Enhanced Precision Therapy of Multiple Myeloma Through Engineered Biomimetic Nanoparticles with Dual Targeting

Multiple myeloma(MM)is the second most prevalent hematological malignancy.Current MM treatment strategies are hampered by systemic toxicity and suboptimal therapeutic efficacy.This study addressed these limitations through the development of a potent MM-targeting chemotherapy strategy,which capitalized on the high binding affinity of alendronate for hydroxyapatite in the bone matrix and the homologous targeting of myeloma cell membranes,termed T-PB@M.The results from our investigations highlight the considerable bone affinity of T-PB@M,both in vitro and in vivo.Additionally,this material demonstrated a capability for drug release triggered by low pH conditions.Moreover,T-PB@M induced the generation of reactive oxygen species and triggered cell apoptosis through the poly(ADP-ribose)polymerase 1(PARP1)-Caspase-3-B-cell lymphoma-2(Bcl-2)pathway in MM cells.Notably,T-PB@M preferentially targeted bone-involved sites,thereby circumventing systemic toxic side effects and leading to prolonged survival of MM orthotopic mice.Therefore,this designed target-MM nanocarrier presents a promising and potentially effective platform for the precise treatment of MM.

The Importance of the Shape Parameter in a Bulk Parameterization Scheme to the Evolution of the Cloud Droplet Spectrum during Condensation

The shape parameter of the Gamma size distribution plays a key role in the evolution of the cloud droplet spectrum in the bulk parameterization schemes. However, due to the inaccurate specification of the shape parameter in the commonly used bulk double-moment schemes, the cloud droplet spectra cannot reasonably be described during the condensation process. Therefore, a newly-developed triple-parameter condensation scheme with the shape parameter diagnosed through the number concentration, cloud water content, and reflectivity factor of cloud droplets can be applied to improve the evolution of the cloud droplet spectrum. The simulation with the new parameterization scheme was compared to those with a high-resolution Lagrangian bin scheme, the double-moment schemes in a parcel model, and the observation in a 1.5D Eulerian model that consists of two cylinders. The new scheme with the shape parameter varying with time and space can accurately simulate the evolution of the cloud droplet spectrum. Furthermore, the volume-mean radius and cloud water content simulated with the new scheme match the Lagrangian analytical solutions well, and the errors are steady, within approximately 0.2%.

Evaluation of a Lagrangian advection scheme for cloud droplet diffusion growth with a maritime shallow cumulus cloud case

A Lagrangian advection scheme(LAS)for solving cloud drop diffusion growth was previously proposed(in 2020)and validated with simulations of cloud droplet spectra with a one-and-a-half dimensional(1.5D)cloud bin model for a deep convection case.The simulation results were improved with the new scheme over the original Eulerian scheme.In the present study,the authors simulated rain embryo formation with the LAS for a maritime shallow cumulus cloud case from the RICO(Rain in Cumulus over the Ocean)campaign.The model used to simulate the case was the same 1.5D cloud bin model coupled with the LAS.Comparing the model simulation results with aircraft observation data,the authors conclude that both the general microphysical properties and the detailed cloud droplet spectra are well captured.The LAS is robust and reliable for the simulation of rain embryo formation.

A sustainable synthesis of 3,3-disubstituted oxindoles via CuBr-catalysed capture of carboxylic oxonium ylides with isatylidene malononitrile

We herein reported a sustainable synthesis of 3,3-disubstituted oxindoles via a Michael-type reaction based on the CuBr-catalysed capture of carboxylic oxonium ylides with isatylidene malononitrile.The reaction is characterized by a high atom economy and low economic constraints.The catalyst CuBr could be conveniently recyclized.The products of the reaction were found to be inhibitory against Na ion channels.We expect the reaction to shed the light on synthesis of biologically interesting molecules directed by principles of green chemistry.

Design, Synthesis and Biological Evaluation of Isothiazole Based 1,2,4-Trizaole Derivatives

A series of novel 3,4-dichloroisothiazole based 1,2,4-triazole derivatives were rationally designed and synthesized. Their structures were confirmed by IH NMR, 13C NMR, HRMS or elemental analysis; the typical crystal structure was determined by X-ray diffraction for validation. All target compounds were evaluated for their in vitro fungicidal and in vivo anti-TMV activities. The bioassay results indicated that compound 6b, namely 1-（3,4-dichloroisothiazol-5-yo）-o-（4-ouorophenyo）-2-（OH-o,2o4-triazol-o-yl）ethanol, exhibited excellent growth inhibition against B. cinerea, C. arachldico;a and P. piricola with median effective concentrations （EC50） of 6.98, 2.73 and 3.07μg/mL, respectively, and good in vivo anti-TMV activity of over 60% of inactivation and induction activity at 100 μg/mL. These data demonstrate that compound 6b is both a fungicide and an anti-TMV lead, deserving further studies.

