Publications by authors named "Jeremy M Berg"

50 Publications

Cancer Yield Exceeds 2% for BI-RADS 3 Probably Benign Findings in Women Older Than 60 Years in the National Mammography Database.

Radiology 2021 Mar 30:204031. Epub 2021 Mar 30.

From the Department of Radiology, New York University Langone Medical Center, 765 Stewart Ave, Garden City, NY 11530 (C.S.L.); Departments of Computational and Systems Biology (J.M.B.) and Radiology (W.A.B.), University of Pittsburgh School of Medicine, Pittsburgh, Pa; and Magee-Womens Hospital of University of Pittsburgh Medical Center, Pittsburgh, Pa (W.A.B.).

Background Breast Imaging Reporting and Data System (BI-RADS) category 3 (BR3) (probably benign) mammographic assessments are reserved for imaging findings known to have likelihood of malignancy of 2% or less. Purpose To determine the effect of age, finding type, and prior mammography on cancer yield for BR3 findings in the National Mammography Database (NMD). Materials and Methods This HIPAA-compliant retrospective cohort institutional review board-exempt study evaluated women recalled from screening mammography followed by BR3 assessment at diagnostic evaluation from January 2009 to March 2018 and from 471 NMD facilities. Only the first BR3 occurrence was included for women with biopsy or imaging follow-up of at least 2 years. Women with a history of breast cancer or who underwent biopsy at time of initial BR3 assessment were excluded. Women were stratified by age in 10-year intervals. Cancer yield was calculated for each age group, with (for presumed new findings) and without prior mammographic comparison, and by lesion type, where available. Linear regression with weighted-age binning was performed to assess for differences between groups; < .05 was indicative of a significant difference. Results A total of 1 380 652 (18.2%) women were recalled after screening mammography, of whom 157 130 (11.4%) were given a BR3 assessment within 90 days after screening. Of these, 43 628 women (median age, 55 years; age range, 25-90 years) had adequate follow-up for analysis. Cancer yield increased with increasing age decile, ranging from 0.51% (six of 1167) in women aged 30-39 years to 4.63% (41 of 885) in women aged 80-90 years; cancer yield exceeded 2% at and after age 59.7 years for baseline findings and at and after age 53.6 years for presumed new findings, although there was no effect on stage distribution. Cancer yield for baseline BR3 masses was 10 of 2111 (0.47% [95% CI: 0.24, 0.90]) versus 47 of 3003 (1.57% [95% CI: 1.16, 2.09]) with prior comparisons ( < .001); cancer yield for baseline calcifications was eight of 929 (0.86% [95% CI: 0.40, 1.76]) versus 84 of 2999 (2.80% [95% CI: 2.23, 3.47]) with prior comparisons ( < .001). Difference in cancer yield was 0.51% (95% CI: 0.16, 0.86) between women with and women without prior comparison at the same age ( = .006). Conclusion Cancer yield exceeded the 2% threshold for women aged 60 years or older and reached 4.6% for women aged 80-89 years. Breast Imaging Reporting and Data System 3 findings in women with a prior comparison had higher cancer yield than in those without a prior comparison at the same age. © RSNA, 2021
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http://dx.doi.org/10.1148/radiol.2021204031DOI Listing
March 2021

Cancer Yield and Patterns of Follow-up for BI-RADS Category 3 after Screening Mammography Recall in the National Mammography Database.

Radiology 2020 07 19;296(1):32-41. Epub 2020 May 19.

From the Departments of Radiology (W.A.B., M.L.Z.) and Computational and Systems Biology (J.M.B.), University of Pittsburgh School of Medicine, Pittsburgh, Pa; Magee-Women's Hospital of University of Pittsburgh Medical Center, 300 Halket St, Pittsburgh, PA 15213 (W.A.B., M.L.Z.); Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, Calif (E.A.S.); Department of Radiology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, Wis (E.S.B.); Radiology Associates of Albuquerque, Albuquerque, NM (R.D.R.); and Department of Radiology, New York University Langone Medical Center, New York, NY (C.S.L.).

