Publications by authors named "Mark E Davis"

114 Publications

Inhibition of interleukin-6 on matrix protein production by glomerular mesangial cells and the pathway involved.

Am J Physiol Renal Physiol 2020 06 11;318(6):F1478-F1488. Epub 2020 May 11.

Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, Texas.

Activation of immunological pathways and disturbances of extracellular matrix (ECM) dynamics are important contributors to the pathogenesis of chronic kidney diseases. Glomerular mesangial cells (MCs) are critical for homeostasis of glomerular ECM dynamics. Interleukin-6 (IL-6) can act as a pro/anti-inflammatory agent relative to cell types and conditions. This study investigated whether IL-6 influences ECM protein production by MCs and the regulatory pathways involved. Experiments were carried out in cultured human MCs (HMCs) and in mice. We found that overexpression of IL-6 and its receptor decreased the abundance of fibronectin and collagen type IV in MCs. ELISA and immunoblot analysis demonstrated that thapsigargin [an activator of store-operated Ca entry (SOCE)], but not the endoplasmic reticulum stress inducer tunicamycin, significantly increased IL-6 content. This thapsigargin effect was abolished by GSK-7975A, a selective inhibitor of SOCE, and by silencing Orai1 (the channel protein mediating SOCE). Furthermore, inhibition of NF-κB pharmacologically and genetically significantly reduced SOCE-induced IL-6 production. Thapsigargin also stimulated nuclear translocation of the p65 subunit of NF-κB. Moreover, MCs overexpressing IL-6 and its receptor in HMCs increased the content of the glucagon-like peptide-1 receptor (GLP-1R), and IL-6 inhibition of fibronectin was attenuated by the GLP-1R antagonist exendin 9-39. In agreement with the HMC data, specific knockdown of Orai1 in MCs using the targeted nanoparticle delivery system in mice significantly reduced glomerular GLP-1R levels. Taken together, our results suggest a novel SOCE/NF-κB/IL-6/GLP-1R signaling pathway that inhibits ECM protein production by MCs.
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http://dx.doi.org/10.1152/ajprenal.00043.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311714PMC
June 2020

Nanoparticles Containing a Combination of a Drug and an Antibody for the Treatment of Breast Cancer Brain Metastases.

Mol Pharm 2020 02 14;17(2):717-721. Epub 2020 Jan 14.

Chemical Engineering , California Institute of Technology , 1200 East California Boulevard , Pasadena , California 91125 , United States.

In women with human epidermal growth factor 2 (HER2)-positive breast cancer, the improved control of systemic disease with new therapies has unmasked brain metastases that historically would have remained clinically silent. The efficacy of therapeutic agents against brain metastases is limited by their inability to permeate the blood-brain and blood-tumor barriers (BBB and BTB) in therapeutic amounts. Here, we investigate the potential of mucic acid-based, targeted nanoparticles designed to transcytose the BBB/BTB to deliver a small molecule drug, camptothecin (CPT), and therapeutic antibody, Herceptin, to brain metastases in mice. Treatment with BBB-targeted combination CPT/Herceptin nanoparticles significantly inhibits tumor growth compared to free CPT/Herceptin and BBB-targeted nanoparticles carrying CPT alone. Though not as efficacious, BBB-targeted nanoparticles carrying only Herceptin also elicit considerable antitumor activity. These results demonstrate the potential of the targeted nanoparticle system for the delivery of an antibody alone or in combination with other drugs across the BBB/BTB to improve the therapeutic outcome.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b01167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061347PMC
February 2020

Integration of thermochemical water splitting with CO direct air capture.

Proc Natl Acad Sci U S A 2019 Dec 21;116(50):25001-25007. Epub 2019 Nov 21.

Center for Catalytic Science and Technology, Chemical and Biomolecular Engineering, University of Delaware, Newark, DE 19716;

Renewable production of fuels and chemicals from direct air capture (DAC) of CO is a highly desired goal. Here, we report the integration of the DAC of CO with the thermochemical splitting of water to produce CO, H, O, and electricity. The produced CO and H can be converted to value-added chemicals via existing technologies. The integrated process uses thermal solar energy as the only energy input and has the potential to provide the dual benefits of combating anthropogenic climate change while creating renewable chemicals. A sodium-manganese-carbonate (Mn-Na-CO) thermochemical water-splitting cycle that simultaneously drives renewable H production and DAC of CO is demonstrated. An integrated reactor is designed and fabricated to conduct all steps of the thermochemical water-splitting cycle that produces close to stoichiometric amounts (∼90%) of H and O (illustrated with 6 consecutive cycles). The ability of the cycle to capture 75% of the ∼400 ppm CO from air is demonstrated also. A technoeconomic analysis of the integrated process for the renewable production of H, O, and electricity, as well as DAC of CO shows that the proposed scheme of solar-driven H production from thermochemical water splitting coupled with CO DAC may be economically viable under certain circumstances.
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http://dx.doi.org/10.1073/pnas.1915951116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911180PMC
December 2019

Host immune response to anti-cancer camptothecin conjugated cyclodextrin-based polymers.

J Biomed Sci 2019 Oct 23;26(1):85. Epub 2019 Oct 23.

TMU Research Center of Cancer Translational Medicine, Taipei Medical University, 11031, Taipei, Taiwan.

Introduction: Efficacy and safety are critical concerns when designing drug carriers. Nanoparticles are a particular type of carrier that has gained recent attention in cancer therapeutics.

Methods: In this study, we assess the safety profile of IT-101, a nanoparticle formed by self-assembly of camptothecin (CPT) conjugated cyclodextrin-based polymers. IT-101 delivers CPT to target cancer cells in animal models of numerous human cancers and in humans. Previous data from preclinical and clinical trials indicate that IT-101 has no notable immunological side effects. However, there have been no published studies focused on evaluating the effects of IT-101 on host immune systems.

