Nonproliferation Research Articles

Isorhamnetin induces cell cycle arrest and apoptosis by triggering DNA damage and regulating the AMPK/mTOR/p70S6K signaling pathway in doxorubicin-resistant breast cancer

BackgroundAcquired resistance to doxorubicin (DOX) inevitably limits its clinical use against breast cancer (BC). Isorhamnetin (IS), a native flavonoid which extensively available in vegetables, fruits, and phytomedicine, has been deemed to the probable cancer chemopreventive agent in preceding explorations since it exhibits satisfied antitumor activity. So far, the strategy for alleviating DOX resistance by using IS as a sensitizer against resistant BC has not yet been covered. PurposeTo investigate the effect of IS on potentiating the chemoreceptivity of drug-resistant BC cells to DOX in vitro and in vivo and elucidate the possible molecular mechanisms. MethodsMTS assays, colony formation assays, three-dimensional (3D) tumor spheroid model, and migration assay were deployed to verify the inhibiting action of IS in the presence or absence of DOX on resistant BC cells in vitro. Apoptosis, cell cycle regulation, and endocellular reactive oxygen species (ROS) were determined by flow cytometry. Protein levels were monitored by western blotting. Nuclear staining and EdU proliferation were photographed with a confocal laser scanning microscope. The effects of the IS and DOX combination on the tumorigenesis in the xenograft experiments were evaluated for further confirming the in vitro cytotoxicity. ResultsIS significantly inhibited cell proliferation and migration and enhanced the antitumor competence of DOX against resistant BC cells both in vitro and in vivo. Adjuvant IS (50 μM) effectively enhanced the proapoptotic impacts of DOX in resistant BC cells (35.38 ± 3.18%, vs. 5.83 ± 0.68% in the DOX group) by suppressing the expression of bcl 2 in addition to enhancing cleaved caspase 3, ultimately leading to DNA condensation and fragmentation. IS (20, 30, and 50 μM) treatments induced significant increases in the G2/M populations (41.60 ± 1.28%, 44.60 ± 1.14%, and 50.64 ± 0.67%, vs. 35.84 ± 1.56% in the untreated control in MCF7/ADR cells, p < 0.01) via regulating CDK1/Cyclin B1 complex expression, subsequently triggering the inhibition of BC proliferation. In addition, IS (10, 20, 30, and 50 μM) stimulated the production of interstitial ROS in MCF7/ADR cells, by 3.99-, 4.20-, 6.29-, and 6.78-fold, respectively, versus the untreated group (p < 0.001), which were involved in DNA damage and AMPK-caused intercept of the mTOR/p70S6K signaling. ConclusionOur study suggested the anti-breast cancer actions of IS as a DOX sensitizer and expounded the underlying molecular mechanisms, showing that IS could be deemed to a capable alternative for resistant BC cure.

A ‘Uniform’ for All States?

A ‘Uniform’ for All States?

Military Regimes and Resistance to Nuclear Weapons Development

Few military regimes have seriously pursued a nuclear weapons capability, and only Pakistan has succeeded. I argue that military regimes governing nonnuclear weapons states are likely to prefer to invest in conventional rather than nuclear forces, even in the presence of external security threats. I identify two domestic sources of nuclear proliferation behavior in military regimes: the resource distribution preferences of the military organization and the need to manage the domestic conflicts that threaten the regime’s political survival. I test this theory using case evidence from Egypt, Brazil, and Pakistan. This study suggests that while external conditions are certainly important, domestic factors also have a significant impact on state security behavior.

The ‘greatest threat’ to Australian and global security? A history of the Howard government’s evolving perception of nuclear proliferation, 1996–2007

For many observers Australia’s approach to the threat of nuclear proliferation under the government of Prime Minister John Howard (1996–2007) was simply the product of its steadfast alignment of Australian foreign policy with that of the United States in the post-9/11 context. The Howard government’s enthusiastic support for the 2003 US-led ‘coalition of the willing’ invasion of Iraq on the basis of Baghdad’s alleged possession of ‘weapons of mass destruction’ (WMD) is taken as the most egregious example of this tendency. Yet this assumption ignores that the potential threat of nuclear proliferation had been an abiding concern for the government since it had entered office. This paper argues that there was an enduring dynamic in Australian foreign and strategic policy of perceiving a direct link between the fate of the prevailing international system and that of Australia’s own national security. To this end, the Howard government’s perception of the threat of nuclear proliferation was sensitive to trends at the global level, most particularly the strategic posture and preferences of its alliance partner, the United States. The paper demonstrates, however, that this weakened the Howard government’s ability to maintain fidelity with what had become Australia’s traditional activist diplomacy within the non-proliferation regime.

