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Manufacturing titanium alloys with simultaneous enhancement in strength and ductility has motivated extensive research into various strategies for regulating the arrangement and texture of α and β phases. The present study explores a novel α + β titanium alloy, TIMETAL 639 (Ti-639), produced by replacing a portion of vanadium in Ti-64 with molybdenum. The low diffusivity and β-stabilizing effects of molybdenum help retain bimodal characteristics within solution heat-treated Ti-639 microstructures. EBSD and TEM were used to examine β-phase evolution after thermal processing and recrystallization of new globular α grains within pre-existing colonies in a depleted bimodal microstructure. These depleted bimodal colonies in solution heat-treated Ti-639 also led to lower misorientation spreads and dislocation densities within neighboring primary α grains. Quasi-static compression along the plate normal direction demonstrated the ability of the depleted bimodal microstructure to simultaneously enhance strength and ductility in Ti-639 (~90 MPa stronger, ~6% higher failure strain) versus identically processed Ti-64. Only one solution heat-treatment step (1 h at 900 °C) is needed to achieve these properties in Ti-639, whereas comparable properties in Ti-64 required prolonged aging heat treatment (24 h at 600 °C) after the same solution heat-treatment step, making Ti-639 a viable α + β alloy candidate.

Background: Medical assistance in dying (MAID) was legislatively enacted in Canada in June 2016. Most studies of patients who received MAID grouped patients with cancer and non-cancer diagnoses. Our goal was to analyze the characteristics of oncology patients who received MAID in a Canadian tertiary care hospital. Methods: We conducted a retrospective review of all patients with cancer who received MAID between June 2016 and July 2020 at London Health Sciences Centre (LHSC). We describe patients’ demographics, oncologic characteristics, symptoms, treatments, and palliative care involvement. Results: Ninety-two oncology patients received MAID. The median age was 72. The leading cancer diagnoses among these patients were lung, colorectal, and pancreatic. At the time of MAID request, 68% of patients had metastatic disease. Most patients (90%) had ECOG performance status of 3 or 4 before receiving MAID. Ninety-nine percent of patients had distressing symptoms at time of MAID request, most commonly pain. One-third of patients with metastatic or recurrent cancer received early palliative care. The median time interval between the first MAID assessment and receipt of MAID was 7 days. Interpretation: Most oncology patients who received MAID at LHSC had poor performance status and almost all had distressing symptoms. The median time interval between first MAID assessment and receipt of MAID was shorter than expected. Only one-third of patients with metastatic or recurrent cancer received early palliative care. Improving access to early palliative care is a priority in patients with advanced cancer. Study registration: We received research approval from Western University’s Research Ethics Board (REB) with project ID number 115367, and from Lawson’s Research Database Application (ReDA) with study ID number 9579.

The high-velocity impact of powder particles in cold-spray additively manufactured (CSAM) parts creates intersplat boundaries with regions of high dislocation densities and sub-grain structures. Upon microstructure and mechanical characterization, CSAM Aluminum 6061 showed non-uniformity with spatial variation in the microstructure and mechanical properties, affecting the overall response of the additively manufactured parts. Post-processing treatments are conducted in as-printed samples to improve particle bonding, relieve residual stresses, and improve mechanical properties. In this work, we attempt to implement the effects of grain size and distribution of smaller grains along the intersplat boundaries using the grain size distribution function and powder size information to accurately predict the deformation response of cold-sprayed material using a mean-field viscoplastic self-consistent (VPSC) model. The incorporation of an intersplat boundary term in the VPSC model resulted in a stress–strain response closely matching the experimental findings, preventing the superficially high stresses observed due to Hall–Petch effects from ultra-fine-grain structures. Likewise, the results from the grain analysis showed the combined effects of grain size, orientation, and intersplat mechanisms that captured the stresses experienced and strain accommodated by individual grains.

The “electron wind effect” has long been cited as a potential catalyst of solid-state transformations in metals, particularly when high current densities are involved. However, the literature exploring similar effects at lower current densities, such as those occurring during Gleeble thermomechanical simulation, remains scarce. The present work compares recrystallization activity in cold-rolled low-carbon steel during heat treatment by conventional furnace versus direct resistance heating (Gleeble). Multiple levels of cold work, annealing durations, and soak temperatures were examined, allowing for an in-depth comparison of recrystallization rates and activation energies between samples subjected to identical time–temperature profiles in the furnace and Gleeble. In addition to the expected increase in recrystallization behavior with the increases in temperature and cold-reduction levels, the use of the Gleeble system as the heating method resulted in faster initial microstructural transformation than a conventional furnace. The variability in recrystallized fractions persisted until the microstructures had saturated to their nearly fully recrystallized levels, at which point the microhardness and electron backscatter diffraction (EBSD) revealed convergence to equivalent behavior irrespective of the heating method. Analysis of the recrystallization kinetics by fitting to a JMAK relationship reflected the increased transformation activity during Gleeble treatment, with the value of the kinetic exponent also indicating greater grain growth activity at higher temperature.

Parsing the effect of slip-twin interactions on the strain rate and thermal sensitivities of Magnesium (Mg) alloys has been a challenging endeavor for scientists preoccupied with the mechanical behavior of hexagonal close-packed alloys, especially those with great latent economic potential such as Mg. One of the main barriers is the travail entailed in fitting the various stress–strain behaviors at different temperatures, strain rates, loading directions applied to different starting textures. Taking on this task for two different Mg alloys presenting different textures and as such various levels of slip-twin interactions were modeled using visco-plastic self-consistent (VPSC) code. A recently developed routine that captures dislocation transmutation by twinning interfaces on strain hardening within the twin lamellae was employed. While the strong texture was exemplified by traditional rolled AZ31 Mg alloys, the weak texture was represented by ZEK100 Mg alloy sheets. The transmutation model incorporated within a dislocation density based hardening model showed enhanced flexibility in predicting the complex strain rate and thermal sensitive behavior of Mg textures’ response to various mechanical loading schemes.

