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991.
Siem Jakob Veenstra Heinrich Rueeger Markus Voegtle Rainer Lueoend Philipp Holzer Konstanze Hurth Marina Tintelnot-Blomley Mathias Frederiksen Jean-Michel Rondeau Laura Jacobson Matthias Staufenbiel Ulf Neumann Rainer Machauer 《Bioorganic & medicinal chemistry letters》2018,28(12):2195-2200
New amino-1,4-oxazine derived BACE-1 inhibitors were explored and various synthetic routes developed. The binding mode of the inhibitors was elucidated by co-crystallization of 4 with BACE-1 and X-ray analysis. Subsequent optimization led to inhibitors with low double digit nanomolar activity in a biochemical and single digit nanomolar potency in a cellular assays. To assess the inhibitors for their permeation properties and potential to cross the blood-brain-barrier a MDR1-MDCK cell model was successfully applied. Compound 8a confirmed the in vitro results by dose-dependently reducing Aβ levels in mice in an acute treatment regimen. 相似文献
992.
993.
Christian?A.?S?ldner Anselm?H.?C.?Horn Heinrich?StichtEmail authorView authors OrcID profile 《Journal of molecular modeling》2018,24(12):346
Binding of histamine to the G-protein coupled histamine H1 receptor plays an important role in the context of allergic reactions; however, no crystal structure of the resulting complex is available yet. To deduce the histamine binding site, we performed unbiased molecular dynamics (MD) simulations on a microsecond time scale, which allowed to monitor one binding event, in which particularly the residues of the extracellular loop 2 were involved in the initial recognition process. The final histamine binding pose in the orthosteric pocket is characterized by interactions with Asp1073.32, Tyr1083.33, Thr1945.43, Asn1985.46, Trp4286.48, Tyr4316.51, Phe4326.52, and Phe4356.55, which is in agreement with existing mutational data. The conformational stability of the obtained complex structure was subsequently confirmed in 2 μs equilibrium MD simulations, and a metadynamics simulation proved that the detected binding site represents an energy minimum. A complementary investigation of a D107A mutant, which has experimentally been shown to abolish ligand binding, revealed that this exchange results in a significantly weaker interaction and enhanced ligand dynamics. This finding underlines the importance of the electrostatic interaction between the histamine ammonium group and the side chain of Asp1073.32 for histamine binding. 相似文献
994.
The dynamic recruitment of TRBP to neuronal membranes mediates dendritogenesis during development
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Anna Antoniou Sharof Khudayberdiev Agata Idziak Silvia Bicker Ralf Jacob Gerhard Schratt 《EMBO reports》2018,19(3)
MicroRNAs are important regulators of local protein synthesis during neuronal development. We investigated the dynamic regulation of microRNA production and found that the majority of the microRNA‐generating complex, consisting of Dicer, TRBP, and PACT, specifically associates with intracellular membranes in developing neurons. Stimulation with brain‐derived neurotrophic factor (BDNF), which promotes dendritogenesis, caused the redistribution of TRBP from the endoplasmic reticulum into the cytoplasm, and its dissociation from Dicer, in a Ca2+‐dependent manner. As a result, the processing of a subset of neuronal precursor microRNAs, among them the dendritically localized pre‐miR16, was impaired. Decreased production of miR‐16‐5p, which targeted the BDNF mRNA itself, was rescued by expression of a membrane‐targeted TRBP. Moreover, miR‐16‐5p or membrane‐targeted TRBP expression blocked BDNF‐induced dendritogenesis, demonstrating the importance of neuronal TRBP dynamics for activity‐dependent neuronal development. We propose that neurons employ specialized mechanisms to modulate local gene expression in dendrites, via the dynamic regulation of microRNA biogenesis factors at intracellular membranes of the endoplasmic reticulum, which in turn is crucial for neuronal dendrite complexity and therefore neuronal circuit formation and function. 相似文献
995.
996.
Takao Hikita Fatemeh Mirzapourshafiyi Pedro Barbacena Meghan Riddell Ayesha Pasha Mengnan Li Takuji Kawamura Ralf P Brandes Tomonori Hirose Shigeo Ohno Holger Gerhardt Michiyuki Matsuda Claudio A Franco Masanori Nakayama 《EMBO reports》2018,19(9)
Impaired cell polarity is a hallmark of diseased tissue. In the cardiovascular system, laminar blood flow induces endothelial planar cell polarity, represented by elongated cell shape and asymmetric distribution of intracellular organelles along the axis of blood flow. Disrupted endothelial planar polarity is considered to be pro‐inflammatory, suggesting that the establishment of endothelial polarity elicits an anti‐inflammatory response. However, a causative relationship between polarity and inflammatory responses has not been firmly established. Here, we find that a cell polarity protein, PAR‐3, is an essential gatekeeper of GSK3β activity in response to laminar blood flow. We show that flow‐induced spatial distribution of PAR‐3/aPKCλ and aPKCλ/GSK3β complexes controls local GSK3β activity and thereby regulates endothelial planar polarity. The spatial information for GSK3β activation is essential for flow‐dependent polarity to the flow axis, but is not necessary for flow‐induced anti‐inflammatory response. Our results shed light on a novel relationship between endothelial polarity and vascular homeostasis highlighting avenues for novel therapeutic strategies. 相似文献
997.
