Bachelor of Science, Tsinghua University (2007)
Master of Science, Tsinghua University (2010)
Doctor of Philosophy, Universitat Bern (2014)
Michael Snyder, Postdoctoral Faculty Sponsor
MISTERMINATE Mechanistically Links Mitochondrial Dysfunction with Proteostasis Failure.
Mitochondrial dysfunction and proteostasis failure frequently coexist as hallmarks of neurodegenerative disease. How these pathologies are related is notwell understood. Here, we describe a phenomenon termed MISTERMINATE (mitochondrial-stress-induced translational termination impairment and protein carboxyl terminal extension), which mechanistically links mitochondrial dysfunction with proteostasis failure. We show that mitochondrial dysfunction impairs translational termination of nuclear-encoded mitochondrial mRNAs, including complex-I 30kD subunit (C-I30) mRNA, occurring on the mitochondrial surface in Drosophila and mammalian cells. Ribosomes stalled at the normal stop codon continue to add to the C terminus of C-I30 certain amino acids non-coded by mRNA template. C-terminally extended C-I30 is toxic when assembled into C-I and forms aggregates in the cytosol. Enhancing co-translational quality control prevents C-I30 C-terminal extension and rescues mitochondrial and neuromuscular degeneration in a Parkinson's disease model. These findings emphasize theimportance of efficient translation termination and reveal unexpected link between mitochondrial health and proteome homeostasis mediated by MISTERMINATE.
View details for DOI 10.1016/j.molcel.2019.06.031
View details for PubMedID 31378462
Longitudinal multi-omics of host-microbe dynamics in prediabetes.
2019; 569 (7758): 663–71
Type 2 diabetes mellitus (T2D) is a growing health problem, but little is known about its early disease stages, its effects on biological processes or the transition to clinical T2D. To understand the earliest stages of T2Dbetter, we obtained samples from 106 healthy individuals and individuals with prediabetes over approximately four years and performed deep profiling of transcriptomes, metabolomes, cytokines, and proteomes, as well as changes in the microbiome. This rich longitudinal data set revealed many insights: first, healthy profiles are distinct among individuals while displaying diverse patterns of intra- and/or inter-personal variability. Second, extensive host and microbial changes occur during respiratory viral infections and immunization, and immunization triggers potentially protective responses that are distinct from responses to respiratory viral infections. Moreover, during respiratory viral infections, insulin-resistant participants respond differently than insulin-sensitive participants. Third, global co-association analyses among the thousands of profiled molecules reveal specific host-microbe interactions that differ between insulin-resistant and insulin-sensitive individuals. Last, we identified early personal molecular signatures in one individual that preceded the onset of T2D, including the inflammation markers interleukin-1 receptor agonist (IL-1RA) and high-sensitivity C-reactive protein (CRP) paired with xenobiotic-induced immune signalling. Our study reveals insights into pathways and responses that differ between glucose-dysregulated and healthy individuals during health and disease and provides an open-access data resource to enable further research into healthy, prediabetic and T2D states.
View details for DOI 10.1038/s41586-019-1236-x
View details for PubMedID 31142858
- The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight SCIENCE 2019; 364 (6436): 144-+
Multi-Omics Profiling, Microscopic Cervical Remodeling, and Parturition: Insights from the Smart Diaphragm Study.
SAGE PUBLICATIONS INC. 2019: 216A
View details for Web of Science ID 000459610400452
The Metabolomic Clock of Human Pregnancy.
SAGE PUBLICATIONS INC. 2019: 118A–119A
View details for Web of Science ID 000459610400163
- Smart Diaphragm Study: Multi-omics profiling and cervical device measurements during pregnancy MOSBY-ELSEVIER. 2019: S649
The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight.
Science (New York, N.Y.)
2019; 364 (6436)
To understand the health impact of long-duration spaceflight, one identical twin astronaut was monitored before, during, and after a 1-year mission onboard the International Space Station; his twin served as a genetically matched ground control. Longitudinal assessments identified spaceflight-specific changes, including decreased body mass, telomere elongation, genome instability, carotid artery distension and increased intima-media thickness, altered ocular structure, transcriptional and metabolic changes, DNA methylation changes in immune and oxidative stress-related pathways, gastrointestinal microbiota alterations, and some cognitive decline postflight. Although average telomere length, global gene expression, and microbiome changes returned to near preflight levels within 6 months after return to Earth, increased numbers of short telomeres were observed and expression of some genes was still disrupted. These multiomic, molecular, physiological, and behavioral datasets provide a valuable roadmap of the putative health risks for future human spaceflight.
