Publications by authors named "Yehudit Bergman"

62 Publications

Chromosomal coordination and differential structure of asynchronous replicating regions.

Nat Commun 2021 02 15;12(1):1035. Epub 2021 Feb 15.

Department of Microbiology and Molecular Genetics, IMRIC, Hebrew University Medical School, Jerusalem, Israel.

Stochastic asynchronous replication timing (AS-RT) is a phenomenon in which the time of replication of each allele is different, and the identity of the early allele varies between cells. By taking advantage of stable clonal pre-B cell populations derived from C57BL6/Castaneous mice, we have mapped the genome-wide AS-RT loci, independently of genetic differences. These regions are characterized by differential chromatin accessibility, mono-allelic expression and include new gene families involved in specifying cell identity. By combining population level mapping with single cell FISH, our data reveal the existence of a novel regulatory program that coordinates a fixed relationship between AS-RT regions on any given chromosome, with some loci set to replicate in a parallel and others set in the anti-parallel orientation. Our results show that AS-RT is a highly regulated epigenetic mark established during early embryogenesis that may be used for facilitating the programming of mono-allelic choice throughout development.
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http://dx.doi.org/10.1038/s41467-021-21348-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884787PMC
February 2021

Metagenomic Next-Generation Sequencing of Nasopharyngeal Specimens Collected from Confirmed and Suspect COVID-19 Patients.

mBio 2020 11 20;11(6). Epub 2020 Nov 20.

Division of Medical Microbiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Metagenomic next-generation sequencing (mNGS) offers an agnostic approach for emerging pathogen detection directly from clinical specimens. In contrast to targeted methods, mNGS also provides valuable information on the composition of the microbiome and might uncover coinfections that may associate with disease progression and impact prognosis. To evaluate the use of mNGS for detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and/or other infecting pathogens, we applied direct Oxford Nanopore long-read third-generation metatranscriptomic and metagenomic sequencing. Nasopharyngeal (NP) swab specimens from 50 patients under investigation for CoV disease 2019 (COVID-19) were sequenced, and the data were analyzed by the CosmosID bioinformatics platform. Further, we characterized coinfections and the microbiome associated with a four-point severity index. SARS-CoV-2 was identified in 77.5% (31/40) of samples positive by RT-PCR, correlating with lower cycle threshold (Ct) values and fewer days from symptom onset. At the time of sampling, possible bacterial or viral coinfections were detected in 12.5% of SARS-CoV-2-positive specimens. A decrease in microbial diversity was observed among COVID-19-confirmed patients (Shannon diversity index,  = 0.0082; Chao richness estimate,  = 0.0097; Simpson diversity index,  = 0.018), and differences in microbial communities were linked to disease severity ( = 0.022). Furthermore, statistically significant shifts in the microbiome were identified among SARS-CoV-2-positive and -negative patients, in the latter of whom a higher abundance of ( = 0.028) and a reduction in the abundance of ( = 0.025) were observed. Our study corroborates the growing evidence that increased SARS-CoV-2 RNA detection from NP swabs is associated with the early stages rather than the severity of COVID-19. Further, we demonstrate that SARS-CoV-2 causes a significant change in the respiratory microbiome. This work illustrates the utility of mNGS for the detection of SARS-CoV-2, for diagnosing coinfections without viral target enrichment or amplification, and for the analysis of the respiratory microbiome. SARS-CoV-2 has presented a rapidly accelerating global public health crisis. The ability to detect and analyze viral RNA from minimally invasive patient specimens is critical to the public health response. Metagenomic next-generation sequencing (mNGS) offers an opportunity to detect SARS-CoV-2 from nasopharyngeal (NP) swabs. This approach also provides information on the composition of the respiratory microbiome and its relationship to coinfections or the presence of other organisms that may impact SARS-CoV-2 disease progression and prognosis. Here, using direct Oxford Nanopore long-read third-generation metatranscriptomic and metagenomic sequencing of NP swab specimens from 50 patients under investigation for COVID-19, we detected SARS-CoV-2 sequences by applying the CosmosID bioinformatics platform. Further, we characterized coinfections and detected a decrease in the diversity of the microbiomes in these patients. Statistically significant shifts in the microbiome were identified among COVID-19-positive and -negative patients, in the latter of whom a higher abundance of and a reduction in the abundance of were observed. Our study also corroborates the growing evidence that increased SARS-CoV-2 RNA detection from NP swabs is associated with the early stages of disease rather than with severity of disease. This work illustrates the utility of mNGS for the detection and analysis of SARS-CoV-2 from NP swabs without viral target enrichment or amplification and for the analysis of the respiratory microbiome.
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http://dx.doi.org/10.1128/mBio.01969-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686804PMC
November 2020

Cefiderocol Antimicrobial Susceptibility Testing against Multidrug-Resistant Gram-Negative Bacilli: a Comparison of Disk Diffusion to Broth Microdilution.

J Clin Microbiol 2020 Dec 17;59(1). Epub 2020 Dec 17.

