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BLOOD 2023年第9期142卷 755-756页

作者： Eweje, Feyisayo Bauer, Daniel E. MIT Cambridge MA 02142 USA Harvard MIT MD PhD Program Cambridge MA 02115 USA Boston Childrens Hosp Boston MA USA Harvard Med Sch Boston MA USA

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Enhanced killing of antibiotic-resistant bacteria enabled by massively parallel combinatorial genetics

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2014年第34期111卷 12462-12467页

作者： Cheng, Allen A. Ding, Huiming Lu, Timothy K. MIT MIT Synthet Biol Ctr Dept Elect Engn & Comp Sci Elect Res LabSynthet Biol Grp Cambridge MA 02139 USA MIT MIT Synthet Biol Ctr Dept Biol Engn Elect Res LabSynthet Biol Grp Cambridge MA 02139 USA MIT Harvard MIT Hlth Sci & Technol Med Engn & Med Phys Program Cambridge MA 02139 USA MIT MIT BioMicro Ctr Dept Biol Engn Cambridge MA 02139 USA MIT MIT Microbiol Program Cambridge MA 02139 USA Harvard Univ Harvard Biophys Program Boston MA 02115 USA Harvard Univ Harvard MD PhD Program Boston MA 02115 USA

New therapeutic strategies are needed to treat infections caused by drug-resistant bacteria, which constitute a major growing threat to human health. Here, we use a high-throughput technology to identify combinatorial genetic perturbations that can enhance the killing of drug-resistant bacteria with antibiotic treatment. This strategy, Combinatorial Genetics En Masse (Com-biGEM), enables the rapid generation of high-order barcoded combinations of genetic elements for high-throughput multiplexed characterization based on next-generation sequencing. We created similar to 34,000 pairwise combinations of Escherichia coli transcription factor (TF) overexpression constructs. Using Illumina sequencing, we identified diverse perturbations in antibiotic-resistance phenotypes against carbapenem-resistant Enterobacteriaceae. Specifically, we found multiple TF combinations that potentiated antibiotic killing by up to 10(6)-fold and delivered these combinations via phagemids to increase the killing of highly drug-resistant E. coli harboring New Delhi metallo-beta-lactamase-1. Moreover, we constructed libraries of three-wise combinations of transcription factors with >4 million unique members and demonstrated that these could be tracked via next-generation sequencing. We envision that CombiGEM could be extended to other model organisms, disease models, and phenotypes, where it could accelerate massively parallel combinatorial genetics studies for a broad range of biomedical and biotechnology applications, including the treatment of antibiotic-resistant infections.

关键词： synthetic biology combination therapy systems biology drug resistance multifactorial genetics

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βIV spectrin abundancy, cellular distribution and sensitivity to AKT/GSK3 regulation in schizophrenia

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MOLECULAR PSYCHIATRY 2025年 1-13页

作者： Di Re, Jessica Marini, Michela Hussain, Syed Ibrar Singh, Aditya K. Venkatesh, Akshaya Alshammari, Musaad A. Alshammari, Tahani K. Hamoud, Abdul-Rizaq Ali Imami, Ali Sajid Haghighijoo, Zahra Fularcyzk, Nickolas Stertz, Laura Hawes, Derek Mosebarger, Angela Jernigan, Jordan Chaljub, Claire Nehme, Ralda Walss-Bass, Consuelo Schulmann, Anton Vawter, Marquis P. Mccullumsmith, Robert Damoiseaux, Robert D. Limon, Agenor Labate, Demetrio Wells, Michael F. Laezza, Fernanda Univ Texas Med Branch Galveston Dept Pharmacol & Toxicol Galveston TX USA Univ Houston Dept Math Houston TX USA Univ Texas Med Branch Combined MD PhD Program Galveston TX USA King Saud Univ Coll Pharm Dept Pharmacol & Toxicol Riyadh 11451 Saudi Arabia Univ Toledo Coll Med & Life Sci Dept Neurosci & Psychiat Toledo OH USA Univ Texas Hlth Sci Ctr Houston UTHealth McGovern Med Sch Louis A Faillace MD Dept Psychiat & Behav Sci Houston TX USA Broad Inst MIT & Harvard Stanley Ctr Psychiat Res Cambridge MA 02142 USA Harvard Univ Dept Stem Cell & Regenerat Biol Cambridge MA USA Columbia Univ Irving Med Ctr New York State Psychiat Inst Dept Psychiat New York NY USA Univ Calif Irvine Dept Psychiat & Human Behav Funct Genom Lab Irvine CA USA Promedica Neurosci Inst Toledo OH USA Univ Calif Los Angeles Dept Mol & Med Pharmacol Los Angeles CA USA Univ Calif Los Angeles Dept Bioengn Los Angeles CA USA Univ Calif Los Angeles Calif NanoSyst Inst Los Angeles CA USA Univ Calif Los Angeles Jonsson Comprehens Canc Ctr Los Angeles CA USA Univ Texas Med Branch Galveston Dept Neurol Galveston TX USA Univ Texas Med Branch Galveston Mitchell Ctr Neurodegenerat Dis Galveston TX USA Univ Calif Los Angeles David Geffen Sch Med Dept Human Genet Los Angeles CA USA Univ Calif Los Angeles Mol Biol Inst Los Angeles CA USA