Studies on the aerobic utilization of synthesis gas (syngas) by wild type and recombinant strains of Ralstonia eutropha H16
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The biotechnical platform strain Ralstonia eutropha H16 was genetically engineered to express a cox subcluster of the carboxydotrophic Oligotropha carboxidovoransOM5, including (i) the structural genes coxM, ‐S and ‐L, coding for an aerobic carbon monoxide dehydrogenase (CODH) and (ii) the genes coxD, ‐E, ‐F and ‐G, essential for the maturation of CODH. The coxOc genes expressed under control of the CO2‐inducible promoter PL enabled R. eutropha to oxidize CO to CO2 for the use as carbon source, as demonstrated by 13CO experiments, but the recombinant strains remained dependent on H2 as external energy supply. Therefore, a synthetic metabolism, which could be described as ‘carboxyhydrogenotrophic’, was established in R. eutropha. With this extension of the bacterium's substrate range, growth in CO‐, H2‐ and CO2‐containing artificial synthesis gas atmosphere was enhanced, and poly(3‐hydroxybutyrate) synthesis was increased by more than 20%. 相似文献
998.
Pollen germination and in vivo fertilization in response to high‐temperature during flowering in hybrid and inbred rice
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Wanju Shi Xiang Li Ralf C. Schmidt Paul C. Struik Xinyou Yin S.V. Krishna Jagadish 《Plant, cell & environment》2018,41(6):1287-1297
High‐temperature during flowering in rice causes spikelet sterility and is a major threat to rice productivity in tropical and subtropical regions, where hybrid rice development is increasingly contributing to sustain food security. However, the sensitivity of hybrids to increasing temperature and physiological responses in terms of dynamic fertilization processes is unknown. To address these questions, several promising hybrids and inbreds were exposed to control temperature and high day‐time temperature (HDT) in Experiment 1, and hybrids having contrasting heat tolerance were selected for Experiment 2 for further physiological investigation under HDT and high‐night‐time‐temperature treatments. The day‐time temperature played a dominant role in determining spikelet fertility compared with the night‐time temperature. HDT significantly induced spikelet sterility in tested hybrids, and hybrids had higher heat susceptibility than the high‐yielding inbred varieties. Poor pollen germination was strongly associated with sterility under high‐temperature. Our novel observations capturing the series of dynamic fertilization processes demonstrated that pollen tubes not reaching the viable embryo sac was the major cause for spikelet sterility under heat exposure. Our findings highlight the urgent need to improve heat tolerance in hybrids and incorporating early‐morning flowering as a promising trait for mitigating HDT stress impact at flowering. 相似文献
999.
Ralf M. Luche Robert Maiwald Elaine J. Carlson Charles J. Epstein 《Molecular and cellular biochemistry》1997,168(1-2):191-194
All mutations in the human gene for CuZn superoxide dismutase (CuZnSOD) reported to date are associated with the disease amyotrophic lateral sclerosis (ALS). These mutations, mostly of a familial nature (ALS 1, MIM 105400), span all of the coding region of this enzyme except for a highly conserved centrally located domain that includes all of exon III. We describe the identification and characterization of two mutations in this region, both found in mice. One mutation, a glutamate to lysine amino acid substitution was found in position 77 (E77K) of the strain SOD1/Ei distributed by the Jackson Laboratory. The other mutation, a lysine to glutamate substitution at position 70 (K70E) of a human transgene, was discovered in mouse line TgHS/SF-155. Enzyme activity measurements and heterodimer analysis of the CuZn SOD variant in SOD1/Ei suggest a mild loss of activity, which differs from the enzyme activity losses detected in patients with autosomal dominant ALS 1. Similarly, the presence of the mutant transgene in TgHS/SF 155 does not produce any phenotypic manifestations. 相似文献
1000.
Hans Heinrich Janssen 《Polar Biology》1997,17(5):437-447
Specimens of the epizoic bivalve Lissarca notorcadensis Melville and Standen, 1907 (Philobryidae) were collected from the spines of cidaroid sea-urchins in the Weddell Sea during
austral summer 1991. Soft tissues were investigated by means of transmission electron microscopy. Epizoic bacteria were discovered
on the foot in 14 out of 15 specimens of the bivalve, and in juveniles as well as in adults. The presence of bacteria was
restricted to a certain area of the foot's surface, where they were populating the brushborder of the epidermal epithelium.
This is the first time that epizoic bacteria have been described, either from an Antarctic bivalve or from the foot epithelium
of any bivalve species. Aspects of the fine structure were studied with regard to future work on this symbiosis. The bacteria
undergo a full life-cycle in the brushborder. Whereas young or dividing bacteria are found more distally between the microvilli,
senescent stages seem to disintegrate and be absorbed between their bases. The bacteria could contribute to the nutrition
of their host by breaking down macromolecular or particulate organic matter, which would facilitate parenteral absorption
by the bivalve, as well as eventual digestion. The ultrastructural findings suggest that the bacteria are neither sulphidotrophic
nor methylotrophic. Based on their appearance, they are classified as sub-cuticular bacteria, which have been recently described
from the surface epithelia in various marine invertebrate species. The phenomenon is discussed in respect to seasonal food
limitation for Antarctic suspension feeders and the brooding behaviour of the host species and its ecological success.
Received: 26 April 1996 / Accepted: 8 September 1996 相似文献