The functional properties of neural circuits are defined by the patterns of synaptic connections between their partnering neurons, but the mechanisms that stabilize circuit connectivity are poorly ...understood. We systemically examined this question at synapses onto newly characterized dendritic spines of C. elegans GABAergic motor neurons. We show that the presynaptic adhesion protein neurexin/NRX-1 is required for stabilization of postsynaptic structure. We find that early postsynaptic developmental events proceed without a strict requirement for synaptic activity and are not disrupted by deletion of neurexin/nrx-1. However, in the absence of presynaptic NRX-1, dendritic spines and receptor clusters become destabilized and collapse prior to adulthood. We demonstrate that NRX-1 delivery to presynaptic terminals is dependent on kinesin-3/UNC-104 and show that ongoing UNC-104 function is required for postsynaptic maintenance in mature animals. By defining the dynamics and temporal order of synapse formation and maintenance events in vivo, we describe a mechanism for stabilizing mature circuit connectivity through neurexin-based adhesion.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The present research tested the hypothesis that concepts of gratitude are prototypically organized and explored whether lay concepts of gratitude are broader than researchers' concepts of gratitude. ...In five studies, evidence was found that concepts of gratitude are indeed prototypically organized. In Study 1, participants listed features of gratitude. In Study 2, participants reliably rated the centrality of these features. In Studies 3a and 3b, participants perceived that a hypothetical other was experiencing more gratitude when they read a narrative containing central as opposed to peripheral features. In Study 4, participants remembered more central than peripheral features in gratitude narratives. In Study 5a, participants generated more central than peripheral features when they wrote narratives about a gratitude incident, and in Studies 5a and 5b, participants generated both more specific and more generalized types of gratitude in similar narratives. Throughout, evidence showed that lay conceptions of gratitude are broader than current research definitions.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
The most conserved part of the vertebrate dopaminergic system is the orthopedia (otp)-expressing diencephalic neuronal population that constitutes the dopaminergic diencephalospinal tract (DDT). ...Although studies in the neonatal murine spinal cord in vitro suggest an early locomotor role of the DDT, the function of the DDT in developing vertebrates in vivo remains unknown. Here, we investigated the role of the DDT in the locomotor development of zebrafish larvae. To assess the development of the behavioral and neural locomotor pattern, we used high-throughput video tracking in combination with peripheral nerve recordings. We found a behavioral and neural correspondence in the developmental switch from an immature to mature locomotor pattern. Blocking endogenous dopamine receptor 4 (D(4)R) signaling in vivo either before or after the developmental switch prevented or reversed the switch, respectively. Spinal transections of post-switch larvae reestablished the immature locomotor pattern, which was rescued to a mature-like pattern via spinal D(4)R agonism. Selective chemogenetic ablation of otp b (otpb) neurons that contribute to the DDT perpetuated the immature locomotor pattern in vivo. This phenotype was recapitulated by diencephalic transections that removed the dopaminergic otpb population and was rescued to a mature-like locomotor pattern by D(4)R agonism. We conclude that the dopaminergic otpb population, via the DDT, is responsible for spinal D(4)R signaling to mediate the developmental switch to the mature locomotor pattern of zebrafish. These results, integrated with the mammalian literature, suggest that the DDT represents an evolutionarily conserved neuromodulatory system that is necessary for normal vertebrate locomotor development.
The Residual Lesion Score (RLS) was developed as a novel tool for assessing residual lesions after congenital heart operations based on widely available clinical and echocardiographic ...characteristics. The RLS ranks postoperative findings as follows: Class 1 (no/trivial residua), Class 2 (minor residua), or Class 3 (major residua or reintervention before discharge for residua). The multicenter prospective RLS study aims to analyze the influence of residual lesions on outcomes in common congenital cardiac operations. We hypothesize that RLS will predict postoperative adverse events, resource utilization, mortality, and reinterventions by 1 year postoperatively.
The study cohort consisted of infants aged ≤12 months undergoing definitive surgery for complete atrioventricular septal defect, tetralogy of Fallot, dextro-transposition of the great arteries with or without intact ventricular septum, single ventricle (Norwood procedure), and coarctation or interrupted/hypoplastic arch with ventricular septal defect. Children with major congenital or acquired extracardiac anomalies that could independently affect the primary end point, which was number of days alive and out of the hospital within 30 days of surgery (60 days for Norwood procedure), were excluded. Secondary outcomes included ≥1 early major postoperative adverse event; days of intensive care unit and hospital stay, and initial and total ventilator time; mortality/transplant after discharge; unplanned reinterventions after discharge; and cost. All analyses will be performed separately by surgical operation.
