Wnt Signaling Through Nitric Oxide Synthase Promotes the Formation of Multi-Innervated Spines

Structural plasticity of synapses correlates with changes in synaptic strength. Dynamic modifications in dendritic spine number and size are crucial for long-term potentiation (LTP), the cellular correlate of learning and memory. Recent studies have suggested the generation of multi-innervated spines (MIS), in the form of several excitatory presynaptic inputs onto one spine, are crucial for hippocampal memory storage. However, little is known about the molecular mechanisms underlying MIS formation and their contribution to LTP. Using 3D enhanced resolution confocal images, we examined the contribution of Wnt synaptic modulators in MIS formation in the context of LTP. We show that blockage of endogenous Wnts with specific Wnt antagonists supresses the formation of MIS upon chemical LTP induction in cultured hippocampal neurons. Gain- and loss-of-function studies demonstrate that Wnt7a signaling promotes MIS formation through the postsynaptic Wnt scaffold protein Disheveled 1 (Dvl1) by stimulating neuronal nitric oxide (NO) synthase (nNOS). Subsequently, NO activates soluble guanylyl cyclase (sGC) to increase MIS formation. Consistently, we observed an enhanced frequency and amplitude of excitatory postsynaptic currents. Collectively, our findings identify a unique role for Wnt secreted proteins through nNOS/NO/sGC signaling to modulate MIS formation during LTP

Adaptation of the Bergen Social Media Addiction Scale (BSMAS) in Spanish

The impact of social networks on people's daily lives is worrisome, particularly in adolescents and young people, who seem to exceed the limits of normal use. Constant excessive use can lead to pathological behaviors linked to social media addiction (SMA). Our objectives were to 1) adapt the Bergen Social Media Addiction Scale (BSMAS) to Spanish and 2) evaluate its psychometric properties in a young population. The BSMAS was adapted to Spanish, involving experts on social media addiction and people from the target population during the adaptation process. For the psychometric evaluation, 650 Peruvian college students responded to the Spanish version (53.5 % women aged 18 to 40, M = 21.5 SD = 2.7). The one-dimensional measurement model proposed for the original BSMAS was confirmed for our version (X2(9) = 23.9315, CFI = 0.994, TLI = 0.990, SRMR = 0.032, RMSEA = 0.061). The reliability was good (α = 0.863; 95 % CI: 0.848–0.870; ω = 0.864; 95 % CI: 0.846–0.844), and the measurement invariance was confirmed for sex and age by fitting models. The concurrent validity with external social media addiction and mental health indicators was also confirmed. This study provides new and relevant information on the BSMAS validity and allows its application to Spanish-speaker college students from Peru and similar countries

Epigenetic repression of Wnt receptors in AD: a role for Sirtuin2-induced H4K16ac deacetylation of Frizzled1 and Frizzled7 promoters

Growing evidence supports a role for deficient Wnt signalling in Alzheimer’s disease (AD). First, the Wnt antagonist DKK1 is elevated in AD brains and is required for amyloid-β-induced synapse loss. Second, LRP6 Wnt co-receptor is required for synapse integrity and three variants of this receptor are linked to late-onset AD. However, the expression/role of other Wnt signalling components remain poorly explored in AD. Wnt receptors Frizzled1 (Fzd1), Fzd5, Fzd7 and Fzd9 are of interest due to their role in synapse formation/plasticity. Our analyses showed reduced FZD1 and FZD7 mRNA levels in the hippocampus of human early AD stages and in the hAPPNLGF/NLGF mouse model. This transcriptional downregulation was accompanied by reduced levels of the pro-transcriptional histone mark H4K16ac and a concomitant increase of its deacetylase Sirt2 at Fzd1 and Fzd7 promoters in AD. In vitro and in vivo inhibition of Sirt2 rescued Fzd1 and Fzd7 mRNA expression and H4K16ac levels at their promoters. In addition, we showed that Sirt2 recruitment to Fzd1 and Fzd7 promoters is dependent on FoxO1 activity in AD, thus acting as a co-repressor. Finally, we found reduced levels of SIRT2 inhibitory phosphorylation in nuclear samples from human early AD stages with a concomitant increase in the SIRT2 phosphatase PP2C. This results in hyperactive nuclear Sirt2 and favours Fzd1 and Fzd7 repression in AD. Collectively, our findings define a novel role for nuclear hyperactivated SIRT2 in repressing Fzd1 and Fzd7 expression via H4K16ac deacetylation in AD. We propose SIRT2 as an attractive target to ameliorate AD pathology

Beyond literacy and numeracy in patient provider communication: Focus groups suggest roles for empowerment, provider attitude and language