Seeking the bomb: strategies of nuclear proliferation

In a recent report on Iran's nuclear programme, American physicist David Albright argued that the country ‘threatens the world with a program ready to produce nuclear weapons on-demand’. For Albright, understanding the pace of Tehran's nuclear build-up is critical if the United States is serious about stopping Iran from ‘going nuclear’. While there is a rich literature on what drives nuclear proliferation, there is less substantive work that focuses on how countries go about ‘seeking’ the bomb. Thus, the proliferation scholarship's emphasis on why states go nuclear does not tell the whole story. In fact, it leaves room for assumptions that fill in the gaps and subsequently dictate counter-proliferation policies. Nuclear scholar Vipin Narang is aware of this vacuum, and his new book brilliantly dissects and theorizes how states pursue nuclear weapons. Focusing on the pathways that aspirants take towards nuclearization, Narang targets the misconceptions and generalizations about nuclear proliferation that abound. For instance, he explains that not all states that develop a nuclear weapons programme end up building a fully functional arsenal. In the book, Narang introduces four strategies of proliferation: hedging, sprinting, sheltered pursuit and hiding. With his categories in place, the author develops a ‘proliferation strategy theory’ that sheds light on why different states opt for a particular strategy (and why they discard the others) (p. 27).

Molecular regulation of prostate cancer by Galectin-3 and estrogen receptor.

Prostate cancer remains the most prevalent cancer among men worldwide. This cancer is hormone-dependent; therefore, androgen, estrogen, and their receptors play an important role in development and progression of this disease, and in emergence of the castration-resistant prostate cancer (CRPC). Galectins are a family of β-galactoside-binding proteins which are frequently altered (upregulated or downregulated) in a wide range of tumors, participating in different stages of tumor development and progression, but the molecular mechanisms which regulate its expression are still poorly understood. This review provides an overview of the current and emerging knowledge on Galectin-3 in cancer biology with focus on prostate cancer and the interplay with estrogen receptor (ER) signaling pathways, present in androgen-independent prostate cancer cells. We suggest a molecular mechanism where ER, Galectin-3 and β-catenin can modulate nuclear transcriptional events, such as, proliferation, migration, invasion, and anchorage-independent growth of androgen-independent prostate cancer cells. Despite a number of achievements in targeted therapy for prostate cancer, CRPC may eventually develop, therefore new effective drug targets need urgently to be found. Further understanding of the role of Galectin-3 and ER in prostate cancer will enhance our understanding of the molecular mechanisms of prostate cancer development and the future treatment of this disease.

The Destiny of Phenomenology: Gadamer on Value, Globalism, and the Growth of Being

The Destiny of Phenomenology: Gadamer on Value, Globalism, and the Growth of Being

The Long-run Impact of Childhood Wartime Violence on Preferences for Nuclear Proliferation

How do childhood experiences of wartime violence affect individuals’ preferences for nuclear proliferation? This paper argues that individuals who experienced severe war violence during childhood are more likely to value the security-enhancing aspects of nuclear weapons. These individuals are more concerned about being exposed to additional wartime violence, so they view nuclear weapons as a deterrent against large-scale invasions. By utilizing the geographic variation of violence intensity during the Korean War, this paper compares the pre-war and post-war cohorts who resided in severely damaged regions and relatively safe areas. Within the pre-war cohort, I find that individuals who resided in war-torn areas are more supportive of nuclear proliferation than those who were exposed to less violence. This regional difference, however, is not substantial in the post-war generation. The results suggest that direct exposure to wartime violence during childhood increases public demand for nuclear weapons when confronted with security threats.

Contextually aware roadside radiation measurement testbed

We demonstrate a contextually aware multimodal roadside radiation measurement detection testbed for traffic monitoring applications in nuclear nonproliferation. Many variables in traffic such as vehicle or cargo size, mass, speed, shape, and distance of closest approach can have significant impacts on the radiation measured from a vehicle-transported radiation source. These factors can lead to uncertainties in the analysis of the radiation source, especially for lower-strength radiation sources of interest. Our testbed, known as the Multimodal Measurement System (MMS) uses non-radiation sensors including magnetometers, geophones, radiofrequency receivers, cameras, and LiDAR to extract contextual information about vehicles passing by the system. These contextual data can then be fused with data from radiation measurements to increase the system’s sensitivity and accuracy in nuclear threat detection applications. This work describes the instrumentation of the MMS and its data acquisition pipeline. Furthermore, we describe the pre-analysis performed on the raw multimodal data streams for data fusion, and the high-level machine learning analyses for detection and characterization. The variety of sensors within the MMS provides a valuable testbed that can be used to identify the combinations of contextual sensors that provide the greatest improvements to radiation source detection and characterization within the restrictions for various proliferation detection applications. The MMS is also modular so that additional combinations of sensors can be explored in the future.