Results: In this work, we demonstrate that IT-101 diminished initial host immune response following first injection of the nanopharmaceutical and induced NK cell activation and T cell proliferation upon further IT-101 exposure. Additionally, IT-101 could attenuate tumor growth more efficiently than CPT treatment only.

Conclusions: Drugs administration in whole-body circulation may lead to poorly bioavailable in central nervous system and often has toxic effects on peripheral tissues. Conjugated with cyclodextrin-based polymers not only reduce adverse effects but also modulate the immune responses to elevate drug efficacy. These immune responses may potentially facilitate actions of immune blockage, such as PD1/PDL1 in cancer treatment.
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http://dx.doi.org/10.1186/s12929-019-0583-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806548PMC
October 2019

Method of establishing breast cancer brain metastases affects brain uptake and efficacy of targeted, therapeutic nanoparticles.

Bioeng Transl Med 2019 Jan 5;4(1):30-37. Epub 2018 Nov 5.

Chemical Engineering California Institute of Technology Pasadena CA.

HER2-targeted therapies effectively control systemic disease, but their efficacy against brain metastases is hindered by their low penetration of the blood-brain and blood-tumor barriers (BBB and BTB). We investigate brain uptake and antitumor efficacy of transferrin receptor (TfR)-targeted, therapeutic nanoparticles designed to transcytose the BBB/BTB in three murine models. Two known models involving intracranial (IC) or intracardiac (ICD) injection of human breast cancer cells were employed, as was a third model developed here involving intravenous (IV) injection of the cells to form whole-body tumors that eventually metastasize to the brain. We show the method of establishing brain metastases significantly affects therapeutic BBB/BTB penetration. Free drug accumulates and delays growth in IC- and ICD-formed brain tumors, while non-targeted nanoparticles show uptake and inhibition only in IC-established metastases. TfR-targeted nanoparticles accumulate and significantly delay growth in all three models, suggesting the IV model maintains a more intact BBB/BTB than the other models.
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http://dx.doi.org/10.1002/btm2.10108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336738PMC
January 2019

Small-Pore Zeolites: Synthesis and Catalysis.

Chem Rev 2018 06 10;118(11):5265-5329. Epub 2018 May 10.

Chemical Engineering , California Institute of Technology , Mail Code 210-41, Pasadena , California 91125 , United States.

In the past decade or so, small-pore zeolites have received greater attention than large- and medium-pore molecular sieves that have historically dominated the literature. This is primarily due to the commercialization of two major catalytic processes, NOx exhaust removal and methanol conversion to light olefins, that take advantage of the properties of these materials with smaller apertures. Small-pore zeolites possess pores that are constructed of eight tetrahedral atoms (Si and Al), each time linked by a shared oxygen These eight-member ring pores (8MR) provide small molecules access to the intracrystalline void space, e.g., to NOx during car exhaust cleaning (NOx removal) or to methanol en route to its conversion into light olefins, while restricting larger molecule entrance and departure that is critical to overall catalyst performance. In total, there are forty-four structurally different small-pore zeolites. Forty-one of these zeolites can be synthesized, and the first synthetic zeolite (KFI, 1948) was in fact a small-pore material. Although the field of 8MR zeolite chemistry has expanded in many directions, the progress in synthesis is framework-specific, leaving insights and generalizations difficult to realize. This review first focuses on the relevant synthesis details of all 8MR zeolites and provides some generalized findings and related insights. Next, catalytic applications where 8MR zeolites either have been commercialized or have dominated investigations are presented, with the aim of providing structure-activity relationships. The review ends with a summary that discusses (i) both synthetic and catalytic progress, (ii) a list of opportunities in the 8MR zeolite field, and (iii) a brief future outlook.
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http://dx.doi.org/10.1021/acs.chemrev.7b00738DOI Listing
June 2018

A Chromium Hydroxide/MIL-101(Cr) MOF Composite Catalyst and Its Use for the Selective Isomerization of Glucose to Fructose.

Angew Chem Int Ed Engl 2018 04 23;57(18):4926-4930. Epub 2018 Mar 23.

Department of Chemical Engineering and Materials Science, University of Minnesota, 421 Washington Ave SE, Minneapolis, MN, 55455, USA.

A metal-organic framework (MOF)-based catalyst, chromium hydroxide/MIL-101(Cr), was prepared by a one-pot synthesis method. The combination of chromium hydroxide particles on and within Lewis acidic MIL-101 accomplishes highly selective conversion of glucose to fructose in the presence of ethanol, matching the performance of optimized Sn-containing Lewis acidic zeolites. Differently from zeolites, NMR spectroscopy studies with isotopically labeled molecules demonstrate that isomerization of glucose to fructose on this catalyst, proceeds predominantly via a proton transfer mechanism.
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http://dx.doi.org/10.1002/anie.201712818DOI Listing
April 2018

Pilot trial of CRLX101 in patients with advanced, chemotherapy-refractory gastroesophageal cancer.

J Gastrointest Oncol 2017 Dec;8(6):962-969

The Graduate Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.

Background: CRLX101 is an investigational nanoparticle-drug conjugate with a camptothecin payload. Preclinical evidence indicated preferential uptake in tumors, and tumor xenograft models demonstrate superiority of CRLX101 over irinotecan. A pilot trial was conducted at recommended phase 2 dosing (RP2D) using the bimonthly schedule to assess preferential uptake of CRLX101 in tumor . adjacent normal tissue in endoscopically accessible tumors in chemotherapy-refractory gastroesophageal cancer. Results from the biopsies were previously reported and herein we present the clinical outcomes.