View details for PubMedID 30975860
A terpy-functionalized benzodifuran-based fluorescent probe for in vitro monitoring cellular Zn(II) uptake
2017; 134: 287
View details for DOI 10.1016/j.poly.2017.06.037
- Low-Dimensional Tin(II) Iodide Perovskite Structures Templated by an Aromatic Heterocyclic Cation CRYSTAL GROWTH & DESIGN 2016; 16 (9): 5230–37
Control of Reactivity and Regioselectivity for On-Surface Dehydrogenative Aryl-Aryl Bond Formation
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2016; 138 (17): 5585–93
Regioselectivity is of fundamental importance in chemical synthesis. Although many concepts for site-selective reactions are well established for solution chemistry, it is not a priori clear whether they can easily be transferred to reactions taking place on a metal surface. A metal will fix the chemical potential of the electrons and perturb the electronic states of the reactants because of hybridization. Additionally, techniques to characterize chemical reactions in solution are generally not applicable to on-surface reactions. Only recent developments in resolving chemical structures by atomic force microscopy (AFM) and scanning tunneling microscopy (STM) paved the way for identifying individual reaction products on surfaces. Here we exploit a combined STM/AFM technique to demonstrate the on-surface formation of complex molecular architectures built up from a heteroaromatic precursor, the tetracyclic pyrazino[2,3-f][4,7]phenanthroline (pap) molecule. Selective intermolecular aryl-aryl coupling via dehydrogenative C-H activation occurs on Au(111) upon thermal annealing under ultrahigh vacuum (UHV) conditions. A full atomistic description of the different reaction products based on an unambiguous discrimination between pyrazine and pyridine moieties is presented. Our work not only elucidates that ortho-hydrogen atoms of the pyrazine rings are preferentially activated over their pyridine equivalents, but also sheds new light onto the participation of substrate atoms in metal-organic coordination bonding during covalent C-C bond formation.
View details for DOI 10.1021/jacs.5b13461
View details for Web of Science ID 000375521100024
View details for PubMedID 27059121
Controlling Electrical Conductance through a pi-Conjugated Cruciform Molecule by Selective Anchoring to Gold Electrodes
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
2015; 54 (48): 14304–7
Tuning charge transport at the single-molecule level plays a crucial role in the construction of molecular electronic devices. Introduced herein is a promising and operationally simple approach to tune two distinct charge-transport pathways through a cruciform molecule. Upon in situ cleavage of triisopropylsilyl groups, complete conversion from one junction type to another is achieved with a conductance increase by more than one order of magnitude, and it is consistent with predictions from ab initio transport calculations. Although molecules are well known to conduct through different orbitals (either HOMO or LUMO), the present study represents the first experimental realization of switching between HOMO- and LUMO-dominated transport within the same molecule.
View details for DOI 10.1002/anie.201506026
View details for Web of Science ID 000367724000014
View details for PubMedID 26444184
Exploitation of desilylation chemistry in tailor-made functionalization on diverse surfaces
2015; 6: 6403
Interface engineering to attain a uniform and compact self-assembled monolayer at atomically flat surfaces plays a crucial role in the bottom-up fabrication of organic molecular devices. Here we report a promising and operationally simple approach for modification/functionalization not only at ultraflat single-crystal metal surfaces, M(111) (M=Au, Pt, Pd, Rh and Ir) but also at the highly oriented pyrolytic graphite surface, upon efficient in situ cleavage of trimethylsilyl end groups of the molecules. The obtained self-assembled monolayers are ultrastable within a wide potential window. The carbon-surface bonding on various substrates is confirmed by shell-isolated nanoparticle-enhanced Raman spectroscopy. Application of this strategy in tuning surface wettability is also demonstrated. The most valuable finding is that a combination of the desilylation with the click chemistry represents an efficient method for covalent and tailor-made functionalization of diverse surfaces.
View details for DOI 10.1038/ncomms7403
View details for Web of Science ID 000352693700001
View details for PubMedID 25758661
View details for PubMedCentralID PMC4382705
Electronic transport in benzodifuran single-molecule transistors
2015; 7 (17): 7665–73
Benzodifuran (BDF) single-molecule transistors have been fabricated in electromigration break junctions for electronic measurements. The inelastic electron tunneling spectrum validates that the BDF molecule is the pathway of charge transport. The gating effect is analyzed in the framework of a single-level tunneling model combined with transition voltage spectroscopy (TVS). The analysis reveals that the highest occupied molecular orbital (HOMO) of the thiol-terminated BDF molecule dominates the charge transport through Au-BDF-Au junctions. Moreover, the energy shift of the HOMO caused by the gate voltage is the main reason for conductance modulation. In contrast, the electronic coupling between the BDF molecule and the gold electrodes, which significantly affects the low-bias junction conductance, is only influenced slightly by the applied gate voltage. These findings will help in the design of future molecular electronic devices.