Schizophrenia (SCZ) is a complex psychiatric disorder with unclear biological mechanisms. Spectrins, cytoskeletal proteins linked to neurodevelopmental disorders, are regulated by the AKT/GSK3 pathway, which is implicated in SCZ. However, the impact of SCZ-related dysregulation of this pathway on spectrin expression and distribution remains unexplored. Here, we show that beta IV spectrin protein levels were reduced in neurons of the dorsolateral prefrontal cortex in SCZ postmortem samples compared to healthy control (HC) from the Human Brain Collection Core (HBCC). To investigate potential links between beta IV spectrin and the AKT/GSK3 pathway, we analyzed the PsychEncode dataset, revealing elevated SPTBN4 and AKT2 mRNA levels with correlated gene transcription in both HCs and individuals with SCZ. Next, computational tools were employed to identify potential AKT and GSK3 phosphorylation sites on beta IV spectrin, and two GSK3 sites were validated through in vitro assays. To assess whether beta IV spectrin distribution and sensitivity to AKT/GSK3 are altered in SCZ, we used iPSC-derived neurons from two independent cohorts of patients with significantly increased familial genetic risk for the disorder. Alteration in beta IV spectrin levels and sensitivity to AKT/GSK3 inhibitors were consistently observed across both cohorts. Importantly, a Random Forest classifier applied to beta IV spectrin imaging achieved up to 98% accuracy in classifying cells by diagnosis in postmortem samples, and by diagnosis or diagnosis x perturbation in iPSC samples. These findings reveal altered beta IV spectrin levels and AKT/GSK3 sensitivity in SCZ, identifying beta IV spectrin image-based endophenotypes as robust, generalizable predictive biomarkers of SCZ, with the potential for scalable clinical applications.

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Clinical Applications of Naturally Derived Biopolymer-Based Scaffolds for Regenerative Medicine (vol 43, pg 657, 2014)

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ANNALS OF BIOMEDICAL ENGINEERING 2015年第8期43卷 2023-2023页

作者： Stoppel, Whitney L. Ghezzi, Chiara E. McNamara, Stephanie L. Black, Lauren D., III Kaplan, David L. Tufts Univ Dept Biomed Engn Medford MA 02155 USA Tufts Univ Sackler Sch Grad Biomed Sci Sch Med Cellular Mol & Dev Biol Program Boston MA 02111 USA Harvard Univ Sch Med Harvard MIT MD PhD Program Boston MA 02115 USA

Naturally derived polymeric biomaterials, such as collagens, silks, elastins, alginates, and fibrins are utilized in tissue engineering due to their biocompatibility, bioactivity, and tunable mechanical and degradation kinetics. The use of these natural biopolymers in biomedical applications is advantageous because they do not release cytotoxic degradation products, are often processed using environmentally-friendly aqueous-based methods, and their degradation rates within biological systems can be manipulated by modifying the starting formulation or processing conditions. For these reasons, many recent in vivo investigations and FDA-approval of new biomaterials for clinical use have utilized natural biopolymers as matrices for cell delivery and as scaffolds for cell-free support of native tissues. This review highlights biopolymer-based scaffolds used in clinical applications for the regeneration and repair of native tissues, with a focus on bone, skeletal muscle, peripheral nerve, cardiac muscle, and cornea substitutes.

关键词： Biopolymers Scaffolds Regenerative medicine

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Plasmonic Photothermal Heating of Intraperitoneal Tumors through the Use of an Implanted Near-Infrared Source

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ACS NANO 2013年第9期7卷 8089-8097页

作者： Bagley, Alexander F. Hill, Samuel Rogers, Gary S. Bhatia, Sangeeta N. MIT Koch Inst Integrat Canc Res Cambridge MA 02139 USA MIT Cambridge MA 02139 USA MIT Dept Elect Engn & Comp Sci Cambridge MA 02139 USA Harvard Univ Biophys Program Boston MA 02115 USA Harvard Univ Sch Med MD PhD Program Boston MA USA Tufts Univ Sch Med Tufts Med Ctr Boston MA 02111 USA Howard Hughes Med Inst Chevy Chase MD USA

