Neuroligins are postsynaptic adhesion molecules that are essential for postsynaptic specialization and synaptic function. But the underlying molecular mechanisms of neuroligin functions remain unclear. We found that Drosophila Neuroligin 1 (DNlg1) regulates synaptic structure and function through WAVE regulatory complex (WRC)-mediated postsynaptic actin reorganization. The disruption of DNlg1, DNlg2, or their presynaptic partner neurexin (DNrx) led to a dramatic decrease in the amount of F-actin. Further study showed that DNlg1, but not DNlg2 or DNlg3, directly interacts with the WRC via its C-terminal interacting receptor sequence. That interaction is required to recruit WRC to the postsynaptic membrane to promote F-actin assembly. Furthermore, the interaction between DNlg1 and the WRC is essential for DNlg1 to rescue the morphological and electrophysiological defects in dnlg1 mutants. Our results reveal a novel mechanism by which the DNrx-DNlg1 trans-synaptic interaction coordinates structural and functional properties at the neuromuscular junction.
Piled embankments rely upon arching of the embankment material onto underlying piles, thus potentially significantly reducing load on the soft subsoil that more generally prevails beneath the embankment. Finite-element modelling of a piled embankment in plane strain has previously been reported; the ‘subsoil' was not explicitly modelled, but was represented by a vertical stress acting on the underside of the embankment. This technical note considers extension of this work to three dimensions. The results make particular reference to prediction of the stress on the subsoil at the point of ‘maximum arching' and the height of influence of arching within the embankment.
Studies on myotonic dystrophy type 1 (DM1) have led to the RNAmediated disease model for hereditary disorders caused by noncoding microsatellite expansions. This model proposes that DM1 disease manifestations are caused by a reversion to fetal RNA processing patterns in adult tissues due to the expression of toxic CUG RNA expansions (CUG exp ) leading to decreased muscleblind-like, but increased CUGBP1/ETR3-like factor 1 (CELF1), alternative splicing activities. Here, we test this model in vivo, using the mouse HSA LR poly(CUG) model for DM1 and recombinant adeno-associated virus (rAAV)-mediated transduction of specific splicing factors. Surprisingly, systemic overexpression of HNRNPA1, not previously linked to DM1, also shifted DM1-relevant splicing targets to fetal isoforms, resulting in more severe muscle weakness/myopathy as early as 4 to 6 wk posttransduction, whereas rAAV controls were unaffected. Overexpression of HNRNPA1 promotes fetal exon inclusion of representative DM1-relevant splicing targets in differentiated myoblasts, and HITS-CLIP of rAAV-mycHnrnpa1-injected muscle revealed direct interactions of HNRNPA1 with these targets in vivo. Similar to CELF1, HNRNPA1 protein levels decrease during postnatal development, but are elevated in both regenerating mouse muscle and DM1 skeletal muscle. Our studies suggest that CUG exp RNA triggers abnormal expression of multiple nuclear RNA binding proteins, including CELF1 and HNRNPA1, that antagonize MBNL activity to promote fetal splicing patterns.M icrosatellite expansions in the noncoding regions of several human genes are associated with hereditary neurological diseases, including fragile X mental retardation (FRAXA) and myotonic dystrophy (DM) (1). In DM type 1 (DM1), the transcription of a CTG microsatellite expansion (CTG exp ) in the 3′ untranslated region (3′ UTR) of the DMPK gene results in the expression of toxic CUG exp RNA, which sequesters muscleblindlike (MBNL) proteins and blocks their splicing activity (2, 3). MBNL inhibition in DM1 tissues leads to a shift from adult to fetal splicing events for MBNL-targeted RNAs and results in tissuespecific disease manifestations, including muscle hyperexcitability (myotonia) and insulin resistance. In addition, CUG exp RNA also activates protein kinase C (PKC), resulting in the hyperphosphorylation and elevated levels of CUGBP1/ETR3-like factor 1 (CELF1) in DM1 muscle and heart (4). In contrast to MBNL, CELF1 induces fetal splicing events in embryonic and early neonatal stages, and increased CELF1 levels in adult DM1 tissues causes a reversion to fetal isoforms. Thus, the current DM1 disease model is that coordinate MBNL sequestration and CELF1 accumulation caused by CUG exp RNA expression synergistically promote aberrant fetal splicing patterns in DM1 (3, 5). Support for both MBNL loss of function and CELF gain of function has come from mouse knockout and transgenic models (6-8). Mbnl1 knockout adults develop muscle myotonia and myopathy, subcapsular dust-like cataracts, and alternative splicing changes ch...
