Search

Notable thermal shifts in diselenides have been documented in 77Se NMR for more than 50 years, but no satisfactory explanation has been found. Here, five hypotheses are considered as possible explanations for the large temperature dependence of the 77Se chemical shifts of diaryl and dialkyl diselenides compared to monoselenides and selenols. Density functional theory calculations are provided to bolster hypotheses and better understand the effects of barrier height and dipole energies. It is proposed that the temperature dependence of diselenide 77Se NMR chemical shifts is due to rotation around the Se–Se bond and sampling of twisted conformers at higher temperatures. The molecular twisting is solvent dependent; here, DMSO-d6and toluene-d8were evaluated. No correlation was established between para-substituents on diaryl diselenides and the magnitude of the change in the 77Se NMR shift (Δδ) with temperature.

I INTRODUCTION The U.S. federal government runs a $10.2 trillion lending portfolio. (1) That is a very large portfolio. How large? Well, it is slightly larger than the entire U.S. [...]

Palladium complexes are emerging as potential antitumor compounds. Recent experimental evidence suggests that the mechanism of action of some organopalladium derivatives might involve the target of proteins such as Thioredoxin Reductase (TrxR). In this work, we investigate different possible chemical mechanisms of interaction between selected palladium(II)-η3-allyl complexes and thiolates or selenolates, which are key functional groups present in the catalytic pocket of TrxR. Our investigation, focusing on both anionic and cationic complexes, suggests that in all cases, the interaction between the organopalladium species and chalcogenolates occurs via a ligand exchange reaction, which leads to the formation of a new Pd–S or Pd–Se bond. Allyl substitution, which takes place with the formation of a new C–S or C–Se bond, always appears to be the least favored reaction, from both the kinetic and thermodynamic points of view.

A series of macrocyclic ligands were considered for the chelation of Pb2+: 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), 1,7-bis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane-4,10-diacetic acid (DO2A2S), 1,5,9-tris[2-(methylsulfanyl)ethyl]-1,5,9-triazacyclododecane (TACD3S), 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetrazacyclotridecane (TRI4S), and 1,4,8,11-tetrakis[2-(methylsulfanyl)ethyl]-1,4,8,11-tetrazacyclotetradecane (TE4S). The equilibrium, the acid-mediated dissociation kinetics, and the structural properties of the Pb2+complexes formed by these chelators were examined by UV–Visible and nuclear magnetic resonance (NMR) spectroscopies, combined with potentiometry and density functional theory (DFT) calculations. The obtained results indicated that DO4S, DO3S, DO3SAm, and DO2A2S were able to efficiently chelate Pb2+and that the most suitable macrocyclic scaffold for Pb2+is 1,4,7,10-tetrazacyclododecane. NMR spectroscopy gave insights into the solution structures of the Pb2+complexes, and 1H–207Pb interactions confirmed the involvement of S and/or O donors in the metal coordination sphere. Highly fluxional solution behavior was discovered when Pb2+was coordinated to symmetric ligands (i.e., DO4S and DO2A2S) while the introduction of structural asymmetry in DO3S and DO3SAm slowed down the intramolecular dynamics. The ligand ability to chelate [203Pb]Pb2+under highly dilute reaction conditions was explored through radiolabeling experiments. While DO4S and DO3S possessed modest performance, DO3SAm and DO2A2S demonstrated high complexation efficiency under mild reaction conditions (pH = 7, 5 min reaction time). The [203Pb]Pb2+complexes’ integrity in human serum over 24 h was appreciably good for [203Pb][Pb(DO4S)]2+(80 ± 5%) and excellent for [203Pb][Pb(DO3SAm)]2+(93 ± 1%) and [203Pb][Pb(DO2A2S)] (94 ± 1%). These results reveal the promise of DO2A2S and DO3SAm as chelators in cutting-edge theranostic [203/212Pb]Pb2+radiopharmaceuticals.

The contribution of deubiquitylating enzymes (DUBs) to β-Catenin stabilization in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, and by using an unbiassed screen, we discovered that the DUB USP10 stabilizes β-Catenin specifically in APC-truncated CRC in vitro and in vivo. Mechanistic studies, including in vitro binding together with computational modelling, revealed that USP10 binding to β-Catenin is mediated via the unstructured N-terminus of USP10 and is outcompeted by intact APC, favouring β-catenin degradation. However, in APC-truncated cancer cells USP10 binds to β-catenin, increasing its stability which is critical for maintaining an undifferentiated tumour identity. Elimination of USP10 reduces the expression of WNT and stem cell signatures and induces the expression of differentiation genes. Remarkably, silencing of USP10 in murine and patient-derived CRC organoids established that it is essential for NOTUM signalling and the APC super competitor-phenotype, reducing tumorigenic properties of APC-truncated CRC. These findings are clinically relevant as patient-derived organoids are highly dependent on USP10, and abundance of USP10 correlates with poorer prognosis of CRC patients. Our findings reveal, therefore, a role for USP10 in CRC cell identity, stemness, and tumorigenic growth by stabilising β-Catenin, leading to aberrant WNT signalling and degradation resistant tumours. Thus, USP10 emerges as a unique therapeutic target in APCtruncated CRC.

The execution of deep neural network (DNN) algorithms suffers from significant bottlenecks due to the separation of the processing and memory units in traditional computer systems. Emerging memristive computing systems introduce an in situ approach that overcomes this bottleneck. The nonvolatility of memristive devices, however, may expose the DNN weights stored in memristive crossbars to potential theft attacks. Therefore, this article proposes a 2-D permutation-based protection (TDPP) method that thwarts such attacks. We first introduce the underlying concept that motivates the TDPP method: permuting both the rows and columns of the DNN weight matrices. This contrasts with previous methods, which focused solely on permuting a single dimension of the weight matrices, either the rows or columns. While it is possible for an adversary to access the matrix values, the original arrangement of rows and columns in the matrices remains concealed. As a result, the extracted DNN model from the accessed matrix values would fail to operate correctly. We consider two different memristive computing systems (designed for layer-by-layer and layer-parallel processing, respectively), and demonstrate the design of the TDPP method that could be embedded into the two systems. Finally, we present a security analysis. Our experiments demonstrate that TDPP can achieve comparable effectiveness to prior approaches, with a high level of security when appropriately parameterized. In addition, TDPP is more scalable than previous methods and results in reduced area and power overheads. The area and power are reduced by, respectively, $1218\times $ and $2815\times $ for the layer-by-layer system and by $178\times $ and $203\times $ for the layer-parallel system compared to prior works.

