Histamine beyond its effects on allergy: Potential therapeutic benefits for the treatment of Amyotrophic Lateral Sclerosis (ALS)

ALS currently remains a challenge despite many efforts in performing successful clinical trials and formulating therapeutic solutions. By learning from current failures and striving for success, scientists and clinicians are checking every possibility to search for missing hints and efficacious treatments. Because the disease is very complex and heterogeneous and, moreover, targeting not only motor neurons but also several different cell types including muscle, glial, and immune cells, the right answer to ALS is conceivably a multidrug strategy or the use of broad-spectrum molecules. The aim of the present work is to gather evidence about novel perspectives on ALS pathogenesis and to present recent and innovative paradigms for therapy. In particular, we describe how an old molecule possessing immunomodulatory and neuroprotective functions beyond its recognized effects on allergy, histamine, might have a renewed and far-reaching momentum in ALS

Nerve growth factor employs multiple pathways to induce primary response genes in PC12 cells

Nerve growth factor (NGF) leads to neuronal differentiation of PC12 cells and promotes their survival in serum-free medium. Past studies have shown that purine analogues block some of the effects of NGF but not others and thus that they can be used to dissect the mechanistic pathways of its action. In the present work we used 2-aminopurine (2-AP) and 6-thioguanine (6-TG) to examine whether NGF causes activation of primary response genes through a single signaling pathway or via multiple pathways. Northern blot analysis and nuclear run-off transcription assays were used to assess the activation of c-fos, c-jun, TIS1, TIS8, and TIS11 after exposure of PC12 cells to NGF in the presence or absence of 2-AP and 6-TG. Our findings indicate that NGF appears to employ at least three distinct pathways to induce early genes in PC12 cells. This suggests that the NGF signaling mechanism diverges at an early point after interaction of NGF with its receptor.Mol Biol Cel

3D gaze in virtual reality: vergence, calibration, event detection

Eye movement analysis in modern 3D rendering systems is reviewed and three new techniques are derived inspired by work developed in early Virtual Reality so-called 2:5D implementations, namely (a) gaze depth (i.e., vergence) estimation, (b) vergence calibration, and (c) real-time 3D event detection that considers eye- and head-coupling. The new 3D calibration shows excellent error reduction in terms of Mean Squared Error (MSE)

S100B protein as a therapeutic target in multiple sclerosis: The S100B inhibitor arundic acid protects from chronic experimental autoimmune encephalomyelitis

S100B is an astrocytic protein behaving at high concentration as a damage-associated molecular pattern molecule. A direct correlation between the increased amount of S100B and inflammatory processes has been demonstrated, and in particular, the inhibitor of S100B activity pentamidine has been shown to ameliorate clinical scores and neuropathologic-biomolecular parameters in the relapsing-remitting experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. This study investigates the effect of arundic acid (AA), a known inhibitor of astrocytic S100B synthesis, in the chronic experimental autoimmune encephalomyelitis, which is another mouse model of multiple sclerosis usually studied. By the daily evaluation of clinical scores and neuropathologic-molecular analysis performed in the spinal cord, we observed that the AA-treated group showed lower severity compared to the vehicle-treated mice, particularly in the early phase of disease onset. We also observed a significant reduction of astrocytosis, demyelination, immune infiltrates, proinflammatory cytokines expression and enzymatic oxidative reactivity in the AA-treated group. Overall, our results reinforce the involvement of S100B in the development of animal models of multiple sclerosis and propose AA targeting the S100B protein as a focused potential drug to be considered for multiple sclerosis treatment

Non-adenine based purines accelerate wound healing

Wound healing is a complex sequence of cellular and molecular processes that involves multiple cell types and biochemical mediators. Several growth factors have been identified that regulate tissue repair, including the neurotrophin nerve growth factor (NGF). As non-adenine based purines (NABPs) are known to promote cell proliferation and the release of growth factors, we investigated whether NABPs had an effect on wound healing. Full-thickness, excisional wound healing in healthy BALB/c mice was significantly accelerated by daily topical application of NABPs such as guanosine (50% closure by days 2.5′.8). Co-treatment of wounds with guanosine plus anti-NGF reversed the guanosine-promoted acceleration of wound healing, indicating that this effect of guanosine is mediated, at least in part, by NGF. Selective inhibitors of the NGF-inducible serine/threonine protein kinase (protein kinase N), such as 6-methylmercaptopurine riboside abolished the acceleration of wound healing caused by guanosine, confirming that activation of this enzyme is required for this effect of guanosine. Treatment of genetically diabetic BKS.Cg-m+/+lepr db mice, which display impaired wound healing, with guanosine led to accelerated healing of skin wounds (25% closure by days 2.8′.0). These results provide further confirmation that the NABP-mediated acceleration of cutaneous wound healing is mediated via an NGF-dependent mechanism. Thus, NABPs may offer an alternative and viable approach for the treatment of wounds in a clinical setting