Division of Medical Microbiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Antimicrobial susceptibility testing (AST) of cefiderocol poses challenges because of its unique mechanism of action (i.e., requiring an iron-depleted state) and due to differences in interpretative criteria established by the Clinical and Laboratory Standards Institute (CLSI), U.S. Food and Drug Administration (FDA), and European Committee on Antimicrobial Susceptibility Testing (EUCAST). Our objective was to compare cefiderocol disk diffusion methods (DD) to broth microdilution (BMD) for AST of Gram-negative bacilli (GNB). Cefiderocol AST was performed on consecutive carbapenem-resistant (CRE; 58 isolates) and non-glucose-fermenting GNB (50 isolates) by BMD (lyophilized panels; Sensititre; Thermo Fisher) and DD (30 μg; research-use-only [RUO] MASTDISCS and FDA-cleared HardyDisks). Results were interpreted using FDA (prior to 28 September 2020 update), EUCAST, and investigational CLSI breakpoints (BPs). Categorical agreement (CA), minor errors (mE), major errors (ME), and very major errors (VME) were calculated for DD methods. The susceptibilities of all isolates by BMD were 72% (FDA), 75% (EUCAST) and 90% (CLSI). For DD methods, EUCAST BPs demonstrated lower susceptibility at 65% and 66%, compared to 74% and 72% (FDA) and 87% and 89% (CLSI) by HardyDisks and MASTDISCS, respectively. CA ranged from 75% to 90%, with 8 to 25% mE, 0 to 19% ME, and 0 to 20% VME and varied based on disk, GNB, and BPs evaluated. Both DD methods performed poorly for complex. There is considerable variability when cefiderocol ASTs are interpreted using CLSI, FDA, and EUCAST breakpoints. DD offers a convenient alternative approach to BMD methods for cefiderocol AST, with the exception of complex isolates.
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http://dx.doi.org/10.1128/JCM.01649-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771458PMC
December 2020

Modifiable Risk Factors for the Emergence of Ceftolozane-Tazobactam Resistance.

Clin Infect Dis 2020 Sep 3. Epub 2020 Sep 3.

Johns Hopkins University School of Medicine, Department of Pathology, Division of Medical Microbiology, Baltimore, Maryland.

Background: Ceftolozane-tazobactam (TOL-TAZ) affords broad coverage against Pseudomonas aeruginosa. Regrettably, TOL-TAZ resistance has been reported. We sought to identify modifiable risk factors that may reduce the emergence of TOL-TAZ resistance.

Methods: Twenty-eight patients infected with carbapenem-resistant P. aeruginosa isolates susceptible to TOL-TAZ and treated with ≥72 hours of TOL-TAZ between January 2018 and December 2019 in Baltimore, Maryland were included. The 28 patients had P. aeruginosa isolates available both before and after TOL-TAZ exposure. Cases were defined as patients with at least a four-fold increase in P. aeruginosa TOL-TAZ MICs after exposure to TOL-TAZ. Independent risk factors for the emergence of TOL-TAZ resistance comparing cases and controls were investigated using logistic regression. Whole genome sequencing of paired isolates was used to identify mechanisms of resistance that emerged during TOL-TAZ exposure.

Results: Fourteen patients (50%) had P. aeruginosa isolates which developed high-level TOL-TAZ resistance (i.e., cases). Cases were more likely to have inadequate source control (29% vs. 0%, p=0.04) and were less likely to receive TOL-TAZ as an extended 3-hour infusion (0% vs. 29%; p=0.04). Eighty-six percent of index isolates susceptible to ceftazidime-avibactam (CAZ-AVI) had subsequent P. aeruginosa isolates with high-level resistance to CAZ-AVI, after TOL-TAZ exposure. Common mutations identified in TOL-TAZ resistant isolates involved AmpC, a known binding site for both ceftolozane and ceftazidime, and DNA polymerase.

Conclusion: Due to our small sample size, our results remain exploratory but forewarn of the potential emergence of TOL-TAZ resistance during therapy and suggest extending TOL-TAZ infusions may be protective. Larger studies are needed to investigate this association.
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http://dx.doi.org/10.1093/cid/ciaa1306DOI Listing
September 2020

Evaluation of NG-Test Carba 5 for Rapid Phenotypic Detection and Differentiation of Five Common Carbapenemase Families: Results of a Multicenter Clinical Evaluation.

J Clin Microbiol 2020 06 24;58(7). Epub 2020 Jun 24.

Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

NG-Test Carba 5 is a rapid multiplex immunoassay for the phenotypic detection and differentiation of five common carbapenemase families (KPC, OXA-48-like, VIM, IMP, and NDM) directly from bacterial colonies. The assay is simple to perform and has recently received U.S. Food and Drug Administration clearance. A method comparison study was performed at geographically diverse medical centers (= 3) in the United States, where 309 and isolates were evaluated by NG-Test Carba 5 (NG Biotech, Guipry, France), the Xpert Carba-R assay (Cepheid, Inc., Sunnyvale, CA), the modified carbapenem inactivation method (mCIM), the EDTA-modified carbapenem inactivation method, and disk diffusion with carbapenems. Colonies from tryptic soy agar with 5% sheep blood (blood agar) and MacConkey agar were tested, and the results were compared to those obtained by a composite reference method. Additionally, a fourth medical center performed a medium comparison study by evaluating the performance characteristics of NG-Test Carba 5 from blood, MacConkey, and Mueller-Hinton agars with 110 isolates of and These results were compared to the expected genotypic and mCIM results. For the multicenter method comparison study, the overall positive percent agreement (PPA) and the overall negative percent agreement (NPA) of NG-Test Carba 5 with the composite reference method were 100% for both blood and MacConkey agars. The medium comparison study at the fourth site showed that the PPA ranged from 98.9% to 100% and that the NPA ranged from 95.2% to 100% for blood, MacConkey, and Mueller-Hinton agars. NG-Test Carba 5 accurately detected and differentiated five common carbapenemase families from and colonies on commonly used agar media. The results of this test will support a streamlined laboratory work flow and will expedite therapeutic and infection control decisions.
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http://dx.doi.org/10.1128/JCM.00344-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315033PMC
June 2020

The microbiota programs DNA methylation to control intestinal homeostasis and inflammation.

Nat Microbiol 2020 04 3;5(4):610-619. Epub 2020 Feb 3.

Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.

