Mechanisms of the FMR1 Repeat Instability: How Does the CGG Sequence Expand?

A dynamic mutation in exon 1 of the FMR1 gene causes Fragile X-related Disorders (FXDs), due to the expansion of an unstable CGG repeat sequence. Based on the CGG sequence size, two types of FMR1 alleles are possible: “premutation” (PM, with 56-200 CGGs) and “full mutation” (FM, with >200 triplets). Premutated females are at risk of transmitting a FM allele that, when methylated, epigenetically silences FMR1 and causes Fragile X syndrome (FXS), a very common form of inherited intellectual disability (ID). Expansions events of the CGG sequence are predominant over contractions and are responsible for meiotic and mitotic instability. The CGG repeat usually includes one or more AGG interspersed triplets that influence allele stability and the risk of transmitting FM to children through maternal meiosis. A unique mechanism responsible for repeat instability has not been identified, but several processes are under investigations using cellular and animal models. The formation of unusual secondary DNA structures at the expanded repeats are likely to occur and contribute to the CGG expansion. This review will focus on the current knowledge about CGG repeat instability addressing the CGG sequence expands.     

ILB®, a Low Molecular Weight Dextran Sulphate,Restores Glutamate Homeostasis,Amino Acid Metabolism and Neurocognitive Functions in a Rat Model of Severe Traumatic Brain Injury

In a previous study, we found that administration of ILB^®, a new low molecular weight dextran sulphate, significantly improved mitochondrial functions and energy metabolism, as well as decreased oxidative/nitrosative stress, of brain tissue of rats exposed to severe traumatic brain injury (sTBI), induced by the closed-head weight-drop model of diffused TBI. Using aliquots of deproteinized brain tissue of the same animals of this former study, we here determined the concentrations of 24 amino acids of control rats, untreated sTBI rats (sacrificed at 2 and 7 days post-injury) and sTBI rats receiving a subcutaneous ILB^® administration (at the dose levels of 1, 5 and 15 mg/kg b.w.) 30 min post-impact (sacrificed at 2 and 7 days post-injury). Additionally, in a different set of experiments, new groups of control rats, untreated sTBI rats and ILB^®-treated rats (administered 30 min after sTBI at the dose levels of 1 or 5 mg/kg b.w.) were studied for their neurocognitive functions (anxiety, locomotor capacities, short- and long-term memory) at 7 days after the induction of sTBI. Compared to untreated sTBI animals, ILB^® significantly decreased whole brain glutamate (normalizing the glutamate/glutamine ratio), glycine, serine and γ-aminobutyric acid. Furthermore, ILB^® administration restored arginine metabolism (preventing nitrosative stress), levels of amino acids involved in methylation reactions (methionine, L-cystathionine, S-adenosylhomocysteine), and N-acetylaspartate homeostasis. The macroscopic evidences of the beneficial effects on brain metabolism induced by ILB^® were the relevant improvement in neurocognitive functions of the group of animals treated with ILB^® 5 mg/kg b.w., compared to the marked cognitive decline measured in untreated sTBI animals. These results demonstrate that ILB^® administration 30 min after sTBI prevents glutamate excitotoxicity and normalizes levels of amino acids involved in crucial brain metabolic functions. The ameliorations of amino acid metabolism, mitochondrial functions and energy metabolism in ILB^®-treated rats exposed to sTBI produced significant improvement in neurocognitive functions, reinforcing the concept that ILB^® is a new effective therapeutic tool for the treatment of sTBI, worth being tested in the clinical setting.     

Fenretinide in Cancer and Neurological Disease: A Two-Face Janus Molecule

Recently, several chemotherapeutic drugs have been repositioned in neurological diseases, based on common biological backgrounds and the inverse comorbidity between cancer and neurodegenerative diseases. Fenretinide (all-trans-N-(4-hydroxyphenyl) retinamide, 4-HPR) is a synthetic derivative of all-trans-retinoic acid initially proposed in anticancer therapy for its antitumor effects combined with limited toxicity. Subsequently, fenretinide has been proposed for other diseases, for which it was not intentionally designed for, due to its ability to influence different biological pathways, providing a broad spectrum of pharmacological effects. Here, we review the most relevant preclinical and clinical findings from fenretinide and discuss its therapeutic role towards cancer and neurological diseases, highlighting the hormetic behavior of this pleiotropic molecule.     