This article proposes an innovative method to retrieve the complex permittivities of the two faces composing dihedral structures. We use the HH and VV radar signals backscattered by a dihedral arrangement at two incidence angles to form two co-pol ratios. As the permittivity of a material does not depend on the incidence angle, we have two independent values. In addition, physical constraints on this permittivity (real part superior to 1, imaginary part negative or null) allow us to solve a polynomial equation derived from the Fresnel reflection coefficients. As we consider co-pol ratios, we alleviate the requirements for calibration for the intensity and the phase of the radar returns. Furthermore, we no longer need an a priori on the dimensions of the dihedral structure under observation. We tested this method experimentally, first in an anechoic chamber and then in real conditions. The results are promising.

Silver-111 is an attractive unconventional candidate for targeted cancer therapy as well as for single photon emission computed tomography and can be complemented by silver-103 for positron emission tomography noninvasive diagnostic procedures. However, the shortage of chelating agents capable of forming stable complexes tethered to tumor-seeking vectors has hindered their in vivoapplication so far. In this study, a comparative investigation of a series of sulfur-containing structural homologues, namely, 1,4,7-tris[2-(methylsulfanyl)ethyl)]-1,4,7-triazacyclononane (NO3S), 1,5,9-tris[2-(methylsulfanyl)ethyl]-1,5,9-triazacyclododecane (TACD3S), 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclotridecane (TRI4S), and 1,4,8,11-tetrakis[2-(methylsulfanyl)ethyl]-1,4,8,11-tetraazacyclotetradecane (TE4S) was conducted to appraise the influence of different polyazamacrocyclic backbones on Ag+complexation. The performances of these macrocycles were also compared with those of the previously reported Ag+/[111Ag]Ag+-chelator 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S). Nuclear magnetic resonance data supported by density functional theory calculations and X-ray crystallographic results gave insights into the coordination environment of these complexes, suggesting that all of the donor atoms are generally involved in the metal coordination. However, the modifications of the macrocycle topology alter the dynamic binding of the pendant arms or the conformation of the ring around the metal center. Combined pH/pAg-potentiometric and spectroscopic experiments revealed that the 12-member N4backbone of DO4S forms the most stable Ag+complex while both the enlargement and the shrinkage of the macrocyclic frame dwindle the stability of the complexes. Radiolabeling experiments, conducted with reactor-produced [111Ag]Ag+, evidenced that the thermodynamic stability trend is reflected in the ligand’s ability to incorporate the radioactive ion at high molar activity, even in the presence of a competing cation (Pd2+), as well as in the integrity of the corresponding complexes in human serum. As a consequence, DO4S proved to be the most favorable candidate for future in vivoapplications.

AbstractAcid Sphingomyelinase (ASM) is a human phosphodiesterase that catalyzes the metabolism of sphingomyelin (SM) to ceramide and phosphocholine. ASM is involved in the plasma membrane cell repair and is associated with the lysosomal inner lipid membrane by nonbonding interactions. The disruption of those interaction would result in ASM release into the lysosomal lumen and consequent degradation of its structure. Furthermore, SARS-CoV-2 infection has been linked with ASM activation and with a ceramide domain formation in the outer leaflet of the plasma membrane that is thought to be crucial for the viral particles recognition by the host cells. In this study, we have explored in silicothe behavior of fluoxetine and related drugs as potential inhibitors of ASM. Theoretically, these drugs would be able to overpass lysosomal membrane and reach the interactions that sustain ASM structure, breaking them and inhibiting the ASM. The analyses of docking data indicated that fluoxetine allocated mainly in the N-terminal saposin domain via nonbonding interactions, mostly of hydrophobic nature. Similar results were obtained for venlafaxine, citalopram, atomoxetine, nisoxetine and fluoxetine’s main metabolite norfluoxetine. In conclusion, it was observed that the saposin allocation may be a good indicative of the drugs inhibition mechanism, once this domain is responsible for the binding of ASM to lysosomal membrane and some of those drugs have previously been reported to inhibit the phosphodiesterase by releasing its structure in the lysosomal lumen. Our MD data also provides some insight about natural ligand C18 sphingomyelin conformations on saposin.Communicated by Ramaswamy H. Sarma

PhSeZnCl, which is also known as Santi’s reagent, can catalyze the reduction of hydrogen peroxide by thiols with a GPx-like mechanism. In this work, the first step of this catalytic cycle, i.e., the reduction of H2O2by PhSeZnCl, is investigated in silicousing state-of-the-art density functional theory calculations. Then, the role of the metal is evaluated by replacing Zn with its group 12 siblings (Cd and Hg). The thermodynamic and kinetic factors favoring Zn are elucidated. Furthermore, the role of the halogen is considered by replacing Cl with Br in all three metal compounds, and this turns out to be negligible. Finally, the overall GPx-like mechanism of PhSeZnCl and PhSeZnBr is discussed by evaluating the energetics of the mechanistic path leading to the disulfide product.

The article titled "CHOSES CASSÉES" discusses the author's feelings of despair and disappointment in the world. The author reflects on the destruction and conflict that exists, both externally and within their relationship. They express a desire for peace and a return to a normal life, where they can find solace in the memories of their past. The article conveys a sense of longing and a plea for their loved one not to abandon them in their current state of turmoil. [Extracted from the article]

Deoxyribonucleic acid (DNA) sequence classification is a fundamental task in computational biology with vast implications for applications such as disease prevention and drug design. Therefore, fast high-quality sequence classifiers are significantly important. This article introduces ClaPIM, a scalable DNA sequence classification architecture based on the emerging concept of hybrid in-crossbar and near-crossbar memristive processing-in-memory (PIM). We enable efficient and high-quality classification by uniting the filter and search stages within a single algorithm. Specifically, we propose a custom filtering technique that drastically narrows the search space and a search approach that facilitates approximate string matching through a distance function. ClaPIM is the first PIM architecture for scalable approximate string matching that benefits from the high density of memristive crossbar arrays and the massive computational parallelism of PIM. Compared with Kraken2, a state-of-the-art software classifier, ClaPIM provides significantly higher classification quality (up to $20 \times $ improvement in F1 score) and also demonstrates a $1.8 \times $ throughput improvement. Compared with edit distance tolerant approximate matching (EDAM), a recently proposed static random-access memory (SRAM)-based accelerator that is restricted to small datasets, we observe both a $30.4 \times $ improvement in normalized throughput per area and a 7% increase in classification precision.