Methods: Patients initiated CRLX101 dosed at RP2D (15 mg/m) on days 1 and 15 of a 28-day cycle. Detection of preferential CRLX101 tumor uptake was the primary endpoint and objective response rate (ORR) was a secondary endpoint. With a sample size of ten patients, the study had 90% power to detect ≥1 responder if the true response rate is ≥21%.

Results: Between Dec. 2012 and Dec. 2014, ten patients with chemotherapy-refractory (median 2 prior lines of therapy, range 1-4) gastric adenocarcinoma were enrolled. The median time-to-progression was 1.7 months. Best response was seen in one patient with stable disease (SD) for 8 cycles. Only ≥ grade 3 drug-related toxicity occurred in one patient with grade 3 cardiac chest pain who was able to resume therapy after CRLX101 was reduced to 12 mg/m.

Conclusions: Bimonthly CRLX101 demonstrated minimal activity with SD as best response in this heavily pretreated population. Future efforts with CRLX101 in gastric cancer should focus on combination and more dose-intensive strategies given its favorable toxicity profile and evidence of preferential tumor uptake.
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http://dx.doi.org/10.21037/jgo.2017.08.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750185PMC
December 2017

Further Studies on How the Nature of Zeolite Cavities That Are Bounded by Small Pores Influences the Conversion of Methanol to Light Olefins.

Chemphyschem 2018 Feb 10;19(4):412-419. Epub 2018 Jan 10.

Chevron Energy Technology Company, 100 Chevron Way, Richmond, CA, 94802, USA.

A series of small-pore zeolites are synthesized and investigated as catalysts for the methanol-to-olefins (MTO) reaction. Small-pore zeolites SSZ-13, SSZ-16, SSZ-27, SSZ-28, SSZ-52, SSZ-98, SSZ-99, SSZ-104, SSZ-105 and an ITQ-3-type material are synthesized, and the results from their use as catalytic materials in the MTO reaction compared to those obtained from SAPO-34. The production of propane that tends to correlate with catalytic material lifetime (higher initial propane yields lead to shorter lifetimes) declines with increasing Si/Al (as has been observed previously for SSZ-13), and a larger cage dimension leads to higher propane yields at a fixed Si/Al. Data from these materials and others reported previously, for example, SSZ-39 and Rho, that were tested at the same reaction conditions, revealed four different patterns of light olefin selectivities: 1) ethylene greater than propylene with low butene, for example, SSZ-17, SSZ-98, SSZ-105, 2) ethylene equal to propylene and low butene, for example, SAPO-34, SSZ-13, SSZ-16, SSZ-27, SSZ-52, SSZ-99, SSZ-104, 3) propylene greater than ethylene with butene similar to ethylene, for example, SSZ-28, SSZ-39, and 4) ethylene equal to propylene equal to butene, for example, Rho. No clear relationships between zeolite cage architecture and light olefin selectivity emerged from this investigation, although several trends are presented as suggestions for further study.
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http://dx.doi.org/10.1002/cphc.201701197DOI Listing
February 2018

CIT-9: A Fault-Free Gmelinite Zeolite.

Angew Chem Int Ed Engl 2017 10 21;56(43):13475-13478. Epub 2017 Sep 21.

Chemical Engineering, California Institute of Technology, 1200 E. California Blvd., Pasadena, CA, 91125, USA.

A synthetic, fault-free gmelinite (GME) zeolite is prepared using a specific organic structure-directing agent (OSDA), cis-3,5-dimethylpiperidinium. The cis-isomers align in the main 12-membered ring (MR) channel of GME. Trans-isomer OSDA leads to the small-pore zeolite SSZ-39 with the OSDA in its cages. Data from N -physisorption and rotation electron diffraction provide evidence for the openness of the 12 MR channel in the GME 12×8×8 pore architecture and the absence of stacking faults, respectively. CIT-9 is hydrothermally stable when K -exchanged, while in the absence of exchange, the material transforms into an aluminous AFI-zeolite. The process of this phase-change was followed by in situ variable temperature powder X-ray diffraction. CIT-9 has the highest Si/Al ratio reported for GME, and along with its good porosity, opens the possibility of using GME in a variety of applications including catalysis.
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http://dx.doi.org/10.1002/anie.201707452DOI Listing
October 2017

Store-operated calcium entry suppressed the TGF-β1/Smad3 signaling pathway in glomerular mesangial cells.

Am J Physiol Renal Physiol 2017 09 21;313(3):F729-F739. Epub 2017 Jun 21.

Institute for Cardiovascular and Metabolic Diseases, University of North Texas Health Science Center, Fort Worth, Texas;

Our previous study demonstrated that the abundance of extracellular matrix proteins was suppressed by store-operated Ca entry (SOCE) in mesangial cells (MCs). The present study was conducted to investigate the underlying mechanism focused on the transforming growth factor-β1 (TGF-β1)/Smad3 pathway, a critical pathway for ECM expansion in diabetic kidneys. We hypothesized that SOCE suppressed ECM protein expression by inhibiting this pathway in MCs. In cultured human MCs, we observed that TGF-β1 (5 ng/ml for 15 h) significantly increased Smad3 phosphorylation, as evaluated by immunoblot. However, this response was markedly inhibited by thapsigargin (1 µM), a classical activator of store-operated Ca channels. Consistently, both immunocytochemistry and immunoblot showed that TGF-β1 significantly increased nuclear translocation of Smad3, which was prevented by pretreatment with thapsigargin. Importantly, the thapsigargin effect was reversed by lanthanum (La; 5 µM) and GSK-7975A (10 µM), both of which are selective blockers of store-operated Ca channels. Furthermore, knockdown of Orai1, the pore-forming subunit of the store-operated Ca channels, significantly augmented TGF-β1-induced Smad3 phosphorylation. Overexpression of Orai1 augmented the inhibitory effect of thapsigargin on TGF-β1-induced phosphorylation of Smad3. In agreement with the data from cultured MCs, in vivo knockdown of Orai1 specific to MCs using a targeted nanoparticle small interfering RNA delivery system resulted in a marked increase in abundance of phosphorylated Smad3 and in nuclear translocation of Smad3 in the glomerulus of mice. Taken together, our results indicate that SOCE in MCs negatively regulates the TGF-β1/Smad3 signaling pathway.
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http://dx.doi.org/10.1152/ajprenal.00483.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625109PMC
September 2017

Enantiomerically enriched, polycrystalline molecular sieves.