Background The literature supports the use of short-interval follow-up as an alternative to biopsy for lesions assessed as probably benign, Breast Imaging Reporting and Data System (BI-RADS) category 3, with an expected malignancy rate of less than 2%. Purpose To assess outcomes from 6-, 12-, and 24-month follow-up of probably benign findings first identified at recall from screening mammography in the National Mammography Database (NMD). Materials and Methods This retrospective study included women recalled from screening mammography with BI-RADS category 3 assessment at additional evaluation from January 2009 through March 2018 from 471 NMD facilities. Only the first BI-RADS category 3 occurrence for women aged 25 years or older with no personal history of breast cancer was analyzed, with biopsy or 2-year imaging follow-up. Cancer yield and positive predictive value of biopsies performed (PPV3) were determined at each follow-up. Results Among 45 202 women (median age, 55 years; range, 25-90 years) with a BI-RADS category 3 lesion, 1574 (3.5%) underwent biopsy at the time of lesion detection, yielding 72 cancers (cancer yield, 4.6%; 72 of 1574 women). For the remaining 43 628 women who accepted surveillance, 922 were seen within 90 days (with 78 lesions biopsied and 12 [15%] classified as malignant). The women still in surveillance (31 465 of 43 381 women [72.5%]) underwent follow-up mammography at 6 months. Of 3001 (9.5%) lesions biopsied, 456 (15.2%) were malignant (cancer yield, 1.5%; 456 of 31 465 women; 95% confidence interval [CI]: 1.3%, 1.6%). Among 18 748 of 25 997 women (72.1%) in surveillance who underwent follow-up at 12 months, 1219 (6.5%) underwent biopsy with 230 (18.9%) malignant lesions found (cancer yield, 1.2%; 230 of 18 748 women; 95% CI: 1.1%, 1.4%). Through 2-year follow-up, the biopsy rate was 11.2% (4894 of 43 628 women) with a cancer yield of 1.86% (810 malignancies found among 43 628 women; 95% CI: 1.73%, 1.98%) and a PPV3 of 16.6% (810 malignancies found among 4894 women). Conclusion In the National Mammography Database, Breast Imaging Reporting and Data System (BI-RADS) category 3 use is appropriate, with 1.86% cumulative cancer yield through 2-year follow-up. Of 810 malignancies, 468 (57.8%) were diagnosed at or before 6 months, validating necessity of short-interval follow-up of mammographic BI-RADS category 3 findings. © RSNA, 2020 See also the editorial by Moy in this issue.
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http://dx.doi.org/10.1148/radiol.2020192641DOI Listing
July 2020

Donald A. B. Lindberg (1933-2019).

Science 2019 Oct;366(6461):37

Editor-in-Chief, Science, Washington, DC 20005, USA.

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http://dx.doi.org/10.1126/science.aaz3644DOI Listing
October 2019

Editorial retraction.

Sci Transl Med 2017 06;9(393)

Editor.

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http://dx.doi.org/10.1126/scitranslmed.aan8388DOI Listing
June 2017

TCGA Expedition: A Data Acquisition and Management System for TCGA Data.

PLoS One 2016 27;11(10):e0165395. Epub 2016 Oct 27.

Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States of America.

Background: The Cancer Genome Atlas Project (TCGA) is a National Cancer Institute effort to profile at least 500 cases of 20 different tumor types using genomic platforms and to make these data, both raw and processed, available to all researchers. TCGA data are currently over 1.2 Petabyte in size and include whole genome sequence (WGS), whole exome sequence, methylation, RNA expression, proteomic, and clinical datasets. Publicly accessible TCGA data are released through public portals, but many challenges exist in navigating and using data obtained from these sites. We developed TCGA Expedition to support the research community focused on computational methods for cancer research. Data obtained, versioned, and archived using TCGA Expedition supports command line access at high-performance computing facilities as well as some functionality with third party tools. For a subset of TCGA data collected at University of Pittsburgh, we also re-associate TCGA data with de-identified data from the electronic health records. Here we describe the software as well as the architecture of our repository, methods for loading of TCGA data to multiple platforms, and security and regulatory controls that conform to federal best practices.

