Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension

Moyamoya disease (MMD) is a progressive vasculopathy characterized by occlusion of the terminal portion of the internal carotid arteries and its branches, and the formation of compensatory moyamoya collateral vessels. Homozygous mutations in GUCY1A3 have been reported as a cause of MMD and achalasia. Probands (n = 96) from unrelated families underwent sequencing of GUCY1A3. Functional studies were performed to confirm the pathogenicity of identified GUCY1A3 variants. Two affected individuals from the unrelated families were found to have compound heterozygous mutations in GUCY1A3. MM041 was diagnosed with achalasia at 4 years of age, hypertension and MMD at 18 years of age. MM149 was diagnosed with MMD and hypertension at the age of 20 months. Both individuals carry one allele that is predicted to lead to haploinsufficiency and a second allele that is predicted to produce a mutated protein. Biochemical studies of one of these alleles, GUCY1A3 Cys517Tyr, showed that the mutant protein (a subunit of soluble guanylate cyclase) has a significantly blunted signaling response with exposure to nitric oxide (NO). GUCY1A3 missense and haploinsufficiency mutations disrupt NO signaling leading to MMD and hypertension, with or without achalasia

Orally Administrated Cinnamon Extract Reduces β-Amyloid Oligomerization and Corrects Cognitive Impairment in Alzheimer's Disease Animal Models

An increasing body of evidence indicates that accumulation of soluble oligomeric assemblies of β-amyloid polypeptide (Aβ) play a key role in Alzheimer's disease (AD) pathology. Specifically, 56 kDa oligomeric species were shown to be correlated with impaired cognitive function in AD model mice. Several reports have documented the inhibition of Aβ plaque formation by compounds from natural sources. Yet, evidence for the ability of common edible elements to modulate Aβ oligomerization remains an unmet challenge. Here we identify a natural substance, based on cinnamon extract (CEppt), which markedly inhibits the formation of toxic Aβ oligomers and prevents the toxicity of Aβ on neuronal PC12 cells. When administered to an AD fly model, CEppt rectified their reduced longevity, fully recovered their locomotion defects and totally abolished tetrameric species of Aβ in their brain. Furthermore, oral administration of CEppt to an aggressive AD transgenic mice model led to marked decrease in 56 kDa Aβ oligomers, reduction of plaques and improvement in cognitive behavior. Our results present a novel prophylactic approach for inhibition of toxic oligomeric Aβ species formation in AD through the utilization of a compound that is currently in use in human diet

Overcoming degradation in spatial multiplexing systems with stochastic nonlinear impairments

Single-mode optical fibres now underpin telecommunication systems and have allowed continuous increases in traffic volume and bandwidth demand whilst simultaneously reducing cost- and energy-per-bit over the last 40 years. However, it is now recognised that such systems are rapidly approaching the limits imposed by the nonlinear Kerr effect. To address this, recent research has been carried out into mitigating Kerr nonlinearities to increase the nonlinear threshold and into spatial multiplexing to offer additional spatial pathways. However, given the complexity associated with nonlinear transmission in spatial multiplexed systems subject to random inter-spatial-path nonlinearities it is widely believed that these technologies are mutually exclusive. By investigating the linear and nonlinear crosstalk in few-mode fibres based optical communications, we numerically demonstrate, for the first time, that even in the presence of significant random mixing of signals, substantial performance benefits are possible. To achieve this, the impact of linear mixing on the Kerr nonlinearities should be taken into account using different compensation strategies for different linear mixing regimes. For the optical communication systems studied, we demonstrate that the performance may be more than doubled with the appropriate selection of compensation method for fibre characteristics which match those presented in the literature

Single molecule tracking fluorescence microscopy in mitochondria reveals highly dynamic but confined movement of Tom40

