Microglia-derived PDGFB promotes neuronal potassium currents to suppress basal sympathetic tonicity and limit hypertension.

Although many studies have addressed the regulatory circuits affecting neuronal activities, local non-synaptic mechanisms that determine neuronal excitability remain unclear. Here, we found that microglia prevented overactivation of pre-sympathetic neurons in the hypothalamic paraventricular nucleus (PVN) at steady state. Microglia constitutively released platelet-derived growth factor (PDGF) B, which signaled via PDGFRα on neuronal cells and promoted their expression of Kv4.3, a key subunit that conducts potassium currents. Ablation of microglia, conditional deletion of microglial PDGFB, or suppression of neuronal PDGFRα expression in the PVN elevated the excitability of pre-sympathetic neurons and sympathetic outflow, resulting in a profound autonomic dysfunction. Disruption of the PDGFBMG-Kv4.3Neuron pathway predisposed mice to develop hypertension, whereas central supplementation of exogenous PDGFB suppressed pressor response when mice were under hypertensive insult. Our results point to a non-immune action of resident microglia in maintaining the balance of sympathetic outflow, which is important in preventing cardiovascular diseases.

MARK2 phosphorylates KIF13A at a 14-3-3 binding site to polarize vesicular transport of transferrin receptor within dendrites.

Neurons regulate the microtubule-based transport of certain vesicles selectively into axons or dendrites to ensure proper polarization of function. The mechanism of this polarized vesicle transport is still not fully elucidated, though it is known to involve kinesins, which drive anterograde transport on microtubules. Here, we explore how the kinesin-3 family member KIF13A is regulated such that vesicles containing transferrin receptor (TfR) travel only to dendrites. In experiments involving live-cell imaging, knockout of KIF13A, BioID assay, we found that the kinase MARK2 phosphorylates KIF13A at a 14-3-3 binding motif, strengthening interaction of KIF13A with 14-3-3 such that it dissociates from TfR-containing vesicles, which therefore cannot enter axons. Overexpression of KIF13A or knockout of MARK2 leads to axonal transport of TfR-containing vesicles. These results suggest a unique kinesin-based mechanism for polarized transport of vesicles to dendrites.

Tailoring short-chain sulfur molecules to drive redox dynamics for sulfur-based aqueous battery.

Solid-solid reactions stand out in rechargeable sulfur-based batteries due to the robust redox couples and high sulfur utilization in theory. However, conventional solid-solid reactions in sulfur cathode always present slow reaction kinetics and huge redox polarization due to the low electronic conductivity of sulfur and the generation of various electrochemical inert intermediates. In view of this, it is crucial to improve the electrochemical activity of sulfur cathode and tailor the redox direction. Guided by thermodynamics analysis, short-chain sulfur molecules (S2-4) are successfully synthesized by space-limited domain principle. Unlike conventional cyclic S8 molecules with complex routes in solid-solid reaction, short-chain sulfur molecules not only shorten the length of the redox chain but also inhibit the formation of irreversible intermediates, which brings excellent redox dynamics and reversibility. As a result, the Cu-S battery built by short-chain sulfur molecules can deliver a high reversible capacity of 3,133 mAh g-1. To put this into practice, quasi-solid-state aqueous flexible battery based on short-chain sulfur molecules is also designed and evaluated, showing superior mechanical flexibility and electrochemical property. It indicates that the introduction of short-chain sulfur molecules in rechargeable battery can promote the development and application of high-performance sulfur-based aqueous energy storage systems.

Dual synergistic effects assisting Cu-SeS2 electrochemistry for energy storage.