<p>Abstract</p> <p>Background</p> <p>Although the number of people living in the United States with limited English proficiency (LEP) is substantial, the impact of language on patients' experience of provider-patient communication has been little explored.</p> <p>Methods</p> <p>We conducted a series of 12 exploratory focus groups in English, Spanish and Cantonese to elicit discussion about patient-provider communication, particularly with respect to the concerns of the health literacy framework, i.e. ability to accurately understand, interpret and apply information given by providers. Within each language, 2 groups had high education and 2 had low education participants to partially account for literacy levels, which cannot be assessed consistently across three languages. Eighty-five (85) adults enrolled in the focus groups. The resulting video tapes were transcribed, translated and analyzed via content analysis.</p> <p>Results</p> <p>We identified 5 themes: 1) language discordant communication; 2) language concordant communication; 3) empowerment; 4) providers' attitudes; 5) issues with the health care system. Despite efforts by facilitators to elicit responses related to cognitive understanding, issues of interpersonal process were more salient, and respondents did not readily separate issues of accurate understanding from their overall narratives of experience with health care and illness. Thematic codes often appeared to be associated with education level, language and/or culture.</p> <p>Conclusion</p> <p>Our most salient finding was that for most of our participants there was no clear demarcation between literacy and numeracy, language interpretation, health communication, interpersonal relations with their provider and the rest of their experience with the health care system.</p

The diacylglycerol kinase α/Atypical PKC/β1 integrin pathway in SDF-1α mammary carcinoma invasiveness

Diacylglycerol kinase α (DGKα), by phosphorylating diacylglycerol into phosphatidic acid, provides a key signal driving cell migration and matrix invasion. We previously demonstrated that in epithelial cells activation of DGKα activity promotes cytoskeletal remodeling and matrix invasion by recruiting atypical PKC at ruffling sites and by promoting RCP-mediated recycling of α5β1 integrin to the tip of pseudopods. In here we investigate the signaling pathway by which DGKα mediates SDF-1α-induced matrix invasion of MDA-MB-231 invasive breast carcinoma cells. Indeed we showed that, following SDF-1α stimulation, DGKα is activated and localized at cell protrusion, thus promoting their elongation and mediating SDF-1α induced MMP-9 metalloproteinase secretion and matrix invasion. Phosphatidic acid generated by DGKα promotes localization at cell protrusions of atypical PKCs which play an essential role downstream of DGKα by promoting Rac-mediated protrusion elongation and localized recruitment of β1 integrin and MMP-9. We finally demonstrate that activation of DGKα, atypical PKCs signaling and β1 integrin are all essential for MDA-MB-231 invasiveness. These data indicates the existence of a SDF-1α induced DGKα - atypical PKC - β1 integrin signaling pathway, which is essential for matrix invasion of carcinoma cells

The Antibacterial Activity of Honey Derived from Australian Flora

Chronic wound infections and antibiotic resistance are driving interest in antimicrobial treatments that have generally been considered complementary, including antimicrobially active honey. Australia has unique native flora and produces honey with a wide range of different physicochemical properties. In this study we surveyed 477 honey samples, derived from native and exotic plants from various regions of Australia, for their antibacterial activity using an established screening protocol. A level of activity considered potentially therapeutically useful was found in 274 (57%) of the honey samples, with exceptional activity seen in samples derived from marri (Corymbia calophylla), jarrah (Eucalyptus marginata) and jellybush (Leptospermum polygalifolium). In most cases the antibacterial activity was attributable to hydrogen peroxide produced by the bee-derived enzyme glucose oxidase. Non-hydrogen peroxide activity was detected in 80 (16.8%) samples, and was most consistently seen in honey produced from Leptospermum spp. Testing over time found the hydrogen peroxide-dependent activity in honey decreased, in some cases by 100%, and this activity was more stable at 4°C than at 25°C. In contrast, the non-hydrogen peroxide activity of Leptospermum honey samples increased, and this was greatest in samples stored at 25°C. The stability of non-peroxide activity from other honeys was more variable, suggesting this activity may have a different cause. We conclude that many Australian honeys have clinical potential, and that further studies into the composition and stability of their active constituents are warranted

Effect of human leukocyte antigen heterozygosity on infectious disease outcome: The need for allele-specific measures

BACKGROUND: Doherty and Zinkernagel, who discovered that antigen presentation is restricted by the major histocompatibility complex (MHC, called HLA in humans), hypothesized that individuals heterozygous at particular MHC loci might be more resistant to particular infectious diseases than the corresponding homozygotes because heterozygotes could present a wider repertoire of antigens. The superiority of heterozygotes over either corresponding homozygote, which we term allele-specific overdominance, is of direct biological interest for understanding the mechanisms of immune response; it is also a leading explanation for the observation that MHC loci are extremely polymorphic and that these polymorphisms have been maintained through extremely long evolutionary periods. Recent studies have shown that in particular viral infections, heterozygosity at HLA loci was associated with a favorable disease outcome, and such findings have been interpreted as supporting the allele-specific overdominance hypothesis in humans. METHODS: An algebraic model is used to define the expected population-wide findings of an epidemiologic study of HLA heterozygosity and disease outcome as a function of allele-specific effects and population genetic parameters of the study population. RESULTS: We show that overrepresentation of HLA heterozygotes among individuals with favorable disease outcomes (which we term population heterozygote advantage) need not indicate allele-specific overdominance. On the contrary, partly due to a form of confounding by allele frequencies, population heterozygote advantage can occur under a very wide range of assumptions about the relationship between homozygote risk and heterozygote risk. In certain extreme cases, population heterozygote advantage can occur even when every heterozygote is at greater risk of being a case than either corresponding homozygote. CONCLUSION: To demonstrate allele-specific overdominance for specific infections in human populations, improved analytic tools and/or larger studies (or studies in populations with limited HLA diversity) are necessary