Tom40 is an integral protein of the mitochondrial outer membrane, which as the central component of the Translocase of the Outer Membrane (TOM) complex forms a channel for protein import. We characterize the diffusion properties of individual Tom40 molecules fused to the photoconvertable fluorescent protein Dendra2 with millisecond temporal resolution. By imaging individual Tom40 molecules in intact isolated yeast mitochondria using photoactivated localization microscopy with sub-diffraction limited spatial precision, we demonstrate that Tom40 movement in the outer mitochondrial membrane is highly dynamic but confined in nature, suggesting anchoring of the TOM complex as a whole

Self-Organized Criticality in Developing Neuronal Networks

Recently evidence has accumulated that many neural networks exhibit self-organized criticality. In this state, activity is similar across temporal scales and this is beneficial with respect to information flow. If subcritical, activity can die out, if supercritical epileptiform patterns may occur. Little is known about how developing networks will reach and stabilize criticality. Here we monitor the development between 13 and 95 days in vitro (DIV) of cortical cell cultures (n = 20) and find four different phases, related to their morphological maturation: An initial low-activity state (≈19 DIV) is followed by a supercritical (≈20 DIV) and then a subcritical one (≈36 DIV) until the network finally reaches stable criticality (≈58 DIV). Using network modeling and mathematical analysis we describe the dynamics of the emergent connectivity in such developing systems. Based on physiological observations, the synaptic development in the model is determined by the drive of the neurons to adjust their connectivity for reaching on average firing rate homeostasis. We predict a specific time course for the maturation of inhibition, with strong onset and delayed pruning, and that total synaptic connectivity should be strongly linked to the relative levels of excitation and inhibition. These results demonstrate that the interplay between activity and connectivity guides developing networks into criticality suggesting that this may be a generic and stable state of many networks in vivo and in vitro

The impact of corporate social responsibility disclosure on financial performance : evidence from the GCC Islamic banking sector.

This paper examines the relationship between corporate social responsibility (CSR) and financial performance for Islamic banks in the Gulf Cooperation Council (GCC) region over the period 2000–2014 by generating CSR-related data through disclosure analysis of the annual reports of the sampled banks. The findings of this study indicate that there is a significant positive relationship between CSR disclosure and the financial performance of Islamic banks in the GCC countries. The results also show a positive relationship between CSR disclosure and the future financial performance of GCC Islamic banks, potentially indicating that current CSR activities carried out by Islamic banks in the GCC could have a long-term impact on their financial performance. Furthermore, despite demonstrating a significant positive relationship between the composite measure of the CSR disclosure index and financial performance, the findings show no statistically significant relationship between the individual dimensions of the CSR disclosure index and the current financial performance measure except for ‘mission and vision’ and ‘products and services’. Similarly, the empirical results detect a positive significant association only between ‘mission and vision’ dimension and future financial performance of the examined banks

Depolarization-Evoked Secretion Requires Two Vicinal Transmembrane Cysteines of Syntaxin 1A

BACKGROUND: The interactions of the voltage-gated Ca(2+) channel (VGCC) with syntaxin 1A (Sx 1A), Synaptosome-associated protein of 25 kD (SNAP-25), and synaptotagmin, couple electrical excitation to evoked secretion. Two vicinal Cys residues, Cys 271 and Cys 272 in the Sx 1A transmembrane domain, are highly conserved and participate in modulating channel kinetics. Each of the Sx1A Cys mutants, differently modify the kinetics of Cav1.2, and neuronal Cav2.2 calcium channel. METHODOLOGY/PRINCIPLE FINDINGS: We examined the effects of various Sx1A Cys mutants and the syntaxin isoforms 2, 3, and 4 each of which lack vicinal Cys residues, on evoked secretion, monitoring capacitance transients in a functional release assay. Membrane capacitance in Xenopus oocytes co-expressing Cav1.2, Sx1A, SNAP-25 and synaptotagmin, which is Bot C- and Bot A-sensitive, was elicited by a double 500 ms depolarizing pulse to 0 mV. The evoked-release was obliterated when a single Cys Sx1A mutant or either one of the Sx isoforms were substituted for Sx 1A, demonstrating the essential role of vicinal Cys residues in the depolarization mediated process. Protein expression and confocal imaging established the level of the mutated proteins in the cell and their targeting to the plasma membrane. CONCLUSIONS/SIGNIFICANCE: We propose a model whereby the two adjacent transmembranal Cys residues of Sx 1A, lash two calcium channels. Consistent with the necessity of a minimal fusion complex termed the excitosome, each Sx1A is in a complex with SNAP-25, Syt1, and the Ca(2+) channel. A Hill coefficient >2 imply that at least three excitosome complexes are required for generating a secreting hetero-oligomer protein complex. This working model suggests that a fusion pore that opens during membrane depolarization could be lined by alternating transmembrane segments of Sx1A and VGCC. The functional coupling of distinct amino acids of Sx 1A with VGCC appears to be essential for depolarization-evoked secretion