Selenium sulfide (SeS2) features higher electronic conductivity than sulfur and higher theoretical capacity and lower cost than selenium, attracting considerable interest in energy storage field. Although nonaqueous Li/Na/K-SeS2 batteries are attractive for their high energy density, the notorious shuttle effect of polysulfides/polyselenides and the intrinsic limitations of organic electrolyte have hindered the deployment of this technology. To circumvent these issues, here we design an aqueous Cu-SeS2 battery by encapsulating SeS2 in a defect-enriched nitrogen-doped porous carbon monolith. Except the intrinsic synergistic effect between Se and S in SeS2, the porous structure of carbon matrix has sufficient internal voids to buffer the volume change of SeS2 and provides abundant pathways for both electrons and ions. In addition, the synergistic effect of nitrogen doping and topological defect not only enhances the chemical affinity between reactants and carbon matrix but also offers catalytic active sites for electrochemical reactions. Benefiting from these merits, the Cu-SeS2 battery delivers superior initial reversible capacity of 1,905.1 mAh g-1 at 0.2 A g-1 and outstanding long-span cycling performance over 1,000 cycles at 5 A g-1. This work applies variable valence charge carriers to aqueous metal-SeS2 batteries, providing valuable inspiration for the construction of metal-chalcogen batteries.

A triple-synergistic small-molecule sulfur cathode promises energetic Cu-S electrochemistry.

Metal-sulfur batteries have received great attention for electrochemical energy storage due to high theoretical capacity and low cost, but their further development is impeded by low sulfur utilization, poor electrochemical kinetics, and serious shuttle effect of the sulfur cathode. To avoid these problems, herein, a triple-synergistic small-molecule sulfur cathode is designed by employing N, S co-doped hierarchical porous bamboo charcoal as a sulfur host in an aqueous Cu-S battery. Expect the enhanced conductivity and chemisorption induced by N, S synergistic co-doping, the intrinsic synergy of macro-/meso-/microporous triple structure also ensures space-confined small-molecule sulfur as high utilization reactant and effectively alleviates the volume expansion during conversion reaction. Under a further joint synergy between hierarchical structure and heteroatom doping, the resulting sulfur cathode endows the Cu-S battery with outstanding electrochemical performance. Cycled at 5 A g-1, it can deliver a high reversible capacity of 2,509.8 mAh g-1 with a good capacity retention of 97.9% after 800 cycles. In addition, a flexible hybrid pouch cell built by a small-molecule sulfur cathode, Zn anode, and gel electrolytes can firmly deliver high average operating voltage of about 1.3 V with a reversible capacity of over 2,500 mAh g-1 under various destructive conditions, suggesting that the triple-synergistic small-molecule sulfur cathode promises energetic metal-sulfur batteries.

PI4KIIIß-Mediated Phosphoinositides Metabolism Regulates Function of the VTA Dopaminergic Neurons and Depression-Like Behavior.

Phosphoinositides, including phosphatidylinositol-4,5-bisphosphate (PIP2), play a crucial role in controlling key cellular functions such as membrane and vesicle trafficking, ion channel, and transporter activity. Phosphatidylinositol 4-kinases (PI4K) are essential enzymes in regulating the turnover of phosphoinositides. However, the functional role of PI4Ks and mediated phosphoinositide metabolism in the central nervous system has not been fully revealed. In this study, we demonstrated that PI4KIIIß, one of the four members of PI4Ks, is an important regulator of VTA dopaminergic neuronal activity and related depression-like behavior of mice by controlling phosphoinositide turnover. Our findings provide new insights into possible mechanisms and potential drug targets for neuropsychiatric diseases, including depression. Both sexes were studied in basic behavior tests, but only male mice could be used in the social defeat depression model.

Efficient methods for multiple types of precise gene-editing in Chlamydomonas.