Artificial Intelligence (AI) is becoming increasingly prevalent in our daily lives. Although AI systems bring many benefits, several legal and regulatory challenges remain as well. A field that has already attracted much attention is extra-contractual and product liability for damage involving AI systems. Accidents involving self-driving vehicles or surgical robots surely are a reason why tort and product liability are increasingly being discussed. Another reason relates to the intrinsic characteristics of AI such as opaqueness, autonomy, connectivity, data dependency or self-learning abilities, which make it difficult to trace back potentially problematic decisions made with the involvement of such systems. The attention for this academic field will only increase following the recent proposal by the European Commission (EC) regarding new liability rules for AI. Instead of focusing on one specific element, giving a rather general overview of the impact of AI on tort law or discussing the new rules, this article will take a more conceptual perspective and show that each policy decision regarding tort liability for damage involving AI actually entails several additional choices to be made. We will illustrate this with two use cases, namely the allocation of the burden of proof in an AI-context on the one hand and the adoption of strict liability regimes on the other hand. This starting point is important as normative recommendations and proposals risk to be one-layered and, consequently, too 'simple' or not realistic to directly implement. Our research emphasizes the 'multi-faceted' reality of any proposal regarding the adoption of a new liability regime or modification to existing rules. [ABSTRACT FROM AUTHOR]

'So,' he said, as he was walking me into his new study, 'you're the journalist?' His tone was so unimpressed, that I didn't even bother to challenge him. Actually, this [...]

The SARS-CoV-2 pandemic has prompted global efforts to develop therapeutics. The main protease of SARS-CoV-2 (Mpro) and the papain-like protease (PLpro) are essential for viral replication and are key targets for therapeutic development. In this work, we investigate the mechanisms of SARS-CoV-2 inhibition by diphenyl diselenide (PhSe)2which is an archetypal model of diselenides and a renowned potential therapeutic agent. The in vitroinhibitory concentration of (PhSe)2against SARS-CoV-2 in Vero E6 cells falls in the low micromolar range. Molecular dynamics (MD) simulations and density functional theory (DFT) calculations [level of theory: SMD-B3LYP-D3(BJ)/6-311G(d,p), cc-pVTZ] are used to inspect non-covalent inhibition modes of both proteases via π-stacking and the mechanism of covalent (PhSe)2+ Mproproduct formation involving the catalytic residue C145, respectively. The in vitroCC50(24.61 μM) and EC50(2.39 μM) data indicate that (PhSe)2is a good inhibitor of the SARS-CoV-2 virus replication in a cell culture model. The in silicofindings indicate potential mechanisms of proteases’ inhibition by (PhSe)2; in particular, the results of the covalent inhibition here discussed for Mpro, whose thermodynamics is approximatively isoergonic, prompt further investigation in the design of antiviral organodiselenides.

Binary compositions of surface ligands are known to improve the colloidal stability and fluorescence quantum yield of nanocrystals (NCs), due to ligand–ligand interactions and surface organization. Herein, we follow the thermodynamics of a ligand exchange reaction of CdSe NCs with alkylthiol mixtures. The effects of ligand polarity and length difference on ligand packing were investigated using isothermal titration calorimetry (ITC). The thermodynamic signature of the formation of mixed ligand shells was observed. Correlating the experimental results with thermodynamic mixing models has allowed us to calculate the interchain interactions and to infer the final ligand shell configuration. Our findings demonstrate that, in contrast to macroscopic surfaces, the small dimensions of the NCs and the subsequent increased interfacial region between dissimilar ligands allow the formation of a myriad of clustering patterns, controlled by the interligand interactions. This work provides a fundamental understanding of the parameters determining the ligand shell structure and should help guide smart surface design toward NC-based applications.

Mitochondria are critical to the governance of metabolism and bioenergetics in cancer cells1. The mitochondria form highly organized networks, in which their outer and inner membrane structures define their bioenergetic capacity2,3. However, in vivo studies delineating the relationship between the structural organization of mitochondrial networks and their bioenergetic activity have been limited. Here we present an in vivo structural and functional analysis of mitochondrial networks and bioenergetic phenotypes in non-small cell lung cancer (NSCLC) using an integrated platform consisting of positron emission tomography imaging, respirometry and three-dimensional scanning block-face electron microscopy. The diverse bioenergetic phenotypes and metabolic dependencies we identified in NSCLC tumours align with distinct structural organization of mitochondrial networks present. Further, we discovered that mitochondrial networks are organized into distinct compartments within tumour cells. In tumours with high rates of oxidative phosphorylation (OXPHOSHI) and fatty acid oxidation, we identified peri-droplet mitochondrial networks wherein mitochondria contact and surround lipid droplets. By contrast, we discovered that in tumours with low rates of OXPHOS (OXPHOSLO), high glucose flux regulated perinuclear localization of mitochondria, structural remodelling of cristae and mitochondrial respiratory capacity. Our findings suggest that in NSCLC, mitochondrial networks are compartmentalized into distinct subpopulations that govern the bioenergetic capacity of tumours.

Despite its narrow therapeutic index and the toxicity issues related to renal injuries, lithium is still a first-line choice for the treatment of mania and for preventing recurrences in bipolar disorder. Nevertheless, side effects and limited efficacy in some of the cases push the search for novel tools to ameliorate these conditions, which still represent a social burden, and great efforts are being made toward the identification of alternative therapeutic options. In this context, rational drug design, drug repurposing, and computer-aided drug discovery represent time-saving and efficient strategies to pursue this goal. Inositol monophosphatase (IMPase) represents the molecular target of lithium which acts as an uncompetitive inhibitor. In this context, a screening on NIH Clinical Collection of drug-like compounds highlighted the polypharmacological drug ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) as a non-competitive, irreversible IMPase inhibitor, suggesting that this molecule could represent a valid therapeutic alternative. In this perspective article, we aim at providing a historical overview of the uses of ebselen with particular attention to its potential use as lithium-mimetic. We critically analyse this aspect by investigating in silico the molecular mechanism leading to the formation of the Se-S bond between IMPase Cys141 and ebselen. Evidence of the bond formation is supported by the crystallographic data Fenn et al. We hypothesize that the IMPase-ebselen complex promotes the association with other IMPase chains, improving the formation of the tetramer adduct, suggesting that ebselen may stabilize the human IMPase in a form that could be less active, resulting in a decreased enzymatic activity.