Rapid visual detection of Vibrio parahaemolyticus by combining LAMP-CRISPR/Cas12b with heat-labile uracil-DNA glycosylase to eliminate carry-over contamination

Vibrio parahaemolyticus is a major pathogen frequently found in seafood.Rapid and accurate detection of this pathogen is important for the control of bacterial foodborne diseases and to ensure food safety.In this study,we established a one-pot system that combines uracil-DNA glycosylase(UDG),loopmediated isothermal amplification(LAMP),and clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 12b(Cas12b)for detecting V.parahaemolyticus in seafood.This detection system can effectively perform identification using a single tube and avoid the risk of carryover contamination.

Gold-catalyzed ketene dual functionalization and mechanistic insights:divergent synthesis of indenes and benzo[d]oxepines

An unprecedented gold-catalyzed ketene C=O/C=C bifunctionalization method has been developed.Mechanistic studies and density function theory(DFT)calculations indicate that the reaction is initiated by gold-catalyzed Wolff rearrangement of diazoketone to form the ketene intermediate,followed by intermolecular nucleophilic addition and terminated with two divergent cyclization processes via enol intermediates.In the case with alcohols as the nucleophiles,the reaction goes through a C-5-endodig carbocyclization to give the indene products;whereas,O-7-endo-dig cyclization occurs dominantly when indoles/pyrroles are used as the nucleophiles,delivering the 7-membered benzo[d]oxepines.In comparison with the well-documented cycloaddition and nucleophilic addition reactions,this cascade reaction features a novel reaction pattern for the ketene dual functionalization through addition with nucleophile and electrophile in sequence.

Chiral rhodium(Ⅱ)-catalyzed asymmetric aldol-type interception of an oxonium ylide to assemble chiral 2,3-dihydropyrans

A chiral dirhodium complex is an effective and robust catalyst for asymmetric carbene transformations.However,dirhodiumcatalyzed asymmetric ylide interception processes are rare,mainly because of the dissociation of the metal catalyst before the stereo-determining step.Herein,we report a chiral dirhodium(Ⅱ)-catalyzed asymmetric annulation of vinyl diazoesters withα-hydroxyl ketones,which provides an efficient way to form chiral 2,3-dihydropyrans in good yields with excellent diastereoselectivities and enantioselectivities.This article is the first example of the chiral dirhodium complex–controlled asymmetric aldol-type interception of an in situ–formed oxonium ylide.The origin of the high stereoselectivity is well expounded via experimental and computational studies.These generated chiral products exhibit potent antiproliferation activity in three tested cancer cell lines,namely HCT116(colon cancer),A549(lung adenocarcinoma),and SJSA-1(osteosarcoma cancer).

Recent advances in gold-complex and chiral organocatalyst cooperative catalysis for asymmetric alkyne functionalization

Homogeneous gold catalysis has demonstrated the preponderant capability of realizing a broad range of synthetically versatile alkyne functionalization over the last two decades.Though catalytic asymmetric alkyne transformation has focused on the principle of using gold catalysts either associated with chiral phosphine ligand or combined with chiral counterion,a variety of breakthroughs have been reported with the application of gold-complex and chiral organocatalyst cooperative catalysis strategy,which could enable the challenging transformations that cannot be realized by mono-catalysis with excellent stereoselectivity.This review will cover two general protocols in this field,including relay catalysis and synergistic catalysis,with emphasis on the detailed cooperative catalysts models to illustrate the roles of the two catalysts and highlight the potential synthetic opportunities offered by asymmetric cooperative catalysis.

Highly Enantioselective Trapping of Carboxylic Oxonium Ylides with Imines for Direct Assembly of Enantioenriched γ-Butenolides

Enantioenrichedγ-butenolides are valuable structural cores in many pharmaceuticals and natural products,but their direct and catalytically asymmetric assembly remains rare.Here,we report an efficient,atom-economic synthetic strategy for enantioenrichedγ-butenolides via a unique enantioselective reaction of cyclopropene carboxylic acids with imines under the synergistic catalysis of Rh2(esp)2/chiral Brønsted acid system.The reaction involved trapping of carboxylic oxonium ylides,generated from cyclopropene carboxylic acids,which presented as the first asymmetric trapping reactive intermediate in the process.

