The phosphatidylinositol 3-kinase (PI3K)/Akt pathway plays a crucial role in various cellular processes and is aberrantly activated in cancers, contributing to the occurrence and progression of ...tumors. Examining the upstream and downstream nodes of this pathway could allow full elucidation of its function. Based on accumulating evidence, strategies targeting major components of the pathway might provide new insights for cancer drug discovery. Researchers have explored the use of some inhibitors targeting this pathway to block survival pathways. However, because oncogenic PI3K pathway activation occurs through various mechanisms, the clinical efficacies of these inhibitors are limited. Moreover, pathway activation is accompanied by the development of therapeutic resistance. Therefore, strategies involving pathway inhibitors and other cancer treatments in combination might solve the therapeutic dilemma. In this review, we discuss the roles of the PI3K/Akt pathway in various cancer phenotypes, review the current statuses of different PI3K/Akt inhibitors, and introduce combination therapies consisting of signaling inhibitors and conventional cancer therapies. The information presented herein suggests that cascading inhibitors of the PI3K/Akt signaling pathway, either alone or in combination with other therapies, are the most effective treatment strategy for cancer.
Studies of human mobility in the past decade revealed a number of general scaling laws. However, to reproduce the scaling behaviors quantitatively at both the individual and population levels ...simultaneously remains to be an outstanding problem. Moreover, recent evidence suggests that spatial scales have a significant effect on human mobility, raising the need for formulating a universal model suited for human mobility at different levels and spatial scales. Here we develop a general model by combining memory effect and population-induced competition to enable accurate prediction of human mobility based on population distribution only. A variety of individual and collective mobility patterns such as scaling behaviors and trajectory motifs are accurately predicted for different countries and cities of diverse spatial scales. Our model establishes a universal underlying mechanism capable of explaining a variety of human mobility behaviors, and has significant applications for understanding many dynamical processes associated with human mobility.
Herein, a type of light- and heat-driven flexible supramolecular polymer with reversibly long-lived phosphorescence and photochromism is constructed from acrylamide copolymers with 4-phenylpyridinium ...derivatives containing a cyano group (P-CN, P-oM, P-mM), sulfobutylether-β-cyclodextrin (SBCD), and polyvinyl alcohol (PVA). Compared to their parent solid polymers, these flexible supramolecules based on the non-covalent cross-linking of copolymers, SBCD, and PVA efficiently boost the phosphorescence lifetimes (723.0 ms for P-CN, 623.0 ms for P-oM, 945.8 ms for P-mM) through electrostatic interaction and hydrogen bonds. The phosphorescence intensity/lifetime, showing excellent responsiveness to light and heat, sharply decreased after irradiation with a 275 nm flashlight or sunlight and gradually recovered through heating. This is accompanied by the occurrence and fading of visible photochromism, manifesting as dark green for P-CN and pink for P-oM and P-mM. These reversible photochromism and phosphorescence behaviors are mainly attributed to the generation and disappearance of organic radicals in the 4-phenylpyridinium derivatives with a cyano group, which can guide tunable luminescence and photochromism.
A spiro‐axis skeleton not only introduces circularly polarized luminescence (CPL) into thermally activated delayed fluorescence (TADF) molecules but also enhances the intramolecular through space ...charge transfer (TSCT) process. Spiral distributed phenoxazine and 2‐(trifluoromethyl)‐9H‐thioxanthen‐9‐one‐10,10‐dioxide act as donor and acceptor units, respectively. The resulting TADF enantiomers, (rac)‐OSFSO, display emission maxima at 470 nm, small singlet‐triplet energy gap (ΔEST) of 0.022 eV and high photoluminescence quantum yield (PLQY) of 81.2 % in co‐doped film. The circularly polarized OLEDs (CP‐OLEDs) based on (R)‐OSFSO and (S)‐OSFSO display obvious circularly polarized electroluminescence (CPEL) signals with dissymmetry factor up to 3.0×10−3 and maximum external quantum efficiency (EQEmax) of 20.0 %. Moreover, the devices show remarkably low efficiency roll‐off with an EQE of 19.3 % at 1000 cd m−2 (roll‐off ca. 3.5 %), which are among the top results of CP‐OLEDs.
