Works (27)

Updated: August 7th, 2023 06:30

2020 journal article

Glucose-responsive insulin patch for the regulation of blood glucose in mice and minipigs

NATURE BIOMEDICAL ENGINEERING, 4(5), 499–506.

MeSH headings : Animals; Blood Glucose / metabolism; Diabetes Mellitus, Experimental / blood; Disease Models, Animal; Drug Delivery Systems; Humans; Insulin / pharmacology; Insulin Secretion / drug effects; Male; Mice, Inbred C57BL; Needles; Swine; Swine, Miniature; Transdermal Patch
TL;DR: It is shown that a single removable transdermal patch, bearing microneedles loaded with insulin and a non-degradable glucose-responsive polymeric matrix, and fabricated via in situ photopolymerization, regulated blood glucose in insulin-deficient diabetic mice and minipigs. (via Semantic Scholar)
UN Sustainable Development Goal Categories
Source: Web Of Science
Added: February 17, 2020

2020 journal article

Targeted Delivery of Notch Inhibitor Attenuates Obesity-Induced Glucose Intolerance and Liver Fibrosis

ACS NANO, 14(6), 6878–6886.

By: L. Richter*, Q. Wan*, D. Wen n, Y. Zhang n, J. Yu*, J. Kang*, C. Zhu*, E. McKinnon* ...

author keywords: drug delivery; nanomedicine; Notch inhibitor; nonalcoholic steatohepatitis; obesity; liver fibrosis
MeSH headings : Animals; Diabetes Mellitus, Type 2 / pathology; Disease Models, Animal; Glucose Intolerance / drug therapy; Glucose Intolerance / pathology; Liver / pathology; Liver Cirrhosis / drug therapy; Liver Cirrhosis / pathology; Mice; Obesity / drug therapy
TL;DR: A nanoparticle-mediated delivery system to target γ-secretase inhibitor to liver (GSI NPs) reduces hepatic glucose production in diet-induced obese mice and reduced hepatic fibrosis and inflammation in mice fed a NASH-provoking diet, without apparent gastrointestinal toxicity. (via Semantic Scholar)
UN Sustainable Development Goal Categories
3. Good Health and Well-being (Web of Science; OpenAlex)
Source: Web Of Science
Added: July 20, 2020

2019 journal article

A Therapeutic Microneedle Patch Made from Hair-Derived Keratin for Promoting Hair Regrowth

ACS NANO, 13(4), 4354–4360.

By: G. Yang n, Q. Chen n, D. Wen n, Z. Chen n, J. Wang n, G. Chen n, Z. Wang*, X. Zhang n ...

author keywords: drug delivery; microneedle; exosome; keratin; hair regrowth; transdermal drug delivery
MeSH headings : Animals; Cell Line; Delayed-Action Preparations / chemistry; Drug Delivery Systems / instrumentation; Equipment Design; Hair / chemistry; Hair / drug effects; Hair / growth & development; Hair Follicle / drug effects; Hair Follicle / growth & development; Humans; Injections, Subcutaneous; Keratins / chemistry; Mice, Inbred C57BL; Transdermal Patch
TL;DR: It was demonstrated that this microneedle device integrated with mesenchymal stem cell (MSC)-derived exosomes and a small molecular drug, UK5099, could enhance the treatment efficiency at a reduced dosage, leading to promoted pigmentation and hair regrowth within 6 days through two rounds of administration in a mouse model. (via Semantic Scholar)
UN Sustainable Development Goal Categories
3. Good Health and Well-being (Web of Science; OpenAlex)
Source: Web Of Science
Added: June 4, 2019

2019 journal article

A forskolin-conjugated insulin analog targeting endogenous glucose-transporter for glucose-responsive insulin delivery

BIOMATERIALS SCIENCE, 7(11), 4508–4513.

