Jing Sun

We introduce dynamic light scattering imaging (DLSI) to enable the wide-field measurement of the speckle temporal intensity autocorrelation function. DLSI uses the full temporal sampling of speckle fluctuations and a comprehensive model to identify the dynamic scattering regime and obtain a quantitative image of the scatterer dynamics. It reveals errors in the traditional theory of laser Doppler flowmetry and laser speckle contrast imaging and provides guidance on the best model to use in cerebral blood flow imaging.

Few studies assess the amino acid transport properties of synthetic carriers using liposomal and cell membranes. Herein, we apply an optimized radiometric assay to demonstrate the selective transport of L-Pro across liposomal membranes by the means of a synthetic calix[4]pyrrole cavitand. Moreover, we show that the carrier also contributes to the overall uptake of L-Pro in HeLa cells. These unprecedented results augur well for the potential application of calix[4]pyrroles as therapeutic tools for L-Pro-dependent diseases, including some cancers and hyperprolinemia.

A plausible scenario for the prebiotic generation of activated RNA substrates under mild aqueous conditions is presented. Using water‐soluble diamidophosphate, in situ production of 2′,3′‐cyclic phosphate‐activated oligoribonucleotides and their subsequent ligation by a ribozyme can be achieved.

Abstract

RNA‐catalyzed RNA ligation is widely believed to be a key reaction for primordial biology. However, since typical chemical routes towards activating RNA substrates are incompatible with ribozyme catalysis, it remains unclear how prebiotic systems generated and sustained pools of activated building blocks needed to form increasingly larger and complex RNA. Herein, we demonstrate in situ activation of RNA substrates under reaction conditions amenable to catalysis by the hairpin ribozyme. We found that diamidophosphate (DAP) and imidazole drive the formation of 2′,3′‐cyclic phosphate RNA mono‐ and oligonucleotides from monophosphorylated precursors in frozen water‐ice. This long‐lived activation enables iterative enzymatic assembly of long RNAs. Our results provide a plausible scenario for the generation of higher‐energy substrates required to fuel ribozyme‐catalyzed RNA synthesis in the absence of a highly evolved metabolism.

All‐cis 1,2,4,5‐tetrakis (trifluoromethyl)‐ and all‐cis 1,2,3,4,5,6‐hexakis (trifluoromethyl)‐ cyclohexanes were prepared by direct aryl hydrogenation. All‐cis 1,2,3,4,5,6‐hexakis(trifluoromethyl)cyclohexane has a high barrier to ring inversion (ΔG^≠=27 kcal mol⁻¹) and a Janus face profile with a large diffuse negative density on the fluorine face, and a focused positive density on the hydrogen face which coordinates carbonyls and halides.

Abstract

We report the synthesis of all‐cis 1,2,4,5‐tetrakis (trifluoromethyl)‐ and all‐cis 1,2,3,4,5,6‐hexakis (trifluoromethyl)‐ cyclohexanes by direct hydrogenation of precursor tetrakis‐ or hexakis‐ (trifluoromethyl)benzenes. The resultant cyclohexanes have a stereochemistry such that all the CF₃ groups are on the same face of the cyclohexyl ring. All‐cis 1,2,3,4,5,6‐hexakis(trifluoromethyl)cyclohexane is the most sterically demanding of the all‐cis hexakis substituted cyclohexanes prepared to date, with a barrier (ΔG) to ring inversion calculated at 27 kcal mol⁻¹. The X‐ray structure of all‐cis 1,2,3,4,5,6‐hexakis(trifluoromethyl)cyclohexane displays a flattened chair conformation and the electrostatic profile of this compound reveals a large diffuse negative density on the fluorine face and a focused positive density on the hydrogen face. The electropositive hydrogen face can co‐ordinate chloride (K≈10³) and to a lesser extent fluoride and iodide ions. Dehydrofluorination promoted decomposition occurs with fluoride ion acting as a base.

Naturally occurring amino acid containing nucleobases could be vestiges of an extinct early Earth RNA‐peptide world. Today they help to translate genetic information, but in the RNA‐peptide world, they might have been the units that equipped RNA with broad catalytic functions. These genotype‐phenotype bridging nucleosides were synthesized, and their properties were investigated. This study shows that these nucleosides do not base pair, which allows them to position amino acids in unpaired parts of complex RNA structures.

