What Currently Limits Charge Carrier Mobility in Crystals of Molecular Semiconductors?

Charge carrier mobility is a central property that characterizes the performances of organic semiconductors and is mostly measured in field-effect transistors. High mobility values are sought by many research teams. This article, that provides an overview of best performing molecular semiconductors is constructed on the question: What currently limits charge carrier mobility in crystals of molecular semiconductors? With this in mind, we confront, in a critical way, the current theoretical understanding to the most salient experimental results with the hope to reach a deeper understanding based on first principles and order of magnitudes of the main physical parameters.     

Highly Dense,Transparent α‐Al2O3 Ceramics From Ultrafine Nanoparticles Via a Standard SPS Sintering

Using discrete, ultrafine alumina, highly dense transparent (71% real in‐line transmission, RIT, λ = 640 nm) ceramics were achieved with grain size as small as 260 nm using standard SPS sintering. We show that use of La³⁺ as a dopant greatly reduces sensitivity to the sintering temperatures. Transparent alumina were achieved in a large range of sintering temperatures, 1140°C < T < 1200°C, thus providing better reliability and flexibility into the fabrication of large sintered transparent ceramic bodies.     

Novel Insights into Structure–Activity Relationships of N‐Terminally Modified PACE4 Inhibitors

PACE4 plays important roles in prostate cancer cell proliferation. The inhibition of this enzyme has been shown to slow prostate cancer progression and is emerging as a promising therapeutic strategy. In previous work, we developed a highly potent and selective PACE4 inhibitor, the multi‐Leu (ML) peptide, an octapeptide with the sequence Ac‐LLLLRVKR‐NH₂. Here, with the objective of developing a useful compound for in vivo administration, we investigate the effect of N‐terminal modifications. The inhibitory activity, toxicity, stability, and cell penetration properties of the resulting analogues were studied and compared to the unmodified inhibitor. Our results show that the incorporation of a polyethylene glycol (PEG) moiety leads to a loss of antiproliferative activity, whereas the attachment of a lipid chain preserves or improves it. However, the lipidated peptides are significantly more toxic when compared with their unmodified counterparts. Therefore, the best results were achieved not by the N‐terminal extension but by the protection of both ends with the d ‐Leu residue and 4‐amidinobenzylamide, which yielded the most stable inhibitor, with an excellent activity and toxicity profile.     

Ligand Specific Efficiency (LSE) Index for PET Tracer Optimization

Ligand efficiency indices are widely used to guide chemical optimization in drug discovery, due to their predictive value in the early steps of optimization. At later stages, however, as more complex properties become critical for success, indices relying on calculated, rather than experimental, parameters become less informative. This problem is particularly acute when developing positron emission tomography (PET) imaging agents, for which nonspecific binding (NSB) to membranes and non‐target proteins is a frequent cause of failure. NSB cannot be predicted using in silico parameters. To address this gap, we explored the use of the experimentally determined chromatographic hydrophobicity index on immobilized artificial membranes, CHI(IAM), to guide the optimization of NSB. The ligand specific efficiency (LSE) index was defined as the ratio between affinity (pIC₅₀ or pK_d) and the logarithmic value of CHI(IAM). It allows for quantification of binding affinity to the target of interest, relative to NSB. Its use was illustrated by the optimization of PET tracer candidates for the prostacyclin receptor.     

Evaluation of 5H-Thiazolo[3,2-α]pyrimidin-5-ones as Potential GluN2A PET Tracers

We describe here our efforts to develop a PET tracer for imaging GluN2A-containing NMDA receptors, based on a 5H-thiazolo[3,2-α]pyrimidin-5-one scaffold. The metabolic stability and overall properties could be optimized satisfactorily, although binding affinities remained a limiting factor for in vivo imaging. We nevertheless identified 7-(((2-fluoroethyl)(3-fluorophenyl)amino)-methyl)-3-(2-(hydroxymethyl)cyclopropyl)-2-methyl-5H-thiazolo-[3,2-α]pyrimidin-5-one ([¹⁸F] 7b ) as a radioligand providing good-quality images in autoradiographic studies, as well as a tritiated derivative, 2-(7-(((2-fluoroethyl)(4-fluorophenyl)amino)methyl)-2-methyl-5-oxo-5H-thiazolo[3,2-α]pyrimidin-3-yl)cyclopropane-1-carbonitrile ([³H₂] 15b ), which was used for the successful development of a radioligand binding assay. These are valuable new tools for the study of GluN2A-containing NMDA receptors, and for the optimization of allosteric modulators binding to the pharmacophore located at the dimer interface of the GluN1-GluN2A ligand-binding domain.     