Tell us what you think! Click here to take Tablet's reader survey. I was raised and educated in the Givat Gonen School, founded on 'the spirit of the Labor Party.' [...]

ABSTRACTMaturation of the HIV-1 viral particles shortly after budding is required for infectivity. During this process, the Pr55Gagprecursor undergoes a cascade of proteolytic cleavages, and whilst the structural rearrangements of the viral proteins are well understood, the concomitant maturation of the genomic RNA (gRNA) structure is unexplored, despite evidence that it is required for infectivity. To get insight into this process, we systematically analysed the interactions between Pr55Gagor its maturation products (NCp15, NCp9 and NCp7) and the 5ʹ gRNA region and their structural consequences, in vitro. We show that Pr55Gagand its maturation products mostly bind at different RNA sites and with different contributions of their two zinc knuckle domains. Importantly, these proteins have different transient and permanent effects on the RNA structure, the late NCp9 and NCp7 inducing dramatic structural rearrangements. Altogether, our results reveal the distinct contributions of the different Pr55Gagmaturation products on the gRNA structural maturation.

OBJECTIVE--The role of uncoupling protein 2 (UCP2) in pancreatic β-cells is highly debated, partly because of the broad tissue distribution of UCP2 and thus limitations of whole-body UCP2 knockout mouse models. To investigate the function of UCP2 in the β-cell, β-cell-specific UCP2 knockout mice (UCP2BKO) were generated and characterized. RESEARCH DESIGN AND METHODS--UCP2BKO mice were generated by crossing loxUCP2 mice with mice expressing rat insulin promoter-driven Cre recombinase. Several in vitro and in vivo parameters were measured, including respiration rate, mitochondrial membrane potential, islet ATP content, reactive oxygen species (ROS) levels, glucose-stimulated insulin secretion (GSIS), glucagon secretion, glucose and insulin tolerance, and plasma hormone levels. RESULTS--UCP2BKO β-cells displayed mildly increased glucose-induced mitochondrial membrane hyperpolarization but unchanged rates of uncoupled respiration and islet ATP content. UCP2BKO islets had elevated intracellular ROS levels that associated with enhanced GSIS. Surprisingly, UCP2BKO mice were glucose-intolerant, showing greater α-cell area, higher islet glucagon content, and aberrant ROS-dependent glucagon secretion under high glucose conditions. CONCLUSIONS--Using a novel β-cell-specific UCP2KO mouse model, we have shed light on UCP2 function in primary β-cells. UCP2 does not behave as a classical metabolic uncoupler in the β-cell, but has a more prominent role in the regulation of intracellular ROS levels that contribute to GSIS amplification. In addition, β-cell UCP2 contributes to the regulation of intraislet ROS signals that mediate changes in α-cell morphology and glucagon secretion. Diabetes 60:2710-2719, 2011, Uncoupling protein 2 (UCP2) was discovered based on sequence homology to UCP1 (1), a well-studied UCP involved in thermogenesis. UCP1 induces a strong proton leak in the inner mitochondrial membrane, [...]

Mitochondria mediate β-cell responses to extracellular glucose by generating ATP and initiating a cascade of events culminating in the release of insulin. It is not surprising that β-cell mitochondria have [...], OBJECTIVE--Previous studies have reported that β-cell mitochondria exist as discrete organelles that exhibit heterogeneous bioenergetic capacity. To date, networking activity, and its role in mediating β-cell mitochondrial morphology and function, remains unclear. In this article, we investigate β-cell mitochondrial fusion and fission in detail and report alterations in response to various combinations of nutrients. RESEARCH DESIGN AND METHODS--Using matrix-targeted photoactivatable green fluorescent protein, mitochondria were tagged and tracked in β-cells within intact islets, as isolated cells and as cell lines, revealing frequent fusion and fission events. Manipulations of key mitochondrial dynamics proteins OPA1, DRP1, and Fis1 were tested for their role in β-cell mitochondrial morphology. The combined effects of free fatty acid and glucose on β-cell survival, function, and mitochondrial morphology were explored with relation to alterations in fusion and fission capacity. RESULTS--β-Cell mitochondria are constantly involved in fusion and fission activity that underlies the overall morphology of the organelle. We find that networking activity among mitochondria is capable of distributing a localized green fluorescent protein signal throughout an isolated β-cell, a β-cell within an islet, and an INS1 cell. Under noxious conditions, we find that β-cell mitochondria become fragmented and lose their ability to undergo fusion. Interestingly, manipulations that shift the dynamic balance to favor fusion are able to prevent mitochondrial fragmentation, maintain mitochondrial dynamics, and prevent apoptosis. CONCLUSIONS--These data suggest that alterations in mitochondrial fusion and fission play a critical role in nutrient-induced β-cell apoptosis and may be involved in the pathophysiology of type 2 diabetes.

The selenoxide elimination is a well-known reaction in organochalcogen chemistry, with wide synthetic, biological, and toxicological implications. In this work, we apply benchmarked density functional theory (DFT) calculations to investigate different aspects of the title reaction in three (bio)chemically relevant models, spanning minimal systems of theoretical interests as well as biological or synthetic organochalcogenides. The activation strain analysis (ASA) methodology is employed along a suitable reaction coordinate to obtain insight into the role of the chalcogen and of the oxidation state, to pinpoint the factors that tune the elimination reactivity of the investigated systems. Lastly, we computationally validate the hypothesis that telluroxides eliminate more slowly than selenoxides because of a detrimental hydration process that leads to unreactive hydrates.

