif 10 element (MTE), the downstream core promoter element (DPE) and the Bridge, a bipartite core promoter element. We had previously shown that Caudal, an enhancer-binding homeodomain transcription factor and a key regulator of the Hox gene network, is a DPE-specific activator. Interestingly, pair-rule proteins have been implicated in enhancer-promoter communication at the engrailed locus. Fushi tarazu (Ftz) is an enhancer-binding homeodomain transcription factor encoded by the ftz pair-rule gene. Ftz works in concert with its co-factor, Ftz-F1, to activate transcription. Here, we examined whether Ftz and Ftz-F1 activate transcription with a preference for a specific core promoter motif. Our analysis revealed that similarly to Caudal, Ftz and Ftz-F1 activate the promoter containing a TATA box mutation to significantly higher levels than the promoter containing a DPE mutation, thus demonstrating a preference for the DPE motif. We further discovered that Ftz target genes are enriched for a combination of functional downstream core promoter elements that are conserved among Drosophila species. Thus, the unique combination (Inr, Bridge and DPE) of functional downstream core promoter elements within Ftz target genes highlights the complexity of transcriptional regulation via the core promoter in the transcription of different developmental gene regulatory networks.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215695PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472829PMC
January 2020

Small nucleolar RNAs controlling rRNA processing in Trypanosoma brucei.

Nucleic Acids Res 2019 03;47(5):2609-2629

The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 52900 Israel.

In trypanosomes, in contrast to most eukaryotes, the large subunit (LSU) ribosomal RNA is fragmented into two large and four small ribosomal RNAs (srRNAs) pieces, and this additional processing likely requires trypanosome-specific factors. Here, we examined the role of 10 abundant small nucleolar RNAs (snoRNAs) involved in rRNA processing. We show that each snoRNA involved in LSU processing associates with factors engaged in either early or late biogenesis steps. Five of these snoRNAs interact with the intervening sequences of rRNA precursor, whereas the others only guide rRNA modifications. The function of the snoRNAs was explored by silencing snoRNAs. The data suggest that the LSU rRNA processing events do not correspond to the order of rRNA transcription, and that srRNAs 2, 4 and 6 which are part of LSU are processed before srRNA1. Interestingly, the 6 snoRNAs that affect srRNA1 processing guide modifications on rRNA positions that span locations from the protein exit tunnel to the srRNA1, suggesting that these modifications may serve as check-points preceding the liberation of srRNA1. This study identifies the highest number of snoRNAs so far described that are involved in rRNA processing and/or rRNA folding and highlights their function in the unique trypanosome rRNA maturation events.
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http://dx.doi.org/10.1093/nar/gky1287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411936PMC
March 2019

Contact Order Is a Determinant for the Dependence of GFP Folding on the Chaperonin GroEL.

Biophys J 2019 01 22;116(1):42-48. Epub 2018 Nov 22.

Department of Structural Biology, Weizmann Institute of Science, Rehovot, Israel. Electronic address:

The GroE chaperonin system facilitates protein folding in an ATP-dependent manner. It has remained unclear why some proteins are obligate clients of the GroE system, whereas other closely related proteins are able to fold efficiently in its absence. Factors that cause folding to be slower affect kinetic partitioning between spontaneous folding and chaperone binding in favor of the latter. One such potential factor is contact order (CO), which is the average separation in sequence between residues that are in contact in the native structure. Here, we generated variants of enhanced green fluorescent protein with different COs using circular permutations. We found that GroE dependence in vitro and in vivo increases with increasing CO. Thus, our results show that CO is relevant not only for folding in vitro of relatively simple model systems but also for chaperonin dependence and folding in vivo.
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http://dx.doi.org/10.1016/j.bpj.2018.11.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342685PMC
January 2019

Iatrogenic hypertension: a bioinformatic analysis.

Pharmacogenomics J 2019 08 5;19(4):337-346. Epub 2018 Nov 5.

The Mina & Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel.

