Investigating Age-Dependent Arthropathy in a Circadian Mutant Mouse Model: A Dissertation

Ectopic calcification can cause pain and limit mobility. Studies suggest that circadian genes may play a role in the calcification process. Core circadian genes Clock, Npas2, and Bmal1 are transcription factors that form CLOCK:BMAL1 or NPAS2:BMAL1 transactivator complexes that drive the rhythmic expression of circadian oscillator genes and output genes. Circadian oscillator genes Period1-3 and Cryptochrome1-2 encode proteins that form transcription repressor complexes that feedback to inhibit CLOCK/NPAS2:BMAL1 activity, thus completing the feedback loop that is the basis of the molecular circadian clockwork. Arrhythmic Bmal1-/- mice exhibit site-specific, age-dependent arthropathy. While studying the circadian phenotype of Clock-/-;Npas2m/m double mutant mice, we discovered that these double mutant mice develop site-specific arthropathy similar to the arthropathy described in Bmal1-/- mice. Based on the circadian clockwork mechanism, we hypothesized that CLOCK/NPAS2:BMAL1 transactivator complexes drive the expression of a gene (or genes) that prevents age-dependent arthropathy. To investigate Clock-/-;Npas2m/m double mutant mouse arthropathy, we evaluated mutant mice using X-ray, micro-computed tomography, and histology, and found that Clock-/-;Npas2m/m double mutant mice exhibit age-dependent, site-specific arthropathy that phenocopies that of Bmal1-/- mice. The costosternal junction and calcaneal tendon are most prominently affected, in that calcification of those tissues is detectable as early as 4-5 weeks and 11-12 weeks, respectively. The arthropathic lesions in these tissues consist of calcium phosphate vii deposits, and in Bmal1-/- costosternal junction calcifications, the deposits contain calcium pyrophosphate dihydrate crystals. Mechanical stress, disregulation of centrally-regulated circadian rhythms, and systemic serum mineral imbalances likely do not contribute to this pathology. In vitro micromass cultures generated from Clock-/-;Npas2m/m double mutant mouse embryonic fibroblasts do not exhibit irregular chondrocyte differentiation compared to wild-type cultures, suggesting that chondrocyte cell-autonomous mechanisms are insufficient to induce this arthropathy. Analysis of Clock-/-;Npas2m/m double mutant intersternebral tissue RNA did not reveal significant changes in chondrocyte or calcification-related gene expression. Histological stains showed an absence of osteoblasts and osteoclasts around costosternal junction calcifications, suggesting that these cell types are not contributing to this pathology. Instead, chondrocytes are localized to the costosternal junction but there were no significant changes in the distribution of chondrocyte markers in this tissue, as evaluated by immunohistochemistry. These findings suggest that Clock or Npas2, and Bmal1, regulate ectopic calcification through a combination of systemic and local factors, and that the cells affected by Clock and Npas2, or Bmal1, disruption are a subset of the cells distributed in specific tissues that develop age-dependent arthropathy. The significance of these findings is that “circadian genes” play a role in the regulation of ectopic calcification in a non-oscillator capacity. Understanding this new mechanism by which ectopic calcification is controlled could lead to novel approaches for the treatment of some human calcification diseases

FPGA-Based PUF Designs: A Comprehensive Review and Comparative Analysis

Field-programmable gate arrays (FPGAs) have firmly established themselves as dynamic platforms for the implementation of physical unclonable functions (PUFs). Their intrinsic reconfigurability and profound implications for enhancing hardware security make them an invaluable asset in this realm. This groundbreaking study not only dives deep into the universe of FPGA-based PUF designs but also offers a comprehensive overview coupled with a discerning comparative analysis. PUFs are the bedrock of device authentication and key generation and the fortification of secure cryptographic protocols. Unleashing the potential of FPGA technology expands the horizons of PUF integration across diverse hardware systems. We set out to understand the fundamental ideas behind PUF and how crucially important it is to current security paradigms. Different FPGA-based PUF solutions, including static, dynamic, and hybrid systems, are closely examined. Each design paradigm is painstakingly examined to reveal its special qualities, functional nuances, and weaknesses. We closely assess a variety of performance metrics, including those related to distinctiveness, reliability, and resilience against hostile threats. We compare various FPGA-based PUF systems against one another to expose their unique advantages and disadvantages. This study provides system designers and security professionals with the crucial information they need to choose the best PUF design for their particular applications. Our paper provides a comprehensive view of the functionality, security capabilities, and prospective applications of FPGA-based PUF systems. The depth of knowledge gained from this research advances the field of hardware security, enabling security practitioners, researchers, and designers to make wise decisions when deciding on and implementing FPGA-based PUF solutions.publishedVersio

Ingress of threshold voltage-triggered hardware trojan in the modern FPGA fabric–detection methodology and mitigation

The ageing phenomenon of negative bias temperature instability (NBTI) continues to challenge the dynamic thermal management of modern FPGAs. Increased transistor density leads to thermal accumulation and propagates higher and non-uniform temperature variations across the FPGA. This aggravates the impact of NBTI on key PMOS transistor parameters such as threshold voltage and drain current. Where it ages the transistors, with a successive reduction in FPGA lifetime and reliability, it also challenges its security. The ingress of threshold voltage-triggered hardware Trojan, a stealthy and malicious electronic circuit, in the modern FPGA, is one such potential threat that could exploit NBTI and severely affect its performance. The development of an effective and efficient countermeasure against it is, therefore, highly critical. Accordingly, we present a comprehensive FPGA security scheme, comprising novel elements of hardware Trojan infection, detection, and mitigation, to protect FPGA applications against the hardware Trojan. Built around the threat model of a naval warship’s integrated self-protection system (ISPS), we propose a threshold voltage-triggered hardware Trojan that operates in a threshold voltage region of 0.45V to 0.998V, consuming ultra-low power (10.5nW), and remaining stealthy with an area overhead as low as 1.5% for a 28 nm technology node. The hardware Trojan detection sub-scheme provides a unique lightweight threshold voltage-aware sensor with a detection sensitivity of 0.251mV/nA. With fixed and dynamic ring oscillator-based sensor segments, the precise measurement of frequency and delay variations in response to shifts in the threshold voltage of a PMOS transistor is also proposed. Finally, the FPGA security scheme is reinforced with an online transistor dynamic scaling (OTDS) to mitigate the impact of hardware Trojan through run-time tolerant circuitry capable of identifying critical gates with worst-case drain current degradation

