Lysosome Targeting Chimaeras for Glut1-Facilitated Targeted Protein Degradation.

Targeted protein degradation technology holds great potential in biomedicine, particularly in treating tumors and other protein-related diseases. Research on intracellular protein degradation using molecular glues and PROTAC technology is leading, while research on the degradation of membrane proteins and extracellular proteins through the lysosomal pathway is still in the preclinical stage. The scarcity of useful targets is an immense limitation to technological advancement, making it essential to explore novel, potentially effective approaches for targeted lysosomal degradation. Here, we employed the glucose transporter Glut1 as an innovative lysosome-targeting receptor and devised the Glut1-Facilitated Lysosomal Degradation (GFLD) strategy. We synthesized potential Glut1 ligands via reversible addition-fragmentation chain transfer (RAFT) polymerization and acquired antibody-glycooligomer conjugates through bioorthogonal reactions as lysosome-targeting protein degradation molecules, utilized in the management of PD-L1 high-expressing triple-negative breast cancer. The glucose transporter Glut1 as a lysosome-targeting receptor exhibits potential for the advancement of a broader array of medications in the future.

Tailoring the Coordination Micro-Environment in Nanotraps for Efficient Platinum/Palladium Separation.

Recovering platinum group metals from secondary resources is crucial to meet the growing demand for high-tech applications. Various techniques are explored, and adsorption using porous materials has emerged as a promising technology due to its efficient performance and environmental beingness. However, the challenge lies in effectively recovering and separating individual platinum group metals (PGMs) given their similar chemical properties. Herein, a breakthrough approach is presented by sophisticatedly tailoring the coordination micro-environment in a series of aminopyridine-based porous organic polymers, which enables the creation of platinum-specific nanotraps for efficient separation of binary PGMs (platinum/palladium). The newly synthesized POP-o2NH2-Py demonstrates record uptakes and selectivity toward platinum over palladium, with the amino groups adjacent to the pyridine moieties being vital in improving platinum binding performance. Further breakthrough experiments underline its remarkable ability to separate platinum and palladium. Spectroscopic analysis reveals that POP-o2NH2-Py offers a more favorable coordination fashion to platinum ions compared to palladium ions owing to the greater interaction between N and Pt4+ and stronger intramolecular hydrogen bonding between the amino groups and four coordinating chlorines at platinum. These findings underscore the importance of fine-tuning the coordination micro-environment of nanotraps through subtle modifications that can greatly enhance the selectivity toward the desired metal ions.

Creation of Cationic Polymeric Nanotrap Featuring High Anion Density and Exceptional Alkaline Stability for Highly Efficient Pertechnetate Removal from Nuclear Waste Streams.

There is an urgent need for highly efficient sorbents capable of selectively removing 99TcO4- from concentrated alkaline nuclear wastes, which has long been a significant challenge. In this study, we present the design and synthesis of a high-performance adsorbent, CPN-3 (CPN denotes cationic polymeric nanotrap), which achieves excellent 99TcO4- capture under strong alkaline conditions by incorporating branched alkyl chains on the N3 position of imidazolium units and optimizing the framework anion density within the pores of a cationic polymeric nanotrap. CPN-3 features exceptional stability in harsh alkaline and radioactive environments as well as exhibits fast kinetics, high adsorption capacity, and outstanding selectivity with full reusability and great potential for the cost-effective removal of 99TcO4-/ReO4- from contaminated water. Notably, CPN-3 marks a record-high adsorption capacity of 1052 mg/g for ReO4- after treatment with 1 M NaOH aqueous solutions for 24 h and demonstrates a rapid removal rate for 99TcO4- from simulated Hanford and Savannah River Site waste streams. The mechanisms for the superior alkaline stability and 99TcO4- capture performances of CPN-3 are investigated through combined experimental and computational studies. This work suggests an alternative perspective for designing functional materials to address nuclear waste management.

Complete separation of benzene-cyclohexene-cyclohexane mixtures via temperature-dependent molecular sieving by a flexible chain-like coordination polymer.