It is well known that a myriad of medications and substances can induce side effects that are related to blood pressure (BP) regulation. This study aims to investigate why certain drugs tend to cause iatrogenic hypertension (HTN) and focus on drug targets that are implicated in these conditions.Databases and resources such as SIDER, DrugBank, and Genomatix were utilized in order to bioinformatically investigate HTN-associated drug target-genes for which HTN is a side effect. A tree-like map was created, representing interactions between 198 human genes that relate to the blood pressure system. 72 HTN indicated drugs and 160 HTN-inducing drugs were investigated. HTN-associated genes affected by these drugs were identified. HTN indicated drugs, which target nearly all branches of the interaction tree, were shown to exert an effect on most functional sub-systems of the BP regulatory system; and specifically, for the adrenergic and dopaminergic receptor pathways. High prevalence (25 genes) of shared targets between the HTN indicated and HTN-inducing drug categories was demonstrated. We focus on six drug families which are not indicated for HTN treatment, yet are reported as a major cause for blood pressure side effects. We show the molecular mechanisms that may lead to this iatrogenic effect. Such an analysis may have clinical implications that could allow for the development of tailored medicine with fewer side effects.
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http://dx.doi.org/10.1038/s41397-018-0062-0DOI Listing
August 2019

Dietary patterns are positively associated with semen quality.

Fertil Steril 2018 05;109(5):809-816

Department of Nutrition, Faculty of Health Sciences, Ariel University, Ariel, West Bank, Israel. Electronic address:

Objective: To study association of semen quality with a priori whole dietary pattern indexes, which reflect real-world dietary practices and the numerous combinations by which foods are consumed: Healthy Eating Index (HEI), Dietary Approaches to Stop Hypertension (DASH), alternate Mediterranean Diet score (aMED), and Alternative Healthy Eating Index (AHEI).

Design: A cross-sectional single-center study.

Setting: Hospital fertility center and university.

Patient(s): A total of 280 men attending fertility center from 2012 to 2015.

Intervention(s): Food frequency questionnaire (FFQ) and semen and sperm analysis.

Main Outcome Measure(s): Food consumption with the use of FFQ and HEI, AHEI, aMED, DASH nutritional individual scoring indexes. Semen parameters, including semen volume, sperm concentration, motility, total count, and morphology.

Result(s): Comparing the highest and lowest quartiles of the nutritional indexes, men in the highest quartiles of HEI, AHEI, aMed, and DASH indexes had significantly higher adjusted means of sperm concentration (by 10%, 45%, and 24% for HEI, AHEI, and DASH, respectively), normal sperm morphology (by 21% and 8% for AHEI and DASH, respectively), total sperm count (by 29% for AHEI), and sperm motility (by 6% and 11% for aMed and HEI, respectively).

Conclusion(s): Adherence to any of the four dietary indexes is associated with better overall sperm quality, with AHEI best associated. Following our novel findings, we recommend using AHEI as a clinical and practical tool for public whole nutritional recommendation for semen quality.
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http://dx.doi.org/10.1016/j.fertnstert.2018.01.010DOI Listing
May 2018

Comparative genomic analysis of mollicutes with and without a chaperonin system.

PLoS One 2018 13;13(2):e0192619. Epub 2018 Feb 13.

The Mina Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel.

The GroE chaperonin system, which comprises GroEL and GroES, assists protein folding in vivo and in vitro. It is conserved in all prokaryotes except in most, but not all, members of the class of mollicutes. In Escherichia coli, about 60 proteins were found to be obligatory clients of the GroE system. Here, we describe the properties of the homologs of these GroE clients in mollicutes and the evolution of chaperonins in this class of bacteria. Comparing the properties of these homologs in mollicutes with and without chaperonins enabled us to search for features correlated with the presence of GroE. Interestingly, no sequence-based features of proteins such as average length, amino acid composition and predicted folding/disorder propensity were found to be affected by the absence of GroE. Other properties such as genome size and number of proteins were also found to not differ between mollicute species with and without GroE. Our data suggest that two clades of mollicutes re-acquired the GroE system, thereby supporting the view that gaining the system occurred polyphyletically and not monophyletically, as previously debated. Our data also suggest that there might have been three isolated cases of lateral gene transfer from specific bacterial sources. Taken together, our data indicate that loss of GroE does not involve crossing a high evolutionary barrier and can be compensated for by a small number of changes within the few dozen client proteins.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192619PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5810989PMC
April 2018

A system view and analysis of essential hypertension.