By: J. Wang*, Z. Wang*, J. Yu n, Y. Zhang n, Y. Zeng* & Z. Gu*

MeSH headings : Animals; Colforsin / administration & dosage; Colforsin / pharmacology; Diabetes Mellitus, Experimental / drug therapy; Diabetes Mellitus, Experimental / metabolism; Diabetes Mellitus, Type 1 / drug therapy; Diabetes Mellitus, Type 1 / metabolism; Drug Delivery Systems; Glucose / metabolism; Glucose Tolerance Test; Glucose Transport Proteins, Facilitative / antagonists & inhibitors; Glucose Transport Proteins, Facilitative / metabolism; Hypoglycemic Agents / administration & dosage; Hypoglycemic Agents / pharmacology; Injections, Subcutaneous; Insulin / administration & dosage; Insulin / metabolism; Insulin / pharmacology; Mice
TL;DR: A new insulin analog is prepared by modifying insulin with forskolin (designated as insulin-F), a glucose-transporter (Glut) inhibitor that binds to endogenous Gluts and rapidly restores BGLs to the normal range. (via Semantic Scholar)
UN Sustainable Development Goal Categories
Source: Web Of Science
Added: December 16, 2019

2019 journal article

Adipocytes as Anticancer Drug Delivery Depot

MATTER, 1(5), 1203–1214.

By: D. Wen n, J. Wang n, G. Van Den Driessche n, Q. Chen n, Y. Zhang n, G. Chen n, H. Li*, J. Soto* ...

TL;DR: The lipid metabolism is exploited to engineer adipocytes that serve as a depot to deliver cancer therapeutics at the tumor site, promoting antitumor efficacy and downregulation of PD-L1 expression is observed in tumor cells. (via Semantic Scholar)
UN Sustainable Development Goal Categories
3. Good Health and Well-being (Web of Science; OpenAlex)
Source: Web Of Science
Added: April 6, 2020

2019 review

Advances in transdermal insulin delivery

[Review of ]. ADVANCED DRUG DELIVERY REVIEWS, 139, 51–70.

By: Y. Zhang n, J. Yu n, A. Kahkoska*, J. Wang n, J. Buse* & Z. Gu n

author keywords: Drug delivery; Transdermal delivery; Insulin; Diabetes; Iontophoresis; Electroporation; Ultrasound; Jet injection; Microneedle
MeSH headings : Administration, Cutaneous; Animals; Electroporation; Humans; Hypoglycemic Agents / administration & dosage; Insulin / administration & dosage; Iontophoresis; Microinjections; Needles; Ultrasonic Waves
TL;DR: Different transdermal insulin delivery techniques and their respective advantages and limitations are focused on, including chemical enhancers-promoted, electrically enhanced, mechanical force-triggered, and microneedle-assisted methods. (via Semantic Scholar)
UN Sustainable Development Goal Categories
3. Good Health and Well-being (Web of Science; OpenAlex)
Source: Web Of Science
Added: September 9, 2019

2019 journal article

Charge-switchable polymeric complex for glucose-responsive insulin delivery in mice and pigs

SCIENCE ADVANCES, 5(7).

By: J. Wang n, J. Yu n, Y. Zhang n, X. Zhang*, A. Kahkoska*, G. Chen*, Z. Wang*, W. Sun* ...

MeSH headings : Animals; Blood Glucose / drug effects; Diabetes Mellitus, Experimental / drug therapy; Drug Carriers / chemical synthesis; Drug Carriers / chemistry; Drug Delivery Systems; Insulin / administration & dosage; Mice; Molecular Structure; Polymers / chemical synthesis; Polymers / chemistry; Swine
TL;DR: A new strategy to form a micro-sized complex between a charge-switchable polymer with a glucose-sensing moiety and insulin driven by electrostatic interaction achieves high insulin loading efficiency and loading capacity and promotes release under hyperglycemic conditions. (via Semantic Scholar)
Source: Web Of Science
Added: August 19, 2019

2019 journal article

Glucose transporter inhibitor-conjugated insulin mitigates hypoglycemia

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 116(22), 10744–10748.

author keywords: drug delivery; diabetes; glucose-responsive; insulin; insulin analog
MeSH headings : Animals; Blood Glucose / analysis; Blood Glucose / drug effects; Diabetes Mellitus, Experimental; Drug Delivery Systems / methods; Glucose Transport Proteins, Facilitative / antagonists & inhibitors; Hyperglycemia / drug therapy; Hypoglycemia / prevention & control; Hypoglycemic Agents / chemistry; Hypoglycemic Agents / pharmacology; Insulin / analogs & derivatives; Insulin / chemistry; Insulin / pharmacology; Mice
TL;DR: An insulin-facilitated glucose transporter (Glut) inhibitor conjugate is reported, in which the insulin molecule is rendered glucose-responsive via conjugation to an inhibitor of Glut to regulate blood glucose levels within a normal range while mitigating the risk of hypoglycemia in a type 1 diabetic mouse model. (via Semantic Scholar)
UN Sustainable Development Goal Categories
Source: Web Of Science
Added: June 17, 2019

2019 journal article

In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment

NATURE NANOTECHNOLOGY, 14(1), 89-+.

