Tuning the mechanical properties of functionally graded nickel and aluminium alloy at the nanoscale

In this article, Molecular Dynamics (MD) simulation is used to investigate the tensile mechanical properties of functional graded Ni–Al (Ni₃Al) alloy with Ni coating. The grading profile, temperature, crystallographic direction, and concentration of vacancy defects have been varied and corresponding changes in the tensile properties are reported. In general, it has been revealed that functional grading may reduce the ultimate tensile strength (UTS) of this homogeneous alloy but increase Young''s modulus (YM). Furthermore, MD simulations suggest that elliptically graded Ni–Al alloy has the highest UTS at low temperature while at high temperature, the largest UTS is recorded for the parabolic grading. Besides, at any temperature, the parabolically graded Ni–Al alloy shows the largest YM, followed by linear grading and elliptical grading. Moreover, it is also observed that the [111] crystallographic direction for this alloy demonstrates the highest UTS and YM. At extremely low temperatures, lattice mismatch is also observed to exert a significant impact on the failure characteristics of functional graded Ni–Al alloys. This investigation also suggests that the vacancy defects introduced via removing either Al or Ni atoms degrades the UTS and YM of FGM alloys remarkably. Besides, it is also found that the UTS and YM of Ni–Al FGM alloys are very sensitive to Ni vacancies compared to Al vacancies. Parabolic grading demonstrates more resilience against vacancy defects, followed by linear and elliptical grading. This paper provides a comprehensive understanding of the mechanical properties of Ni–Al FGM alloys at the atomic level as a potential substitute for homogeneous alloys.

We revealed that the mechanical properties of Ni₃Al (homogeneous alloy) could be modulated utilizing functional grading.     

Exploring the Mechanical Properties and Performance of Type-I Collagen at Various Length Scales: A Progress Report

Collagen is the basic protein of animal tissues and has a complex hierarchical structure. It plays a crucial role in maintaining the mechanical and structural stability of biological tissues. Over the years, it has become a material of interest in the biomedical industries thanks to its excellent biocompatibility and biodegradability and low antigenicity. Despite its significance, the mechanical properties and performance of pure collagen have been never reviewed. In this work, the emphasis is on the mechanics of collagen at different hierarchical levels and its long-term mechanical performance. In addition, the effect of hydration, important for various applications, was considered throughout the study because of its dramatic influence on the mechanics of collagen. Furthermore, the discrepancies in reports of the mechanical properties of collagenous tissues (basically composed of 20–30% collagen fibres) and those of pure collagen are discussed.     

Automated Detection of Caffeinated Coffee-Induced Short-Term Effects on ECG Signals Using EMD,DWT, and WPD

The effect of coffee (caffeinated) on electro-cardiac activity is not yet sufficiently researched. In the current study, the occurrence of coffee-induced short-term changes in electrocardiogram (ECG) signals was examined. Further, a machine learning model that can efficiently detect coffee-induced alterations in cardiac activity is proposed. The ECG signals were decomposed using three different joint time–frequency decomposition methods: empirical mode decomposition, discrete wavelet transforms, and wavelet packet decomposition with varying decomposition parameters. Various statistical and entropy-based features were computed from the decomposed coefficients. The statistical significance of these features was computed using Wilcoxon’s signed-rank (WSR) test for significance testing. The results of the WSR tests infer a significant change in many of these parameters after the consumption of coffee (caffeinated). Further, the analysis of the frequency bands of the decomposed coefficients reveals that most of the significant change was localized in the lower frequency band (<22.5 Hz). Herein, the performance of nine machine learning models is compared and a gradient-boosted tree classifier is proposed as the best model. The results suggest that the gradient-boosted tree (GBT) model that was developed using a db2 mother wavelet at level 2 decomposition shows the highest mean classification accuracy of 78%. The outcome of the current study will open up new possibilities in detecting the effects of drugs, various food products, and alcohol on cardiac functionality.     

Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase for ovarian cancer treatment

Protein disulfide isomerase (PDI), an endoplasmic reticulum chaperone protein, catalyzes disulfide bond breakage, formation, and rearrangement. The effect of PDI inhibition on ovarian cancer progression is not yet clear, and there is a need for potent, selective, and safe small-molecule inhibitors of PDI. Here, we report a class of propynoic acid carbamoyl methyl amides (PACMAs) that are active against a panel of human ovarian cancer cell lines. Using fluorescent derivatives, 2D gel electrophoresis, and MS, we established that PACMA 31, one of the most active analogs, acts as an irreversible small-molecule inhibitor of PDI, forming a covalent bond with the active site cysteines of PDI. We also showed that PDI activity is essential for the survival and proliferation of human ovarian cancer cells. In vivo, PACMA 31 showed tumor targeting ability and significantly suppressed ovarian tumor growth without causing toxicity to normal tissues. These irreversible small-molecule PDI inhibitors represent an important approach for the development of targeted anticancer agents for ovarian cancer therapy, and they can also serve as useful probes for investigating the biology of PDI-implicated pathways.     