Results: TCGA Expedition software consists of a set of scripts written in Bash, Python and Java that download, extract, harmonize, version and store all TCGA data and metadata. The software generates a versioned, participant- and sample-centered, local TCGA data directory with metadata structures that directly reference the local data files as well as the original data files. The software supports flexible searches of the data via a web portal, user-centric data tracking tools, and data provenance tools. Using this software, we created a collaborative repository, the Pittsburgh Genome Resource Repository (PGRR) that enabled investigators at our institution to work with all TCGA data formats, and to interrogate these data with analysis pipelines, and associated tools. WGS data are especially challenging for individual investigators to use, due to issues with downloading, storage, and processing; having locally accessible WGS BAM files has proven invaluable.

Conclusion: Our open-source, freely available TCGA Expedition software can be used to create a local collaborative infrastructure for acquiring, managing, and analyzing TCGA data and other large public datasets.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165395PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082933PMC
June 2017

Retraction.

Authors:
Jeremy M Berg

Science 2016 10 13;354(6309):190. Epub 2016 Oct 13.

Editor-in-Chief.

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http://dx.doi.org/10.1126/science.aai9397DOI Listing
October 2016

A Perspective on Implementing a Quantitative Systems Pharmacology Platform for Drug Discovery and the Advancement of Personalized Medicine.

J Biomol Screen 2016 Jul 8;21(6):521-34. Epub 2016 Mar 8.

Department of Computational and Systems Biology, Pittsburgh, PA, USA University of Pittsburgh Drug Discovery Institute, Pittsburgh, PA, USA The University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

Drug candidates exhibiting well-defined pharmacokinetic and pharmacodynamic profiles that are otherwise safe often fail to demonstrate proof-of-concept in phase II and III trials. Innovation in drug discovery and development has been identified as a critical need for improving the efficiency of drug discovery, especially through collaborations between academia, government agencies, and industry. To address the innovation challenge, we describe a comprehensive, unbiased, integrated, and iterative quantitative systems pharmacology (QSP)-driven drug discovery and development strategy and platform that we have implemented at the University of Pittsburgh Drug Discovery Institute. Intrinsic to QSP is its integrated use of multiscale experimental and computational methods to identify mechanisms of disease progression and to test predicted therapeutic strategies likely to achieve clinical validation for appropriate subpopulations of patients. The QSP platform can address biological heterogeneity and anticipate the evolution of resistance mechanisms, which are major challenges for drug development. The implementation of this platform is dedicated to gaining an understanding of mechanism(s) of disease progression to enable the identification of novel therapeutic strategies as well as repurposing drugs. The QSP platform will help promote the paradigm shift from reactive population-based medicine to proactive personalized medicine by focusing on the patient as the starting and the end point.
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http://dx.doi.org/10.1177/1087057116635818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917453PMC
July 2016

No myth: Benefits of breast screening.

Nature 2016 Jan;529(7586):283

University of Pittsburgh, Pennsylvania, USA.

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http://dx.doi.org/10.1038/529283bDOI Listing
January 2016

Toward a sustainable biomedical research enterprise: Finding consensus and implementing recommendations.

Proc Natl Acad Sci U S A 2015 Sep 20;112(35):10832-6. Epub 2015 Jul 20.

Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.

The US research enterprise is under significant strain due to stagnant funding, an expanding workforce, and complex regulations that increase costs and slow the pace of research. In response, a number of groups have analyzed the problems and offered recommendations for resolving these issues. However, many of these recommendations lacked follow-up implementation, allowing the damage of stagnant funding and outdated policies to persist. Here, we analyze nine reports published since the beginning of 2012 and consolidate over 250 suggestions into eight consensus recommendations made by the majority of the reports. We then propose how to implement these consensus recommendations, and we identify critical issues, such as improving workforce diversity and stakeholder interactions, on which the community has yet to achieve consensus.
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http://dx.doi.org/10.1073/pnas.1509901112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568264PMC
September 2015

Research in academic medical centers: two threats to sustainable support.