Proc Natl Acad Sci U S A 2017 05 1;114(20):5101-5106. Epub 2017 May 1.

Chemical Engineering, California Institute of Technology, Pasadena, CA 91125;

Zeolite and zeolite-like molecular sieves are being used in a large number of applications such as adsorption and catalysis. Achievement of the long-standing goal of creating a chiral, polycrystalline molecular sieve with bulk enantioenrichment would enable these materials to perform enantioselective functions. Here, we report the synthesis of enantiomerically enriched samples of a molecular sieve. Enantiopure organic structure directing agents are designed with the assistance of computational methods and used to synthesize enantioenriched, polycrystalline molecular sieve samples of either enantiomer. Computational results correctly predicted which enantiomer is obtained, and enantiomeric enrichment is proven by high-resolution transmission electron microscopy. The enantioenriched and racemic samples of the molecular sieves are tested as adsorbents and heterogeneous catalysts. The enantioenriched molecular sieves show enantioselectivity for the ring opening reaction of epoxides and enantioselective adsorption of 2-butanol (the R enantiomer of the molecular sieve shows opposite and approximately equal enantioselectivity compared with the S enantiomer of the molecular sieve, whereas the racemic sample of the molecular sieve shows no enantioselectivity).
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http://dx.doi.org/10.1073/pnas.1704638114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441830PMC
May 2017

Negative regulation of Smad1 pathway and collagen IV expression by store-operated Ca entry in glomerular mesangial cells.

Am J Physiol Renal Physiol 2017 06 15;312(6):F1090-F1100. Epub 2017 Mar 15.

Institute for Cardiovascular and Metabolic Disease, University of North Texas Health Science Center, Fort Worth, Texas;

Collagen IV (Col IV) is a major component of expanded glomerular extracellular matrix in diabetic nephropathy and Smad1 is a key molecule regulating Col IV expression in mesangial cells (MCs). The present study was conducted to determine if Smad1 pathway and Col IV protein abundance were regulated by store-operated Ca entry (SOCE). In cultured human MCs, pharmacological inhibition of SOCE significantly increased the total amount of Smad1 protein. Activation of SOCE blunted high-glucose-increased Smad1 protein content. Treatment of human MCs with ANG II at 1 µM for 15 min, high glucose for 3 days, or TGF-β1 at 5 ng/ml for 30 min increased the level of phosphorylated Smad1. However, the phosphorylation of Smad1 by those stimuli was significantly attenuated by activation of SOCE. Knocking down Smad1 reduced, but expressing Smad1 increased, the amount of Col IV protein. Furthermore, activation of SOCE significantly attenuated high-glucose-induced Col IV protein production, and blockade of SOCE substantially increased the abundance of Col IV. To further verify those in vitro findings, we downregulated SOCE specifically in MCs in mice using small-interfering RNA (siRNA) against Orai1 (the channel protein mediating SOCE) delivered by the targeted nanoparticle delivery system. Immunohistochemical examinations showed that expression of both Smad1 and Col IV proteins was significantly greater in the glomeruli with positively transfected Orai1 siRNA compared with the glomeruli from the mice without Orai1 siRNA treatment. Taken together, our results indicate that SOCE negatively regulates the Smad1 signaling pathway and inhibits Col IV protein production in MCs.
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http://dx.doi.org/10.1152/ajprenal.00642.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495888PMC
June 2017

CRLX101 nanoparticles localize in human tumors and not in adjacent, nonneoplastic tissue after intravenous dosing.

Proc Natl Acad Sci U S A 2016 Apr 21;113(14):3850-4. Epub 2016 Mar 21.

Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125;

Nanoparticle-based therapeutics are being used to treat patients with solid tumors. Whereas nanoparticles have been shown to preferentially accumulate in solid tumors of animal models, there is little evidence to prove that intact nanoparticles localize to solid tumors of humans when systemically administered. Here, tumor and adjacent, nonneoplastic tissue biopsies are obtained through endoscopic capture from patients with gastric, gastroesophageal, or esophageal cancer who are administered the nanoparticle CRLX101. Both the pre- and postdosing tissue samples adjacent to tumors show no definitive evidence of either the nanoparticle or its drug payload (camptothecin, CPT) contained within the nanoparticle. Similar results are obtained from the predosing tumor samples. However, in nine of nine patients that were evaluated, CPT is detected in the tumor tissue collected 24-48 h after CRLX101 administration. For five of these patients, evidence of the intact deposition of CRLX101 nanoparticles in the tumor tissue is obtained. Indications of CPT pharmacodynamics from tumor biomarkers such as carbonic anhydrase IX and topoisomerase I by immunohistochemistry show clear evidence of biological activity from the delivered CPT in the posttreatment tumors.
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http://dx.doi.org/10.1073/pnas.1603018113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833237PMC
April 2016

Catalysis by framework zinc in silica-based molecular sieves.

Chem Sci 2016 Mar 4;7(3):2264-2274. Epub 2016 Jan 4.

