Post Zygotic,Somatic, Deletion in KERATIN 1 V1 Domain Generates Structural Alteration of the K1/K10 Dimer,Producing a Monolateral Palmar Epidermolytic Nevus

Palmoplantar keratodermas (PPKs) are characterized by thickness of stratum corneum and epidermal hyperkeratosis localized in palms and soles. PPKs can be epidermolytic (EPPK) or non epidermolytic (NEPPK). Specific mutations of keratin 16 (K16) and keratin 1 (K1) have been associated to EPPK, and NEPPK. Cases of mosaicism in PPKs due to somatic keratin mutations have also been described in scientific literature. We evaluated a patient presenting hyperkeratosis localized monolaterally in the right palmar area, characterized by linear yellowish hyperkeratotic lesions following the Blaschko lines. No other relatives of the patient showed any dermatological disease. Light and confocal histological analysis confirmed the presence of epidermolityic hyperkeratosis. Genetic analysis performed demonstrates the heterozygous deletion {"type":"entrez-nucleotide","attrs":{"text":"NM_006121.4","term_id":"1519311739"}}NM_006121.4:r.274_472del for a total of 198 nucleotides, in KRT1 cDNA obtained by a palmar lesional skin biopsy, corresponding to the protein mutation {"type":"entrez-protein","attrs":{"text":"NP_006112.3","term_id":"119395750"}}NP_006112.3:p.Gly71_Gly137del. DNA extracted from peripheral blood lymphocytes did not display the presence of the mutation. These results suggest a somatic mutation causing an alteration in K1 N-terminal variable domain (V1). The deleted sequence involves the ISIS subdomain, containing a lysine residue already described as fundamental for epidermal transglutaminases in the crosslinking of IF cytoskeleton. Moreover, a computational analysis of the wild-type and V1-mutated K1/K10 keratin dimers, suggests an unusual interaction between these keratin filaments. The mutation taster in silico analysis also returned a high probability for a deleterious mutation. These data demonstrate once again the importance of the head domain (V1) of K1 in the formation of a functional keratinocyte cytoskeleton. Moreover, this is a further demonstration of the presence of somatic mutations arising in later stages of the embryogenesis, generating a mosaic phenotype.     

How Cells Communicate with Each Other in the Tumor Microenvironment: Suggestions to Design Novel Therapeutic Strategies in Cancer Disease

Connexin- and pannexin (Panx)-formed hemichannels (HCs) and gap junctions (GJs) operate an interaction with the extracellular matrix and GJ intercellular communication (GJIC), and on account of this they are involved in cancer onset and progression towards invasiveness and metastatization. When we deal with cancer, it is not correct to omit the immune system, as well as neglecting its role in resisting or succumbing to formation and progression of incipient neoplasia until the formation of micrometastasis, nevertheless what really occurs in the tumor microenvironment (TME), which are the main players and which are the tumor or body allies, is still unclear. The goal of this article is to discuss how the pivotal players act, which can enhance or contrast cancer progression during two important process: “Activating Invasion and Metastasis” and the “Avoiding Immune Destruction”, with a particular emphasis on the interplay among GJIC, Panx-HCs, and the purinergic system in the TME without disregarding the inflammasome and cytokines thereof derived. In particular, the complex and contrasting roles of Panx1/P2X7R signalosome in tumor facilitation and/or inhibition is discussed in regard to the early/late phases of the carcinogenesis. Finally, considering this complex interplay in the TME between cancer cells, stromal cells, immune cells, and focusing on their means of communication, we should be capable of revealing harmful messages that help the cancer growth and transform them in body allies, thus designing novel therapeutic strategies to fight cancer in a personalized manner.     

Dihydroartemisinin–Bile Acid Hybridization as an Effective Approach to Enhance Dihydroartemisinin Anticancer Activity

A series of hybrid compounds based on natural products—bile acids and dihydroartemisinin—were prepared by different synthetic methodologies and investigated for their in vitro biological activity against HL-60 leukemia and HepG2 hepatocellular carcinoma cell lines. Most of these hybrids presented significantly improved antiproliferative activities with respect to dihydroartemisinin and the parent bile acid. The two most potent hybrids of the series exhibited a 10.5- and 15.4-fold increase in cytotoxic activity respect to dihydroartemisinin alone in HL-60 and HepG2 cells, respectively. Strong evidence that an ursodeoxycholic acid hybrid induced apoptosis was obtained by flow cytometric analysis and western blot analysis.     