A PhotoClick cholesterol-based quantitative proteomics screen for cytoplasmic sterol-binding proteins in Saccharomyces cerevisiae

Ergosterol is a prominent component of the yeast plasma membrane and essential for yeast cell viability. It is synthesized in the endoplasmic reticulum and transported to the plasma membrane by nonvesicular mechanisms requiring carrier proteins. Oxysterol-binding protein homologues and yeast StARkin proteins have been proposed to function as sterol carriers. Although many of these proteins are capable of transporting sterols between synthetic lipid vesicles in vitro, they are not essential for ergosterol transport in cells, indicating that they may be functionally redundant with each other or with additional—as yet unidentified—sterol carriers. To address this point, we hypothesized that sterol transport proteins are also sterol-binding proteins (SBPs), and used an in vitro chemoproteomic strategy to identify all cytosolic SBPs. We generated a cytosol fraction enriched in SBPs and captured the proteins with a photoreactive clickable cholesterol analogue. Quantitative proteomics of the captured proteins identified 342 putative SBPs. Analysis of these identified proteins based on their annotated function, reported drug phenotypes, interactions with proteins regulating lipid metabolism, gene ontology, and presence of mammalian orthologues revealed a subset of 62 characterized and nine uncharacterized candidates. Five of the uncharacterized proteins play a role in maintaining plasma membrane integrity as their absence affects the ability of cells to grow in the presence of nystatin or myriocin. We anticipate that the dataset reported here will be a comprehensive resource for functional analysis of sterol-binding/transport proteins and provide insights into novel aspects of non-vesicular sterol trafficking.     

The ultrafiltration molecular weight cut-off has a limited effect on the concentration and protein profile during preparation of human milk protein concentrates

Optimizing protein intake for very low birth weight (<1,500 g) infants is fundamental to prevent faltering postnatal growth with the potential association of impaired neurodevelopment. The protein content of human milk is not sufficient to support the growth of very low birth weight infants. To meet their elevated protein requirements, human milk is currently fortified using typically bovine milk-based protein isolates (>85% on a dry basis). However, these products have several limitations for use in this vulnerable population. To overcome the shortcomings of bovine milk-based protein supplement, a human milk protein concentrate (HMPC) was developed. In preliminary attempts using 10 kDa ultrafiltration (UF) membranes, it was not possible to reach the protein content of commercial protein isolates, presumably due to the retention of human milk oligosaccharides (HMO). Consequently, it was hypothesized that the use of a UF membrane with a higher molecular weight cut-off (50 kDa rather than 10 kDa) could improve the transmission of carbohydrates, including HMO, in the permeate, thus increasing the protein purity of the subsequent HMPC. The results showed that permeate fluxes during the concentration step were similar to either UF molecular weight cut-off, but the 50-kDa membrane had a higher permeate flux during the diafiltration sequence. However, it was not sufficient to increase the protein purity of the human milk retentate, as both membranes generated HMPC with similar protein contents of 48.8% (10 kDa) and 50% (50 kDa) on a dry basis. This result was related to the high retention of HMO, mainly during the concentration step, although the diafiltration step was efficient to decrease their content in the HMPC. As the major bioactive proteins (lactoferrin, lysozyme, bile salt stimulated lipase, and α1-antitrypsin) in human milk were detected in both HMPC, the 50-kDa membrane seems the most appropriate to the preparation of HMPC in terms of permeation flux values. However, improving the separation of HMO from proteins is essential to increase the protein purity of HMPC.     

Enterprise modelling: from early languages to models transformation

During the last 30 years, enterprise modelling has been recognised as an efficient tool to externalise the knowledge of companies in order to understand their operations, to analyse their running and to design new systems from several points of view: functions, processes, decisions, resources and information technology. This paper aims at describing the long evolution of enterprise modelling techniques as well as one of the future challenges of these techniques: the transformation of enterprise models. So, in a first part, the paper describes the evolution of enterprise modelling techniques from the divergence era to the convergence period. In a second time, the paper focuses on the recent advances in the use of enterprise models through model-driven approaches, interoperability problem-solving and simulation, all these advances having the same characteristic to use the transformation of enterprise models.     

Electrically controlled fluorescence in a nematic liquid crystal doped by a chiral fluorophore

We have discovered a strong electric field sensitivity of the fluorescence intensity while studying the diffusion processes of a chiral fluorescent molecule (CFM) in a nematic liquid crystal (NLC) host. The experimental and theoretical study of this phenomenon indicates that the alignment of the CFM along two privileged orientation directions (with asymmetric distribution with respect to the NLC’s optical axis) is in the origin of this phenomenon. As a result, the obtained guest–host system demonstrates noticeable dichroism. Thus, the application of an electric field allows the reorientation of the anisotropy axis of the host, the change of CFM’s absorption (at the wavelength of excitation) and the dynamic electric control of its fluorescence intensity. The study of these phenomena allows also the identification of the angular distribution of guest CFMs suggesting that the elastic energy of orientation of the host molecules might be in the origin of the asymmetric angular distribution of CFM.     

Cloud providers viability

A major part of the commercial Internet is moving toward the cloud paradigm. This phenomenon has a drastic impact on the organizational structures of enterprizes and introduces new challenges that must be properly addressed to avoid major setbacks. One such challenge is that of cloud provider viability, that is, the reasonable certainty that the Cloud Service Provider (CSP) will not go out of business, either by filing for bankruptcy or by simply shutting down operations, thus leaving its customers stranded without an infrastructure and, depending on the type of cloud service used, even without their applications or data. This article attempts to address the issue of cloud provider viability, defining a possible way of modeling viability as a non-functional requirement and proposing some approaches that can be used to mitigate the problem, both from a technical and from a legal perspective. By introducing a structured perspective into the topic of cloud viability, describing the risks, factors and possible mitigators, the contribution of this work is twofold: it gives the customer a better understanding to determine when it can rely on the cloud infrastructure on the long term and what precautions it should take in any case, and provides the CSP with means to address some of the viability issues and thus increase its customers’ trust.