Impact of High-Molecular-Weight Hyaluronic Acid on Gene Expression in Rabbit Achilles Tenocytes In Vitro

(1) Background: Surgical tendon repair often leads to adhesion formation, leading to joint stiffness and a reduced range of motion. Tubular implants set around sutured tendons might help to reduce peritendinous adhesions. The lubricant hyaluronic acid (HA) is a viable option for optimizing such tubes with the goal of further enhancing the anti-adhesive effect. As the implant degrades over time and diffusion is presumed, the impact of HA on tendon cells is important to know. (2) Methods: A culture medium of rabbit Achilles tenocytes was supplemented with high-molecular-weight (HMW) HA and the growth curves of the cells were assessed. Additionally, after 3, 7 and 14 days, the gene expression of several markers was analyzed for matrix assembly, tendon differentiation, fibrosis, proliferation, matrix remodeling, pro-inflammation and resolution. (3) Results: The addition of HA decreased matrix marker genes, downregulated the fibrosis marker α-SMA for a short time and slightly increased the matrix-remodeling gene MMP-2. Of the pro-inflammatory marker genes, only IL-6 was significantly upregulated. IL-6 has to be kept in check, although IL-6 is also needed for a proper initial inflammation and efficient resolution. (4) Conclusions: The observed effects in vitro support the intended anti-adhesion effect and therefore, the use of HMW HA is promising as a biodegradable implant for tendon repair.     

A Novel Morphological Parameter Predicting Fibrotic Evolution in Myeloproliferative Neoplasms: New Evidence and Molecular Insights

Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) represent a group of hematological disorders that are traditionally considered as indistinct slow progressing conditions; still, a subset of cases shows a rapid evolution towards myelofibrotic bone marrow failure. Specific abnormalities in the megakaryocyte lineage seem to play a central role in this evolution, especially in the bone marrow fibrosis but also in the induction of myeloproliferation. In this review, we analyze the current knowledge of prognostic factors of MPNs related to their evolution to myelofibrotic bone marrow failure. Moreover, we focused the role of the megakaryocytic lineage in the various stages of MPNs, with updated examples of MPNs in vitro and in vivo models and new therapeutic implications.     

Evolutionary gaming approach for decision making of Tier‐3 Internet service provider networks migration to SoDIP6 networks

With the increasing number of Internet of Things (IoT) devices, current networking world is suffering in terms of management and operations with lack of IPv4 addresses leading to issues like network address translation (NAT) proliferation, security and quality of services. Software‐defined networking (SDN) and Internet Protocol version 6 (IPv6) are the new networking paradigms evolved to address related issues of legacy IPv4 networking. To adapt with global competitive environment and avoid all existing issues in legacy networking system, network service providers have to migrate their networks into IPv6 and SDN‐enabled networks. But immediate transformations of existing network are not viable due to several factors like higher cost of migration, lack of technical human resources, lack of standards and protocols during transitions, and many more. In this paper, we present the migration analysis for proper decision making of network transition in terms of customer demand, traffic engineering, and organizational strength with operation expenditure for network migration using evolutionary gaming approach. Joint migration to SDN‐enabled IPv6 network from game theoretic perspective is modeled and is validated using numerical results obtained from simulations. Our empirical analysis shows the evolutionary process of network migration while different internal and external factors in the organization affect the overall migration. Evolutionary game in migration planning is supportive in decision making for service providers to develop suitable strategy for their network migration. The proposed approach for migration decision making is mostly applicable to fairly sustained service providers who lack economics, regulation/policy, and resources strengths.     

A Low-Cost and Low-Power Messaging System Based on the LoRa Wireless Technology

Mobile Networks and Applications - In this paper we describe a low-cost and low-power consumption messaging system based on LoRa technology. More that one billion people worldwide cannot access...     

Dielectric properties of two phases of crystalline lutetium oxide

High-dielectric constant oxides are the focus of intense current research. As a contribution to the rationalization of the search for candidate materials, we compare the dielectric properties obtained from first-principles linear-response calculations for two phases—the ground state bixbyite and the competing hexagonal structures—of the crystalline oxide Lu₂O₃. The dielectric constants of bixbyite is about 12 and that of hexagonal is about 19 (the electronic constant being about 4.5 in both cases). This difference is due almost exclusively to the vibrational properties, with minor or no influence of charge anomaly differences; as these are related mainly to oxygen vibrations, we argue that the dielectric properties of sesquioxides will be determined mostly by their preferred structure, i.e. they will be poorer for bixbyite (e.g. Y₂O₃) than for hexagonal (e.g. La₂O₃) sesquioxides.     

A synthesis methodology for AMS/RF circuit reliability: Application to a DCO design

Circuit ageing degradation is becoming worse in advanced technologies, while application fields like military, medical and energy demand more reliability. Thus, reliability is one of the most important challenges of the semiconductor industry [1]. In this work, we review the physical ageing phenomena, their simulation model, and how they can be avoided. Then, we propose a synthesis methodology composed of classical circuit optimization with the reliability analysis in earlier stages. Also, the variability of the integration process technology is taken into account. We compare a classical and a reliable designed digital controlled oscillator (DCO) in order to show a reduction of 16% in the oscillation frequency ageing degradation. In this way, the reliable design makes the circuit lifetime five times longer, if we fix the maximum frequency ageing degradation at 2.0%. Finally, we present the reliability as a design criterion, advantages and disadvantages of our methodology.