Sci Transl Med 2015 May;7(289):289fs22

The Marilyn and Stanley M. Katz Dean, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Reductions in federal support and clinical revenue jeopardize biomedical research and, in turn, clinical medicine.
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http://dx.doi.org/10.1126/scitranslmed.aac5200DOI Listing
May 2015

Scientific approaches to science policy.

Authors:
Jeremy M Berg

Mol Biol Cell 2013 Nov;24(21):3273-4

Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213.

The development of robust science policy depends on use of the best available data, rigorous analysis, and inclusion of a wide range of input. While director of the National Institute of General Medical Sciences (NIGMS), I took advantage of available data and emerging tools to analyze training time distribution by new NIGMS grantees, the distribution of the number of publications as a function of total annual National Institutes of Health support per investigator, and the predictive value of peer-review scores on subsequent scientific productivity. Rigorous data analysis should be used to develop new reforms and initiatives that will help build a more sustainable American biomedical research enterprise.
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http://dx.doi.org/10.1091/mbc.E13-07-0400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814158PMC
November 2013

High priority preparedness research and its support.

J Public Health Manag Pract 2013 Sep-Oct;19 Suppl 2:S9-11

The US Federal Government has considerable interest in supporting research into preparedness. Because of the diverse nature of possible threats and the responsibilities of different agencies, a number of different programs have been developed. Perspectives from representatives from 3 of the leading agencies; the Department of Homeland Security, the Centers from Disease Control and Prevention, and the National Institutes of Health, are described herein.
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http://dx.doi.org/10.1097/PHH.0b013e3182972287DOI Listing
June 2014

Science policy: Well-funded investigators should receive extra scrutiny.

Authors:
Jeremy M Berg

Nature 2012 Sep;489(7415):203

University of Pittsburgh, Pennsylvania 15260, USA.

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http://dx.doi.org/10.1038/489203aDOI Listing
September 2012

Secondary interactions involving zinc-bound ligands: roles in structural stabilization and macromolecular interactions.

J Inorg Biochem 2012 Jun 1;111:146-9. Epub 2011 Dec 1.

Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases/NIH, Bethesda, MD 20892, United States.

A large number of proteins contain bound zinc ions. These zinc ions are frequently coordinated by a combination of histidine and cysteine residues. In addition to atoms that coordinate directly to the zinc ions, these side chains have groups that can donate or accept hydrogen bonds from other groups. These secondary interactions can help stabilize the zinc-binding sites, can contribute to protein folding and stability, and, on occasion, can participate in interactions with other macromolecules. Five examples of these secondary interactions are discussed: carbonic anhydrase (where secondary interactions involving histidine residues stabilize the zinc-binding site thermodynamically and kinetically), retroviral nucleocapsid proteins and TRAF proteins (where cysteinate sulfur to peptide NH hydrogen bonds contribute to the structural relationships between adjacent domains), and nucleic acid binding proteins, Zif268 and TIS11 where secondary interactions participate in protein-nucleic acid interactions.
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http://dx.doi.org/10.1016/j.jinorgbio.2011.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371127PMC
June 2012

Identification of nucleic acid binding residues in the FCS domain of the polycomb group protein polyhomeotic.

Biochemistry 2011 Jun 12;50(22):4998-5007. Epub 2011 May 12.

Department of Biochemistry, University of Texas Health Science Center at San Antonio, MSC 7760, San Antonio, Texas 78229-3990, United States.

Polycomb group (PcG) proteins maintain the silent state of developmentally important genes. Recent evidence indicates that noncoding RNAs also play an important role in targeting PcG proteins to chromatin and PcG-mediated chromatin organization, although the molecular basis for how PcG and RNA function in concert remains unclear. The Phe-Cys-Ser (FCS) domain, named for three consecutive residues conserved in this domain, is a 30-40-residue Zn(2+) binding motif found in a number of PcG proteins. The FCS domain has been shown to bind RNA in a non-sequence specific manner, but how it does so is not known. Here, we present the three-dimensional structure of the FCS domain from human Polyhomeotic homologue 1 (HPH1, also known as PHC1) determined using multidimensional nuclear magnetic resonance methods. Chemical shift perturbations upon addition of RNA and DNA resulted in the identification of Lys 816 as a potentially important residue required for nucleic acid binding. The role played by this residue in Polyhomeotic function was demonstrated in a transcription assay conducted in Drosophila S2 cells. Mutation of the Arg residue to Ala in the Drosophila Polyhomeotic (Ph) protein, which is equivalent to Lys 816 in HPH1, was unable to repress transcription of a reporter gene to the level of wild-type Ph. These results suggest that direct interaction between the Ph FCS domain and nucleic acids is required for Ph-mediated repression.
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http://dx.doi.org/10.1021/bi101487sDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938326PMC
June 2011

