Late-stage guanine C8-H alkylation of nucleosides, nucleotides, and oligonucleotides via photo-mediated Minisci reaction.

Chemically modified nucleosi(ti)des and functional oligonucleotides (ONs, including therapeutic oligonucleotides, aptamer, nuclease, etc.) have been identified playing an essential role in the areas of medicinal chemistry, chemical biology, biotechnology, and nanotechnology. Introduction of functional groups into the nucleobases of ONs mostly relies on the laborious de novo chemical synthesis. Due to the importance of nucleosides modification and aforementioned limitations of functionalizing ONs, herein, we describe a highly efficient site-selective alkylation at the C8-position of guanines in guanosine (together with its analogues), GMP, GDP, and GTP, as well as late-stage functionalization of dinucleotides and single-strand ONs (including ssDNA and RNA) through photo-mediated Minisci reaction. Addition of catechol to assist the formation of alkyl radicals via in situ generated boronic acid catechol ester derivatives (BACED) markedly enhances the yields especially for the reaction of less stable primary alkyl radicals, and is the key to success for the post-synthetic alkylation of ONs. This method features excellent chemoselectivity, no necessity for pre-protection, wide range of substrate scope, various free radical precursors, and little strand lesion. Downstream applications in disease treatment and diagnosis, or as biochemical probes to study biological processes after linking with suitable fluorescent compounds are expected.

Photoprogrammable Moisture-Responsive Actuation of a Shape Memory Polymer Film.

Humidity-responsive polymeric actuators have gained considerable interest due to their great potential in the fields including soft robotics, artificial muscles, smart sensors, and actuators. However, most of them can only exhibit invariable shape changes, which severely restricts their further exploration and practical use. Herein, we report that programmable humidity-responsive actuating behaviors can be realized by introducing photoprogrammable hygroscopic patterns into shape memory polymers. Poly(ethylene-co-acrylic acid) is selected as a model polymer and the solvent-processed thin films are soft and elastic, whose external shapes can be programmed by a modified shape memory process. On another aspect, an Fe3+-carboxylate coordinating network formed by surface treatments can be spatially dissociated under UV, resulting in transient hygroscopic gradients as active joints for moisture-driven actuation. Moreover, we show that the shape memory effect can be an effective means to adjust the direction as well as the amplitude of the moisture-driven actuating behavior. The proposed strategy is convenient and can be generally extended to other shape memory polymers to realize programmable moisture-responsive actuating behaviors.

Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial.

BACKGROUND: Safe and effective vaccines are urgently needed to end the COVID-19 pandemic caused by SARS-CoV-2 infection. We aimed to assess the preliminary safety, tolerability, and immunogenicity of an mRNA vaccine ARCoV, which encodes the SARS-CoV-2 spike protein receptor-binding domain (RBD). METHODS: This single centre, double-blind, randomised, placebo-controlled, dose-escalation, phase 1 trial of ARCoV was conducted at Shulan (Hangzhou) hospital in Hangzhou, Zhejiang province, China. Healthy adults aged 18-59 years negative for SARS-CoV-2 infection were enrolled and randomly assigned using block randomisation to receive an intramuscular injection of vaccine or placebo. Vaccine doses were 5 µg, 10 µg, 15 µg, 20 µg, and 25 µg. The first six participants in each block were sentinels and along with the remaining 18 participants, were randomly assigned to groups (5:1). In block 1 sentinels were given the lowest vaccine dose and after a 4-day observation with confirmed safety analyses, the remaining 18 participants in the same dose group proceeded and sentinels in block 2 were given their first administration on a two-dose schedule, 28 days apart. All participants, investigators, and staff doing laboratory analyses were masked to treatment allocation. Humoral responses were assessed by measuring anti-SARS-CoV-2 RBD IgG using a standardised ELISA and neutralising antibodies using pseudovirus-based and live SARS-CoV-2 neutralisation assays. SARS-CoV-2 RBD-specific T-cell responses, including IFN-γ and IL-2 production, were assessed using an enzyme-linked immunospot (ELISpot) assay. The primary outcome for safety was incidence of adverse events or adverse reactions within 60 min, and at days 7, 14, and 28 after each vaccine dose. The secondary safety outcome was abnormal changes detected by laboratory tests at days 1, 4, 7, and 28 after each vaccine dose. For immunogenicity, the secondary outcome was humoral immune responses: titres of neutralising antibodies to live SARS-CoV-2, neutralising antibodies to pseudovirus, and RBD-specific IgG at baseline and 28 days after first vaccination and at days 7, 15, and 28 after second vaccination. The exploratory outcome was SARS-CoV-2-specific T-cell responses at 7 days after the first vaccination and at days 7 and 15 after the second vaccination. This trial is registered with www.chictr.org.cn (ChiCTR2000039212). FINDINGS: Between Oct 30 and Dec 2, 2020, 230 individuals were screened and 120 eligible participants were randomly assigned to receive five-dose levels of ARCoV or a placebo (20 per group). All participants received the first vaccination and 118 received the second dose. No serious adverse events were reported within 56 days after vaccination and the majority of adverse events were mild or moderate. Fever was the most common systemic adverse reaction (one [5%] of 20 in the 5 µg group, 13 [65%] of 20 in the 10 µg group, 17 [85%] of 20 in the 15 µg group, 19 [95%] of 20 in the 20 µg group, 16 [100%] of 16 in the 25 µg group; p<0·0001). The incidence of grade 3 systemic adverse events were none (0%) of 20 in the 5 µg group, three (15%) of 20 in the 10 µg group, six (30%) of 20 in the 15 µg group, seven (35%) of 20 in the 20 µg group, five (31%) of 16 in the 25 µg group, and none (0%) of 20 in the placebo group (p=0·0013). As expected, the majority of fever resolved in the first 2 days after vaccination for all groups. The incidence of solicited systemic adverse events was similar after administration of ARCoV as a first or second vaccination. Humoral immune responses including anti-RBD IgG and neutralising antibodies increased significantly 7 days after the second dose and peaked between 14 and 28 days thereafter. Specific T-cell response peaked between 7 and 14 days after full vaccination. 15 µg induced the highest titre of neutralising antibodies, which was about twofold more than the antibody titre of convalescent patients with COVID-19. INTERPRETATION: ARCoV was safe and well tolerated at all five doses. The acceptable safety profile, together with the induction of strong humoral and cellular immune responses, support further clinical testing of ARCoV at a large scale. FUNDING: National Key Research and Development Project of China, Academy of Medical Sciences China, National Natural Science Foundation China, and Chinese Academy of Medical Sciences.