Although much research has been done on the diversity of the gut microbiome, little is known about how it influences intestinal homeostasis under normal and pathogenic conditions. Epigenetic mechanisms have recently been suggested to operate at the interface between the microbiota and the intestinal epithelium. We performed whole-genome bisulfite sequencing on conventionally raised and germ-free mice, and discovered that exposure to commensal microbiota induced localized DNA methylation changes at regulatory elements, which are TET2/3-dependent. This culminated in the activation of a set of 'early sentinel' response genes to maintain intestinal homeostasis. Furthermore, we demonstrated that exposure to the microbiota in dextran sodium sulfate-induced acute inflammation results in profound DNA methylation and chromatin accessibility changes at regulatory elements, leading to alterations in gene expression programs enriched in colitis- and colon-cancer-associated functions. Finally, by employing genetic interventions, we show that microbiota-induced epigenetic programming is necessary for proper intestinal homeostasis in vivo.
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http://dx.doi.org/10.1038/s41564-019-0659-3DOI Listing
April 2020

Evaluation of the NG-Test MCR-1 Lateral Flow Assay and EDTA-Colistin Broth Disk Elution Methods To Detect Plasmid-Mediated Colistin Resistance among Gram-Negative Bacterial Isolates.

J Clin Microbiol 2020 03 25;58(4). Epub 2020 Mar 25.

Division of Medical Microbiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Plasmid-mediated colistin resistance (PMCR) is a global public health concern, given its ease of transmissibility. The purpose of this study was to evaluate two methods for the detection of PMCR from bacterial colonies: (i) the NG-Test MCR-1 lateral flow immunoassay (LFA; NG Biotech, Guipry, France) and (ii) the EDTA-colistin broth disk elution (EDTA-CBDE) screening test method. These methods were evaluated using a cohort of contemporary, clinical Gram-negative bacillus isolates from 3 U.S. academic medical centers (126 isolates of the , 50 isolates, and 50 species isolates; 1 isolate was positive) and 12 -positive CDC-FDA Antibiotic Resistance (AR) Isolate Bank isolates for which reference broth microdilution colistin susceptibility results were available. Eleven (4.6%) isolates were strongly positive by the MCR-1 LFA, with an additional 8 (3.4%) isolates yielding faintly positive results. The positive percent agreement (PPA) and negative percent agreement (NPA) for MCR-1 detection were 100% and 96.1%, respectively. Upon repeat testing, only a single false-positive MCR-2 producer remained, as the isolates with initially faintly positive results were negative. The EDTA-CBDE screening method had an overall PPA and NPA of 100% and 94.3%, respectively. The NPA for the EDTA-CBDE method was slightly lower at 94.2% with , whereas it was 96.0% with The MCR-1 LFA and EDTA-CBDE methods are both accurate and user-friendly methods for the detection of PMCR. Despite the rarity of PMCR among clinical isolates in the United States, these methods are valuable tools that may be implemented in public health and clinical microbiology laboratories to further discern the mechanism of resistance among colistin-resistant Gram-negative isolates and to detect PMCR for infection prevention and control purposes.
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http://dx.doi.org/10.1128/JCM.01823-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098752PMC
March 2020

Multicenter Evaluation of Colistin Broth Disk Elution and Colistin Agar Test: a Report from the Clinical and Laboratory Standards Institute.

J Clin Microbiol 2019 11 23;57(11). Epub 2019 Oct 23.

Division of Medical Microbiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Susceptibility testing of the polymyxins (colistin and polymyxin B) is challenging for clinical laboratories. The Clinical and Laboratory Standards Institute (CLSI) Antimicrobial Susceptibility Testing Subcommittee evaluated two methods to enable accurate testing of these agents. These methods were a colistin broth disk elution (CBDE) and a colistin agar test (CAT), the latter of which was evaluated using two inoculum volumes, 1 μl (CAT-1) and 10 μl (CAT-10). The methods were evaluated using a collection of 270 isolates of , 122 isolates, and 106 spp. isolates. Overall, 94.4% of CBDE results were in essential agreement and 97.9% in categorical agreement (CA) with reference broth microdilution MICs. Nine very major errors (VME; 3.2%) and 3 major errors (ME; 0.9%) were observed. With the CBDE, 98.6% CA was observed for (2.5% VME, 0% ME), 99.3% CA was observed for (0% VME, 0.7% ME), and 93.1% CA was observed for spp. (5.6% VME, 3.3% ME). Overall, CA was 94.9% with 6.8% VME using CAT-1 and improved to 98.3% with 3.9% VME using CAT-10. No ME were observed using either CAT-1 or CAT-10. Using the CAT-1/CAT-10, the CA observed was 99.4%/99.7% for (1%/0.5% VME), 98.7%/100% for (8.3%/0% VME), and 88.5%/92.3% for spp. (21.4%/14.3% VME). Based on these data, the CLSI antimicrobial susceptibility testing (AST) subcommittee endorsed the CBDE and CAT-10 methods for colistin testing of and .
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http://dx.doi.org/10.1128/JCM.01269-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813006PMC
November 2019

Imported Cases of Extensively Drug-Resistant Salmonella.

Pediatr Infect Dis J 2019 12;38(12):e340

Division of Medical Microbiology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland Division of Pediatric Infectious Diseases, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1097/INF.0000000000002450DOI Listing
December 2019

Determining gestational age using genome methylation profile: A novel approach for fetal medicine.

Prenat Diagn 2019 10 12;39(11):1005-1010. Epub 2019 Aug 12.

Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.

Gestational age determination by traditional tools (last menstrual period, ultrasonography measurements and Ballard Maturational Assessment in newborns) has major limitations and therefore there is a need to find different approaches. In this study, we looked for a molecular marker that can be used to determine the accurate gestational age of the newborn. To this end, we performed reduced representation bisulfite sequencing (RRBS) on 41 cord blood and matching placenta samples from women between 25 and 40 weeks of gestation and generated an epigenetic clock based on the methylation level at different loci in the genome. We identified a set of 332 differentially methylated regions (DMRs) that undergo demethylation in late gestational age in cord blood cells and can predict the gestational age (r = -.7, P = 2E-05). Once the set of 411 DMRs that undergo de novo methylation in late gestational age was used in combination with the first set, it generated a more accurate clock (R = .77, P = 1.87E-05). We have compared gestational age determined by Ballard score assessment with our epigenetic clock and found high concordance. Taken together, this study demonstrates that DNA methylation can accurately predict gestational age and thus may serve as a good clinical predictor.
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http://dx.doi.org/10.1002/pd.5535DOI Listing
October 2019

The Likelihood of Developing a Carbapenem-Resistant Infection during a Hospital Stay.