This is the first multicenter prospective validation of a tool for surgical outcome assessment and quality improvement specific to congenital heart surgery.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We proposed that expressing gratitude would increase positive perception of a relationship partner, thereby increasing comfort in expressing relationship concerns, which is a form of relationship ...maintenance. Study 1 (
n
= 159) showed a relationship between naturally occurring expressions of gratitude and comfort in voicing relationship concerns. Study 2 (
n
= 178) provided longitudinal evidence for direction of effects because Time 1 gratitude expression predicted Time 2 comfort in voicing relationship concerns, controlling for baseline comfort in voicing relationship concerns. Study 3 (
n
= 225) showed that expressing gratitude to a friend did increase voicing relationship concerns, compared with positive thought and neutral control conditions. In Study 4 (
n
= 74), we explored the mechanism through a longitudinal, experimental design and found that participants assigned to express gratitude reported higher comfort voicing concerns and more positive perception of partner than did control participants. Moreover, positive perception of partner mediated the relationship between condition and comfort in voicing relationship concerns.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
The renewal of interest in Herodotus as an effective and creative historian within a predominantly oral tradition has been a feature of prolific research during the last twenty years. In the very ...year in which the arrival of the 1820 settlers in the east of the former Cape Colony in South Africa is being remembered, and even commemorated, I attempt a reading of Herodotus' celebrated account of the Greek colonization of Cyrene in Libya (North Africa) through the historiographical lens of accounts of the arrival of these British settlers, focussing on the narratives of colonization common to these exempla more than two millennia apart. My intention is to continue the conversation, especially amongst South African classicists, about how to tackle the thorny question of decolonizing the content and teaching of the Classics in our universities.
Obesity is characterised by altered gut microbiota, low‐grade inflammation and increased endocannabinoid (eCB) system tone; however, a clear connection between gut microbiota and eCB signalling has ...yet to be confirmed. Here, we report that gut microbiota modulate the intestinal eCB system tone, which in turn regulates gut permeability and plasma lipopolysaccharide (LPS) levels. The impact of the increased plasma LPS levels and eCB system tone found in obesity on adipose tissue metabolism (e.g. differentiation and lipogenesis) remains unknown. By interfering with the eCB system using CB1 agonist and antagonist in lean and obese mouse models, we found that the eCB system controls gut permeability and adipogenesis. We also show that LPS acts as a master switch to control adipose tissue metabolism both in vivo and ex vivo by blocking cannabinoid‐driven adipogenesis. These data indicate that gut microbiota determine adipose tissue physiology through LPS‐eCB system regulatory loops and may have critical functions in adipose tissue plasticity during obesity.
Synopsis
Obesity and type II diabetes have reached epidemic proportions and are associated with a massive expansion of the adipose tissue. Recent data have shown that these metabolic disorders are characterised by low‐grade inflammation of unknown molecular origin (Hotamisligil and Erbay, 2008; Shoelson and Goldfine, 2009); therefore, it is of the utmost importance to identify the link between inflammation and adipose tissue metabolism and plasticity. Among the latest important discoveries published in the field, two new concepts have driven this study. First, emerging data have shown that gut microbiota is involved in the control of energy homeostasis (Ley et al, 2005; Turnbaugh et al, 2006; Claus et al, 2008) Obesity is characterised by the massive expansion of adipose tissues and is associated with inflammation (Weisberg et al, 2003). It is possible that both this expansion and the associated inflammation are controlled by microbiota and lipopolysaccharide (LPS) (Cani et al, 2007a, 2008), a cell wall component of Gram‐negative bacteria that is among the most potent inducers of inflammation (Cani et al, 2007a, 2007b, 2008; Cani and Delzenne, 2009). Second, obesity is also characterised by greater endocannabinoid (eCB) system tone (increased eCB plasma levels, altered expression of the cannabinoid receptor 1 (CB1 mRNA) and increased eCB levels in the adipose tissue) (Engeli et al, 2005; Bluher et al, 2006; Matias et al, 2006; Cote et al, 2007; D'Eon et al, 2008; Starowicz et al, 2008; Di Marzo et al, 2009; Izzo et al, 2009).
