Multiple Ligands Research Articles

Activity of Different AunSn+1 Staples in the Ligand Exchange of Au23(SR)16- with a Single Foreign Thiolate Ligand.

Ligand exchange has been widely used to synthesize novel thiolated gold nanoclusters and to regulate their specific properties. Herein, density functional theory (DFT) calculations were conducted to investigate the kinetic profiles of the ligand exchange of the [Au23(SCy)16]- nanocluster with an aromatic thiolate (2-napthalenethiol). The three types of staple motifs (i.e., trimetallic Au3S4, monometallic AuS2, and the bridging thiolates) of the Au23 cluster precursor could be categorized into eight groups of S sites with different chemical environments. The ligand exchange of all of them occurs favorably via the SN1-like pathway, with one site starting with the Au-S dissociation and seven other sites starting with the H-transfer steps. By contrast, the SN2-like pathway (i.e., the synergistic SCy-to-SAr exchange prior to the H-transfer step) is unlikely in the target systems. Meanwhile, the Au-S bond on the capping Au atom of the bicapped icosahedral Au15 core is the most active one, while the S sites on Au3S4 (except for the one remote from the metallic core) are all competitive exchanging sites. The ligand exchange activity of the bridging thiolate and the remote S site on Au3S4 is significantly less reactive. The calculation results correlate with the multiple ligand exchange within only a few minutes and the preferential etching of the AuS2 staple with the foreign ligands reported in earlier experiments. The relative activity of different staples might be helpful in elucidating the inherent principles in the ligand exchange-induced size-evolution of metal nanoclusters.

The Neutrophil Dynamic Mass Redistribution Assay as a Medium throughput Primary Cell Screening Assay.

In a typical G protein coupled receptor drug discovery campaign, an in vitro primary functional screening assay is often established in a recombinant system overexpressing the target of interest, which offers advantages with respect to overall throughput and robustness of compound testing. Subsequently, compounds are then progressed into more physiologically relevant but lower throughput ex vivo primary cell assays and finally in vivo studies. Here we describe a dynamic mass redistribution (DMR) assay that has been developed in a format suitable to support medium throughput drug screening in primary human neutrophils. Neutrophils are known to express both CXC chemokine receptor (CXCR) 1 and CXCR2 that are thought to play significant roles in various inflammatory disorders and cancer. Using multiple relevant chemokine ligands and a range of selective and nonselective small and large molecule antagonists that block CXCR1 and CXCR2 responses, we demonstrate distinct pharmacological profiles in neutrophil DMR from those observed in recombinant assays but predictive of activity in neutrophil chemotaxis and CD11b upregulation, a validated target engagement marker previously used in clinical studies of CXCR2 antagonists. The primary human neutrophil DMR cell system is highly reproducible, robust, and less prone to donor variability observed in CD11b and chemotaxis assays and thus provides a unique, more physiologically relevant, and higher throughput assay to support drug discovery and translation to early clinical trials. SIGNIFICANCE STATEMENT: Neutrophil dynamic mass redistribution assays provide a higher throughput screening assay to profile compounds in primary cells earlier in the screening cascade enabling a higher level of confidence in progressing the development of compounds toward the clinic. This is particularly important for chemokine receptors where redundancy contributes to a lack of correlation between recombinant screening assays and primary cells, with the coexpression of related receptors confounding results.

Bifunctional Interface Passivation via Copper Acetylacetonate for Efficient and Stable Perovskite Solar Cells.

Manipulating interface defects can minimize interfacial nonradiative recombination, thus increasing the stability and performance of perovskite solar cells (PSCs). Here, copper acetylacetonate [Cu(acac)2] as a passivator is used to treat the interface between Spiro-OMeTAD and perovskite. Owing to the strong chelation, the uncoordinated Pb2+ could react with -C═O/-COH functional groups, firmly anchoring acetylacetonate at this interface or the grain boundaries (GBs) of perovskite films to construct multiple ligand bridges, accompanied by the p-type copper iodide formation with copper substituting lead. Simultaneously, Cu+-Cu2+ pairs transfer electrons from Pb0 to I0, suppressing deep level defects of Pb0 and I0 near the perovskite interface. These can be beneficial to hole-transferring. Moreover, the Schiff base complexes with hydrophobicity, from the reaction of acetylacetonate with perovskite, can lead to tightly packed adjacent perovskite surfaces and self-seal the GBs of the perovskite, inhibiting moisture diffusion for long-term stability. Consequently, the Cu(acac)2-based PSC has achieved more than 24% champion efficiency while retaining ca. 92% of the initial power conversion efficiency after 1680 h of storage.

