Prefrontal GABAA(δ)R Promotes Fear Extinction through Enabling the Plastic Regulation of Neuronal Intrinsic Excitability.

Extinguishing the previously acquired fear is critical for the adaptation of an organism to the ever-changing environment, a process requiring the engagement of GABAA receptors (GABAARs). GABAARs consist of tens of structurally, pharmacologically, and functionally heterogeneous subtypes. However, the specific roles of these subtypes in fear extinction remain largely unexplored. Here, we observed that in the medial prefrontal cortex (mPFC), a core region for mood regulation, the extrasynaptically situated, δ-subunit-containing GABAARs [GABAA(δ)Rs], had a permissive role in tuning fear extinction in male mice, an effect sharply contrasting to the established but suppressive role by the whole GABAAR family. First, the fear extinction in individual mice was positively correlated with the level of GABAA(δ)R expression and function in their mPFC. Second, knockdown of GABAA(δ)R in mPFC, specifically in its infralimbic (IL) subregion, sufficed to impair the fear extinction in mice. Third, GABAA(δ)R-deficient mice also showed fear extinction deficits, and re-expressing GABAA(δ)Rs in the IL of these mice rescued the impaired extinction. Further mechanistic studies demonstrated that the permissive effect of GABAA(δ)R was associated with its role in enabling the extinction-evoked plastic regulation of neuronal excitability in IL projection neurons. By contrast, GABAA(δ)R had little influence on the extinction-evoked plasticity of glutamatergic transmission in these cells. Altogether, our findings revealed an unconventional and permissive role of extrasynaptic GABAA receptors in fear extinction through a route relying on nonsynaptic plasticity.SIGNIFICANCE STATEMENT The medial prefrontal cortex (mPFC) is one of the kernel brain regions engaged in fear extinction. Previous studies have repetitively shown that the GABAA receptor (GABAAR) family in this region act to suppress fear extinction. However, the roles of specific GABAAR subtypes in mPFC are largely unknown. We observed that the GABAAR-containing δ-subunit [GABAA(δ)R], a subtype of GABAARs exclusively situated in the extrasynaptic membrane and mediating the tonic neuronal inhibition, works oppositely to the whole GABAAR family and promotes (but does not suppress) fear extinction. More interestingly, in striking contrast to the synaptic GABAARs that suppress fear extinction by breaking the extinction-evoked plasticity of glutamatergic transmission, the GABAA(δ)R promotes fear extinction through enabling the plastic regulation of neuronal excitability in the infralimbic subregion of mPFC. Our findings thus reveal an unconventional role of GABAA(δ)R in promoting fear extinction through a route relying on nonsynaptic plasticity.

Synergistic photothermal-photodynamic-chemotherapy toward breast cancer based on a liposome-coated core-shell AuNS@NMOFs nanocomposite encapsulated with gambogic acid.

A multifunctional nanoplatform with core-shell structure was constructed in one-pot for the synergistic photothermal, photodynamic, and chemotherapy against breast cancer. In the presence of gambogic acid (GA) as the heat-shock protein 90 (HSP90) inhibitor and the gold nanostars (AuNS) as the photothermal reagent, the assembly of Zr4+ with tetrakis (4-carboxyphenyl) porphyrin (TCPP) gave rise to the nanocomposite AuNS@ZrTCPP-GA (AZG), which in turn, further coated with PEGylated liposome (LP) to enhance the stability and biocompatibility, and consequently the antitumor effect of the particle. Upon cellular uptake, the nanoscale metal - organic framework (NMOF) of ZrTCPP in the resulted AuNS@ZrTCPP-GA@LP (AZGL) could be slowly degraded in the weak acidic tumor microenvironment to release AuNS, Zr4+, TCPP, and GA to exert the synergistic treatment of tumors via the combination of AuNS-mediated mild photothermal therapy (PTT) and TCPP-mediated photodynamic therapy (PDT). The introduction of GA serves to reduce the thermal resistance of the cell to re-sensitize PTT and the constructed nanoplatform demonstrated remarkable anti-tumor activity in vitro and in vivo. Our work highlights a facile strategy to prepare a pH-dissociable nanoplatform for the effective synergistic treatment of breast cancer.