J Hypertens 2018 05;36(5):1094-1103

The Mina & Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan.

Objectives: The goal of this study was to investigate genes associated with essential hypertension from a system perspective, making use of bioinformatic tools to gain insights that are not evident when focusing at a detail-based resolution.

Methods: Using various databases (pathways, Genome Wide Association Studies, knockouts etc.), we compiled a set of about 200 genes that play a major role in hypertension and identified the interactions between them. This enabled us to create a protein-protein interaction network graph, from which we identified key elements, based on graph centrality analysis. Enriched gene regulatory elements (transcription factors and microRNAs) were extracted by motif finding techniques and knowledge-based tools.

Results: We found that the network is composed of modules associated with functions such as water retention, endothelial vasoconstriction, sympathetic activity and others. We identified the transcription factor SP1 and the two microRNAs miR27 (a and b) and miR548c-3p that seem to play a major role in regulating the network as they exert their control over several modules and are not restricted to specific functions. We also noticed that genes involved in metabolic diseases (e.g. insulin) are central to the network.

Conclusion: We view the blood-pressure regulation mechanism as a system-of-systems, composed of several contributing subsystems and pathways rather than a single module. The system is regulated by distributed elements. Understanding this mode of action can lead to a more precise treatment and drug target discovery. Our analysis suggests that insulin plays a primary role in hypertension, highlighting the tight link between essential hypertension and diseases associated with the metabolic syndrome.
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http://dx.doi.org/10.1097/HJH.0000000000001680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927246PMC
May 2018

Sonographic large fetal head circumference and risk of cesarean delivery.

Am J Obstet Gynecol 2018 Mar 2;218(3):339.e1-339.e7. Epub 2018 Jan 2.

Division of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Electronic address:

Background: Persistently high rates of cesarean deliveries are cause for concern for physicians, patients, and health systems. Prelabor assessment might be refined by identifying factors that help predict an individual patient's risk of cesarean delivery. Such factors may contribute to patient safety and satisfaction as well as health system planning and resource allocation. In an earlier study, neonatal head circumference was shown to be more strongly associated with delivery mode and other outcome measures than neonatal birthweight.

Objective: In the present study we aimed to evaluate the association of sonographically measured fetal head circumference measured within 1 week of delivery with delivery mode.

Study Design: This was a multicenter electronic medical record-based study of birth outcomes of primiparous women with term (37-42 weeks) singleton fetuses presenting for ultrasound with fetal biometry within 1 week of delivery. Fetal head circumference and estimated fetal weight were correlated with maternal background, obstetric, and neonatal outcome parameters. Elective cesarean deliveries were excluded. Multinomial regression analysis provided adjusted odds ratios for instrumental delivery and unplanned cesarean delivery when the fetal head circumference was ≥35 cm or estimated fetal weight ≥3900 g, while controlling for possible confounders.