Precise gene-editing using CRISPR/Cas9 technology remains a long-standing challenge, especially for genes with low expression and no selectable phenotypes in Chlamydomonas reinhardtii, a classic model for photosynthesis and cilia research. Here, we developed a multi-type and precise genetic manipulation method in which a DNA break was generated by Cas9 nuclease and the repair was mediated using a homologous DNA template. The efficacy of this method was demonstrated for several types of gene editing, including inactivation of two low-expression genes (CrTET1 and CrKU80), the introduction of a FLAG-HA epitope tag into VIPP1, IFT46, CrTET1 and CrKU80 genes, and placing a YFP tag into VIPP1 and IFT46 for live-cell imaging. We also successfully performed a single amino acid substitution for the FLA3, FLA10 and FTSY genes, and documented the attainment of the anticipated phenotypes. Lastly, we demonstrated that precise fragment deletion from the 3'-UTR of MAA7 and VIPP1 resulted in a stable knock-down effect. Overall, our study has established efficient methods for multiple types of precise gene editing in Chlamydomonas, enabling substitution, insertion and deletion at the base resolution, thus improving the potential of this alga in both basic research and industrial applications.

Tf2O/2-Chloropyridine-Triggered Synthesis of Benzo[b]thiophene 1,1-Dioxides from Sulfonium α-Acyl Sulfonylmethylides.

Triflic anhydride and 2-chloropyridine-comediated tandem activation, intramolecular aromatic electrophilic addition, and 1,2-sulfonyl shift via spirocyclic intermediates of sulfonium α-acyl sulfonylmethylides realize the efficient synthesis of 2-alkyl/arylthiobenzo[b]thiophene 1,1-dioxides. The deactivated sulfonyl group determines the site-selectivity of the electrophilic addition via the ipso-attack, while the following S-migration controls the regioselectivity. Some of 2-methylthiobenzo[b]thiophene 1,1-dioxides show fluorescence properties in the solid state and in their solutions.

π-Stacking-Controlled Dearomatic Sulfur-Shifted Ene Reaction of Ketenes and Polycyclic Arylthiiranes: Access to Areno[d]-ε-thiolactones.

Electrophilic ring-expansion of polycyclic arylthiiranes and ketenes generated from alkoxy/aryloxyacetyl chlorides in the presence of triethylamine (TEA) is developed and provides a new strategy for the synthesis of areno[d]-ε-thiolactones, areno[d]thiepinones, directly without catalysts or additives. This strategy features atom- and step-economic one-pot characteristic via a tandem sequence of in situ ketene generation, π-stacking-controlled dearomatic sulfur-shifted ene, and aromatization. The current reaction is a novel strategy of electrophilic ring expansions of three-membered saturated heterocycles.

Covalent post-synthetic modification of MOFs as a fluorescent sensor for the efficient detection of the biomarker of cystinuria.

Cystinuria is a genetic disorder, and in severe cases, it might lead to kidney failure. As an important biomarker for cystinuria, the level of arginine (Arg) in urine is a vital indicator for cystinuria screening. Therefore, it is urgently needed to detect Arg with high selectivity and sensitivity. In this work, a boric acid functionalized Zr-based metal-organic framework UiO-PhbA is prepared by grafting phenylboronic acid on UiO-66-NH2 through a Schiff base reaction using a covalent post-synthesis modification (CPSM) strategy. The prepared UiO-PhbA exhibits a sensitive and specific fluorescence "turn-on" response to Arg and can be exploited to detect Arg in human serum and urine samples with a broad linear range of 0.6-350 µM and low limit of detection (LOD) of 18.45 nM. This study provides a new and reliable rapid screening protocol for sulfite oxidase deficiency-related diseases.

Recent Advances in π-Stacking Interaction-Controlled Asymmetric Synthesis.

The π-stacking interaction is one of the most important intramolecular and intermolecular noncovalent interactions in organic chemistry. It plays an important role in stabilizing some structures and transition states in certain reactions via both intramolecular and intermolecular interactions, facilitating different selectivities, such as chemo-, regio-, and stereoselectivities. This minireview focuses on the recent examples of the π-stacking interaction-controlled asymmetric synthesis, including auxiliary-induced asymmetric synthesis, kinetic resolution, asymmetric synthesis of helicenes and heterohelicenes, and multilayer 3D chiral molecules.

Y(OTf)3-Salazin-Catalyzed Asymmetric Aldol Condensation.