By: Q. Chen n, C. Wang n, X. Zhang*, G. Chen*, Q. Hu n, H. Li*, J. Wang n, D. Wen* ...

MeSH headings : Animals; Biocompatible Materials / chemistry; Calcium Carbonate / chemistry; Female; Fibrin / chemistry; Gels / chemistry; Humans; Immunity; Immunotherapy / methods; Luminescent Measurements; Melanoma, Experimental / pathology; Mice, Inbred C57BL; Nanoparticles / chemistry; Nanoparticles / ultrastructure; Neoplasm Recurrence, Local / pathology; Neoplasms / pathology; Neoplasms / surgery; Phagocytosis
TL;DR: The findings indicate that the immunotherapeutic fibrin gel ‘awakens’ the host innate and adaptive immune systems to inhibit both local tumour recurrence post surgery and potential metastatic spread. (via Semantic Scholar)
UN Sustainable Development Goal Categories
3. Good Health and Well-being (Web of Science; OpenAlex)
Source: Web Of Science
Added: January 21, 2019

2019 journal article

Shape-controlled synthesis of liquid metal nanodroplets for photothermal therapy

NANO RESEARCH, 12(6), 1313–1320.

By: J. Yan n, X. Zhang n, Y. Liu n, Y. Ye n, J. Yu n, Q. Chen n, J. Wang n, Y. Zhang n ...

author keywords: liquid metal; melanin nanoparticles; nanomedicine; shape-controlled synthesis; photothermal therapy
TL;DR: Interestingly, shape-controlled synthesis of LM nanodroplets can be achieved by the incorporation of MNPs, and among these shapes, EGaIn nanorice has the best photothermal conversion efficiency, which could be leveraged for photothermal therapy. (via Semantic Scholar)
Source: Web Of Science
Added: June 17, 2019

2018 journal article

Advances in bioresponsive closed-loop drug delivery systems

INTERNATIONAL JOURNAL OF PHARMACEUTICS, 544(2), 350–357.

author keywords: Closed-loop; Drug delivery; Bioresponsive; Glucose-responsive; Enzyme-responsive
MeSH headings : Anticoagulants / administration & dosage; Diabetes Mellitus, Type 1 / blood; Diabetes Mellitus, Type 1 / drug therapy; Drug Delivery Systems / methods; Feedback, Physiological / drug effects; Homeostasis / drug effects; Humans; Hypoglycemic Agents / administration & dosage; Thrombosis / blood; Thrombosis / drug therapy
TL;DR: The recent advances in bioresponsive closed‐loop drug delivery systems, including glucose‐responsive, enzyme‐activated, and other biosignal‐mediated delivery systems are surveyed. (via Semantic Scholar)
UN Sustainable Development Goal Categories
3. Good Health and Well-being (Web of Science; OpenAlex)
Source: Web Of Science
Added: August 6, 2018

2018 journal article

Bioresponsive Microneedles with a Sheath Structure for H2O2 and pH Cascade-Triggered Insulin Delivery

SMALL, 14(14).

author keywords: diabetes; drug delivery; insulin; microneedles; stimuli-responsive
MeSH headings : Animals; Drug Delivery Systems / methods; Humans; Hydrogen Peroxide / chemistry; Hydrogen-Ion Concentration; Insulin / administration & dosage; Insulin / chemistry; Mice; Oxidation-Reduction
TL;DR: The resulting microneedle patch can release insulin with rapid responsiveness under hyperglycemic conditions owing to an oxidative and acidic environment because of glucose oxidation, and can therefore effectively regulate blood glucose levels within a normal range on a chemically induced type 1 diabetic mouse model with enhanced biocompatibility. (via Semantic Scholar)
Source: Web Of Science
Added: August 6, 2018

2018 article

The potential of a microneedle patch for reducing obesity

EXPERT OPINION ON DRUG DELIVERY, Vol. 15, pp. 431–433.

