The Most Severe Test for Hydrophobicity Scales: Two Proteins with 88% Sequence Identity but Different Structure and Function

Protein-protein interactions (protein functionalities) are mediated by water, which compacts individual proteins and promotes close and temporarily stable large-area protein-protein interfaces. In their classic paper Kyte and Doolittle (KD) concluded that the "simplicity and graphic nature of hydrophobicity scales make them very useful tools for the evaluation of protein structures". In practice, however, attempts to develop hydrophobicity scales (for example, compatible with classical force fields (CFF) in calculating the energetics of protein folding) have encountered many difficulties. Here we suggest an entirely different approach, based on the idea that proteins are self-organized networks, subject to finite-scale criticality (like some network glasses). We test this proposal against two small proteins that are delicately balanced between alpha and alpha/beta structures, with different functions encoded with only 12% of their amino acids. This example explains why protein structure prediction is so challenging, and it provides a severe test for the accuracy and content of hydrophobicity scales. The new method confirms KD's evaluation, and at the same time suggests that protein structure, dynamics and function can be best discussed without using CFF

Primary Blast Traumatic Brain Injury in the Rat: Relating Diffusion Tensor Imaging and Behavior

The incidence of traumatic brain injury (TBI) among military personnel is at its highest point in U.S. history. Experimental animal models of blast have provided a wealth of insight into blast injury. The mechanisms of neurotrauma caused by blast, however, are still under debate. Specifically, it is unclear whether the blast shockwave in the absence of head motion is sufficient to induce brain trauma. In this study, the consequences of blast injury were investigated in a rat model of primary blast TBI. Animals were exposed to blast shockwaves with peak reflected overpressures of either 100 or 450 kPa (39 and 110 kPa incident pressure, respectively) and subsequently underwent a battery of behavioral tests. Diffusion tensor imaging (DTI), a promising method to detect blast injury in humans, was performed on fixed brains to detect and visualize the spatial dependence of blast injury. Blast TBI caused significant deficits in memory function as evidenced by the Morris Water Maze, but limited emotional deficits as evidenced by the Open Field Test and Elevated Plus Maze. Fractional anisotropy, a metric derived from DTI, revealed significant brain abnormalities in blast-exposed animals. A significant relationship between memory deficits and brain microstructure was evident in the hippocampus, consistent with its role in memory function. The results provide fundamental insight into the neurological consequences of blast TBI, including the evolution of injury during the sub-acute phase and the spatially dependent pattern of injury. The relationship between memory dysfunction and microstructural brain abnormalities may provide insight into the persistent cognitive difficulties experienced by soldiers exposed to blast neurotrauma and may be important to guide therapeutic and rehabilitative efforts

Epidermal stem cells are retained in vivo throughout skin aging

In healthy individuals, skin integrity is maintained by epidermal stem cells which self-renew and generate daughter cells that undergo terminal differentiation. It is currently unknown whether epidermal stem cells influence or are affected by skin aging. We therefore compared young and aged skin stem cell abundance, organization, and proliferation. We discovered that despite age-associated differences in epidermal proliferation, dermal thickness, follicle patterning, and immune cell abundance, epidermal stem cells were maintained at normal levels throughout life. These findings, coupled with observed dermal gene expression changes, suggest that epidermal stem cells themselves are intrinsically aging resistant and that local environmental or systemic factors modulate skin aging

Editorial: Current Perspectives on Insulin-Like Growth Factor Binding Protein (IGFBP) Research

Copyright © 2018 Hoeflich, Pintar and Forbes. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.The insulin-like growth factor binding proteins (IGFBPs), as high affinity IGF binding partners, are the principal regulators of IGF-1 and IGF-2 action. Accordingly, effects of IGFBPs can be observed on the levels of growth and differentiation, development, metabolism, and lifespan. The diversity of IGFBP-actions arises due to time-, sex-, and tissue-specific expression of the six distinct IGFBPs (IGFBP-1 to−6), which have redundant functions as seen from the analysis of double-, triple-, or quadruple IGFBP-knockout mice. The complexity of IGFBP functions is related not only to their roles as IGF carriers within the circulation but also to actions within the extracellular space and in distinct subcellular compartments, such as the cell nucleus. IGFBP functions have been attributed to structural motifs in the three conserved IGFBP subdomains, with specific residues being posttranslationally modified by glycosylation or phosphorylation to regulate IGFBP action. In addition, multiple binding partners inside and outside the cell have been identified that regulate IGFBP functions, including their IGF-independent activities. Furthermore, an in-depth understanding is emerging of the role of IGFBP proteolysis in the regulation of both IGF-dependent and IGF-independent actions through generation of potentially bioactive IGFBP-fragments. Accordingly, proteolytic degradation of IGFBPs as a physiologically relevant mechanism in disease has been revealed both in a malignant context but also in other acute or chronic pathophysiological conditions. Finally, the IGFBPs e.g., as sensors of GH/IGF-status have tremendous biomarker potential. Measurement of IGFBP-3/IGFBP-2 ratios provides ultimate sensitivity for the GH-status of a given cellular system. Similarly, detection of intact and fragmented IGFBPs may provide an indication of disease status. Accordingly, for the future we may expect an evolution of IGFBP-related diagnostic approaches, which extend to the characterization of both structural and functional properties of IGFBPs and their fragments in preclinical and clinical research

