Charles W. O'Donnell's research while affiliated with Massachusetts Institute of Technology and other places

Publications (32)

Article
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The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin struct...
Article
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The Encylopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms...
Article
Full-text available
HLA-G, a nonclassical HLA molecule uniquely expressed in the placenta, is a central component of fetus-induced immune tolerance during pregnancy. The tissue-specific expression of HLA-G, however, remains poorly understood. Here, systematic interrogation of theHLA-Glocus using massively parallel reporter assay (MPRA) uncovered a previously unidentif...
Poster
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During pregnancy, semi-allogeneic fetal extravillous trophoblasts (EVT) invade the uterine mucosa without eliciting rejection by the maternal immune cells present at the fetal-maternal interface. EVT uniquely express HLA-G, a nonclassical MHC class I molecule believed to be paramount to induce immune tolerance. However, how the trophoblast-specific...
Conference Paper
Full-text available
Human pregnancy poses an immunological paradox: at the fetal-maternal interface, semi-allogeneic fetal extravillous trophoblasts (EVT) invade the uterine mucosa without being rejected by the maternal immune system. HLA-G is a nonclassical MHC class I molecule specifically expressed on the surface of EVT and is believed to be a key to fetus-induced...
Article
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Transcriptional profiling is a key technique in the study of cell biology that is limited by the availability of reagents to uniquely identify specific cell types and isolate high quality RNA from them. We report a Method for Analyzing RNA following Intracellular Sorting (MARIS) that generates high quality RNA for transcriptome profiling following...
Article
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Human pluripotent stem cells (hPSCs) have the potential to generate any human cell type, and one widely recognized goal is to make pancreatic β cells. To this end, comparisons between differentiated cell types produced in vitro and their in vivo counterparts are essential to validate hPSC-derived cells. Genome-wide transcriptional analysis of sorte...
Article
We describe protein interaction quantitation (PIQ), a computational method for modeling the magnitude and shape of genome-wide DNase I hypersensitivity profiles to identify transcription factor (TF) binding sites. Through the use of machine-learning techniques, PIQ identified binding sites for >700 TFs from one DNase I hypersensitivity analysis fol...
Conference Paper
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This paper introduces Lynx, an incremental programmatic SAT solver that allows non-expert users to introduce domain-specific code into modern conflict-driven clause-learning (CDCL) SAT solvers, thus enabling users to guide the behavior of the solver. The key idea of Lynx is a callback interface that enables non-expert users to specialize the SAT so...
Article
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The development of algorithms for designing artificial RNA sequences that fold into specific secondary structures has many potential biomedical and synthetic biology applications. To date, this problem remains computationally difficult, and current strategies to address it resort to heuristics and stochastic search techniques. The most popular meth...
Article
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The supersecondary structure of amyloids and prions, proteins of intense clinical and biological interest, are difficult to determine by standard experimental or computational means. In addition, significant conformational heterogeneity is known or suspected to exist in many amyloid fibrils. Previous work has demonstrated that probability-based pre...
Article
Molecular dynamics (MD) simulations can now predict ms-timescale folding processes of small proteins; however, this presently requires hundreds of thousands of CPU hours and is primarily applicable to short peptides with few long-range interactions. Larger and slower-folding proteins, such as many with extended β-sheet structure, would require orde...
Article
Sequences rich in glutamine (Q) and asparagine (N) residues often fail to fold at the monomer level. This, coupled to their unusual hydrogen-bonding abilities, provides the driving force to switch between disordered monomers and amyloids. Such transitions govern processes as diverse as human protein-folding diseases, bacterial biofilm assembly, and...
Article
Full-text available
Proteins of all kinds can self-assemble into highly ordered β-sheet aggregates known as amyloid fibrils, important both biologically and clinically. However, the specific molecular structure of a fibril can vary dramatically depending on sequence and environmental conditions, and mutations can drastically alter amyloid function and pathogenicity. E...