Although much attention has been paid to chemical elucidation of the catalytic cycle of glutathione peroxidase (GPx), it has been hampered by instability of selenocysteine selenenic acid (Sec–SeOH) intermediates. In this study, not only chemical processes of the canonical catalytic cycle but also those involved in the bypass mechanism, including the intramolecular cyclization of a Sec–SeOH to the corresponding five-membered ring selenenyl amide were demonstrated experimentally by utilizing selenopeptide model systems in which reactive intermediates can be stabilized by a nano-sized molecular cradle. The resulting cyclic selenenyl amide exhibited higher durability under oxidative conditions than in the state of a Sec–SeOH, corroborating its role as the protective form of GPx. The cyclization of Sec–SeOHs of the Sec-Gly-Thr and Sec-Gly-Lys models, which mimic the catalytic site of isozymes GPx1 and GPx4, respectively, was found to proceed at lower temperature than in the Sec-Gly-Gly model, which corresponds to the generalized form of the tripeptides in the catalytic site of GPx. The role of the hydrogen-bond accepting moieties in the cyclization process was elucidated by DFT calculation. It was indicated that, if the selenocysteine centers are incorporated in appropriate microenvironments, the bypass mechanism can function efficiently.The protective bypass mechanism in the catalytic cycle of glutathione peroxidase (GPx), i.e., the cyclization of selenocysteine selenenic acids (Sec–SeOHs) to the corresponding cyclic selenenyl amides, was investigated using NMR-observable Sec–SeOHs modeling the tripeptides in the active site of GPx. Depending on the neighboring amino acid residue, the cyclization was found to proceed efficiently.

OBJECTIVE--β-Cell response to glucose is characterized by mitochondrial membrane potential (ΔΨ) hyperpolarization and the production of metabolites that serve as insulin secretory signals. We have previously shown that glucose-induced mitochondrial hyperpolarization accompanies the concentration-dependent increase in insulin secretion within a wide range of glucose concentrations. This observation represents the integrated response of a large number of mitochondria within each individual cell. However, it is currently unclear whether all mitochondria within a single β-cell represent a metabolically homogenous population and whether fuel or other stimuli can recruit or silence sizable subpopulations of mitochondria. This study offers insight into the different metabolic states of β-cell mitochondria. RESULTS--We show that mitochondria display a wide heterogeneity in ΔΨ and a millivolt range that is considerably larger than the change in millivolts induced by fuel challenge. Increasing glucose concentration recruits mitochondria into higher levels of homogeneity, while an in vitro diabetes model results in increased ΔΨ heterogeneity. Exploration of the mechanism behind heterogeneity revealed that temporary changes in ΔΨ of individual mitochondria, ATP-hydrolyzing mitochondria, and uncoupling protein 2 are not significant contributors to ΔΨ heterogeneity. We identified BAD, a proapoptotic BCL-2 family member previously implicated in mitochondrial recruitment of glucoldnase, as a significant factor influencing the level of heterogeneity. CONCLUSIONS--We suggest that mitochondrial ΔΨ heterogeneity in β-cells reflects a metabolic reservoir recruited by an increased level of fuels and therefore may serve as a therapeutic target. Diabetes 56:2569-2578, 2007, Mitochondria play essential roles in pancreatic β-cell function and dysfunction (1,2). They generate secretagogues for insulin secretion and produce factors that function to induce and propagate apoptosis. Essential to these [...]

The soft lattice of lead-halide perovskite nanocrystals (NCs) allows tuning their optoelectronic characteristics via anion exchange by introducing halide salts to a solution of perovskite NCs. Similarly, cross-anion exchange can occur upon mixing NCs of different perovskite halides. This process, though, is detrimental for applications requiring perovskite NCs with different halides in close proximity. We study the effects of various stabilizing surface ligands on the kinetics of the cross-anion exchange reaction, comparing zwitterionic and ionic ligands. The kinetic analysis, inspired by the “cage effect” for solution reactions, showcases a mechanism where the surface capping ligands act as anion carriers that diffuse to the NC surface, forming an encounter pair enclosed by the surrounding ligands that initiates the anion exchange process. The zwitterionic ligands considerably slow down the cross-anion exchange process, and while they do not fully inhibit it, they confer improved stability alongside enhanced solubility relevant for various applications.

Literature supporting the use of point‐of‐care ultrasound (POCUS) for both identification and aspiration of effusions in large joints in the pediatric emergency department (PED) is sparse. We collected a case series of five patients who presented to the PED from August 2020 to December 2020 with an effusion in the hip, shoulder, knee, or elbow identified and aspirated under POCUS performed by pediatric emergency medicine (PEM) physicians. POCUS confirms effusion location and size and visualization of a completely evacuated effusion. POCUS can also guide the decision to start antibiotics earlier in the course of illness, can prevent unnecessary transfers for formal sonographic imaging or for potentially unnecessary radiographic imaging. This series supports the role of a PEM physician and POCUS guidance in the identification and aspiration of large‐joint effusions.

Surface ligands of semiconductor nanocrystals (NCs) play key roles in determining their colloidal stability and physicochemical properties and are thus enablers also for the NCs flexible manipulation toward numerous applications. Attention is usually paid to the ligand binding group, while the impact of the ligand chain backbone structure is less discussed. Using isothermal titration calorimetry (ITC), we studied the effect of structural changes in the ligand chain on the thermodynamics of the exchange reaction for oleate coated CdSe NCs, comparing linear and branched alkylthiols. The investigated alkylthiol ligands differed in their backbone length, branching position, and branching group length. Compared to linear ligands, lower exothermicity and entropy loss were observed for an exchange with branched ligands, due to steric hindrance in ligand packing, thereby justifying their previous classification as “entropic ligands”. Mean-field calculations for ligand binding demonstrate the contribution to the overall entropy originating from ligand conformational entropy, which is diminished upon binding mainly by packing of NC-bound ligands. Model calculations and the experimental ITC data both point to an interplay between the branching position and the backbone length in determining the entropic nature of the branched ligand. Our findings suggest that the most entropic ligand should be a short, branched ligand with short branching group located toward the middle of the ligand chain. The insights provided by this work also contribute to a future smarter NC surface design, which is an essential tool for their implementation in diverse applications.

Low-molecular-mass selenium (LMM-Se) molecules, such as ebselen and diphenyldiselenide, have many biological and potential therapeutic activities; however, little is known about their mechanism of action. It has been stipulated that LMM-Se can modify the physiological chemistry of endogenous thiol (–SH) and selenol (–SeH) groups by different mechanisms. Generically, LMM-Se compounds are poor mimetics of glutathione peroxidase (GPx) enzyme, suggesting that their thiol-modifier effect is more reasonable to justify their biological action. Unfortunately, the LMM-Se interactions with their targets are relatively non-specific. Here, the action of LMM-Se as potential therapeutic agents will be discussed, as well as the bottleneck and myths about their potential use as therapeutic agents.

