Structural evolution of spark plasma sintered AlFeCuCrMgx (x = 0, 0.5, 1, 1.7) high entropy alloys

The present paper reports synthesis of novel AlFeCuCrMgx (x = 0, 0.5, 1, 1.7 mol) high entropy alloys (HEAs) by mechanical alloying (MA) followed by spark plasma sintering (SPS). Phase evolution, microstructure and phase transformation study of the sintered alloy were investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM) and differential scanning calorimetry (DSC). XRD of the sintered alloys revealed the formation of two BCC phases in the AlFeCuCr alloy and more complex structures in AlFeCuCrMgx (x = 0.5, 1, 1.7) alloys containing AlFe type, BCC, and Cu2Mg type phases. TEM bright field image and selected area diffraction pattern (SAED) revealed the formation of tetragonal closed packed Cr precipitates within the Cu2Mg phase of AlFeCuCrMgx alloys (x = 0.5, 1, 1.7). DSC study of the alloys revealed no substantial phase change up to 1000 °C for AlFeCuCr alloy. Although, for x = 0.5, 1 & 1.7 phase transformation occurs at 818 °C, 885 °C & 483 °C respectively. Mg content had a significant effect on hardness, increasing to a peak hardness of 853 HVN for AlFeCuCrMg0.5 alloy before decreasing to 533 HVN for the AlFeCuCrMg1.7 alloy. The phase evolution in these alloys has been considered using thermodynamic parameters, and the structure-property relationship has also been proposed by conventional strengthening mechanisms.

Structural function and evolution of the subarctometatarsus

Compares the metatarsal structural design (subarctometatarsus) of recently discovered Chinese feathered dinosaurs with the metatarsus (arctometatarsus) possessed by more advanced theropod dinosaurs and the metatarsus of more primitive forms. The subarctometatarsus was proved to be an intermediate structure. Additionally the metatarsus appears to co-incide with the evolution of the avian feather suggesting a possible relationship between the subarctometatarsus's evolution and the evolution of avian flight.

Evolution of class I cytokine receptors

Background
The Class I cytokine receptors have a wide range of actions, including a major role in the development and function of immune and blood cells. However, the evolution of the genes encoding them remains poorly understood. To address this we have used bioinformatics to analyze the Class I receptor repertoire in sea squirt (Ciona intestinalis) and zebrafish (Danio rerio).
Results
Only two Class I receptors were identified in sea squirt, one with homology to the archetypal GP130 receptor, and the other with high conservation with the divergent orphan receptor CLF-3. In contrast, 36 Class I cytokine receptors were present in zebrafish, including representative members for each of the five structural groups found in mammals. This allowed the identification of 27 core receptors belonging to the last common ancestor of teleosts and mammals.
Conclusion
This study suggests that the majority of diversification of this receptor family occurred after the divergence of urochordates and vertebrates approximately 794 million years ago (MYA), but before the divergence of ray-finned from lobe-finned fishes around 476 MYA. Since then, only relatively limited lineage-specific diversification within the different Class I receptor structural groups has occurred.