By: Y. Zhang n, J. Yu n, D. Wen n, G. Chen n & Z. Gu n

author keywords: Obesity; browning; microneedle; intradermal delivery
TL;DR: This work presents a novel approach to drug delivery called “nanotechnology in drug delivery” that combines “ nanofiltration” and “ Nanolysis” techniques. (via Semantic Scholar)
UN Sustainable Development Goal Categories
Source: Web Of Science
Added: August 6, 2018

2017 journal article

A melanin-mediated cancer immunotherapy patch

SCIENCE IMMUNOLOGY, 2(17).

By: Y. Ye n, C. Wang n, X. Zhang n, Q. Hu n, Y. Zhang n, Q. Liu n, D. Wen n, J. Milligan n ...

MeSH headings : Animals; Cancer Vaccines / immunology; Cancer Vaccines / metabolism; Cell Line, Tumor; Dendritic Cells / immunology; Dendritic Cells / metabolism; Female; Immunotherapy / instrumentation; Immunotherapy / methods; Infrared Rays; Kaplan-Meier Estimate; Melanins / immunology; Melanins / metabolism; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Needles; Neoplasms, Experimental / immunology; Neoplasms, Experimental / pathology; Neoplasms, Experimental / therapy; Transdermal Patch; Tumor Burden / immunology
TL;DR: It is found that the spatiotemporal photoresponsive immunotherapy increases infiltration of polarized T cells and local cytokine release in mice after tumor challenge and elicited antitumor effects toward established primary tumor and distant tumor. (via Semantic Scholar)
Source: Web Of Science
Added: August 6, 2018

2017 review

Bioresponsive transcutaneous patches

[Review of ]. CURRENT OPINION IN BIOTECHNOLOGY, 48, 28–32.

By: J. Yu n, Y. Zhang n, A. Kahkoska* & Z. Gu n

MeSH headings : Administration, Cutaneous; Animals; Drug Delivery Systems / methods; Drug Monitoring / methods; Humans; Needles; Skin; Transdermal Patch
TL;DR: Recent advances in the development and use of bioresponsive transcutaneous patches for on-demand smart and precise drug delivery, exploiting different physiological signals including pH, serum glucose levels, and enzyme activity are surveyed. (via Semantic Scholar)
UN Sustainable Development Goal Categories
3. Good Health and Well-being (Web of Science; OpenAlex)
Source: Web Of Science
Added: August 6, 2018

2017 journal article

Hypoxia and H2O2 Dual-Sensitive Vesicles for Enhanced Glucose-Responsive Insulin Delivery

NANO LETTERS, 17(2), 733–739.

By: J. Yu n, C. Qian n, Y. Zhang n, Z. Cui n, Y. Zhu n, Q. Shen*, F. Ligler n, J. Buse*, Z. Gu n

author keywords: Drug delivery; diabetes; insulin; glucose-responsive; hypoxia-sensitive; H2O2-sensitive
MeSH headings : Animals; Blood Glucose / metabolism; Cell Hypoxia; Diabetes Mellitus, Experimental / drug therapy; Diabetes Mellitus, Experimental / metabolism; Diabetes Mellitus, Type 1 / drug therapy; Diabetes Mellitus, Type 1 / metabolism; Drug Carriers / chemistry; Drug Liberation; Glucose / metabolism; Glucose Oxidase / metabolism; HeLa Cells; Humans; Hydrogen Peroxide / metabolism; Hypoglycemic Agents / administration & dosage; Hypoglycemic Agents / chemistry; Insulin / administration & dosage; Insulin / chemistry; Male; Mice, Inbred C57BL; Nitroimidazoles / chemistry; Oxidation-Reduction; Peptides / chemistry; Polyethylene Glycols / chemistry
TL;DR: In vivo experiments indicated that this smart insulin patch could efficiently regulate the blood glucose in the chemically induced type 1 diabetic mice for 10 h and eliminate the excess H2O2, which may lead to free radical-induced damage to skin tissue during the long-term usage and reduce the activity of GOx. (via Semantic Scholar)
UN Sustainable Development Goal Categories
Source: Web Of Science
Added: August 6, 2018

2017 journal article

Insulin-responsive glucagon delivery for prevention of hypoglycemia

Small (Weinheim An Der Bergstrasse, Germany), 13(19).