Abstract

Fossils of extinct species allow us to reconstruct the process of Darwinian evolution that led to the species diversity we see on Earth today. The origin of the first functional molecules able to undergo molecular evolution and thus eventually able to create life, are largely unknown. The most prominent idea in the field posits that biology was preceded by an era of molecular evolution, in which RNA molecules encoded information and catalysed their own replication. This RNA world concept stands against other hypotheses, that argue for example that life may have begun with catalytic peptides and primitive metabolic cycles. The question whether RNA or peptides were first is addressed by the RNA‐peptide world concept, which postulates a parallel existence of both molecular species. A plausible experimental model of how such an RNA‐peptide world may have looked like, however, is absent. Here we report the synthesis and physicochemical evaluation of amino acid containing adenosine bases, which are closely related to molecules that are found today in the anticodon stem‐loop of tRNAs from all three kingdoms of life. We show that these adenosines lose their base pairing properties, which allow them to equip RNA with amino acids independent of the sequence context. As such we may consider them to be living molecular fossils of an extinct molecular RNA‐peptide world.

This study demonstrates transient, multivalency-driven liquid-liquid phase separation (LLPS) of sequence-defined functionalized nucleic acid polymers to prepare functional all-DNA coacervates. The coacervates need ATP as a fuel to drive their formation and disappear once the ATP is consumed in a fuel-driven process—an autonomous system with tunable lifetime. The programmable nature of the DNA system allows to run sorted LLPS of two different species in parallel for multicomponent coacervates and can be used to entrap bioactive species to generate functions.

Nature Chemistry, Published online: 22 October 2020; doi:10.1038/s41557-020-00564-3

Life requires a constant supply of energy, but the energy sources that drove the transition from prebiotic chemistry to biochemistry on the early Earth are unknown. Now, a potentially prebiotic chemical activating reagent has been shown to enable the synthesis, in aqueous conditions and catalysed by small molecules, of peptides, peptidyl–RNAs, RNA oligomers and primordial phospholipids.

Synthetic oligosaccharides and microED analysis enable the molecular level characterization of carbohydrate materials. The local crystal organization is correlated to the supramolecular architecture, allowing for the design of helical structures as well as flat lamellae.

Abstract

Hierarchical carbohydrate architectures serve multiple roles in nature. Hardly any correlations between the carbohydrate chemical structures and the material properties are available due to the lack of standards and suitable analytic techniques. Therefore, designer carbohydrate materials remain highly unexplored, as compared to peptides and nucleic acids. A synthetic D‐glucose disaccharide, DD, was chosen as a model to explore carbohydrate materials. Microcrystal electron diffraction (MicroED), optimized for oligosaccharides, revealed that DD assembled into highly crystalline left‐handed helical fibers. The supramolecular architecture was correlated to the local crystal organization, allowing for the design of the enantiomeric right‐handed fibers, based on the L‐glucose disaccharide, LL, or flat lamellae, based on the racemic mixture. Tunable morphologies and mechanical properties suggest the potential of carbohydrate materials for nanotechnology applications.

Bis‐imidazole‐based anion transporters have been complexed to Au^III to switch off their anion transport properties. In the presence of reducing agents such as GSH the gold is sequestered from the transporter and transport is switched on. This provides a method of targeting anion transporters to tissue with higher concentrations of GSH including tumors.

Abstract

Anion transporters have shown potential application as anti‐cancer agents that function by disrupting homeostasis and triggering cell death. In this research article we report switchable anion transport by gold complexes of anion transporters that are “switched on” in situ in the presence of the reducing agent GSH by decomplexation of gold. GSH is found in higher concentrations in tumors than in healthy tissue and hence this approach offers a strategy to target these systems to tumors.

Polymersomes with nucleobase pairs in their membrane become transiently permeable for substrates when shear forces are applied. These force‐responsive polymersomes allow to switch on enzymatic reactions by turbulent mixing of vesicle dispersions, which is demonstrated with colorimetric and chemoluminescent reactions, as well as the curing of hydrogels.

