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Poly(3,4-ethylenedioxythiophene) (PEDOT), a very stable and biocompatible conducting polymer, and alginate (Alg), a natural water-soluble polysaccharide mainly found in the cell wall of various species of brown algae, exhibit very different but at the same complementary properties. In the last few years, the remarkable capacity of Alg to form hydrogels and the electro-responsive properties of PEDOT have been combined to form not only layered composites (PEDOT-Alg) but also interpenetrated multi-responsive PEDOT/Alg hydrogels. These materials have been found to display outstanding properties, such as electrical conductivity, piezoelectricity, biocompatibility, self-healing and re-usability properties, pH and thermoelectric responsiveness, among others. Consequently, a wide number of applications are being proposed for PEDOT-Alg composites and, especially, PEDOT/Alg hydrogels, which should be considered as a new kind of hybrid material because of the very different chemical nature of the two polymeric components. This review summarizes the applications of PEDOT-Alg and PEDOT/Alg in tissue interfaces and regeneration, drug delivery, sensors, microfluidics, energy storage and evaporators for desalination. Special attention has been given to the discussion of multi-tasking applications, while the new challenges to be tackled based on aspects not yet considered in either of the two polymers have also been highlighted.

The taxonomic identification of organisms based on the amplification of specific genetic markers (metabarcoding) implicitly requires adequate discriminatory information and taxonomic coverage of environmental DNA sequences in taxonomic databases. These requirements were quantitatively examined by comparing the determination of cyanobacteria and microalgae obtained by metabarcoding and light microscopy. We used planktic and biofilm samples collected in 37 lakes and 22 rivers across the Alpine region. We focused on two of the most used and best represented genetic markers in the reference databases, namely the 16S rRNA and 18S rRNA genes. A sequence gap analysis using blastn showed that, in the identity range of 99-100%, approximately 30% (plankton) and 60% (biofilm) of the sequences did not find any close counterpart in the reference databases (NCBI GenBank). Similarly, a taxonomic gap analysis showed that approximately 50% of the cyanobacterial and eukaryotic microalgal species identified by light microscopy were not represented in the reference databases. In both cases, the magnitude of the gaps differed between the major taxonomic groups. Even considering the species determined under the microscope and represented in the reference databases, 22% and 26% were still not included in the results obtained by the blastn at percentage levels of identity ≥95% and ≥97%, respectively. The main causes were the absence of matching sequences due to amplification and/or sequencing failure and potential misidentification in the microscopy step. Our results quantitatively demonstrated that in metabarcoding the main obstacles in the classification of 16S rRNA and 18S rRNA sequences and interpretation of high-throughput sequencing biomonitoring data were due to the existence of important gaps in the taxonomic completeness of the reference databases and the short length of reads. The study focused on the Alpine region, but the extent of the gaps could be much greater in other less investigated geographic areas.

Peptide derivatives and, most specifically, their self-assembled supramolecular structures are being considered in the design of novel biofunctional materials. Although the self-assembly of triphenylalanine homopeptides has been found to be more versatile than that of homopeptides containing an even number of residues (i.e. diphenylalanine and tetraphenylalanine), only uncapped triphenylalanine (FFF) and a highly aromatic analog blocked at both the N- and C-termini with fluorenyl-containing groups (Fmoc-FFF-OFm), have been deeply studied before. In this work, we have examined the self-assembly of a triphenylalanine derivative bearing 9-fluorenylmethyloxycarbonyl and benzyl ester end-capping groups at the N- and C-termini, respectively (Fmoc-FFF-OBzl). The antiparallel arrangement clearly dominates in β-sheets formed by Fmoc-FFF-OBzl, whereas the parallel and antiparallel dispositions are almost isoenergetic in Fmoc-FFF-OFm β-sheets and the parallel one is slightly favored for FFF. The effects of both the peptide concentration and the medium on the self-assembly process have been examined considering Fmoc-FFF-OBzl solutions in a wide variety of solvent:co-solvent mixtures. In addition, Fmoc-FFF-OBzl supramolecular structures have been compared to those obtained for FFF and Fmoc-FFF-OFm under identical experimental conditions. The strength of π-π stacking interactions involving the end-capping groups plays a crucial role in the nucleation and growth of supramolecular structures, which determines the resulting morphology. Finally, the influence of a non-invasive external stimulus, ultrasounds, on the nucleation and growth of supramolecular structures has been examined. Overall, FFF-based peptides provide a wide range of supramolecular structures that can be of interest in the biotechnological field., The authors gratefully acknowledge financial support provided by Ministerio de Asuntos Económicos y Transformación Digital, con Fondos de la Unión Europea - FEDER (MINECO/FEDER; RTI2018-098951-B-I00), Agència de Gestió d'Ajuts Universitaris i de Recerca (2017SGR359), and Gobierno de Aragón (research group Aminoácidos y Péptidos; E19_20R). M.M.P.-M. is thankful for the Junior Beatriz Galindo Fellowship (BG20/00216).