The separation and purification of C6 cyclic hydrocarbons (benzene, cyclohexene, cyclohexane) represent a critically important but energy intensive process. Developing adsorptive separation technique to replace thermally driven distillation processes holds great promise to significantly reduce energy consumption. Here we report a flexible one-dimensional coordination polymer as an efficient adsorbent to discriminate ternary C6 cyclic hydrocarbons via an ideal molecular sieving mechanism. The compound undergoes fully reversible structural transformation associated with removal/re-coordination of water molecules and between activated and hydrocarbon-loaded forms. It exhibits distinct temperature- and adsorbate-dependent adsorption behavior which facilitates the complete separation of benzene, cyclohexene and cyclohexane from their binary and ternary mixtures, with the record-high uptake ratios for C6H6/C6H12 and C6H10/C6H12 in vapor phase and highest binary and ternary selectivities in liquid phase. In situ infrared spectroscopic analysis and ab initio calculations provide insight into the host-guest interactions and their effect on the preferential adsorption and structural transformation.

Immobilization of Amino-site into a Pore-Partitioned Metal-Organic Framework for Highly Efficient Separation of Propyne/Propylene.

Adsorptive separation of propyne/propylene (C3H4/C3H6) is a crucial yet complex process, however, it remains a great difficulty in developing porous materials that can meet the requirements for practical applications, particularly with an exceptional ability to bind and store trace amounts of C3H4. Functionalization of pore-partitioned metal-organic frameworks (ppMOFs) is methodically suited for this challenge owing to the possibility of dramatically increasing binding sites on highly porous and confined domains. We here immobilized Lewis-basic (-NH2) and Lewis-acidic (-NO2) sites on this platform. Along with an integrated nature of high uptake of C3H4 at 1 kPa, high uptake difference of C3H4-C3H6, moderated binding strength, promoted kinetic selectivity, trapping effect and high stability, the NH2-decorated ppMOF (NTU-100-NH2) can efficiently produce polymer-grade C3H6 (99.95 %, 8.3 mmol ⋅ g-1) at room temperature, which is six times more than the NO2-decorated crystal (NTU-100-NO2). The in situ infrared spectroscopy, crystallographic analysis, and sequential blowing tests showed that the densely packed amino group in this highly porous system has a unique ability to recognize and stabilize C3H4 molecules. Moving forward, the strategy of organic functionalization can be extended to other porous systems, making it a powerful tool to customize advanced materials for challenging tasks.

Metal-Free Heterogeneous Asymmetric Hydrogenation of Olefins Promoted by Chiral Frustrated Lewis Pair Framework.

The development of metal-free and recyclable catalysts for significant yet challenging transformations of naturally abundant feedstocks has long been sought after. In this work, we contribute a general strategy of combining the rationally designed crystalline covalent organic framework (COF) with a newly developed chiral frustrated Lewis pair (CFLP) to afford chiral frustrated Lewis pair framework (CFLPF), which can efficiently promote the asymmetric olefin hydrogenation in a heterogeneous manner, outperforming the homogeneous CFLP counterpart. Notably, the metal-free CFLPF exhibits superior activity/enantioselectivity in addition to excellent stability/recyclability. A series of in situ spectroscopic studies, kinetic isotope effect measurements, and density-functional theory computational calculations were also performed to gain an insightful understanding of the superior asymmetric hydrogenation catalysis performances of CFLPF. Our work not only increases the versatility of catalysts for asymmetric catalysis but also broadens the reactivity of porous organic materials with the addition of frustrated Lewis pair (FLP) chemistry, thereby suggesting a new approach for practical and substantial transformations through the advancement of novel catalysts from both concept and design perspectives.

Visible-Light-Promoted C(sp3)-C(sp3) Cross-Coupling of Amino Acids and Aryl Trifluoromethyl Ketones Through Simultaneous Decarboxylation and Defluorination.

A photoredox-catalyzed approach for the difluoroalkylation of amino acids was achieved through simultaneous decarboxylation and defluorination processes. This innovative protocol employs commonly available amino acids and trifluoroacetophenones as the primary starting materials, eliminating the necessity for preactivation. This strategy has enabled the synthesis of several difluoroketone functionalized amines in moderate to impressive yields. These synthesized compounds are presented as foundational molecules for subsequent modification. The underlying mechanism for the transformation is anchored in a single electron transfer (SET) radical pathway.

Affinity-Switchable Interaction of Biotin and Streptavidin for the Signal-ON Detection of Small Molecules.

