查看更多>>摘要：Lipiodol chemotherapeutic emulsions remain one of the main choices for the treatment of unresectable hepatocellular carcinoma(HCC)via transarterial chemoembolization(TACE).However,the limited stability of Lipiodol chemotherapeutic emulsions would lead to rapid drug diffusion,which would reduce the therapeutic benefit and cause systemic toxicity of administrated chemotherapeutics.Therefore,the development of enhanced Lipiodol-based formulations is of great significance to enable effective and safe TACE treatment.Herein,a stable water-in-oil Lipiodol Pickering emulsion(LPE)stabilized by pH-dissociable calcium carbonate nanoparticles and hemin is prepared and utilized for efficient encapsulation of lipoxygenase(LOX).The obtained LOX-loaded CaCO3&hemin-stabilized LPE(LHCa-LPE)showing greatly improved emulsion stability could work as a pH-responsive and self-fueling microreactor to convert polyunsaturated fatty acids(PUFAs),a main component of Lipiodol,to cytotoxic lipid radicals through the cascading catalytic reaction driven by LOX and hemin,thus inducing ferroptosis of cancer cells.As a result,such LHCa-LPE upon transcatheter embolization can effectively suppress the progression of orthotopic N1S1 HCC in rats.This study highlights a concise strategy to prepare pH-responsive and stable LPE-based self-fueling microreactors,which could serve as bifunctional embolic and ferroptosis-inducing agents to enable proof-of-concept transarterial ferro-embolization therapy of HCC.
查看更多>>摘要：The nature of catalysis has been hotly pursued for over a century,and current research is focused on understanding active centers and their electronic structures.Herein,the concept of conductive catalysis is proposed and verified by theoretical simulations and experimental observations.Metallic systems containing buried catalytically active transitional metals and exposed catalytically inert main group metals are constructed,and the electronic interaction between them via metallic bonding is disclosed.Through the electronic interaction,the catalytic properties of subsurface transitional metals(Pd or Rh)can be transferred to outermost main group metals(Al or Mg)for several important transformations like semi-hydrogenation,Suzuki-coupling and hydroformylation.The catalytic force is conductive,in analogy with the magnetic force and electrostatic force.The traditional definition of active centers is challenged by the concept of conductive catalysis and the electronic nature of catalysis is more easily understood.It might provide new opportunities for shielding traditional active centers against poisoning or leaching and allow for precise regulation of their catalytic properties by the conductive layer.
查看更多>>摘要：Cell-free RNA(cfRNA)allows assessment of health,status,and phenotype of a variety of human organs and is a potential biomarker to non-invasively diagnose numerous diseases.Nevertheless,there is a lack of highly efficient and bias-free cfRNA isolation technologies due to the low abundance and instability of cfRNA.Here,we developed a reproducible and high-efficiency isolation technology for different types of cell-free nucleic acids(containing cfRNA and viral RNA)in serum/plasma based on the inclusion of nucleic acids by metal-organic framework(MOF)materials,which greatly improved the isolation efficiency and was able to preserve RNA integrity compared with the most widely used research kit method.Importantly,the quality of cfRNA extracted by the MOF method is about 10-fold that of the kit method,and the MOF method isolates more than three times as many different RNA types as the kit method.The whole transcriptome mapping characteristics of cfRNA in serum from patients with liver cancer was described and a cfRNA signature with six cfRNAs was identified to diagnose liver cancer with high diagnostic efficiency(area under curve=0.905 in the independent validation cohort)using this MOF method.Thus,this new MOF isolation technique will advance the field of liquid biopsy,with the potential to diagnose liver cancer.
查看更多>>摘要：Mounting evidence suggests that strategies combining DNA-damaging agents and stimulator of interferon genes(STING)agonists are promising cancer therapeutic regimens because they can amplify STING activation and remodel the immunosuppressive tumor microenvironment.However,a single molecular entity comprising both agents has not yet been developed.Herein,we designed two PtⅣ-MSA-2 conjugates(Ⅰ and Ⅱ)containing the DNA-damaging chemotherapeutic drug cisplatin and the innate immune-activating STING agonist MSA-2;these conjugates showed great potential as multispecific small-molecule drugs against pancreatic cancer.Mechanistic studies revealed that conjugate I upregulated the expression of transcripts associated with innate immunity and metabolism in cancer cells,significantly differing from cisplatin and MSA-2.An analysis of the tumor microenvironment demonstrated that conjugate I could enhance the infiltration of natural killer(NK)cells into tumors and promote the activation of T cells,NK cells and dendritic cells in tumor tissues.These findings indicated that conjugate I,which was created by incorporating a Pt chemotherapeutic drug and STING agonist into one molecule,is a promising and potent anticancer drug candidate,opening new avenues for small-molecule-based cancer metalloimmunotherapy.
