Biotechnology Commons^™

Deep Learning Prediction Of Chemical-Induced Dose-Dependent And Context-Specific Multiplex Phenotype Responses And Its Application To Personalized Alzheimer’S Disease Drug Repurposing, You Wu, Qiao Liu, Yue Qiu, Lei Xie

Publications and Research

Predictive modeling of drug-induced gene expressions is a powerful tool for phenotype-based compound screening and drug repurposing. State-of-the-art machine learning methods use a small number of fixed cell lines as a surrogate for predicting actual expressions in a new cell type or tissue, although it is well known that drug responses depend on a cellular context. Thus, the existing approach has limitations when applied to personalized medicine, especially for many understudied diseases whose molecular profiles are dramatically different from those characterized in the training data. Besides the gene expression, dose-depen- dent cell viability is another important phenotype readout and is …

Interfacial Stress In The Development Of Biologics: Fundamental Understanding, Current Practice, And Future Perspective, Jinjiang Li, Mary E. Krause, Xiaodong Cheng, Yuan Cheng, Weiguo Dai, John J. Hill, Min Huang, Susan Jordan, Daniel Lacasse, Linda Narhi, Evgenyi Shalaev, Ian C. Shieh, Justin C. Thomas, Raymond Tu, Songyan Zheng, Lily Zhu

Publications and Research

Biologic products encounter various types of interfacial stress during development, manufacturing, and clinical administration. When proteins come in contact with vapor–liquid, solid–liquid, and liquid–liquid surfaces, these interfaces can significantly impact the protein drug product quality attributes, including formation of visible particles, subvisible particles, or soluble aggregates, or changes in target protein concentration due to adsorption of the molecule to various interfaces. Protein aggregation at interfaces is often accompanied by changes in conformation, as proteins modify their higher order structure in response to interfacial stresses such as hydrophobicity, charge, and mechanical stress. Formation of aggregates may elicit immunogenicity concerns; therefore, it …

Enabling Precision Medicine Via Standard Communication Of Hts Provenance, Analysis, And Results, Gil Alterovitz, Dennis Dean, Carole Globe, Michael R. Crusoe, Stiam Soiland-Reyes, Amanda Bell, Anais Hayes, Anita Suresh, Anjan Purkkayastha, Charles H. King, Dan Taylor, Elaine Johanson, Elaine E. Thompson, Eric Donaldson, Hiroki Morizono, Hsinyi Tsang, Jeet K. Vora, Jeremy Goecks, Jianchao Yao, Jonas S. Almeida, Jonathon Keeney, Kanakadurga Addepalli, Konstantinos Krampis, Krista M. Smith, Lydia Guo, Mark Walderhaug, Marco Schito, Matthew Ezewudo, Nuria Guimera, Paul Walsh, Robel Kahsay, Srikanth Gottipati, Timothy C. Rodwell, Toby Bloom, Yuching Lai, Vahan Simonyan, Raja Mazumder

Publications and Research

A personalized approach based on a patient's or pathogen’s unique genomic sequence is the foundation of precision medicine. Genomic findings must be robust and reproducible, and experimental data capture should adhere to findable, accessible, interoperable, and reusable (FAIR) guiding principles. Moreover, effective precision medicine requires standardized reporting that extends beyond wet-lab procedures to computational methods. The BioCompute framework (https://w3id.org/biocompute/1.3.0) enables standardized reporting of genomic sequence data provenance, including provenance domain, usability domain, execution domain, verification kit, and error domain. This framework facilitates communication and promotes interoperability. Bioinformatics computation instances that employ the BioCompute framework are easily relayed, repeated …

Nanoparticles As Multimodal Photon Transducers Of Ionizing Radiation, Edwin C. Pratt, Travis M. Shaffer, Qize Zhang, Charles Michael Drain, Jan Grimm

Publications and Research

In biomedical imaging, nanoparticles combined with radionuclides that generate Cerenkov luminescence are used in diagnostic imaging, photon-induced therapies, and as activatable probes. In these applications, the nanoparticle is often viewed as a carrier inert to ionizing radiation from the radionuclide. However, certain phenomena such as enhanced nanoparticle luminescence and generation of reactive oxygen species cannot be explained by only Cerenkov luminescence interactions with nanoparticles. Herein, we report methods to examine the mechanisms of nanoparticle excitation by radionuclides, including interactions with Cerenkov luminescence, β particles, and γ radiation. We demonstrate that β scintillation contributes appreciably to excitation and reactivity in certain …