Several studies have suggested a close relationship between LPS, gut microbiota and the eCB system. Indeed, LPS controls the synthesis of eCB in macrophages, whereas macrophage infiltration in the adipose tissue occurring during obesity is an important factor in the development of the metabolic disorders (Weisberg et al, 2003). We have shown that macrophage infiltration is not only dependent on the activation of the receptor CD14 by LPS, but is also dependent on the gut microbiota composition and the gut barrier function (gut permeability) (Cani et al, 2007a, 2008). Moreover, LPS controls the synthesis of eCBs both in vivo (Hoareau et al, 2009) and in vitro (Di Marzo et al, 1999; Maccarrone et al, 2001) through mechanisms dependent of the LPS receptor signalling pathway (Liu et al, 2003). Thus, obesity is nowadays associated with changes in gut microbiota and a higher endocannabinoid system tone, both having a function in the disease's pathophysiology.
Given that the convergent molecular mechanisms that may affect these different supersystem activities and adiposity remain to be elucidated, we tested the hypothesis that the gut microbiota and the eCB system control gut permeability and adipogenesis, by a LPS‐dependent mechanism, under both physiological and obesity‐related conditions.
First, we found that high‐fat diet‐induced obese and diabetic animals exhibit threefold higher colonic CB1 mRNA, whereas no modification was observed in the small intestinal segment (jejunum). Moreover, selective modulation of gut microbiota using prebiotics (i.e. non‐digestible compounds fermented by specific bacteria in the gut) (Gibson and Roberfroid, 1995) reduces by about one half this effect. Similarly, in genetically obese mice (ob/ob), prebiotic treatment decreases colonic CB1 mRNA and colonic eCB concentrations (AEA) (Figure 2A). In addition, we have observed a modulation of FAAH and MGL mRNA (Figure 2A). Furthermore, we have found that antibiotic treatment decreasing the number of gut bacteria content was associated with a strong reduction of the CB1 receptor levels in the colon of healthy mice.
Second, we show that the endocannabinoid system controls gut barrier function (in vivo and in vitro) and endotoxaemia. More precisely, we designed two in vivo experiments in obese and lean mice (Figure 2). In a first experiment, we blocked the CB1 receptor in obese mice with a specific and selective antagonist (SR141716A) and found that the blockade of the CB1 receptor reduces plasma LPS levels by a mechanism linked to the improvement of the gut barrier function (Figure 2C) as shown by the lower alteration of tight junctions proteins (zonula occludens‐1 (ZO‐1) and occludin) distribution and localisation, and independently of food intake behaviour (Figures 2D and 3). In a second set of experiments performed in lean wild‐type mice, we mimicked the increased eCB system tone observed during obesity by chronic (4‐week) infusion of a cannabinoid receptor agonist (HU‐210) through mini‐pumps implanted subcutaneously. We found that cannabinoid agonist administration significantly increased plasma LPS levels. Furthermore, increased plasma fluorescein isothiocyanate‐dextran levels were observed after oral gavage (Figure 2F and G). These sets of in vivo experiments strongly suggest that an overactive eCB system increases gut permeability. Finally, in a cellular model of intestinal epithelial barrier (Caco‐2 cells monolayer), we found that CB1 receptor antagonist normalised LPS and the cannabinoid receptors agonist HU‐210‐induced epithelial barrier alterations.
Third, we provide evidence that adipogenesis is under the control of the gut microbiota, through the modulation of the gut and adipose tissue endocannabinoid systems in both physiological and pathological conditions. We found that the higher eCB system tone (found in obesity or mimicked by eCB agonist) participates to the regulation of adipogenesis by directly acting on the adipose tissue, but also indirectly by increasing plasma LPS levels, which consequently impair adipogenesis and promote inflammatory states. Here, we found that both the specific modulation of the gut microbiota and the blockade of the CB1 receptor decrease plasma LPS levels and is associated with higher adipocyte differentiation and lipogenesis rate. One possible explanation for these surprising data could be as follows: plasma LPS levels might be under the control of CB1 in the intestine (gut barrier function); therefore, under particular pathophysiological conditions in vivo (e.g. obesity/type II diabetes), this could lead to higher circulating LPS levels. Furthermore, CB1 receptor blockade might paradoxically increase adipogenesis because of the ability of CB1 antagonist to reduce gut permeability and counteract the LPS‐induced inhibitory effect on adipocyte differentiation and lipogenesis (i.e. a disinhibition mechanism). In summary, given that these treatments reduce gut permeability and, hence, plasma LPS levels and inflammatory tone, we hypothesised that LPS could act as a regulator in this process. This hypothesis was further supported in vitro and in vivo by the observation that cannabinoid‐induced adipocyte differentiation and lipogenesis were directly altered (i.e. reduced) in the presence of physiological levels of LPS. In summary, because these treatments reduce gut permeability, hence, plasma LPS and inflammatory tone, we hypothesised that LPS acts as a regulator in this process. Altogether, our data provide the evidence that the consequences of obesity and gut microbiota dysregulation on gut permeability and metabolic endotoxaemia are clearly mediated by the eCB system, those observed on adiposity are likely the result of two systems interactions: LPS‐dependent pathways activities and eCB system tone dysregulation (Figure 9).