Panel 7: otitis media:treatment and complications

Objective: We aimed to summarize key articles published between 2011 and 2015 on the treatment of (recurrent) acute otitis media, otitis media with effusion, tympanostomy tube otorrhea, chronic suppurative otitis media and complications of otitis media, and their implications for clinical practice. Data Sources: PubMed, Ovid Medline, the Cochrane Library, and Clinical Evidence (BMJ Publishing). Review Methods: All types of articles related to otitis media treatment and complications between June 2011 and March 2015 were identified. A total of 1122 potential related articles were reviewed by the panel members; 118 relevant articles were ultimately included in this summary. Conclusions: Recent literature and guidelines emphasize accurate diagnosis of acute otitis media and optimal management of ear pain. Watchful waiting is optional in mild to moderate acute otitis media; antibiotics do shorten symptoms and duration of middle ear effusion. The additive benefit of adenoidectomy to tympanostomy tubes in recurrent acute otitis media and otitis media with effusion is controversial and age dependent. Topical antibiotic is the treatment of choice in acute tube otorrhea. Symptomatic hearing loss due to persistent otitis media with effusion is best treated with tympanostomy tubes. Novel molecular and biomaterial treatments as adjuvants to surgical closure of eardrum perforations seem promising. There is insufficient evidence to support the use of complementary and alternative treatments. Implications for Practice: Emphasis on accurate diagnosis of otitis media, in its various forms, is important to reduce overdiagnosis, overtreatment, and antibiotic resistance. Children at risk for otitis media and its complications deserve special attention

Malignant mesothelioma

Malignant mesothelioma is a fatal asbestos-associated malignancy originating from the lining cells (mesothelium) of the pleural and peritoneal cavities, as well as the pericardium and the tunica vaginalis. The exact prevalence is unknown but it is estimated that mesotheliomas represent less than 1% of all cancers. Its incidence is increasing, with an expected peak in the next 10–20 years. Pleural malignant mesothelioma is the most common form of mesothelioma. Typical presenting features are those of chest pain and dyspnoea. Breathlessness due to a pleural effusion without chest pain is reported in about 30% of patients. A chest wall mass, weight loss, sweating, abdominal pain and ascites (due to peritoneal involvement) are less common presentations. Mesothelioma is directly attributable to occupational asbestos exposure with a history of exposure in over 90% of cases. There is also evidence that mesothelioma may result from both para-occupational exposure and non-occupational "environmental" exposure. Idiopathic or spontaneous mesothelioma can also occur in the absence of any exposure to asbestos, with a spontaneous rate in humans of around one per million. A combination of accurate exposure history, along with examination radiology and pathology are essential to make the diagnosis. Distinguishing malignant from benign pleural disease can be challenging. The most helpful CT findings suggesting malignant pleural disease are 1) a circumferential pleural rind, 2) nodular pleural thickening, 3) pleural thickening of > 1 cm and 4) mediastinal pleural involvement. Involvement of a multidisciplinary team is recommended to ensure prompt and appropriate management, using a framework of radiotherapy, chemotherapy, surgery and symptom palliation with end of life care. Compensation issues must also be considered. Life expectancy in malignant mesothelioma is poor, with a median survival of about one year following diagnosis