The Molecular Mechanisms of Complement Receptor 1-It Is Complicated.

Human complement receptor 1 (CR1) is a membrane-bound regulator of complement that has been the subject of recent attempts to generate soluble therapeutic compounds comprising different fragments of its extracellular domain. This review will focus on the extracellular domain of CR1 and detail how its highly duplicated domains work both separately and together to mediate binding to its main ligands C3b and C4b, and to inhibit the classical, lectin, and alternative pathways of the complement cascade via the mechanisms of decay acceleration activity (DAA) and co-factor activity (CFA). Understanding the molecular basis of CR1 activity is made more complicated by the presence not only of multiple ligand binding domains within CR1 but also the fact that C3b and C4b can interact with CR1 as both monomers, dimers, and heterodimers. Evidence for the interaction of CR1 with additional ligands such as C1q will also be reviewed. Finally, we will bring the mechanistic understanding of CR1 activity together to provide an explanation for the differential complement pathway inhibition recently observed with CSL040, a soluble CR1-based therapeutic candidate in pre-clinical development.

“From shadows to shores”-quantitative analysis of CuO nanoparticle-induced apoptosis and DNA damage in fish erythrocytes: A multimodal approach combining experimental, image-based quantification, docking and molecular dynamics

The usage of copper (II) oxide nanoparticles (CuO NPs) has significantly expanded across industries and biomedical fields. However, the potential toxic effects on non-target organisms and humans lack comprehensive understanding due to limited research on molecular mechanisms. With this study, by combining the 96 h in vivo exposure of crucian carp fish, Carassius carassius, to sub-lethal CuO NPs doses (0.5 and 1 mg/dL) with image-based quantification, and docking and molecular dynamics approaches, we aimed to understand the mechanism of CuO NPs-induced cyto-genotoxicity in the fish erythrocytes. The results revealed that both doses of copper NPs used were toxic to erythrocytes causing oxidative stress response and serious red blood cell morphological abnormalities, and genotoxicity. Docking and 10-ns molecular dynamics confirmed favorable interactions (ΔG = −2.07 kcal mol−1) and structural stability of Band3-CuO NP complex, mainly through formation of H-bonds, implying the potential of CuO NPs to induce mitotic nuclear abnormalities in C. carassius erythrocytes via Band3 inhibition. Moreover, conventional and multiple ligand simultaneous docking with DNA revealed that single, double and triple CuO NPs bind preferentially to AT-rich regions consistently in the minor grooves of DNA. Of note, the DNA-binding strength subtantially increased (ΔG = −2.13 kcal mol−1, ΔG = −4.08 kcal mol−1, and ΔG = −6.03 kcal mol−1, respectively) with an increasing number of docked CuO NPs, suggesting that direct structural perturbation on DNA could also count for the molecular basis of in-vivo induced DNA damage in C. carassius erythrocytes. This study introduces the novel term “erythrotope” to describe comprehensive red blood cell morphological abnormalities. It proves to be a reliable and cost-effective biomarker for evaluating allostatic erythrocyte load in response to metallic nanoparticle exposure, serving as a distinctive fingerprint to assess fish erythrocyte health and physiological fitness.

THU610 Distribution Of Cortisol In Human Serum In Vitro: Role Of Competitive Ligand-protein Interactions In Women On Oral Contraceptives