Sunk in my bath, much depressed under the water, I was thinking, as always, of the great masters. As an artist of very small caliber I was constantly obsessing on [...]

ABSTRACTAn oral antiviral against SARS-CoV-2 that also attenuates inflammatory instigators of severe COVID-19 is not available to date. Herein, we show that the apoA-I mimetic peptide 4 F inhibits Spike mediated viral entry and has antiviral activity against SARS-CoV-2 in human lung epithelial Calu3 and Vero-E6 cells. In SARS-CoV-2 infected Calu3 cells, 4 F upregulated inducers of the interferon pathway such as MX-1 and Heme oxygenase 1 (HO-1) and downregulated mitochondrial reactive oxygen species (mito-ROS) and CD147, a host protein that mediates viral entry. 4 F also reduced associated cellular apoptosis and secretion of IL-6 in both SARS-CoV-2 infected Vero-E6 and Calu3 cells. Thus, 4 F attenuates in vitroSARS-CoV-2 replication, associated apoptosis in epithelial cells and secretion of IL-6, a major cytokine related to COVID-19 morbidity. Given established safety of 4 F in humans, clinical studies are warranted to establish 4 F as therapy for COVID-19.

Gallium 68 prostate-specific membrane antigen PET/MRI improved specificity for clinically significant prostate cancer, with a similar sensitivity to multiparametric MRI.

The human eye can distinguish as many as 10,000 different colours but is far less sensitive to variations in intensity1, meaning that colour is highly desirable when interpreting images. However, most biological samples are essentially transparent, and nearly invisible when viewed using a standard optical microscope2. It is therefore highly desirable to be able to produce coloured images without needing to add any stains or dyes, which can alter the sample properties. Here we demonstrate that colorimetric histology images can be generated using full-sized plasmonically active microscope slides. These slides translate subtle changes in the dielectric constant into striking colour contrast when samples are placed upon them. We demonstrate the biomedical potential of this technique, which we term histoplasmonics, by distinguishing neoplastic cells from normal breast epithelium during the earliest stages of tumorigenesis in the mouse MMTV-PyMT mammary tumour model. We then apply this method to human diagnostic tissue and validate its utility in distinguishing normal epithelium, usual ductal hyperplasia, and early-stage breast cancer (ductal carcinoma in situ). The colorimetric output of the image pixels is compared to conventional histopathology. The results we report here support the hypothesis that histoplasmonics can be used as a novel alternative or adjunct to general staining. The widespread availability of this technique and its incorporation into standard laboratory workflows may prove transformative for applications extending well beyond tissue diagnostics. This work also highlights opportunities for improvements to digital pathology that have yet to be explored.

In a way, the next war is always the previous war. The image of war is of assault and conquest of vast terrain. But in fact, war is always characterized [...]

So, we were walking down Rothschild Boulevard, hand in hand: she, 10 years old, and me, 38. Both divorced. In her case, involuntarily, and perhaps in mine as well. Naturally, [...]

Acute myeloid leukemia (AML) has a poor prognosis under the current standard of care. In recent years, venetoclax, a BCL-2 inhibitor, was approved to treat patients who are ineligible for intensive induction chemotherapy. However, complete remission rates with venetoclax-based therapies are hampered by minimal residual disease (MRD) in a proportion of patients, leading to relapse. MRD is a result of leukemic stem cells being retained in bone marrow protective environments; activation of the CXCL12-CXCR4 pathway was shown to be relevant to this process. An important role is also played by cell adhesion molecules such as CD44, which has been shown to be crucial for the development of AML. Here we show that CD44 is involved in CXCL12 promotion of resistance to venetoclax-induced apoptosis in human AML cell lines and AML patient samples, which could be abrogated by CD44 knock down, knockout, or blocking with an anti-CD44 antibody. Split-Venus bimolecular fluorescence complementation showed that CD44 and CXCR4 physically associate at the cell membrane upon CXCL12 induction. In the venetoclax-resistant OCI-AML3 cell line, CXCL12 promoted an increase in the proportion of cells expressing high levels of embryonic stem cell core transcription factors (ESC-TFs: Sox2, Oct4, Nanog) abrogated by CD44 knockdown. This ESC-TF–expressing subpopulation which could be selected by venetoclax treatment, exhibited a basally enhanced resistance to apoptosis and expressed higher levels of CD44. Finally, we developed a novel AML xenograft model in zebrafish, which showed that CD44 knockout sensitizes OCI-AML3 cells to venetoclax treatment in vivo. Our study shows that CD44 is a potential molecular target for sensitizing AML cells to venetoclax-based therapies.

The Cu2+complexes formed by a series of cyclen derivatives bearing sulfur pendant arms, 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7-bis[2-(methylsulfanyl)ethyl]-4,10-diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S), were studied in aqueous solution at 25 °C from thermodynamic and structural points of view to evaluate their potential as chelators for copper radioisotopes. UV–vis spectrophotometric out-of-cell titrations under strongly acidic conditions, direct in-cell UV–vis titrations, potentiometric measurements at pH >4, and spectrophotometric Ag+–Cu2+competition experiments were performed to evaluate the stoichiometry and stability constants of the Cu2+complexes. A highly stable 1:1 metal-to-ligand complex (CuL) was found in solution at all pH values for all chelators, and for DO2A2S, protonated species were also detected under acidic conditions. The structures of the Cu2+complexes in aqueous solution were investigated by UV–vis and electron paramagnetic resonance (EPR), and the results were supported by relativistic density functional theory (DFT) calculations. Isomers were detected that differed from their coordination modes. Crystals of [Cu(DO4S)(NO3)]·NO3and [Cu(DO2A2S)] suitable for X-ray diffraction were obtained. Cyclic voltammetry (CV) experiments highlighted the remarkable stability of the copper complexes with reference to dissociation upon reduction from Cu2+to Cu+on the CV time scale. The Cu+complexes were generated in situ by electrolysis and examined by NMR spectroscopy. DFT calculations gave further structural insights. These results demonstrate that the investigated sulfur-containing chelators are promising candidates for application in copper-based radiopharmaceuticals. In this connection, the high stability of both Cu2+and Cu+complexes can represent a key parameter for avoiding in vivodemetalation after bioinduced reduction to Cu+, often observed for other well-known chelators that can stabilize only Cu2+.

