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Article ; Online: Engineered Bacterial Production of Volatile Methyl Salicylate.

Chien, Tiffany / Jones, Drew R / Danino, Tal

ACS synthetic biology

2020 Volume 10, Issue 1, Page(s) 204–208

Abstract: The engineering of microbial metabolic pathways over the last two decades has led to numerous examples of cell factories used for the production of small molecules. These molecules have an array of utility in commercial industries and ... ...

Abstract	The engineering of microbial metabolic pathways over the last two decades has led to numerous examples of cell factories used for the production of small molecules. These molecules have an array of utility in commercial industries and as
MeSH term(s)	Bacteria/chemistry ; Bacteria/metabolism ; Chromatography, High Pressure Liquid ; Gas Chromatography-Mass Spectrometry ; Mass Spectrometry ; Metabolic Engineering/methods ; Methyltransferases/genetics ; Petunia/metabolism ; Plant Proteins/genetics ; Plasmids/genetics ; Plasmids/metabolism ; Salicylates/analysis ; Salicylates/metabolism
Chemical Substances	Plant Proteins ; Salicylates ; Methyltransferases (EC 2.1.1.-) ; methyl salicylate (LAV5U5022Y)
Language	English
Publishing date	2020-12-17
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2161-5063
ISSN (online)	2161-5063
DOI	10.1021/acssynbio.0c00497
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Book ; Online: Adversarial Analysis of Natural Language Inference Systems

Chien, Tiffany / Kalita, Jugal

2019

Abstract: The release of large natural language inference (NLI) datasets like SNLI and MNLI have led to rapid development and improvement of completely neural systems for the task. Most recently, heavily pre-trained, Transformer-based models like BERT and MT-DNN ... ...

Abstract	The release of large natural language inference (NLI) datasets like SNLI and MNLI have led to rapid development and improvement of completely neural systems for the task. Most recently, heavily pre-trained, Transformer-based models like BERT and MT-DNN have reached near-human performance on these datasets. However, these standard datasets have been shown to contain many annotation artifacts, allowing models to shortcut understanding using simple fallible heuristics, and still perform well on the test set. So it is no surprise that many adversarial (challenge) datasets have been created that cause models trained on standard datasets to fail dramatically. Although extra training on this data generally improves model performance on just that type of data, transferring that learning to unseen examples is still partial at best. This work evaluates the failures of state-of-the-art models on existing adversarial datasets that test different linguistic phenomena, and find that even though the models perform similarly on MNLI, they differ greatly in their robustness to these attacks. In particular, we find syntax-related attacks to be particularly effective across all models, so we provide a fine-grained analysis and comparison of model performance on those examples. We draw conclusions about the value of model size and multi-task learning (beyond comparing their standard test set performance), and provide suggestions for more effective training data. Comment: 8 pages, accepted by IEEE ICSC 2020
Keywords	Computer Science - Computation and Language
Subject code	006
Publishing date	2019-12-07
Publishing country	us
Document type	Book ; Online
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Article ; Online: Can an interactive case-based activity help bridge the theory-practice gap in operative dentistry?

Chutinan, Supattriya / Kim, Jiyeon / Chien, Tiffany / Meyer, Helen Yang / Ohyama, Hiroe

European journal of dental education : official journal of the Association for Dental Education in Europe

2020 Volume 25, Issue 1, Page(s) 199–206

Abstract: Introduction: A theory-practice gap in pre-doctoral dental education is a common source of stress for dental students. An interactive, small-group, case-based activity was designed to bridge the gap between pre-clinical and clinical experiences. The aim ...

Abstract	Introduction: A theory-practice gap in pre-doctoral dental education is a common source of stress for dental students. An interactive, small-group, case-based activity was designed to bridge the gap between pre-clinical and clinical experiences. The aim of our study was to assess the effectiveness of the case-based activity by evaluating students' comfort level in operative procedures. Materials and methods: Over 5 years, a total of 172 second-year students from the classes of 2017 through 2021 participated in the case-based activity delivered after the completion of the core operative dentistry course. The exercise included a pre-activity online quiz, an in-class case-based session and a laboratory exercise. Students' self-reported comfort levels in performing operative procedures were collected by surveys at three different times. They included the post-course survey distributed after the completion of the core operative dentistry course, the post-activity survey distributed after the completion of the case-based activity, and the follow-up survey distributed after students completed their first operative procedures in clinic. Results: There was a 93% response rate. The average rating of all eight statements revealed statistically significant increase in students' comfort level after completing the case-based activity and after performing their first operative procedures in the teaching practice. Conclusion: This observation suggests that the case-based activity was effective in raising students' comfort levels. The activity may serve as an important tool in bridging the theory-practice gap between pre-clinical and clinical operative experiences.
MeSH term(s)	Curriculum ; Dentistry, Operative ; Education, Dental ; Humans ; Professional Practice Gaps ; Students, Dental ; Surveys and Questionnaires
Language	English
Publishing date	2020-10-13
Publishing country	England
Document type	Journal Article
ZDB-ID	1386587-0
ISSN	1600-0579 ; 1396-5883
ISSN (online)	1600-0579
ISSN	1396-5883
DOI	10.1111/eje.12591
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Article: Advances in bacterial cancer therapies using synthetic biology.