Chemical Engineering , California Institute of Technology , Pasadena , 91125 , USA . Email:

Microporous and mesoporous zincosilicates (, CIT-6, VPI-8, Zn-MFI, and Zn-MCM-41) synthesized in the presence of alkali cations contain two broad types of Zn sites: one that is a dication analog of the monocation ion-exchangeable Al-site in aluminosilicates, while the other resembles isolated Zn sites on amorphous silica. The ratio of these sites varies, depending on the synthesis conditions of the zincosilicate. Post-synthetic strategies based on ion-exchange can alter the site distribution towards either population. Furthermore, post-synthetic introduction of isolated Zn sites of the latter type is possible for materials possessing silanol nests. Both types of sites behave as Lewis acid centers in probe-molecule IR spectroscopy, but have very different catalytic properties. Due to the unusually high adsorption energies of Lewis bases on such materials, Lewis acid catalysis is difficult at low temperatures and in solvents bearing Lewis basic functionality. However, at high temperatures, in hydrocarbon solvents, CIT-6 (Zn-beta) is able to selectively catalyze the Lewis-acid-catalyzed Diels-Alder cycloaddition-dehydration reactions of ethylene with methyl 5-(methoxymethyl)furan-2-carboxylate, a furan that can be derived quantitatively by partial oxidation of biomass-based 5-hydroxymethylfurfural. Additionally, zinc in silica-based molecular sieves is shown here to enable chemistries previously not accessible with framework Sn-, Ti- and Zr-based Lewis acid sites, , the direct production of dimethyl terephthalate by Diels-Alder cycloaddition-dehydration reactions of ethylene and the dimethyl ester of furan-2,5-dicarboxilic acid.
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http://dx.doi.org/10.1039/c5sc03889hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977500PMC
March 2016

Facile Synthesis, Characterization, and Catalytic Behavior of a Large-Pore Zeolite with the IWV Framework.

Chemistry 2016 Mar 2;22(12):4022-9. Epub 2016 Feb 2.

Chemical Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.

Large-pore microporous materials are of great interest to process bulky hydrocarbon and biomass-derived molecules. ITQ-27 (IWV) has a two-dimensional pore system bounded by 12-membered rings (MRs) that lead to internal cross-sections containing 14 MRs. Investigations into the catalytic behavior of aluminosilicate (zeolite) materials with this framework structure have been limited until now due to barriers in synthesis. The facile synthesis of aluminosilicate IWV in both hydroxide and fluoride media is reported herein using simple, diquaternary organic structure-directing agents (OSDAs) that are based on tetramethylimidazole. In hydroxide media, a zeolite product with Si/Al=14.8-23.2 is obtained, while in fluoride media an aluminosilicate product with Si/Al up to 82 is synthesized. The material produced in hydroxide media is tested for the hydroisomerization of n-hexane, and results from this test reaction suggest that the effective pore size of zeolites with the IWV framework structure is similar to but slightly larger than that of ZSM-12 (MTW), in fairly good agreement with crystallographic data.
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http://dx.doi.org/10.1002/chem.201504717DOI Listing
March 2016

The Engineering of Biology and Medicine.

Proc Natl Acad Sci U S A 2015 Nov;112(47):14423

Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139

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http://dx.doi.org/10.1073/pnas.1517450112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664332PMC
November 2015

Clinical experiences with systemically administered siRNA-based therapeutics in cancer.

Nat Rev Drug Discov 2015 Dec 16;14(12):843-56. Epub 2015 Nov 16.

Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.

Small interfering RNA (siRNA)-based therapies are emerging as a promising new anticancer approach, and a small number of Phase I clinical trials involving patients with solid tumours have now been completed. Encouraging results from these pioneering clinical studies show that these new therapeutics can successfully and safely inhibit targeted gene products in patients with cancer, and have taught us important lessons regarding appropriate dosages and schedules. In this Review, we critically assess these Phase I studies and discuss their implications for future clinical trial design. Key challenges and future directions in the development of siRNA-containing anticancer therapeutics are also considered.
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http://dx.doi.org/10.1038/nrd4685DOI Listing
December 2015

Synthesis of the RTH-type layer: the first small-pore, two dimensional layered zeolite precursor.

Chem Sci 2015 Oct 27;6(10):5955-5963. Epub 2015 Jul 27.

Chemical Engineering , California Institute of Technology , Pasadena , CA 91125 , USA . Email:

There are several distinct two-dimensional zeolite building layers that can condense through different stacking arrangements of the layers to form various three-dimensional framework materials. All known building layers are dense layers in that they do not contain 8-membered ring (MR) or larger pores perpendicular to the two-dimensional layers. Herein, we report a new material (CIT-10) that consists of a two-dimensional layer (termed "rth" layer) that contains an 8 MR perpendicular to the layer. Calcination of CIT-10 forms pure-silica (SSZ-50). CIT-10 can be pillared to form a new framework material with a three-dimensional pore system of 8 and 10 MRs, denoted CIT-11, that can be calcined to form a new microporous material, denoted CIT-12.
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http://dx.doi.org/10.1039/c5sc02325dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5950832PMC
October 2015

Increased brain uptake of targeted nanoparticles by adding an acid-cleavable linkage between transferrin and the nanoparticle core.

Proc Natl Acad Sci U S A 2015 Oct 21;112(40):12486-91. Epub 2015 Sep 21.

Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125

Most therapeutic agents are excluded from entering the central nervous system by the blood-brain barrier (BBB). Receptor mediated transcytosis (RMT) is a common mechanism used by proteins, including transferrin (Tf), to traverse the BBB. Here, we prepared Tf-containing, 80-nm gold nanoparticles with an acid-cleavable linkage between the Tf and the nanoparticle core to facilitate nanoparticle RMT across the BBB. These nanoparticles are designed to bind to Tf receptors (TfRs) with high avidity on the blood side of the BBB, but separate from their multidentate Tf-TfR interactions upon acidification during the transcytosis process to allow release of the nanoparticle into the brain. These targeted nanoparticles show increased ability to cross an in vitro model of the BBB and, most important, enter the brain parenchyma of mice in greater amounts in vivo after systemic administration compared with similar high-avidity nanoparticles containing noncleavable Tf. In addition, we investigated this design with nanoparticles containing high-affinity antibodies (Abs) to TfR. With the Abs, the addition of the acid-cleavable linkage provided no improvement to in vivo brain uptake for Ab-containing nanoparticles, and overall brain uptake was decreased for all Ab-containing nanoparticles compared with Tf-containing ones. These results are consistent with recent reports of high-affinity anti-TfR Abs trafficking to the lysosome within BBB endothelium. In contrast, high-avidity, Tf-containing nanoparticles with the acid-cleavable linkage avoid major endothelium retention by shedding surface Tf during their transcytosis.
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http://dx.doi.org/10.1073/pnas.1517048112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603510PMC
October 2015

Tandem catalysis for the production of alkyl lactates from ketohexoses at moderate temperatures.

Proc Natl Acad Sci U S A 2015 Sep 8;112(38):11777-82. Epub 2015 Sep 8.

Chemical Engineering, California Institute of Technology, Pasadena, CA 91125

Retro-aldol reactions have been implicated as the limiting steps in catalytic routes to convert biomass-derived hexoses and pentoses into valuable C2, C3, and C4 products such as glycolic acid, lactic acid, 2-hydroxy-3-butenoic acid, 2,4-dihydroxybutanoic acid, and alkyl esters thereof. Due to a lack of efficient retro-aldol catalysts, most previous investigations of catalytic pathways involving these reactions were conducted at high temperatures (≥160 °C). Here, we report moderate-temperature (around 100 °C) retro-aldol reactions of various hexoses in aqueous and alcoholic media with catalysts traditionally known for their capacity to catalyze 1,2-intramolecular carbon shift (1,2-CS) reactions of aldoses, i.e., various molybdenum oxide and molybdate species, nickel(II) diamine complexes, alkali-exchanged stannosilicate molecular sieves, and amorphous TiO2-SiO2 coprecipitates. Solid Lewis acid cocatalysts that are known to catalyze 1,2-intramolecular hydride shift (1,2-HS) reactions that enable the formation of α-hydroxy carboxylic acids from tetroses, trioses, and glycolaldehyde, but cannot readily catalyze retro-aldol reactions of hexoses and pentoses at these moderate temperatures, are shown to be compatible with the aforementioned retro-aldol catalysts. The combination of a distinct retro-aldol catalyst with a 1,2-HS catalyst enables lactic acid and alkyl lactate formation from ketohexoses at moderate temperatures (around 100 °C), with yields comparable to best-reported chemocatalytic examples at high temperature conditions (≥160 °C). The use of moderate temperatures enables numerous desirable features such as lower pressure and significantly less catalyst deactivation.
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http://dx.doi.org/10.1073/pnas.1516466112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586831PMC
September 2015

Self-Pillared, Single-Unit-Cell Sn-MFI Zeolite Nanosheets and Their Use for Glucose and Lactose Isomerization.

Angew Chem Int Ed Engl 2015 Sep 23;54(37):10848-51. Epub 2015 Jul 23.

Department of Chemical Engineering and Materials Science, University of Minnesota, 421 Washington Avenue SE, Minneapolis, MN 55455 (USA).

Single-unit-cell Sn-MFI, with the detectable Sn uniformly distributed and exclusively located at framework sites, is reported for the first time. The direct, single-step, synthesis is based on repetitive branching caused by rotational intergrowths of single-unit-cell lamellae. The self-pillared, meso- and microporous zeolite is an active and selective catalyst for sugar isomerization. High yields for the conversion of glucose into fructose and lactose to lactulose are demonstrated.
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http://dx.doi.org/10.1002/anie.201505334DOI Listing
September 2015

Cationic Mucic Acid Polymer-Based siRNA Delivery Systems.

Bioconjug Chem 2015 Aug 8;26(8):1791-803. Epub 2015 Jul 8.

Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.

Nanoparticle (NP) delivery systems for small interfering RNA (siRNA) that have good systemic circulation and high nucleic acid content are highly desired for translation into clinical use. Here, a family of cationic mucic acid-containing polymers is synthesized and shown to assemble with siRNA to form NPs. A cationic mucic acid polymer (cMAP) containing alternating mucic acid and charged monomers is synthesized. When combined with siRNA, cMAP forms NPs that require steric stabilization by poly(ethylene glycol) (PEG) that is attached to the NP surface via a 5-nitrophenylboronic acid linkage (5-nitrophenylboronic acid-PEGm (5-nPBA-PEGm)) to diols on mucic acid in the cMAP in order to inhibit aggregation in biological fluids. As an alternative, cMAP is covalently conjugated with PEG via two methods. First, a copolymer is prepared with alternating cMAP-PEG units that can form loops of PEG on the surface of the formulated siRNA-containing NPs. Second, an mPEG-cMAP-PEGm triblock polymer is synthesized that could lead to a PEG brush configuration on the surface of the formulated siRNA-containing NPs. The copolymer and triblock polymer are able to form stable siRNA-containing NPs without and with the addition of 5-nPBA-PEGm. Five formulations, (i) cMAP with 5-nPBA-PEGm, (ii) cMAP-PEG copolymer both (a) with and (b) without 5-nPBA-PEGm, and (iii) mPEG-cMAP-PEGm triblock polymer both (a) with and (b) without 5-nPBA-PEGm, are used to produce NPs in the 30-40 nm size range, and their circulation times are evaluated in mice using tail vein injections. The mPEG-cMAP-PEGm triblock polymer provides the siRNA-containing NP with the longest circulation time (5-10% of the formulation remains in circulation at 60 min postdosing), even when a portion of the excess cationic components used in the formulation is filtered away prior to injection. A NP formulation using the mPEG-cMAP-PEGm triblock polymer that is free of excess components could contain as much as ca. 30 wt % siRNA.
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http://dx.doi.org/10.1021/acs.bioconjchem.5b00324DOI Listing
August 2015

Lack of in vivo antibody dependent cellular cytotoxicity with antibody containing gold nanoparticles.

