Aberrant Transferrin and Ferritin Upregulation Elicits Iron Accumulation and Oxidative Inflammaging Causing Ferroptosis and Undermines Estradiol Biosynthesis in Aging Rat Ovaries by Upregulating NF-Κb-Activated Inducible Nitric Oxide Synthase: First Demonstration of an Intricate Mechanism

We report herein a novel mechanism, unraveled by proteomics and validated by in vitro and in vivo studies, of the aberrant aging-associated upregulation of ovarian transferrin and ferritin in rat ovaries. The ovarian mass and serum estradiol titer plummeted while the ovarian labile ferrous iron and total iron levels escalated with age in rats. Oxidative stress markers, such as nitrite/nitrate, 3-nitrotyrosine, and 4-hydroxy-2-nonenal, accumulated in the aging ovaries due to an aberrant upregulation of the ovarian transferrin, ferritin light/heavy chains, and iron regulatory protein 2(IRP2)-mediated transferrin receptor 1 (TfR1). Ferritin inhibited estradiol biosynthesis in ovarian granulosa cells in vitro via the upregulation of a nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and p65/p50-induced oxidative and inflammatory factor inducible nitric oxide synthase (iNOS). An in vivo study demonstrated how the age-associated activation of NF-κB induced the upregulation of iNOS and the tumor necrosis factor α (TNFα). The downregulation of the keap1-mediated nuclear factor erythroid 2-related factor 2 (Nrf2), that induced a decrease in glutathione peroxidase 4 (GPX4), was observed. The aberrant transferrin and ferritin upregulation triggered an iron accumulation via the upregulation of an IRP2-induced TfR1. This culminates in NF-κB-iNOS-mediated ovarian oxi-inflamm-aging and serum estradiol decrement in naturally aging rats. The iron accumulation and the effect on ferroptosis-related proteins including the GPX4, TfR1, Nrf2, Keap1, and ferritin heavy chain, as in testicular ferroptosis, indicated the triggering of ferroptosis. In young rats, an intraovarian injection of an adenovirus, which expressed iron regulatory proteins, upregulated the ovarian NF-κB/iNOS and downregulated the GPX4. These novel findings have contributed to a prompt translational research on the ovarian aging-associated iron metabolism and aging-associated ovarian diseases

A study of real-time spindle error compensation in single-point diamond turning of optical micro-structured patterns on precision rollers

Micro-structured patterns are widely used in optics since the optical performance can be significantly improved in many applications [1]. One of the most common methods to fabricate the micro-structure is using Single-Point Diamond Turning on Precision Rollers [2]. The accuracy requirement of the Precision Rollers is stringent because the dimension of the microstructure is very small (pitch lengths and depths 10-100μm) and surface finishing is ultra-smooth (Ra<3nm) [2]. In order to achieve this level of accuracy, the manufacturing errors of the machine tool are required to be reduced while error compensation methods are needed to be developed. Spindle errors can be classified as synchronous error and asynchronous error [3]. Synchronous error occurs at integer times of spindle rotation frequency and can be represented as repeatable error while asynchronous error occurs at noninteger times of spindle rotation frequency and can be represented as non-repeatable error. Most of the existing error compensation techniques are based on offline error compensation methods (OECM) which can only compensate the synchronous error [4,5]. The asynchronous error is fluctuating without a predictable value and it is different from the synchronous error so it cannot be eliminated using OECM. One of the most promising methods to compensate the asynchronous error is real-time error compensation method (RECM). Some researchers have studied the RECM and their results showed that it was effective to enhance the machine accuracy [6,7]. However, most of the previous research work is focused on the machine tools with a relatively low accuracy and there is relatively few studies focused on the Single-Point Diamond Turning. Kim and Kim developed a feed-forward control of fast tool servo system for real-time correction of spindle error for diamond turning of flat surfaces [8]. A capacitive displacement sensor was used to measurement the spindle axial error motion and the motion error was compensated using a fast tool servo. A flatness of 0.1μm was achieved with a 100mm diameter aluminum specimen. However, the study only considered the axial error, when it is diamond turned on precision rollers, both the radial error and axial error have to be compensated. This paper attempts to investigate the RECM in Single-Point Diamond Turning of Optical Microstructured Patterns on Precision Rollers. The radial error and axial error were simulated and the compensated results of OECM and RECM were presented considering both synchronous errors and asynchronous errors in radial and axial directions. The results of OECM and RECM were also compared and discussed. Furthermore, the effects of time delay in RECM were studied. An adaptive time-series modeling method was also proposed to predict the realtime error to reduce the time delay effect of RECM. The results show that the RECM is effective and promising to further improve the accuracy of the Single-Point Diamond Turning Precision Rollers

Pathway aberrations of murine melanoma cells observed in Paired-End diTag transcriptomes