Lateral flow assay (LFA) based on gold nanoparticles (AuNPs) is a widely used analytical device for the rapid analysis of environmental hazards and biomarkers. Typically, a sandwich-type format is used for macromolecule detection, in which the appearance of a red test line indicates a positive result (Signal-ON). In contrast, small molecule detection usually relies on a competitive assay, where the absence of a test line indicates positive testing (Signal-OFF). However, such a "Signal-OFF" reading is usually detected within a narrower dynamic range and tends to generate false-negative signals at a low concentration. Moreover, inconsistent readings between macromolecule and small molecule testing might lead to misinterpretation when used by nonskilled individuals. Herein, we report a "Signal-ON" small molecule competitive assay based on the sterically modulated affinity-switchable interaction of biotin and streptavidin. In the absence of a small molecule target, a large steric hindrance can be imposed on the biotin to prevent interaction with streptavidin. However, in the presence of the small molecule target, this steric effect is removed, allowing the biotin to bind to streptavidin and generate the desired test line. In this article, we demonstrate the selective detection of two small molecule drugs, sulfonamides and trimethoprim, using this simple and modular affinity-switchable lateral flow assay (ASLFA). We believe that this affinity-switchable approach can also be adapted in drug discovery and clinical diagnosis, where the competitive assay format is always used for the rapid analysis of small molecules.

Small Plasma Membrane-Targeted Fluorescent Dye for Long-Time Imaging and Protein Degradation Analyses.

Plasma membrane (PM)-targeted fluorescent dyes have become an important tool to visualize morphological and dynamic changes in the cell membrane. However, most of these PM dyes are either too large and thus might potentially perturb the membrane and affect its functions or exhibit a short retention time on the cell membrane. The rapid internalization problem is particularly severe for PM dyes based on cationic and neutral hydrophobic fluorescent dyes, which can be easily transported into the cells by transmembrane potential and passive diffusion mechanisms. In this paper, we report a small but highly specific PM fluorescent dye, PM-1, which exhibits a very long retention time on the plasma membrane with a half-life of approximately 15 h. For biological applications, we demonstrated that PM-1 can be used in combination with protein labeling probes to study ectodomain shedding and endocytosis processes of cell surface proteins and successfully demonstrated that native transmembrane human carbonic anhydrase IX (hCAIX) is degraded via the ectodomain shedding mechanism. In contrast, hCAIX undergoes endocytic degradation in the presence of sheddase inhibitors. We believe that PM-1 can be a versatile tool to provide detailed insights into the dynamic processes of the cell surface proteins.

Luminescent Metal-Organic Framework for the Selective Detection of Aldehydes.

The detection of toxic, hazardous chemical species is an important task because they pose serious risks to either the environment or human health. Luminescent metal-organic frameworks (LMOFs) as alternative sensors offer rapid and sensitive detection of chemical species. Interactions between chemical species and LMOFs result in changes in the photoluminescence (PL) profile of the LMOFs which can be readily detected using a simple fluorometer. Herein, we report the use of a robust, Zn-based LMOF, [Zn5(µ3-OH)2(adtb)2(H2O)5·5 DMA] (Zn-adtb, LMOF-341), for the selective detection of benzaldehyde. Upon exposure to benzaldehyde, Zn-adtb experiences significant luminescent quenching, as characterized through PL experiments. Photoluminescent titration experiments reveal that LMOF-341 has a detection limit of 64 ppm and a Ksv value of 179 M-1 for benzaldehyde. Furthermore, we study the guest-host interactions that occur between LMOF-341 and benzaldehyde through in situ Fourier transform infrared and computational modeling employing density functional theory. The results show that benzaldehyde interacts more strongly with LMOF-341 compared to formaldehyde and propionaldehyde. Our combined studies also reveal that the mechanism of luminescence quenching originates from an electron-transfer process.

Incorporation of Chiral Frustrated Lewis Pair into Metal-Organic Framework with Tailored Microenvironment for Heterogeneous Enantio- and Chemoselective Hydrogenation.