Plasmonic nanomaterials including gold nanorods are effective agents for inducing heating in tumors. Because near-infrared (NIR) light has traditionally been delivered using extracorporeal sources, most applications of plasmonic photothermal therapy have focused on isolated subcutaneous tumors. For more complex models of disease such as advanced ovarian cancer, one of the primary barriers to gold nanorod-based strategies is the adequate delivery of NIR light to tumors located at varying depths within the body. To address this limitation, a series of implanted NIR illumination sources are described for the specific heating of gold nanorod-containing tissues. Through computational modeling and ex vivo studies, a candidate device is identified and validated in a model of orthotopic ovarian cancer. As the therapeutic, imaging, and diagnostic applications of plasmonic nanomaterials progress, effective methods for NIR light delivery to challenging anatomical regions will complement ongoing efforts to advance plasmonic photothermal therapy toward clinical use.

关键词： gold nanorods implanted illumination near-infrared photothermal therapy cancer

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Quantitative assessment of auditory cortex responses induced by imager acoustic noise

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HUMAN BRAIN MAPPING 1999年第2期7卷 79-88页

作者： Talavage, TM Edmister, WB Ledden, PJ Weisskoff, RM Massachusetts Gen Hosp Dept Radiol NMR Ctr MGH Boston MA 02114 USA Harvard Univ MIT Div Hlth Sci & Technol Speech & Hearing Sci Program Cambridge MA 02139 USA Harvard Univ MIT Div Hlth Sci & Technol Med Engn Med Phys Program Cambridge MA 02139 USA Harvard Univ Sch Med MD PhD Program Boston MA USA

A clustered volume acquisition functional MRT pulse sequence was modified to assess the response to the acoustic noise of echo-planar imaging in the auditory cortex and to determine whether it is possible to obtain data which is relatively free of acoustic contamination. The spatial location and strength (percent signal change) of cortical responses to the imager noise were examined by introducing extra gradient readouts, without slice excitation, to provide acoustic stimulation immediately prior to acquisition of a cerebral volume. The duration of acoustic stimulation was controlled by varying the number of extra gradient readouts. Slice acquisitions were clustered at the end of the repetition time (TR) period to prevent a response from being induced by the volume acquisition itself ("Intra-Acquisition Response"). The cerebral volumes were acquired using a long TR in order to limit the integration of the cortical response across volume acquisitions ("Inter-Acquisition Response"). Cortical responses were observed to be largest and most significant on the medial two-thirds of Heschl's gyrus, the location of primary auditory cortex. Mean signal changes induced by the imager noise were observed to be as high as 0.95%. A 2 sec delay prior to onset of the BOLD response was empirically determined. These results demonstrate that clustered volume acquisitions may be utilized for up to 2 sec of volume acquisition without inducing an appreciable Intra-Acquisition Response and can be used, with a sufficiently long TR, to provide data which are similarly free of any Inter-Acquisition Response. (C) 1999 Wiley-Liss, Inc.

关键词： fMRI pulse sequence brain mapping stimulus masking response suppression

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Improved auditory cortex imaging using clustered volume acquisitions

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HUMAN BRAIN MAPPING 1999年第2期7卷 89-97页

作者： Edmister, WB Talavage, TM Ledden, PJ Weisskoff, RM Massachusetts Gen Hosp NMR Ctr Dept Radiol Charlestown MA 02129 USA Harvard Univ MIT Div Hlth Sci & Technol Med Engn Med Phys Program Cambridge MA 02139 USA Harvard Univ Sch Med MD PhD Program Boston MA USA Harvard Univ MIT Div Hlth Sci & Technol Speech & Hearing Sci Program Cambridge MA 02139 USA

The effects of the noise of echo-planar functional magnetic resonance imaging on auditory cortex responses were compared for two methods of acquiring functional MR data. Responses observed with a distributed volume acquisition sequence were compared to those obtained with clustered volume acquisition sequence. In the former case, slices from the volume were acquired at equal intervals within the repetition time, whereas the latter acquired all slices in rapid succession at the end of the imaging period. The clustered volume acquisition provides a period of quiet during which a stimulus may be presented uninterrupted and uncontaminated by the noise of echo-planar imaging. Both sequences were implemented on a General Electric Signa imager retrofitted for echo-planar imaging by Advanced NMR Systems, Inc. The sequences were used to acquire 60 images per slice of a fixed volume of cerebral cortex while subjects were presented an instrumental music stimulus in an On vs. OK paradigm. Data were acquired for both sequences using TR values of 2, 3, 4, 6 and 8 sec. The clustered volume acquisition sequence was found to yield greater measures of dynamic range (percent signal change, mean statistical power per unit imaging time) across the tested range of TR values. Observations of more consistent spatial extent of responses, greater mean signal changes, and higher and more consistent values of mean t-statistic per unit imaging time demonstrate the efficacy of using a clustered volume acquisition for fMRI of auditory cortex. (C) 1999 Wiley-Liss, Inc.