Transmetalation of a dodecahedral Na9 aggregate-based polymer: a facile route to water stable Cu(II) coordination networks.

A variety of network structures have been prepared by transmetalation of a polymer {Na3[Na9(Cbdcp)6(H2O)18]}n (1) (Cbdcp = N-(4-carboxybenzyl)-(3,5-dicarboxyl)pyridinium) containing dodecahedral Na9 aggregate secondary building units with Cu(II) by modulating the temperature, solvent, and pH. These complexes include a large, zwitterionic hexa-cuprometallocycle [Cu6(Cbdcp)6(H2O)18] (2) formed in H2O at room temperature, two three-dimensional polymers [Cu3(Cbdcp)2(OH)2(H2O)2]n (3) and {[Cu3(Cbdcp)2(OH)2]·2H2O}n (4) isolated from H2O and DMF/H2O at 135 °C, and a mononuclear complex [Cu(HCbdcp)2(H2O)3]·H2O (5) from H2O at 100 °C and pH = 6. All the complexes are robust and water stable. The crystal framework of macrocycle 2 is stable up to 100 °C under vacuum and selectively adsorbs CO2.

Stitching 2D polymeric layers into flexible interpenetrated metal-organic frameworks within single crystals.

A 2D coordination polymer prepared with bulky diethylformamide solvates exhibits channels which allow dipyridyl bridging ligands to diffuse into the crystal lattice. The absorbed dipyridyls thread through the pores of one layer and substitute the surface diethylformamide molecules on the neighboring layers to stitch alternate layers to form flexible interpenetrated metal-orgaic frameworks. The threading process also results in exchange of the bulky diethylformamide solvates for aqua to minimize congestion and, more strikingly, forces the slippage of two-dimensional layers, while still maintaining crystallinity.

NIR-PTT/ROS-Scavenging/Oxygen-Enriched Synergetic Therapy for Rheumatoid Arthritis by a pH-Responsive Hybrid CeO2-ZIF-8 Coated with Polydopamine.

Rheumatoid arthritis (RA) is an inflammatory type of arthritis that causes joint pain and damage. The inflammatory cell infiltration (e.g., M1 macrophages), the poor O2 supply at the joint, and the excess reactive oxygen species (ROS)-induced oxidative injury are the main causes of RA. We herein report a polydopamine (PDA)-coated CeO2-dopped zeolitic imidazolate framework-8 (ZIF-8) nanocomposite CeO2-ZIF-8@PDA (denoted as CZP) that can synergistically treat RA. Under near-infrared (NIR) light irradiation, PDA efficiently scavenges ROS and results in an increased temperature in the inflamed area because of its good light-to-heat conversion efficiency. The rise of temperature serves to obliterate hyper-proliferative inflammatory cells accumulated in the diseased area while vastly promoting the collapse of the acidic-responsive skeleton of ZIF-8 to release the encapsulated CeO2. The released CeO2 exerts its catalase-like activity to relieve hypoxia by generating oxygen via the decomposition of H2O2 highly expressed in the inflammatory sites. Thus, the constructed CZP composite can treat RA through NIR-photothermal/ROS-scavenging/oxygen-enriched combinative therapy and show good regression of pro-inflammatory cytokines and hypoxia-inducible factor-1α (HIF-1α) in vitro and promising therapeutic effect on RA in rat models. The multimodal nano-platform reported herein is expected to shed light on the design of synergistic therapeutic nanomedicine for effective RA therapy.

A pH-responsive supramolecular draw solute that achieves high-performance in arsenic removal via forward osmosis.

A pH-responsive, charge switchable piperazine derivative, 1,4-bis(3-propane- sulphonate sodium)-piperazinediethanesulfonic acid disodium-sulfate (4), has been designed via a stepwise synthesis and proposed as a draw solute to remove arsenics (AsIII, AsV) from water through forward osmosis (FO). Having multiple sulfonic groups, 4 generates a high osmotic pressure and produces a water flux as high as 58.4 LMH at a dilute concentration (0.24 M), surpassing most of the existing draw solutes in water transfer rate under the similar experimental conditions. Compound 4 at 0.24 M yields a water flux of 52.9 LMH with a 100% AsV rejection, and 57.8 LMH with a 96.0% AsIII rejection when 50 ppm AsV or AsIII as the corresponding feed, manifesting the best performance in arsenic removal and concurrent water recovery efficiency. Remarkably, being a polymeric configuration in water, 4 has a negligible solute loss in the FO process. 4 can be readily regenerated for reuse in FO by precipitation from its solution through acidification. The abundance in ionic groups and the pH-responsive property coupled with a supramolecular configuration make 4 an ideal draw solute for FO wastewater treatment.

