Instead of assuming that all actors are equally likely to clash, and that they do so independently of previous clashes, rivalry analysis can focus on the small number of feuding dyads that cause much of the trouble in the international system. But the value added of this approach will hinge in part on how rivalries are identified. Rivalry dyads are usually identified by satisfying thresholds in the frequency of militarized disputes occurring within some prespecified interval of time. But this approach implies a number of analytical problems including the possibility that rivalry analyses are simply being restricted to a device for distinguishing between states that engage in frequent and infrequent conflict. An alternative approach defines rivalry as a perceptual categorizing process in which actors identify which states are sufficiently threatening competitors to qualify as enemies. A systematic approach to identifying these strategic rivalries is elaborated. The outcome, 174 rivalries in existence between 1816 and 1999 are named and compared to the rivalry identification lists produced by three dispute density approaches. The point of the comparison is not necessarily to assert the superiority of one approach over others as it is to highlight the very real costs and benefits associated with different operational assumptions. The question must also be raised whether all approaches are equally focused on what we customarily mean by rivalries. Moreover, in the absence of a consensus on basic concepts and measures, rivalry findings will be anything but additive even if the subfield continues to be monopolized by largely divergent dispute density approaches.The analysis of rivalry in world politics possesses some considerable potential for revolutionizing the study of conflict. Rather than assume all actors are equally likely to engage in conflictual relations, a focus on rivalries permits analysts to focus in turn on the relatively small handful of actors who, demonstrably, are the ones most likely to generate conflict vastly disproportionate to their numbers. For instance, strategic rivals, a conceptualization that will be developed further in this article, opposed each other in 58~77.3 percent! of 75 wars since 1816. If we restrict our attention to the twentieth century, strategic rivals opposed one another in 41~87.2 percent! of 47 wars. A focus on the post-1945 era yields an opposing rival ratio of 21~91.3 percent! of 23 wars. Moreover, their conflicts are not independent across time-another frequent and major assumption in conflict studies. They are part of an historical process in which a pair of states create
A wide range of cell types depend on mechanically induced signals to enable appropriate physiological responses. The skeleton is particularly dependent on mechanical information to guide the resident cell population towards adaptation, maintenance and repair. Research at the organ, tissue, cell and molecular levels has improved our understanding of how the skeleton can recognize the functional environment, and how these challenges are translated into cellular information that can site-specifically alter phenotype. This review first considers those cells within the skeleton that are responsive to mechanical signals, including osteoblasts, osteoclasts, osteocytes and osteoprogenitors. This is discussed in light of a range of experimental approaches that can vary parameters such as strain, fluid shear stress, and pressure. The identity of mechanoreceptor candidates is approached, with consideration of integrins, pericellular tethers, focal adhesions, ion channels, cadherins, connexins, and the plasma membrane including caveolar and non-caveolar lipid rafts and their influence on integral signaling protein interactions. Several mechanically regulated intracellular signaling cascades are detailed including activation of kinases (Akt, MAPK, FAK), β-catenin, GTPases, and calcium signaling events. While the interaction of bone cells with their mechanical environment is complex, an understanding of mechanical regulation of bone signaling is crucial to understanding bone physiology, the etiology of diseases such as osteoporosis, and to the development of interventions to improve bone strength.
Marrow adipose tissue (MAT), associated with skeletal fragility and hematologic insufficiency, remains poorly understood and difficult to quantify. We tested the response of MAT to high fat diet (HFD) and exercise using a novel volumetric analysis, and compared it to measures of bone quantity. We hypothesized that HFD would increase MAT and diminish bone quantity, while exercise would slow MAT acquisition and promote bone formation. Eight week-old female C57BL/6 mice were fed a regular (RD) or HFD, and exercise groups were provided voluntary access to running wheels (RD-E, HFD-E). Femoral MAT was assessed by μCT (lipid binder osmium) using a semi-automated approach employing rigid co-alignment, regional bone masks and was normalized for total femoral volume (TV) of the bone compartment. MAT was 2.6-fold higher in HFD relative to RD mice. Exercise suppressed MAT in RD-E mice by more than half compared with RD. Running similarly inhibited MAT acquisition in HFD mice. Exercise significantly increased bone quantity in both diet groups. Thus, HFD caused significant accumulation of MAT; importantly running exercise limited MAT acquisition while promoting bone formation during both diets. That MAT is exquisitely responsive to diet and exercise, and its regulation by exercise appears to be inversely proportional to effects on exercise induced bone formation, is relevant for an aging and sedentary population.