Chien, Tiffany / Doshi, Anjali / Danino, Tal

Current opinion in systems biology

2017 Volume 5, Page(s) 1–8

Abstract: Synthetic biology aims to apply engineering principles to biology by modulating the behavior of living organisms. An emerging application of this field is the engineering of bacteria as a cancer therapy by the programming of therapeutic, safety, and ... ...

Abstract	Synthetic biology aims to apply engineering principles to biology by modulating the behavior of living organisms. An emerging application of this field is the engineering of bacteria as a cancer therapy by the programming of therapeutic, safety, and specificity features through genetic modification. Here, we review progress in this engineering including the targeting of bacteria to tumors, specific sensing and response to tumor microenvironments, remote induction methods, and controllable release of therapeutics. We discuss the most prominent bacteria strains used and their specific properties and the types of therapeutics tested thus far. Finally, we note current challenges, such as genetic stability, that researchers must address for successful clinical implementation of this novel therapy in humans.
Language	English
Publishing date	2017-05-23
Publishing country	England
Document type	Journal Article
ISSN	2452-3100
ISSN	2452-3100
DOI	10.1016/j.coisb.2017.05.009
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Article ; Online: A Systematic Network of Autism Primary Care Services (SYNAPSE): A Model of Coproduction for the Management of Autism Spectrum Disorder.

Kong, Xuejun / Liu, Jun / Chien, Tiffany / Batalden, Maren / Hirsh, David A

Journal of autism and developmental disorders

2019 Volume 50, Issue 5, Page(s) 1847–1853

Abstract: The prevalence of Autism Spectrum Disorder (ASD) is growing rapidly, affecting 1 in 59 children in the United States in 2018. Individuals with ASD currently receive fragmented care that threatens their health and well-being. Challenges of autism care ... ...

Abstract	The prevalence of Autism Spectrum Disorder (ASD) is growing rapidly, affecting 1 in 59 children in the United States in 2018. Individuals with ASD currently receive fragmented care that threatens their health and well-being. Challenges of autism care include disconnections between the medical system and school supports, poor care coordination between primary care and specialists, and saturation of neuropsychiatry-based centers' capacity to care for the ASD population. ASD treatment also lacks of a coordinated system of care for patients' multi-system comorbidities. Families are calling for an ASD care delivery system to meet their needs and the needs of their children. To serve people with ASD and their medical and other providers, we propose a coordinated approach to care grounded in primary care. We call the model the "Systematic Network of Autism Primary Care Services (SYNAPSE)." We develop the model by applying the frameworks of "coproduction" of care and chronic disease management. In this Commentary we discuss the model's rationale, underpinnings, and the implications for clinical practice. We advance these ideas to align with policy makers' recognition of the importance of primary care for ASD, as reflected by the most recent Interagency Autism Coordinating Committee (IACC) meeting at the National Institute of Mental Health.
MeSH term(s)	Autism Spectrum Disorder ; Delivery of Health Care/organization & administration ; Disease Management ; Humans ; Primary Health Care/organization & administration ; Program Development ; United States
Language	English
Publishing date	2019-02-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	391999-7
ISSN	1573-3432 ; 0162-3257
ISSN (online)	1573-3432
ISSN	0162-3257
DOI	10.1007/s10803-019-03922-4
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Article ; Online: Enhancing the tropism of bacteria via genetically programmed biosensors.

Chien, Tiffany / Harimoto, Tetsuhiro / Kepecs, Benjamin / Gray, Kelsey / Coker, Courtney / Hou, Nicholas / Pu, Kelly / Azad, Tamjeed / Nolasco, Andoni / Pavlicova, Martina / Danino, Tal

Nature biomedical engineering

2021 Volume 6, Issue 1, Page(s) 94–104

Abstract: Engineered bacteria for therapeutic applications would benefit from control mechanisms that confine the growth of the bacteria within specific tissues or regions in the body. Here we show that the tropism of engineered bacteria can be enhanced by ... ...

