Hippocampal overexpression of NOS1AP promotes endophenotypes related to mental disorders

BACKGROUND\nMETHODS\nFINDINGS\nINTERPRETATION\nFUNDING\nNitric 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.\nTo 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.\nWe 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.\nOur 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.\nThis 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

Nitric Oxide Synthase Inhibitors into the Clinic at Last

The 1998 nobel prize in medicine and physiology for the discovery of nitric oxide, a nitrogen containing reactive oxygen species (also termed reactive nitrogen or reactive nitrogen/oxygen species) stirred great hopes. Clinical applications, however, have so far pertained exclusively to the downstream signaling of cgmp enhancing drugs such as phosphodiesterase inhibitors and soluble guanylate cyclase stimulators. All clinical attempts, so far, to inhibit nos have failed even though preclinical models were strikingly positive and clinical biomarkers correlated perfectly. This rather casts doubt on our current way of target identification in drug discovery in general and our way of patient stratification based on correlating but not causal biomarkers or symptoms. The opposite, no donors, nitrite and enhancing no synthesis by enos/nos3 recoupling in situations of no deficiency, are rapidly declining in clinical relevance or hold promise but need yet to enter formal therapeutic guidelines, respectively. Nevertheless, nos inhibition in situations of no overproduction often jointly with enhanced superoxide (or hydrogen peroxide production) still holds promise, but most likely only in acute conditions such as neurotrauma (stover et al., j neurotrauma 31(19):1599–1606, 2014) and stroke (kleinschnitz et al., j cereb blood flow metab 1508–1512, 2016; casas et al., proc natl acad sci u s a 116(14):7129–7136, 2019). Conversely, in chronic conditions, long-term inhibition of nos might be too risky because of off-target effects on enos/nos3 in particular for patients with cardiovascular risks or metabolic and renal diseases.graphical abstractnitric oxide synthases (nos) and their role in health (green) and disease (red). Only neuronal/type 1 nos (nos1) has a high degree of clinical validation and is in late stage development for traumatic brain injury, followed by a phase ii safety/efficacy trial in ischemic stroke. The pathophysiology of nos1 (kleinschnitz et al., j cereb blood flow metab 1508–1512, 2016) is likely to be related to parallel superoxide or hydrogen peroxide formation (kleinschnitz et al., j cereb blood flow metab 1508–1512, 2016; casas et al., proc natl acad sci u s a 114(46):12315–12320, 2017; casas et al., proc natl acad sci u s a 116(14):7129–7136, 2019) leading to peroxynitrite and protein nitration, etc. Endothelial/type 3 nos (nos3) is considered protective only and its inhibition should be avoided. The preclinical evidence for a role of high-output inducible/type 2 nos (nos2) isoform in sepsis, asthma, rheumatic arthritis, etc. Was high, but all clinical development trials in these indications were neutral despite target engagement being validated. This casts doubt on the role of nos2 in humans in health and disease (hence the neutral, black coloring).keywordsnitric oxidenitric oxide synthasenosnos inhibitor nos isoforms

Efficiency analysis of dairy farms in the province of Izmir (Turkey): Data envelopment analysis (DEA)

WOS: 000237043100015The production efficiency of dairy farms based on cross section data of 2003 covering 80 farms chosen by the method of proportional sampling, was determined by Data Envelopment Analysis (DEA) using three outputs and seven inputs. Fortynine percent of the dairy farms appeared to be fully efficient according to the assumption of constant return to scale (CRS). The average efficiency indices obtained under CRS and variable return to scale (VRS) were 0.934 and 0.954, respectively. Mean scale efficiency, on the other hand, was 0.978. Out of the selected dairy farms 21.2% were observed to be efficient in measuring the efficiency of single output milk production. Average efficiency indices under CRS and VRS and scale efficiency index were measured to be 0.782, 0.832 and 0.938, respectively. This information will contribute to extensive dairy farm projects to be carried out in future

Relativistic quantum motion of the scalar bosons in the background space–time around a chiral cosmic string

In this paper, a relativistic behavior of spin-zero bosons is studied in a chiral cosmic string space–time. The Duffin–Kemmer–Petiau (DKP) equation and DKP oscillator are written in this curved space–time and are solved by using an appropriate ansatz and the Nikiforov–Uvarov method, respectively. The influences of the topology of this space–time on the DKP spinor and energy levels and current density are also discussed in detail. </jats:p

Effect of sequential coronary artery bypass venous grafting on right ventricular functions assessed by tissue Doppler echocardiography

Background: Coronary artery bypass graft surgery is a well-known and proven method of treatment for coronary artery disease. A modification of this method is complete revascularisation of the right ventricle by sequential bypass grafting of the right coronary artery, the effects of which on ventricular function need to be clarified. We sought to determine the effect of the sequential bypass graft method on right ventricular (RV) function utilising tissue Doppler echocardiography. Methods: A total of 35 coronary artery disease patients (group A: 20 sequential grafts; group B: 15 individual grafts) were enrolled. Patients were examined pre-operatively with tissue Doppler echocardiography for RV function, and again postoperatively after the first month. Results: Pre-operatively, there were no significant differences with regard to demographics or basal echocardiographic findings. On the other hand, postoperative right ventricular diastolic function was found to have improved significantly as the right ventricular E wave and E/A increased (9.5 +/- 1.6 vs 7.6 +/- 2.7 cm/s, p = 0.009 and 1.4 +/- 0.2 vs 0.9 +/- 0.2, p = 0.01, respectively), while the A wave and isovolumic relaxation times (6.8 +/- 2.1 vs 8.3 +/- 3.4 cm/s, p < 0.03 and 55.2 +/- 11.9 vs 87.2 +/- 16.2 ms, p < 0.001, respectively) decreased. Although the S-wave peak amplitude decreased in group A patients, it did not reach statistical significance. Conclusions: Sequential, but not single, complete revascularisation of the right coronary artery appeared to improve the diastolic function of the right ventricle