Common structural basis for central nervous system drug design

The main theme of this thesis is that there is a common structural basis for drugs acting on the central nervous system (CNS), and that this concept may be used to design new CNS-active drugs which have greater specificity and hence less side-effects. To develop these ideas, the biological basis of how drugs modify CMS neurotransmission is described, and illustrated using dopaminergic pathways. An account is then given of the use of physicochemical concepts in contemporary drug design. The complete conformational analysis of several antipsychotic drugs is used to illustrate some of these techniques in the development of a model for antipsychotic drug action. After reviewing current structure-activity studies in several classes of CNS drugs (antipsychotics, anti-depressants, stimulants, hal1ucinogens, anticonvulsants and analgesics), a hypothesis for a common structural basis of CNS drug action is proposed- This is based on a topographical comparison of the X-ray structures of eight representative CNS-active drugs, and consists of three parts: 1.there is a common structural basis for the activity of many different CNS-active drug classes; 2. an aromatic ring and a nitrogen atom are the primary binding groups whose topographical arrangement is fundamental to the activity of these drug classes; 3. the nature and placement of secondary binding determines different classes of CNS drug activity. A four-Point model for this common structural basis is then defined using 14- CNS-active drug structures that include the original eight used in proposing the hypothesis. The coordinates of this model are: R1 (0. 3.5, 0), R2 (0, -3.5, O), N (4.8. -0.3, 1.4), and R3 (6.3, 1.3, 0), where R1 and R2 represent the point locations of a hydrophobic interaction of the common aromatic ring with a receptor, and R3 locates the receptor point for a hydrogen bond involving the common nitrogen, N. Extended structures were used to define the receptor points R1, R2 and R3, and the complete conformational space of each of the 14 molecules was considered. It is then shoun that the model may be used to predict whether a given structure is likely to show CNS activity: a search over 1,000 entries in the current Merck Index shows a high probability (82%) of CNS activity in compounds fitting the structural model. Analysis of CNS neurotransmitters and neuropeptides shows that these fit the common model well. Based on the available evidence supporting chemical evolution, protein evolution, and the evolution of neurotransmitter functions, it is surmised that the aromatic ring/nitrogen atom pharmacophore proposed in the common model supports the idea of the evolution of CNS receptors and their neurotransmitters, possibly from an aromatic amine or acety1cho1ine acting as a primaeval communicating molecule. The third point in the hypothesis trilogy is then addressed. The extensive conformation-activity analyses that have resulted in well-defined models for five separate CNS drug classes are used to map out the locations of secondary binding groups relative to the common model for anti-psychotics, antidepressants, analgesics, anticholinergics, and anticonvulsants. With this information, and knowledge derived from receptor-binding data, it is postulated that drugs having specified activity could be designed. In order to generate novel structures having a high probability of CNS-activity, a process of drug design is described in which known CNS structures are superimposed topographically using the common model as a template. Atoms regarded as superfluous may be selectively deleted and the required secondary binding groups added in predicted locations to give novel structures. It is concluded that this process provides the basis for the rational design of new lead compounds which could further be optimized for potent and specific CNS activity.

A despecialization step underlying evolution of a family of serine proteases

In the trypsin superfamily of serine proteases, non-trypsin-like primary specificities have arisen in only two monophyletic descendent subbranches. We have recreated an ancestor to one of these subbranches (granzyme) using phylogenetic inference, gene synthesis, and protein expression. This ancestor has two unusual properties. First, it has broad primary specificity encompassing the entire repertoire of novel primary specificities found in its descendents. Second, unlike extant members that have narrow primary specificities, the ancestor exhibits tolerance to mutational changes in primary specificity-conferring residues—that is, structural plasticity. Molecular modeling and mutagenesis studies indicate that these unusual properties are due to a particularly wide substrate binding pocket. These two crucial properties of the ancestor not only distinguish it from its extant descendents but also from the trypsin-like proteases that preceded it. This indicates that a despecialization step, characterized by broad specificity and structural plasticity, underlies evolution of new primary specificities in this protease superfamily.

Evolution of distinct EGF domains with specific functions

EGF domains are extracellular protein modules cross-linked by three intradomain disulfides. Past studies suggest the existence of two types of EGF domain with three-disulfides, human EGF-like (hEGF) domains and complement C1r-like (cEGF) domains, but to date no functional information has been related to the two different types, and they are not differentiated in sequence or structure databases. We have developed new sequence patterns based on the different C-termini to search specifically for the two types of EGF domains in sequence databases. The exhibited sensitivity and specificity of the new pattern-based method represents a significant advancement over the currently available sequence detection techniques. We re-annotated EGF sequences in the latest release of Swiss-Prot looking for functional relationships that might correlate with EGF type. We show that important post-translational modifications of three-disulfide EGFs, including unusual forms of glycosylation and post-translational proteolytic processing, are dependent on EGF subtype. For example, EGF domains that are shed from the cell surface and mediate intercellular signaling are all hEGFs, as are all human EGF receptor family ligands. Additional experimental data suggest that functional specialization has accompanied subtype divergence. Based on our structural analysis of EGF domains with three-disulfide bonds and comparison to laminin and integrin-like EGF domains with an additional interdomain disulfide, we propose that these hEGF and cEGF domains may have arisen from a four-disulfide ancestor by selective loss of different cysteine residues.

