Switchable Dual Circularly Polarized Luminescence in Through-Space Conjugated Chiral Foldamers.

Organic materials with switchable dual circularly polarized luminescence (CPL) are highly desired because they can not only directly radiate tunable circularly polarized light themselves but also induce CPL for guests by providing chiral environment in self-assembled structures or serving as the hosts for energy transfer systems. However, most organic molecules only exhibit single CPL and it remains challenging to develop organic molecules with dual CPL. Herein, novel through-space conjugated chiral foldamers are constructed by attaching two biphenyl arms to the 9,10-positions of phenanthrene, and switchable dual CPL with opposite signs at different emission wavelengths are successfully realized in the foldamers containing high-polarizability substitutes (cyano, methylthio and methylsulfonyl). The combined experimental and computational results demonstrate that the intramolecular through-space conjugation has significant contributions to stabilizing the folded conformations. Upon photoexcitation in high-polar solvents, strong interactions between the biphenyl arms substituted with cyano, methylthio or methylsulfonyl and the polar environment induce conformation transformation for the foldamers, resulting in two transformable secondary structures of opposite chirality, accounting for the dual CPL with opposite signs. These findings highlight the important influence of the secondary structures on chiroptical property of the foldamers and pave a new avenue towards efficient and tunable dual CPL materials.

Integrated analysis of single cell-RNA sequencing and Mendelian randomization identifies lactate dehydrogenase B as a target of melatonin in ischemic stroke.

AIMS: Despite the success of single-cell RNA sequencing in identifying cellular heterogeneity in ischemic stroke, clarifying the mechanisms underlying these associations of differently expressed genes remains challenging. Several studies that integrate gene expression and gene expression quantitative trait loci (eQTLs) with genome wide-association study (GWAS) data to determine their causal role have been proposed. METHODS: Here, we combined Mendelian randomization (MR) framework and single cell (sc) RNA sequencing to study how differently expressed genes (DEGs) mediating the effect of gene expression on ischemic stroke. The hub gene was further validated in the in vitro model. RESULTS: We identified 2339 DEGs in 10 cell clusters. Among these DEGs, 58 genes were associated with the risk of ischemic stroke. After external validation with eQTL dataset, lactate dehydrogenase B (LDHB) is identified to be positively associated with ischemic stroke. The expression of LDHB has also been validated in sc RNA-seq with dominant expression in microglia and astrocytes, and melatonin is able to reduce the LDHB expression and activity in vitro ischemic models. CONCLUSION: Our study identifies LDHB as a novel biomarker for ischemic stroke via combining the sc RNA-seq and MR analysis.

Derivation of induced pluripotent stem cell SHEHDNi002-A from a 68-year-old Chinese Han Parkinson's disease patient carrying LRRK2 and DNAJC6 mutations.

Parkinson's disease (PD) is a common movement disorder. In this study, we generated an induced pluripotent stem cell (iPSC) line from the dermal fibroblasts of a 68-year-old female patient, carrying LRRK2 and DNAJC6 mutations. This iPSC line will be a useful tool for investigating the pathogenesis and for developing treatment for PD.

In-situ electro-responsive through-space coupling enabling foldamers as volatile memory elements.

Voltage-gated processing units are fundamental components for non-von Neumann architectures like memristor and electric synapses, on which nanoscale molecular electronics have possessed great potentials. Here, tailored foldamers with furan‒benzene stacking (f-Fu) and thiophene‒benzene stacking (f-Th) are designed to decipher electro-responsive through-space interaction, which achieve volatile memory behaviors via quantum interference switching in single-molecule junctions. f-Fu exhibits volatile turn-on feature while f-Th performs stochastic turn-off feature with low voltages as 0.2 V. The weakened orbital through-space mixing induced by electro-polarization dominates stacking malposition and quantum interference switching. f-Fu possesses higher switching probability and faster responsive time, while f-Th suffers incomplete switching and longer responsive time. High switching ratios of up to 91 for f-Fu is realized by electrochemical gating. These findings provide evidence and interpretation of the electro-responsiveness of non-covalent interaction at single-molecule level and offer design strategies of molecular non-von Neumann architectures like true random number generator.

A Tale of Two: When Neural Stem Cells Encounter Hypoxia.