Design of single-stranded nucleic acid binding peptides based on nucleocapsid CCHC-box zinc-binding domains.

J Am Chem Soc 2010 Jul;132(28):9638-43

Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA.

The solution structures of nucleocapsid (NC)-like CCHC zinc-binding domains bound to nucleic acid targets have revealed that these domains bind guanosine residues within single-stranded nucleic acids. Here, we have performed initial studies examining the potential use of NC-like CCHC zinc-binding domains as modules to construct single-stranded nucleic acid binding peptides. The affinity for guanosine-containing single-stranded deoxyribooligonucleotides increases with the number of CCHC domains in the peptide. The length of the linker between domains affects the spacing of guanosine residues in oligonucleotides that are preferentially bound. These studies provide a proof of principle that NC-like CCHC zinc-binding domains can be utilized as a basis for designing peptides that bind specific single-stranded nucleic acid sequences.
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http://dx.doi.org/10.1021/ja910942vDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990226PMC
July 2010

Probing the DNA-binding affinity and specificity of designed zinc finger proteins.

Biophys J 2010 Mar;98(5):852-60

Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA.

Engineered transcription factors and endonucleases based on designed Cys(2)His(2) zinc finger domains have proven to be effective tools for the directed regulation and modification of genes. The introduction of this technology into both research and clinical settings necessitates the development of rapid and accurate means of evaluating both the binding affinity and binding specificity of designed zinc finger domains. Using a fluorescence anisotropy-based DNA-binding assay, we examined the DNA-binding properties of two engineered zinc finger proteins that differ by a single amino acid. We demonstrate that the protein with the highest affinity for a particular DNA site need not be the protein that binds that site with the highest degree of specificity. Moreover, by comparing the binding characteristics of the two proteins at varying salt concentrations, we show that the ionic strength makes significant and variable contributions to both affinity and specificity. These results have significant implications for zinc finger design as they highlight the importance of considering affinity, specificity, and environmental requirements in designing a DNA-binding domain for a particular application.
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http://dx.doi.org/10.1016/j.bpj.2009.11.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2830443PMC
March 2010

A proteome-wide perspective on peroxisome targeting signal 1(PTS1)-Pex5p affinities.

J Am Chem Soc 2010 Mar;132(11):3973-9

Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.

Most proteins are targeted to the peroxisomal matrix by virtue of a peroxisomal targeting signal-1 (PTS1), a short carboxy-terminal sequence specifically recognized by the PTS1 receptor Pex5p. We had previously developed a model that allowed the estimation of the affinities of many PTS1 sequences within the human proteome for Pex5p that revealed a wide range of predicted affinities. We have now experimentally determined the affinities of the PTS1-containing peptides from 42 proteins from the human proteome for Pex5p and show that these range over 4 orders of magnitude. These affinities correlate reasonably well with the predicted values and are substantially more precise. In an attempt to provide a possible explanation for the wide range of PTS1-Pex5p affinities, we compared these affinities with mRNA levels (as a proxy for rates of protein production) of the genes encoding these proteins in 79 human tissues and cell types. We note that high affinity PTS1-Pex5p interactions tend to correspond to proteins encoded by genes expressed at relatively low levels, whereas lower affinity PTS1-Pex5p interactions tend to correspond to proteins encoded by genes exhibiting higher levels and wider ranges of expression. Further analysis revealed that these relationships are consistent with the notion that a relatively uniform pool of protein-Pex5p complexes is maintained for appropriate peroxisome assembly.
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http://dx.doi.org/10.1021/ja9109049DOI Listing
March 2010

Homodimerization and heterodimerization of minimal zinc(II)-binding-domain peptides of T-cell proteins CD4, CD8alpha, and Lck.