Pioneer Anomaly and the Kuiper Belt mass distribution

Pioneer 10 and 11 were the first probes sent to study the outer planets of the Solar System and Pioneer 10 was the first spacecraft to leave the Solar System. Besides their already epic journeys, Pioneer 10 and 11 spacecraft were subjected to an unaccounted effect interpreted as a constant acceleration toward the Sun, the so-called Pioneer anomaly. One of the possibilities put forward for explaining the Pioneer anomaly is the gravitational acceleration of the Kuiper Belt. In this work we examine this hypothesis for various models for the Kuiper Belt mass distribution. We find that the gravitational effect due to the Kuiper Belt cannot account for the Pioneer anomaly. Furthermore, we have also studied the hypothesis that drag forces can explain the the Pioneer anomaly; however we conclude that the density required for producing the Pioneer anomaly is many orders of magnitude greater than those of interplanetary and interstellar dust. Our conclusions suggest that only through a mission, the Pioneer anomaly can be confirmed and further investigated. If a mission with these aims is ever sent to space, it turns out, on account of our results, that it will be also a quite interesting probe to study the mass distribution of the Kuiper Belt.Comment: Plain latex; 17 pages, 12 figures. Version to appear in Classical and Quantum Gravity (2006

Proof of Concept: Wearable Augmented Reality Video See-Through Display for Neuro-Endoscopy

In mini-invasive surgery and in endoscopic procedures, the surgeon operates without a direct visualization of the patient’s anatomy. In image-guided surgery, solutions based on wearable augmented reality (AR) represent the most promising ones. The authors describe the characteristics that an ideal Head Mounted Display (HMD) must have to guarantee safety and accuracy in AR-guided neurosurgical interventions and design the ideal virtual content for guiding crucial task in neuro endoscopic surgery. The selected sequence of AR content to obtain an effective guidance during surgery is tested in a Microsoft Hololens based app

Roles of P2 receptors in glial cells: focus on astrocytes

Central nervous system glial cells release and respond to nucleotides under both physiological and pathological conditions, suggesting that these molecules play key roles in both normal brain function and in repair after damage. In particular, ATP released from astrocytes activates P2 receptors on astrocytes and other brain cells, allowing a form of homotypic and heterotypic signalling, which also involves microglia, neurons and oligodendrocytes. Multiple P2X and P2Y receptors are expressed by both astrocytes and microglia; however, these receptors are differentially recruited by nucleotides, depending upon specific pathophysiological conditions, and also mediate the long-term trophic changes of these cells during inflammatory gliosis. In astrocytes, P2-receptor-induced gliosis occurs via activation of the extracellular-regulated kinases (ERK) and protein kinase B/Akt pathways and involves induction of inflammatory and anti-inflammatory genes, cyclins, adhesion and antiapoptotic molecules. While astrocytic P2Y1 and P2Y2,4 are primarily involved in short-term calcium-dependent signalling, multiple P2 receptor subtypes seem to cooperate to astrocytic long-term changes. Conversely, in microglia, exposure to inflammatory and immunological stimuli results in differential functional changes of distinct P2 receptors, suggesting highly specific roles in acquisition of the activated phenotype. We believe that nucleotide-induced activation of astrocytes and microglia may originally start as a defence mechanism to protect neurons from cytotoxic and ischaemic insults; dysregulation of this process in chronic inflammatory diseases eventually results in neuronal cell damage and loss. On this basis, full elucidation of the specific roles of P2 receptors in these cells may help exploit the beneficial neuroprotective features of activated glia while attenuating their harmful properties and thus provide the basis for novel neuroprotective strategies that specifically target the purinergic system

Reasons behind the worldwide diversity in identity and issuance of good governance codes

This study examines the impact of socio-economic factors on the number of good governance codes and issuers of the first codes at the macro-country level. By covering 3200 observations for 160 countries over 1995–2014, this study reports that countries with Anglo-Saxon culture and strong investor protection laws have developed a large number of good governance codes to meet the efficiency needs of legal, political, and cultural values. Moreover, this paper shows that countries with English common law origin alongside civil or religious law have developed a large number of good governance codes. Furthermore, this study indicates that countries with high regulatory quality index have issued a large number of governance codes as a response to the external forces that emerge from coercive associations. However, this study found a positive and significant association between the control of corruption index and the number of governance codes issued by governments to mitigate corruption risk. Additionally, this study reports that countries that issued a large number of good governance codes have gained substantial foreign direct investments inflows and financial aid. This study, therefore, provides meaningful implications for governments and policymakers in countries with weak regulations to issue new governance codes for protecting investors’ rights, thus gain more financial resources

Role of N-terminal tau domain integrity on the survival of cerebellar granule neurons

Although the role of the microtubule-binding domain of the tau protein in the modulation of microtubule assembly is widely established, other possible functions of this protein have been poorly investigated. We have analyzed the effect of adenovirally mediated expression of two fragments of the N-terminal portion - free of microtubule-binding domain - of the tau protein in cerebellar granule neurons (CGNs). We found that while the expression of the tau (1-230) fragment, as well as of full-length tau, inhibits the onset of apoptosis, the tau (1-44) fragment exerts a powerful toxic action on the same neurons. The antiapoptotic action of tau (1-230) is exerted at the level of Akt-mediated activation of the caspase cascade. On the other hand, the toxic action of the (1-44) fragment is not prevented by inhibitors of CGN apoptosis, but is fully inhibited by NMDA receptor antagonists. These findings point to a novel, physiological role of the N-terminal domain of tau, but also underlay that its possible proteolytic truncation mediated by apoptotic proteases may generate a highly toxic fragment that could contribute to neuronal death