Normoxia is defined as an oxygen concentration of 20.9%, as in room air, whereas hypoxia refers to any oxygen concentration less than this. Any physiological oxygen deficiency or tissue oxygen deficiency relative to demand is called hypoxia. Neural stem cells (NSCs) are multipotent stem cells that can differentiate into multiple cell lines such as neurons, oligodendrocytes, and astrocytes. Under hypoxic conditions, the apoptosis rate of NSCs increases remarkably in vitro or in vivo. However, some hypoxia promotes the proliferation and differentiation of NSCs. The difference is related to the oxygen concentration, the duration of hypoxia, the hypoxia tolerance threshold of the NSCs, and the tissue source of the NSCs. The main mechanism of hypoxia-induced proliferation and differentiation involves an increase in cyclin and erythropoietin concentrations, and hypoxia-inducible factors play a key role. Multiple molecular pathways are activated during hypoxia, including Notch, Wnt/ß-catenin, PI3K/Akt, and altered microRNA expression. In addition, we review the protective effect of exogenous NSCs transplantation on ischemic or anoxic organs, the therapeutic potential of hypoxic preconditioning on exogenous NSCs and clinical application of NSCs.

A multicentre single arm phase 2 trial of neoadjuvant pyrotinib and letrozole plus dalpiciclib for triple-positive breast cancer.

Current therapies for HER2-positive breast cancer have limited efficacy in patients with triple-positive breast cancer (TPBC). We conduct a multi-center single-arm phase 2 trial to test the efficacy and safety of an oral neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib (a CDK4/6 inhibitor) in patients with treatment-naïve, stage II-III TPBC with a Karnofsky score of ≥70 (NCT04486911). The primary endpoint is the proportion of patients with pathological complete response (pCR) in the breast and axilla. The secondary endpoints include residual cancer burden (RCB)-0 or RCB-I, objective response rate (ORR), breast pCR (bpCR), safety and changes in molecular targets (Ki67) from baseline to surgery. Following 5 cycles of 4-week treatment, the results meet the primary endpoint with a pCR rate of 30.4% (24 of 79; 95% confidence interval (CI), 21.3-41.3). RCB-0/I is 55.7% (95% CI, 44.7-66.1). ORR is 87.4%, (95% CI, 78.1-93.2) and bpCR is 35.4% (95% CI, 25.8-46.5). The mean Ki67 expression reduces from 40.4% at baseline to 17.9% (P < 0.001) at time of surgery. The most frequent grade 3 or 4 adverse events are neutropenia, leukopenia, and diarrhoea. There is no serious adverse event- or treatment-related death. This fully oral, chemotherapy-free, triplet combined therapy has the potential to be an alternative neoadjuvant regimen for patients with TPBC.

Achieving Multiple Quantum-Interfered States via Through-Space and Through-Bond Synergistic Effect in Foldamer-Based Single-Molecule Junctions.

The construction of multivalued logic circuits by multiple quantum-interfered states at the molecular level can make full use of molecular diversity and versatility, broadening the application of molecular electronics. Understanding charge transport through different conducting pathways and how they interact with each other in molecules with a secondary structure is an indispensable foundation to achieve this goal. Herein, we elucidate the synergistic effect from through-space and through-bond conducting pathways in foldamers derived from ortho-pentaphenylene by the separate modulation on these pathways. The shrinkage of central heterocycles' sizes allows foldamers to stack with larger overlap degrees, resulting in level-crossing and thus transformation from constructive quantum interference (CQI) to destructive quantum interference (DQI) in a through-space pathway. The alteration of central heterocycles' connection sites enhances through-bond conjugation, leading to amplified contribution from a through-bond pathway. The enhanced through-bond pathway destructively interferes with the through-space pathway, exerting a suppression effect on transmission. Therefore, four quantum-interfered states of through-space and through-bond combination are generated, including through-space CQI-dominated states, through-space DQI-dominated states, through-space CQI states with through-bond suppression, and through-space DQI states with through-bond suppression. These findings enable us to regulate charge transport within high-order structures via multiple conducting pathways and provide a proof of concept to construct multivalued logic circuits.

Mechanical single-molecule potentiometers with large switching factors from ortho-pentaphenylene foldamers.