Abstract

Some marine plankton called dinoflagellates emit light in response to the movement of surrounding water, resulting in a phenomenon called milky seas or sea sparkle. The underlying concept, a shear‐stress induced permeabilisation of biocatalytic reaction compartments, is transferred to polymer‐based nanoreactors. Amphiphilic block copolymers that carry nucleobases in their hydrophobic block are self‐assembled into polymersomes. The membrane of the vesicles can be transiently switched between an impermeable and a semipermeable state by shear forces occurring in flow or during turbulent mixing of polymersome dispersions. Nucleobase pairs in the hydrophobic leaflet separate when mechanical force is applied, exposing their hydrogen bonding motifs and therefore making the membrane less hydrophobic and more permeable for water soluble compounds. This polarity switch is used to release payload of the polymersomes on demand, and to activate biocatalytic reactions in the interior of the polymersomes.

Nature Materials, Published online: 21 September 2020; doi:10.1038/s41563-020-0797-2

A carbazole isomer, typically present as an impurity in commercially produced carbazole batches, is shown to be responsible for the ultralong phosphorescence observed in these compounds and their derivatives.

A highly alternating copolymer composed of acrylic acid and styrene (AASTY) is synthesized with controlled radical polymerization by exploiting the reactivity ratios of the monomers to control the monomer sequence. The AASTY copolymers are effective solubilizers of cellular membranes and their embedded proteins, which improves structural characterization by single-particle cryo-electron microscopy (cryo-EM). These copolymers are promising tools for exploring detergent-free membrane protein solubilization and direct formation of native nanodiscs, facilitating structural and functional analysis of the mammalian proteome.

Nature Nanotechnology, Published online: 07 September 2020; doi:10.1038/s41565-020-0761-y

Genetically improved artificial metalloenzymes in DNA protocells convert signalling molecules into DNA-interacting metabolites that induce downstream growth, functional adaptation and fusion processes inside protocells and between protocells.

Peptido RNAs are a novel class of hybrid molecules that form in spontaneous reactions of amino acids and nucleotides in condensation buffer. A convenient method for accessing such species in monodisperse form from unprotected peptides and 5'‐phosphorylated oligoribonucleotides in aqueous solution was developed. It uses a two‐step protocol of activation and organocatalytic coupling.

Peptido RNAs are hybrid molecules with a phosphoramidate link between the N‐terminus of a peptide and the 5'‐phosphate of an oligoribonucleotide. Such species are formed in spontaneous co‐oligomerizations of amino acids and ribonucleotides in aqueous condensation buffer. To shed light on the properties of these fascinating molecules, a synthetic method for their preparation in monodisperse form is needed. Herein, we report how peptido RNAs can be prepared via solution‐phase coupling of unprotected peptides and oligoribonucleotides in aqueous solution. The preferred protocol uses pre‐activation of the 5'‐phosphate of the RNA as an imidazolide at pH 6.5, followed by precipitation and coupling to the peptide at pH 8 with an organocatalyst. The procedure gave peptido RNAs from water‐soluble peptides and synthetic oligoribonucleotides in up to 68 % yield. The method is convenient and inexpensive and can produce NMR quantities, opening the door to the systematic exploration of the chemistry of peptido RNAs.

The selective interaction of nucleotides with metalloamphiphiles results in the templated self‐assembly of nanoreactors that accelerate a bimolecular reaction. Temporal control over chemical up‐regulation is obtained by adding an enzyme to the system, which dephosphorylates the nucleotides causing dissociation of the assemblies.

Abstract

Nature adopts complex chemical networks to finely tune biochemical processes. Indeed, small biomolecules play a key role in regulating the flux of metabolic pathways. Chemistry, which was traditionally focused on reactions in simple mixtures, is dedicating increasing attention to the network reactivity of highly complex synthetic systems, able to display new kinetic phenomena. Herein, we show that the addition of monophosphate nucleosides to a mixture of amphiphiles and reagents leads to the selective templated formation of self‐assembled structures, which can accelerate a reaction between two hydrophobic reactants. The correct matching between nucleotide and the amphiphile head group is fundamental for the selective formation of the assemblies and for the consequent up‐regulation of the chemical reaction. Transient stability of the nanoreactors is obtained under dissipative conditions, driven by enzymatic dephosphorylation of the templating nucleotides. These results show that small molecules can play a key role in modulating network reactivity, by selectively templating self‐assembled structures that are able to up‐regulate chemical reaction pathways.

NIR‐light‐responsive and injectable DNA–inorganic hybrid hydrogels with high photothermal efficiency are fabricated. This is due to the formed network between the DNA and UCNP‐Au nanoparticles. The ultrastrong photothermal effect in the system endows the soft material with extraordinary cancer therapy. Potential tattoo treatment is also realized by the hybrid gels.