Antimicrob Agents Chemother 2019 08 25;63(8). Epub 2019 Jul 25.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Of 1,455 unique patients in U.S. intensive care units (ICUs), 4% were rectally colonized with CRE on admission. A total of 297 patients were initially negative for carbapenem-resistant (CRE) and remained in the ICU long enough to contribute additional swabs; 22% of these patients had a subsequent CRE-positive swab, with a median time to CRE colonization of 13 days (interquartile range, 7 to 21 days). Patients colonized with carbapenemase-producing CRE were more likely than those colonized with non-carbapenemase-producing CRE to develop CRE infections during their hospitalizations (36% versus 3%; < 0.05).
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http://dx.doi.org/10.1128/AAC.00757-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658786PMC
August 2019

Lysyl oxidase-like 2 depletion is protective in age-associated vascular stiffening.

Am J Physiol Heart Circ Physiol 2019 07 19;317(1):H49-H59. Epub 2019 Apr 19.

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University , Baltimore, Maryland.

Vascular stiffening and its sequelae are major causes of morbidity and mortality in the elderly. The increasingly accepted concept of "smooth muscle cell (SMC) stiffness syndrome" along with matrix deposition has emerged in vascular biology to account for the mechanical phenotype of arterial aging, but the molecular targets remain elusive. In this study, using an unbiased proteomic analysis, we identified lysyl oxidase-like 2 (LOXL2) as a critical SMC mediator for age-associated vascular stiffening. We tested the hypothesis that loss of LOXL2 function is protective in aging-associated vascular stiffening. We determined that exogenous and endogenous nitric oxide markedly decreased LOXL2 abundance and activity in the extracellular matrix of isolated SMCs and LOXL2 endothelial cells suppress LOXL2 abundance in the aorta. In a longitudinal study, LOXL2 mice were protected from age-associated increase in pulse-wave velocity, an index of vascular stiffening, as occurred in littermate wild-type mice. Using isolated aortic segments, we found that LOXL2 mediates vascular stiffening in aging by promoting SMC stiffness, augmented SMC contractility, and vascular matrix deposition. Together, these studies establish LOXL2 as a nodal point for a new therapeutic approach to treat age-associated vascular stiffening. Increased central vascular stiffness augments risk of major adverse cardiovascular events. Despite significant advances in understanding the genetic and molecular underpinnings of vascular stiffening, targeted therapy has remained elusive. Here, we show that lysyl oxidase-like 2 (LOXL2) drives vascular stiffening during aging by promoting matrix remodeling and vascular smooth muscle cell stiffening. Reduced LOXL2 expression protects mice from age-associated vascular stiffening and delays the onset of isolated systolic hypertension, a major consequence of stiffening.
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http://dx.doi.org/10.1152/ajpheart.00670.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692735PMC
July 2019

A Novel Phenotypic Method To Screen for Plasmid-Mediated Colistin Resistance among .

J Clin Microbiol 2019 05 26;57(5). Epub 2019 Apr 26.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Plasmid-mediated colistin resistance (PMCR), a consequence of the genes, is a significant public health concern given its potential to easily spread among clinical pathogens. Recently, it was discovered that MCR enzymes require zinc for activity. Thus, we modified the colistin broth-disk elution (CBDE) test to screen for plasmid-mediated colistin resistance (PMCR) genes based on any reduction of colistin MIC in the presence of EDTA. Eighty-five isolates of the order (12 positive) were tested by CBDE ± EDTA. The sensitivity and specificity of the EDTA-CBDE method to detect PMCR compared to the molecular genotype results were 100% and 95.8%, respectively. Isolates positive by the EDTA-CBDE test should be further evaluated to confirm the presence of genes.
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http://dx.doi.org/10.1128/JCM.00040-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498019PMC
May 2019

Applying Rapid Whole-Genome Sequencing To Predict Phenotypic Antimicrobial Susceptibility Testing Results among Carbapenem-Resistant Klebsiella pneumoniae Clinical Isolates.

Antimicrob Agents Chemother 2019 01 21;63(1). Epub 2018 Dec 21.

Johns Hopkins University School of Medicine, Department of Pathology, Division of Medical Microbiology, Baltimore, Maryland, USA

Standard antimicrobial susceptibility testing (AST) approaches lead to delays in the selection of optimal antimicrobial therapy. Here, we sought to determine the accuracy of antimicrobial resistance (AMR) determinants identified by Nanopore whole-genome sequencing in predicting AST results. Using a cohort of 40 clinical isolates (21 carbapenemase-producing carbapenem-resistant , 10 non-carbapenemase-producing carbapenem-resistant , and 9 carbapenem-susceptible isolates), three separate sequencing and analysis pipelines were performed, as follows: (i) a real-time Nanopore analysis approach identifying acquired AMR genes, (ii) an assembly-based Nanopore approach identifying acquired AMR genes and chromosomal mutations, and (iii) an approach using short-read correction of Nanopore assemblies. The short-read correction of Nanopore assemblies served as the reference standard to determine the accuracy of Nanopore sequencing results. With the real-time analysis approach, full annotation of acquired AMR genes occurred within 8 h from subcultured isolates. Assemblies sufficient for full resistance gene and single-nucleotide polymorphism annotation were available within 14 h from subcultured isolates. The overall agreement of genotypic results and anticipated AST results for the 40  isolates was 77% (range, 30% to 100%) and 92% (range, 80% to 100%) for the real-time approach and the assembly approach, respectively. Evaluating the patients contributing the 40 isolates, the real-time approach and assembly approach could shorten the median time to effective antibiotic therapy by 20 h and 26 h, respectively, compared to standard AST. Nanopore sequencing offers a rapid approach to both accurately identify resistance mechanisms and to predict AST results for isolates. Bioinformatics improvements enabling real-time alignment, coupled with rapid extraction and library preparation, will further enhance the accuracy and workflow of the Nanopore real-time approach.
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http://dx.doi.org/10.1128/AAC.01923-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325187PMC
January 2019

Two-Site Evaluation of the Colistin Broth Disk Elution Test To Determine Colistin Activity against Gram-Negative Bacilli.