Directly Light-Regulated Binding Of Rgs-Lov Photoreceptors To Anionic Membrane Phospholipids, Spencer T. Glantz, Erin E. Berlew, Zaynab Jaber, Benjamin S. Schuster, Kevin H. Gardner, Brian Y. Chow

Publications and Research

We report natural light–oxygen–voltage (LOV) photoreceptors with a blue light-switched, high-affinity (KD ∼ 10−7 M), and direct electrostatic interaction with anionic phospholipids. Membrane localization of one such photoreceptor, BcLOV4 from Botrytis cinerea, is directly coupled to its flavin photocycle, and is mediated by a polybasic amphipathic helixinthelinker regionbetween the LOV sensor and its C-terminal domain of unknown function (DUF), as revealed through a combination of bioinformatics, computational protein modeling, structure–function studies, and optogenetic assays in yeast and mammalian cell line expression systems. In model systems, BcLOV4 rapidly translocates from the cytosol to plasma membrane (∼1 second). The reversible electrostatic interaction …

Nlrp10 Enhances Cd4+ T-Cell-Mediated Ifnγ Response Via Regulation Of Dendritic Cell-Derived Il-12 Release, Maurizio Vacca, Julia Böhme, Lisa Zambetti, Hanif Javanmard Khameneh, Bhairav S. Paleja, Federica Laudisi, Adrian W. S. Ho, Kurt Neo, Keith Weng Kit Leong, Mardiana Marzuki, Bernett Lee, Michael Poidinger, Laura Santambrogio, Liana Tsenova, Francesca Zolezzi, Gennaro De Libero, Amit Singhal, Alessandra Mortellaro

Publications and Research

NLRP10 is a nucleotide-binding oligomerization domain-like receptor that functions as an intracellular pattern recognition receptor for microbial products. Here, we generated a Nlrp10−/− mouse to delineate the role of NLRP10 in the host immune response and found that Nlrp10−/− dendritic cells (DCs) elicited sub-optimal IFNγ production by antigenspecific CD4+ T cells compared to wild-type (WT) DCs. In response to T-cell encounter, CD40 ligation or Toll-like receptor 9 stimulation, Nlrp10−/− DCs produced low levels of IL-12, due to a substantial decrease in NF-κB activation. Defective IL-12 production was also evident in vivo and affected IFNγ production by CD4+ T cells. Upon …

Bio-Docklets: Virtualization Containers For Single-Step Execution Of Ngs Pipelines, Baekdoo Kim, Thahmina Ali, Carlos Lijeron, Enis Afgan, Konstantinos Krampis

Publications and Research

Processing of next-generation sequencing (NGS) data requires significant technical skills, involving installation, configuration, and execution of bioinformatics data pipelines, in addition to specialized postanalysis visualization and data mining software. In order to address some of these challenges, developers have leveraged virtualization containers toward seamless deployment of preconfigured bioinformatics software and pipelines on any computational platform. We present an approach for abstracting the complex data operations of multistep, bioinformatics pipelines for NGS data analysis. As examples, we have deployed 2 pipelines for RNA sequencing and chromatin immunoprecipitation sequencing, preconfigured within Docker virtualization containers we call Bio-Docklets. Each Bio-Docklet exposes a single …

Large-Scale Off-Target Identification Using Fast And Accurate Dual Regularized One- Class Collaborative Filtering And Its Application To Drug Repurposing, Hansaim Lim, Aleksandar Poleksic, Yuan Yao, Hanghang Tong, Di He, Luke Zhuang, Patrick Meng, Lei Xie

Publications and Research

Target-based screening is one of the major approaches in drug discovery. Besides the intended target, unexpected drug off-target interactions often occur, and many of them have not been recognized and characterized. The off-target interactions can be responsible for either therapeutic or side effects. Thus, identifying the genome-wide off-targets of lead compounds or existing drugs will be critical for designing effective and safe drugs, and providing new opportunities for drug repurposing. Although many computational methods have been developed to predict drug-target interactions, they are either less accurate than the one that we are proposing here or computationally too intensive, thereby limiting …