By: J. Yu n, Y. Zhang n, W. Sun n, A. Kahkoska*, J. Wang n, J. Buse*, Z. Gu n

Source: NC State University Libraries
Added: August 6, 2018

2017 journal article

Locally Induced Adipose Tissue Browning by Microneedle Patch for Obesity Treatment

ACS NANO, 11(9), 9223–9230.

By: Y. Zhang n, Q. Liu*, J. Yu n, S. Yu n, J. Wang n, L. Qiang*, Z. Gu n

author keywords: drug delivery; microneedle patch; obesity; browning agent; adipose tissue
MeSH headings : Adipocytes, White / drug effects; Adipose Tissue, White / drug effects; Animals; Anti-Obesity Agents / administration & dosage; Anti-Obesity Agents / therapeutic use; Drug Delivery Systems / instrumentation; Hypoglycemic Agents / administration & dosage; Hypoglycemic Agents / therapeutic use; Male; Mice, Inbred C57BL; Obesity / drug therapy; Rosiglitazone / administration & dosage; Rosiglitazone / therapeutic use; Transdermal Patch
TL;DR: A transcutaneous browning agent patch is developed to locally induce adipose tissue transformation and reduces treated fat pad size, increases whole body energy expenditure, and improves type-2 diabetes in vivo in a diet-induced obesity mouse model. (via Semantic Scholar)
UN Sustainable Development Goal Categories
3. Good Health and Well-being (Web of Science; OpenAlex)
Source: Web Of Science
Added: August 6, 2018

2017 review

Photoacoustic Drug Delivery

[Review of ]. SENSORS, 17(6).

By: Y. Zhang n, J. Yu n, A. Kahkoska* & Z. Gu n

author keywords: photoacoustic imaging; drug delivery; chemotherapy; photothermal therapy
MeSH headings : Drug Delivery Systems; Humans; Optical Imaging; Photoacoustic Techniques; Spectrum Analysis; Theranostic Nanomedicine
TL;DR: This review focuses on the recent development of PAI-mediated drug delivery systems and provides an overview of the design of different PAI agents for drug delivery. (via Semantic Scholar)
UN Sustainable Development Goal Categories
3. Good Health and Well-being (Web of Science; OpenAlex)
Source: Web Of Science
Added: August 6, 2018

2017 journal article

Smart materials and systems as artificial pancreas for diabetes treatment

Smart Materials for Tissue Engineering: Applications, 25, 358–381.

By: Y. Zhang, M. Wang, J. Yu & Z. Gu

Source: NC State University Libraries
Added: August 6, 2018

2017 journal article

Thrombin-responsive transcutaneous patch for auto-anticoagulant regulation

Advanced Materials, 29(4).

By: Y. Zhang n, J. Yu n, J. Wang n, N. Hanne n, Z. Cui n, C. Qian n, C. Wang n, H. Xin n ...

UN Sustainable Development Goal Categories
3. Good Health and Well-being (OpenAlex)
Sources: NC State University Libraries, NC State University Libraries
Added: August 6, 2018

2016 article

Elastic drug delivery: could treatments be triggered by patient movement?

NANOMEDICINE, Vol. 11, pp. 323–325.

By: Y. Zhang n, J. Yu n, Y. Zhu n & Z. Gu n

author keywords: drug delivery; mechanical-responsive; nanoparticle; wearable devices
MeSH headings : Drug Delivery Systems; Elasticity; Humans; Movement; Patients
UN Sustainable Development Goal Categories
Source: Web Of Science
Added: August 6, 2018

2016 journal article

Hypoxia-Sensitive Materials for Biomedical Applications

ANNALS OF BIOMEDICAL ENGINEERING, 44(6), 1931–1945.