Diffuse Reflectance Spectroscopy and Principal Component Analysis to Retrospectively Determine Production History of Plutonium Dioxide.

Diffuse reflectance spectroscopy measurements in the shortwave infrared (930-1600 nm) spectral region were acquired for Pu2(C2O4)3•9H2O and its thermal decomposition product, PuO2. We analyzed a total of eight PuO2 samples that were produced at different calcination temperatures (300, 350, 450, 525, 600, 675, 750, and 900°C). Our goal was to identify spectroscopic fingerprints that could be used to gain retrospective information regarding the production parameters of these important nuclear compounds. The diffuse reflectance spectrum of Pu2(C2O4)3•9H2O features several broad bands that currently preclude detailed analysis. However, all PuO2 samples produced relatively sharp spectral features that got sharper and more intense for samples that were produced at higher calcination temperatures. The electronic band observed at 1433 nm in the diffuse reflectance spectra of PuO2 was found to be a sensitive indicator of crystallinity; a result that is corroborated by ancillary Raman spectroscopy measurements. Principal component analysis of diffuse reflectance spectra was able to clearly rank and categorize PuO2 samples based on the calcination temperature that was employed during their production. Thus, we show herein that important retrospective information pertaining to the process history of PuO2 can be gained through the relatively simplistic combination of diffuse reflectance spectroscopy and principal component analysis. This discovery presents a new method for determining the provenance and process history of PuO2 and should have an impact in the fields of nuclear forensics and nuclear nonproliferation.

Searching for on-site nuclear balance against North Korea

As North Korea succeeds in developing hydrogen bombs, ICBMs, and SLBMs capable of destroying U.S. cities, the current U.S. extended deterrence may not work. The United States must empower South Korea with a nuclear option to exercise its right of self-defense by prescribing an on-site nuclear balance. This article presents and compares two options for the United States: (1) South Korea’s nuclear armament and (2) another nuclear sharing system in Northeast Asia. As a result, this article recommends the second option with sea-borne sharing and incremental implementation.

Identification and validation of a novel ubiquitination-related gene UBE2T in Ewing's sarcoma.

Ewing's sarcoma (ES) is one of the most prevalent malignant bone tumors worldwide. However, the molecular mechanisms of the genes and signaling pathways of ES are still not well sufficiently comprehended. To identify candidate genes involved in the development and progression of ES, the study screened for key genes and biological pathways related to ES using bioinformatics methods. The GSE45544 and GSE17618 microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified, and functional enrichment analysis was performed. A protein-protein interaction (PPI) network was built, and key module analysis was performed using STRING and Cytoscape. A core-gene was gained and was validated by the validation dataset GSE67886 and immunohistochemistry (IHC). The diagnostic value and prognosis evaluation of ES were executed using, respectively, the ROC approach and Cox Regression. A total of 187 DEGs, consisting of 56 downregulated genes and 131 upregulated genes, were identified by comparing the tumor samples to normal samples. The enriched functions and pathways of the DEGs, including cell division, mitotic nuclear division, cell proliferation, cell cycle, oocyte meiosis, and progesterone-mediated oocyte maturation, were analyzed. There were 149 nodes and 1246 edges in the PPI network, and 15 hub genes were identified according to the degree levels. The core gene (UBE2T) showed high expression in ES, validated by using GSE67886 and IHC. The ROC analysis revealed UBE2T had outstanding diagnostic value in ES (AUC = 0.75 in the training set, AUC = 0.90 in the validation set). Kaplan-Meier (analysis of survival rate) and Cox Regression analyses indicated that UBE2T was a sign of adverse results for sufferers with ES. UBE2T was a significant value biomarker for diagnosis and treatment of ES, thereby presenting a novel potential therapeutic target for ES as well as a new perspective for assessing the effect of treatment and prognostic prediction.

