Hippocampal overexpression of NOS1AP promotes endophenotypes related to mental disorders.

BACKGROUND Nitric oxide synthase 1 adaptor protein (NOS1AP; previously named CAPON) is linked to the glutamatergic postsynaptic density through interaction with neuronal nitric oxide synthase (nNOS). NOS1AP and its interaction with nNOS have been associated with several mental disorders. Despite the high levels of NOS1AP expression in the hippocampus and the relevance of this brain region in glutamatergic signalling as well as mental disorders, a potential role of hippocampal NOS1AP in the pathophysiology of these disorders has not been investigated yet. METHODS To uncover the function of NOS1AP in hippocampus, we made use of recombinant adeno-associated viruses to overexpress murine full-length NOS1AP or the NOS1AP carboxyterminus in the hippocampus of mice. We investigated these mice for changes in gene expression, neuronal morphology, and relevant behavioural phenotypes. FINDINGS We found that hippocampal overexpression of NOS1AP markedly increased the interaction of nNOS with PSD-95, reduced dendritic spine density, and changed dendritic spine morphology at CA1 synapses. At the behavioural level, we observed an impairment in social memory and decreased spatial working memory capacity. INTERPRETATION Our data provide a mechanistic explanation for a highly selective and specific contribution of hippocampal NOS1AP and its interaction with the glutamatergic postsynaptic density to cross-disorder pathophysiology. Our findings allude to therapeutic relevance due to the druggability of this molecule. FUNDING This study was funded in part by the DFG, the BMBF, the Academy of Finland, the NIH, the Japanese Society of Clinical Neuropsychopharmacology, the Ministry of Education of the Russian Federation, and the European Community

The para-disciplinary role of Design transforming innovation in organisations

The research addresses the role of Design creating value at the intersections of disciplines in organisations. It presents a revision to the discourse on the nature of and relationship between Design and other disciplines. This paper advocates a new para-disciplinary term for the post-disciplinary state of Design in its contemporary practices, acting as the ‘inter-discipline’ within organisations that are intent on the strategic development of their innovation capacity and potential. The work is based on the synthesis of findings from a longitudinal range of practice based design research projects undertaken across industry and the third sector over the last four years. Case studies of these projects demonstrate that the involvement of Design has resulted in successive levels of influence leading to the radical transformation of the organisations’ innovation strategies. The implication for the generic aspect of these findings is discussed in terms of inter-disciplinary discourses

How Industrial Design supports a Customer-Centric Innovation approach in a Technology-Centric business environment

This paper provides a case-study whereby a UK University has been working in close partnership with Parker Hannifin Corporation, a Fortune 500 US manufacturing company, to develop new innovation practices. It discusses how Industrial Design has been introduced as an in-house function to one of the company’s divisional headquarters, in Gateshead, UK, through a collaborative research partnership over three years. Case material from four projects is presented, which illustrates a progressive, negotiated adoption by the company of the capabilities of Industrial Design as an essential component of a Customer-Centric Innovation approach. It has involved developing the organisation’s own confidence about the value and fit of Industrial Design through a series of projects and regular reflection on what is working well, not-so-well and what is raising concerns. The approach described provides an alternative to attempting to develop and implement a pre-formulated ‘grand-plan’ for Design. Keywords: customer-centric innovation; industrial design; large organisations; design-led innovation; manufacturin

MEMS piezoelectric artificial basilar membrane with passive frequency selectivity for short pulse width signal modulation

We demonstrated a novel MEMS artificial basilar membrane composed of a piezoelectric beam array that mimics the passive frequency selectivity of the cochlea and exhibits acoustic-to-electrical energy conversion. Each beam was designed to have a unique resonance frequency. To determine the resonance frequencies of the beams, the displacement and piezoelectric voltage were measured by applying a periodic chirped signal with a sound pressure level of 109.7 dB. The measured resonance frequencies were in the range 10-37 kHz. The piezoelectric signal was used to modulate a finite pulse-width signal for electrical stimulation; the pulse widths were in the range 0.43-5.1 ms with sound pressure levels in the range 84.9-112.4 dB. © 2013 Elsevier B.V.1

Ultrasound imaging of dorsal neck muscles with speckle tracking analyses - the relationship between muscle deformation and force