J Clin Microbiol 2019 02 30;57(2). Epub 2019 Jan 30.

Department of Pathology and Laboratory Medicine, UCLA Health, Los Angeles, California, USA.

Limited methods for colistin MIC determination are available to clinical microbiology laboratories. The purpose of this study was to evaluate the accuracy of the colistin broth disk elution (CBDE) test compared to that of broth microdilution (BMD) for identifying colistin MICs. CBDE was compared to colistin BMD using a collection of Gram-negative bacilli tested at two U.S. microbiology laboratories. The isolates tested included 121 retrospective clinical isolates, 45 prospective clinical isolates, and 6 -positive isolates. CBDE was performed with four 10-ml cation-adjusted Mueller-Hinton broth tubes per isolate, to which 0, 1, 2, and 4 colistin 10-µg disks were added, generating final concentrations in the tubes of 0 (growth control), 1, 2, and 4 µg/ml, respectively. MICs were evaluated visually and interpreted using Clinical and Laboratory Standards Institute breakpoints. Site 2 also compared CBDE to the reference broth macrodilution (BMAD) method ( = 110 isolates). Overall, CBDE yielded a categorical agreement (CA) and essential agreement (EA) of 98% and 99%, respectively, compared to the results of colistin BMD. Very major errors occurred for -producing strains, with MICs fluctuating from 2 to 4 µg/ml on repeat testing. The results for all other isolates were in CA with those of BMD. CBDE versus BMAD had an EA of 100% and a CA of 100%. Compared to currently used techniques, CBDE is an easy and practical method to perform colistin MIC testing. Some -producing isolates yielded MICs of 2 µg/ml by CBDE and 4 µg/ml by BMD. As such, the results for isolates with colistin MICs of 2 µg/ml by CBDE should be confirmed by the reference BMD method, and isolates with MICs of ≥2 µg/ml should be evaluated for the presence of genes.
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http://dx.doi.org/10.1128/JCM.01163-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355542PMC
February 2019

Neutralizing Gatad2a-Chd4-Mbd3/NuRD Complex Facilitates Deterministic Induction of Naive Pluripotency.

Cell Stem Cell 2018 09 16;23(3):412-425.e10. Epub 2018 Aug 16.

Department of Molecular Genetics, Weizmann Institute of Science, 234 Herzl, Rehovot 76100, Israel. Electronic address:

Mbd3, a member of nucleosome remodeling and deacetylase (NuRD) co-repressor complex, was previously identified as an inhibitor for deterministic induced pluripotent stem cell (iPSC) reprogramming, where up to 100% of donor cells successfully complete the process. NuRD can assume multiple mutually exclusive conformations, and it remains unclear whether this deterministic phenotype can be attributed to a specific Mbd3/NuRD subcomplex. Moreover, since complete ablation of Mbd3 blocks somatic cell proliferation, we aimed to explore functionally relevant alternative ways to neutralize Mbd3-dependent NuRD activity. We identify Gatad2a, a NuRD-specific subunit, whose complete deletion specifically disrupts Mbd3/NuRD repressive activity on the pluripotency circuitry during iPSC differentiation and reprogramming without ablating somatic cell proliferation. Inhibition of Gatad2a facilitates deterministic murine iPSC reprogramming within 8 days. We validate a distinct molecular axis, Gatad2a-Chd4-Mbd3, within Mbd3/NuRD as being critical for blocking reestablishment of naive pluripotency and further highlight signaling-dependent and post-translational modifications of Mbd3/NuRD that influence its interactions and assembly.
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http://dx.doi.org/10.1016/j.stem.2018.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116536PMC
September 2018

Cell-of-Origin DNA Methylation Signatures Are Maintained during Colorectal Carcinogenesis.

Cell Rep 2018 06;23(11):3407-3418

Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, 69120 Heidelberg, Germany. Electronic address:

Colorectal adenomas are precursor lesions of colorectal cancers and represent clonal amplifications of single cells from colonic crypts. DNA methylation patterns specify cell-type identity during cellular differentiation and, therefore, provide opportunities for the molecular analysis of tumors. We have now analyzed DNA methylation patterns in colorectal adenomas and identified three biologically defined subclasses that describe different intestinal crypt differentiation stages. Importantly, colorectal carcinomas could be classified into the same methylation subtypes, reflecting their shared cell types of origin with adenomas. Further data analysis also revealed significantly reduced overall survival for one of the subtypes. Our results provide a concept for understanding the methylation patterns observed in colorectal cancer and provide opportunities for tumor subclassification and patient stratification.
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http://dx.doi.org/10.1016/j.celrep.2018.05.045DOI Listing
June 2018

Global Effects of DDX3 Inhibition on Cell Cycle Regulation Identified by a Combined Phosphoproteomics and Single Cell Tracking Approach.

Transl Oncol 2018 Jun 24;11(3):755-763. Epub 2018 Apr 24.

