Specificity Rendering ‘Hot-Spots’ for Aurora Kinase Inhibitor Design: The Role of Non-Covalent Interactions and Conformational Transitions

The present study examines the conformational transitions occurring among the major structural motifs of Aurora kinase (AK) concomitant with the DFG-flip and deciphers the role of non-covalent interactions in rendering specificity. Multiple sequence alignment, docking and structural analysis of a repertoire of 56 crystal structures of AK from Protein Data Bank (PDB) has been carried out. The crystal structures were systematically categorized based on the conformational disposition of the DFG-loop [in (D_I) 42, out (D_O) 5 and out-up (D_OU) 9], G-loop [extended (G_E) 53 and folded (G_F) 3] and αC-helix [in (C_I) 42 and out (C_O) 14]. The overlapping subsets on categorization show the inter-dependency among structural motifs. Therefore, the four distinct possibilities a) 2W1C (D_I, C_I, G_E) b) 3E5A (D_I, C_I, G_F) c) 3DJ6 (D_I, C_O, G_F) d) 3UNZ (D_OU, C_O, G_F) along with their co-crystals and apo-forms were subjected to molecular dynamics simulations of 40 ns each to evaluate the variations of individual residues and their impact on forming interactions. The non-covalent interactions formed by the 157 AK co-crystals with different regions of the binding site were initially studied with the docked complexes and structure interaction fingerprints. The frequency of the most prominent interactions was gauged in the AK inhibitors from PDB and the four representative conformations during 40 ns. Based on this study, seven major non-covalent interactions and their complementary sites in AK capable of rendering specificity have been prioritized for the design of different classes of inhibitors.     

Dynamics of Inter-Molecular Interactions Between Single Aβ42 Oligomeric and Aggregate Species by High-Speed Atomic Force Microscopy

Within the amyloid hypothesis in Alzheimer's disease, current focus has shifted to earlier stages of amyloid beta (Aβ) peptide assembly, involving soluble oligomers and smaller aggregates, which are more toxic to cells compared to their morphological distinct fibril forms. Critical to the Aβ field is unlocking the molecular-level kinetic pathways of oligomerization, leading to the culprit subset or specific species of Aβ oligomer populations responsible for the disease etiology. Here, we apply high-speed atomic force microscopy to enable direct visualization of dynamic interactions between single Aβ₄₂ oligomers and aggregate forms, with combined nanometre structural and millisecond temporal resolution in liquid. Analysis of dimensions revealed up to three main Aβ₄₂ species distributions, in addition to the appearance of monomers that showed fast surface diffusion compared to the larger Aβ₄₂ species. Significantly, we devised a new single-molecule analysis based on image contrast in high-speed atomic force microscopy movies to quantify rate determining kinetic constants for interactions between the different Aβ₄₂ species. The findings revealed that smaller Aβ₄₂ species show an exponential decay of lifetime distribution, indicating that all molecules undergo the same process with a single well-defined energy barrier. In contrast, larger aggregates show randomized lifetimes, indicating a distribution of interactions energies/barriers that must be overcome in order to dissociate. We interpret the latter as being due to “permissive” binding, arising from different conformation states of the aggregates, along with a variety of accessible interacting groups. Inevitably, this may lead to the formation of different complexes or alloforms, which is known to contribute to difficulties in identifying Aβ oligomer toxicity and has implications for mechanisms underlying neuronal death accompanying Alzheimer's disease.     

Size-structured Interactions between Native and Introduced Species: Can Intraguild Predation Facilitate Invasion by Stream Salmonids?