Background The lack of epidemiological and clinical data is a major obstacle in health service planning for rare diseases. Patient registries are examples of real-world data that may fill the information gap. Objective We describe the Rare Disease Registry of the Friuli Venezia Giulia region of Italy and its potential for research and health planning. Methods The Rare Disease Registry data were linked with information on mortality, hospital discharges, ambulatory care, and drug prescriptions contained in administrative databases. All information is anonymous, and data linkage was based on a stochastic key univocal for each patient. Average annual costs owing to hospitalizations, outpatient care, and medications were estimated. Results Implementation of the Registry started in 2010, and 4250 participants were registered up to 2017. A total of 2696 patients were living in the region as of January 1, 2017. The overall raw prevalence of rare diseases was 22 per 10,000 inhabitants, with higher prevalence in the pediatric population. The most common disease groups were congenital malformations, chromosomal and genetic syndromes, and circulatory and nervous diseases. In 2017, 30 patients died, 648 were hospitalized, and 2355 received some type of ambulatory care. The total annual estimated cost was approximately €6.5 million, with great variability in the average patient cost across diseases. Conclusions The possibility of following the detailed real-world care experience of patients with each specific rare disease and assessing the costs related to each step in their care path represents a unique opportunity to identify inefficiencies, optimize care, and reduce waste of resources.

In this paper, an analytical formulation of the layouts of three-shaft hydromechanical transmissions is presented. The formulation was obtained starting from the Willis equation for the planetary gears. Its graphical representation results in a polar plot dependent only on the angular coordinate: by varying the latter between 0 and 2π, all the transmission layouts can be continuously described. In this way, the layout, together with the transmission ratios of the gears and the displacements of the hydraulic machines, can enter as a degree of freedom in the problem of mathematical optimization of the hydromechanical transmissions. The potential of this analytical formulation will be shown by studying the case of a transmission for a forklift of 75 kW.

This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).

β2-glycoprotein I (β2GPI) is an abundant multi-domain plasma protein that plays various roles in the clotting and complement cascades. It is also the main target of antiphospholipid antibodies (aPL) in the acquired coagulopathy known as Antiphospholipid Syndrome (APS). Previous studies have shown that β2GPI adopts two interconvertible biochemical conformations, oxidized and reduced, depending on the integrity of the disulfide bonds. However, the precise contribution of the disulfide bonds to β2GPI structure and function is unknown. Here, we substituted cysteine residues with serine to investigate how the disulfide bonds C32-C60 in domain I (DI) and C288-C326 in domain V (DV) regulate β2GPI's structure and function. Results of our biophysical and biochemical studies support the hypothesis that the C32-C60 disulfide bond plays a structural role, whereas the disulfide bond C288-C326 is allosteric. We demonstrate that absence of the C288-C326 bond, unlike absence of the C32-C60 bond, diminishes membrane binding without affecting the thermodynamic stability and overall structure of the protein, which remains elongated in solution. We also document that, while absence of the C32-C60 bond directly impairs recognition of β2GPI by pathogenic anti-DI antibodies, absence of the C288-C326 disulfide bond is sufficient to abolish complex formation in the presence of anionic phospholipids. We conclude that the disulfide bond C288-C326 operates as a molecular switch capable of regulating β2GPI's physiological functions in a redox-dependent manner. We propose that in APS patients with anti-DI antibodies, selective rupture of the C288-C326 disulfide bond may be a valid strategy to lower the pathogenic potential of aPL.

Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson’s disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu4 PAMs, leading to 9i (hmGlu4 EC50 = 43 nM; AhR activation = 2.3-fold).

We describe an efficient and convergent synthesis of a series of (1'S,2R,4'S)-3H-4'-azaspiro[benzo[4,5]imidazo[2,1-b]oxazole-2,2'-bicyclo[2.2.2]octanes] displaying potency for the α7 nicotinic acetylcholine receptor (nAChR) and good selectivity vs. the related 5-HT3A receptor.

In our efforts to identify orally bioavailable CGRP receptor antagonists, we previously discovered a novel series of orally available azepinone derivatives that unfortunately also exhibited the unwanted property of potent time-dependent human CYP3A4 inhibition. Through heterocyclic replacement of the indazole ring, we discovered a series of heterocycle derivatives as high-affinity CGRP receptor antagonists. Some of them showed reasonable oral exposures, and the imidazolone derivatives that showed good oral exposure also exhibited substantially reduced time-dependent CYP3A4 inhibition. Several compounds showed strong in vivo efficacy in our marmoset facial blood flow assay with up to 87% inhibition of CGRP-induced activity. However, oral bioavailability generally remained low, emphasizing the challenges we and others encountered in discovering clinical development candidates for this difficult Class B GPCR target.