Department of Radiology and Radiological Sciences, Johns Hopkins University, School of Medicine, Baltimore, MD, USA; Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Oncology, Johns Hopkins University, School of Medicine, Baltimore, MD, USA. Electronic address:

DDX3 is an RNA helicase with oncogenic properties. The small molecule inhibitor RK-33 is designed to fit into the ATP binding cleft of DDX3 and hereby block its activity. RK-33 has shown potent activity in preclinical cancer models. However, the mechanism behind the antineoplastic activity of RK-33 remains largely unknown. In this study we used a dual phosphoproteomic and single cell tracking approach to evaluate the effect of RK-33 on cancer cells. MDA-MB-435 cells were treated for 24 hours with RK-33 or vehicle control. Changes in phosphopeptide abundance were analyzed with quantitative mass spectrometry using isobaric mass tags (Tandem Mass Tags). At the proteome level we mainly observed changes in mitochondrial translation, cell division pathways and proteins related to cell cycle progression. Analysis of the phosphoproteome indicated decreased CDK1 activity after RK-33 treatment. To further evaluate the effect of DDX3 inhibition on cell cycle progression over time, we performed timelapse microscopy of Fluorescent Ubiquitin Cell Cycle Indicators labeled cells after RK-33 or siDDX3 exposure. Single cell tracking indicated that DDX3 inhibition resulted in a global delay in cell cycle progression in interphase and mitosis. In addition, we observed an increase in endoreduplication. Overall, we conclude that DDX3 inhibition affects cells in all phases and causes a global cell cycle progression delay.
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http://dx.doi.org/10.1016/j.tranon.2018.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050443PMC
June 2018

Successful Treatment of Persistent Burkholderia cepacia Complex Bacteremia with Ceftazidime-Avibactam.

Antimicrob Agents Chemother 2018 04 27;62(4). Epub 2018 Mar 27.

Division of Infectious Diseases, University of Texas Southwestern, Dallas, Texas, USA

We report our clinical experience treating a 2-month-old infant with congenital diaphragmatic hernia who experienced prolonged bacteremia with complex (Bcc) despite conventional antibiotic therapy and appropriate source control measures. The infection resolved after initiation of ceftazidime-avibactam. Whole-genome sequencing revealed that the isolate most closely resembled and identified the mechanism of resistance that likely contributed to clinical cure with this agent. Ceftazidime-avibactam should be considered salvage therapy for Bcc infections if other treatment options have been exhausted.
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http://dx.doi.org/10.1128/AAC.02213-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913954PMC
April 2018

Programming asynchronous replication in stem cells.

Nat Struct Mol Biol 2017 Dec 13;24(12):1132-1138. Epub 2017 Nov 13.

Department of Developmental Biology and Cancer Research, Hebrew University Medical School, Jerusalem, Israel.

Many regions of the genome replicate asynchronously and are expressed monoallelically. It is thought that asynchronous replication may be involved in choosing one allele over the other, but little is known about how these patterns are established during development. We show that, unlike somatic cells, which replicate in a clonal manner, embryonic and adult stem cells are programmed to undergo switching, such that daughter cells with an early-replicating paternal allele are derived from mother cells that have a late-replicating paternal allele. Furthermore, using ground-state embryonic stem (ES) cells, we demonstrate that in the initial transition to asynchronous replication, it is always the paternal allele that is chosen to replicate early, suggesting that primary allelic choice is directed by preset gametic DNA markers. Taken together, these studies help define a basic general strategy for establishing allelic discrimination and generating allelic diversity throughout the organism.
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http://dx.doi.org/10.1038/nsmb.3503DOI Listing
December 2017

Clonally stable Vκ allelic choice instructs Igκ repertoire.

Nat Commun 2017 05 30;8:15575. Epub 2017 May 30.

Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem 91120, Israel.

Although much has been done to understand how rearrangement of the Igκ locus is regulated during B-cell development, little is known about the way the variable (V) segments themselves are selected. Here we show, using B6/Cast hybrid pre-B-cell clones, that a limited number of V segments on each allele is stochastically activated as characterized by the appearance of non-coding RNA and histone modifications. The activation states are clonally distinct, stable across cell division and developmentally important in directing the Ig repertoire upon differentiation. Using a new approach of allelic ATAC-seq, we demonstrate that the Igκ V alleles have differential chromatin accessibility, which may serve as the underlying basis of clonal maintenance at this locus, as well as other instances of monoallelic expression throughout the genome. These findings highlight a new level of immune system regulation that optimizes gene diversity.
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http://dx.doi.org/10.1038/ncomms15575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459994PMC
May 2017

Tissue Transglutaminase Modulates Vascular Stiffness and Function Through Crosslinking-Dependent and Crosslinking-Independent Functions.

J Am Heart Assoc 2017 02 3;6(2). Epub 2017 Feb 3.

Department of Anesthesiology & Critical Care Medicine, Johns Hopkins University, Baltimore, MD

Background: The structural elements of the vascular wall, namely, extracellular matrix and smooth muscle cells (SMCs), contribute to the overall stiffness of the vessel. In this study, we examined the crosslinking-dependent and crosslinking-independent roles of tissue transglutaminase (TG2) in vascular function and stiffness.

Methods And Results: SMCs were isolated from the aortae of TG2-/- and wild-type (WT) mice. Cell adhesion was examined by using electrical cell-substrate impedance sensing and PicoGreen assay. Cell motility was examined using a Boyden chamber assay. Cell proliferation was examined by electrical cell-substrate impedance sensing and EdU incorporation assays. Cell micromechanics were studied using magnetic torsion cytometry and spontaneous nanobead tracer motions. Aortic mechanics were examined by tensile testing. Vasoreactivity was studied by wire myography. SMCs from TG2-/- mice had delayed adhesion, reduced motility, and accelerated de-adhesion and proliferation rates compared with those from WT. TG2-/- SMCs were stiffer and displayed fewer cytoskeletal remodeling events than WT. Collagen assembly was delayed in TG2-/- SMCs and recovered with adenoviral transduction of TG2. Aortic rings from TG2-/- mice were less stiff than those from WT; stiffness was partly recovered by incubation with guinea pig liver TG2 independent of crosslinking function. TG2-/- rings showed augmented response to phenylephrine-mediated vasoconstriction when compared with WT. In human coronary arteries, vascular media and plaque, high abundance of fibronectin expression, and colocalization with TG2 were observed.