Results: In all, 11,500 cases were collected; 906 elective cesarean deliveries were excluded. A fetal head circumference ≥35 cm increased the risk for unplanned cesarean delivery: 174 fetuses with fetal head circumference ≥35 cm (32%) were delivered by cesarean, vs 1712 (17%) when fetal head circumference <35 cm (odds ratio, 2.49; 95% confidence interval, 2.04-3.03). A fetal head circumference ≥35 cm increased the risk of instrumental delivery (odds ratio, 1.48; 95% confidence interval, 1.16-1.88), while estimated fetal weight ≥3900 g tended to reduce it (nonsignificant). Multinomial regression analysis showed that fetal head circumference ≥35 cm increased the risk of unplanned cesarean delivery by an adjusted odds ratio of 1.75 (95% confidence interval, 1.4-2.18) controlling for gestational age, fetal gender, and epidural anesthesia. The rate of prolonged second stage of labor was significantly increased when either the fetal head circumference was ≥35 cm or the estimated fetal weight ≥3900 g, from 22.7% in the total cohort to 31.0%. A fetal head circumference ≥35 cm was associated with a higher rate of 5-minute Apgar score ≤7: 9 (1.7%) vs 63 (0.6%) of infants with fetal head circumference <35 cm (P = .01). The rate among fetuses with an estimated fetal weight ≥3900 g was not significantly increased. The rate of admission to the neonatal intensive care unit did not differ among the groups.

Conclusion: Sonographic fetal head circumference ≥35 cm, measured within 1 week of delivery, is an independent risk factor for unplanned cesarean delivery but not instrumental delivery. Both fetal head circumference ≥35 cm and estimated fetal weight ≥3900 g significantly increased the risk of a prolonged second stage of labor. Fetal head circumference measurement in the last days before delivery may be an important adjunct to estimated fetal weight in labor management.
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http://dx.doi.org/10.1016/j.ajog.2017.12.230DOI Listing
March 2018

RNA editing by ADAR1 leads to context-dependent transcriptome-wide changes in RNA secondary structure.

Nat Commun 2017 11 13;8(1):1440. Epub 2017 Nov 13.

Cancer Research Center, Sheba Medical Center, Tel Hashomer, 52621, Ramat-Gan, Israel.

Adenosine deaminase acting on RNA 1 (ADAR1) is the master RNA editor, catalyzing the deamination of adenosine to inosine. RNA editing is vital for preventing abnormal activation of cytosolic nucleic acid sensing pathways by self-double-stranded RNAs. Here we determine, by parallel analysis of RNA secondary structure sequencing (PARS-seq), the global RNA secondary structure changes in ADAR1 deficient cells. Surprisingly, ADAR1 silencing resulted in a lower global double-stranded to single-stranded RNA ratio, suggesting that A-to-I editing can stabilize a large subset of imperfect RNA duplexes. The duplexes destabilized by editing are composed of vastly complementary inverted Alus found in untranslated regions of genes performing vital biological processes, including housekeeping functions and type-I interferon responses. They are predominantly cytoplasmic and generally demonstrate higher ribosomal occupancy. Our findings imply that the editing effect on RNA secondary structure is context dependent and underline the intricate regulatory role of ADAR1 on global RNA secondary structure.
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http://dx.doi.org/10.1038/s41467-017-01458-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682290PMC
November 2017

Local energetic frustration affects the dependence of green fluorescent protein folding on the chaperonin GroEL.

J Biol Chem 2017 12 24;292(50):20583-20591. Epub 2017 Oct 24.

From the Departments of Structural Biology and

The GroE chaperonin system in comprises GroEL and GroES and facilitates ATP-dependent protein folding and Proteins with very similar sequences and structures can differ in their dependence on GroEL for efficient folding. One potential but unverified source for GroEL dependence is frustration, wherein not all interactions in the native state are optimized energetically, thereby potentiating slow folding and misfolding. Here, we chose enhanced green fluorescent protein as a model system and subjected it to random mutagenesis, followed by screening for variants whose folding displays increased or decreased GroEL dependence. We confirmed the altered GroEL dependence of these variants with folding assays. Strikingly, mutations at positions predicted to be highly frustrated were found to correlate with decreased GroEL dependence. Conversely, mutations at positions with low frustration were found to correlate with increased GroEL dependence. Further support for this finding was obtained by showing that folding of an enhanced green fluorescent protein variant designed computationally to have reduced frustration is indeed less GroEL-dependent. Our results indicate that changes in local frustration also affect partitioning between spontaneous and chaperonin-mediated folding. Hence, the design of minimally frustrated sequences can reduce chaperonin dependence and improve protein expression levels.
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http://dx.doi.org/10.1074/jbc.M117.808576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733594PMC
December 2017

Machine learning for prediction of 30-day mortality after ST elevation myocardial infraction: An Acute Coronary Syndrome Israeli Survey data mining study.

