Nuclear Tension Research Articles

Advances in mechanotransduction and sonobiology: effects of audible acoustic waves and low-vibration stimulations on mammalian cells

AbstractIn recent decades, research on mechanotransduction has advanced considerably, focusing on the effects of audible acoustic waves (AAWs) and low-vibration stimulation (LVS), which has propelled the field of sonobiology forward. Taken together, the current evidence demonstrates the influence of these biosignals on key cellular processes, such as growth, differentiation and migration in mammalian cells, emphasizing the determining role of specific physical parameters during stimulation, such as frequency, sound pressure level/amplitude and exposure time. These mechanical waves interact with various cellular elements, including ion channels, primary cilia, cell–cell adhesion receptors, cell–matrix and extracellular matrix proteins, and focal adhesion complexes. These components connect with the cytoskeletal fibre network, enabling the transmission of mechanical stimuli towards the nucleus. The nucleus, in turn, linked to the cytoskeleton via the linkers of the nucleoskeleton and cytoskeleton complex, acts as a mechanosensitive centre, not only responding to changes in cytoskeletal stiffness and nuclear tension but also regulating gene expression through the transcriptional co-activator YAP/TAZ and interactions between chromatin and the nuclear envelope. This intricate chain of mechanisms highlights the potential of sonobiology in various fields, including dentistry, regenerative medicine, tissue engineering and cancer research. However, progress in these fields requires the establishment of standardized measurement methodologies and biocompatible experimental setups to ensure the reproducibility of results.

A Global Campus Beyond the Cold War. Peace and Disarmament Among Spanish Academics during the Debate on Joining and Remaining in NATO (1981-1986)

Historiography has recently shown a special interest in assessing the cultural impact of the social engagement of academics during the Cold War through their advocacy of disarmament or human rights. This academic social activism became part of a complex “transnational civil society,” which was to influence international relations. In light of these considerations, this article aims to delve into the distinctive characteristics of the “nuclear culture” and “science diplomacy” of the Spanish academic world between 1981 and 1986. Spain’s experience of the final stage of the Cold War was somewhat unusual. The resurgence of nuclear tension between the two superpowers was mediated by the domestic political transition from a military dictatorship to a parliamentary democracy, but also by the democratisation of foreign policy and the accession of Spain to NATO. To understand how this took place and with what effects, this article will focus on three main points. Firstly, it will set out an analysis of the impact of historian E.P. Thompson’s critical thinking on the Cold War and the European Campaign for Disarmament among Spanish academics. Secondly, it will examine how certain academics, who played an active part in the debate either for or against joining and remaining in NATO, shaped the nuclear culture of the time through the daily press. Finally, it will argue the involvement, or lack thereof, of Spain’s scientific sector in transnational networks for peace and disarmament and how, through civil society itself, the foundations were laid for the first centres aimed at the dissemination and study of peace.

Exploiting mechanoregulation via FAK/YAP to overcome platinum resistance in ovarian cancer

Cancer cells mechanically interact with the tumor microenvironment during cancer development. Mechano-reciprocity has emerged as a crucial factor affecting anti-cancer drug resistance during adjuvant therapy. Here, we investigated the focal adhesion kinase (FAK)/Yes-associated protein (YAP) signaling axis as a prospective strategy for circumventing cisplatin resistance in ovarian cancer (OC). The Cancer Genome Atlas (TCGA) data analysis revealed that FAK overexpression significantly correlated with unfavorable clinical outcomes in patients with ovarian cancer. AFM indentation experiments showed that cell elasticity depends on FAK activity. Notably, the combination of FAK inhibition and cisplatin treatment led to a 69 % reduction in the IC50 of cisplatin. This combined treatment also increased apoptosis compared to the individual treatments, along with the upregulation of the pro-apoptotic factor BAX and cleaved PARP. Suppressing FAK expression sequestered YAP in the cytosol, potentially reducing cellular proliferation and promoting apoptosis. Moreover, reduced FAK expression sensitized drug-resistant OC cells to cisplatin treatment owing to a decrease in nuclear tension, allowing the relocation of YAP to the cytosol. In a mouse model, the co-administration of an FAK inhibitor and cisplatin significantly suppressed tumor growth and increased apoptotic events and DNA fragmentation. Our findings suggest that drug resistance can be attributed to the perturbation of mechanosensing signaling pathways, which drive the mechanical reinforcement of cancer cells. OC cells can restore their sensitivity to cisplatin treatment by strategically reducing YAP localization in the nucleus through FAK downregulation.