Conclusions: TG2 modulates vascular function/tone by altering SMC contractility independent of its crosslinking function and contributes to vascular stiffness by regulating SMC proliferation and matrix remodeling.
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http://dx.doi.org/10.1161/JAHA.116.004161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5523743PMC
February 2017

Genomic pathways modulated by Twist in breast cancer.

BMC Cancer 2017 01 13;17(1):52. Epub 2017 Jan 13.

Division of Cancer Imaging Research, Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

Background: The basic helix-loop-helix transcription factor TWIST1 (Twist) is involved in embryonic cell lineage determination and mesodermal differentiation. There is evidence to indicate that Twist expression plays a role in breast tumor formation and metastasis, but the role of Twist in dysregulating pathways that drive the metastatic cascade is unclear. Moreover, many of the genes and pathways dysregulated by Twist in cell lines and mouse models have not been validated against data obtained from larger, independant datasets of breast cancer patients.

Methods: We over-expressed the human Twist gene in non-metastatic MCF-7 breast cancer cells to generate the estrogen-independent metastatic breast cancer cell line MCF-7/Twist. These cells were inoculated in the mammary fat pad of female severe compromised immunodeficient mice, which subsequently formed xenograft tumors that metastasized to the lungs. Microarray data was collected from both in vitro (MCF-7 and MCF-7/Twist cell lines) and in vivo (primary tumors and lung metastases) models of Twist expression. Our data was compared to several gene datasets of various subtypes, classes, and grades of human breast cancers.

Results: Our data establishes a Twist over-expressing mouse model of breast cancer, which metastasizes to the lung and replicates some of the ontogeny of human breast cancer progression. Gene profiling data, following Twist expression, exhibited novel metastasis driver genes as well as cellular maintenance genes that were synonymous with the metastatic process. We demonstrated that the genes and pathways altered in the transgenic cell line and metastatic animal models parallel many of the dysregulated gene pathways observed in human breast cancers.

Conclusions: Analogous gene expression patterns were observed in both in vitro and in vivo Twist preclinical models of breast cancer metastasis and breast cancer patient datasets supporting the functional role of Twist in promoting breast cancer metastasis. The data suggests that genetic dysregulation of Twist at the cellular level drives alterations in gene pathways in the Twist metastatic mouse model which are comparable to changes seen in human breast cancers. Lastly, we have identified novel genes and pathways that could be further investigated as targets for drugs to treat metastatic breast cancer.
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http://dx.doi.org/10.1186/s12885-016-3033-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237254PMC
January 2017

Tissue-specific DNA demethylation is required for proper B-cell differentiation and function.

Proc Natl Acad Sci U S A 2016 May 18;113(18):5018-23. Epub 2016 Apr 18.

Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel 91120;

There is ample evidence that somatic cell differentiation during development is accompanied by extensive DNA demethylation of specific sites that vary between cell types. Although the mechanism of this process has not yet been elucidated, it is likely to involve the conversion of 5mC to 5hmC by Tet enzymes. We show that a Tet2/Tet3 conditional knockout at early stages of B-cell development largely prevents lineage-specific programmed demethylation events. This lack of demethylation affects the expression of nearby B-cell lineage genes by impairing enhancer activity, thus causing defects in B-cell differentiation and function. Thus, tissue-specific DNA demethylation appears to be necessary for proper somatic cell development in vivo.
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http://dx.doi.org/10.1073/pnas.1604365113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983829PMC
May 2016

Embryonic Stem Cell (ES)-Specific Enhancers Specify the Expression Potential of ES Genes in Cancer.

PLoS Genet 2016 Feb 17;12(2):e1005840. Epub 2016 Feb 17.

Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.

Cancers often display gene expression profiles resembling those of undifferentiated cells. The mechanisms controlling these expression programs have yet to be identified. Exploring transcriptional enhancers throughout hematopoietic cell development and derived cancers, we uncovered a novel class of regulatory epigenetic mutations. These epimutations are particularly enriched in a group of enhancers, designated ES-specific enhancers (ESSEs) of the hematopoietic cell lineage. We found that hematopoietic ESSEs are prone to DNA methylation changes, indicative of their chromatin activity states. Strikingly, ESSE methylation is associated with gene transcriptional activity in cancer. Methylated ESSEs are hypermethylated in cancer relative to normal somatic cells and co-localized with silenced genes, whereas unmethylated ESSEs tend to be hypomethylated in cancer and associated with reactivated genes. Constitutive or hematopoietic stem cell-specific enhancers do not show these trends, suggesting selective reactivation of ESSEs in cancer. Further analyses of a hypomethylated ESSE downstream to the VEGFA gene revealed a novel regulatory circuit affecting VEGFA transcript levels across cancers and patients. We suggest that the discovered enhancer sites provide a framework for reactivation of ES genes in cancer.
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http://dx.doi.org/10.1371/journal.pgen.1005840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757527PMC
February 2016

MPST but not CSE is the primary regulator of hydrogen sulfide production and function in the coronary artery.

Am J Physiol Heart Circ Physiol 2016 Jan 30;310(1):H71-9. Epub 2015 Oct 30.