Abstract Disclosure: R.I. Dorin: None. I. Perogamvros: None. C.R. Qualls: None. Background: The relationship between serum concentrations of total (XTotF) and free (XF) cortisol (test tube equilibrium at 37°C) is influenced by many factors. These include concentrations and affinities of serum binding proteins (BP), such as CBG and albumin (A). Among women taking oral contraceptives (OC), XF was found to be higher than predicted using ligand-BP association parameters developed in healthy volunteers (HV). We hypothesized that ligand(s) (XP) competing for XF binding to CBG may contribute to altered relationships between XTotF and XF observed in OC relative to HV. Methods: Feldman’s system of iterative, non-linear equilibrium equations1 were developed in (nxm) matrix format. Data included measured XTotF and XF at each time point (0-480 min) after 20 mg hydrocortisone2. Groups were stratified by (i) mode of administration (iv vs. po) and (ii) condition (HV, n=13 vs. OC, n=12). The matrix was interrupted to obtain iterative equilibrium solutions for parameters of interest using (1x2) minimal model (MM) and (2x2) ligand competition model (LCM). Solutions were optimized by minimizing least squares differences between measured and model predicted XF. Albumin-bound cortisol was parameterized as a constant ratio of XF (N) to simplify the matrix problem. Comparisons and interactions within the 2x2x2 design (delivery, group, and model) were analyzed by ANOVA. Results: In OC, LCM provided significantly better fit to measured XF relative to MM (13 vs. 19% error, P=0.003). MM solutions for CBG-cortisol affinities were significantly higher in HV (KD=26.6) vs. OC (KD=71.9 nmol/L), but LCM yielded similar affinities in both groups (KD = 23.9 in HV and 16.1 nmol/L in OC, interaction P<0.001). LCM solutions for concentrations and CBG-binding affinities of XP were significantly increased in OCP vs. HV (both P<0.001). LCM solutions for HV yielded higher N for po (3.1±1.2) vs. iv (1.4±0.4) (P=0.007). Limitations: Model solutions depend on the precision and accuracy of measurements made in clinical samples. Although the competitor (XP) is treated as a single compound in LCM, it may represent the combined effects (e.g., harmonic means) of multiple ligands. Conclusions: (i) matrix notation was useful to development of non-linear, iterative equations for competitive ligand-BP interactions, which were applicable to both forward and inverse solutions of the matrix problems (ii) LCM provided a better fit to experimental data for OC compared to MM, providing (indirect) evidence that competing ligand(s) (XP) influence the distribution of cortisol in serum samples obtained from women on OC, (iii) inter- and intra-subject variability for N was observed for both models, suggesting that assignment of a single population value for cortisol-albumin binding constant may be unrealistic.

Trade‐Off Between Efficiency and Stability of CsPbBr3 Perovskite Quantum Dot‐Based Light‐Emitting Diodes by Optimized Passivation Ligands for Br/Pb

AbstractAlthough significant progress has been made in improving the external quantum efficiencies (EQEs) of perovskite quantum dot (QD) light‐emitting diodes (QLEDs), understanding the degradation mechanism and enhancing stability remain a challenge. Herein, increasing the content of Br‐based passivation ligands is shown to enhance the EQE up to 16.1% by reducing the defects of CsPbBr3 QDs in a Br‐rich environment. However, the operational lifetimes of perovskite QLEDs gradually decrease with the increase of halide content, owing to the intensified ion migration under continuous electric field confirmed by the current behavior of QLEDs and time‐of‐flight secondary‐ion mass spectrometry. Furthermore, a thorough analysis of the relationship between electricity and luminance of QLEDs suggests that a small amount of residue oleic acid ligands could weaken ion migration. Accordingly, a halide‐ and acid‐hybrid (HAH) co‐passivation strategy is proposed to optimize the content of Br‐ and acid‐based ligands, and achieve a maximum EQE of 18.6% and an operational lifetime (T50, extrapolated) of 213 h for CsPbBr3 QLEDs. This approach for passivating QDs combines the high efficiency of Br‐based ligands with the improved stability of acid‐based ligands. The study elucidates the correlation between ligands and device performance, highlighting the significance of two or even multiple ligands for efficient and stable perovskite QLEDs.

Response of Photonic Hydrogels of Homogeneous Particles to Uranyl Ions in Aqueous Solutions

We study here the response of photonic hydrogels (PHs), made of photonic crystals of homogeneous silica particles in polyacrylamide hydrogels (SPHs), to the uranyl ions UO22+ in aqueous solutions. It is found that the reflection spectra of the SPH show a peak due to the Bragg diffraction, which exhibits a blue shift in the presence of UO22+. Upon exposure to the SPH, UO22+ gets adsorbed on the SPH and forms complex coordinate bonds with multiple ligands on the SPH, which causes shrinking of hydrogel and leads to the blue shift in the diffraction peak. The amount of the blue shift in the diffraction peak increases monotonically up to UO22+ concentrations as high as 2300µM. The equilibration time for the shift in the Bragg peak upon exposure to UO22+ is found to be ~30 min. These results are in contrast to the earlier reports on photonic hydrogels of inhomogeneous microgel particles hydrogel (MPH), which shows the threshold UO22+ concentration of ~600 µM, below which the diffraction peak exhibits a blue shift and a change to a red shift above it. The equilibration time for MPH is ~300min. The observed monotonic blue shift and the faster time response of the SPH to UO22+ as compared to the MPH are explained in terms of homogeneous nature of silica particles in the SPH, against the porous and polymeric nature of microgels in the MPH. We also study the extraction of UO22+ from aqueous solutions using the SPH. The extraction capacity estimated by the arsenazo-III analysis is found to be 112 mM/kg.