Pathogenic tau decreases nuclear tension in cultured neurons.

Neurodegenerative tauopathies, including Alzheimer's disease, are pathologically defined by the presence of aggregated forms of tau protein in brains of affected individuals. Previous studies report that the negative effects of pathogenic tau on the actin cytoskeleton and microtubules cause a toxic destabilization of the lamin nucleoskeleton and formation of nuclear invaginations and blebs. Based on the known function of the nucleus as a mechanosensor, as well as the high incidence of nuclear pleomorphism in human Alzheimer's disease and related tauopathies, we investigated the effects of pathogenic tau on nuclear tension. We first find that tau-dependent nuclear envelope invagination and relocalization of LInker of Nucleoskeleton and Cytoskeleton (LINC) complex components are conserved in a newly-developed neuroblastoma cell line that features doxycycline-inducible expression of a tau mutant associated with autosomal dominant frontotemporal dementia. We next determine that a Förster resonance energy transfer (FRET)-based sensor of nuclear tension responds to cytoskeletal stabilization and destabilization when expressed in neuroblastoma cells. Using this nuclear tension sensor, we find that induced expression of pathogenic tau is sufficient to decrease nuclear tension. This work provides the initial proof-of-concept evidence that pathogenic forms of tau alter nuclear tension, paving the way for the future study of altered nuclear mechanosensing in the context of tau-mediated neurodegenerative disorders.

Nuclear tension controls mitotic entry by regulating cyclin B1 nuclear translocation.

As cells prepare to divide, they must ensure that enough space is available to assemble the mitotic machinery without perturbing tissue homeostasis. To do so, cells undergo a series of biochemical reactions regulated by cyclin B1-CDK1 that trigger cytoskeletal reorganization and ensure the coordination of cytoplasmic and nuclear events. Along with the biochemical events that control mitotic entry, mechanical forces have recently emerged as important players in cell-cycle regulation. However, the exact link between mechanical forces and the biochemical pathways that control mitotic progression remains unknown. Here, we identify a tension-dependent signal on the nucleus that sets the time for nuclear envelope permeabilization (NEP) and mitotic entry. This signal relies on actomyosin contractility, which unfolds the nucleus during the G2-M transition, activating the stretch-sensitive cPLA2 on the nuclear envelope and regulating the nuclear translocation of cyclin B1. Our data demonstrate how nuclear tension during the G2-M transition contributes to timely and efficient mitotic spindle assembly and prevents chromosomal instability.

DNA damage alters nuclear mechanics through chromatin reorganization.

DNA double-strand breaks drive genomic instability. However, it remains unknown how these processes may affect the biomechanical properties of the nucleus and what role nuclear mechanics play in DNA damage and repair efficiency. Here, we have used Atomic Force Microscopy to investigate nuclear mechanical changes, arising from externally induced DNA damage. We found that nuclear stiffness is significantly reduced after cisplatin treatment, as a consequence of DNA damage signalling. This softening was linked to global chromatin decondensation, which improves molecular diffusion within the organelle. We propose that this can increase recruitment for repair factors. Interestingly, we also found that reduction of nuclear tension, through cytoskeletal relaxation, has a protective role to the cell and reduces accumulation of DNA damage. Overall, these changes protect against further genomic instability and promote DNA repair. We propose that these processes may underpin the development of drug resistance.

Creating Change in the Ecology of Religious Education for Overcoming Racism

This study reflects the regional context of Northeast Asian countries embodied in US-North Korean nuclear tension. The researcher uses the methodological inquiry of practical theology to analyze the political affairs and intertwine with religious education. The ecology of religious education to dismantle the threat of ethnic and racial discrimination such as white supremacy supports a shared pedagogy between students and their teachers in the narrative of Jesus to challenge all forms of oppression as the democratic presence of God.