J Am Chem Soc 2009 Aug;131(32):11492-7

Laboratory of Molecular Biology, National Institute of Diabetes, Digestive & Kidney Disorders, National Institutes of Health, Bethesda, Maryland 20892, USA.

Metal-mediated protein oligomerization is an emerging mode of protein-protein interaction. The C-terminal cytosolic domains of T-cell coreceptors CD4 and CD8alpha form zinc-bridged heterodimers with the N-terminal region of the kinase Lck, with each protein contributing two cysteinate ligands to the complex. Using size exclusion chromatography, (1)H NMR, and UV/visible absorption spectroscopy with cobalt(II) as a spectroscopic probe, we demonstrate that small peptides derived from these regions form metal-bridged heterodimers but also homodimers, in contrast to previous reports. The Lck-CD4 and Lck-CD8alpha cobalt(II)-bridged heterodimer complexes are more stable than the corresponding (Lck)(2)cobalt(II) complex by factors of 11 +/- 4 and 22 +/- 9, respectively. These studies were aided by the discovery that cobalt(II) complexes with a cobalt(II)(-Cys-X-X-Cys-)(-Cys-X-Cys-) chromophore show unusual optical spectra with one component of the visible d-d ((4)A(2)-to-(4)T(1)(P)) transition red-shifted and well separated from the other components. These results provide insights into the basis of specificity of metal-bridged complex formation and on the potential biological significance of metal-bridged homodimers in T-cells.
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http://dx.doi.org/10.1021/ja9028928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2769085PMC
August 2009

Structure and function of the sterol carrier protein-2 N-terminal presequence.

Biochemistry 2008 Jun 9;47(22):5915-34. Epub 2008 May 9.

Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, Texas 77843-4466, USA.

Although sterol carrier protein-2 (SCP-2) is encoded as a precursor protein (proSCP-2), little is known regarding the structure and function of the 20-amino acid N-terminal presequence. As shown herein, the presequence contains significant secondary structure and alters SCP-2: (i) secondary structure (CD), (ii) tertiary structure (aqueous exposure of Trp shown by UV absorbance, fluorescence, and fluorescence quenching), (iii) ligand binding site [Trp response to ligands, peptide cross-linked by photoactivatable free cholesterol (FCBP)], (iv) selectivity for interaction with anionic phospholipid-rich membranes, (v) interaction with a peroxisomal import protein [FRET studies of Pex5p(C) binding], the N-terminal presequence increased SCP-2's affinity for Pex5p(C) by 10-fold, and (vi) intracellular targeting in living and fixed cells (confocal microscopy). Nearly 5-fold more SCP-2 than proSCP-2 colocalized with plasma membrane lipid rafts and caveolae (AF488-CTB); 2.8-fold more SCP-2 than proSCP-2 colocalized with a mitochondrial marker (Mitotracker), but nearly 2-fold less SCP-2 than proSCP-2 colocalized with peroxisomes (AF488 antibody to PMP70). These data indicate the importance of the N-terminal presequence in regulating SCP-2 structure, cholesterol localization within the ligand binding site, membrane association, and, potentially, intracellular targeting.
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http://dx.doi.org/10.1021/bi800251eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2474712PMC
June 2008

[Protein structure initiative].

Tanpakushitsu Kakusan Koso 2008 Apr;53(5):655-7

National Institute of General Medical Sciences, National Institutes of Health, USA.

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April 2008

A Nobel lesson: the grant behind the prize.

Authors:
Jeremy M Berg

Science 2008 Feb;319(5865):900-1

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http://dx.doi.org/10.1126/science.319.5865.900dDOI Listing
February 2008

Update on the protein structure initiative.

Structure 2007 Dec;15(12):1519-22

NIGMS, NIH, 45 Center Drive MSC 6200, Bethesda, MD 20892-6200, USA.