During oncogenesis, alterations in driver genes called driver alterations (DAs) modulate the transcriptome, methylome and proteome through oncogenic signaling pathways. These modulatory effects of any DA may be analyzed by examining differentially expressed mRNAs (DEMs), differentially methylated genes (DMGs) and differentially expressed proteins (DEPs) between tumor samples with and without that DA. We aimed to analyze these modulations with 12 common driver genes in Isocitrate Dehydrogenase 1 wildtype glioblastomas (IDH1-W-GBs). Using Cbioportal, groups of tumor samples with and without DAs in these 12 genes were generated from the IDH1-W-GBs available from “The Cancer Genomics Atlas Firehose Legacy Study Group” (TCGA-FL-SG) on Glioblastomas (GBs). For all 12 genes, samples with and without DAs were compared for DEMs, DMGs and DEPs. We found that DAs in PTEN were unassociated with any DEM or DMG in contrast to DAs in all other drivers, which were associated with several DEMs and DMGs. This contrasting PTEN-related property of being unassociated with differential gene expression or methylation in IDH1-W-GBs was unaffected by concurrent DAs in other common drivers or by the types of DAs affecting PTEN. From the lists of DEMs and DMGs associated with some common drivers other than PTEN, enriched gene ontology terms and insights into the co-regulatory effects of these drivers on the transcriptome were obtained. The findings from this study can improve our understanding of the molecular mechanisms underlying gliomagenesis with potential therapeutic benefits.

The molecular interplay between nucleosomal packaging and the chromatin landscape regulates the transcriptional programming and biological outcomes of downstream genes. An array of epigenetic modifications plays a pivotal role in shaping the chromatin architecture, which controls DNA access to the transcriptional machinery. Acetylation of the amino acid lysine is a widespread epigenetic modification that serves as a marker for gene activation, which intertwines the maintenance of cellular homeostasis and the regulation of signaling during stress. The biochemical horizon of acetylation ranges from orchestrating the stability and cellular localization of proteins that engage in the cell cycle to DNA repair and metabolism. Furthermore, lysine acetyltransferases (KATs) modulate the functions of transcription factors that govern cellular response to microbial infections, genotoxic stress, and inflammation. Due to their central role in many biological processes, mutations in KATs cause developmental and intellectual challenges and metabolic disorders. Despite the availability of tools for detecting acetylation, the mechanistic knowledge of acetylation-mediated cellular processes remains limited. This review aims to integrate molecular and structural bases of KAT functions, which would help design highly selective tools for understanding the biology of KATs toward developing new disease treatments.

Through in situ electron backscatter diffraction (EBSD) experiments, this paper uncovers dominant damage mechanisms in traditional magnesium alloys exhibiting deformation twinning. The findings emphasize the level of deleterious strain incompatibility induced by twin interaction with other deformation modes and microstructural defects. A double fiber obtained by plane-strain extrusion as a starting texture of AM30 magnesium alloy offered the opportunity to track deformation by EBSD in neighboring grains where some undergo profuse {1 0 1 2} twinning and others do not. For a tensile loading applied along extrusion transverse (ET) direction, those experiencing profuse twinning reveal a major effect of grain boundaries on non-Schmid behavior affecting twin variant selection and growth. Similarly, a neighboring grain, with its 〈c〉-axis oriented nearly perpendicular to tensile loading, showed an abnormally early nucleation of {1 0 1 1} contraction twins (2% strain) while the same {1 0 1 1} twin mode triggering under 〈c〉-axis uniaxial compression have higher value of critical resolved shear stress exceeding the values for pyramidal 〈c + a〉 dislocations. The difference in nucleation behavior of contraction vs. compression {1 0 1 1} twins is attributed to the hydrostatic stresses that promote the required atomic shuffles at the core of twinning disconnections.

Tumor suppressor p53-directed apoptosis triggers loss of normal cells, which contributes to the side-effects from anticancer therapies. Thus, small molecules with potential to downregulate the activation of p53 could minimize pathology emerging from anticancer therapies. Acetylation of p53 by the histone acetyltransferase (HAT) domain is the hallmark of coactivator CREB-binding protein (CBP) epigenetic function. During genotoxic stress, CBP HAT-mediated acetylation is essential for the activation of p53 to transcriptionally govern target genes, which control cellular responses. Here, we present a small molecule, NiCur, which blocks CBP HAT activity and downregulates p53 activation upon genotoxic stress. Computational modeling reveals that NiCur docks into the active site of CBP HAT. On CDKN1A promoter, the recruitment of p53 as well as RNA Polymerase II and levels of acetylation on histone H3 were diminished by NiCur. Specifically, NiCur reduces the levels of acetylation at lysine 27 on histone H3, which concomitantly increases the levels of trimethylation at lysine 27. Finally, NiCur attenuates p53-directed apoptosis by inhibiting the Caspase 3 activity and cleavage of Poly (ADP-ribose) polymerase (PARP) in normal gastrointestinal epithelial cells. Collectively, NiCur demonstrates the potential to reprogram the chromatin landscape and modulate biological outcomes of CBP-mediated acetylation under normal and disease conditions.