Dynamics of biological invasions may be complicated in size-structured animal populations. Differences in timing of life history events such as juvenile emergence create complex interaction webs where different life stages of native and non-native species act as predators, competitors, and prey. Stream salmonids are an ideal group for studying these phenomena because they display competition and predation in size-structured populations and have been introduced worldwide. For example, introduced rainbow trout (Oncorhynchus mykiss) are invading streams of Hokkaido Island, Japan and have caused declines in native masu salmon (O. masou) populations. However, age-0 rainbow trout emerge later than age-0 masu salmon and are smaller, which raises the question of why they are able to recruit and therefore invade in the face of a larger competitor. We conducted experiments in laboratory stream channels to test effects of increasing density of age-0 and age-1 rainbow trout on age-0 masu salmon. Age-1 rainbow trout dominated age-0 masu salmon by aggressive interference, relegating them to less favorable foraging positions downstream and reducing their foraging frequency and growth. The age-1 trout also reduced masu salmon survival by predation of about 40% of the individuals overall. In contrast, age-0 rainbow trout had little effect on age-0 masu salmon. Instead, the salmon dominated the age-0 trout by interference competition and reduced their survival by predation of 60% of the individuals. In each case, biotic interactions by the larger species on the smaller were strongly negative due to a combination of interspecific competition and intraguild predation. We predict that together these produce a positive indirect effect in the interaction chain that will allow the recruitment of rainbow trout in the face of competition and predation from age-0 masu salmon, and thereby facilitate their invasion in northern Japan.     

The Association Between Arsenic and Children’s Intelligence: A Meta-analysis

This present study was undertaken to investigate whether arsenic exposure increases the risk of children’s low intelligence quotient (IQ) in China. MEDLINE, SCI, CNKI, and CBM search were organized for all documents published, in English and Chinese, between 1988 and 2008 using the following keywords: arsenic, intelligence, and IQ. As a result, four cross-sectional studies that assessed the development of low IQ in children who had been exposed to arsenic earlier in their life were included in this study. The summary weighted mean difference of IQ was calculated in this meta-analyses, when arsenicosis areas or slight arsenicosis areas were compared with non-arsenicosis areas; it is ?6.85 (95% confidence interval [CI]?=??8.30 to ?5.41; p?<?0.01, using a fixed effect model) and ?6.54 (95%CI?=??8.93 to ?4.15; p?<?0.01, using a random effect model), which means that children who live in an arsenicosis area or a slight arsenicosis area have lower IQ than those who live in a non-arsenicosis area, and there may be a strong association between arsenic and children’s intelligence.     

Functional Interactions of Fibronectin and TNFα: A Paradigm of Physiological Linkage Between Cytokines and Extracellular Matrix Moieties

The ECM is composed of various cell-adhesive glycoproteins, such as, fibronectin (FN), laminin (LN), and different types of glycosaminoglycans and proteoglycans. These building blocks of the ECM are linked together to form a dense and complex tissue that fills the interstitial spaces and comprises the boundaries between cells and tissues. The ECM is the major milieu in which immune cells function during inflammatory processes (Shimizu and Shaw, 1991; Yamada, 1991). Recognition of ECM-glycoproteins by immune cells is mediated by very late activation (VLA) receptors, also referred to as integrins of the β₁-subfamily (Hynes, 1992). A prerequisite of lymphocyte-ECM interactions is activation of the cells by mitogens, or via their CD3-T cell receptor complex, either of these types of activation modulates the affinity of otherwise inactive β₁-integrins (Shimizu, et al., 1990).     

A Sense of Belonging and Exclusion: ‘Touchability’ and ‘Untouchability’ in Tamil Nadu

In India, touch is a prime marker of status and social relations. Those who are impure are ‘untouchable’,1 The terms ‘Untouchable’ and ‘Untouchability’ have been abandoned due to the humiliating meaning these terms confer, therefore I use them in inverted commas. The politically correct and common terms today are Scheduled Castes, in short sc, or Dalits, or sometimes Harijan. I use them here synonymously. but those who are of a relatively higher purity are also, depending on the context, either ‘untouchable’ or ‘touchable’ only under certain fixed rules. In this paper, I will explore the contexts in which body contact and touch can be part of personal relations. I describe how these body contacts signify important social relations and establish community identity. Further, I will analyse how patterns of body contact on the one hand change during childhood, and on the other hand produce changes in the status of a social persona. The last point to be investigated is the meaning of touch as a sign for public representations.     