Evolution of cuticular hydrocarbon diversity in ants

The cuticular hydrocarbons (CHCs) of ants provide important cues for nestmate and caste recognition. There is enormous diversity in the composition of these CHCs, but the manner in which this diversity has evolved is poorly understood. We gathered data on CHC profiles for 56 ant species, relating this information to their phylogeny. We deduced the mode of evolution of CHC profiles by reconstructing character evolution and then relating the number of changes in CHC components along each branch of the phylogeny to the length of the branch. There was a strong correlation between branch length and number of component changes, with fewer changes occurring on short branches. Our analysis thereby indicated a gradual mode of evolution. Different ant species tend to use specific CHC structural types that are exclusive of other structural types, indicating that species differences may be generated in part by switching particular biosynthetic pathways on or off in different lineages. We found limited, and contradictory, evidence for abiotic factors (temperature and rainfall) driving change in CHC profiles.

Photochemical formation of silver nanodecahedra : structural selection by the excitation wavelength

Silver decahedra have been successfully synthesized with high yield via a photochemical reaction using blue light-emitting diodes (LEDs) as the exciting light source. The decahedra display distinct properties with respect to the ability of light scattering. The photochemical growth process of silver decahedra was monitored by both extinction and scattering spectral evolution. A suggested formation mechanism of silver decahedron is discussed.

The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications

In some patients with major depressive disorder (MDD), individual illness characteristics appear consistent with those of a neuroprogressive illness. Features of neuroprogression include poorer symptomatic, treatment and functional outcomes in patients with earlier disease onset and increased number and length of depressive episodes. In such patients, longer and more frequent depressive episodes appear to increase vulnerability for further episodes, precipitating an accelerating and progressive illness course leading to functional decline. Evidence from clinical, biochemical and neuroimaging studies appear to support this model and are informing novel therapeutic approaches. This paper reviews current knowledge of the neuroprogressive processes that may occur in MDD, including structural brain consequences and potential molecular mechanisms including the role of neurotransmitter systems, inflammatory, oxidative and nitrosative stress pathways, neurotrophins and regulation of neurogenesis, cortisol and the hypothalamic–pituitary–adrenal axis modulation, mitochondrial dysfunction and epigenetic and dietary influences. Evidence-based novel treatments informed by this knowledge are discussed.

Hierarchical dirichlet process for tracking complex topical structure evolution and its application to autism research literature

In this paper we describe a novel framework for the discovery of the topical content of a data corpus, and the tracking of its complex structural changes across the temporal dimension. In contrast to previous work our model does not impose a prior on the rate at which documents are added to the corpus nor does it adopt the Markovian assumption which overly restricts the type of changes that the model can capture. Our key technical contribution is a framework based on (i) discretization of time into epochs, (ii) epoch-wise topic discovery using a hierarchical Dirichlet process-based model, and (iii) a temporal similarity graph which allows for the modelling of complex topic changes: emergence and disappearance, evolution, splitting and merging. The power of the proposed framework is demonstrated on the medical literature corpus concerned with the autism spectrum disorder (ASD) - an increasingly important research subject of significant social and healthcare importance. In addition to the collected ASD literature corpus which we made freely available, our contributions also include two free online tools we built as aids to ASD researchers. These can be used for semantically meaningful navigation and searching, as well as knowledge discovery from this large and rapidly growing corpus of literature.

Signaling via the CytoR/JAK/STAT/SOCS pathway: emergence during evolution

Cell-cell signaling represents an essential hallmark of multicellular organisms, which necessarily require a means of communicating between different cell populations, particularly immune cells. Cytokine receptor signaling through the Janus kinase/Signal Transducer and Activator of Transcription/Suppressor of Cytokine Signaling (CytoR/JAK/STAT/SOCS) pathway embodies one important paradigm by which this is achieved. This pathway has been extensively studied in vertebrates and protostomes and shown to play fundamental roles in development and function of immune and other cells. However, our understanding of the origins of the individual pathway components and their assembly into a functional pathway has remained limited. This study examined the origins of each component of this pathway through bioinformatics analysis of key extant species. This has revealed step-wise accretion of individual components over a large evolutionary time-frame, but only in bilateria did a series of innovations allow their final coalescence to form a complete pathway. Assembly of the CytoR/JAK/STAT pathway has followed the retrograde model of pathway evolution, whereas addition of the SOCS component has adhered to the patchwork model.