Experimental studies have indicated that electrophilic mercury forms (e.g., methylmercury, MeHg+) can accelerate the breakage of selenocysteine in vitro. Particularly, in 2009, Khan et al. (Environ. Toxicol. Chem. 2009, 28, 1567–1577) proposed a mechanism for the degradation of a free methylmercury selenocysteinate complex that was theoretically supported by Asaduzzaman et al. (Inorg. Chem. 2010, 50, 2366–2372). However, little is known about the fate of methylmercury selenocysteinate complexes embedded in an enzyme, especially in conditions of oxidative stress in which methylmercury target enzymes operate. Here, an accurate computational study on molecular models (level of theory: COSMO-ZORA-BLYP-D3(BJ)/TZ2P) was carried out to investigate the formation of dehydroalanine (Dha) in selenoenzymes, which irreversibly impairs their function. Methylselenocysteine as well as methylcysteine and methyltellurocysteine were included to gain insight on the peculiar behavior of selenium. Dha forms in a two-step process, i.e., the oxidation of the chalcogen nucleus followed by a syn-elimination leading to the alkene and the chalcogenic acid. The effect of an excess of hydrogen peroxide, which may lead to the formation of chalcogenones before the elimination, and of MeHg+, a severe toxicant targeting selenoproteins, which leads to the formation of methylmercury selenocysteinate, are also studied with the aim of assessing whether these pathological conditions facilitate the formation of Dha. Indeed, elimination occurs after chalcogen oxidation and MeHg+facilitates the process. These results indicate a possible mechanism of toxicity of MeHg+in selenoproteins.

Methylmercury (CH3Hg+) binding to catalytically fundamental cysteine and selenocysteine of peroxide-reducing enzymes has long been postulated as the origin of its toxicological activity. Only very recently, CH3Hg+binding to the selenocysteine of thioredoxin reductase has been directly observed [Pickering, I. J.Inorg. Chem., 2020, 59, 2711−2718], but the precise influence of the toxicant on the peroxide-reducing potential of such a residue has never been investigated. In this work, we employ state-of-the-art density functional theory calculations to study the reactivity of molecular models of the free and toxified enzymes. Trends in activation energies are discussed with attention to the biological consequences and are rationalized within the chemically intuitive framework provided by the activation strain model. With respect to the free, protonated amino acids, CH3Hg+binding promotes oxidation of the S or Se nucleus, suggesting that chalcogenoxide formation might occur in the toxified enzyme, even if the actual rate of peroxide reduction is almost certainly lowered as suggested by comparison with fully deprotonated amino acids models.

As an initial step towards the implementation of an ecosystem‐based approach to management, the Caribbean Fishery Management Council has recently ratified three island‐based fishery management plans that will supplant the existing regional plans. The newly formed management plans account for nuances among the island platforms in the U.S. Caribbean, including ecological, cultural, and social considerations. The island‐based approach represents a novel strategy among the eight fishery management councils in the United States and therefore remains an untested technique. This study evaluated the decision to separate fishery management among the island platforms by comparing fish assemblages through time in the region. The results suggest that the structure and function of fish communities are spatially driven, with little temporal influence. Combined with the ecological, cultural, and social differences among the islands, the spatial nature of the fish community data support the Caribbean Fishery Management Council decision to transition to island‐based management plans.

The invention of phase contrast microscopy revolutionized optics, enabling the visualization of highly optically transparent samples without the need for staining. The technique utilizes phase shifts within the sample and is routinely employed in the characterization of biological material and other weakly interacting objects. However, the demand for increased contrast and quantification has continued to drive research into more advanced approaches to phase imaging. Here, we demonstrate that the combination of ptychographic coherent diffractive imaging with plasmonically active metamaterials yields a massive enhancement of both the reconstructed phase and amplitude by exploiting near-field interactions at the metamaterial surface. We present results from nanofabricated samples and tissue sections with thickness ranging from 4 nm to 4 μm. In addition to enabling quantitative phase imaging of metamaterials, this approach opens the way to imaging a wide range of extremely thin or highly transparent objects previously inaccessible to optical microscopy.

The importance of selenium in biology, in organic catalysis, and green chemistry is well established. Selenoproteins, among which are ubiquitous Glutathione Peroxidases (GPx), play a key role in mitigating oxidative stress by reducing H2O2 and hydroperoxides using glutathione as a cofactor. Organoselenides, particularly diphenyl diselenide, in the presence of H2O2, are efficient and often green oxygen transfer agents in important organic reactions, such as Baeyer-Villiger oxidations of ketones/aldehydes, the conversion of alkenes into epoxides, and the oxidations of alcohols and nitrogen- containing compounds. NMR spectroscopy can facilitate the investigation of the properties of this element in a biological environment and the characterization of the peculiar species of its chemistry. In this short review, a brief overview of the experimental and computational 77Se NMR-based techniques is outlined, with a particular focus on their applications to the study of biologically relevant organoselenium compounds and bio-mimetic systems. Experimental protocols, together with computational methods used in different contexts, are presented and their potential as efficient investigation tools is critically discussed. It emerges that while the 77Se NMR measurement is a consolidated technique, no standard computational protocol is available to compute the shielding constant of the chalcogen nucleus with accuracy and the optimal approach combines molecular dynamics in solution and quantum chemistry calculations to take into account the conformational freedom.

Mitochondrial abnormalities have been noted in lupus, but the causes and consequences remain obscure. Autophagy-related genes ATG5, ATG7and IRGMhave been previously implicated in autoimmune disease. We reasoned that failure to clear defective mitochondria via mitophagy might be a foundational driver in autoimmunity by licensing mitochondrial DNA–dependent induction of type I interferon. Here, we show that mice lacking the GTPase IRGM1 (IRGM homolog) exhibited a type I interferonopathy with autoimmune features. Irgm1deletion impaired the execution of mitophagy with cell-specific consequences. In fibroblasts, mitochondrial DNA soiling of the cytosol induced cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING)-dependent type I interferon, whereas in macrophages, lysosomal Toll-like receptor 7 was activated. In vivo, Irgm1–/–tissues exhibited mosaic dependency upon nucleic acid receptors. Whereas salivary and lacrimal gland autoimmune pathology was abolished and lung pathology was attenuated by cGAS and STING deletion, pancreatic pathology remained unchanged. These findings reveal fundamental connections between mitochondrial quality control and tissue-selective autoimmune disease.