A cell’s ability to recognize and adapt to the physical environment is central to its survival and function, but how mechanical cues are perceived and transduced into intracellular signals remains unclear. In mesenchymal stem cells (MSC), high magnitude substrate strain (HMS, ≥2%) effectively suppresses adipogenesis via induction of FAK/mTORC2/Akt signaling generated at focal adhesions . Physiologic systems also rely on a persistent barrage of low level signals to regulate behavior . Exposing MSC to extremely low magnitude mechanical signals (LMS) suppresses adipocyte formation  despite the virtual absence of substrate strain (<0.001%) , suggesting that LMS-induced dynamic accelerations can generate force within the cell. Here we show that MSC response to LMS is enabled through mechanical coupling between the cytoskeleton and the nucleus, in turn activating focal adhesion kinase (FAK) and Akt signaling followed by FAK-dependent induction of RhoA. While LMS and HMS synergistically regulated FAK activity at the focal adhesions, LMS-induced actin remodeling was concentrated at the perinuclear domain. Preventing nuclear-actin cytoskeleton mechanocoupling by disrupting LINC (Linker of Nucleoskeleton and Cytoskeleton) complexes inhibited these LMS-induced signals as well as prevented LMS repression of adipogenic differentiation, highlighting that LINC connections are critical for sensing LMS. In contrast, FAK activation by high magnitude strain (HMS) was unaffected by LINC decoupling, consistent with signal initiation at the focal adhesion (FA) mechanosome. These results indicate that the MSC responds to its dynamic physical environment not only with “outside-in” signaling initiated by substrate strain, but vibratory signals enacted through the LINC complex enable matrix independent “inside-inside” signaling.
The cell cytoskeleton interprets and responds to physical cues from the microenvironment. Applying mechanical force to mesenchymal stem cells induces formation of a stiffer cytoskeleton, which biases against adipogenic differentiation and toward osteoblastogenesis. mTORC2, the mTOR complex defined by its binding partner rictor, is implicated in resting cytoskeletal architecture and is activated by mechanical force. We asked if mTORC2 played a role in mechanical adaptation of the cytoskeleton. We found that during bi-axial strain-induced cytoskeletal restructuring, mTORC2 and Akt colocalize with newly assembled focal adhesions (FA). Disrupting the function of mTORC2, or that of its downstream substrate Akt, prevented mechanically induced F-actin stress fiber development. mTORC2 becomes associated with vinculin during strain, and knockdown of vinculin prevents mTORC2 activation. In contrast, mTORC2 is not recruited to the FA complex during its activation by insulin, nor does insulin alter cytoskeletal structure. Further, when rictor was knocked down, the ability of mesenchymal stem cells (MSC) to enter the osteoblastic lineage was reduced, and when cultured in adipogenic medium, rictor-deficient MSC showed accelerated adipogenesis. This indicated that cytoskeletal remodeling promotes osteogenesis over adipogenesis. In sum, our data show that mTORC2 is involved in stem cell responses to biophysical stimuli, regulating both signaling and cytoskeletal reorganization. As such, mechanical activation of mTORC2 signaling participates in mesenchymal stem cell lineage selection, preventing adipogenesis by preserving b-catenin and stimulating osteogenesis by generating a stiffer cytoskeleton.
