Docking and molecular dynamics studies of peripheral site ligand–oximes as reactivators of sarin-inhibited human acetylcholinesterase

In the present work, we performed docking and molecular dynamics simulations studies on two groups of long-tailored oximes designed as peripheral site binders of acetylcholinesterase (AChE) and potential penetrators on the blood brain barrier. Our studies permitted to determine how the tails anchor in the peripheral site of sarin-inhibited human AChE, and which aminoacids are important to their stabilization. Also the energy values obtained in the docking studies corroborated quite well with the experimental results obtained before for these oximes.     

On the PBB Designs for Multiresponse Experiments

We present the idea of using multiresponse incomplete block designs when not all responses can be observed in all experimental units. For a special class of such designs, in which partial designs are PBB designs, a method for estimating natural treatment contrast is given. We also consider the problem of testing the hypotheses concerning the natural and any estimable treatment contrasts. For testing this hypothesis the Wald statistics, being asymptotically chi-square distributed, is proposed.     

Absence of the myelin-associated glycoprotein (MAG) and the neural cell adhesion molecule (N-CAM) interferes with the maintenance,but not with the formation of peripheral myelin

We have previously shown that mice deficient in the gene for the myelin-associated glycoprotein (MAG) develop normal myelin in the peripheral nerves, but show axon and myelin degeneration at eight months of age, suggesting that MAG is involved in the maintenance of axon-Schwann cell integrity. The search for molecules that might replace MAG during myelination revealed an overexpression of the neural cell adhesion molecule (N-CAM) at those aspects where MAG is detectable in wild type mice. To test whether N-CAM might compensate for MAG during myelination in MAG-deficient mice, double mutants deficient in both MAG and N-CAM (MAG⁻/N-CAM⁻mice) were generated by cross-breeding the single mutants. Whereas alterations of myelin development were not detectable in either of the single or double mutants, degeneration of myelin and axons occurred approximately 4 weeks earlier in MAG⁻/N-CAM⁻than in MAG⁻mutants. Furthermore, at 8 weeks of age, single fiber preparation and electron microscopy revealed that the number of profiles indicative of degeneration was substantially increased in MAG⁻/N-CAM⁻mutants when compared to MAG⁻mice. These data suggest that in MAG-deficient mice N-CAM does not compensate for MAG in myelin formation but partially substitutes for it in the maintenance of axon-myelin integrity. Received: 20 May 1996 / Accepted: 19 July 1996     

ERK/MAPK and PI3K/AKT signal channels simultaneously activated in nerve cell and axon after facial nerve injury

BackgroundThe in-vitro study indicated that ERK/MAPK and PI3K/AKT signal channels may play an important role in reparative regeneration process after peripheral nerve injury. But, relevant in-vivo study was infrequent. In particular, there has been no report on simultaneous activation of ERK/MAPK and PI3K/AKT signal channels in facial nerve cell and axon after facial nerve injury.ResultsThe expression of P-ERK enhanced in nerve cells at the injury side on the 1 d after the rat facial nerve was cut and kept on a higher level until 14 d, but decreased on 28 d. The expression of P-AKT enhanced in nerve cells at the injury side on 1 d after injury, and kept on a higher level until 28 d. The expression of P-ERK enhanced at the near and far sections of the injured axon on 1 d, then increased gradually and reached the maximum on 7 d, but decreased on 14 d, until down to the level before the injury on 28 d. The expression of P-AKT obviously enhanced in the injured axon on 1 d, especially in the axon of the rear section, but decreased in the axon of the rear section on 7 d, while the expression of axon in the far section increased to the maximum and kept on till 14 d. On 28 d, the expression of P-AKT decreased in both rear and far sections of the axon.ConclusionThe facial nerve simultaneously activated ERK/MAPK and PI3K/AKT signal channels in facial nerve cells and axons after the cut injury, but the expression levels of P-ERK and P-AKT varied as the function of the time. In particular, they were quite different in axon of the far section. It has been speculated that two signal channels might have different functions after nerve injury. However, their specific regulating effects should still be testified by further studies in regenerative process of peripheral nerve injury.     

PACAP and VIP increase the expression of myelin-related proteins in rat schwannoma cells: Involvement of PAC1/VPAC2 receptor-mediated activation of PI3K/Akt signaling pathways

PACAP and its cognate peptide VIP participate in various biological functions, including myelin maturation and synthesis. However, defining whether these peptides affect peripheral expression of myelin proteins still remains unanswered. To address this issue, we assessed whether PACAP or VIP contribute to regulate the expression of three myelin proteins (MAG, MBP and MPZ, respectively) using the rat schwannoma cell line (RT4-P6D2T), a well-established model to study myelin gene expression. In addition, we endeavored to partly unravel the underlying molecular mechanisms involved. Expression of myelin-specific proteins was assessed in cells grown either in normal serum (10% FBS) or serum starved and treated with or without 100 nM PACAP or VIP. Furthermore, through pharmacological approach using the PACAP/VIP receptor antagonist (PACAP6-38) or specific pathway (MAPK or PI3K) inhibitors we defined the relative contribution of receptors and/or signaling pathways on the expression of myelin proteins. Our data show that serum starvation (24 h) significantly increased both MAG, MBP and MPZ expression. Concurrently, we observed increased expression of endogenous PACAP and related receptors. Treatment with PACAP or VIP further exacerbated starvation-induced expression of myelin markers, suggesting that serum withdrawal might sensitize cells to peptide activity. Stimulation with either peptides increased phosphorylation of Akt at Ser473 residue but had no effect on phosphorylated Erk-1/2. PACAP6-38 (10 μM) impeded starvation- or peptide-induced expression of myelin markers. Similar effects were obtained after pretreatment with the PI3K inhibitor (wortmannin, 10 μM) but not the MAPKK inhibitor (PD98059, 50 μM). Together, the present finding corroborate the hypothesis that PACAP and VIP might contribute to the myelinating process preferentially via the canonical PI3K/Akt signaling pathway, providing the basis for future studies on the role of these peptides in demyelinating diseases.     

