Despite the biological significance of insulin signaling, the molecular mechanisms of activation of the insulin receptor (IR) and other proteins from its family remain elusive. Current hypothesis on signal transduction suggests ligand-triggered structural changes in the extracellular domain followed by transmembrane (TM) domains closure and dimerization leading to trans-autophosphorylation and kinase activity in intracellular segments of the receptor. Using NMR spectroscopy, we detected dimerization of isolated TM segments of IR in DPC micelles and observed multiple signals of NH groups of protein backbone possibly corresponding to several dimer conformations. Taking available experimental data as constraints, several atomistic models of dimeric TM domains of IR and insulin-like growth factor 1 (IGF-1R) receptors were elaborated. Molecular dynamics simulations of IR ectodomain revealed noticeable collective movements potentially responsible for closure of the C-termini of FnIII-3 domains and spatial approaching of TM helices upon insulin-induced receptor activation. In addition, we demonstrated that the intracellular part of the receptor does not impose restrictions on the positioning of TM helices in the membrane. Finally, we used two independent structure prediction methods to generate a series of dimer conformations followed by their cluster analysis and dimerization free energy estimation to select the best dimer models. Biological relevance of the later was further tested via comparison of the hydrophobic organization of TM helices for both wild-type receptors and their mutants. Based on these data, the ability of several segments from other proteins to functionally replace IR and/or IGF-1R TM domains was explained.
N-Methyl-D-aspartate receptors (NMDAr) are involved in multiple physiological functions and neuropsychiatric disorders. Dizocilpine (commonly referred to as MK-801) is a well-known non-competitive NMDAr antagonist with psychotomimetic properties. A combination of electrophysiological and molecular analyses reveals not only the synchrony of baseline oscillations by MK-801, but also more importantly new insight into differential gene expressions in the cerebral cortex, midbrain, hippocampus, ventral striatum, amygdala, and hypothalamus regions after acute low-dose (0.08 mg/kg) MK-801 treatment; only the ventral striatum showed increased gene expression at a high dose (0.16 mg/kg) of MK-801. We believe that our present study will contribute in the understanding of the pathogenic mechanisms of neuropsychiatric disorders.
We often change our behavior to conform to real or imagined group pressure. Social influence on our behavior has been extensively studied in social psychology, but its neural mechanisms have remained largely unknown. Here we demonstrate that the transient downregulation of the posterior medial frontal cortex by theta-burst transcranial magnetic stimulation reduces conformity, as indicated by reduced conformal adjustments in line with group opinion. Both the extent and probability of conformal behavioral adjustments decreased significantly relative to a sham and a control stimulation over another brain area. The posterior part of the medial frontal cortex has previously been implicated in behavioral and attitudinal adjustments. Here, we provide the first interventional evidence of its critical role in social influence on human behavior.
Delineation and analysis of lateral clustering of lipids in model bilayers is an important step toward understanding of the physical processes underlying formation of lipid domains and rafts in cell membranes. Computer modeling methods represent a powerful tool to address the problem since they can detect clusters of only few lipid molecules – this issue still resists easy characterization with modern experimental techniques. In this work, we propose a computational method to detect and analyze parts of membrane with different packing densities and hydrogen bonding patterns. A series of one- and two-component fluid systems containing lipids with the same polar heads and different acyl chains, dioleoylphosphatidylcholine (18:1) and dipalmitoylphosphatidylcholine (16:0), or with same acyl chains and different polar heads, dioleoylphosphatidylserine (18:1) and dioleoylphosphatidylcholine (18:1), were studied via molecular dynamics simulations. Four criteria of clustering were considered. It was shown that the water-lipid interface of biomembranes represents a highly dynamic and “mosaic” picture, whose parameters depend on the bilayer composition. Some systems (e.g., with 20-30% of the anionic lipid) demonstrate unusual clustering properties and demand further investigation at molecular level. Lateral microheterogeneities in fluid lipid bilayers seem to be among the most important factors determining the nature of the membrane-water interface in a cell.
The paper describes changing patterns of commercial fish catch in the downstream part of the Neva River and the eastern Gulf of Finland and analyzes drivers of these changes for the period 1929-1995. We summarize catch data on 20 species and species groups of fishes and lamprey, as well as available abiotic data (salinity, temperature and water transparency). Water transparency gradually decreased during the 20th century being inseparable from a number of non-quantified anthropogenic factors, thus it can be used as an integral index of anthropogenic loading on the ecosystem. Because fisheries statistics were not published regularly, catch data were extracted from archives and various publications. Fishing locations, gear and target species changed over time in relation to each other, reflecting technological developments in fisheries, commercial demands for fishery products and the abundance of fish populations. Until the 18-19th centuries, fisheries took place mostly in rivers where weirs and set nets targeted sturgeon, salmon and whitefish. By the end of the 19th century, herring and smelt were the main targets of fixed nets in coastal areas. A century later, the main commercial species, herring, was harvested with pelagic trawls operating offshore in the Gulf. This evolution in fisheries, along with other anthropogenic activities, caused severe declines in diadromous species. Spawning migrations that make them easy to catch, and their high market value, make diadromous fish more vulnerable than other groups. Canonical correspondence analysis showed that catches of most diadromous species decreased with increasing transparency, which may reflect their response to anthropogenic pressure. Marine and freshwater fish suffered from anthropogenic pressure, but to a lesser extent probably because of a wider distribution and dispersal, and more capital-intensive fishing methods. Catches of marine species, except herring, significantly increased in the 1970-1980s when salinity was comparatively high. We found no correlation of fish catches with temperature.
This paper examines the early history of agricultural entomology in the Russian empire in the decades before Russian universities and learned societies occupied centre stage in the intellectual life of the country. It aims to contribute to the ongoing discussions of historically contingent relations between ‘amateurs’ and ‘professionals’ in scientific research. It explores the social identities of those people who took part in the production and circulation of scientific knowledge, and argues that in this period Russian officialdom played a major role in these processes. The state officials’ engagement with natural history originated out of a broader information gathering agenda, which was characteristic of the early- to mid-nineteenth century. At the same time, the paper highlights the importance of provincial observers who were indispensable for providing field data for bureaucratic ‘inventorying’ of imperial resources. This dependency on local observers had far reaching implications, including the dissemination of the language and practices of natural history among wider audiences.