Molecular potentiometers that can indicate displacement-conductance relationship, and predict and control molecular conductance are of significant importance but rarely developed. Herein, single-molecule potentiometers are designed based on ortho-pentaphenylene. The ortho-pentaphenylene derivatives with anchoring groups adopt multiple folded conformers and undergo conformational interconversion in solutions. Solvent-sensitive multiple conductance originating from different conformers is recorded by scanning tunneling microscopy break junction technique. These pseudo-elastic folded molecules can be stretched and compressed by mechanical force along with a variable conductance by up to two orders of magnitude, providing an impressively higher switching factor (114) than the reported values (ca. 1~25). The multichannel conductance governed by through-space and through-bond conducting pathways is rationalized as the charge transport mechanism for the folded ortho-pentaphenylene derivatives. These findings shed light on exploring robust single-molecule potentiometers based on helical structures, and are conducive to fundamental understanding of charge transport in higher-order helical molecules.

Achieving Efficient Multichannel Conductance in Through-Space Conjugated Single-Molecule Parallel Circuits.

Constructing single-molecule parallel circuits with multiple conduction channels is an effective strategy to improve the conductance of a single molecular junction, but rarely reported. We present a novel through-space conjugated single-molecule parallel circuit (f-4Ph-4SMe) comprised of a pair of closely parallelly aligned p-quaterphenyl chains tethered by a vinyl bridge and end-capped with four SMe anchoring groups. Scanning-tunneling-microscopy-based break junction (STM-BJ) and transmission calculations demonstrate that f-4Ph-4SMe holds multiple conductance states owing to different contact configurations. When four SMe groups are in contact with two electrodes at the same time, the through-bond and through-space conduction channels work synergistically, resulting in a conductance much larger than those of analogous molecules with two SMe groups or the sum of two p-quaterphenyl chains. The system is an ideal model for understanding electron transport through parallel π-stacked molecular systems and may serve as a key component for integrated molecular circuits with controllable conductance.

Through-Space Conjugation: An Effective Strategy for Stabilizing Intramolecular Charge-Transfer States.

Intramolecular charge transfer (ICT) has significant impacts on organic optoelectronic materials, photochemistry, biotechnology, and so on. However, it is hard to stabilize the ICT state because of the rapid nonradiative charge recombination process, which often quenches light emission. In this work, we use new foldamers of the protonated pyridine-modified tetraphenylethene derivatives that possess through-space conjugation (TSC) characters as the models to study the impact of TSC on the ICT state. Steady and transient spectroscopies illustrate that the lifetime of the ICT state in the molecule with strong TSC can be much longer than those of molecules without TSC, giving rise to a higher fluorescence quantum yield. By combining the theoretical calculations, we demonstrate that the strong TSC can stabilize the ICT state and slow the charge recombination rate by more efficiently dispersing charges. This is a conceptually new design strategy for functional optoelectronic materials that require more stable ICT states.

Clean Power Generation from the Intractable Natural Coalfield Fires: Turn Harm into Benefit.

The coal fires, a global catastrophe for hundreds of years, have been proved extremely difficult to control, and hit almost every coal-bearing area globally. Meanwhile, underground coal fires contain tremendous reservoir of geothermal energy. Approximately one billion tons of coal burns underground annually in the world, which could generate ~1000 GW per annum. A game-changing approach, environmentally sound thermal energy extraction from the intractable natural coalfield fires, is being developed by utilizing the waste energy and reducing the temperature of coalfield fires at the same time. Based on the Seebeck effect of thermoelectric materials, the temperature difference between the heat medium and cooling medium was employed to directly convert thermal energy into clean electrical energy. By the time of December 2016, the power generation from a single borehole at Daquan Lake fire district in Xinjiang has been exceeded 174.6 W. The field trial demonstrates that it is possible to exploit and utilize the waste heat resources in the treated coal fire areas. It promises a significant impact on the structure of global energy generation and can also promote progress in thermoelectric conversion materials, geothermal exploration, underground coal fires control and other energy related areas.

[Research on the academic genealogy of physiology in modern China].

The Department of Physiology in Peking Union Medical College was the earliest, largest and most authoritative educational and research organization, and played a significant role in the development of physiology in modern China. The physiology in China entered a new developmental stage, especially after LIN Ke-sheng (K.K.S.Lim), the founder of modern Chinese physiology, the professor and taking the director of the Department in 1925. 14 physiologists, including Academician WANG Zhijun, FENG Depei et al. were the second-generation inheritors. The third-generation successors included 18 physiologists, with academician CHEN Yi-zhang, HAN Ji-sheng as the representatives. The academic genealogy of the Department promoted the formation of scientific community of modern physiology, laid down a good foundation for the further development of physiology, and had far-reaching implications for the institutionalization and academic development of modern Chinese physiology.