Zur Feinstruktur des dorsalen Riesenfasersystems im Bauchmark des Regenwurms

Zusammenfassung Die proximalen Kollateralen der dorsalen Riesenfasern des Regenwurms wurden in Serienschnitten vom Soma bis zum Eintritt in die Riesenfaser verfolgt und im Hinblick auf ihre Feinstruktur und ihre synaptischen Kontakte Untersucht. Es finden sich sowohl chemische als auch elektrische Synapsen. Ihre Feinstruktur wird mit der bekannter Synapsen anderer Wirbellosen und Wirbeltiere verglichen. In beiden Riesenfasersystemen kommen efferente chemische Synapsen mit feinen postsynaptischen Verzweigungen vor, die anscheinend von Bauchmark-Motoneuronen stammen. Das Axon der medianen Riesenfaser weist darüber hinaus nur noch eine elektrische Synapse mit den Rieseninterneuronen auf. Demgegenüber erhalten die Kollateralen der lateralen Riesenfasern zahlreiche Afferenzen, die zum Teil als sensorische Fasern der Epidermis, multisegmentale Fasern der Hauptfaserzüge und Rieseninterneurone identifiziert werden konnten. Weitere Afferenzen stammen vermutlich von unisegmentalen Interneuronen her. Beide lateralen Riesenzellaxone bilden außerdem miteinander eine elektrische Chiasma-Synapse mit besonderen Membraneinfaltungen.

---

Ultrastructure of the dorsal giant fibre system in the ventral nerve cord of the earthwormII. Synaptic connections of the proximal collaterals of the giant fibres

Summary The proximal collaterals of the dorsal giant fibres of the earthworm were traced through serial sections from the cell bodies to the giant axons. Their structure and synaptic connections were examined. There are chemical as well as electrical synapses. Their fine structure is compared to that of other known invertebrate and vertebrate synapses. Both giant fibre systems have efferent chemical connections with thin postsynaptic arborizations which probably belong to ventral cord motoneurons. Moreover the median giant axon is connected by an electrical synapse with the giant interneurons. The lateral giant collaterals on the contrary receive many afferences through chemical synapses which were partly identified as sensory fibers from the epidermis, multisegmental axons from the main fibre bundles or giant interneurones. Other afferences probably come from unisegmental interneurones. In addition both lateral giant axons form an electrical chiasma synapse with special membrane folds.

Mit Unterstützung durch die Deutsche Forschungsgemeinschaft Gu 117/1.     

The laminated sediments of Loch Ness, Scotland: Preliminary report on the construction of a chronology of sedimentation and its potential use in assessing Holocene climatic variability

Two sediment cores, ca. 6 m long, have been recovered from the north basin of Loch Ness, Scotland. Each consists of ca. 4.5 m of laminated gyttja, terminating in a basal grey, unlaminated clay. A suite of three ¹⁴C AMS dates have been obtained, and place the base of the gyttja at ca. 9500 yr B.P. Investigations into the structure, composition and formation of the laminae are in progress. Analysis by Backscatter Scanning Electron Microscopy (BSEM) has demonstrated that they consist of couplets comprising dark, clay-rich sediments thought to be deposited from spring to autumn, and pale, silt-rich layers believed to represent sedimentation through winter. The laminae are thus thought to record incidence and intensity of streamflow into the Loch over the past nine millennia, and thus illustrate environmental change over the region for most of the Holocene. X-ray densitometry has been utilised in order to count the laminations and test the hypothesis that they are varves. It has, however, proved difficult to obtain a continuous sequence of countable laminations, although it has been possible to construct a fragmented, floating chronology which indicates that the hypothesis may be correct. Examination of lamination thickness reveals that although the average rate of sedimentation throughout the time periods studied seems to have remained fairly constant, significant variations have occurred. As Loch Ness is located on the northwest oceanic fringe of Europe, any climatic signal which the laminations contain will be closely related to even larger scale events over and within the North Atlantic Ocean, which is a major controller of global climate. Preliminary statistical investigation of sequences of laminae is being carried out in order to search for periodicity of sedimentation which may then be related to appropriate climatic indices.     

阴部神经痛的解剖学基础及治疗进展

阴部神经痛是发生于会阴部阴部神经支配区域的烧灼样,电击样,针刺样疼痛,是典型的神经病理性疼痛,其目前的患病率尚未准确统计、诊断和治疗均比较困难,患者长期遭受精神和身体上的双重折磨、生活质量低下。阴部神经常与阴部血管伴行共同走行于阴部神经管内,可分为三个主要的分支,即直肠下神经,会阴神经和阴茎/阴蒂背神经。不同分支病变将会导致不同部位的疼痛。其治疗方法目前主要包括保守治疗、阴部神经阻滞、阴部神经外科减压以及神经调控。本文就阴部神经解剖结构,阴部神经痛病因和临床表现,诊断及其治疗进展做一简要综述。