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Using strategic plans, intelligence analysis, and other materials that have only recently been declassified, Emergency War Plan examines the theory and practice of nuclear deterrence during the 1945-1960 period of the Cold War.

\"Winning Armageddon tells the story of General Curtis E. LeMay's advocacy for nuclear first strikes while leading the U.S. Air Force's Strategic Air Command. LeMay argued for striking first in a nuclear conflict--but only if and when it was clear that the enemy was preparing to launch their own surprise attack. This approach, commonly referred to as preemption, was designed to catch an attacker off-guard and prevent the destruction of one's own nation. LeMay hoped that rather than plunging the world into a fruitless nuclear exchange he could diffuse the conflict at its outset\"--.

This provocative and timely work examines various scenarios in which the deployment of nuclear weapons could occur, the probable consequences of such an escalation, the likely world reactions, and the plausible policy ramifications. Rather than projecting the physical damage that would result from nuclear attacks, George H. Quester offers an exploration of the political, psychological, and social aftermath of nuclear conflict. The prospect of nuclear attack—sixty years after atomic bombs destroyed Hiroshima and Nagasaki—is difficult to confront on many levels. We may avoid the discussion for emotional reasons, for fear of generating a self-confirming hypothesis, or simply because of the general \"nuclear taboo.\" But there are also self-denying propositions to be harnessed here: if the world gives some advance thought to how nuclear weapons might be used again, such attacks may be headed off. If the world avoids nuclear weapons use until the year 2045, it will be able to celebrate one hundred years of nuclear concord. Quester suggests that this may be achieved through the careful consideration of possible nuclear deployment scenarios and their consequences. In this insightful analysis, he provides a starting point for informed and focused reflection and preparation.

MicroRNAs (miRNAs) interfere with translation of specific target mRNAs and are thought to thereby regulate many cellular processes. Recent studies have suggested that miRNAs might play a role in osteoblast differentiation and bone formation. Here, we identify a new miRNA (miR-2861) in primary mouse osteoblasts that promotes osteoblast differentiation by repressing histone deacetylase 5 (HDAC5) expression at the post-transcriptional level. miR-2861 was found to be transcribed in ST2 stromal cells during bone morphogenetic protein 2-induced (BMP2-induced) osteogenesis, and overexpression of miR-2861 enhanced BMP2-induced osteoblastogenesis, whereas inhibition of miR-2861 expression attenuated it. HDAC5, an enhancer of runt-related transcription factor 2 (Runx2) degradation, was confirmed to be a target of miR-2861. In vivo silencing of miR-2861 in mice reduced Runx2 protein expression, inhibited bone formation, and decreased bone mass. Importantly, miR-2861 was found to be conserved in humans, and a homozygous mutation in pre-miR-2861 that blocked expression of miR-2861 was shown to cause primary osteoporosis in 2 related adolescents. Consistent with the mouse data, HDAC5 levels were increased and Runx2 levels decreased in bone samples from the 2 affected individuals. Thus, our studies show that miR-2861 plays an important physiological role in osteoblast differentiation and contributes to osteoporosis via its effect on osteoblasts.

Membrane-bound proteases have recently emerged as critical mediators of tumorigenesis, angiogenesis, and metastasis. However, the mechanisms by which they regulate these processes remain unknown. As the cell surface serine protease fibroblast activation protein (FAP) is selectively expressed on tumor-associated fibroblasts and pericytes in epithelial tumors, we set out to investigate the role of FAP in mouse models of epithelial-derived solid tumors. In this study, we demonstrate that genetic deletion and pharmacologic inhibition of FAP inhibited tumor growth in both an endogenous mouse model of lung cancer driven by the K-rasG12D mutant and a mouse model of colon cancer, in which CT26 mouse colon cancer cells were transplanted into immune competent syngeneic mice. Interestingly, growth of only the K-rasG12D-driven lung tumors was also attenuated by inhibition of the closely related protease dipeptidyl peptidase IV (DPPIV). Our results indicate that FAP depletion inhibits tumor cell proliferation indirectly, increases accumulation of collagen, decreases myofibroblast content, and decreases blood vessel density in tumors. These data provide proof of principle that targeting stromal cell-mediated modifications of the tumor microenvironment may be an effective approach to treating epithelial-derived solid tumors.