Hybrid materials based on metal oxides and poly(organophosphazenes)

In this paper the sol-gel preparation of hybrid materials made of metal oxide and polytorganophosphazenel components is described. The main problem focused on during this research was to avoid phase separation in order to get homogeneous materials. This problem was pursued looking at the formation of genuine chemical bonds between the exploited polyphosphazenes and the inorganic composite networks. Investigations on the thermal, mechanical, and electroconductive properties of the synthesized, phosphazene-containing composite materials showed that these matrices presented improved mechanical and thermal features with respect to those of the original phosphazene macromolecule, while the ionic conductivities of the prepared molecular hybrids doped with lithium or silver trillate are of the same order of magnitude as those measured for the neat, original phosphazene substrate.Presented at the Ist Italian Workshop on Cyclo- and Polytphosphazenel Materials. February 15–16, 1996. at the CNR Research Area in Padova, Italy.     

Natural and NH<Subscript>4</Subscript><Superscript>+</Superscript>-enriched zeolitite amendment effects on nitrate leaching from a reclaimed agricultural soil (Ferrara Province,Italy)

In this paper we report an overview of the main outcomes of a 3-years experimental cultivation carried out in an Italian reclaimed agricultural field amended with different types of zeolitites (rock containing > 50% of zeolites), under cereals cultivation (Sorghum vulgare Pers, Zea mays and Triticum durum). The aim of the experiment was to exploit the properties of zeolite-rich volcanic rocks (zeolitites) for reducing the excessively high NO₃^? content in the soil and in waters flowing out the sub-surface drainage system of the field and flushing into the surface water system, reducing concomitantly also chemical fertilization application rates (up to 50%). Zeolitites were tested both in their natural state and in a NH₄⁺-enriched form, obtained through an enrichment process with NH₄⁺-rich zoo-technical effluents (pig slurry). NO₃^? content in soils and in waters discharged through SSDS were periodically monitored during the experimentation and crop yield quantified. Results showed that, for three consecutive cultivation cycles, the overall NO₃^? concentrations in water extracts was reduced by 45% in the zeolitite treated soils, while in SSDS waters the reduction reached the 64%. Notwithstanding the lower N input from chemical fertilizers, crop yield was not negatively affected in the zeolitite amended soils with respect to the control. Zeolitite addition increased thus soil NH₄⁺ retention and probably influenced several pathways of N losses, allowing a better fertilizer use efficiency by plants and a reduction of the overall NO₃^? concentrations in the surface waters.     

Heuristic approaches for the optimal wiring in large scale robotic skin design

This paper faces the problem of optimizing the wiring and the connections in a tactile skin for robots. The robotic skin is a device composed of a network of tactile sensors, whose wiring can be very complex: the control of this complexity is a key problem. In the considered robotic skin, skin elements are grouped into skin patches, which output tactile data that have to be read by a micro-controller. The logical connections between the sensors must be defined in order to route signals through the network. A finite set of micro-controllers is given and a set of constraints is imposed on the given assignment and routing. The considered problem has a combinatorial nature and it can be formulated as a Minimum Constrained Spanning Forest problem with costs on arcs that cannot be a priori defined as they are solution-dependent. The problem is NP-hard. The paper introduces a mathematical formulation and then proposes a Multi-Start Heuristic algorithm and an Ant Colony Optimization approach whose effectiveness is evaluated through experimental tests performed on both real and synthetically generated instances.     

Feedforward networks in financial predictions: the future that modifies the present

The main goal of this paper is to show how relatively minor modifications of well-known algorithms (in particular, back propagation) can dramatically increase the performance of an artificial neural network (ANN) for time series prediction. We denote our proposed sets of modifications as the 'self-momentum', 'Freud' and 'Jung' rules. In our opinion, they provide an example of an alternative approach to the design of learning strategies for ANNs, one that focuses on basic mathematical conceptualization rather than on formalism and demonstration. The complexity of actual prediction problems makes it necessary to experiment with modelling possibilities whose inherent mathematical properties are often not well understood yet. The problem of time series prediction in stock markets is a case in point. It is well known that asset price dynamics in financial markets are difficult to trace, let alone to predict with an operationally interesting degree of accuracy. We therefore take financial prediction as a meaningful test bed for the validation of our techniques. We discuss in some detail both the theoretical underpinnings of the technique and our case study about financial prediction, finding encouraging evidence that supports the theoretical and operational viability of our new ANN specifications. Ours is clearly only a preliminary step. Further developments of ANN architectures with more and more sophisticated 'learning to learn' characteristics are now under study and test.