In early 2020, the European Union Aviation Safety Agency (EASA) published its long anticipated ‘Roadmap for Artificial Intelligence in Aviation’. This document builds upon previous European initiatives such as the High-Level Expert Group’s Ethical Guidelines on artificial intelligence (‘AI’), where the concept of ‘trustworthiness’ is embedded as a key pillar and a pre-requisite for developing and deploying AI technologies. The roadmap assesses the associated ethical, safety and regulatory challenges that may arise from the deployment and use of AI applications in aviation. This article provides an overview of the main takeaways, strengths and weaknesses of this roadmap. It critically analyses the main challenges of AI-driven technologies throughout the entire aviation domain. The article argues the roadmap would benefit from considering new regulatory tools and processes, such as regulatory sandboxing and AI-driven certification, and contends any efforts for standardization of AI in aviation must be reconciled with existing standardization of automation and that this may not always be a straightforward process as far as interoperability is concerned. Finally, the article argues that further exploration of the identification and allocation of liability will be indispensable in fostering increased levels of trust in AI-enabled aviation.

There is increasing attention given to the concept of trustworthiness for artificial intelligence and robotics. However, trust is highly context-dependent, varies among cultures, and requires reflection on others’ trustworthiness, appraising whether there is enough evidence to conclude that these agents deserve to be trusted. Moreover, little research exists on what happens when too much trust is placed in robots and autonomous systems. Conceptual clarity and a shared framework for approaching overtrust are missing. In this contribution, we offer an overview of pressing topics in the context of overtrust and robots and autonomous systems. Our review mobilizes insights solicited from in-depth conversations from a multidisciplinary workshop on the subject of trust in human–robot interaction (HRI), held at a leading robotics conference in 2020. A broad range of participants brought in their expertise, allowing the formulation of a forward-looking research agenda on overtrust and automation biases in robotics and autonomous systems. Key points include the need for multidisciplinary understandings that are situated in an eco-system perspective, the consideration of adjacent concepts such as deception and anthropomorphization, a connection to ongoing legal discussions through the topic of liability, and a socially embedded understanding of overtrust in education and literacy matters. The article integrates diverse literature and provides a ground for common understanding for overtrust in the context of HRI.

Among the hallmarks of melanoma are impaired proteostasis and rapid development of resistance to targeted therapy that represent a major clinical challenge. However, the molecular machinery that links these processes is unknown. Here we describe that by stabilizing key melanoma oncoproteins, the ubiquitin ligase RNF4 promotes tumorigenesis and confers resistance to targeted therapy in melanoma cells, xenograft mouse models, and patient samples. In patients, RNF4 protein and mRNA levels correlate with poor prognosis and with resistance to MAPK inhibitors. Remarkably, RNF4 tumorigenic properties, including therapy resistance, require the translation initiation factor initiation elongation factor alpha (eIF2α). RNF4 binds, ubiquitinates, and stabilizes the phosphorylated eIF2α (p-eIF2α) but not activating transcription factor 4 or C/EBP homologous protein that mediates the eIF2α−dependent integrated stress response. In accordance, p-eIF2α levels were significantly elevated in high-RNF4 patient-derived melanomas. Thus, RNF4 and p-eIF2α establish a positive feed-forward loop connecting oncogenic translation and ubiquitin-dependent protein stabilization in melanoma.

The surface ligands of semiconductor nanocrystals (NCs) are central for determining their properties and for their flexible implementation in diverse applications. Thus far, the thermodynamic characteristics of ligand exchange reactions were attained by indirect methods. Isothermal titration calorimetry is utilized to directly and independently measure both the equilibrium constant and the reaction enthalpy of a model ligand exchange reaction from oleate-capped CdSe NCs to a series of alkylthiols. Increased reaction exothermicity for longer chains, accompanied by a decrease in reaction entropy with an overall enthalpy–entropy compensation behavior is observed, explained by the length-dependent interchain interactions and the organization of the bound ligands on the NCs’ surface. An increase in the spontaneity of the reaction with decreasing NC size is also revealed, due to their enhanced surface reactivity. This work provides a fundamental understanding of the physicochemical properties of the NC surface with implications for NC surface ligand design.

With a half-life of 7.45 days, silver-111 (βmax1.04 MeV, Eγ245.4 keV [Iγ1.24%], Eγ342.1 keV [Iγ6.7%]) is a promising candidate for targeted cancer therapy with β–emitters as well as for associated SPECT imaging. For its clinical use, the development of suitable ligands that form sufficiently stable Ag+-complexes in vivois required. In this work, the following sulfur-containing derivatives of tetraazacyclododecane (cyclen) have been considered as potential chelators for silver-111: 1,4,7,10-tetrakis(2-(methylsulfanyl)ethyl)-1,4,7,10-tetraazacyclododecane (DO4S), (2S,5S,8S,11S)-2,5,8,11-tetramethyl-1,4,7,10-tetrakis(2-(methylsulfanyl)ethyl)-1,4,7,10-tetraazacyclododecane (DO4S4Me), 1,4,7-tris(2-(methylsulfanyl)ethyl)-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris(2-(methylsulfanyl)ethyl)-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7-bis(2-(methylsulfanyl)ethyl)-4,10,diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S). Natural Ag+was used in pH/Ag-potentiometric and UV–vis spectrophotometric studies to determine the metal speciation existing in aqueous NaNO30.15 M at 25 °C and the equilibrium constants of the complexes, whereas NMR and DFT calculations gave structural insights. Overall results indicated that sulfide pendant arms coordinate Ag+allowing the formation of very stable complexes, both at acidic and physiological pH. Furthermore, radiolabeling, stability in saline phosphate buffer, and metal-competition experiments using the two ligands forming the strongest complexes, DO4S and DO4S4Me, were carried out with [111Ag]Ag+and promising results were obtained.

Ideology plays a central role in conflicts, both on the intergroup and intragroup levels. On the intergroup level, ideology can either contribute to the preservation and escalation of conflicts or serve as the key to resolving them. On the intragroup level, ideology can generate and induce conflicts between opposing ideological groups. However, the interaction between these two levels of conflict and the unique role of ideology in such interactions have not received sufficient systematic scholarly attention so far. We suggest a new theoretical framework emphasizing a possible reciprocal relationship between intractable intergroup conflicts and intragroup ideological polarization: intergroup conflict enhances inner polarization, which in turn, hinders the resolution of the external conflict.