The British 'Code of practice for strengthened/reinforced soils and other fills' (BS 8006) was substantially revised in 2010, with a further 'Corrigendum' in 2012. Historically, BS 8006 considered arching in a piled embankment, based on an interpretation of the 'Marston' equation. The 2010 revision included an alternative method related to the analysis of arching in a piled embankment, which was proposed by Hewlett and Randolph in 1988, and later itself amended in the 2012 Corrigendum. This contribution considers BS 8006 predictions of reinforcement tension using these methods as a basis for embankment load on the reinforcement, for a wide range of piled embankment geometries. The predictions are compared with results from three-dimensional finite-element analysis, demonstrating encouraging correspondence with the Hewlett and Randolph approach (but noting that the 2010 revision overpredicts the data whereas the 2012 revision underpredicts it). Good predictions of maximum reinforcement sag are also achieved by slight modification of the BS 8006 method.
This paper presents a simplified finite-element model, based on which the arching in highway piled embankments subjected to moving vehicle loads is investigated. The analyses demonstrated that the pile spacing was a more sensitive factor than embankment height, whose increase from 2·0 to 3·0 m led to a 60–68% increase of the normalised maximum settlement at the base of the embankment. The effect of moving vehicle loads was of particular interest, increasing the normalised maximum settlement and vertical stress at the base of the embankment by approximately 23% and 19%, respectively, compared to the static situation. The influence height of soil arching related to the pile spacing and embankment height was investigated, and showed that the vertical extent of arching was within a normalised distance of 2·0 from the base of the embankment. Factors of the embankment properties – that is, elastic modulus, friction angle, dilation angle and cohesion – were examined and showed that the cohesion was a most sensitive factor, whose increase from 1 to 10 kPa reduced the normalised maximum settlement and vertical stress by approximately 56% and 42%, respectively. Also shown was that the increase in the velocity of a moving vehicle from 30 to 120 km/h slightly increased the normalised maximum settlement and vertical stress by approximately 9% and 10%, respectively. Finally, a modified analytical method was developed by considering the additional vertical stress induced by moving vehicle loads based on the Boussinesq equation, whose solution was found to be in good agreement with the finite-element results.
Biaxial geogrid in current research is oversimplified, and the 1 three-dimensional orthotropic nature of the biaxial geogrid has not been fully 2 understood in numerical investigations. A comparative study on three modeling 3 approaches for the biaxial geogrid is presented in this paper, including the isotropic 4 membrane model, the orthotropic membrane model and the truss element model. It 5 shows that the orthotropic membrane model yields practically identical results of the 6 maximum geogrid tension when compared with the truss element model, whereas the 7 isotropic membrane model tends to yield values that are approximately 33% larger. A 8 parametric study shows that the pile spacing has the strongest influence on the 9 maximum geogrid tension. The comparison of four analytical methods with the 10 orthotropic membrane model shows that the BS8006 (2010), EBGEO (2011) all 11 greatly overestimate the geogrid tension, while the method presented by Zhuang et al. 12 (2014) results in closer agreement.13
Zhuang & Ellis (2014) considered predictions of reinforcement tension in a piled embankment from BS 8006 (BSI, 2010 and 2012), comparing the results with finite element model predictions. In keeping with BS 8006 any contribution from the subsoil beneath the embankment was ignored. This paper extends that work by also considering the potentially beneficial contribution of a lightly overconsolidated clay subsoil layer, both in the finite element predictions and as a simple modification to the BS 8006 predictive method. It is assumed that there is no 'working platform' (granular) material below the pile cap level, and that the water table in the subsoil does not drop, since either of these factors would be likely to significantly reduce the ability of the subsoil to carry load from the embankment. As anticipated the subsoil support reduces reinforcement tension. When compared to the finite element results the proposed modified BS 8006 prediction is quite accurate. The BSI (2012) modified prediction is 'best' (but sometimes slightly unconservative), whilst the BSI (2010) modified prediction is conservative in all cases considered.
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