The development of efficient heterogeneous catalysts with multiselectivity (e.g., enantio- and chemoselectivity) has long been sought after but with limited progress being made so far. To achieve enantio- and chemoselectivity in a heterogeneous system, as inspired by enzymes, we illustrate herein an approach of creating an enzyme-mimic region (EMR) within the nanospace of a metal-organic framework (MOF) as exemplified in the context of incorporating a chiral frustrated Lewis pair (CFLP) into a MOF with a tailored pore environment. Due to the high density of the EMR featuring the active site of CFLP and auxiliary sites of the hydroxyl group/open metal site within the vicinity of CFLP, the resultant EMR@MOF demonstrated excellent catalysis performance in heterogeneous hydrogenation of α,ß-unsaturated imines to afford chiral ß-unsaturated amines with high yields and high enantio- and chemoselectivity. The role of the hydroxyl group/open metal site in regulating chemoselectivity was proved by the observation of a catalyst-substrate interaction experimentally, which was also rationalized by computational results. This work not only contributes a MOF as a new platform for multiselective catalysis but also opens a promising avenue to develop heterogeneous catalysts with multiselectivity for challenging yet important transformations.

Confinement of 1D Chain and 2D Layered CuI Modules in K-INA-R Frameworks via Coordination Assembly: Structure Regulation and Semiconductivity Tuning.

Herein, we present a new series of CuI-based hybrid materials with tunable structures and semiconducting properties. The CuI inorganic modules can be tailored into a one-dimensional (1D) chain and two-dimensional (2D) layer and confined/stabilized in coordination frameworks of potassium isonicotinic acid (HINA) and its derivatives (HINA-R, R = OH, NO2, and COOH). The resulting CuI-based hybrid materials exhibit interesting semiconducting behaviors associated with the dimensionality of the inorganic module; for instance, the structures containing the 2D-CuI module demonstrate significantly enhanced photoconductivity with a maximum increase of five orders of magnitude compared to that of the structures containing the 1D-CuI module. They also represent the first CuI-bearing hybrid chemiresistive gas sensors for NO2 with boosted sensing performance and sensitivity at multiple orders of magnitude over that of the pristine CuI. Particularly, the sensing ability of CuI-K-INA containing both 1D- and 2D-CuI modules is comparable to those of the best NO2 chemiresistors reported thus far.

Magnetically Induced Binary Ferrocene with Oxidized Iron.

Ferrocene is perhaps the most popular and well-studied organometallic molecule, but our understanding of its structure and electronic properties has not changed for more than 70 years. In particular, all previous attempts of chemically oxidizing pure ferrocene by binding directly to the iron center have been unsuccessful, and no significant change in structure or magnetism has been reported. Using a metal organic framework host material, we were able to fundamentally change the electronic and magnetic structure of ferrocene to take on a never-before observed physically stretched/bent high-spin Fe(II) state, which readily accepts O2 from air, chemically oxidizing the iron from Fe(II) to Fe(III). We also show that the binding of oxygen is reversible through temperature swing experiments. Our analysis is based on combining Mößbauer spectroscopy, extended X-ray absorption fine structure, in situ infrared, SQUID, thermal gravimetric analysis, and energy dispersive X-ray fluorescence spectroscopy measurements with ab initio modeling.

Neoadjuvant PD-1/PD-L1 axis blockade for patients with head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a common type of cancer, and approximately 64 % are in a locally advanced stage at diagnosis. Therefore, neoadjuvant therapy is of great importance. However, traditional neoadjuvant strategies for HNSCC have shown limited efficacy and high complications. And it is urgent to explore new neoadjuvant approaches. With the breakthrough progress of PD-1/PD-L1 axis blockade in recurrent/metastatic HNSCC, neoadjuvant PD-1/PD-L1 axis blockade is gradually showing positive prospects for HNSCC. This study found that the combination of PD-1/PD-L1 axis blockade and chemotherapy or radiotherapy are potential with the overall response rate (ORR) of 45.0 %-96.7 % and 47.6 %-56.7 %, the pathological complete response (pCR) of 16.7 %-42.3 % and 33.3 %-100.0 %, and the main pathological response (MPR) of 26.9 %-74.1 % and 60.0 %-100.0 %, respectively. But the combination of PD-1/PD-L1 axis blockade and CTLA-4 blockade is worth questioning. And we also found pCR and MPR can be early indicators for long-term prognosis and provide five directions for neoadjuvant PD-1/PD-L1 axis blockade in the future.

