Phase transformation pathways in a Ti-5.9Cu alloy modified with Fe and Al

Titanium alloys have been gaining importance in various industries due to their advantageous combination of strength, low density, excellent corrosion/oxidation resistance, and superior mechanical properties at elevated temperatures. Recently, eutectoid Ti–Cu alloys have been explored as promising candidates for advanced processes. This work investigates the effects of Fe and Al on a Ti-5.9Cu alloy using multi-scale characterization techniques. While Fe acts as a β-stabilizing element (despite being a sluggish eutectoid former), Al acts as an α-stabilizer. This work focuses on the effects of combined addition of these elements, studied in different heat treatment conditions. The results show that a fine, equiaxed microstructure is obtained in the binary Ti-5.9Cu alloy, whereas the addition of 2 wt% Fe, or 2 wt% Fe combined with 2 wt% Al to the Ti-5.9Cu alloy deteriorates the effect of grain refinement and coarse, columnar grains result and a small amount of β-phase is retained. Further, the microstructure resulting from the eutectoid decomposition is altered dramatically from a lamellar pearlitic in the binary alloy to a lath-like α-phase with diverse decomposition products in the ternary and quaternary alloys accompanied by increasing hardness values. Evaluation of the α misorientation suggests that a substantial amount of non-Burgers α is present in the Ti-Cu alloy in contrast to the results of the ternary and quaternary alloys. The observed Cu-rich intermetallic compound was identified as Ti$_2$Cu phase with off-stoichiometric composition. Results obtained explain how adding either Fe or Fe and Al leads to substantial hardening

Differential scanning calorimetry (DSC) and thermodynamic prediction of liquid fraction vs temperature for two high-performance alloys for semi-solid processing (Al-Si-Cu-Mg (319s) and Al-Cu-Ag (201))

There is a need to extend the application of semi-solid processing (SSP) to higher performance alloys such as 319s (Al-Si-Cu-Mg) and 201 (Al-Cu-Ag). The melting of these two alloys was investigated using differential scanning calorimetry (DSC) and thermodynamic prediction. The alloys had been processed by magneto-hydrodynamic (MHD) stirring before receipt to produce a microstructure suitable for SSP. The DSC results for the as-received MHD material were compared with those for material which has been taken through a complete DSC cycle and then reheated for a second DSC run. The effects of microsegregation were then analyzed. A higher liquid fraction for a particular temperature is found in the second DSC run than the first. Microstructural observations suggest this is because the intermetallics which form during the first cooling cycle tend to co-located. Quaternary and ternary reactions then occur during the second DSC heat and the co-location leads to enhanced peaks. The calculated liquid fraction is lower with 10 K/min DSC heating rate comparing with 3 K/min at a given temperature. The DSC scan rate must therefore be carefully considered if it is to be used to identify temperature parameters or the suitability of alloys for SSP. In addition, the starting material for DSC must represent the starting material for the SSP. With thermodynamic prediction, the equilibrium condition will provide better guidance for the thixoforming of MHD stirred starting material than the Scheil condition. The Scheil mode approximates more closely with a strongly microsegregated state

Suppression of MAPK11 or HIPK3 reduces mutant Huntingtin levels in Huntington's disease models.

Most neurodegenerative disorders are associated with accumulation of disease-relevant proteins. Among them, Huntington disease (HD) is of particular interest because of its monogenetic nature. HD is mainly caused by cytotoxicity of the defective protein encoded by the mutant Huntingtin gene (HTT). Thus, lowering mutant HTT protein (mHTT) levels would be a promising treatment strategy for HD. Here we report two kinases HIPK3 and MAPK11 as positive modulators of mHTT levels both in cells and in vivo. Both kinases regulate mHTT via their kinase activities, suggesting that inhibiting these kinases may have therapeutic values. Interestingly, their effects on HTT levels are mHTT-dependent, providing a feedback mechanism in which mHTT enhances its own level thus contributing to mHTT accumulation and disease progression. Importantly, knockout of MAPK11 significantly rescues disease-relevant behavioral phenotypes in a knockin HD mouse model. Collectively, our data reveal new therapeutic entry points for HD and target-discovery approaches for similar diseases

Deficiency of Huntingtin Has Pleiotropic Effects in the Social Amoeba Dictyostelium discoideum