Programmable Humidity-Responsive Actuation of Polymer Films Enabled by Combining Shape Memory Property and Surface-Tunable Hygroscopicity.

Most humidity-responsive polymeric actuators can only exhibit shape transformations between a planar shape in the dry state and a bended three-dimensional (3D) shape when exposed to moisture, and it is challenging to design and prepare hygroscopic actuators with programmable actuating behaviors displayed from sophisticated 3D structures. Herein, we demonstrate that the integration of shape memory property and surface treatment enabled hygromorphic responsivity endows a single-component polymer film with programmable moisture-driven actuating behaviors. The solvent-processed polyethylene-co-acrylic acid (EAA) copolymer film is soft and stretchable at room temperature, and has a good thermal-responsive shape memory property. By surface treatment using base/acid solutions, the reversible gradient conversion between carboxyl groups and carboxylate salts along the thickness direction enables the film to exhibit designed hygroscopic actuations. The shape memory property and moisture-driven actuating behaviors can be combined to realize 3D-3D morphing by first programming the films into 3D shapes and then conducting the surface treatments. Both shape programming and surface treatment processes can be reprogrammed to make the actuation behavior readily tunable. We also show that the created surface patterns can act as moisture-sensitive conducting paths to detect human breathes, and the combination of shape memory, moisture-responsive morphing and conductivity change leads to some interesting applications such as smart switch in conducting circuit. This work provides a new and general strategy for the design of advanced humidity-responsive actuators.

Access to benzene-modified 2nd generation strigolactams and GR24 by merging C-H olefination with decarboxylative Giese cyclization.

Herein, we reported an efficient and general synthetic route to assemble benzene-modified 2nd generation strigolactams and GR24. The key features of this synthesis include a palladium-catalyzed ortho-selective olefination of the commercially available substituted N-Boc phenylalanine and a decarboxylative Giese radical cyclization. The bioactivities of these compounds to stimulate the seed germination of Orobanche aegyptiaca parasitic weed were also analysed. 2nd generation strigolactam 15f derived from para-OMe phenylalanine showed superior bioactivity to the original unsubstituted 15b.

Biomimetic Total Syntheses of Ergot Alkaloids via Decarboxylative Giese Coupling.

Biomimetic total syntheses of Festuclavine and Pyroclavine were achieved by a sequential radical coupling. The key steps include intramolecular decarboxylative Giese reaction to form the central C ring and 4-nitrobenzenesulfonyl (Ns)-directed indole C4-H olefination to introduce the indole C4 component. In addition, D-ring formation was completed by decarboxylative alkenylation and intramolecular SN2 reaction.

Low serum testosterone level was associated with extensive coronary artery calcification in elderly male patients with stable coronary artery disease.