Optics and Quantum Electronics

Contains table of contents for Section 2 and reports on eighteen research projects.National Science Foundation (Grant EET 87-00474)Joint Services Electronics Program (Contract DAAL03-86-K-0002)Joint Services Electronics Program (Contract DAALO3-89-C-0001)Charles Stark Draper Laboratory (Grant DL-H-285408)Charles Stark Draper Laboratory (Grant DL-H-2854018)National Science Foundation (Grant EET 87-03404)National Science Foundation (Grant ECS 84-06290)U.S. Air Force - Office of Scientific Research (Contract F49620-88-C-0089)AT&T Bell FoundationNational Science Foundation (Grant ECS 85-52701)National Institutes of Health (Grant 5-RO1-GM35459)Massachusetts General Hospital (Office of Naval Research Contract N00014-86-K-0117)Lawrence Livermore National Laboratory (Subcontract B048704

Aging and Health

Aging is a major risk factor for chronic diseases, which in turn can provide information about the aging of a biological system. This publication serves as an introduction to systems biology and its application to biological aging. Key pathways and processes that impinge on aging are reviewed, and how they contribute to health and disease during aging is discussed. The evolution of this situation is analyzed, and the consequences for the study of genetic effects on aging are presented. Epigenetic programming of aging, as a continuation of development, creates an interface between the genome and the environment. New research into the gut microbiome describes how this interface may operate in practice with marked consequences for a variety of disorders. This analysis is bolstered by a view of the aging organism as a whole, with conclusions about the mechanisms underlying resilience of the organism to change, and is expanded with a discussion of circadian rhythms in aging

Review on VUV to MIR absorption spectroscopy of atmospheric pressure plasma jets

Absorption spectroscopy (AS) represents a reliable method for the characterization of cold atmospheric pressure plasma jets. The method's simplicity stands out in comparison to competing diagnostic techniques. AS is an in situ, non-invasive technique giving absolute densities, free of calibration procedures, which other diagnostics, such as laser-induced fluorescence or optical emission spectroscopy, have to rely on. Ground state densities can be determined without the knowledge of the influence of collisional quenching. Therefore, absolute densities determined by absorption spectroscopy can be taken as calibration for other methods. In this paper, fundamentals of absorption spectroscopy are presented as an entrance to the topic. In the second part of the manuscript, a review of AS performed on cold atmospheric pressure plasma jets, as they are used e.g. in the field of plasma medicine, is presented. The focus is set on special techniques overcoming not only the drawback of spectrally overlapping absorbing species, but also the line-of-sight densities that AS usually provides or the necessity of sufficiently long absorption lengths. Where references are not available for measurements on cold atmospheric pressure plasma jets, other plasma sources including low-pressure plasmas are taken as an example to give suggestions for possible approaches. The final part is a table summarizing examples of absorption spectroscopic measurements on cold atmospheric pressure plasma jets. With this, the paper provides a 'best practice' guideline and gives a compendium of works by groups performing absorption spectroscopy on cold atmospheric pressure plasma jets

Interface Circuits for Microsensor Integrated Systems

ca. 200 words; this text will present the book in all promotional forms (e.g. flyers). Please describe the book in straightforward and consumer-friendly terms. [Recent advances in sensing technologies, especially those for Microsensor Integrated Systems, have led to several new commercial applications. Among these, low voltage and low power circuit architectures have gained growing attention, being suitable for portable long battery life devices. The aim is to improve the performances of actual interface circuits and systems, both in terms of voltage mode and current mode, in order to overcome the potential problems due to technology scaling and different technology integrations. Related problems, especially those concerning parasitics, lead to a severe interface design attention, especially concerning the analog front-end and novel and smart architecture must be explored and tested, both at simulation and prototype level. Moreover, the growing demand for autonomous systems gets even harder the interface design due to the need of energy-aware cost-effective circuit interfaces integrating, where possible, energy harvesting solutions. The objective of this Special Issue is to explore the potential solutions to overcome actual limitations in sensor interface circuits and systems, especially those for low voltage and low power Microsensor Integrated Systems. The present Special Issue aims to present and highlight the advances and the latest novel and emergent results on this topic, showing best practices, implementations and applications. The Guest Editors invite to submit original research contributions dealing with sensor interfacing related to this specific topic. Additionally, application oriented and review papers are encouraged.

Aging and Health

Aging is a major risk factor for chronic diseases, which in turn can provide information about the aging of a biological system. This publication serves as an introduction to systems biology and its application to biological aging. Key pathways and processes that impinge on aging are reviewed, and how they contribute to health and disease during aging is discussed. The evolution of this situation is analyzed, and the consequences for the study of genetic effects on aging are presented. Epigenetic programming of aging, as a continuation of development, creates an interface between the genome and the environment. New research into the gut microbiome describes how this interface may operate in practice with marked consequences for a variety of disorders. This analysis is bolstered by a view of the aging organism as a whole, with conclusions about the mechanisms underlying resilience of the organism to change, and is expanded with a discussion of circadian rhythms in aging