<p>Abstract</p> <p>Background</p> <p>Melanoma is the major cause of skin cancer deaths and melanoma incidence doubles every 10 to 20 years. However, little is known about melanoma pathway aberrations. Here we applied the robust Gene Identification Signature Paired End diTag (GIS-PET) approach to investigate the melanoma transcriptome and characterize the global pathway aberrations.</p> <p>Methods</p> <p>GIS-PET technology directly links 5' mRNA signatures with their corresponding 3' signatures to generate, and then concatenate, PETs for efficient sequencing. We annotated PETs to pathways of KEGG database and compared the murine B16F1 melanoma transcriptome with three non-melanoma murine transcriptomes (Melan-a2 melanocytes, E14 embryonic stem cells, and E17.5 embryo). Gene expression levels as represented by PET counts were compared across melanoma and melanocyte libraries to identify the most significantly altered pathways and investigate the expression levels of crucial cancer genes.</p> <p>Results</p> <p>Melanin biosynthesis genes were solely expressed in the cells of melanocytic origin, indicating the feasibility of using the PET approach for transcriptome comparison. The most significantly altered pathways were metabolic pathways, including upregulated pathways: purine metabolism, aminophosphonate metabolism, tyrosine metabolism, selenoamino acid metabolism, galactose utilization, nitrobenzene degradation, and bisphenol A degradation; and downregulated pathways: oxidative phosphorylation, ATPase synthesis, TCA cycle, pyruvate metabolism, and glutathione metabolism. The downregulated pathways concurrently indicated a slowdown of mitochondrial activities. Mitochondrial permeability was also significantly altered, as indicated by transcriptional activation of ATP/ADP, citrate/malate, Mg⁺⁺, fatty acid and amino acid transporters, and transcriptional repression of zinc and metal ion transporters. Upregulation of cell cycle progression, MAPK, and PI3K/Akt pathways were more limited to certain region(s) of the pathway. Expression levels of c-<it>Myc </it>and <it>Trp53 </it>were also higher in melanoma. Moreover, transcriptional variants resulted from alternative transcription start sites or alternative polyadenylation sites were found in <it>Ras </it>and genes encoding adhesion or cytoskeleton proteins such as integrin, β-catenin, α-catenin, and actin.</p> <p>Conclusion</p> <p>The highly correlated results unmistakably point to a systematic downregulation of mitochondrial activities, which we hypothesize aims to downgrade the mitochondria-mediated apoptosis and the dependency of cancer cells on angiogenesis. Our results also demonstrate the advantage of using the PET approach in conjunction with KEGG database for systematic pathway analysis.</p

Annealing studies in cold-rolled -brass

published_or_final_versionMechanical EngineeringDoctoralDoctor of Philosoph

Product family design through ontology-based faceted component analysis, selection, and optimization

Product family design (PFD) is a widely adopted strategy for product realization, especially when design requirements are diversified and multi-faceted. Due to ever-changing customer needs and the increasingly complex and integrated product design structure, PFD and its optimization have been concerned more about a rapid and contextual product analysis and variant derivation based on a multi-objective optimization scheme subject to design concerns, which are often cross disciplinary, such as product service, carbon footprint, user experience, esthetics, etc. Existing PFD modeling approaches, which are primarily structured using component attributes and assembly relationships, possess notable limitations in representing complex component and design relationships. Hence, it has restricted comprehensive PFD analysis in an agile and contextual manner. Previously, we have studied and demonstrated the feasibility of using ontology for product family modeling and have suggested a framework of faceted information search and retrieval for product family design. In this paper, several new perspectives towards PFD based on ontology modeling are presented. Firstly, new metrics of ontology-based commonality that better reveal conceptual similarity under various design perspectives are formed. Secondly, faceted concept ranking is proposed as a new ranking approach for ontology-based component search under complex and heterogeneous design requirements. Thirdly, using these ranked results, a platform selection approach that considers a maximum aggregated ranking with a minimal platform modification among various platform choices is researched. From the selected platform and the newly proposed metrics, a modified multi-objective evolutionary algorithm with an embedded feature of configuration incompatibility check is studied and deployed for the optimal selection of components. A case study of PFD using four laptop computer families is reported as our first attempt to showcase how faceted component analysis, selection, and optimization can be accomplished based on the proposed family ontology

Multi-facet product information search and retrieval using semantically annotated product family ontology

With the advent of various services and applications of Semantic Web, semantic annotation has emerged as an important research topic. The application of semantically annotated ontology had been evident in numerous information processing and retrieval tasks. One of such tasks is utilizing the semantically annotated ontology in product design which is able to suggest many important applications that are critical to aid various design related tasks. However, ontology development in design engineering remains a time consuming and tedious task that demands considerable human efforts. In the context of product family design, management of different product information that features efficient indexing, update, navigation, search and retrieval across product families is both desirable and challenging. For instance, an efficient way of retrieving timely information on product family can be useful for tasks such as product family redesign and new product variant derivation when requirements change. However, the current research and application of information search and navigation in product family is mostly limited to its structural aspect which is insufficient to handle advanced information search especially when the query targets at multiple aspects of a product. This paper attempts to address this problem by proposing an information search and retrieval framework based on the semantically annotated multi-facet product family ontology. Particularly, we propose a document profile (DP) model to suggest semantic tags for annotation purpose. Using a case study of digital camera families, we illustrate how the faceted search and retrieval of product information can be accomplished. We also exemplify how we can derive new product variants based on the designer’s query of requirements via the faceted search and retrieval of product family information. Lastly, in order to highlight the value of our current work, we briefly discuss some further research and applications in design decision support, e.g. commonality analysis and variety comparison, based on the semantically annotated multi-facet product family ontology