The development of methods of non-invasive measurement of neck muscle function remains a priority in the clinical sciences. In this study, dorsal neck muscle deformation vs time curves (deformation area) were evaluated against incremental force, recorded from non-invasive real-time ultrasound measurement. The results revealed subject-specific moderate to strong linear or non-linear relationships between deformation and force. Test-retest variability showed strong reliability for all five neck muscles summed together and fair to good reliability for the five muscles evaluated separately. Multivariate statistics were used to analyse the interactions between the dorsal neck muscles during different percentages of maximal voluntary contraction (MVC). Low force (10-20% MVC) was related to muscle shortening; higher force (40-80% MVC) showed combination of shortening and elongation deformation in the muscle interactions. The muscle interactions during isometric MVC test were subject-specific, with different combinations and deformations of the five neck muscles. Force amp;gt;= 40% MVC were associated with a forward movement of the cervical spine that affected the ultrasound measurement of the dorsal neck muscles. Ultrasound with speckle-tracking analyses may be best used to detect low levels (amp;lt;40% MVC) of neck muscle activity.Funding Agencies|Swedish government; Swedish Social Insurance Agency through the REHSAM foundation; Swedish Research CouncilSwedish Research Council; Centre for Clinical Research Sormland at Uppsala University Sweden; Swedish Society of Medicine</p

STING-dependent type I IFN production inhibits cell-mediated immunity to Listeria monocytogenes.

Infection with Listeria monocytogenes strains that enter the host cell cytosol leads to a robust cytotoxic T cell response resulting in long-lived cell-mediated immunity (CMI). Upon entry into the cytosol, L. monocytogenes secretes cyclic diadenosine monophosphate (c-di-AMP) which activates the innate immune sensor STING leading to the expression of IFN-β and co-regulated genes. In this study, we examined the role of STING in the development of protective CMI to L. monocytogenes. Mice deficient for STING or its downstream effector IRF3 restricted a secondary lethal challenge with L. monocytogenes and exhibited enhanced immunity that was MyD88-independent. Conversely, enhancing STING activation during immunization by co-administration of c-di-AMP or by infection with a L. monocytogenes mutant that secretes elevated levels of c-di-AMP resulted in decreased protective immunity that was largely dependent on the type I interferon receptor. These data suggest that L. monocytogenes activation of STING downregulates CMI by induction of type I interferon

Psychiatric disorder as a risk factor for cancer : different analytic strategies produce different findings

Reported associations between psychiatric disorders and cancer incidence are inconsistent, with cancer rates in psychiatric patients that are variously higher than, similar to, or lower than the general population. Understanding these associations is complicated by difficulties in establishing the timing of onset of psychiatric disorders and cancer, and by the possibility of reverse causality. Some studies have dealt with this problem by excluding patients with cancers predating their psychiatric illness; others have not considered the issue. We examined associations between psychiatric hospitalization and cancer incidence in a cohort of 1,165,039 Swedish men, and we explored the impact of different analytic strategies on these associations using real and simulated data. Relative to men without psychiatric hospitalization, we observed consistent increases in smoking-related cancers in those with psychiatric hospitalizations, regardless of analytic approach (eg, hazard ratio = 1.73 [95% confidence interval = 1.52-1.96]). However, associations with cancers unrelated to smoking were highly dependent on analytic strategy. In analyses based on the full cohort, we observed no association or a modest increase in cancer incidence in those with psychiatric hospitalizations (1.14 [1.07-1.22 ]). In contrast, when men whose cancer predated their psychiatric hospitalizations were excluded, future cancer incidence was lower in psychiatric patients (0.72 [0.67-0.78]). Results from simulated data suggest that even modest exclusions of this type can lead to strong artifactual associations. Psychiatric disorder-cancer incidence associations are complex and influenced by analytic strategy. A better understanding of the temporal relationship between psychiatric disorder and cancer incidence is required

Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy

OBJECTIVE: ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series. METHODS: We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant. RESULTS: We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an in vitro splicing assay, we show that c.1516A>G ACTN2 does not impair normal splicing. INTERPRETATION: This series further establishes ACTN2 as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult-onset progressive muscle disease

Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy.

OBJECTIVE: ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series. METHODS: We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant. RESULTS: We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A&gt;G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an in vitro splicing assay, we show that c.1516A&gt;G ACTN2 does not impair normal splicing. INTERPRETATION: This series further establishes ACTN2 as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult-onset progressive muscle disease