Conference Paper
Molecular Dynamics (MD) simulations can now predict mstimescale folding processes of small proteins — however, this presently requires hundreds of thousands of CPU hours and is primarily applicable to short peptides with few long-range interactions. Larger and slowerfolding proteins, such as many with extended β-sheet structure, would require order...
Conference Paper
Accurate comparative analysis tools for low-homology proteins remains a difficult challenge in computational biology, especially sequence alignment and consensus folding problems. We presentpartiFold-Align, the first algorithm for simultaneous alignment and consensus folding of unaligned protein sequences; the algorithm’s complexity is polynomial i...
Article
In this article, we introduce a single-chip secure processor called Aegis. In addition to supporting mechanisms to authenticate the platform and software, our processor incorporates mechanisms to protect the integrity and privacy of applications from physical attacks as well as software attacks. Therefore, physically secure systems can be built usi...
Conference Paper
Application source code protection is a major concern for software architects today. Secure platforms have been proposed that protect the secrecy of application algorithms and enforce copy protection assurances. Unfortunately, these capabilities incur a sizeable performance overhead. Partitioning an application into secure and insecure regions can...
Article
Transmembrane beta-barrel (TMB) proteins are embedded in the outer membrane of gram-negative bacteria, mitochondria, and chloroplasts. Despite their importance, very few nonhomologous TMB structures have been determined by X-ray diffraction because of the experimental difficulty encountered in crystallizing transmembrane proteins. We introduce the...
Article
Full-text available
Our goal is to develop a state-of-the-art protein secondary structure predictor, with an intuitive and biophysically-motivated energy model. We treat structure prediction as an optimization problem, using parameterizable cost functions representing biological "pseudo-energies". Machine learning methods are applied to estimate the values of the para...
Article
A trusted monotonic counter is a valuable primitive thatenables a wide variety of highly scalable offlineand decentralized applications that would otherwise be prone to replay attacks, including offline payment, e-wallets, virtual trusted storage, and digital rights management (DRM).In this paper, we show how one can implement a very large number o...
Conference Paper
Our goal is to develop a state-of-the-art secondary structure predictor with an intuitive and biophysically-motivated energy model through the use of Hidden Markov Support Vector Machines (HM- SVMs), a recent innovation in the field of machine learning. We focus on the prediction of alpha helices and show that by using HM-SVMs, a simple 7-state HMM...
Article
This article presents the AEGIS secure processor architecture, which enables new applications by ensuring private and authentic program execution even in the face of physical attack. Our architecture uses two new primitives to achieve physical security. First, we describe Physical Random Functions which reliably protect and share secrets in a manne...
Article
Our goal is to develop a state-of-the-art predictor with an intuitive and biophysically-motivated energy model through the use of Hidden Markov Support Vector Machines (HM-SVMs), a recent innovation in the field of machine learning. We focus on the prediction of alpha helices in proteins and show that using HM-SVMs, a simple 7-state HMM with 302 pa...
Conference Paper
Secure processors enable new applications by ensuring private and authentic program execution even in the face of physical attack. In this paper, we present the AEGIS secure processor architecture, and evaluate its RTL implementation on FPGAs. By using physical random functions, we propose a new way of reliably protecting and sharing secrets that i...
Article
Trigger factor is a 48-kDa cytosolic chaperone protein found in all eubacteria. It has been shown to assist folding in two ways: by protecting nascent chains with long hydrophobic stretches during synthesis and initial folding stages, and by accelerating peptidyl-prolyl cis-trans isomerization (PPI). Depending on the length and hydrophobicity of th...
Article
Full-text available
mitochondria and chloroplasts. These proteins display a wide variety of functions and are relevant to various aspects of cell metabolism. In particular, outer-membrane proteins (omps) are used in active ion transport, passive nutrient intake, membrane anchors, membrane-bound enzymes, and defense against membrane-attack proteins. Current TMB structu...