Nuclear mechanosensing controls MSC osteogenic potential through HDAC epigenetic remodeling

Cells sense mechanical cues from the extracellular matrix to regulate cellular behavior and maintain tissue homeostasis. The nucleus has been implicated as a key mechanosensor and can directly influence chromatin organization, epigenetic modifications, and gene expression. Dysregulation of nuclear mechanosensing has been implicated in several diseases, including bone degeneration. Here, we exploit photostiffening hydrogels to manipulate nuclear mechanosensing in human mesenchymal stem cells (hMSCs) in vitro. Results show that hMSCs respond to matrix stiffening by increasing nuclear tension and causing an increase in histone acetylation via deactivation of histone deacetylases (HDACs). This ultimately induces osteogenic fate commitment. Disrupting nuclear mechanosensing by disconnecting the nucleus from the cytoskeleton up-regulates HDACs and prevents osteogenesis. Resetting HDAC activity back to healthy levels rescues the epigenetic and osteogenic response in hMSCs with pathological nuclear mechanosensing. Notably, bone from patients with osteoarthritis displays similar defective nuclear mechanosensing. Collectively, our results reveal that nuclear mechanosensing controls hMSC osteogenic potential mediated by HDAC epigenetic remodeling and that this cellular mechanism is likely relevant to bone-related diseases.

A peaceful solution to the nuclear tension in the Korean peninsula

In spite of the efforts of the international community to solve the Democratic People’s Republic of Korea (DPRK) nuclear crisis, this issue remains unsolved. The relevance of this matter lies in the need to find a permanent solution to the crisis that leads to a total denuclearization of the Korean Peninsula. Therefore, the aim of this article is to demonstrate the need of a peaceful solution to the DPRK nuclear issue in which the security concerns of North Korea are addressed by signing a peace treaty with Pyongyang that ensures that the United States will not attack the regime, will remove its troops from South Korea and will finish its military drills with this ally. This article will discuss what elements will be necessary to achieve a peaceful solution to this nuclear conundrum.

Progerin phosphorylation in interphase is lower and less mechanosensitive than lamin-A,C in iPS-derived mesenchymal stem cells

ABSTRACTInterphase phosphorylation of lamin-A,C depends dynamically on a cell's microenvironment, including the stiffness of extracellular matrix. However, phosphorylation dynamics is poorly understood for diseased forms such as progerin, a permanently farnesylated mutant of LMNA that accelerates aging of stiff and mechanically stressed tissues. Here, fine-excision alignment mass spectrometry (FEA-MS) is developed to quantify progerin and its phosphorylation levels in patient iPS cells differentiated to mesenchymal stem cells (MSCs). The stoichiometry of total A-type lamins (including progerin) versus B-type lamins measured for Progeria iPS-MSCs prove similar to that of normal MSCs, with total A-type lamins more abundant than B-type lamins. However, progerin behaves more like farnesylated B-type lamins in mechanically-induced segregation from nuclear blebs. Phosphorylation of progerin at multiple sites in iPS-MSCs cultured on rigid plastic is also lower than that of normal lamin-A and C. Reduction of nuclear tension upon i) cell rounding/detachment from plastic, ii) culture on soft gels, and iii) inhibition of actomyosin stress increases phosphorylation and degradation of lamin-C > lamin-A > progerin. Such mechano-sensitivity diminishes, however, with passage as progerin and DNA damage accumulate. Lastly, transcription-regulating retinoids exert equal effects on both diseased and normal A-type lamins, suggesting a differential mechano-responsiveness might best explain the stiff tissue defects in Progeria.

Coordinated increase of nuclear tension and lamin-A with matrix stiffness outcompetes lamin-B receptor that favors soft tissue phenotypes.

Matrix stiffness that is sensed by a cell or measured by a purely physical probe reflects the intrinsic elasticity of the matrix and also how thick or thin the matrix is. Here, mesenchymal stem cells (MSCs) and their nuclei spread in response to thickness-corrected matrix microelasticity, with increases in nuclear tension and nuclear stiffness resulting from increases in myosin-II and lamin-A,C. Linearity between the widely varying projected area of a cell and its nucleus across many matrices, timescales, and myosin-II activity levels indicates a constant ratio of nucleus-to-cell volume, despite MSCs' lineage plasticity. Nuclear envelope fluctuations are suppressed on the stiffest matrices, and fluctuation spectra reveal a high nuclear tension that matches trends from traction force microscopy and from increased lamin-A,C. Transcriptomes of many diverse tissues and MSCs further show that lamin-A,C's increase with tissue or matrix stiffness anti-correlates with lamin-B receptor (LBR), which contributes to lipid/sterol biosynthesis. Adipogenesis (a soft lineage) indeed increases LBR:lamin-A,C protein stoichiometry in MSCs versus osteogenesis (stiff). The two factors compete for lamin-B in response to matrix elasticity, knockdown, myosin-II inhibition, and even constricted migration that disrupts and segregates lamins in situ. Matrix stiffness-driven contractility thus tenses the nucleus to favor lamin-A,C accumulation and suppress soft tissue phenotypes.