Spatial Engineering Of Osteochondral Tissue Constructs Through Microfluidically Directed Differentiation Of Mesenchymal Stem Cells, Stephen M. Goldman, Gilda A. Barabino

Publications and Research

The development of tissue engineered osteochondral units has been slowed by a number of technical hurdles associated with recapitulating their heterogeneous nature ex vivo. Subsequently, numerous approaches with respect to cell sourcing, scaffolding composition, and culture media formulation have been pursued, which have led to high variability in outcomes and ultimately the lack of a consensus bioprocessing strategy. As such, the objective of this study was to standardize the design process by focusing on differentially supporting formation of cartilaginous and bony matrix by a single cell source in a spatially controlled manner within a single material system. A cell-polymer solution …

A Model Of Blood Pressure, Heart Rate, And Vaso-Vagal Responses Produced By Vestibulo-Sympathetic Activation, Theodore Raphan, Bernard Cohen, Yongqing Xiang, Sergei B. Yakushin

Publications and Research

Blood Pressure (BP), comprised of recurrent systoles and diastoles, is controlled by central mechanisms to maintain blood flow. Periodic behavior of BP was modeled to study how peak amplitudes and frequencies of the systoles are modulated by vestibular activation. The model was implemented as a relaxation oscillator, driven by a central signal related to Desired BP. Relaxation oscillations were maintained by a second order system comprising two integrators and a threshold element in the feedback loop. The output signal related to BP was generated as a nonlinear function of the derivative of the first state variable, which is a summation …

Attention Strongly Modulates Reliability Of Neural Responses To Naturalistic Narrative Stimuli, Jason J. Ki, Simon P. Kelly, Lucas C. Parra

Publications and Research

Attentional engagement is a major determinant of how effectively we gather information through our senses. Alongside the sheer growth in the amount and variety of information content that we are presented with through modern media, there is increased variability in the degree to which we “absorb” that information. Traditional research on attention has illuminated the basic principles of sensory selection to isolated features or locations, but it provides little insight into the neural underpinnings of our attentional engagement with modern naturalistic content. Here, we show inhumansubjects that the reliability of an individual’s neural responses with respect to a larger group …

Genesis And Growth Of Extracellular Vesicle-Derived Microcalcification In Atherosclerotic Plaques, Joshua D. Hutcheson, Claudia Goettsch, Sergio Bertazzo, Natalia Maldonado, Jessica L. Ruiz, Wilson Goh, Katsumi Yabusaki, Tyler Faits, Carlijn Bouten, Gregory Franck, Thibaut Quillard, Peter Libby, Masanori Aikawa, Sheldon Weinbaum, Elena Aikawa

Publications and Research

Clinical evidence links arterial calcification and cardiovascular risk. Finite-element modelling of the stress distribution within atherosclerotic plaques has suggested that subcellular microcalcifications in the fibrous cap may promote material failure of the plaque, but that large calcifications can stabilize it. Yet the physicochemical mechanisms underlying such mineral formation and growth in atheromata remain unknown. Here, by using three-dimensional collagen hydrogels that mimic structural features of the atherosclerotic fibrous cap, and high-resolution microscopic and spectroscopic analyses of both the hydrogels and of calcified human plaques, we demonstrate that calcific mineral formation and maturation results from a series of events involving the …

Engineered Protein Polymer-Gold Nanoparticle Hybrid Materials For Small Molecule Delivery, Min Dai, Ja Frezzo, E Sharma, R Chen, N Singh, C Yuvienco, E Caglar, S Xiao, A Saxena, Jk Montclare

Publications and Research

We have fabricated protein polymer-gold nanoparticle (P-GNP) nanocomposites that exhibit enhanced binding and delivery properties of the small hydrophobic molecule drug, curcumin, to the model breast cancer cell line, MCF-7. These hybrid biomaterials are constructed via in situ GNP templated-synthesis with genetically engineered histidine tags. The P-GNP nanocomposites exhibit enhanced small molecule loading, sustained release and increased uptake by MCF-7 cells. When compared to the proteins polymers alone, the P-GNPs demonstrate a greater than 7-fold increase in curcumin binding, a nearly 50% slower release profile and more than 2-fold increase in cellular uptake of curcumin. These results suggest that P-GNP …