7‑hydroxymitragynine is an active metabolite of mitragynine and a key mediator of its analgesic effects

Mitragynina speciosa, more commonly known as kratom, is a plant native to Southeast Asia, the leaves of which have been used traditionally as a stimulant, analgesic, and treatment for opioid addiction. Recently, growing use of the plant in the United States and concerns that kratom represents an uncontrolled drug with potential abuse liability, have highlighted the need for more careful study of its pharmacological activity. The major active alkaloid found in kratom, mitragynine, has been reported to have opioid agonist and analgesic activity in vitro and in animal models, consistent with the purported effects of kratom leaf in humans. However, preliminary research has provided some evidence that mitragynine and related compounds may act as atypical opioid agonists, inducing therapeutic effects such as analgesia, while limiting the negative side effects typical of classical opioids. Here we report evidence that an active metabolite plays an important role in mediating the analgesic effects of mitragynine. We find that mitragynine is converted in vitro in both mouse and human liver preparations to the much more potent mu-opioid receptor agonist 7-hydroxymitragynine, and that this conversion is mediated by cytochrome P450 3A isoforms. Further, we show that 7-hydroxymitragynine is formed from mitragynine in mice and that brain concentrations of this metabolite are sufficient to explain most or all of the opioid-receptor-mediated analgesic activity of mitragynine. At the same time, mitragynine is found in the brains of mice at very high concentrations relative to its opioid receptor binding affinity, suggesting that it does not directly activate opioid receptors. The results presented here provide a metabolism-dependent mechanism for the analgesic effects of mitragynine and clarify the importance of route of administration for determining the activity of this compound. Further, they raise important questions about the interpretation of existing data on mitragynine and highlight critical areas for further research in animals and humans.</p

Structured fibrous carbon-based catalyst for continuous nitrate removal from natural water

[EN] Bimetallic (Pd–Cu, Pd–Sn) nanoparticles supported on structured fibrous carbons (activated carbon fibers and carbon nanofibers grown on sintered metal fibers) were tested in nitrate removal of natural polluted water by hydrogen (a batch and continuous mode). Dependence of the activity/selectivity on catalyst chemical composition, promoter nature and metal particle size was studied. Sn-modified Pd nanoparticles showed higher N2 selectivity as compared to Cu-modified ones. The structured (Pd–Sn) nanoparticles supported on carbon nanofibers grown on Inconel sintered metal fibers demonstrated the best catalytic performance in an open flow reactor, providing optimal hydrodynamics properties.This work was carried out with the financial support of the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 226347.Yuranova, T.; Franch Martí, C.; Palomares Gimeno, AE.; García-Bordejé, E.; Kiwi-Minsker, L. (2012). Structured fibrous carbon-based catalyst for continuous nitrate removal from natural water. Applied Catalysis B: Environmental. 123-124:221-228. https://doi.org/10.1016/j.apcatb.2012.04.007S221228123-12

Biomechanical experimental data curation: an example for main lumbar spine ligaments characterization for a MBS spine model

Series : Mechanisms and machine science, ISSN 2211-0984, vol. 24This work overviews an extensive analysis in the context of mechanical characterization of human biomaterials, carried out over a broad set of published experimental data. Focused on main lumbar spine ligaments, several test procedures are exhaustively analyzed, in order to identify possible causes for divergences that have been found in some results. Moreover, guidelines are proposed for da-ta filtering and selection. The main objective of the task was to retrieve trustworthy inputs to a hybrid Finite Element Analysis / Multibody System dynamic simulation model of the human intervertebral disc, which can be used on the prediction of nucleus prosthetics working performance

Retention of Supraspinal Delta-like Analgesia and Loss of Morphine Tolerance in δ Opioid Receptor Knockout Mice

AbstractGene targeting was used to delete exon 2 of mouse DOR-1, which encodes the δ opioid receptor. Essentially all 3H-[D-Pen2,D-Pen5]enkephalin (3H-DPDPE) and 3H-[D-Ala2,D-Glu4]deltorphin (3H-deltorphin-2) binding is absent from mutant mice, demonstrating that DOR-1 encodes both δ1 and δ2 receptor subtypes. Homozygous mutant mice display markedly reduced spinal δ analgesia, but peptide δ agonists retain supraspinal analgesic potency that is only partially antagonized by naltrindole. Retained DPDPE analgesia is also demonstrated upon formalin testing, while the nonpeptide δ agonist BW373U69 exhibits enhanced activity in DOR-1 mutant mice. Together, these findings suggest the existence of a second delta-like analgesic system. FinallyDOR-1 mutant mice do not develop analgesic tolerance to morphine, genetically demonstrating a central role for DOR-1 in this process