Abstract	Engineered bacteria for therapeutic applications would benefit from control mechanisms that confine the growth of the bacteria within specific tissues or regions in the body. Here we show that the tropism of engineered bacteria can be enhanced by coupling bacterial growth with genetic circuits that sense oxygen, pH or lactate through the control of the expression of essential genes. Bacteria that were engineered with pH or oxygen sensors showed preferential growth in physiologically relevant acidic or oxygen conditions, and reduced growth outside the permissive environments when orally delivered to mice. In syngeneic mice bearing subcutaneous tumours, bacteria engineered with both hypoxia and lactate biosensors coupled through an AND gate showed increased tumour specificity. The multiplexing of genetic circuits may be more broadly applicable for enhancing the localization of bacteria to specified niches.
MeSH term(s)	Animals ; Bacteria/metabolism ; Biosensing Techniques ; Lactic Acid ; Mice ; Oxygen/metabolism ; Tropism
Chemical Substances	Lactic Acid (33X04XA5AT) ; Oxygen (S88TT14065)
Language	English
Publishing date	2021-07-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2157-846X
ISSN (online)	2157-846X
DOI	10.1038/s41551-021-00772-3
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Article ; Online: Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia.

Gurbatri, Candice R / Radford, Georgette A / Vrbanac, Laura / Im, Jongwon / Thomas, Elaine M / Coker, Courtney / Taylor, Samuel R / Jang, YoungUk / Sivan, Ayelet / Rhee, Kyu / Saleh, Anas A / Chien, Tiffany / Zandkarimi, Fereshteh / Lia, Ioana / Lannagan, Tamsin R M / Wang, Tongtong / Wright, Josephine A / Kobayashi, Hiroki / Ng, Jia Q /

Lawrence, Matt / Sammour, Tarik / Thomas, Michelle / Lewis, Mark / Papanicolas, Lito / Perry, Joanne / Fitzsimmons, Tracy / Kaazan, Patricia / Lim, Amanda / Stavropoulos, Alexandra M / Gouskos, Dion A / Marker, Julie / Ostroff, Cheri / Rogers, Geraint / Arpaia, Nicholas / Worthley, Daniel L / Woods, Susan L / Danino, Tal

Nature communications

2024 Volume 15, Issue 1, Page(s) 646

Abstract: Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment. Here, first, we demonstrate selective colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) ...

Abstract	Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment. Here, first, we demonstrate selective colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition and orthotopic models of CRC. We next undertake an interventional, double-blind, dual-centre, prospective clinical trial, in which CRC patients take either placebo or EcN for two weeks prior to resection of neoplastic and adjacent normal colorectal tissue (ACTRN12619000210178). We detect enrichment of EcN in tumor samples over normal tissue from probiotic-treated patients (primary outcome of the trial). Next, we develop early CRC intervention strategies. To detect lesions, we engineer EcN to produce a small molecule, salicylate. Oral delivery of this strain results in increased levels of salicylate in the urine of adenoma-bearing mice, in comparison to healthy controls. To assess therapeutic potential, we engineer EcN to locally release a cytokine, GM-CSF, and blocking nanobodies against PD-L1 and CTLA-4 at the neoplastic site, and demonstrate that oral delivery of this strain reduces adenoma burden by ~50%. Together, these results support the use of EcN as an orally-deliverable platform to detect disease and treat CRC through the production of screening and therapeutic molecules.
MeSH term(s)	Animals ; Humans ; Mice ; Adenoma/diagnosis ; Adenoma/therapy ; Colorectal Neoplasms/diagnosis ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/therapy ; Escherichia coli/genetics ; Prospective Studies ; Salicylates ; Double-Blind Method
Chemical Substances	Salicylates
Language	English
Publishing date	2024-01-20
Publishing country	England
Document type	Clinical Trial ; Journal Article ; Multicenter Study
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-44776-4
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Article: Colorectal cancer detection and treatment with engineered probiotics.

Gurbatri, Candice R / Radford, Georgette / Vrbanac, Laura / Coker, Courtney / Im, Jong-Won / Taylor, Samuel R / Jang, YoungUk / Sivan, Ayelet / Rhee, Kyu / Saleh, Anas A / Chien, Tiffany / Zandkarimi, Fereshteh / Lia, Ioana / Lannagan, Tamsin Rm / Wang, Tongtong / Wright, Josephine A / Thomas, Elaine / Kobayashi, Hiroki / Ng, Jia Q /

Lawrence, Matt / Sammour, Tarik / Thomas, Michelle / Lewis, Mark / Papanicolas, Lito / Perry, Joanne / Fitzsimmons, Tracy / Kaazan, Patricia / Lim, Amanda / Marker, Julie / Ostroff, Cheri / Rogers, Geraint / Arpaia, Nicholas / Worthley, Daniel L / Woods, Susan L / Danino, Tal

bioRxiv : the preprint server for biology

2023

Abstract: Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment strategies. Here, we demonstrate the phenomenon of selective, long-term colonization of colorectal adenomas after oral delivery of ... ...