查看更多>>摘要：Using first-principles calculations and crystal structure search methods,we found that many covalently bonded molecules such as H2,N2,CO2,NH3,H2O and CH4 may react with NaCl,a prototype ionic solid,and form stable compounds under pressure while retaining their molecular structure.These molecules,despite whether they are homonuclear or heteronuclear,polar or non-polar,small or large,do not show strong chemical interactions with surrounding Na and Cl ions.In contrast,the most stable molecule among all examples,N2,is found to transform into cyclo-N5-anions while reacting with NaCl under high pressures.It provides a new route to synthesize pentazolates,which are promising green energy materials with high energy density.Our work demonstrates a unique and universal hybridization propensity of covalently bonded molecules and solid compounds under pressure.This surprising miscibility suggests possible mixing regions between the molecular and rock layers in the interiors of large planets.
查看更多>>摘要：The neocortex contains a vast collection of diverse neurons organized into distinct layers.While nearly all neocortical neurons are generated by radial glial progenitors(RGPs),it remains largely unclear how a complex yet organized neocortex is constructed reliably and robustly.Here,we show that the division behavior and neuronal output of RGPs are highly constrained with patterned variabilities to support the reliable and robust construction of the mouse neocortex.The neurogenic process of RGPs can be well-approximated by a consistent Poisson-like process unfolding over time,producing deep to superficial layer neurons progressively.The exact neuronal outputs regarding layer occupation are variable;yet,this variability is constrained systematically to support all layer formation,largely reflecting the variable intermediate progenitor generation and RGP neurogenic entry and exit timing differences.Together,these results define the fundamental features of neocortical neurogenesis with a balanced reliability and variability for the construction of the complex neocortex.
查看更多>>摘要：Nausea and vomiting are important defensive responses to cope with pathogens and toxins that invade the body.The nucleus of the solitary tract(NTS)is important for initiating these responses.However,the molecular heterogeneities and cellular diversities of the NTS occlude a better understanding of these defensive responses.Here,we constructed the single-nucleus transcriptomic atlas of NTS cells and found multiple populations of NTS neurons that maybe involved in these defensive responses.Among these,we identified Calbindin1-positive(Calb1+)NTS neurons that are molecularly distinct from Tac1+neurons.These Calbl+neurons are critical for nausea and retching induced by cereulide;an emetic toxin secreted by Bacillus Cereus.Strikingly,we found that cereulide can directly modulate vagal sensory neurons that innervate Calb1+NTS neurons,a novel mechanism distinct from that for nausea and retching induced by Staphylococcal enterotoxin A.Together,our transcriptomic atlas of NTS neurons and the functional analyses revealed the neural mechanism for cereulide-induced retching-like behavior.These results demonstrate the molecular and cellular complexities in the brain that underlie defensive responses to the diversities of pathogens and toxins.
查看更多>>摘要：To investigate the circuit-level neural mechanisms of behavior,simultaneous imaging of neuronal activity in multiple cortical and subcortical regions is highly desired.Miniature head-mounted microscopes offer the capability of calcium imaging in freely behaving animals.However,implanting multiple microscopes on a mouse brain remains challenging due to space constraints and the cumbersome weight of the equipment.Here,we present TINIscope,a Tightly Integrated Neuronal Imaging microscope optimized for electronic and opto-mechanical design.With its compact and lightweight design of 0.43 g,TINIscope enables unprecedented simultaneous imaging of behavior-relevant activity in up to four brain regions in mice.Proof-of-concept experiments with TINIscope recorded over 1000 neurons in four hippocampal subregions and revealed concurrent activity patterns spanning across these regions.Moreover,we explored potential multi-modal experimental designs by integrating additional modules for optogenetics,electrical stimulation or local field potential recordings.Overall,TINIscope represents a timely and indispensable tool for studying the brain-wide interregional coordination that underlies unrestrained behaviors.
查看更多>>摘要：New particle formation(NPF)in the tropical free troposphere(FT)is a globally important source of cloud condensation nuclei,affecting cloud properties and climate.Oxidized organic molecules(OOMs)produced from biogenic volatile organic compounds are believed to contribute to aerosol formation in the tropical FT,but without direct chemical observations.We performed in situ molecular-level OOMs measurements at the Bolivian station Chacaltaya at 5240 m above sea level,on the western edge of Amazonia.For the first time,we demonstrate the presence of OOMs,mainly with 4-5 carbon atoms,in both gas-phase and particle-phase(in terms of mass contribution)measurements in tropical FT air from Amazonia.These observations,combined with air mass history analyses,indicate that the observed OOMs are linked to isoprene emitted from the rainforests hundreds of kilometers away.Based on particle-phase measurements,we find that these compounds can contribute to NPF,at least the growth of newly formed nanoparticles,in the tropical FT on a continental scale.Thus,our study is a fundamental and significant step in understanding the aerosol formation process in the tropical FT.
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