Int J Cardiol 2017 Nov;246:7-13

The Heart Institute, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Israel.

Background: Risk scores for prediction of mortality 30-days following a ST-segment elevation myocardial infarction (STEMI) have been developed using a conventional statistical approach.

Objective: To evaluate an array of machine learning (ML) algorithms for prediction of mortality at 30-days in STEMI patients and to compare these to the conventional validated risk scores.

Methods: This was a retrospective, supervised learning, data mining study. Out of a cohort of 13,422 patients from the Acute Coronary Syndrome Israeli Survey (ACSIS) registry, 2782 patients fulfilled inclusion criteria and 54 variables were considered. Prediction models for overall mortality 30days after STEMI were developed using 6 ML algorithms. Models were compared to each other and to the Global Registry of Acute Coronary Events (GRACE) and Thrombolysis In Myocardial Infarction (TIMI) scores.

Results: Depending on the algorithm, using all available variables, prediction models' performance measured in an area under the receiver operating characteristic curve (AUC) ranged from 0.64 to 0.91. The best models performed similarly to the Global Registry of Acute Coronary Events (GRACE) score (0.87 SD 0.06) and outperformed the Thrombolysis In Myocardial Infarction (TIMI) score (0.82 SD 0.06, p<0.05). Performance of most algorithms plateaued when introduced with 15 variables. Among the top predictors were creatinine, Killip class on admission, blood pressure, glucose level, and age.

Conclusions: We present a data mining approach for prediction of mortality post-ST-segment elevation myocardial infarction. The algorithms selected showed competence in prediction across an increasing number of variables. ML may be used for outcome prediction in complex cardiology settings.
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http://dx.doi.org/10.1016/j.ijcard.2017.05.067DOI Listing
November 2017

An Integrative Scoring System for Survival Prediction Following Umbilical Cord Blood Transplantation in Acute Leukemia.

Clin Cancer Res 2017 Nov 28;23(21):6478-6486. Epub 2017 Jul 28.

Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel-HaShomer, Ramat-Gan, Israel.

Survival of acute leukemia (AL) patients following umbilical cord blood transplantation (UCBT) is dependent on an array of individual features. Integrative models for risk assessment are lacking. We sought to develop a scoring system for prediction of overall survival (OS) and leukemia-free survival (LFS) at 2 years following UCBT in AL patients. The study cohort included 3,140 pediatric and adult AL UCBT patients from the European Society of Blood and Marrow Transplantation and Eurocord registries. Patients received single or double cord blood units. The dataset was geographically split into a derivation ( = 2,362, 65%) and validation set ( = 778, 35%). Top predictors of OS were identified using the Random Survival Forest algorithm and introduced into a Cox regression model, which served for the construction of the UCBT risk score. The score includes nine variables: disease status, diagnosis, cell dose, age, center experience, cytomegalovirus serostatus, degree of HLA mismatch, previous autograft, and anti-thymocyte globulin administration. Over the validation set an increasing score was associated with decreasing probabilities for 2 years OS and LFS, ranging from 70.21% [68.89-70.71, 95% confidence interval (CI)] and 64.76% (64.33-65.86, 95% CI) to 14.78% (10.91-17.41) and 18.11% (14.40-22.30), respectively. It stratified patients into six distinct risk groups. The score's discrimination (AUC) over multiple imputations of the validation set was 68.76 (68.19-69.04, range) and 65.78 (65.20-66.28) for 2 years OS and LFS, respectively. The UCBT score is a simple tool for risk stratification of AL patients undergoing UCBT. Widespread application of the score will require further independent validation. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0489DOI Listing
November 2017

Working toward precision medicine: Predicting phenotypes from exomes in the Critical Assessment of Genome Interpretation (CAGI) challenges.