Potential role of glutathione in evolution of thiol-based redox signaling sites in proteins.

Cysteine is susceptible to a variety of modifications by reactive oxygen and nitrogen oxide species, including glutathionylation; and when two cysteines are involved, disulfide formation. Glutathione-cysteine adducts may be removed from proteins by glutaredoxin, whereas disulfides may be reduced by thioredoxin. Glutaredoxin is homologous to the disulfide-reducing thioredoxin and shares similar binding modes of the protein substrate. The evolution of these systems is not well characterized. When a single Cys is present in a protein, conjugation of the redox buffer glutathione may induce conformational changes, resulting in a simple redox switch that effects a signaling cascade. If a second cysteine is introduced into the sequence, the potential for disulfide formation exists. In favorable protein contexts, a bistable redox switch may be formed. Because of glutaredoxin's similarities to thioredoxin, the mutated protein may be immediately exapted into the thioredoxin-dependent redox cycle upon addition of the second cysteine. Here we searched for examples of protein substrates where the number of redox-active cysteine residues has changed throughout evolution. We focused on cross-strand disulfides (CSDs), the most common type of forbidden disulfide. We searched for proteins where the CSD is present, absent and also found as a single cysteine in protein orthologs. Three different proteins were selected for detailed study-CD4, ERO1, and AKT. We created phylogenetic trees, examining when the CSD residues were mutated during protein evolution. We posit that the primordial cysteine is likely to be the cysteine of the CSD which undergoes nucleophilic attack by thioredoxin. Thus, a redox-active disulfide may be introduced into a protein structure by stepwise mutation of two residues in the native sequence to Cys. By extension, evolutionary acquisition of structural disulfides in proteins can potentially occur via transition through a redox-active disulfide state.

Investigation of progress of reactions and evolution of radial heterogeneity in the initial stage of thermal stabilization of PAN precursor fibres

The relationship between process parameters and structural transformations in the fibres at each stage of the carbon fibre manufacturing process play a crucial role in developing high performance carbon fibres. Here we report a systematic method which uses the combination of Taguchi approach and scientific evaluation techniques to establish these relationships for the initial stage of thermal stabilization. Density, cyclization index and fraction of reacted nitriles of a precursor containing acrylonitrile, methacrylate and itaconic acid (AN/MA/IA) were used to assess the progress of stabilization in the fibres with respect to various combinations of process parameters. The extent of progress of stabilization improved with increase in temperature (from 225 to 235 °C) and time (from 12 to 24 min) whereas an opposite trend was observed with increase in the tension on the fibres from (1600-2550 cN). According to optical microscopy, radial heterogeneity was observed in the fibres treated at 235 °C. Interestingly, we were able to identify the existence of heterogeneous modulus distribution from skin to core of the precursor fibres which was further transferred to treated fibres. The overall radial modulus of treated fibres was higher than the precursor fibres. In contrast to the literature, the fracture morphology of the fibre samples indicated that initiation of crack is caused by surface defects rather than radial heterogeneity.

Evolution of elastic modulus in roll forming

Roll forming is a continuous process in which a flat strip is incrementally bent to a desired profile. This process is increasingly used in automotive industry to form High Strength Steel (HSS) and Advanced High Strength Steel (AHSS) for structural components. Because of the large variety of applications of roll forming in the industry, Finite Element Analysis (FEA) is increasingly employed for roll forming process design. Formability and springback are two major concerns in the roll forming AHSS materials. Previous studies have shown that the elastic modulus (Young’s modulus) of AHSS materials can change when the material undergoes plastic deformation and the main goal of this study is to investigate the effect of a change in elastic modulus during forming on springback in roll forming. FEA has been applied for the roll forming simulation of a V-section using material data determined by experimental loading-unloading tests performed on mild, XF400, and DP780 steel. The results show that the reduction of the elastic modulus with pre-strain significantly influences springback in the roll forming of high strength steel while its effect is less when a softer steel is formed.