Hydrodynamic Loading In Concomitance With Exogenous Cytokine Stimulation Modulates Differentiation Of Bovine Mesenchymal Stem Cells Towards Osteochondral Lineages, Stephen M. Goldman, Gilda A. Barabino

Publications and Research

Background: Mesenchymal stem cells (MSCs) are viewed as a having significant potential for tissue engineering and regenerative medicine therapies. Clinical implementation of MSCs, however, demands that their preparation be stable and reproducible. Given that environmental and bioprocessing parameters such as substrate stiffness, seeding densities, culture medium composition, and mechanical loading can result in undirected differentiation of the MSC population, the objective of this study was to systematically investigate how hydrodynamic loading influences the differentiation of bone marrow-derived mesenchymal stem cells (MSCs) towards the osteochondral lineages both in the presence and absence of exogenous, inductive factors.

Methods: Expanded bovine MSCs were …

Biomechanical Performances Of Networked Polyethylene Glycol Diacrylate: Effect Of Photoinitiator Concentration, Temperature, And Incubation Time, Morshed Khandaker, Albert Orock, Stefano Tarantini, Jeremiah White, Ozlem Yasar

Publications and Research

Nutrient conduit networks can be introduced within the Polyethylene Glycol Diacrylate (PEGDA) tissue construct to enable cells to survive in the scaffold. Nutrient conduit networks can be created on PEGDA by macrochannel to nanochannel fabrication techniques. Such networks can influence the mechanical and cell activities of PEGDA scaffold. There is no study conducted to evaluate the effect of nutrient conduit networks on the maximum tensile stress and cell activities of the tissue scaffold.The study aimed to explore the influence of the network architecture on the maximum tensile stress of PEGDA scaffold and compared with the nonnetworked PEGDA scaffold. Our study …

Short Peptides In Minimalistic Biocatalyst Design, Krystyna L. Duncan, Rein V. Ulijn

Publications and Research

We review recent developments in the use of short peptides in the design of minimalistic biocatalysts focusing on ester hydrolysis. A number of designed peptide nanostructures are shown to have (modest) catalytic activity. Five features are discussed and illustrated by literature examples, including primary peptide sequence, nanosurfaces/scaffolds, binding pockets, multivalency and the presence of metal ions. Some of these are derived from natural enzymes, but others, such as multivalency of active sites on designed nanofibers, may give rise to new features not found in natural enzymes. Remarkably, it is shown that each of these design features give rise to similar …

New Functionally-Enhanced Soy Proteins As Food Ingredients With Anti-Viral Activity, Aizhan Sabirzhanovna Turmagambetova, Nadezhda Sergeevna Sokolova, Andrey Pavlinovich Bogoyavlenskiy, Vladimir Eleazvich Berezin, Mary Ann Lila, Diana M. Cheng, Vyacheslav Dushenkov

Publications and Research

Respiratory viruses are a major public health problem because of their prevalence and high morbidity rate leading to considerable social and economic implications. Cranberry has therapeutic potential attributed to a comprehensive list of phytochemicals including anthocyanins, flavonols, and unique A-type proanthocyanidins. Soy flavonoids, including isoflavones, have demonstrated anti-viral effects in vitro and in vivo. Recently, it was demonstrated that edible proteins can efficiently sorb and concentrate cranberry polyphenols, including anthocyanins and proanthocyanins, providing greatly stabilized matrices suitable for food products. The combination of cranberry and soy phytoactives may be an effective dietary anti-viral resource. Anti-viral properties of both cranberry juice-enriched …

Steered Molecular Dynamics Simulations Of A Type Iv Pilus Probe Initial Stages Of A Force-Induced Conformational Transition, Joseph L. Baker, Nicolas Biais, Florence Tama

Publications and Research

Type IV pili are long, protein filaments built from a repeating subunit that protrudes from the surface of a wide variety of infectious bacteria. They are implicated in a vast array of functions, ranging from bacterial motility to microcolony formation to infection. One of the most well-studied type IV filaments is the gonococcal type IV pilus (GC-T4P) from Neisseria gonorrhoeae, the causative agent of gonorrhea. Cryo-electron microscopy has been used to construct a model of this filament, offering insights into the structure of type IV pili. In addition, experiments have demonstrated that GC-T4P can withstand very large tension forces, and …