Cryo EM structures map a post vaccination polyclonal antibody response to canine parvovirus

Canine parvovirus (CPV) is an important pathogen that emerged by cross-species transmission to cause severe disease in dogs. To understand the host immune response to vaccination, sera from dogs immunized with parvovirus are obtained, the polyclonal antibodies are purified and used to solve the high resolution cryo EM structures of the polyclonal Fab-virus complexes. We use a custom software, Icosahedral Subparticle Extraction and Correlated Classification (ISECC) to perform subparticle analysis and reconstruct polyclonal Fab-virus complexes from two different dogs eight and twelve weeks post vaccination. In the resulting polyclonal Fab-virus complexes there are a total of five distinct Fabs identified. In both cases, any of the five antibodies identified would interfere with receptor binding. This polyclonal mapping approach identifies a specific, limited immune response to the live vaccine virus and allows us to investigate the binding of multiple different antibodies or ligands to virus capsids.

Pharmacological characterisation of erenumab, Aimovig, at two calcitonin gene-related peptide responsive receptors.

Calcitonin gene-related peptide (CGRP) is involved in migraine pathophysiology. CGRP can signal through two receptors. The canonical CGRP receptor comprises the calcitonin receptor-like receptor and receptor activity-modifying protein 1 (RAMP1); the AMY1 receptor comprises the calcitonin receptor with RAMP1. Drugs that reduce CGRP activity, such as receptor antagonists, are approved for the treatment and prevention of migraine. Despite being designed to target the canonical CGRP receptor, emerging evidence suggests that these antagonists, including erenumab (a monoclonal antibody antagonist) can also antagonise the AMY1 receptor. However, it is difficult to estimate its selectivity because direct comparisons between receptors under matched conditions have not been made. We therefore characterised erenumab at both CGRP-responsive receptors with multiple ligands, including αCGRP and βCGRP. Erenumab antagonism was quantified through IC50 and pKB experiments, measuring cAMP production. We used SK-N-MC cells which endogenously express the human CGRP receptor, and HEK293S and Cos7 cells transiently transfected to express either human CGRP or AMY1 receptors. Erenumab antagonised both the CGRP and AMY1 receptors with an ~20-120-fold preference for the CGRP receptor, depending on the cells, agonist, analytical approach and/or assay format. Erenumab antagonised both forms of CGRP equally, and appeared to act as a competitive reversible antagonist at both receptors. Despite being designed to target the CGRP receptor, erenumab can antagonise the AMY1 receptor. Its ability to antagonise CGRP activity at both receptors may be useful in better understanding the clinical profile of erenumab.

Natural Bioactive Compounds from Marine Invertebrates That Modulate Key Targets Implicated in the Onset of Type 2 Diabetes Mellitus (T2DM) and Its Complications.

Type 2 diabetes mellitus (T2DM) is an ongoing, risky, and costly health problem that therefore always requires new treatment options. Moreover, although several drugs are available, only 36% of patients achieve glycaemic control, and patient adherence is a major obstacle. With monotherapy, T2DM and its comorbidities/complications often cannot be managed, and the concurrent administration of several hypoglycaemic drugs is required, which increases the risk of side effects. In fact, despite the efficacy of the drugs currently on the market, they generally come with serious side effects. Therefore, scientific research must always be active in the discovery of new therapeutic agents. The present review highlights some of the recent discoveries regarding marine natural products that can modulate the various targets that have been identified as crucial in the establishment of T2DM disease and its complications, with a focus on the compounds isolated from marine invertebrates. The activities of these metabolites are illustrated and discussed. The paper aims to capture the relevant evidence of the great chemical diversity of marine natural products as a key tool that can advance understanding in the T2DM research field, as well as in antidiabetic drug discovery. The variety of chemical scaffolds highlighted by the natural hits provides not only a source of chemical probes for the study of specific targets involved in the onset of T2DM, but is also a helpful tool for the development of drugs that are capable of acting via novel mechanisms. Thus, it lays the foundation for the design of multiple ligands that can overcome the drawbacks of polypharmacology.