A ‘Terror of Tyrannosaurs’: The First Trackways of Tyrannosaurids and Evidence of Gregariousness and Pathology in Tyrannosauridae

The skeletal record of tyrannosaurids is well-documented, whereas their footprint record is surprisingly sparse. There are only a few isolated footprints attributed to tyrannosaurids and, hitherto, no reported trackways. We report the world’s first trackways attributable to tyrannosaurids, and describe a new ichnotaxon attributable to tyrannosaurids. These trackways are from the Upper Cretaceous (Campanian - Maastrichtian) of northeastern British Columbia, Canada. One trackway consists of three tridactyl footprints, and two adjacent trackways consist of two footprints each. All three trackways show animals bearing southeast within an 8.5 meter-wide corridor. Similarities in depth and preservation of the tyrannosaurid tracks indicate that these three trackways were made by track-makers walking concurrently in the same direction. These trackways add significantly to previous osteology-based hypotheses of locomotion and behavior in Tyrannosauridae by providing ichnologic support for gregariousness in tyrannosaurids, and the first record of the walking gait of tyrannosaurids.     

Cooperation and Competition Between Twins: Findings from a Prisoner’s Dilemma Game

Attention to factors influencing cooperation and competition during human social interaction has increased within recent years. This study tested the hypothesis that higher levels of cooperation would be associated with increased genetic relatedness between interactants, and explored questions concerning the expression of cooperative behavior over time. A Prisoner’s Dilemma game, in which participants elect to display cooperative, competitive, or exploitative behaviors relative to a partner, was administered to 59 monozygotic and 37 dizygotic twin pairs, between 10.92 and 82.67 years of age. Results from multivariate analysis of variance procedures, cross-lag sequential analyses, and hierarchical linear modeling supported associations between zygosity, and frequency and continuity of cooperation. Mechanisms by which zygosity may affect cooperation were explored by examining relationships between response combinations, and twins’ IQ similarity and social closeness. The findings are considered with reference to an evolutionary perspective on behavior that offers a theoretical basis for considering how the relative genetic relatedness of social partners affects their social-interactional processes and outcomes. This report is the first in a series of studies designed to address mechanisms underlying differences in cooperation among pairs who vary in average genetic commonality.     

Testing Strength of Biotic Resistance against an Introduced Fish: Inter-Specific Competition or Predation through Facultative Piscivory?

Biotic resistance is the process where aspects of the receiving environment inhibit the establishment and invasion of an introduced species. Resistance against an introduced fish can be through strong competition and/or predation from resident fishes. Here, the biotic resistance against introduced topmouth gudgeon Pseudorasbora parva (a highly invasive fish in Europe) by resident carp Cyprinus carpio was tested in experimental mesocosms. The introduction scenario was six adult P. parva (three male, three female) on a single occasion. Resistance to their establishment was provided by three and six resident C. carpio whose effects on P. parva growth and reproduction were compared to a Control (no resident fish at the time of introduction) and treatments containing three and six P. parva. After 120 days, the growth rates of the introduced P. parva were significantly depressed in C. carpio presence and in mesocosms with three C. carpio present, significantly decreased numbers of 0+P. parva were recorded. Where six C. carpio were present, no 0+P. parva were recorded, indicating resistance strength increased with carp abundance. In contrast, there were no differences in P. parva reproduction and growth rates between the Control and treatments containing conspecifics. Stable isotope analysis (δ(15)N, δ(13)C) revealed C. carpio were feeding at one trophic level above 0+P. parva, suggesting the process of resistance was predation (facultative piscivory) rather than competition. Thus, if P. parva are to establish and invade following an introduction, they must overcome this biotic resistance from cyprinid fishes such as C. carpio.     