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland;

Hydrogen sulfide (H2S) has emerged as an important gasotransmitter in the vasculature. In this study, we tested the hypothesis that H2S contributes to coronary vasoregulation and evaluated the physiological relevance of two sources of H2S, namely, cystathionine-γ-lyase (CSE) and 3-mercaptypyruvate sulfertransferase (MPST). MPST was detected in human coronary artery endothelial cells as well as rat and mouse coronary artery; CSE was not detected in the coronary vasculature. Rat coronary artery homogenates produced H2S through the MPST pathway but not the CSE pathway in vitro. In vivo coronary vasorelaxation response was similar in CSE knockout mice, wild-type mice (WT), and WT mice treated with the CSE inhibitor propargylglycine, suggesting that CSE-produced H2S does not have a significant role in coronary vasoregulation in vivo. Ex vivo, the MPST substrate 3-mercaptopyruvate (3-MP) and H2S donor sodium hydrosulfide (NaHS) elicited similar coronary vasoreactivity responses. Pyruvate did not have any effects on vasoreactivity. The vasoactive effect of H2S appeared to be nitric oxide (NO) dependent: H2S induced coronary vasoconstriction in the presence of NO and vasorelaxation in its absence. Maximal endothelial-dependent relaxation was intact after 3-MP and NaHS induced an increase in preconstriction tone, suggesting that endothelial NO synthase activity was not significantly inhibited. In vitro, H2S reacted with NO, which may, in part explain the vasoconstrictive effects of 3-MP and NaHS. Taken together, these data show that MPST rather than CSE generates H2S in coronary artery, mediating its effects through direct modulation of NO. This has important implications for H2S-based therapy in healthy and diseased coronary arteries.
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http://dx.doi.org/10.1152/ajpheart.00574.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4796461PMC
January 2016

NZ51, a ring-expanded nucleoside analog, inhibits motility and viability of breast cancer cells by targeting the RNA helicase DDX3.

Oncotarget 2015 Oct;6(30):29901-13

Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

DDX3X (DDX3), a human RNA helicase, is over expressed in multiple breast cancer cell lines and its expression levels are directly correlated to cellular aggressiveness. NZ51, a ring-expanded nucleoside analogue (REN) has been reported to inhibit the ATP dependent helicase activity of DDX3. Molecular modeling of NZ51 binding to DDX3 indicated that the 5:7-fused imidazodiazepine ring of NZ51 was incorporated into the ATP binding pocket of DDX3. In this study, we investigated the anticancer properties of NZ51 in MCF-7 and MDA-MB-231 breast cancer cell lines. NZ51 treatment decreased cellular motility and cell viability of MCF-7 and MDA-MB-231 cells with IC50 values in the low micromolar range. Biological knockdown of DDX3 in MCF-7 and MDA-MB-231 cells resulted in decreased proliferation rates and reduced clonogenicity. In addition, NZ51 was effective in killing breast cancer cells under hypoxic conditions with the same potency as observed during normoxia. Mechanistic studies indicated that NZ51 did not cause DDX3 degradation, but greatly diminished its functionality. Moreover, in vivo experiments demonstrated that DDX3 knockdown by shRNA resulted in reduced tumor volume and metastasis without altering tumor vascular volume or permeability-surface area. In initial in vivo experiments, NZ51 treatment did not significantly reduce tumor volume. Further studies are needed to optimize drug formulation, dose and delivery. Continuing work will determine the in vitro-in vivo correlation of NZ51 activity and its utility in a clinical setting.
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http://dx.doi.org/10.18632/oncotarget.4898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4745771PMC
October 2015

Rejuvenating effect of pregnancy on the mother.

Fertil Steril 2015 May 23;103(5):1125-8. Epub 2015 Mar 23.

Rubin Chair in Medical Science, Department of Developmental Biology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel; Department of Obstetrics and Gynecology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. Electronic address:

Aging is associated with reduced tissue regenerative capacity. In recent years, studies in mice have shown that transfusion of blood from young animals to old ones can reverse some aging effects and increase regenerative potential similar to that seen in young animals. Because pregnancy is a unique biological model of a partially shared blood system, we have speculated that pregnancy would have a rejuvenating effect on the mother. Recent studies support this idea. In this review, we will summarize the current knowledge of the rejuvenating effect of pregnancy on the mother.
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http://dx.doi.org/10.1016/j.fertnstert.2015.02.034DOI Listing
May 2015

Chronic inflammation induces a novel epigenetic program that is conserved in intestinal adenomas and in colorectal cancer.

Cancer Res 2015 May 25;75(10):2120-30. Epub 2015 Mar 25.

Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.

Chronic inflammation represents a major risk factor for tumor formation, but the underlying mechanisms have remained largely unknown. Epigenetic mechanisms can record the effects of environmental challenges on the genome level and could therefore play an important role in the pathogenesis of inflammation-associated tumors. Using single-base methylation maps and transcriptome analyses of a colitis-induced mouse colon cancer model, we identified a novel epigenetic program that is characterized by hypermethylation of DNA methylation valleys that are characterized by low CpG density and active chromatin marks. This program is conserved and functional in mouse intestinal adenomas and results in silencing of active intestinal genes that are involved in gastrointestinal homeostasis and injury response. Further analyses reveal that the program represents a prominent feature of human colorectal cancer and can be used to correctly classify colorectal cancer samples with high accuracy. Together, our results show that inflammatory signals establish a novel epigenetic program that silences a specific set of genes that contribute to inflammation-induced cellular transformation.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-3295DOI Listing
May 2015

The rejuvenating effect of pregnancy on muscle regeneration.

Aging Cell 2015 Aug 13;14(4):698-700. Epub 2015 Mar 13.

Rubin Chair in Medical Science, Department of Developmental Biology & Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, 91120, Jerusalem, Israel.

Aging is characterized by reduced tissue regenerative capacity attributed to a diminished responsiveness of tissue-specific stem cells. With increasing age, resident precursor cells in muscle tissues show a markedly impaired propensity to proliferate in response to damage. However, exposure to factors present in the serum of young mice restores the regenerative capacity of aged precursor cells. As pregnancy represents a unique biological model of a partially shared blood system between young and old organisms, we hypothesized that pregnancy in aged mice would have a rejuvenating effect on the mother. To test this hypothesis, we assessed muscle regeneration in response to injury in young and aged pregnant and nonpregnant mice. Muscle regeneration in the aged pregnant mice was improved relative to that in age-matched nonpregnant mice. The beneficial effect of pregnancy was transient, lasting up to 2 months after delivery, and appeared to be attributable to activation of satellite cells via the Notch signaling pathway, thus supporting the possibility that pregnancy induces activation of aged dormant muscle progenitor cells.
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http://dx.doi.org/10.1111/acel.12286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4531083PMC
August 2015