Citations

... Special emphasis was placed on immune cells, as detrimental hyperinflammation is characteristic of severe COVID-19 [2,3]. Analysis of histone 3 lysine 27 acetylation (H3K27Ac) profiles from ENCODE [12] and BLUEPRINT [13] databases revealed cell type-specific active gene regulatory elements (GREs) at 3p21.31, with particularly strong activity seen in monocytes, monocytederived macrophages and neutrophils (Fig. 1b, c, Additional file 1: Fig.S2). The largest fraction of disease-associated SNPs overlapped with monocyte H3K27Ac + GREs, which were concentrated in three active chromatin regions (ACRs) near the CCR1, CCR2, CCR3 and CCR5 genes (Fig. 1b, c). ...
... In order to ensure long-term utility and compatibility, especially with large-scale sequencing projects [25][26][27][28] , a novel genome reference and associated bioinformatics tools should meet the following criteria: (1) accurate representation of diverse genetic information, (2) compatibility with existing methods and standards [29][30][31][32] , (3) aptness for improvements and other modifications (see Fig. 1A), (4) computational efficiency and scalability, and (5) tailorability for targeted populations and/or applications. In this study, we propose a population-specific graph construction method that meets all of these criteria and compare its utility in NGS read alignment and variant calling to other approaches. ...
... We provided a method that efficiently use the structural information embedded in sequences to compute reliable alignments at low sequence identity (10). This method also enable us to improve the structure prediction accuracy. ...
... Gene ontology analysis showed an enrichment for placental development and antigen presentation categories in EVT 1 ( Figure 5-figure supplement 1a). Representative marker genes for these categories in EVT 1 included several lineage-specific transcription factors including GCM1, PPARG, and CEBPB ( Figure 5-figure supplement 1b; Knöfler et al., 2019;Ferreira et al., 2016). In contrast, EVT 2-4 showed enrichment for extracellular structure and matrix organization, glycosylation, and peptidase activity. ...
... Over the years, several purification strategies have been established for the bulk-sequencing of isolated cell types, some of which maintain the integrity of the cells. These methods include sorting of fluorescence-marked cells using UAS-GFP responders and cell-type specific Gal4 drivers(Domsch et al. 2021), INTACT(Deal and Henikoff 2010), or BiTS(Bonn et al. 2012) and MARIS(Hrvatin et al. 2014). ...
... Given that in vitro differentiation protocols have certain limitations, we did not discriminate β-cells and α-cells as well as their endocrine progenitors well. This is due to the fact that the susceptibility of human iPSCs to differentiate into cells with an immature characteristic rather than a fully mature adult state [64]. Those questions are worth being validated by collecting a larger number of patient samples and continuing improvement of the MEN1-iPSC model. ...
... Other TFs such as c-MYC, MYT1L, and SCL do not bind closed chromatin, but modify open chromatin, allowing downstream TFs to bind the DNA and activate transcription 3 . The majority of classicallydefined TFs, such as those identified by reporter gene assays, do not have chromatin modification capabilities and function by binding to chromatin domains that were made available by the chromatin-modifying TFs 5 . ...
... In contrast to F-S0, which was expressed mostly as an insoluble protein, 59% of S0-F was expressed as a soluble protein. Trigger factor chaperone tig was used to enhance solubility, as it has been shown to assist protein folding by protecting long hydrophobic nascent chains during synthesis and initial folding stages [17]. We cotransformed the tig expression vector pTF16 (Fig. 2B) into E. coli BL21(DE3) together with each target protein's expression vector (pS0, pS0-F and pF-S0). ...
... Recently, new approaches such as [30][31][32][33], design sequences on a single secondary structure using a Boltzmann sequence sampler based on the "dual" partition function of with respect to McCaskill's partition function of secondary structures for a fixed sequence [34]. These approaches consider a sequence and a structure as a pair, and the pair can be mapped via Here, η is the energy function of a sequence-structure pair (σ , S) , Q n 4 and S n are the collections of all sequences and secondary structures of length n respectively, K is a constant(the Boltzmann constant), and T is a temperature parameter. ...
... Formally, a blocking clause S|=p ¬p is added to the SAT instance, where S consists of the assignment formed by the completion to be discarded (up to the given level). The solver is then resumed-the blocking clause being added to the SAT instance on-the-fly, i.e., programmatically (Ganesh et al. 2012). ...