BACKGROUND: Coronary artery calcification (CAC) is a pandemic condition in elderly patients with coronary artery disease (CAD) and associated with a worse prognosis. Although available data have shown an association between testosterone levels in men and CAD, the association between testosterone and CAC in elderly male patients with CAD remains unknown. METHODS: A total of 211 consecutive male patients (age ≥ 65 years) who underwent first multidetector computed tomography and following angiography were enrolled from our institution between March 2009 and September 2014. CAD was angiographically documented as significant stenoses (reduction ≥ 50% of the lumen diameter) on any major coronary vessel. The standard Agatston calcium score was calculated. The relationship of serum testosterone level with the CAC score measured by multidetector computed tomography in elderly male patients with stable CAD was evaluated. For data analyses, the CAC score was divided into four categories: ≤ 10, 11-99, 100-399, and ≥ 400, corresponding to minimal, moderate, increased, and extensive calcification. RESULTS: Patients with higher CAC scores had significantly lower testosterone levels than patients with lower CAC scores (P = 0.048). In logistic regression analysis, testosterone level remained an independent predictor of extensive CAC (odds ratio 0.997, 95% confidence interval 0.994-0.999, P = 0.043). CONCLUSION: Our findings indicate an inverse association between testosterone level and the susceptibility to extensive CAC in elderly men with stable CAD.

Electrochemical fabrication of titania nanotube arrays with tunning nature of dimethyl sulfoxide and its application for hydrogen sensing.

In the present work, tuning effects of dimethyl sulphoxide (DMSO) on the length, wall thickness, dimension and morphology of titania nanotube arrays fabricated by anodization was investigated. DMSO presented in both ethylene glycol and glycerol electrolytes provided excellent tunability in length, wall thickness and diameter of the produced TiO2 nanotube arrays by systematically varying the DMSO concentration. At the DMSO concentration of 12 wt% in ethylene glycol, the nanotube length could be up to 13.0 microm at 20 V for 8 h anodization. The TiO2 nanotube arrays produced in DMSO containing ethylene glycol or glycerol electrolytes displayed a high sensitivity to hydrogen at room temperature compared to the absence of DMSO. The further enhancement of resistance response could be achieved by coating a Pt and Pd layer on the surface of TiO2 nanotube-arrays. The presented work provided a simple way to control formation of TiO2 nanotube arrays through the tuning effects of DMSO in ethylene glycol or glycerol electrolytes.

2-(7-Methyl-1H-indol-3-yl)acetonitrile.

In the title compound, C(11)H(10)N(2), the carbonitrile group is twisted away from the indole plane [C(cy)-C(me)-C(ar)-C(ar) = 66.6 (2)°; cy = cyanide, me = methyl-ene and ar = aromatic]. In the crystal, N-H⋯N hydrogen bonds link the mol-ecules into C(7) chains propagating in the [001] direction.

3-[(E)-2-Phenyl-ethen-yl]-1H-indole-6-carbonitrile.

In the title compound, C(17)H(12)N(2), the inter-planar angle between the indole mean plane [max.deviation 0.030 (1) Å] and the phenyl ring is 24.32 (7)°. In the crystal, inter-molecular N-H⋯N C hydrogen bonds form zigzag chains in the a-axis direction augmented by weak C-H⋯N C contacts.

(5-Meth-oxy-1H-indol-3-yl)acetonitrile.

In the title compound, C(11)H(10)N(2)O, the O atom and the C atom of the methyl-ene group deviate only slightly [0.029 (3) and 0.055 (3) Å, respectively] from the approximately planar ring system (r.m.s. deviation = 0.013 Å). In the crystal, N-H⋯O hydrogen bonds link the mol-ecules into zigzag chains running along the b axis.

6-[(E)-2-Phenyl-vin-yl]-1H-indole.

The title compound, C(16)H(13)N, is essentially planar [maximum deviation from the least-squares plane = 0.081 (3) Å], with a dihedral angle of 1.65 (13)° between the planes of the indole and benzene rings. In the crystal, there are no significant inter-molecular π-π inter-actions [minimum ring centroid-centroid separation = 4.217 (5) Å].

6-(1H-Tetra-zol-5-yl)-1H-indole monohydrate.

In the title compound, C(9)H(7)N(5)·H(2)O, the tetra-zole ring forms a dihedral angle of 1.82 (1)° with the mean plane of the indole fragment. In the crystal, mol-ecules are linked by inter-molecular O-H⋯N, N-H⋯O and N-H⋯N hydrogen bonds into a two-dimensional network parallel to (100). Addtional stabilization is provide by weak π-π inter-actions with a centroid-centroid distance of 3.698 (2) Å.

4-(1H-Tetra-zol-5-yl)-1H-indole.

There are two mol-ecules with similar configurations in the asymmetric unit of the title compound, C(9)H(7)N(5), which are linked by inter-molecular N-H⋯N hydrogen bonds into chains with graph-set motif C(2) (2)(8) along the b axis. The indole core has the expected planar geometry in the two mol-ecules, with a maximum deviation of 0.008 (8) Šfrom the least-squares plane defined by the nine constituent atoms, and the dihedral angles between the indole and tetra-zole rings are similar [42.4 (2) and 42.7 (2)°].