The chiral aziridine-containing vicinal iminophenol tridentate ligands (named salazins) are a class of readily prepared chiral ligands from enantiopure aziridines and salicylaldehydes. Their scandium and yttrium triflate complexes show excellent reactivity and enantioselectivities in the catalytic asymmetric aldol condensation of electron-deficient aromatic aldehydes and ketones, including acetone and cycloalkanones. The stereoselectivity is rationalized to the strong π-stacking interaction between aromatic aldehydes and the vicinal iminophenol group in the chiral ligands.

Accessing para-Alkylphenols via Iridium-Catalyzed Site-Specific Deoxygenation of Alcohols.

An iridium-catalyzed and phenol-directed deoxygenation of benzylic alcohols comes as an alternative access to 4-alkylphenols, featuring low catalyst loading (S/C up to 20,000, TOF up to 12,400 h-1), high functionality compatibility, and excellent site-selectivity. The applications in late-stage modification of steroids and gram-scale total synthesis of a Gastrodia elata extract are highlighted. Mechanistically, the intermediacy of quinone methide controls the site-selectivity, and the formation of iridium hydride serves as the rate-limiting step.

Halide-promoted pyridinylation of α-acylmethylides with 2-halo-1-methylpyridinium iodides as reagents.

Halide-promoted pyridinylation between α-acyl sulfonylmethylides and 2-halo-1-methylpyridinium iodides in a transition-metal-free protocol is described. A broad range of α-acyl sulfonylmethylides were transformed to bifunctionalized vinylsulfones in moderate to good yields, thereby providing a facile and practical approach for constructing methylthio- and pyridinoxyl-substituted vinylsulfones. The substrates can be extended to other acyl methylides. The reaction was shown to entail the formation of a C-O bond and consecutive breaking of C-S, C-Cl and C-N bonds.

Demethyl oxidative halogenation of diacyl dimethylsulfonium methylides.

α-Halo-α-methylthio-ß-ketosulfones containing a quaternary halocarbon stereocenter were prepared via selective demethyl oxidative halogenations of diacyl dimethylsulfonium methylides in moderate to excellent yields (39 examples; up to 98%). The current protocols directly and efficiently introduce a halogen atom into organic compounds with high functional group tolerance under metal-free conditions.

Theoretical mechanistic insights into the electrophilic addition of hydrogen halides to alkynes.

The electrophilic addition of hydrogen halides to alkynes, also called polar hydrohalogenation of alkynes, is one of the most classical and important organic reactions. Mechanistic and stereoselective insights into the hydrohalogenation of various structurally different distinct alkynes, including both alkyl and aryl substituted acetylenes, in acetic acid were investigated theoretically via density functional theory (DFT) calculations. The results indicate that π-complexes between hydrogen halides and alkynes are first formed, and then all alkynes can undergo a competitive bimolecular intimate ion-pair syn-addition process and a pentamolecular concerted anti-addition process through the cyclic proton transfer mechanism for proton transfer in the absence of tetraalkylammonium halides or a termolecular electrophilic addition (AdE3) process in the presence of tetraalkylammonium halides. All aliphatic alkynes undergo slightly to obviously predominant anti-addition in hydrohalogenations both in the absence and presence of tetraalkylammonium halides. Aromatic 1-arylalk-1-ynes favour syn-additions through bimolecular intimate ion-pair processes with asynchronous concerted characteristics in the absence of tetraalkylammonium halides, while most of them generally prefer anti-addition in the presence of tetraalkylammonium halides. The stereoselectivity is significantly affected by both the electronic and steric effects of 1-arylalk-1-ynes and halides in the reaction mixture. Strongly electron-rich and bulky 1-arylalk-1-ynes generally favour syn-addition in the presence of tetraalkylammonium halides, especially arylethynes in hydrochlorination. Anti-Markovnikov hydrohalogenations of 1-arylalk-1-ynes also prefer anti-addition both in the absence and presence of tetraalkylammonium halides even in small amounts due to high activation energies. The current investigation provides deep insights into the mechanism and stereoselectivity in polar hydrohalogenations of alkynes.