Protein-Labeling Fluorescent Probe for Folate Receptor α.

GPI-anchored folate receptor α (FRα) is an attractive anticancer drug target and diagnosis marker in fundamental biology and medical research due to its significant expression on many cancer cells. Currently, analyses of FRα expression levels are usually achieved using immunological methods. Due to the continual FRα synthesis and degradation, immunological methods are not suitable for studying real-time dynamic activities of FRα in living cells. In this paper, we introduce a rapid and specific FRα protein-labeling fluorescent probe, FR1, to facilitate the study of the dynamics of expression and degradation processes of endogenous FRα in living cells. With this labeling probe, insights on FRα protein lifetime and shedding from the cell surface can be obtained using fluorescence live-cell imaging and electrophoresis techniques. We revealed that FRα undergoes soluble domain release and endocytosis degradation simultaneously. Imaging results showed that most of the membrane FRα are transported to the lysosomes after 2 h of incubation. Furthermore, we also showed that the secretion of a FRα soluble domain into the environment is most likely accomplished by phospholipase. We believe that this protein-labeling approach can be an important tool for analyzing various dynamic processes involving FRα.

One Atom Can Make All the Difference: Gas-Induced Phase Transformations in Bisimidazole-Linked Diamondoid Coordination Networks.

Coordination networks (CNs) that undergo gas-induced transformation from closed (nonporous) to open (porous) structures are of potential utility in gas storage applications, but their development is hindered by limited control over their switching mechanisms and pressures. In this work, we report two CNs, [Co(bimpy)(bdc)]n (X-dia-4-Co) and [Co(bimbz)(bdc)]n (X-dia-5-Co) (H2bdc = 1,4-benzendicarboxylic acid; bimpy = 2,5-bis(1H-imidazole-1-yl)pyridine; bimbz = 1,4-bis(1H-imidazole-1-yl)benzene), that both undergo transformation from closed to isostructural open phases involving at least a 27% increase in cell volume. Although X-dia-4-Co and X-dia-5-Co only differ from one another by one atom in their N-donor linkers (bimpy = pyridine, and bimbz = benzene), this results in different pore chemistry and switching mechanisms. Specifically, X-dia-4-Co exhibited a gradual phase transformation with a steady increase in the uptake when exposed to CO2, whereas X-dia-5-Co exhibited a sharp step (type F-IV isotherm) at P/P0 ≈ 0.008 or P ≈ 3 bar (195 or 298 K, respectively). Single-crystal X-ray diffraction, in situ powder XRD, in situ IR, and modeling (density functional theory calculations, and canonical Monte Carlo simulations) studies provide insights into the nature of the switching mechanisms and enable attribution of pronounced differences in sorption properties to the changed pore chemistry.

Efficacy of Music Intervention for Dental Anxiety Disorders: A Systematic Review and Meta-Analysis.

Objective To evaluate the effectiveness of music therapy for dental anxiety disorders. Methods In order to gather clinical randomized controlled trials comparing the effectiveness of music interventions to traditional oral manipulation in patients with dental anxiety disorders, computer searches of the electronic databases of Wanfang, CNKI, VIP, PubMed, Web of Science, ScienceDirect, Cochrane library, Scopus, and CINAHL were conducted. The search period covered from 23 December 2022, through to the development of the database. The Cochrane Handbook was used to assess the quality of the included literature, and two researchers independently conducted the literature screening and data extraction. Stata 17.0 and RevMan 5.3 were used to conduct the meta-analysis. Results The preoperative baseline levels of the music intervention group were similar to those of the control group (p > 0.05), according to the meta-analysis, and music intervention significantly decreased heart rate (I2 = 81.2%, WMD (95% CI): -7.33 (-10.07, -4.58), p < 0.0001), systolic blood pressure fluctuations (I2 = 85.6%, WMD (95% CI): -6.10(-9.25, 2.95), p < 0.0001), diastolic blood pressure (I2 = 79.7%, WMD (95% CI): -4.29(-6.57, -2.02), p < 0.0001) fluctuations, anxiety scores (I2 = 19.6%, WMD (95% CI): -9.04(-11.45, 6.63), p < 0.0001), and pain scores (I2 = 32.7%, WMD (95% CI): -7.64(-9.43, -5.85), p < 0.0001), as well as significantly lowered anxiety and pain levels and raised patients' cooperation rates (I2 = 0%, OR (95% CI): 3.03(1.24, 7.40), p = 0.02). Conclusions Music interventions are effective for dental anxiety disorders, but given the limitations of the study, more multicenter, large-sample, high-quality randomized controlled trials are needed to further validate the findings and obtain more objective and reliable clinical evidence.