Depolymerization of the actin cytoskeleton induces nuclear trafficking of regulatory proteins and global effects on gene transcription. We here show that in mesenchymal stem cells (MSCs), cytochalasin D treatment causes rapid cofilin-/importin-9-dependent transfer of G-actin into the nucleus. The continued presence of intranuclear actin, which forms rod-like structures that stain with phalloidin, is associated with induction of robust expression of the osteogenic genes osterix and osteocalcin in a Runx2-dependent manner, and leads to acquisition of osteogenic phenotype. Adipogenic differentiation also occurs, but to a lesser degree. Intranuclear actin leads to nuclear export of Yes-associated protein (YAP); maintenance of nuclear YAP inhibits Runx2 initiation of osteogenesis. Injection of cytochalasin into the tibial marrow space of live mice results in abundant bone formation within the space of 1 week. In sum, increased intranuclear actin forces MSC into osteogenic lineage through controlling Runx2 activity; this process may be useful for clinical objectives of forming bone.
The idea that democracies do not fight other democracies has attracted a considerable amount of analytical energy in recent years. It is a theme that appeals to a variety of people. It emphasizes type of political system as a principal explanatory variable, which attracts partisans of domestic politics explanations in international politics. It can be seen as another nail in the coffin of realism. Moreover, the basic generalization that democracies do not launch wars against other democracies seems to hold up despite repeated attacks on its claim to validity. It therefore appeals to social scientists who have found few other generalizations to hold up as well in the study of international politics. One leading analyst, Jack Levy, has bestowed law-like status on the generalization. 1 Another, Bruce Russett, refers to it as "one of the strongest nontrivial and nontautological generalizations that can be made about international relations." 2 Moreover, the general extrapolation that more democracies implies fewer wars is seductive to optimists who contend that the nature of world politics has changed radically in the last decade of the twentieth century thanks to the end of history, the triumph of the free world in the cold war, or the increasing rejection of war as a plausible instrument of policy in some parts of the world.Despite the many rigorous analyses of the democracy-war question some major problems of interpretation remain. 3 Perhaps the most significant problem is one of explanation. If it is true that democracies do not fight other democracies and, in the process, create zones of peace that expand as the number of democratic states increases, why is that the case? The usual response is to fall back on attributes associated with the obvious causal I am grateful to Jeff Isaac, George Modelski, John Odell, and several anonymous reviewers for their suggestions on improving earlier versions of this article.
Osteocytes project long, slender processes throughout the mineralized matrix of bone, where they connect and communicate with effector cells. The interconnected cellular projections form the functional lacunocanalicular system, allowing fluid to pass for cell-to-cell communication and nutrient and waste exchange. Prevention of mineralization in the pericellular space of the lacunocanalicular pericellular space is crucial for uninhibited interstitial fluid movement. Factors contributing to the ability of the pericellular space of the lacunocanalicular system to remain open and unmineralized are unclear. Immunofluorescence and immunogold localization by transmission electron microscopy demonstrated perlecan/Hspg2 signal localized to the osteocyte lacunocanalicular system of cortical bone, and this proteoglycan was found in the pericellular space of the lacunocanalicular system. In this study we examined osteocyte lacunocanalicular morphology in mice deficient in the large heparan sulfate proteoglycan perlecan/Hspg2 in this tissue. Ultrastructural measurements with electron microscopy of perlecan/Hspg2-deficient mice demonstrated diminished osteocyte canalicular pericellular area, resulting from a reduction in the total canalicular area. Additionally, perlecan/Hspg2-deficient mice showed decreased canalicular density and a reduced number of transverse tethering elements per canaliculus. These data indicated that perlecan/Hspg2 contributed to the integrity of the osteocyte lacunocanalicular system by maintaining the size of the pericellular space, an essential task to promote uninhibited interstitial fluid movement in this mechanosensitive environment. This work thus identified a new barrier function for perlecan/Hspg2 in murine cortical bone. © 2011 American Society for Bone and Mineral Research.
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