‘Us’ and ‘Them’: The role of religion in mediating and challenging the ‘model minority’ and other civic boundaries

This article examines how Korean Americans use the cultural resources of religious communities to mediate race, ethnic, and socio-economic boundaries that have consequences for civic life. Specifically, I compare involvement of Korean Americans in second-generation Korean congregations to those in multiethnic churches. I find Korean Americans who participate in second-generation Korean churches use religion to largely reproduce images of Korean Americans as model minorities, and implicitly distance themselves from those whom they perceive as less financially successful. In contrast, Korean Americans in multiethnic congregations use religion to emphasize the commonality Korean Americans have with other minorities. By using a cultural framework that allows for the agency of individuals in identity and group boundary construction, this work more generally shows the potential for new Americans to use the cultural resources of local organizations to change existing ethnic and racial boundaries in the United States.     

The ‘Checkmate’ for Iron Between Human Host and Invading Bacteria: Chess Game Analogy

Iron is an essential nutrient for all living organisms with critical roles in many biological processes. The mammalian host maintains the iron requirements by dietary intake, while the invading pathogenic bacteria compete with the host to obtain those absorbed irons. In order to limit the iron uptake by the bacteria, the human host employs numerous iron binding proteins and withholding defense mechanisms that capture iron from the microbial invaders. To counteract, the bacteria cope with the iron limitation imposed by the host by expressing various iron acquisition systems, allowing them to achieve effective iron homeostasis. The armamentarium used by the human host and invading bacteria, leads to the dilemma of who wins the ultimate war for iron.     

Parallels Between Major Depressive Disorder and Alzheimer’s Disease: Role of Oxidative Stress and Genetic Vulnerability

The thesis of this review is that oxidative stress is the central factor in major depressive disorder (MDD) and Alzheimer’s disease (AD). The major elements involved are inflammatory cytokines, the hypothalamic–pituitary axis, the hypothalamic–pituitary gonadal, and arginine vasopressin systems, which induce glucocorticoid and “oxidopamatergic” cascades when triggered by psychosocial stress, severe life-threatening events, and mental-affective and somatic diseases. In individuals with a genomic vulnerability to depression, these cascades may result in chronic depression–anxiety–stress spectra, resulting in MDD and other known depressive syndromes. In contrast, in subjects with genomic vulnerability to AD, oxidative stress-induced brain damage triggers specific antioxidant defenses, i.e., increased levels of amyloid-β (Aβ) and aggregation of hyper-phosphorylated tau, resulting in paired helical filaments and impaired functions related to the ApoEε4 isoform, leading to complex pathological cascades culminating in AD. Surprisingly, all the AD-associated molecular pathways mentioned in this review have been shown to be similar or analogous to those found in depression, including structural damage, i.e., hippocampal and frontal cortex atrophy. Other interacting molecular signals, i.e., GSK-3β, convergent survival factors (brain-derived neurotrophic factor and heat shock proteins), and transition redox metals are also mentioned to emphasize the vast array of intermediates that could interact via comparable mechanisms in both MDD and AD.     

The social and ecological costs of an ‘over-extended' phenotype

Extended phenotypes offer a unique opportunity to experimentally manipulate and identify sources of selection acting on traits under natural conditions. The social cichlid fish Neolamprologus multifasciatus builds nests by digging up aquatic snail shells, creating an extended sexual phenotype that is highly amenable to experimental manipulation through addition of extra shells. Here, we find sources of both positive sexual selection and opposing natural selection acting on this trait; augmenting shell nests increases access to mates, but also increases social aggression and predation risk. Increasing the attractiveness of one male also changed social interactions throughout the social network and altered the entire community structure. Manipulated males produced and received more displays from neighbouring females, who also joined augmented male territories at higher rates than unmanipulated groups. However, males in more attractive territories received more aggression from neighbouring males, potentially as a form of social policing. We also detected a significant ecological cost of the ‘over-extended'' phenotype; heterospecific predators usurped augmented nests at higher rates, using them as breeding sites and displacing residents. Using these natural experiments, we find that both social and ecological interactions generate clear sources of selection mediating the expression of an extended phenotype in the wild.