Bioconjug Chem 2015 May 16;26(5):812-6. Epub 2015 Apr 16.

Chemical Engineering, California Institute of Technology, Pasadena, California 91125, United States.

Antibody-dependent cellular cytotoxicity (ADCC) is a cytolytic mechanism that can elicit in vivo antitumor effects and can play a significant role in the efficacy of antibody treatments for cancer. Here, we prepared cetuximab, panitumumab, and rituximab containing gold nanoparticles and investigated their ability to produce an ADCC effect in vivo. Cetuximab treatment of EGFR-expressing H1975 tumor xenografts showed significant tumor regression due to the ADCC activity of the antibody in vivo, while the control antibody, panitumumab, did not. However, all three antibody containing nanoparticles are not able to suppress tumor growth in the same in vivo mouse model. The antibody containing nanoparticles localized in the tumors and did not suppress the immune function of the animals, so the lack of tumor growth suppression of the cetuximab containing nanoparticle suggests that immobilizing antibodies onto a nanoparticle significantly decreases the ability of the antibody to promote an ADCC response.
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http://dx.doi.org/10.1021/acs.bioconjchem.5b00139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445771PMC
May 2015

Store-Operated Ca2+ Channels in Mesangial Cells Inhibit Matrix Protein Expression.

J Am Soc Nephrol 2015 Nov 18;26(11):2691-702. Epub 2015 Mar 18.

Department of Integrative Physiology and Anatomy and Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, Texas;

Accumulation of extracellular matrix derived from glomerular mesangial cells is an early feature of diabetic nephropathy. Ca(2+) signals mediated by store-operated Ca(2+) channels regulate protein production in a variety of cell types. The aim of this study was to determine the effect of store-operated Ca(2+) channels in mesangial cells on extracellular matrix protein expression. In cultured human mesangial cells, activation of store-operated Ca(2+) channels by thapsigargin significantly decreased fibronectin protein expression and collagen IV mRNA expression in a dose-dependent manner. Conversely, inhibition of the channels by 2-aminoethyl diphenylborinate significantly increased the expression of fibronectin and collagen IV. Similarly, overexpression of stromal interacting molecule 1 reduced, but knockdown of calcium release-activated calcium channel protein 1 (Orai1) increased fibronectin protein expression. Furthermore, 2-aminoethyl diphenylborinate significantly augmented angiotensin II-induced fibronectin protein expression, whereas thapsigargin abrogated high glucose- and TGF-β1-stimulated matrix protein expression. In vivo knockdown of Orai1 in mesangial cells of mice using a targeted nanoparticle siRNA delivery system resulted in increased expression of glomerular fibronectin and collagen IV, and mice showed significant mesangial expansion compared with controls. Similarly, in vivo knockdown of stromal interacting molecule 1 in mesangial cells by recombinant adeno-associated virus-encoded shRNA markedly increased collagen IV protein expression in renal cortex and caused mesangial expansion in rats. These results suggest that store-operated Ca(2+) channels in mesangial cells negatively regulate extracellular matrix protein expression in the kidney, which may serve as an endogenous renoprotective mechanism in diabetes.
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http://dx.doi.org/10.1681/ASN.2014090853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625675PMC
November 2015

siRNA delivery to the glomerular mesangium using polycationic cyclodextrin nanoparticles containing siRNA.

Nucleic Acid Ther 2015 Apr 3;25(2):53-64. Epub 2015 Mar 3.

1 Chemical Engineering, California Institute of Technology , Pasadena, California.

There is an urgent need for new therapies that can halt or reverse the course of chronic kidney disease with minimal side-effect burden on the patient. Small interfering RNA (siRNA) nanoparticles are new therapeutic entities in clinical development that could be useful for chronic kidney disease treatment because they combine the tissue-specific targeting properties of nanoparticles with the gene-specific silencing effects of siRNA. Recent reports have emerged demonstrating that the kidney, specifically the glomerulus, is a readily accessible site for nanoparticle targeting. Here, we explore the hypothesis that intravenously administered polycationic cyclodextrin nanoparticles containing siRNA (siRNA/CDP-NPs) can be used for delivery of siRNA to the glomerular mesangium. We demonstrate that siRNA/CDP-NPs localize to the glomerular mesangium with limited deposition in other areas of the kidney after intravenous injection. Additionally, we report that both mouse and human mesangial cells rapidly internalize siRNA/CDP-NPs in vitro and that nanoparticle uptake can be enhanced by attaching the targeting ligands mannose or transferrin to the nanoparticle surface. Lastly, we show knockdown of mesangial enhanced green fluorescent protein expression in a reporter mouse strain following iv treatment with siRNA/CDP-NPs. Altogether, these data demonstrate the feasibility of mesangial targeting using intravenously administered siRNA/CDP-NPs.
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http://dx.doi.org/10.1089/nat.2014.0505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376487PMC
April 2015

CIT-7, a crystalline, molecular sieve with pores bounded by 8 and 10-membered rings.