Role of myristoylation in modulating PCaP1 interaction with calmodulin

Plasma membrane-associated Cation-binding Protein 1 (PCaP1) belongs to the plant-unique DREPP protein family with largely unknown biological functions but ascertained roles in plant development and calcium (Ca2+) signaling. PCaP1 is anchored to the plasma membrane via N-myristoylation and a polybasic cluster, and its N-terminal region can bind Ca2+/calmodulin (CaM). However, the molecular determinants of PCaP1–Ca2+-CaM interaction and the functional impact of myristoylation in the complex formation and Ca2+ sensitivity of CaM remained to be elucidated. Herein, we investigated the direct interaction between Arabidopsis PCaP1 (AtPCaP1) and CaM1 (AtCaM1) using both myristoylated and non-myristoylated peptides corresponding to the N-terminal region of AtPCaP1. ITC analysis showed that AtCaM1 forms a high affinity 1:1 complex with AtPCaP1 peptides and the interaction is strictly Ca2+-dependent. Spectroscopic and kinetic Ca2+ binding studies showed that the myristoylated peptide dramatically increased the Ca2+-binding affinity of AtCaM1 and slowed the Ca2+ dissociation rates from both the C- and N-lobes, thus suggesting that the myristoylation modulates the mechanism of AtPCaP1 recognition by AtCaM1. Furthermore, NMR and CD spectroscopy revealed that the structure of both the N- and C-lobes of Ca2+-AtCaM1 changes markedly in the presence of the myristoylated AtPCaP1 peptide, which assumes a helical structure in the final complex. Overall, our results indicate that AtPCaP1 biological function is strictly related to the presence of multiple ligands, i.e., the myristoyl moiety, Ca2+ ions and AtCaM1 and only a full characterization of their equilibria will allow for a complete molecular understanding of the putative role of PCaP1 as signal protein.

Molecular design of multiple ligand metal–organic framework (ML-MOF) collectors for efficient flotation separation of minerals

Metal–organic framework (MOF) collectors formed by the coordination of lead ions and benzohydroxamic acid (Pb–BHA) are favorably selective for the flotation separation of calcium-containing minerals. However, the large dosage requirement and foam instability have hindered the industrial applications of MOF collectors. To enhance the collecting ability and hydrophobicity of the Pb–BHA structure, this paper introduces new ligands to form multiple ligand–MOF (ML–MOF) collectors. Through a molecular-design approach, the study analyzes the crystal and electronic structures of the target and gangue minerals, calculates the quantum chemical properties of the organic ligands, constructs the ML–MOF collectors, and determines the interaction strengths between the ML–MOF collectors and mineral surfaces to predict the flotation performances. Finally, the flotation performance of the newly developed collector is confirmed through a series of micro-flotation tests. Among the ML–MOF collectors constructed with four candidate ligands—octylhydroxamic acid (OHA), sodium dodecyl sulfate (SDS), oleic acid, and styrene phosphonic acid—Pb–BHA–SDS and Pb–BHA–OHA excellently and selectively absorbed scheelite, wolframite, and cassiterite in flotation. In addition, they form stable froths and can be applied at low dosage. The correctness of the design results was quantified in terms of their collecting-ability index and selectivity index obtained in a flotation test. The proposed design methodology realizes ML–MOF collectors for the flotation separation of complex multi-mineral systems.