Monitoring the Activation of Open Metal Sites in [FexM3-x(µ3-O)] Cluster-Based Metal-Organic Frameworks by Single-Crystal X-ray Diffraction.

While trinuclear [FexM3-x(µ3-O)] cluster-based metal-organic frameworks (MOFs) have found wide applications in gas storage and catalysis, it is still challenging to identify the structure of open metal sites obtained through proper activations and understand their influence on the adsorption and catalytic properties. Herein, we use in situ variable-temperature single-crystal X-ray diffraction to monitor the structural evolution of [FexM3-x(µ3-O)]-based MOFs (PCN-250, M = Ni2+, Co2+, Zn2+, Mg2+) upon thermal activation and provide the snapshots of metal sites at different temperatures. The exposure of open Fe3+ sites was observed along with the transformation of Fe3+ coordination geometries from octahedron to square pyramid. Furthermore, the effect of divalent metals in heterometallic PCN-250 was studied for the purpose of reducing the activation temperature and increasing the number of open metal sites. The metal site structures were corroborated by X-ray absorption and infrared spectroscopy. These results will not only guide the pretreatment of [FexM3-x(µ3-O)]-based MOFs but also corroborate spectral and computational studies on these materials.

Optimal Binding Affinity for Sieving Separation of Propylene from Propane in an Oxyfluoride Anion-Based Metal-Organic Framework.

Highly efficient adsorptive separation of propylene from propane offers an ideal alternative method to replace the energy-intensive cryogenic distillation technology. Molecular sieving-type separation via high-performance adsorbents is targeted for superior selectivity, but the limit in adsorption capacity remains a great challenge. Here, we report an oxyfluoride-based ultramicroporous metal-organic framework UTSA-400, [Ni(WO2F4)(pyz)2] (pyz = pyrazine), featuring one-dimensional pore channels that can accommodate the propylene molecules with optimal binding affinity while specifically excluding the propane molecules. The exposed oxide/fluoride pairs in UTSA-400 serve as strong functional sites for strengthened propylene-host interactions, accounting for a significantly enhanced propylene uptake, while the propane molecules are excluded due to the regulated host framework dynamics. The strong propylene binding enables near-saturation of propylene in the pore confinement at ambient conditions, leading to full utilization of pore space and superior packing density. Combined in situ infrared spectroscopy measurements and dispersion-corrected density functional theory calculations clearly unveil the nature of boosted host-guest binding. Direct production of polymer-grade (>99.5%) propylene with remarkable dynamic productivity is demonstrated by column breakthrough experiments. This work presents an example of pore engineering with atomic precision to break the trade-off in adsorptive separation through guest binding optimization.

Revisiting Competitive Adsorption of Small Molecules in the Metal-Organic Framework Ni-MOF-74.

To precisely evaluate the potential of metal-organic frameworks (MOFs) for gas separation and purification applications, it is crucial to understand how various molecules competitively adsorb inside MOFs. In this paper, we combine in situ infrared spectroscopy with ab initio calculations to investigate the mechanisms associated with coadsorption of several small molecules, including CO, NO, and CO2 inside the prototypical structure Ni-MOF-74. Surprisingly, we find that the displacement of CO bound inside Ni-MOF-74 (binding energy of 53 kJ/mol) is readily driven by CO2 exposure, even though CO2 has a noticeably weaker binding energy of only 41 kJ/mol; meanwhile, the significantly more strongly binding NO molecule (90 kJ/mol) is not able to easily displace bound CO inside Ni-MOF74. These results show that single-phase binding energies of a molecule inside the MOF cannot completely describe their interaction with the MOF in the presence of other guest molecules. We unveil many crucial factors, such as the kinetic barrier, partial pressure, secondary binding sites, and guest-host/lateral interactions that control the coadsorption process and, combined with the binding energy, are better descriptors of the behavior and adsorption of gas mixtures inside MOFs.