Chem Sci 2015 Mar 23;6(3):1728-1734. Epub 2015 Jan 23.

Chemical Engineering , California Institute of Technology , Pasadena , CA 91125 , USA . Email:

A new crystalline molecular sieve, denoted CIT-7, is synthesized using an imidazolium-based diquaternary organic structure directing agent (OSDA). The framework structure is determined from a combination of rotation electron diffraction and synchrotron X-ray powder diffraction data. The structure has 10 crystallographically unique tetrahedral atoms (T-atoms) in the unit cell, and can be described as an ordered arrangement of the [456] building unit and a previously unreported [45] building unit. The framework contains a 2-dimensional pore system that is bounded by 10 T-atom rings (10-ring, 5.1 Å × 6.2 Å opening) that are connected with oval 8-rings (2.9 Å × 5.5 Å opening) through medium-sized cavities (∼7.9 Å) at the channel intersections. CIT-7 can be synthesized over a broad range of compositions including pure-silica and heteroatom, , aluminosilicate and titanosilicate, containing variants.
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http://dx.doi.org/10.1039/c4sc03935aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643978PMC
March 2015

Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA.

Proc Natl Acad Sci U S A 2014 Aug 21;111(31):11449-54. Epub 2014 Jul 21.

College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan;Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA 91010;

Nanoparticle-based experimental therapeutics are currently being investigated in numerous human clinical trials. CALAA-01 is a targeted, polymer-based nanoparticle containing small interfering RNA (siRNA) and, to our knowledge, was the first RNA interference (RNAi)-based, experimental therapeutic to be administered to cancer patients. Here, we report the results from the initial phase I clinical trial where 24 patients with different cancers were treated with CALAA-01 and compare those results to data obtained from multispecies animal studies to provide a detailed example of translating this class of nanoparticles from animals to humans. The pharmacokinetics of CALAA-01 in mice, rats, monkeys, and humans show fast elimination and reveal that the maximum concentration obtained in the blood after i.v. administration correlates with body weight across all species. The safety profile of CALAA-01 in animals is similarly obtained in humans except that animal kidney toxicities are not observed in humans; this could be due to the use of a predosing hydration protocol used in the clinic. Taken in total, the animal models do appear to predict the behavior of CALAA-01 in humans.
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http://dx.doi.org/10.1073/pnas.1411393111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128111PMC
August 2014

Synthesis of a specified, silica molecular sieve by using computationally predicted organic structure-directing agents.

Angew Chem Int Ed Engl 2014 Aug 24;53(32):8372-4. Epub 2014 Jun 24.

Chemical Engineering, California Institute of Technology, Pasadena, CA 91125 (USA).

Crystalline molecular sieves are used in numerous applications, where the properties exploited for each technology are the direct consequence of structural features. New materials are typically discovered by trial and error, and in many cases, organic structure-directing agents (OSDAs) are used to direct their formation. Here, we report the first successful synthesis of a specified molecular sieve through the use of an OSDA that was predicted from a recently developed computational method that constructs chemically synthesizable OSDAs. Pentamethylimidazolium is computationally predicted to have the largest stabilization energy in the STW framework, and is experimentally shown to strongly direct the synthesis of pure-silica STW. Other OSDAs with lower stabilization energies did not form STW. The general method demonstrated here to create STW may lead to new, simpler OSDAs for existing frameworks and provide a way to predict OSDAs for desired, theoretical frameworks.
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http://dx.doi.org/10.1002/anie.201404076DOI Listing
August 2014

Synthesis of terephthalic acid via Diels-Alder reactions with ethylene and oxidized variants of 5-hydroxymethylfurfural.

Proc Natl Acad Sci U S A 2014 Jun 27;111(23):8363-7. Epub 2014 May 27.

Chemical Engineering, California Institute of Technology, Pasadena, CA 91125

Terephthalic acid (PTA), a monomer in the synthesis of polyethylene terephthalate (PET), is obtained by the oxidation of petroleum-derived p-xylene. There is significant interest in the synthesis of renewable, biomass-derived PTA. Here, routes to PTA starting from oxidized products of 5-hydroxymethylfurfural (HMF) that can be produced from biomass are reported. These routes involve Diels-Alder reactions with ethylene and avoid the hydrogenation of HMF to 2,5-dimethylfuran. Oxidized derivatives of HMF are reacted with ethylene over solid Lewis acid catalysts that do not contain strong Brønsted acids to synthesize intermediates of PTA and its equally important diester, dimethyl terephthalate (DMT). The partially oxidized HMF, 5-(hydroxymethyl)furoic acid (HMFA), is reacted with high pressure ethylene over a pure-silica molecular sieve containing framework tin (Sn-Beta) to produce the Diels-Alder dehydration product, 4-(hydroxymethyl)benzoic acid (HMBA), with 31% selectivity at 61% HMFA conversion after 6 h at 190 °C. If HMFA is protected with methanol to form methyl 5-(methoxymethyl)furan-2-carboxylate (MMFC), MMFC can react with ethylene in the presence of Sn-Beta for 2 h to produce methyl 4-(methoxymethyl)benzenecarboxylate (MMBC) with 46% selectivity at 28% MMFC conversion or in the presence of a pure-silica molecular sieve containing framework zirconium (Zr-Beta) for 6 h to produce MMBC with 81% selectivity at 26% MMFC conversion. HMBA and MMBC can then be oxidized to produce PTA and DMT, respectively. When Lewis acid containing mesoporous silica (MCM-41) and amorphous silica, or Brønsted acid containing zeolites (Al-Beta), are used as catalysts, a significant decrease in selectivity/yield of the Diels-Alder dehydration product is observed.
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http://dx.doi.org/10.1073/pnas.1408345111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060660PMC
June 2014