The functional organization of afferent vagal mechanisms controlling special and general visceral reflex responses of the rat esophagus

The functional organization of esophageal afferent mechanisms controlling special (esophageal motility) and general (cardiovascular) visceral reflex responses was investigated in urethane-anesthetized rats. Techniques utilized included esophageal manometry, vagal nerve cooling, single nerve fiber recording, extracellular recording, and pharmacological receptor blockade and stimulation. -- Distal esophageal distension elicits esophageal reflex contractions, and both excitatory and inhibitory cardiovascular reflexes. Based upon the effects of vagal cooling, it is inferred that separate subpopulations of A? vagal mechanosensory afferent fibers mediate these reflexes. -- Single fiber recording experiments demonstrate that vagal mechanosensory afferent fibers innervating the distal esophagus respond to intraluminal pressure increases over a wide dynamic range and show little adaptation. -- The pattern and strength of vagal motor output to the distal esophagus depend on the intensity of vagal afferent input to interneurons at the level of nucleus tractus solitarii (NTS). These interneurons respond to esophageal distension with distinct firing patterns. Increasing strength of stimulation changes the firing pattern or intensifies the responses of these interneurons. Load-dependent changes in esophageal reflex motor activities persist after spinal afferent input is eliminated. -- In the striated muscle tunica muscularis propria of the rat esophagus, distal inhibition is an inhibitory motor reflex evoked by esophageal mechanosensory afferent input from the proximal esophagus. The chief underlying process is the activation of GABAa and/or glycine receptors associated with NTS subnucleus centralis (NTSc) esophageal premotoneurons. In contrast, deglutitive inhibition does not involve inhibitory amino acid mediated neurotransmission in this region. -- Vagal mechanosensory afferent fibers mediating the excitatory component of the esophageal cardiovascular reflex (ECVR) terminate in the immediate vicinity of esophageal premotor neurons comprising the NTSc and activate second-order neurons via glutamate receptors of both the NMD A and non-NMDA subtype. Glutamatergic synapses at the level of the rostral ventrolateral medulla are involved in the mediation of the vasomotor component of the ECVR. -- Taken together, the results of this thesis research lead to a more detailed understanding of the mechanisms by which vagal mechanosensory afferents innervating the rat esophagus evoke special and general visceral reflexes. Distension-evoked esophageal reflex contractions and the two components of the ECVR involve functionally distinct vagal mechanosensory afferent fibers and affect separate central pathways originating from NTS interneurons

Interaction of Acetylcholinesterase with Neurexin-1β regulates Glutamatergic Synaptic stability in Hippocampal neurons

Abstract Background Excess expression of acetylcholinesterase (AChE) in the cortex and hippocampus causes a decrease in the number of glutamatergic synapses and alters the expression of neurexin and neuroligin, trans-synaptic proteins that control synaptic stability. The molecular sequence and three-dimensional structure of AChE are homologous to the corresponding aspects of the ectodomain of neuroligin. This study investigated whether excess AChE interacts physically with neurexin to destabilize glutamatergic synapses. Results The results showed that AChE clusters colocalized with neurexin assemblies in the neurites of hippocampal neurons and that AChE co-immunoprecipitated with neurexin from the lysate of these neurons. Moreover, when expressed in human embryonic kidney 293 cells, N-glycosylated AChE co-immunoprecipitated with non-O–glycosylated neurexin-1β, with N-glycosylation of the AChE being required for this co-precipitation to occur. Increasing extracellular AChE decreased the association of neurexin with neuroligin and inhibited neuroligin-induced synaptogenesis. The number and activity of excitatory synapses in cultured hippocampal neurons were reduced by extracellular catalytically inactive AChE. Conclusions Excessive glycosylated AChE could competitively disrupt a subset of the neurexin–neuroligin junctions consequently impairing the integrity of glutamatergic synapses. This might serve a molecular mechanism of excessive AChE induced neurodegeneration

Identification of Ground Deformation Patterns in Coal Mining Areas via Rapid Topographical Analysis

Coal mining inevitably brings some negative impacts, such as surface subsidence, aquifer breakage, and land degradation, to the eco-geological environment in the mining area. Among these impacts, coal mining-induced ground deformation is the most serious and has threatened the geological, ecological, and human settlement securities of mining areas. Efforts existing in the literature apply to ground deformation identification in mined-out areas at the meso-/micro and short-time scales. However, when looking back at coal mining history, there are few ways to quickly and accurately quantify ground deformation at the regional and long-time scales. In this context, we propose a method for identifying ground deformation patterns in coal mining areas using historical high-precision digital elevation models (DEMs), including data preprocessing, DEM subtraction operations, interpretation, and fitting correction. This method was applied to the Yulin National Energy and Chemical Base and successfully identified the ground deformation characteristics of the Yulin coal mining area from 2015 to 2019. By determining surface subsidence displacement, excavation depth, stacking height, and the position of the goaf suspended roof area, the objective situation of ground deformation in Yulin mining area was obtained, and the mining methods and distribution characteristics of different surface deformations were analyzed and determined. The research results are of great significance for the development of mineral resources in mining areas, reducing geological disaster risks, protecting the ecological environment, and achieving the goal of coordinated development in mining areas

Chemical-defined and albumin-free generation of human atrial and ventricular myocytes from human pluripotent stem cells

Most existing culture media for cardiac differentiation of human pluripotent stem cells (hPSCs) contain significant amounts of albumin. For clinical transplantation applications of hPSC-derived cardiomyocytes (hPSC-CMs), culturing cells in an albumin containing environment raises the concern of pathogen contamination and immunogenicity to the recipient patients. In addition, batch-to-batch variation of albumin may cause the inconsistent of hPSC cardiac differentiation. Here, we demonstrated that antioxidants l-ascorbic acid, trolox, N-acetyl-l-cysteine (NAC) and sodium pyruvate could functionally substitute albumin in the culture medium, and formulated an albumin-free, chemical-defined medium (S12 medium). We showed that S12 medium could support efficient hPSC cardiac differentiation with significantly improved reproducibility, and maintained long-term culture of hPSC-CMs. Furthermore, under chemical-defined and albumin-free conditions, human-induced pluripotent stem cells (hiPSCs) were established, and differentiated into highly homogenous atrial and ventricular myocytes in a scalable fashion with normal electrophysiological properties. Finally, we characterized the activity of three typical cardiac ion channels of those cells, and demonstrated that hPSC-derived ventricular cardiomyocytes (hPSC-vCMs) were suitable for drug cardiac safety evaluation. In summary, this simplified, chemical-defined and albumin-free culture medium supports efficient generation and maintaining of hPSC-CMs and facilitates both research and clinical applications of these cells

Structure-activity relationships of trimethoxybenzyl piperazine N-type calcium channel inhibitors

We previously reported the small organic N-type calcium channel blocker NP078585 that while efficacious in animal models for pain, exhibited modest L-type calcium channel selectivity and substantial off-target inhibition against the hERG potassium channel. Structure-activity studies to optimize NP078585 preclinical properties resulted in compound 16, which maintained high potency for N-type calcium channel blockade, and possessed excellent selectivity over the hERG (~120-fold) and L-type (~3600-fold) channels. Compound 16 shows significant anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain and is also efficacious in the rat formalin model of inflammatory pain