Novel KCND3 Variant Underlying Nonprogressive Congenital Ataxia or SCA19/22 Disrupt KV4.3 Protein Expression and K+ Currents with Variable Effects on Channel Properties

KCND3 encodes the voltage-gated potassium channel K_V4.3 that is highly expressed in the cerebellum, where it regulates dendritic excitability and calcium influx. Loss-of-function K_V4.3 mutations have been associated with dominant spinocerebellar ataxia (SCA19/22). By targeted NGS sequencing, we identified two novel KCND3 missense variants of the K_V4.3 channel: p.S347W identified in a patient with adult-onset pure cerebellar syndrome and p.W359G detected in a child with congenital nonprogressive ataxia. Neuroimaging showed mild cerebellar atrophy in both patients. We performed a two-electrode voltage-clamp recording of K_V4.3 currents in Xenopus oocytes: both the p.G345V (previously reported in a SCA19/22 family) and p.S347W mutants exhibited reduced peak currents by 50%, while no K+ current was detectable for the p.W359G mutant. We assessed the effect of the mutations on channel gating by measuring steady-state voltage-dependent activation and inactivation properties: no significant alterations were detected in p.G345V and p.S347W disease-associated variants, compared to controls. K_V4.3 expression studies in HEK293T cells showed 53% (p.G345V), 45% (p.S347W) and 75% (p.W359G) reductions in mutant protein levels compared with the wildtype. The present study broadens the spectrum of the known phenotypes and identifies additional variants for KCND3-related disorders, outlining the importance of SCA gene screening in early-onset and congenital ataxia.     

In Vitro and In Vivo Pharmaco-Toxicological Characterization of 1-Cyclohexyl-x-methoxybenzene Derivatives in Mice: Comparison with Tramadol and PCP

1-cyclohexyl-x-methoxybenzene is a novel psychoactive substance (NPS), first discovered in Europe in 2012 as unknown racemic mixture of its three stereoisomers: ortho, meta and para. Each of these has structural similarities with the analgesic tramadol and the dissociative anesthetic phencyclidine. In light of these structural analogies, and based on the fact that both tramadol and phencyclidine are substances that cause toxic effects in humans, the aim of this study was to investigate the in vitro and in vivo pharmacodynamic profile of these molecules, and to compare them with those caused by tramadol and phencyclidine. In vitro studies demonstrated that tramadol, ortho, meta and para were inactive at mu, kappa and delta opioid receptors. Systemic administration of the three stereoisomers impairs sensorimotor responses, modulates spontaneous motor activity, induces modest analgesia, and alters thermoregulation and cardiorespiratory responses in the mouse in some cases, with a similar profile to that of tramadol and phencyclidine. Naloxone partially prevents only the visual sensorimotor impairments caused by three stereoisomers, without preventing other effects. The present data show that 1-cyclohexyl-x-methoxybenzene derivatives cause pharmaco-toxicological effects by activating both opioid and non-opioid mechanisms and suggest that their use could potentially lead to abuse and bodily harm.     

Xyloglucan Oligosaccharides Hydrolysis by Exo-Acting Glycoside Hydrolases from Hyperthermophilic Microorganism Saccharolobus solfataricus

In the field of biocatalysis and the development of a bio-based economy, hemicellulases have attracted great interest for various applications in industrial processes. However, the study of the catalytic activity of the lignocellulose-degrading enzymes needs to be improved to achieve the efficient hydrolysis of plant biomasses. In this framework, hemicellulases from hyperthermophilic archaea show interesting features as biocatalysts and provide many advantages in industrial applications thanks to their stability in the harsh conditions encountered during the pretreatment process. However, the hemicellulases from archaea are less studied compared to their bacterial counterpart, and the activity of most of them has been barely tested on natural substrates. Here, we investigated the hydrolysis of xyloglucan oligosaccharides from two different plants by using, both synergistically and individually, three glycoside hydrolases from Saccharolobus solfataricus: a GH1 β-gluco-/β-galactosidase, a α-fucosidase belonging to GH29, and a α-xylosidase from GH31. The results showed that the three enzymes were able to release monosaccharides from xyloglucan oligosaccharides after incubation at 65 °C. The concerted actions of β-gluco-/β-galactosidase and the α-xylosidase on both xyloglucan oligosaccharides have been observed, while the α-fucosidase was capable of releasing all α-linked fucose units from xyloglucan from apple pomace, representing the first GH29 enzyme belonging to subfamily A that is active on xyloglucan.     