A zwitterionic 1D/2D polymer co-crystal and its polymorphic sub-components: a highly selective sensing platform for HIV ds-DNA sequences.

Polymorphic compounds {[Cu(dcbb)2(H2O)2]·10H2O}n (2, 1D chain), [Cu(dcbb)2]n (3, 2D layer) and their co-crystal {[Cu(dcbb)2(H2O)][Cu(dcbb)2]2}n (4) have been prepared from the coordination reaction of a 2D polymer [Na(dcbb)(H2O)]n (1, H2dcbbBr = 1-(3,5-dicarboxybenzyl)-4,4'-bipyridinium bromide) with Cu(NO3)2·3H2O at different temperatures in water. Compounds 2-4 have an identical metal-to-ligand stoichiometric ratio of 1 : 2, but absolutely differ in structure. Compound 3 features a 2D layer structure with aromatic rings, positively charged pyridinium and free carboxylates on its surface, promoting electrostatic, π-stacking and/or hydrogen-bonding interactions with the carboxyfluorescein (FAM) labeled probe single-stranded DNA (probe ss-DNA, delineates as P-DNA). The resultant P-DNA@3 system facilitated fluorescence quenching of FAM via a photoinduced electron transfer process. The P-DNA@3 system functions as an efficient fluorescent sensor selective for HIV double-stranded DNA (HIV ds-DNA) due to the formation of a rigid triplex structure with the recovery of FAM fluorescence. The system reported herein also distinguishes complementary HIV ds-DNA from mismatched target DNA sequences with the detection limit of 1.42 nM.

Solvent effect-driven assembly of W/Cu/S cluster-based coordination polymers from the cluster precursor [Et4N][Tp*WS3(CuBr)3] and CuCN: isolation, structures and enhanced NLO responses.

We herein describe a coordination polymer system built upon the reactions of a W/Cu/S cluster precursor [Et4N][Tp*WS3(CuBr)3] (1, Tp* = hydridotris(3,5-dimethylpyrazol-1-yl)borate) with three equivalents of CuCN through solvent modulation. Four coordination polymers, namely, [Tp*WS3Cu3(µ3-DMF)(CN)3Cu(Py)] (2), [Tp*WS3Cu3(µ3-DMF)(CN)3Cu] (3), [Tp*WS3Cu3(µ3-DMF)(CN)3Cu]·4aniline (4·4aniline) and [Tp*WS3Cu3(µ3-DMF)(CN)3Cu]·2(DMF)0.5 (5·2(DMF)0.5), are isolated in different solvent systems and characterized by means of elemental analysis, FT-IR, UV-Vis, ESI-MS and single-crystal X-ray diffraction. Compounds 2-5 feature µ3-DMF association with the nest-shaped [WS3Cu3] cluster cores, yielding cubane-type [WS3Cu3O] clusters which are further linked to single Cu(I) ions through CN bridges to provide 1D or 2D structures. Compounds 3-5 have identical chemical compositions in their main fragments but with distinctively different structural features, and are therefore topological isomers. Compound 2 has a ladder-type structure in which the side rails contain alternately linked cluster cores and Cu(I) ions. Compound 3 has a 2D (6,3) network with alternately arranged cluster cores and Cu(I) ions. Both 4 and 5 have 2D structures with 4·8(2) topology. In 4, a pair of cluster cores and Cu(I) ions form a 4-membered ring which is further linked to four equivalent rings through four CN ligands via a cluster core-to-Cu arrangement; while in the structure of 5, the same 4-membered rings as those in 4 are extended to equivalent rings via a cluster core-to-cluster and Cu-to-Cu arrangement. The hyperpolarizabilities (γ) of the polymeric networks exhibit an enhancement of more than 10 times compared to their parent cluster, 1.