By: J. Yu n, Y. Zhang n, X. Hu*, G. Wright n & Z. Gu n

author keywords: Hypoxia-responsive; Drug delivery; Bioimaging; Hypoxia inducible factor-1; Bioreductive molecule
MeSH headings : Animals; Cell Hypoxia; Humans; Hypoxia-Inducible Factor 1 / metabolism; Tissue Scaffolds / chemistry
TL;DR: Recent progress in the development of hypoxia-responsive systems for imaging, sensing and therapy was summarized and two types of hyp oxia-sensitive systems were reviewed with comments on their advantages and limitations. (via Semantic Scholar)
UN Sustainable Development Goal Categories
3. Good Health and Well-being (Web of Science; OpenAlex)
Source: Web Of Science
Added: August 6, 2018

2016 journal article

Internalized compartments encapsulated nanogels for targeted drug delivery

NANOSCALE, 8(17), 9178–9184.

By: J. Yu n, Y. Zhang n, W. Sun n, C. Wang n, D. Ranson n, Y. Ye n, Y. Weng*, Z. Gu n

MeSH headings : Doxorubicin / administration & dosage; Drug Delivery Systems; Ferrous Compounds; Hyaluronic Acid; Nanoparticles; Silicon Dioxide
TL;DR: This study illustrates the potential of utilizing an internalized compartments encapsulated formulation for targeted cancer therapy, and offers guidelines for developing a natural particulate-inspired drug delivery system. (via Semantic Scholar)
UN Sustainable Development Goal Categories
3. Good Health and Well-being (Web of Science; OpenAlex)
Source: Web Of Science
Added: August 6, 2018

2016 review

Mechanical Force-Triggered Drug Delivery

[Review of ]. CHEMICAL REVIEWS, 116(19), 12536–12563.

By: Y. Zhang n, J. Yu n, H. Bomba n, Y. Zhu n & Z. Gu n

MeSH headings : Animals; Drug Carriers / chemistry; Drug Carriers / pharmacology; Drug Delivery Systems / methods; Liposomes / chemistry; Liposomes / pharmacology; Magnetic Phenomena; Mechanical Phenomena; Microbubbles; Nanoparticles / chemistry; Ultrasonic Waves
TL;DR: An overview of recent advances in mechanically activated DDS is provided and the opportunities and challenges regarding clinical translations are discussed. (via Semantic Scholar)
UN Sustainable Development Goal Categories
3. Good Health and Well-being (Web of Science; OpenAlex)
Source: Web Of Science
Added: August 6, 2018

2015 review

Glucose-responsive synthetic closed-loop insulin delivery systems

[Review of ]. Progress in Chemistry, 27(1), 11–26.

By: Y. Zhang, J. Yu, Q. Shen & Z. Gu

Source: NC State University Libraries
Added: August 6, 2018

2015 journal article

Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 112(27), 8260–8265.

By: J. Yu n, Y. Zhang n, Y. Ye n, R. DiSanto n, W. Sun n, D. Ranson n, F. Ligler n, J. Buse*, Z. Gu n

author keywords: diabetes; drug delivery; glucose-responsive; hypoxia-sensitive; microneedle
MeSH headings : Animals; Blood Glucose / analysis; Diabetes Mellitus, Experimental / blood; Diabetes Mellitus, Experimental / drug therapy; Diabetes Mellitus, Type 1 / blood; Diabetes Mellitus, Type 1 / drug therapy; Drug Delivery Systems / instrumentation; Drug Delivery Systems / methods; Glucose / metabolism; Glucose Oxidase / metabolism; Humans; Hyaluronic Acid / chemistry; Hyaluronic Acid / metabolism; Hypoglycemic Agents / administration & dosage; Hypoglycemic Agents / chemistry; Hypoxia / metabolism; Insulin / administration & dosage; Insulin / chemistry; Insulin / metabolism; Male; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Molecular Structure; Oxidation-Reduction; Reproducibility of Results
TL;DR: The “smart insulin patch” with a new enzyme-based glucose-responsive mechanism can regulate the blood glucose of type 1 diabetic mice to achieve normal levels, with faster responsiveness compared with the commonly used pH-sensitive formulations, and can avoid the risk of hypoglycemia. (via Semantic Scholar)
Source: Web Of Science
Added: August 6, 2018

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