Our results indicate that the endocannabinoid system tone and the plasma LPS levels have a critical function in the regulation of the adipose tissue plasticity. As obesity is commonly characterised by increased eCB system tone, higher plasma LPS levels, altered gut microbiota and impaired adipose tissue metabolism, it is likely that the increased eCB system tone found in obesity is caused by a failure or a vicious cycle within the pathways controlling the eCB system.
These findings show that two novel therapeutic targets in the treatment of obesity, the gut microbiota and the endocannabinoid system, are closely interconnected. They also provide evidence for the presence of a new integrative physiological axis between gut and adipose tissue regulated by LPS and endocannabinoids. Finally, we propose that the increased endotoxaemia and endocannabinoid system tone found in obesity might explain the altered adipose tissue metabolism.
We investigated several models of gut microbiota modulation: selective (prebiotics, probiotics, high‐fat), drastic (antibiotics, germ‐free mice) and mice bearing specific mutations of a key gene involved in the toll‐like receptors (TLR) bacteria‐host interaction (Myd88−/−). Here we report that gut microbiota modulates the intestinal endocannabinoid (eCB) system‐tone, which in turn regulates gut permeability and plasma lipopolysaccharide (LPS) levels.
The activation of the intestinal endocannabinoid system increases gut permeability which in turn enhances plasma LPS levels and inflamm
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FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Proinflammatory macrophages are key mediators in several pathologies; thus, controlling their activation is necessary. The endocannabinoid system is implicated in various inflammatory processes. Here ...we show that in macrophages, the newly characterized enzyme α/β-hydrolase domain 6 (ABHD6) controls 2-arachidonoylglycerol (2-AG) levels and thus its pharmacological effects. Furthermore, we characterize a unique pathway mediating the effects of 2-AG through its oxygenation by cyclooxygenase-2 to give rise to the anti-inflammatory prostaglandin D ₂-glycerol ester (PGD ₂-G). Pharmacological blockade of cyclooxygenase-2 or of prostaglandin D synthase prevented the effects of increasing 2-AG levels by ABHD6 inhibition in vitro, as well as the 2-AG–induced increase in PGD ₂-G levels. Together, our data demonstrate the physiological relevance of the interaction between the endocannabinoid and prostanoid systems. Moreover, we show that ABHD6 inhibition in vivo allows for fine-tuning of 2-AG levels in mice, therefore reducing lipopolysaccharide-induced inflammation, without the characteristic central side effects of strong increases in 2-AG levels obtained following monoacylglycerol lipase inhibition. In addition, administration of PGD ₂-G reduces lipopolysaccharide-induced inflammation in mice, thus confirming the biological relevance of this 2-AG metabolite. This points to ABHD6 as an interesting therapeutic target that should be relevant in treating inflammation-related conditions, and proposes PGD ₂-G as a bioactive lipid with potential anti-inflammatory properties in vivo.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
This paper presents a new methodology to predict the onset of damage, final failure and failure mode of mechanically fastened joints in composite laminates. The stress distribution at each ply is ...obtained using semi-analytical or numerical methods. The elastic limit of the joint is predicted using the ply strengths and stress distribution in failure criteria. Final failure and failure mode are predicted using point or average stress models. Standardized procedures to measure the characteristic distances used in the point or average stress models are proposed. The methodology proposed is applicable in double-shear joints using quasi-isotropic laminates. The predictions are compared with experimental data obtained in pin- and bolt-loaded joints, and the results indicate that the methodology proposed can accurately and effectively predict ultimate failure loads as well as failure modes in composite bolted joints.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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