Hum Mutat 2017 09 7;38(9):1182-1192. Epub 2017 Jul 7.

Department of Information Engineering, University of Padova, Padova, Italy.

Precision medicine aims to predict a patient's disease risk and best therapeutic options by using that individual's genetic sequencing data. The Critical Assessment of Genome Interpretation (CAGI) is a community experiment consisting of genotype-phenotype prediction challenges; participants build models, undergo assessment, and share key findings. For CAGI 4, three challenges involved using exome-sequencing data: Crohn's disease, bipolar disorder, and warfarin dosing. Previous CAGI challenges included prior versions of the Crohn's disease challenge. Here, we discuss the range of techniques used for phenotype prediction as well as the methods used for assessing predictive models. Additionally, we outline some of the difficulties associated with making predictions and evaluating them. The lessons learned from the exome challenges can be applied to both research and clinical efforts to improve phenotype prediction from genotype. In addition, these challenges serve as a vehicle for sharing clinical and research exome data in a secure manner with scientists who have a broad range of expertise, contributing to a collaborative effort to advance our understanding of genotype-phenotype relationships.
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http://dx.doi.org/10.1002/humu.23280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5600620PMC
September 2017

The Canonical Poly (A) Polymerase PAP1 Polyadenylates Non-Coding RNAs and Is Essential for snoRNA Biogenesis in Trypanosoma brucei.

J Mol Biol 2017 10 26;429(21):3301-3318. Epub 2017 Apr 26.

The Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan 5290002, Israel. Electronic address:

The parasite Trypanosoma brucei is the causative agent of African sleeping sickness and is known for its unique RNA processing mechanisms that are common to all the kinetoplastidea including Leishmania and Trypanosoma cruzi. Trypanosomes possess two canonical RNA poly (A) polymerases (PAPs) termed PAP1 and PAP2. PAP1 is encoded by one of the only two genes harboring cis-spliced introns in this organism, and its function is currently unknown. In trypanosomes, all mRNAs, and non-coding RNAs such as small nucleolar RNAs (snoRNAs) and long non-coding RNAs (lncRNAs), undergo trans-splicing and polyadenylation. Here, we show that the function of PAP1, which is located in the nucleus, is to polyadenylate non-coding RNAs, which undergo trans-splicing and polyadenylation. Major substrates of PAP1 are the snoRNAs and lncRNAs. Under the silencing of either PAP1 or PAP2, the level of snoRNAs is reduced. The dual polyadenylation of snoRNA intermediates is carried out by both PAP2 and PAP1 and requires the factors essential for the polyadenylation of mRNAs. The dual polyadenylation of the precursor snoRNAs by PAPs may function to recruit the machinery essential for snoRNA processing.
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http://dx.doi.org/10.1016/j.jmb.2017.04.015DOI Listing
October 2017

Trade-off between Transcriptome Plasticity and Genome Evolution in Cephalopods.

Cell 2017 04;169(2):191-202.e11

Raymond and Beverly Sackler School of Physics and Astronomy, Tel Aviv University, Tel Aviv 69978, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address:

RNA editing, a post-transcriptional process, allows the diversification of proteomes beyond the genomic blueprint; however it is infrequently used among animals for this purpose. Recent reports suggesting increased levels of RNA editing in squids thus raise the question of the nature and effects of these events. We here show that RNA editing is particularly common in behaviorally sophisticated coleoid cephalopods, with tens of thousands of evolutionarily conserved sites. Editing is enriched in the nervous system, affecting molecules pertinent for excitability and neuronal morphology. The genomic sequence flanking editing sites is highly conserved, suggesting that the process confers a selective advantage. Due to the large number of sites, the surrounding conservation greatly reduces the number of mutations and genomic polymorphisms in protein-coding regions. This trade-off between genome evolution and transcriptome plasticity highlights the importance of RNA recoding as a strategy for diversifying proteins, particularly those associated with neural function. PAPERCLIP.
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http://dx.doi.org/10.1016/j.cell.2017.03.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499236PMC
April 2017