The mammalian LINC complex regulates genome transcriptional responses to substrate rigidity.

Mechanical integration of the nucleus with the extracellular matrix (ECM) is established by linkage between the cytoskeleton and the nucleus. This integration is hypothesized to mediate sensing of ECM rigidity, but parsing the function of nucleus-cytoskeleton linkage from other mechanisms has remained a central challenge. Here we took advantage of the fact that the LINC (linker of nucleoskeleton and cytoskeleton) complex is a known molecular linker of the nucleus to the cytoskeleton, and asked how it regulates the sensitivity of genome-wide transcription to substratum rigidity. We show that gene mechanosensitivity is preserved after LINC disruption, but reversed in direction. Combined with myosin inhibition studies, we identify genes that depend on nuclear tension for their regulation. We also show that LINC disruption does not attenuate nuclear shape sensitivity to substrate rigidity. Our results show for the first time that the LINC complex facilitates mechano-regulation of expression across the genome.

Comments. NPT: Nuclear Weapons and Tension Areas

Comments. NPT: Nuclear Weapons and Tension Areas

“Pilgrim's blues”:Puritan Anxiety in Robert Lowell'sFor the Union Dead

Robert Lowell's For the Union Dead evinces an anxiety over Puritanism that is bound to the sociological conditions of American Cold War culture. His collection envisions an America in which the old Calvinist binary of elect (the few chosen by God for salvation) and preterite (those left behind—everybody else) has imploded under Cold War threats of nuclear annihilation, thus reconfiguring the two driving concepts behind the Puritans' "errand" into the New World: the apocalypse and salvation. Lowell suggests that the Puritan desire for salvation has developed into a secular pursuit of material wealth, and that this pursuit, in turn, has led to a technocratic nuclear tension. With grim irony, For the Union Dead claims that America's capitalist pursuit of wealth and technology to enact its own election and salvation has actually resulted in national preterition. Few critics have considered Lowell's engagement with Puritanism and Calvinism, but my essay addresses this gap in scholarship and attempts to initiate a dialogue on Puritanism as an important trope in post-World War II American literature.

Effects of muscle blood flow on muscle energy metabolism and contractility

Abstract Energy metabolism and contractility of rat's femoral triceps muscles were investigated by varying blood flow levels with ligation of the femoral artery. The triceps were stimulated electrically to produce equivalent conditions as exercise loading, and phosphorus nuclear magnetic resonance ( 31 P-NMR) spectra and muscle tension levels were monitored. The ratio of inorganic phosphate (Pi) to ‘Pi+phosphocreatine (PCr)', i.e. Pi/(Pi+PCr), was obtained from 31 P-NMR spectra. This ratio was related to the reduction of blood flow ratio (BFR) during and after the stimulation period, whereas before starting the stimulation, there was no significant correlation. These findings indicate: (i) muscle energy metabolism during decreased blood flow is influenced by the stimulation (loading) given to the muscle; and (ii) changes of muscle energy metabolism due to decreased muscle blood flow during the loading is evaluable by measuring 31 P-NMR spectra. Muscle tension reached the plateau 8 min after starting the stimulation, regardless of BFR, but muscle tension ratio decreased as BFR became lower. This indicates that decreased blood flow diminishes muscle contractility, and then lowers muscle function levels. Our findings indicate that muscle blood flow plays an important role in muscle function, and blood flow and muscle function levels are evaluable by measuring 31 P-NMR spectra of the muscle.

Commemorating the Cold War in Canada: Considering the DEW Line

The Cold War has yet to become an integral part of the Canadian national identity. The postwar period of nuclear tension remains largely uncommemorated in any official or practical sense, and the limitations of national commemoration policies militate against any quick designations. Canadian federal heritage properties legislation is circumscribed by a fortyyear rule, and the Historic Sites and Monuments Board of Canada