Huntingtin is a large HEAT repeat protein first identified in humans, where a polyglutamine tract expansion near the amino terminus causes a gain-of-function mechanism that leads to selective neuronal loss in Huntington's disease (HD). Genetic evidence in humans and knock-in mouse models suggests that this gain-of-function involves an increase or deregulation of some aspect of huntingtin's normal function(s), which remains poorly understood. As huntingtin shows evolutionary conservation, a powerful approach to discovering its normal biochemical role(s) is to study the effects caused by its deficiency in a model organism with a short life-cycle that comprises both cellular and multicellular developmental stages. To facilitate studies aimed at detailed knowledge of huntingtin's normal function(s), we generated a null mutant of hd, the HD ortholog in Dictyostelium discoideum. Dictyostelium cells lacking endogenous huntingtin were viable but during development did not exhibit the typical polarized morphology of Dictyostelium cells, streamed poorly to form aggregates by accretion rather than chemotaxis, showed disorganized F-actin staining, exhibited extreme sensitivity to hypoosmotic stress, and failed to form EDTA-resistant cell–cell contacts. Surprisingly, chemotactic streaming could be rescued in the presence of the bivalent cations Ca2+ or Mg2+ but not pulses of cAMP. Although hd− cells completed development, it was delayed and proceeded asynchronously, producing small fruiting bodies with round, defective spores that germinated spontaneously within a glassy sorus. When developed as chimeras with wild-type cells, hd− cells failed to populate the pre-spore region of the slug. In Dictyostelium, huntingtin deficiency is compatible with survival of the organism but renders cells sensitive to low osmolarity, which produces pleiotropic cell autonomous defects that affect cAMP signaling and as a consequence development. Thus, Dictyostelium provides a novel haploid organism model for genetic, cell biological, and biochemical studies to delineate the functions of the HD protein

Discovery of Therapeutic Approaches for Polyglutamine Diseases: A Summary of Recent Efforts

Polyglutamine (PolyQ) diseases are a group of neurodegenerative disorders caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the coding region of specific genes. This leads to the production of pathogenic proteins containing critically expanded tracts of glutamines. Although polyQ diseases are individually rare, the fact that these nine diseases are irreversibly progressive over 10 to 30 years, severely impairing and ultimately fatal, usually implicating the full-time patient support by a caregiver for long time periods, makes their economic and social impact quite significant. This has led several researchers worldwide to investigate the pathogenic mechanism(s) and therapeutic strategies for polyQ diseases. Although research in the field has grown notably in the last decades, we are still far from having an effective treatment to offer patients, and the decision of which compounds should be translated to the clinics may be very challenging. In this review, we provide a comprehensive and critical overview of the most recent drug discovery efforts in the field of polyQ diseases, including the most relevant findings emerging from two different types of approaches-hypothesis-based candidate molecule testing and hypothesis-free unbiased drug screenings. We hereby summarize and reflect on the preclinical studies as well as all the clinical trials performed to date, aiming to provide a useful framework for increasingly successful future drug discovery and development efforts.Project ON.2 SR&TD Integrated Program (NORTE-07-0124-FEDER-000021), co-funded by North Portugal Regional Operational Program (ON.2-O Novo Norte), under the National Strategic Reference Framework, through the European Regional Development Fund (ERDF) and also supported by Fundação para a Ciência e Tecnologia through the project POCI-01-0145-FEDER-016818 (PTDC/NEU-NMC/3648/2014)info:eu-repo/semantics/publishedVersio

Rule-Based Cell Systems Model of Aging using Feedback Loop Motifs Mediated by Stress Responses

Investigating the complex systems dynamics of the aging process requires integration of a broad range of cellular processes describing damage and functional decline co-existing with adaptive and protective regulatory mechanisms. We evolve an integrated generic cell network to represent the connectivity of key cellular mechanisms structured into positive and negative feedback loop motifs centrally important for aging. The conceptual network is casted into a fuzzy-logic, hybrid-intelligent framework based on interaction rules assembled from a priori knowledge. Based upon a classical homeostatic representation of cellular energy metabolism, we first demonstrate how positive-feedback loops accelerate damage and decline consistent with a vicious cycle. This model is iteratively extended towards an adaptive response model by incorporating protective negative-feedback loop circuits. Time-lapse simulations of the adaptive response model uncover how transcriptional and translational changes, mediated by stress sensors NF-κB and mTOR, counteract accumulating damage and dysfunction by modulating mitochondrial respiration, metabolic fluxes, biosynthesis, and autophagy, crucial for cellular survival. The model allows consideration of lifespan optimization scenarios with respect to fitness criteria using a sensitivity analysis. Our work establishes a novel extendable and scalable computational approach capable to connect tractable molecular mechanisms with cellular network dynamics underlying the emerging aging phenotype

Thermodynamic characterisation of semi-solid processability in alloys based on AL-SI, AL-CU and AL-MG binary systems