Abstract	Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment strategies. Here, we demonstrate the phenomenon of selective, long-term colonization of colorectal adenomas after oral delivery of probiotic
Language	English
Publishing date	2023-04-05
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.03.535370
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Article ; Online: Recovery of a human natural antibody against the noncollagenous-1 domain of type IV collagen using humanized models.

Worni-Schudel, Inge M / Clark, Amy G / Chien, Tiffany / Hwang, Kwan-Ki / Chen, Benny J / Foster, Mary H

Journal of translational medicine

2015 Volume 13, Page(s) 185

Abstract: Background: Anti-glomerular basement membrane nephritis and Goodpasture syndrome result from autoantibody (Ab)-mediated destruction of kidney and lung. Ab target the noncollagenous 1 (NC1) domain of alpha3(IV) collagen, but little is known about Ab ... ...

Abstract	Background: Anti-glomerular basement membrane nephritis and Goodpasture syndrome result from autoantibody (Ab)-mediated destruction of kidney and lung. Ab target the noncollagenous 1 (NC1) domain of alpha3(IV) collagen, but little is known about Ab origins or structure. This ignorance is due in part to the inability to recover monoclonal Ab by transformation of patients' blood cells. The aim of this study was to assess the suitability of two humanized models for this purpose. Methods: NOD-scid-gamma immunodeficient mice were engrafted either with human CD34+ hematopoietic stem cells (HSC) (Hu-HSC mice) and immunized with alpha3(IV)NC1 collagen containing the Goodpasture epitopes or with nephritis patients' peripheral blood leukocytes (PBL) (Hu-PBL mice). After in vivo immune cell development and/or expansion, recovered human B cells were Epstein Barr virus (EBV)-transformed, screened for antigen (Ag) binding, electrofused with a mouse-human heterohybridoma, subcloned, and human Ab RNA sequenced by PCR after reverse transcription to cDNA. Flow cytometry was used to assess human B cell markers and differentiation in Hu-PBL mice. Results: Sequence analysis of a human Ab derived from an immunized Hu-HSC mouse and reactive with alpha3(IV)NC1 collagen reveals that it is encoded by unmutated heavy and light chain genes. The heavy chain complementarity determining region 3, a major determinant of Ag binding, contains uncommon motifs, including an N-region somatically-introduced highly hydrophobic tetrapeptide and dual cysteines encoded by a uniquely human IGHD2-2 Ab gene segment that lacks a murine counterpart. Comparison of human and mouse autoantibodies suggests that structurally similar murine Ab may arise by convergent selection. In contrast to the Hu-HSC model, transformed human B cells are rarely recovered from Hu-PBL mice, in which human B cells terminally differentiate and lose expression of EBV receptor CD21, thus precluding their transformation and recovery. Conclusions: Hu-HSC mice reveal that potentially pathogenic B cells bearing unmutated Ig receptors reactive with the NC1 domain on alpha3(IV) collagen can be generated in, and not purged from, the human preimmune repertoire. Uniquely human gene elements are recruited to generate the antigen binding site in at least a subset of these autoantibodies, indicating that humanized models may provide insights inaccessible using conventional mouse models.
MeSH term(s)	Amino Acid Sequence ; Animals ; Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/genetics ; Antibodies, Monoclonal/immunology ; B-Lymphocytes/immunology ; Base Sequence ; Collagen Type IV/chemistry ; Collagen Type IV/immunology ; Female ; Hematopoietic Stem Cells/metabolism ; Humans ; Leukocytes/metabolism ; Lymphocyte Subsets/immunology ; Mice ; Models, Animal ; Molecular Sequence Data ; Nephritis/immunology ; Protein Structure, Tertiary ; Receptors, Complement 3d/metabolism ; Sequence Analysis, Protein ; Tissue Donors
Chemical Substances	Antibodies, Monoclonal ; Collagen Type IV ; Receptors, Complement 3d
Language	English
Publishing date	2015-06-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2118570-0
ISSN	1479-5876 ; 1479-5876
ISSN (online)	1479-5876
ISSN	1479-5876
DOI	10.1186/s12967-015-0539-4
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