Aryne and CO2-based formal [2 + 2 + 2] annulation to access tetrahydroisoquinoline-fused benzoxazinones.

Tetrahydroisoquinoline and its fused polyheterocycles are prevalent structural motifs found in numerous natural products. In this study, we report a highly efficient and convergent synthetic approach for the construction of tetrahydroisoquinoline-fused polyheterocycles through a three-component formal [2 + 2 + 2] annulation process by combining 3,4-dihydroisoquinolines, CO2, and benzynes. Notably, electron-rich 3,4-dihydroisoquinolines and electron-deficient benzynes exhibit greater reactivity in this annulation. Moreover, this method benefits from the convergent synthesis and the utilization of carbon dioxide, providing a valuable strategy for the facile synthesis of tetrahydroisoquinoline-fused polyheterocycles, with potential applications in the discovery and development of novel organic molecules.

Direct Regioselective C-H Cyanation of Purines.

A direct regioselective C-H cyanation of purines was developed through a sequential triflic anhydride activation, nucleophilic cyanation with TMSCN, followed by a process of base-mediated elimination of triflous acid (CF3SO2H). In most cases, the direct C-H cyanation occurred on the electron-rich imidazole motif of purines, affording 8-cyanated purine derivatives in moderate to excellent yields. Various functional groups, including allyl, alkynyl, ketone, ester, nitro et al. were tolerated and acted as a C8 directing group. The electron-donating 6-diethylamino, as C2-directing group substituent, can switch the regioselectivity of purine from 8- to 2-position, enabling the synthesis of 8- and 2-cyano 6-dialkylaminopurines from corresponding 6-chloropurine in different reaction order. Further functional manipulations of the cyano group allow the conversions of 8-cyanopurines to corresponding purine amides, imidates, imidothioates, imidamides, oxazolines, and isothiazoles.

Elucidation of the Alternating Copolymerization Mechanism of Epoxides or Aziridines with Cyclic Anhydrides in the Presence of Halide Salts.

Organic halide salts in combination with metal or organic compound are the most common and essential catalysts in ring-opening copolymerizations (ROCOP). However, the role of organic halide salts was neglected. Here, we have uncovered the complex behavior of organic halides in ROCOP of epoxides or aziridine with cyclic anhydride. Coordination of the chain-ends to cations, electron-withdrawing effect, leaving ability of halide atoms, chain-end basicity/nucleophilicity, and terminal steric hindrance cause three types of side reactions: single-site transesterification, substitution, and elimination. Understanding the complex functions of organic halide salts in ROCOP led us to develop highly active and selective aminocyclopropenium chlorides as catalysts/initiators. Adjustable H-bonding interactions of aminocyclopropenium with propagating anions and epoxides create chain-end coordination process that generate highly reactive carboxylate and highly selective alkoxide chain-ends.

Controlling the Fluorescence Performance of AIE Polymers by Controlling the Polymer Microstructure.

Aggregation-induced emission (AIE) polymers with expected emission wavelength/color and fluorescence efficiency are valuable in applications. However, most AIE polymers exhibit irregular emission wavelength/color changes compared to the original AIE monomers. Here, we report the synthesis of AIE polymers with unchanged emission wavelength by ring-opening (co)polymerizations of 4-(triphenylethenyl)phenoxymethyloxirane (TPEO) and other epoxides or phthalic anhydride. The chemical structures/physical properties of all (co)polymers were characterized by NMR, SEC, MALDI-TOF, and DSC. The co-polyether microstructures were revealed by calculating the reactivity ratios and visualized by Monte Carlo simulation. The photoluminescence quantum yields of all the (co)polymers were determined in the solid state. We systematically correlated the fluorescence performance with molecular weights, crystallinity, monomer compositions, glass transition temperatures, side lengths, and flexibility/rigidity.