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http://dx.doi.org/10.1016/j.str.2007.11.004DOI Listing
December 2007

Quantitative analysis of peroxisomal targeting signal type-1 binding to wild-type and pathogenic mutants of Pex5p supports an affinity threshold for peroxisomal protein targeting.

J Mol Biol 2007 May 12;368(5):1259-66. Epub 2007 Mar 12.

Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.

Peroxisomal biogenesis disorders (PBDs) are caused by mutations in 12 distinct genes that encode the components of the peroxisome assembly machinery. Three mutations in the gene encoding Pex5p, the peroxisomal targeting signal type-1 (PTS1) receptor, have been reported, each associated with a disorder of the Zellweger spectrum of different severity. Here, we report studies of the affinities of mutated forms of Pex5p for a series of PTS1 peptides and conclude that PTS1-affinity reductions are correlated with disease severity and cell biological phenotype. A quantitative model has been developed that allows estimation of the dissociation constants for complexes with a wide range of PTS1 sequences bound to wild-type and mutant Pex5p. In the context of this model, the binding measurements suggest that no PTS1-containing proteins are targeted by Pex5p(N489K) and only a relatively small subset of PTS1-containing proteins with the highest affinity for Pex5p are targeted to peroxisomes by Pex5p(S563W). Furthermore, the results of the analysis are consistent with an approximate dissociation constant threshold near 500 nM required for efficient protein targeting to peroxisomes.
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http://dx.doi.org/10.1016/j.jmb.2007.03.005DOI Listing
May 2007

Opportunities for chemical biologists: a view from the National Institutes of Health.

Authors:
Jeremy M Berg

ACS Chem Biol 2006 Oct;1(9):547-8

National Institute of General Medical Sciences, 45 Center Drive, 2As-12, Bethesda, Maryland 20892, USA.

The most exciting and vibrant areas of research often lie at the interfaces between disciplines that have traditionally been separate. In the case of the chemical and biological sciences, such interfaces have been fruitfully explored for more than a century. The fields of pharmacology, biochemistry, and biophysical chemistry are relatively mature, yet they are still quite active and full of challenging problems and opportunities for new discoveries. These fields are integral to biomedical research and have had a tremendous impact on human health.
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http://dx.doi.org/10.1021/cb6003993DOI Listing
October 2006

Response to: "Rescuing the NIH before it is too late".

J Clin Invest 2006 Jun;116(6):1462-3

We, the directors of the 27 NIH institutes and centers, wanted to respond to the points made by Andrew Marks in his recent editorial. While we appreciate that the scientific community has concerns, the current initiatives and directions of the NIH have been developed through planning processes that reflect openness and continued constituency input, all aimed at assessing scientific opportunities and addressing public health needs.
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http://dx.doi.org/10.1172/JCI28894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1449952PMC
June 2006

Binding of two zinc finger nuclease monomers to two specific sites is required for effective double-strand DNA cleavage.

Biochem Biophys Res Commun 2005 Sep;334(4):1191-1197

Department of Environmental Health Sciences, The Johns Hopkins University School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205-2179, USA.

Custom-designed zinc finger nucleases (ZFNs) are becoming powerful tools in gene targeting-the process of replacing a gene within a genome by homologous recombination. Here, we have studied the DNA cleavage by one such ZFN, DeltaQNK-FN, in order to gain insight into how ZFNs cleave DNA and how two inverted sites promote double-strand cleavage. DNA cleavage by DeltaQNK-FN is greatly facilitated when two DeltaQNK-binding sites are close together in an inverted orientation. Substrate cleavage was not first order with respect to the concentration of DeltaQNK-FN, indicating that double-strand cleavage requires dimerization of the FokI cleavage domain. Rates of DNA cleavage decrease as the substrate concentrations increase, suggesting that the DeltaQNK-FN molecules are effectively "trapped" in a 1:1 complex on DNA when the DNA is in excess. The physical association of two ZFN monomers on DNA was monitored by using the biotin-pull-down assay, which showed that the formation of DeltaQNK-FN active complex required both binding of the two DeltaQNK-FN molecules to specific DNA sites and divalent metal ions.
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http://dx.doi.org/10.1016/j.bbrc.2005.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4170802PMC
September 2005