The selective adsorption and flotation separation of spodumene from feldspar using a novel iron-group multiple ligand collector

Spodumene and feldspar have little difference in flotability due to their similar crystal chemistry properties. Fe-octyl hydroxamic acid (OHA) (iron complexes of octyl hydroxamic acid) demonstrates excellent selectivity but restricted collecting performance in spodumene flotation. In this work, we added sodium dodecyl sulfate (SDS) into Fe-OHA to obtain a novel multiple ligand collector, which was named Fe-OHA-SDS to enhance the collection ability of Fe-OHA. The efficient separation of spodumene from feldspar (the recovery difference was about 84 %) was achieved by Fe-OHA-SDS without adding depressants and foaming agents at pH 6.2. The separation mechanisms were explored by Zeta potential, contact angle, in-situ microcalorimetric, Fourier transform infrared spectroscopy (FTIR), and X-ray photoelectron spectroscopy (XPS) measurements. The findings revealed that Fe-OHA-SDS was more easily bonded to the spodumene surface than the feldspar surface. Meanwhile, the adsorption of Fe-OHA-SDS significantly expanded the hydrophobicity differences on these two mineral surfaces. The Fe-OHA-SDS was adsorbed on the spodumene surface through the Fe-O bond, which differed from the interaction mechanism of traditional mixed collectors on mineral surfaces. Therefore, Fe-OHA-SDS was an efficient collector with potential application value in spodumene flotation.

Multiple Ligand Simultaneous Docking of Antiviral Drugs and Cyanine Dyes with Proteins

Protein nanoparticles are currently regarded as promising biocompatible and biodegradable systems for targeted delivery of different types of pharmacological agents. Prior to fabricating such kind of drug nanocarriers it is reasonable to evaluate the drug-protein binding affinity and possible interaction modes using the computational tools, particularly, the molecular docking technique. The present study was undertaken to evaluate the possibility of creating the protein nanoparticles carrying the antiviral drugs and cyanine dyes as visualizing agents. The components of the examined systems included endogenous functional proteins cytochrome c, serum albumin, lysozyme and insulin, antiviral drugs favipiravir, molnupiravir, nirmatrelvir and ritonavir, mono- and heptamethinecyanine dyes. Using the multiple ligand simultaneous docking technique, it was demonstrated that: i) the drugs and the dyes occupy different binding sites on the protein molecule and do not interfere with each other; ii) the heptamethines AK7-5 and AK7-6 possess the highest affinity for the proteins; iii) among the examined systems the strongest complexes are formed between the heptamethine dyes and serum albumin. Taken together, the results obtained indicate that albumin-based nanoparticles functionalized by the heptamethine cyanine dyes can be used for targeted delivery of the explored antiviral agents.

Differences in amino acid composition of carrot α-tubulin potentially confer the resistance to dinitroaniline herbicides

Aim. To reveal the features of amino acid composition of carrot α-tubulin isotypes that potentially determine natural tolerance to dinitroaniline herbicides. Methods. Literature and database search. Comparison of protein sequences and structures: multiple sequence alignment, phylogenetic profiling, protein and ligand structure modeling, etc. Results. Genomic and proteomic analysis of Daucus carota has revealed at least eight unique isotypes of α-tubulin that differ in amino acid sequences and gene loci. Remarkable differences in amino acid composition of the dinitroanilinebinding-like (DBL) region of analyzed α-tubulin have been revealed, which may be the reason of its natural resistance to these compounds. Сonclusions. Differences in amino acids at positions of canonical mutations – Cys4 (TBA1, 2, 3, 6, 7 and 8), Thr53 (TBA6), Ile202 (TBA1 and 7) and Met202 (TBA5), as well as previously undescribed non-canonical substitutions – Ile4 (TBA4 and 5), Cys52 (TBA6), Ser201 (TBA1, 2, 3 and 8) and Val194 (TBA4 and 5), were noted as potentially associated with natural tolerance of the carrot to dinitroaniline herbicides.

Quantitative modeling of EGF receptor ligand discrimination via internalization proofreading.

The epidermal growth factor receptor (EGFR) is a central regulator of cell physiology that is stimulated by multiple distinct ligands. Although ligands bind to EGFR while the receptor is exposed on the plasma membrane, EGFR incorporation into endosomes following receptor internalization is an important aspect of EGFR signaling, with EGFR internalization behavior dependent upon the type of ligand bound. We develop quantitative modeling for EGFR recruitment to and internalization from clathrin domains, focusing on how internalization competes with ligand unbinding from EGFR. We develop two model versions: a kinetic model with EGFR behavior described as transitions between discrete states and a spatial model with EGFR diffusion to circular clathrin domains. We find that a combination of spatial and kinetic proofreading leads to enhanced EGFR internalization ratios in comparison to unbinding differences between ligand types. Various stages of the EGFR internalization process, including recruitment to and internalization from clathrin domains, modulate the internalization differences between receptors bound to different ligands. Our results indicate that following ligand binding, EGFR may encounter multiple clathrin domains before successful recruitment and internalization. The quantitative modeling we have developed describes competition between EGFR internalization and ligand unbinding and the resulting proofreading.