The processing window is important for the semisolid processability of alloys. Applications of semi-solid metal (SSM) processing, especially aluminium alloys have been expanding for their excellent mechanical properties. However, the alloys well suited and commercially used for SSM processing today are limited in types. The main purpose of this Ph.D. project is to understand what makes an alloy suitable for SSM processing on both aspects of thermodynamics and kinetics. This research started with a fundamental study of binary alloys based on Al-Si, Al-Cu and Al-Mg systems (wt%): Al-1Si, Al-5Si, Al-12Si and Al-17Si; Al-1Cu, Al-2Cu and Al-5Cu; Al-0.5Mg, Al-3Mg and Al-5.5Mg. These are representative of Si, Cu and Mg contents in commercial alloys used for SSM processing. The Single-Pan Scanning Calorimeter (SPSC) and Differential Scanning Calorimeter (DSC) were used to investigate the liquid fraction changes during heating and cooling of these binary alloys. Thermo-Calc and DICTRA (DIffusion-Controlled TRAnsformations) software have been used to predict the fraction liquid versus temperature taking into account both thermodynamics and kinetics. Comparison of the predictions with experimental data revealed that the simulation results show the same pattern with experimental results in the fraction liquid-temperature relationship. However, the SPSC results are closer to the prediction than DSC curves are, even with the relatively large sample size associated with SPSC. This is potentially a significant result as predicting the liquid fraction versus temperature for the heating of a billet for semi-solid processing remains one of the challenges. The results also suggest that the fraction liquid sensitivity to time should be identified as a critical parameter of the process window for semi-solid processing in addition to the fraction liquid sensitivity to temperature. For microstructure investigation, microanalysis techniques, including Scanning Electron Microscopy (SEM) and micro-indentation testing, have been used on polished sections, and compared to theoretical predictions. In addition, some parts of this project are in cooperation with General Research Institute for Nonferrous Metals (GRINM), which aims to design and develop high performance semi-solid alloys. Thermodynamic analysis (both predictions and experiments) were carried out on thixoformed 319s (2.95Cu, 6.10Si, 0.37Mg, wt%) and 201 (4.80Cu, 0.7Ag, wt%) aluminium alloys. SEM techniques and Transmission Electron Microscopy (TEM) were used for the microstructural characterisation. The results showed that the DSC curves were sensitive to microsegregation in SSM alloys and resulted in a lower liquid fraction than the cast alloys calculated through the integration method from the DSC results. Al2Cu phase in SSM alloys 319s and 201 can be dissolved into matrix up to 0.4 % before melting temperature under 3K/min heating rate when compared with 10K/min heating rate. The DSC scan rate should be carefully selected as higher heating rate can inhibit dissolution of the intermetallic phases during heating leading to less accurate liquid fractions predictions

What is the Process Window for Semi-solid Processing?

In semi-solid processing, the liquid fraction vs temperature is commonly used to define the process window. Conventionally, it is assumed that a freezing range is required for semi-solid processing but recently both high-purity aluminum and binary Al-Si eutectic alloy have been rheo-processed. Here, the kinetics during melting and solidification of pure metal are analyzed, and a comparison between the liquid fraction vs temperature and the liquid fraction vs time is presented. It is found that liquid fraction vs time is a significant criterion for semi-solid processing

Grain refinement in laser remelted Mg-3Nd-1Gd-0.5Zr alloy

Columnar grains are normally favoured with the high cooling rate and steep thermal gradient in laser-based additive manufacturing. Here, we demonstrate that fine, fully equiaxed grains can be achieved in Mg-3Nd-1Gd-0.5Zr (EV31) alloy by laser surface remelting. The grains in the melt pool are remarkably refined from 74 µm to 3.5 µm, which can be attributed to the growth restriction effect, i.e. the constitutional supercooling formed by Zr solute during solidification in combination with the high cooling rate imposed by laser surface remelting. This novel finding could be applied for the control of grain morphology and alloy design for additive manufacturing applications

Refining As-cast β-Ti Grains Through ZrN Inoculation

The columnar-to-equiaxed transition and remarkable refinement of β-Ti grains occur in an as-cast Ti-13Mo alloy when a new grain refiner, ZrN, was inoculated at a nitrogen level as low as 0.4 wt\ua0pct. The grain refining effect is attributed to in situ-formed TiN particles that provide active nucleation sites and solute Zr that promotes constitutional supercooling. Reproducible orientation relationships were identified between TiN nucleants and β-Ti matrix, and well explained by the edge-to-edge matching model