Beyond deterrence: Uncertain stability in the nuclear era

This paper identifies profound contradictions within and across nuclear deterrence strategies that evolved in response to the proliferation and modernization of nuclear weapons. To reconcile theory with practice, we summarize the theoretical assumptions and implications of nuclear strategy. Informed by these discussions, we develop a decision-theoretic model of deterrence based on power transition theory. We explore conditions for the stability of deterrence and link outcomes to policy decisions. The conditions for conflict emerge when a dissatisfied nuclear nation is threatened with conventional loss, when conventional and nuclear parity is achieved and if dissatisfied non-state actors acquire even minimal nuclear capabilities.

THE ROLE OF NUCLEAR ENERGY IN INTERNATIONAL RELATIONS, THE RUSSIAN-UKRAINIAN WAR AS A MODEL

The emergence of nuclear capabilities and technology at the end of World War II and its uses in the field of lethal weapons led to the emergence of new risks at the global level. The actions of the major countries that possess this technology and their dealings with the issue of trading and exchanging this technology with a number of countries wishing to obtain it, whether for peaceful or military purposes, have varied depending on on strategic, bilateral or economic positions. The paper deals with different stances on its topic, the spread of nuclear technology, and different opinions and positions on this subject. It also deals with, for example, the Iranian nuclear program and the international stance towards it, especially the position of the United States of America on it, and some future possibilities and options if Iran continues with this program. The paper also deals with how the nuclear countries provide assistance for nuclear expertise, which is considered a form of international contribution to achieving the proliferation of nuclear weapons. It will also address some countries that are based on the transfer of nuclear expertise and the extent of its impact on the development of international relations and the effects of the proliferation of nuclear weapons. It also deals with hypotheses. On the conditions that provide for the provision of nuclear assistance and then addresses the potential strategy and characteristics of nuclear suppliers and the most important factors determining the provision of nuclear assistance and emphasize the importance of economic motives.

Modeling study of the impact of actomyosin contractility on cell proliferation in the Drosophila wing imaginal disc.

A fundamental open question in developmental biology is deciphering how the regulation of cell proliferation and the actomyosin cytoskeleton coordinate proper formation and maintenance of tissue shape and size. To address this question, a close integration between experimental work and simulations from a novel multi-scale computational model are used. Specifically, a subcellular element (SCE) model of the Drosophila wing imaginal disc cross-section along the anterior-posterior axis is developed and calibrated using experimental data. This model accounts for actomyosin contractility in different cell regions and incorporates a detailed cell division sub model capable of capturing interkinetic nuclear migration, a fundamental process for proper cell division. Coupled model simulations and experiments reveal that anisotropic patterning of actomyosin contractility can regulate basal local curvature of the wing disc and positioning of nuclei. Moreover, it was found that cell proliferation also plays an important role in regulating basal curvature. However, this model has a simplified representation of actomyosin contractility which is not able to capture the micro level interactions between actin filaments and myosin motors that make up the actomyosin network and thus, the direction of the contractile forces cannot be accounted for explicitly. Therefore, in order to have a more biological representation of actomyosin, a coarse-grained stochastic model of subcellular level actomyosin network dynamics in two-dimensions is being developed. This model describes the actomyosin network via a large system of nodes with their dynamics represented by stochastic ordinary differential equations. The multi-scale SCE model, coupled with the stochastic model, will be used to gain insight into the detailed mechanism of how actomyosin contractility facilitates interkinetic nuclear migration, cell proliferation and formation of the wing shape.

EU Orchestration in the Nuclear Weapons Regime Complex

While often recognised as a difficult actor in global efforts addressing the proliferation, control, and disarmament of nuclear weapons, the EU is also assumed to have the potential to play a more cohesive “state-like” role, especially in multilateral forum such as the Treaty on the Non-Proliferation of Nuclear Weapons review cycle. Such assumptions raise expectations of EU external action and influence, which the EU then invariably fails to meet. This article offers a reframing of how we understand the EU as an actor, focusing on its role in the nuclear weapons regime complex. Specifically, the article considers how, and under what conditions, the EU orchestrates within and across the nuclear weapons regime complex. Drawing on the orchestration and regime complex scholarship, alongside empirical data of EU external action from 2003 to 2019, the article shows how the EU’s natural proclivity for effective multilateralism, coupled with its functional limitations, the political cleavages impeding both the EU and multilateral progress within the regime complex, and the presence of like-minded intermediaries, create ripe conditions for EU orchestration in this field. It further argues that while the EU has struggled to inject agency within individual nuclear negotiation forums, its use of orchestration as a soft and indirect mode of governance is not only well-established but advancing. Orchestration is therefore found to serve as an important metric for understanding and evaluating the scope of EU agency in the nuclear weapons regime complex.