View details for DOI 10.1039/c5nr00402k
View details for Web of Science ID 000353981700022
View details for PubMedID 25833315
- A Cruciform Electron Donor-Acceptor Semiconductor with Solid-State Red Emission: 1D/2D Optical Waveguides and Highly Sensitive/Selective Detection of H2S Gas ADVANCED FUNCTIONAL MATERIALS 2014; 24 (27): 4250–58
Regulating a Benzodifuran Single Molecule Redox Switch via Electrochemical Gating and Optimization of Molecule/Electrode Coupling
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2014; 136 (25): 8867–70
We report a novel strategy for the regulation of charge transport through single molecule junctions via the combination of external stimuli of electrode potential, internal modulation of molecular structures, and optimization of anchoring groups. We have designed redox-active benzodifuran (BDF) compounds as functional electronic units to fabricate metal-molecule-metal (m-M-m) junction devices by scanning tunneling microscopy (STM) and mechanically controllable break junctions (MCBJ). The conductance of thiol-terminated BDF can be tuned by changing the electrode potentials showing clearly an off/on/off single molecule redox switching effect. To optimize the response, a BDF molecule tailored with carbodithioate (-CS2(-)) anchoring groups was synthesized. Our studies show that replacement of thiol by carbodithioate not only enhances the junction conductance but also substantially improves the switching effect by enhancing the on/off ratio from 2.5 to 8.
View details for DOI 10.1021/ja5034606
View details for Web of Science ID 000338184200008
View details for PubMedID 24933522
Directed Metalation Cascade To Access Highly Functionalized Thieno[2,3-f]benzofuran and Exploration as Building Blocks for Organic Electronics
2013; 15 (21): 5586–89
A tandem directed metalation has been successfully applied to the preparation of thieno[2,3-f]benzofuran-4,8-dione, providing an efficient and facile approach to symmetrically and unsymmetrically functionalize the thieno[2,3-f]benzofuran core at the 2,6 positions as well as to introduce the electron-withdrawing or -donating groups (EWG or EDG) at its 4,8 positions. The presence of various functional groups makes late-stage derivatization attainable.
View details for DOI 10.1021/ol402787d
View details for Web of Science ID 000326615100049
View details for PubMedID 24144299
Synthesis and Redox and Photophysical Properties of Benzodifuran-Spiropyran Ensembles
CHEMISTRY-A EUROPEAN JOURNAL
2013; 19 (20): 6459–66
Two benzodifuran (BDF)-coupled spiropyran (SP) systems and their BDF reference compounds were obtained in good yields through Huisgen-Meldal-Sharpless "click" chemistry and then subjected to investigation of their electrochemical and photophysical properties. In both SP and merocyanine (MC) forms of the coupled molecules, the BDF-based emission is quenched to around 1 % of the quantum yield of emission from the BDF reference compounds. Based on electrochemical data, this quenching is attributed to oxidative electron-transfer quenching. Irradiation at 366 nm results in ring opening to the MC forms of the BDF-coupled SP compounds and the SP reference compound with a quantum efficiency of about 50 %. The rate constants for the thermal ring closing are approximately 3.4×10(-3) s(-1). However, in the photostationary states the MC fractions of the coupled molecules are substantially lower than that of the reference SP compound, attributed to the observed acceleration of the ring-closing reaction upon irradiation. As irradiation at 366 nm invariably also excites higher-energy transitions of the BDF units in the coupled compounds, the ring-opening reaction is accelerated relative to the SP reference, which results in lower MC fractions in the photostationary state. Reversible photochromism of these BDF-coupled SP compounds renders them promising in the field of molecular switches.
View details for DOI 10.1002/chem.201204043
View details for Web of Science ID 000318365200036
View details for PubMedID 23494841
- InCl3 center dot 4H(2)O-Catalyzed Trioxane as a New Methylating Agent for multi-Methylated Aromatics Affording Hexamethyl Benzene LETTERS IN ORGANIC CHEMISTRY 2010; 7 (1): 61–63
- An efficient synthesis of unsymmetrical diarylmethanes from the dehydration of arenes with benzyl alcohols using InCl3 center dot 4H(2)O/acetylacetone catalyst system TETRAHEDRON 2007; 63 (41): 10185–88
- An efficient bismuth(III) chloride-catalyzed synthesis of 1,1-diarylalkenes via Friedel-Crafts reaction of acyl chloride or vinyl chloride with arenes ADVANCED SYNTHESIS & CATALYSIS 2006; 348 (14): 1919–25