Proxies and measurement techniques for mineral dust in Antarctic ice cores

To improve quantitative interpretation of ice core aeolian dust records, a systematic methodological comparison was made. This involved methods for water-insoluble particle counting (Coulter counter and laser-sensing particle detector), soluble ion analysis (ion chromatography and continuous flow analysis), elemental analysis (inductively coupled plasma mass spectroscopy at pH 1 and after full acid digestion), and water-insoluble elemental analysis (proton induced X-ray emission). Antarctic ice core samples covering the last deglaciation from the EPICA Dome C (EDC) and the EPICA Dronning Maud Land (EDML) cores were used. All methods correlate very well among each other, but the ratios of glacial age to Holocene concentrations, which are typically a factor approximately 100, differ between the methods by up to a factor of 2 with insoluble particles showing the largest variability. The recovery of ICP-MS measurements depends on the digestion method and is differentfor different elements and during different climatic periods. EDC and EDML samples have similar dust composition, which suggests a common dust source or a common mixture of sources for the two sites. The analyzed samples further reveal a change of dust composition during the last deglaciation.     

Characterization of microstructured optical fibers for wideband dispersion compensation

Microstructured optical fibers (MOFs) with small hole-to-hole spacing and large airholes are designed to compensate the anomalous dispersion and the dispersion slope of single-mode fibers. The geometrical parameters that characterize triangular MOFs are chosen to optimize the fiber length and the compensation over a wide wavelength range. A proper design of the photonic crystal fiber geometry allows us to achieve dispersion values of approximately -1700 ps nm(-1) km(-1) at 1550 nm and to compensate the dispersion of standard fibers within +/- 0.5 ps nm(-1) km(-1) over a 100-nm range. The MOF dispersion properties have been studied by means of a numerical simulator for modal analysis based on the finite-element method.     

Implementation of a real option in a sustainable supply chain: an empirical study of alkaline battery recycling

Green supply chain management (GSCM) has emerged as a key approach for enterprises seeking to become environmentally sustainable. This paper aims to evaluate and describe the advantages of a GSCM approach by analysing practices and performance consequences in the battery recycling sector. It seeks to integrate works in supply chain management (SCM), environmental management, performance management and real option (RO) theory into one framework. In particular, life cycle assessment (LCA) is applied to evaluate the environmental impact of a battery recycling plant project, and life cycle costing (LCC) is applied to evaluate its economic impact. Firms, also understanding the relevance of GSCM, have often avoided applying the green principles because of the elevated costs that such management involved. Such costs could also seem superior to the potential advantages since standard performance measurement systems are internally and business focused; for these reasons, we consider all the possible value deriving also by uncertainty associated to a green project using the RO theory. This work is one of the few and pioneering efforts to investigate GSCM practices in the battery recycling sector.     

Enhancing cultural recommendations through social and linked open data

In this article, we describe a hybrid recommender system (RS) in the artistic and cultural heritage area, which takes into account the activities on social media performed by the target user and her friends, and takes advantage of linked open data (LOD) sources. Concretely, the proposed RS (1) extracts information from Facebook by analyzing content generated by users and their friends; (2) performs disambiguation tasks through LOD tools; (3) profiles the active user as a social graph; (4) provides her with personalized suggestions of artistic and cultural resources in the surroundings of the user’s current location. The last point is performed by integrating collaborative filtering algorithms with semantic technologies in order to leverage LOD sources such as DBpedia and Europeana. Based on the recommended points of cultural interest, the proposed system is also able to suggest to the active user itineraries among them, which meet her preferences and needs and are sensitive to her physical and social contexts as well. Experimental results on real users showed the effectiveness of the different modules of the proposed recommender.