Nematode ascarosides attenuate mammalian type 2 inflammatory responses

Mounting evidence suggests that nematode infection can protect against disorders of immune dysregulation. Administration of live parasites or their excretory/secretory (ES) products has shown therapeutic effects across a wide range of animal models for immune disorders, including asthma. Human clinical trials of live parasite ingestion for the treatment of immune disorders have produced promising results, yet concerns persist regarding the ingestion of pathogenic organisms and the immunogenicity of protein components. Despite extensive efforts to define the active components of ES products, no small molecules with immune regulatory activity have been identified from nematodes. Here we show that an evolutionarily conserved family of nematode pheromones called ascarosides strongly modulates the pulmonary immune response and reduces asthma severity in mice. Screening the inhibitory effects of ascarosides produced by animal-parasitic nematodes on the development of asthma in an ovalbumin (OVA) murine model, we found that administration of nanogram quantities of ascr#7 prevented the development of lung eosinophilia, goblet cell metaplasia, and airway hyperreactivity. Ascr#7 suppressed the production of IL-33 from lung epithelial cells and reduced the number of memory-type pathogenic Th2 cells and ILC2s in the lung, both key drivers of the pathology of asthma. Our findings suggest that the mammalian immune system recognizes ascarosides as an evolutionarily conserved molecular signature of parasitic nematodes. The identification of a nematode-produced small molecule underlying the well-documented immunomodulatory effects of ES products may enable the development of treatment strategies for allergic diseases.

Parasitic nematodes are associated with almost all groups of vertebrates, and nearly one-third of the human population is infected with these helminths (1). Their omnipresence is in part due to their ability to modulate host immune responses to prevent immune attack and expulsion (2). The elimination of nematode infections has been proposed as a possible cause of the increased incidence of autoimmune disorders and allergic diseases in developed countries (3), based on epidemiological data showing a correlation between the decline in helminth infection and the rise in allergic and autoimmune diseases, including asthma, multiple sclerosis (MS), type 1 diabetes, and inflammatory bowel diseases (IBDs) (4).The administration of live nematodes or their excretory/secretory (ES) products has shown therapeutic effects across a wide range of animal models for these immune disorders (5–8). The US Food and Drug Administration recently approved live helminth administration as an investigational drug for the treatment of immune disorders, and relevant human clinical trials are ongoing (9). Despite mounting evidence that helminths have significant therapeutic potential, we do not yet have a comprehensive understanding of the molecules that underlie their immunomodulatory effects; and, in particular, the possible relevance of low-molecular-weight components of ES products has remained largely unexplored.A wide range of nematodes, including many parasitic species, produce ascarosides, a family of small-molecule signals based on glycosides of the dideoxysugar ascarylose (10). Ascarosides have not yet been identified in any other animal phylum, suggesting that they may be a nematode-specific class of small molecules (SI Appendix, Fig. S1A). The first ascaroside-based signaling molecules were identified in the free-living model nematode Caenorhabditis elegans (11, 12). Ascarosides regulate almost every aspect of C. elegans life history, including diapause (dauer) induction, aging, mate finding, and aggregation (11, 12). Subsequently, ascarosides have been shown to be detected by organisms other than nematodes, such as nematophagous fungi that set traps to capture and digest nematodes (13). The perception of ascarosides is sufficient to trigger trap formation in these fungi, demonstrating their longstanding evolutionary association with nematodes. Furthermore, ascarosides produced by plant-pathogenic nematodes have been shown to trigger innate immune responses in monocot and dicot plants (14). Cumulatively, these findings suggest that ascarosides represent a nematode-specific molecular signature that is recognized and interpreted by nematode predators and hosts across multiple kingdoms.In this study, we collected ES products from the gut-resident, rodent-parasitic nematode Nippostrongylus brasiliensis. Previous studies showed that the administration of N. brasiliensis ES (NES) products fully inhibits the development of airway hyperresponsiveness (AHR) in the ovalbumin (OVA) murine model of asthma (15). Specifically, NES products substantially prevented lung eosinophilia, mucus production, and resistance to airflow. Notably, it was found that heat-treated or proteinase K–treated NES mimicked the full effect of untreated NES products in reducing lung eosinophilia and OVA-specific IgG in serum. Therefore, we hypothesized that the therapeutic effect of NES products may be due to the presence of specific small molecules that may in part be bound to secreted proteins, explaining the activity of heat- or proteinase K–treated NES. To test this hypothesis, we isolated the small molecule fraction of heat-treated NES (small molecule ES [smES]) products via filtration through a 3-kDa filter and found that smES products strongly suppresses OVA-induced allergic immune responses. Parallel chemical analyses of several other mammalian parasitic nematodes confirmed the presence of specific ascarosides in smES products of all tested species. Next, we tested synthetic samples of ascarosides and found that ascr#7, a compound produced by N. brasiliensis and other parasitic species, markedly inhibited the development of allergic airway inflammation, comparable to the full effect of smES products. Mechanistically, we found that ascr#7 administration attenuated IL-33 production from lung epithelial cells and suppressed the proliferation of memory-type IL-5–producing pathogenic T helper 2 (Th2) cells and type 2 innate lymphoid cells (ILC2s) in the lung, both key drivers for the pathology of asthma. We thus demonstrate that ascarosides have an immunomodulatory role that attenuates OVA-induced allergic inflammation in a murine model.