A chiral spiro‐axis skeleton introduced the circularly polarized luminescence property into TADF molecules and enhanced the intramolecular through space charge transfer process. The resulting TADF enantiomers display obvious CPEL signals with |gEL| factor up to 3.0×10−3 and EQE of 20.0 % with remarkably low efficiency roll‐off, which are among the top results of CP‐OLEDs.
The lithium–sulfur (Li–S) battery is a promising high‐energy‐density storage system. The strong anchoring of intermediates is widely accepted to retard the shuttle of polysulfides in a working ...battery. However, the understanding of the intrinsic chemistry is still deficient. Inspired by the concept of hydrogen bond, herein we focus on the Li bond chemistry in Li–S batteries through sophisticated quantum chemical calculations, in combination with 7Li nuclear magnetic resonance (NMR) spectroscopy. Identified as Li bond, the strong dipole–dipole interaction between Li polysulfides and Li–S cathode materials originates from the electron‐rich donors (e.g., pyridinic nitrogen (pN)), and is enhanced by the inductive and conjugative effect of scaffold materials with π‐electrons (e.g., graphene). The chemical shift of Li polysulfides in 7Li NMR spectroscopy, being both theoretically predicted and experimentally verified, is suggested to serve as a quantitative descriptor of Li bond strength. These theoretical insights were further proved by actual electrochemical tests. This work highlights the importance of Li bond chemistry in Li–S cell and provides a deep comprehension, which is helpful to the cathode materials rational design and practical applications of Li–S batteries.
Lithium bond chemistry in Li–S batteries is probed by sophisticated quantum chemical calculations in combination with 7Li NMR spectroscopy. The chemical shift in 7Li NMR spectroscopy is suggested to be a quantitative descriptor of Li bond strength, propelling the advances in Li–S chemistry through materials genome design and high throughput screening.
Conspectus The development of highly effective chiral ligands is a key topic in enhancing the catalytic activity and selectivity in metal-catalyzed asymmetric synthesis. Traditionally, the difficulty ...of ligand synthesis, insufficient accuracy in controlling the stereoselectivity, and poor universality of the systems often become obstacles in this field. Using the concept of nonequivalent coordination to the metal, our group has designed and synthesized a series of new chiral catalysts to access various carbon/silicon and/or multiple stereogenic centers containing products with excellent chemo-, diastereo-, and enantioselectivity. In this Account, we summarize a series of new phosphine ligands with multiple stereogenic centers that have been developed in our laboratory. These ligands exhibited good to excellent performance in the transition-metal-catalyzed enantioselective construction of quaternary carbon/silicon and multiple stereogenic centers. In the first section, notable examples of the design and synthesis of new chiral ligands by non-covalent interaction-based multisite activation are described. The integrations of axial chirality, atom-centered chirality, and chiral anions and multifunctional groups into a single scaffold are individually highlighted, as represented by Ar-BINMOLs and their derivative ligands, HZNU-Phos, Fei-Phos, and Xing-Phos. In the second, third, and fourth sections, the enantioselective construction of quaternary carbon stereocenters, multiple stereogenic centers, and silicon stereogenic centers using our newly developed chiral ligands is summarized. These sections refer to detailed reaction information in the chiral-ligand-controlled asymmetric catalysis based on the concept of nonequivalent coordination with multisite activation. Accordingly, a wide array of transition metal and main-group metal catalysts has been applied to the enantioselective synthesis of chiral heterocycles, amino acid derivatives, cyclic ketones, alkenes, and organosilicon compounds bearing one to five stereocenters. This Account shows that this new model of multifunctional ligand-controlled catalysts exhibits excellent stereocontrol and catalytic efficiency, especially in a stereodivergent and atom-economical fashion. Furthermore, a brief mechanistic understanding of the origin of enantioselectivity from our newly developed chiral catalyst systems could inspire further development of new ligands and enhancement of enantioselective synthesis by asymmetric metal catalysis.