Abstract

Surgical excision is one of the main treatments for malignant tumors. However, high risk of tumour recurrence is a major challenge. Near‐infrared (NIR)‐light‐induced tumor photothermal therapy has been studied, while its clinical applications are still restricted due to the limited therapeutic effects. To address this, here, a novel NIR‐light‐responsive and injectable DNA‐mediated upconversion and Au nanoparticle hybrid (DNA–UCNP‐Au) hydrogel is developed. Due to the confined and concentrated environment induced by the interaction between adjacent DNA strands and UCNP‐Au NPs, an ultrastrong photothermal effect is observed. A photothermal efficiency as high as 42.7% is realized in the hydrogel, which is superior to pristine inorganic particles. Upon direct peritumoral injection of the hydrogel and with the treatment of 808 nm laser irradiation, tumors are eradicated and no recurrence is observed. Meanwhile, there are no side effects on normal tissues due to the local treatment. Taking advantage of the high phototherapeutic effect, biocompatibility, and flexible operability in this system, a novel approach for malignant tumor therapy is demonstrated.

Voltage‐controlled translocation through chloride channels in bilayer membranes simultaneously regulated by pH is demonstrated. This voltage/pH regulated channel system represents an unexplored alternative for ion‐pumping along artificial ion‐channels.

Abstract

Transmembrane protein channels are an important inspiration for the design of artificial ion channels. Their dipolar structure helps overcome the high energy barrier to selectively translocate water and ions sharing one pathway, across the cell membrane. Herein, we report that the amino‐imidazole (Imu) amphiphiles self‐assemble via multiple H‐bonding to form stable artificial Cl⁻‐channels within lipid bilayers. The alignment of water/Cl⁻ wires influences the conduction of ions, envisioned to diffuse along the hydrophilic pathways; at acidic pH, Cl⁻/H⁺ symport conducts along a partly protonated channel, while at basic pH, higher Cl⁻/OH⁻ antiport translocate through a neutral channel configuration, which can be greatly activated by applying strong electric field. This voltage/pH regulated channel system represents an unexplored alternative for ion‐pumping along artificial ion‐channels, parallel to that of biology.

Cucurbit[8]uril can stabilize discrete host:guest n:n oligomers of controlled size and shape in water with properties specific to the oligomers. We collected more than 50 examples and identified several factors explaining the formation of linear or cyclic oligomers and provide some rational to design new assemblies and target advanced properties.

Abstract

Proteins are an endless source of inspiration. By carefully tuning the amino‐acid sequence of proteins, nature made them evolve from primary to quaternary structures, a property specific to protein oligomers and often crucial to accomplish their function. On the other hand, the synthetic macrocycles cucurbiturils (CBs) have shown outstanding recognition properties in water, and a growing number of (host)_n:(guest)_n supramolecular polymers involving CBs have been reported. However, the burgeoning field of discrete (n:n) host:guest oligomers has just started to attract attention. While 2:2 complexes are the major oligomers, 3:3 and up to 6:6 oligomers have been described, some associated with emerging applications, specific to the (n:n) arrangements. Design rules to target (n:n) host:guest oligomers are proposed toward new advanced host:guest systems.

Rationally designed peptides control the assembly of α‐helical peptide nanofibers, allowing the adjustment of nanofiber length within the range of >1 µm to 100 nm. Shortened nanofibers, while raising equivalent B‐cell responses compared to full‐length fibers, induce heightened CD8⁺ T‐cell responses in mice.

Abstract

Peptide nanofibers are useful for many biological applications, including immunotherapy, tissue engineering, and drug delivery. The robust lengthwise assembly of these peptides into nanofibers is typically difficult to control, resulting in polydisperse fiber lengths and an incomplete understanding of how nanofiber length affects biological responses. Here, rationally designed capping peptides control the length of helical peptide nanofibers with unique precision. These designed peptides bind the tips of elongated nanofibers to shorten and narrow their length distributions. Demonstrating their use as immunotherapies, capped nanofibers are preferentially cross‐presented by dendritic cells compared to uncapped nanofibers. Due to increased cross‐presentation, these capped nanofibers trigger stronger CD8⁺ T‐cell responses in mice than uncapped nanofibers. This strategy illustrates a means for controlling the length of supramolecular peptide nanofibers to modulate their immunogenicity in the context of immunotherapies.