Analyzing the Nuclear Weapons Proliferation Risk Posed by a Mature Fusion Technology and Economy

Nuclear fusion is widely promoted as the ultimate environmentally friendly solution to the world’s energy demands. However, the medium/long-term nuclear weapons proliferation risks from a hypothetical fusion economy are rarely considered. Using risk assessment tools, this paper undertakes a trial scoping of proliferation hazards arising from fusion energy technologies, focused on the implications of a global ‘Mature Fusion Economy’ (MFE). In the medium term, an MFE could (1) facilitate construction of large, efficient, and reliable nuclear arsenals by producing tritium and the fissile materials Plutonium-239 and Uranium-233; and (2) erode the barriers constraining nuclear weapons acquisition by facilitating the spread of nuclear knowledge, technologies, and materials. Given the potential scale of a global MFE, management via monitoring of proliferation and diplomacy could become unworkable. Therefore, policy development must include independent and comprehensive expert and informed community assessment of such fusion-enhanced risks, transparent oversight by the nuclear disarmament community, and systematic analysis of the issues raised in this paper and their implications for fusion into the very long-term future.

Soluble cyclase-mediated nuclear cAMP synthesis is sufficient for cell proliferation

cAMP, a key player in many physiological processes, was classically considered to originate solely from the plasma membrane (PM). This view was recently challenged by observations showing that upon internalization GsPCRs can sustain signaling from endosomes and/or the trans-Golgi network (TGN). In this new view, after the first PM-generated cAMP wave, the internalization of GsPCRs and ACs generates a second wave that was strictly associated with nuclear transcriptional events responsible for triggering specific biological responses. Here, we report that the endogenously expressed TSHR, a canonical GsPCR, triggers an internalization-dependent, calcium-mediated nuclear sAC activation that drives PKA activation and CREB phosphorylation. Both pharmacological and genetic sAC inhibition, which did not affect the cytosolic cAMP levels, blunted nuclear cAMP accumulation, PKA activation, and cell proliferation, while an increase in nuclear sAC expression significantly enhanced cell proliferation. Furthermore, using novel nuclear-targeted optogenetic actuators, we show that light-stimulated nuclear cAMP synthesis can mimic the proliferative action of TSH by activating PKA and CREB. Therefore, based on our results, we propose a novel three-wave model in which the "third" wave of cAMP is generated by nuclear sAC. Despite being downstream of events occurring at the PM (first wave) and endosomes/TGN (second wave), the nuclear sAC-generated cAMP (third wave) is sufficient and rate-limiting for thyroid cell proliferation.

Actomyosin-mediated cellular tension promotes Yap nuclear translocation and myocardial proliferation through α5 integrin signaling.

The cardiomyocyte phenotypic switch from a proliferative to terminally differentiated state results in the loss of regenerative potential of the mammalian heart shortly after birth. Nonmuscle myosin IIB (NM IIB)-mediated actomyosin contractility regulates cardiomyocyte cytokinesis in the embryonic heart, and NM IIB levels decline after birth, suggesting a role for cellular tension in the regulation of cardiomyocyte cell cycle activity in the postnatal heart. To investigate the role of actomyosin contractility in cardiomyocyte cell cycle arrest, we conditionally activated ROCK2 kinase domain (ROCK2:ER) in the murine postnatal heart. Here, we show that α5/β1 integrin and fibronectin matrix increase in response to actomyosin-mediated tension. Moreover, activation of ROCK2:ER promotes nuclear translocation of Yap, a mechanosensitive transcriptional co-activator, and enhances cardiomyocyte proliferation. Finally, we show that reduction of myocardial α5 integrin rescues the myocardial proliferation phenotype in ROCK2:ER hearts. These data demonstrate that cardiomyocytes respond to increased intracellular tension by altering their intercellular contacts in favor of cell-matrix interactions, leading to Yap nuclear translocation, thus uncovering a function for nonmuscle myosin contractility in promoting cardiomyocyte proliferation in the postnatal heart.

The hegemon's tool kit: US leadership and the politics of the nuclear nonproliferation regime; Atomic friends: how America deals with nuclear-armed allies

The hegemon's tool kit: US leadership and the politics of the nuclear nonproliferation regime; Atomic friends: how America deals with nuclear-armed allies