Mast cell silencing: A novel therapeutic approach for urticaria and other mast cell-mediated diseases.

Chronic urticaria (CU) is a mast cell (MC)-dependent disease with limited therapeutic options. Current management strategies are directed at inhibiting IgE-mediated activation of MCs and antagonizing effects of released mediators. Due to the complexity and heterogeneity of CU and other MC diseases and mechanisms of MC activation-including multiple activating receptors and ligands, diverse signaling pathways, and a menagerie of mediators-strategies of MC depletion or MC silencing (i.e., inhibition of MC activation via binding of inhibitory receptors) have been developed to overcome limitations of singularly targeted agents. MC silencers, such as agonist monoclonal antibodies that engage inhibitory receptors (e.g., sialic acid-binding immunoglobulin-like lectin8 -[Siglec-8] [lirentelimab/AK002], Siglec-6 [AK006], and CD200R [LY3454738]), have reached preclinical and clinical stages of development. In this review, we (1) describe the role of MCs in the pathogenesis of CU, highlighting similarities with other MC diseases in disease mechanisms and response to treatment; (2) explore current therapeutic strategies, categorized by nonspecific immunosuppression, targeted inhibition of MC activation or mediators, and targeted modulation of MC activity; and (3) introduce the concept of MC silencing as an emerging strategy that could selectively block activation of MCs without eliciting or exacerbating on- or off-target, immunosuppressive adverse effects.

Quadruple‐Bidentate Nitrate‐Ligated A2Hg(NO3)4 (A=K, Rb): Strong Second‐Harmonic Generation and Sufficient Birefringence

AbstractThe design of efficient nonlinear optical (NLO) crystals continues to pose significant challenges due to the difficulty of assembling polar NLO‐active modules in an optimal additive fashion. We report herein the first NLO‐active mercuric nitrates A2Hg(NO3)4 (A=(KHNO), Rb (RHNO)), for which assembly is induced by ionic polarization of the d10 cations. The two new crystalline compounds are isostructural, featuring interesting pseudo‐diamond‐like structures with parallel [Hg(NO3)4] modules, and leading to strong powder second‐harmonic generation (SHG) responses of 9.2 (KHNO) and 8.8 (RHNO) times that of KH2PO4. In combination with the simple solution preparation of centimeter‐scale crystals, sufficient birefringence, and short ultraviolet (UV) cutoff edges, these attributes make KHNO and RHNO promising candidates for UV NLO materials. Theoretical calculations and single‐crystal structure analysis reveal that the newly‐developed highly condensed and distorted [Hg(NO3)4] module, with an Hg2+ cation that is quadruply bidentate nitrate‐ligated, is crucial for the significant SHG responses. This work highlights the potential importance of modules with multiple bidentate ligands for the development of high‐performing next‐generation NLO materials.

Quadruple-Bidentate Nitrate-Ligated A2 Hg(NO3 )4 (A=K, Rb): Strong Second-Harmonic Generation and Sufficient Birefringence.

The design of efficient nonlinear optical (NLO) crystals continues to pose significant challenges due to the difficulty of assembling polar NLO-active modules in an optimal additive fashion. We report herein the first NLO-active mercuric nitrates A2 Hg(NO3 )4 (A=(KHNO), Rb (RHNO)), for which assembly is induced by ionic polarization of the d10 cations. The two new crystalline compounds are isostructural, featuring interesting pseudo-diamond-like structures with parallel [Hg(NO3 )4 ] modules, and leading to strong powder second-harmonic generation (SHG) responses of 9.2 (KHNO) and 8.8 (RHNO) times that of KH2 PO4 . In combination with the simple solution preparation of centimeter-scale crystals, sufficient birefringence, and short ultraviolet (UV) cutoff edges, these attributes make KHNO and RHNO promising candidates for UV NLO materials. Theoretical calculations and single-crystal structure analysis reveal that the newly-developed highly condensed and distorted [Hg(NO3 )4 ] module, with an Hg2+ cation that is quadruply bidentate nitrate-ligated, is crucial for the significant SHG responses. This work highlights the potential importance of modules with multiple bidentate ligands for the development of high-performing next-generation NLO materials.