     

Understanding the Selectivity Mechanism of the Human Asialoglycoprotein Receptor (ASGP-R) toward Gal- and Man-type Ligands for Predicting Interactions with Exogenous Sugars

A practical approach for addressing the computer simulation of protein-carbohydrate interactions is described here. An articulated computational protocol was set up and validated by checking its ability to predict experimental data, available in the literature, and concerning the selectivity shown by the Carbohydrate Recognition Domain (CRD) of the human asialoglycoprotein receptor (ASGP-R) toward Gal-type ligands. Some required features responsible for the interactions were identified. Subsequently the same protocol was applied to monomer sugar molecules that constitute the building blocks for alginates and ulvans. Such sugar polymers may supply a low-cost source of rare sugars with a potential impact on several industrial applications, from pharmaceutical to fine chemical industry. An example of their applicative exploitation could be given by their use in developing biomaterial with adhesion properties toward hepatocytes, through interaction with the ASGP-R. Such a receptor has been already proposed as a target for exogenous molecules, specifically in the case of hepatocytes, for diagnostic and therapeutic purposes. The DOCK5.2 program was used to search optimal locations of the above ligands of interest into CRD binding site and to roughly estimate interaction energies. Finally, the binding ΔG of theoretical protein-ligand complexes was estimated by using the DelPhi program in which the solvation free energy is accounted for with a continuum solvent model, by solving the Poisson-Boltzmann equation. The structure analysis of the obtained complexes and their ΔG values suggest that one of the sugar monomers of interest shows the desired characteristics.     

Gastric Adenocarcinomas and Signet-Ring Cell Carcinoma: Unraveling Gastric Cancer Complexity through Microbiome Analysis—Deepening Heterogeneity for a Personalized Therapy

Gastric cancer (GC) is the fifth most prevalent cancer worldwide and the third leading cause of global cancer mortality. With the advances of the omic studies, a heterogeneous GC landscape has been revealed, with significant molecular diversity. Given the multifaceted nature of GC, identification of different patient subsets with prognostic and/or predictive outcomes is a key aspect to allow tailoring of specific treatments. Recently, the involvement of the microbiota in gastric carcinogenesis has been described. To deepen this aspect, we compared microbiota composition in signet-ring cell carcinoma (SRCC) and adenocarcinoma (ADC), two distinct GC subtypes. To this purpose, 10 ADC and 10 SRCC and their paired non-tumor (PNT) counterparts were evaluated for microbiota composition through 16S rRNA analysis. Weighted and unweighted UniFrac and Bray–Curtis dissimilarity showed significant community-level separation between ADC and SRCC. Through the LEfSe (linear discriminant analysis coupled with effect size) tool, we identified potential microbial biomarkers associated with GC subtypes. In particular, SRCCs were significantly enriched in the phyla Fusobacteria, Bacteroidetes, Patescibacteria, whereas in the ADC type, Proteobacteria and Acidobacteria phyla were found. Overall, our data add new insights into GC heterogeneity and may contribute to deepening the GC classification.     

Novel Heterogenized Palladium(II) Complexes Anchored to Polymer Matrices Functionalized with Bis(diphenylphosphino)methane Moieties

The synthesis and structural characterization of a novel bidentate ligand such as bis(diphenylphosphino) methane bound to a cross-linked styrene/divinylbenzene resin and to linear poly(styrene) are reported. Moreover, the anchoring of palladium acetate to the above polymeric ligands is described and the structure of the heterogenized palladium(II) complexes obtained is proposed.