In the agricultural and work machine sectors, the hydro-mechanical transmission competes with traditional mechanical transmission; a tool to improve its competitiveness is the hybridization. The hydraulic branch of the transmission may be integrated with two accumulators which allow the storage of energy derived from braking; the presence of the two hydraulic units facilitates this solution: the hydraulic motor acts as a pump during the braking and as a motor during the starts of the vehicle. This solution appears to be interesting also from the costs point of view, because it does not require a high-level technology. For this reason, in the present work, the hybrid hydro-mechanical transmission is studied with the aim of pointing out its potential for the urban passenger transport sector. At first, a hydro-mechanical transmission for an urban bus is designed; then, the same transmission is modified adding the components for the hydraulic hybridization. After that, the two vehicles is modelled and simulated using the AMESim code, and, finally, compared to each other in terms of energy savings.

Adaptor-associated kinase 1 (AAK1), a member of the Ark1/Prk1 family of serine/threonine kinases, plays a role in modulating clatherin coated endocytosis of specific surface receptors. We have demonstrated that AAK1 inhibitors are efficacious in rodent models of neuropathic pain (Kostich et al., 2016). Here we have characterized the binding properties and distribution pattern of the tritiated AAK1 radioligand, [3H]BMT-046091, in rodents and cynomolgus monkeys, and used the radioligand to measure the brain target occupancy following systemic administration of AAK1 inhibitors. We have found that [3H]BMT-046091 is potent and selective AAK1 inhibitor. It inhibits AAK1 phosphorylation of a peptide derived from a physiologic substrate, the μ2 subunit of the adaptor protein complex, with an IC50 value of 2.8 nM, and is inactive at >5 μM in a panel of functional or binding assays for receptors, transporters and enzymes. [3H]BMT-046091 binding in the brain is absent in the AAK1 knockout mouse, and is displaceable with a high concentration of AAK1 inhibitors in wild type mice. Specific [3H]BMT-046091 binding is widespread in the brain and spinal cord with the highest density in the cortex, hippocampus, amygdala, striatum and thalamus. In the spinal cord, [3H]BMT-046091 binding appears enriched in the dorsal horn superficial layers. Oral administration of LP-935509, an AAK1 inhibitor, results in a dose-dependent occupation of AAK1 binding sites in the brain and spinal cord. The increase in AAK1 binding site occupancy by LP-935509 correlates with the decrease in antinociceptive responses in the rat chronic constriction injury model of neuropathic pain.

A series of phosphate and ester-based prodrugs of anilinopyrazinone 1 (BMS-665053) containing either a methylene or an (acyloxy)alkoxy linker was prepared and evaluated in rat pharmacokinetic studies with the goal of improving the oral bioavailability of the parent (1). The prodrugs, in general, had improved aqueous solubility and oral bioavailability compared to 1. Prodrug 12, which contains an (acyloxy)alkoxy linker, showed the greatest improvement in the oral bioavailability relative to the parent (1), with a seven-fold increase (from 5% to 36%) in rat pharmacokinetic studies.

We describe the synthesis of quinuclidine-containing spiroguanidines and their utility as α7 neuronal nicotinic acetylcholine receptor (nAChR) partial agonists. The convergent synthetic route developed for this study allowed for rapid SAR investigation and provided access to a structurally diverse set of analogs. A potent and selective α7 nAChR partial agonist, N‐(6‐methyl‐1,3‐benzoxazol‐2‐yl)‐3′,5′‐dihydro‐4‐azaspiro[bicyclo[2.2.2]octane‐2,4′‐imidazole]‐2′‐amine (BMS-910731, 16), was identified. This compound induced immediate early genes c-fos and Arc in a preclinical rodent model of α7 nAChR-derived cellular activation and plasticity. Importantly, the ability to incorporate selectivity for the α7 nACh receptor over the 5-HT3A receptor in this series suggested a significant difference in steric requirements between the two receptors.

Triazolopyridine ethers with mGlu2 positive allosteric modulator (PAM) activity are disclosed. The synthesis, in vitro activity, and metabolic stability data for a series of analogs is provided. The effort resulted in the discovery of a potent, selective, and brain penetrant lead molecule BMT-133218 ((+)-7m). After oral administration at 10mg/kg, BMT-133218 demonstrated full reversal of PCP-stimulated locomotor activity and prevented MK-801-induced working memory deficits in separate mouse models. Also, reversal of impairments in executive function were observed in rat set-shifting studies at 3 and 10mg/kg (p.o.). Extensive plasma protein binding as the result of high lipophilicity likely limited activity at lower doses. Optimized triazolopyridine ethers offer utility as mGlu2 PAMs for the treatment of schizophrenia and merit further preclinical investigation.