Asymmetric Three-Component Propargyloxylation for Direct Assembly of Polyfunctionalized Chiral Succinate Derivatives

An enantioselective three-component propargyloxylation reaction of propargyl alcohols,pyridotriazoles,and imines has been realized by cooperative catalysis with dirhodium complex and chiral phosphoric acid under mild conditions.This is the first example of a catalytic asymmetric three-component propargyloxylation reaction,which provides practical access to chiral polyfunctionalized succinate derivatives with adjacent quaternary and tertiary stereocenters in good to high yields with excellent enantioselectivity.In addition to the alkyne motif,pyridyl,alkoxy,amino,and alkenyl species are all tolerated under the reaction conditions.Notably,the utility of the current method is demonstrated by catalytic cyclization of the product alkyne into a variety of heterocyclic structures without loss of enantiomeric purity.

An asymmetric catalytic multi-component reaction enabled the green synthesis of isoserine derivatives and semi-synthesis of paclitaxel

Paclitaxel(Taxol^(@))as a cornerstone of chemotherapy remains in high demand.The semi-synthesis of paclitaxel via coupling of Taxus leaf-produced baccatin III and manually synthesized isoserine(C-13 side chain)is one of the solutions to avoid environmental damage caused by the sacrifice of the whole Taxus brevifolia.A green synthesis of the C-13 side chain is pivotal to the green production of paclitaxel.We herein report a green synthesis of isoserine derivatives and the semi-synthesis of paclitaxel via a straightforward assembly of isoserines based on an Rh2(TPA)3(OAc)/CPA1 co-catalyzed asymmetric multi-component reaction of ethyl diazoacetate,triethyl silanol and N-(anthrancen-9-ylmethyl)benzaldimine.The method is featured by improved atom economy,effective mass yield,and environmental factors compared to our previous racemic method and BMS company's semi-synthesis method.And the method allows for rapid access to paclitaxel derivatives with varied C-13 side chains.

民间美术与祈福禳灾--读《中国民间美术观念》

艺术是民族精神的火炬,在中华民族砥砺前行的奋进过程中,不仅从未缺席,还创造出独具特色的精神体系与视觉语言。在《中国民间美术观念》一书中,作者专门探讨中国民间美术中的“祈福禳灾”主题,作者认为“祈福禳灾”是民间文化观念当中幸福观的显现,寄托了人们对美好事物、幸福生活的向往之情,体现了人们感性与理性、物质与精神的互融贯通。反映出了中国民间对于灾难的达观与睿智,至今仍值得我们借鉴与思考。

Snow-Enhancement Conditions and Seeding Simulation of Stratiform Clouds in the Bayanbulak Test Area in China

In this study,we employed a three-dimensional mesoscale cold-cloud seeding model to simulate the microphysical impacts of artificial ice crystals used as cloud seeding catalysts.Our objective was to elucidate the mechanism of snowfall enhancement in stratiform clouds in the Bayanbulak test area of Xinjiang,China.The results indicated that the optimal seeding time was the early stages of weather system development.In this case,the optimal seeding zone was identified as the northwest of the test area,especially near the cloud top(altitudes between 3500 and 4000 m,temperatures range−11 to−15℃),and the ideal concentration of catalyst was with ice crystal density of 1.0×10^(7)kg^(−1)within the target area.Under such conditions,the total precipitation rate in the seeding-affected area increased to 50.1 mm h^(−1).The results also showed that the favorable seeding region was featured by high content of supercooled water and low population of natural ice crystals,where artificial ice crystals could substantially increase the snowfall.This augmentation typically appeared in a unimodal pattern,with the peak formed within 2–3 h after seeding.Seeding in the ice–water mixed zone of a supercooled cloud facilitated rapid ice crystal growth to snow-flake pieces via the Bergeron process,which in turn consumed more supercooled water via collision–coalescence with cloud water droplets.Simultaneously,the intensive consumption of supercooled water impeded the riming process and reduced the formation of graupel particles within the cloud.The dispersion of artificial ice crystals extended over tens of kilometers horizontally;however,in the vertical direction most particles remained approximately 1 km below the seeding layer,due to limited vertical ascent rate in the stratiform clouds restricting upward movement of artificial ice crystals.The above results help better understand the snowfall enhancement mechanism in stratiform clouds and facilitate related weather modification practice.