Although the taxonomic composition of the human microbiome varies tremendously across individuals, its gene composition or functional capacity is highly conserved - implying an ecological property ...known as functional redundancy. Such functional redundancy has been hypothesized to underlie the stability and resilience of the human microbiome, but this hypothesis has never been quantitatively tested. The origin of functional redundancy is still elusive. Here, we investigate the basis for functional redundancy in the human microbiome by analyzing its genomic content network - a bipartite graph that links microbes to the genes in their genomes. We find that this network exhibits several topological features that favor high functional redundancy. Furthermore, we develop a simple genome evolution model to generate genomic content network, finding that moderate selection pressure and high horizontal gene transfer rate are necessary to generate genomic content networks with key topological features that favor high functional redundancy. Finally, we analyze data from two published studies of fecal microbiota transplantation (FMT), finding that high functional redundancy of the recipient's pre-FMT microbiota raises barriers to donor microbiota engraftment. This work elucidates the potential ecological and evolutionary processes that create and maintain functional redundancy in the human microbiome and contribute to its resilience.
Benzoxepane derivatives were designed and synthesized, and one hit compound emerged as being effective in vitro with low toxicity. In vivo, this hit compound ameliorated both sickness behavior ...through anti‐inflammation in LPS‐induced neuroinflammatory mice model and cerebral ischemic injury through anti‐neuroinflammation in rats subjected to transient middle cerebral artery occlusion. Target fishing for the hit compound using photoaffinity probes led to identification of PKM2 as the target protein responsible for anti‐inflammatory effect of the hit compound. Furthermore, the hit exhibited an anti‐neuroinflammatory effect in vitro and in vivo by inhibiting PKM2‐mediated glycolysis and NLRP3 activation, indicating PKM2 as a novel target for neuroinflammation and its related brain disorders. This hit compound has a better safety profile compared to shikonin, a reported PKM2 inhibitor, identifying it as a lead compound in targeting PKM2 for the treatment of inflammation‐related diseases.
Fishing around: The benzoxepane derivative A was effective in vivo, ameliorating both sickness behavior through anti‐inflammation in LPS‐induced neuroinflammatory mice model and cerebral ischemic injury through anti‐neuroinflammation in rats subjected to transient middle cerebral artery occlusion. Target fishing identified PKM2 as the target protein for A. Furthermore, A exhibited an anti‐neuroinflammatory effect in vitro and in vivo by inhibiting PKM2‐mediated glycolysis and NLRP3 activation.
Abstract This study is part of practitioner inquiry undertaken in an underprivileged, low-achieving primary school in Sydney, Australia, based in a Chinese as a Foreign Language (CFL) classroom with ...9–10-year-olds. The aim was to unpack pedagogic discourse at the micro level of interactions, while delving into students’ perceptions of language learning experiences. Two data sources were used: an audio recording of lessons and students’ focus groups. By applying Bernstein’s pedagogic discourse and Fair Go Project’s (FGP) engagement framework, the findings reveal that consistently shifting pedagogic discourses were likely to overcome students’ social backgrounds and offer them engaging CFL learning experiences. The study makes an original contribution to providing CFL practitioners and pre-service teachers with a delicate, precise language to plan and chart courses, while guiding disadvantaged students through pedagogic mazes. This paper concludes with pedagogic implications for the social inclusion agenda.
A routine to parallelize and increase the throughput of fixed length distribution matching with non-binary output alphabet is presented. The routine performs parallel distribution matchings with ...binary output alphabets, and then maps the binary output streams to symbols from the primary, non-binary alphabet. Fixed length distribution matching is essential for probabilistically shaped coded modulation (PSCM), such as the probabilistic amplitude shaping (PAS). In the PAS setup, the novel bit-level distribution matcher achieves similar rate-versus-SNR performance as the symbol-level constant composition distribution matcher, thus providing a high throughput solution for PSCM.
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