关键词： fMRI pulse sequence brain mapping EPI

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A good step toward low-cost prognostication of liver-related outcome awaits more validation

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JOURNAL OF HEPATOLOGY 2022年第3期77卷 887-889页

作者： Song, Jiunn Jiang, Z. Gordon Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA Harvard Med Sch Beth Israel Deaconess Med Ctr Dept Med Div Gastroenterol & Hepatol Boston MA 02115 USA

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Combinatorial development of nebulized mRNA delivery formulations for the lungs

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NATURE NANOTECHNOLOGY 2024年第3期19卷 364-375页

作者： Jiang, Allen Y. Witten, Jacob Raji, Idris O. Eweje, Feyisayo Macisaac, Corina Meng, Sabrina Oladimeji, Favour A. Hu, Yizong Manan, Rajith S. Langer, Robert Anderson, Daniel G. MIT Dept Chem Engn Cambridge MA 02139 USA MIT David H Koch Inst Integrat Canc Res Cambridge MA 02139 USA MIT Dept Biol Engn Cambridge MA 02139 USA Boston Childrens Hosp Dept Anesthesiol Boston MA 02115 USA MIT Harvard & MIT Div Hlth Sci & Technol Cambridge MA 02139 USA Harvard MIT MD PhD Program Boston MA USA MIT Inst Med Engn & Sci Cambridge MA 02139 USA

Inhaled delivery of mRNA has the potential to treat a wide variety of diseases. However, nebulized mRNA lipid nanoparticles (LNPs) face several unique challenges including stability during nebulization and penetration through both cellular and extracellular barriers. Here we develop a combinatorial approach addressing these barriers. First, we observe that LNP formulations can be stabilized to resist nebulization-induced aggregation by altering the nebulization buffer to increase the LNP charge during nebulization, and by the addition of a branched polymeric excipient. Next, we synthesize a combinatorial library of ionizable, degradable lipids using reductive amination, and evaluate their delivery potential using fully differentiated air-liquid interface cultured primary lung epithelial cells. The final combination of ionizable lipid, charge-stabilized formulation and stability-enhancing excipient yields a significant improvement in lung mRNA delivery over current state-of-the-art LNPs and polymeric nanoparticles. Nebulized mRNA delivery has broad therapeutic potential but has proven challenging. Here, the authors report on a modified lipid nanoparticle with improved conditions to allow nebulization and demonstrate its application for delivering mRNA to the lungs.

关键词： Biomedical engineering Drug delivery Nanomedicine Nanoparticles

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Biophysical principles predict fitness of SARS-CoV-2 variants

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2024年第23期121卷 1页

作者： Wang, Dianzhuo Huot, Marian Mohanty, Vaibhav Shakhnovich, Eugene I. Sali, Andrej Harvard Univ Dept Chem & Chem Biol Cambridge MA 02138 USA Harvard Univ John A Paulson Sch Engn & Appl Sci Cambridge MA 02138 USA Inst Polytech Paris Ecole Polytech F-91128 Palaiseau France Harvard Med Sch Harvard MIT MD PhD Program Boston MA 02115 USA MIT Cambridge MA 02139 USA

SARS-CoV-2 employs its spike protein's receptor binding domain (RBD) to enter host cells. The RBD is constantly subjected to immune responses, while requiring efficient binding to host cell receptors for successful infection. However, our understanding of how RBD's biophysical properties contribute to SARS-CoV-2's epidemiological fitness remains largely incomplete. Through a comprehensive approach, comprising large-scale sequence analysis of SARS-CoV-2 variants and the identification of a fitness function based on binding thermodynamics, we unravel the relationship between the biophysical properties of RBD variants and their contribution to viral fitness. We developed a biophysical model that uses statistical mechanics to map the molecular phenotype space, characterized by dissociation constants of RBD to ACE2, LY-CoV016, LY-CoV555, REGN10987, and S309, onto an epistatic fitness landscape. We validate our findings through experimentally measured and machine learning (ML) estimated binding affinities, coupled with infectivity data derived from population -level sequencing. Our analysis reveals that this model effectively predicts the fitness of novel RBD variants and can account for the epistatic interactions among mutations, including explaining the later reversal of Q493R. Our study sheds light on the impact of specific mutations on viral fitness and delivers a tool for predicting the future epidemiological trajectory of previously unseen or emerging low -frequency variants. These insights offer not only greater understanding of viral evolution but also potentially aid in guiding public health decisions in the battle against COVID-19 and future pandemics.

关键词： viral evolution receptor binding domain fitness landscape SARS-CoV-2 antibody

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