The in vivo application of cytolytic peptides for cancer therapeutics is hampered by toxicity, nonspecificity, and degradation. We previously developed a specific strategy to synthesize a nanoscale delivery vehicle for cytolytic peptides by incorporating the nonspecific amphipathic cytolytic peptide melittin into the outer lipid monolayer of a perfluorocarbon nanoparticle. Here, we have demonstrated that the favorable pharmacokinetics of this nanocarrier allows accumulation of melittin in murine tumors in vivo and a dramatic reduction in tumor growth without any apparent signs of toxicity. Furthermore, direct assays demonstrated that molecularly targeted nanocarriers selectively delivered melittin to multiple tumor targets, including endothelial and cancer cells, through a hemifusion mechanism. In cells, this hemifusion and transfer process did not disrupt the surface membrane but did trigger apoptosis and in animals caused regression of precancerous dysplastic lesions. Collectively, these data suggest that the ability to restrain the wide-spectrum lytic potential of a potent cytolytic peptide in a nanovehicle, combined with the flexibility of passive or active molecular targeting, represents an innovative molecular design for chemotherapy with broad-spectrum cytolytic peptides for the treatment of cancer at multiple stages.

Milk fat globule epidermal growth factor 8 (Mfge8) is a soluble glycoprotein known to regulate inflammation and immunity by mediating apoptotic cell clearance. Since fibrosis can occur as a result of exaggerated apoptosis and inflammation, we set out to investigate the hypothesis that Mfge8 might negatively regulate tissue fibrosis. We report here that Mfge8 does decrease the severity of tissue fibrosis in a mouse model of pulmonary fibrosis; however, it does so not through effects on inflammation and apoptotic cell clearance, but by binding and targeting collagen for cellular uptake through its discoidin domains. Initial analysis revealed that Mfge8-/- mice exhibited enhanced pulmonary fibrosis after bleomycin-induced lung injury. However, they did not have increased inflammation or impaired apoptotic cell clearance after lung injury compared with Mfge8+/+ mice; rather, they had a defect in collagen turnover. Further experiments indicated that Mfge8 directly bound collagen and that Mfge8-/- macrophages exhibited defective collagen uptake that could be rescued by recombinant Mfge8 containing at least one discoidin domain. These data demonstrate a critical role for Mfge8 in decreasing the severity of murine tissue fibrosis by facilitating the removal of accumulated collagen.

A counterforce attack intends to disable an opponent's nuclear arsenal to limit potential damage from that adversary. We postulate a future when hardening and deeply burying fixed sites, transition to mobile strategic systems, and improved defences make executing a counterforce strategy against an adversary's nuclear forces extremely difficult. Additionally, our postulated future has multiple nations possessing nuclear weapons. Consequently, each country needs to consider multiple actors when addressing the question of how to deter a potential adversary's nuclear attack. We examine six nuclear targeting alternatives and consider how to deter them. These strategies include nuclear demonstration, conventional military targets, and attacks consisting of communications/electronics, economic, infrastructure, and population centers that a nation might consider striking with nuclear weapons. Since these alternative strikes require only a few nuclear weapons, executing one of them would not significantly shift the balance of nuclear forces. The attacking country's remaining nuclear forces may inhibit the attacked country or its allies from responding. How can nations deter these limited nuclear attacks? Potentially, threatening economic counter-strikes seems to be the best alternative. How might escalation be controlled in the event of a limited attack? Other instruments of power, such as political or economic, might be employed to bolster deterrence against these types of nuclear strikes.

The last two decades have seen a slow but steady increase in nuclear armed states, and in the seemingly less constrained policy goals of some of the newer \"rogue\" states in the international system. The authors ofOn Limited Nuclear War in the 21st Century argue that a time may come when one of these states makes the conscious decision that using a nuclear weapon against the United States, its allies, or forward deployed forces in the context of a crisis or a regional conventional conflict may be in its interests. They assert that we are unprepared for these types of limited nuclear wars and that it is urgent we rethink the theory, policy, and implementation of force related to our approaches to this type of engagement. Together they critique Cold War doctrine on limited nuclear war and consider a number of the key concepts that should govern our approach to limited nuclear conflict in the future. These include identifying the factors likely to lead to limited nuclear war, examining the geopolitics of future conflict scenarios that might lead to small-scale nuclear use, and assessing strategies for crisis management and escalation control. Finally, they consider a range of strategies and operational concepts for countering, controlling, or containing limited nuclear war.

The need for disease-modifying drugs for Alzheimer's disease has become increasingly important owing to escalating disease prevalence and the associated socio-economic burden. Until recently, reducing brain amyloid accumulation has been the main therapeutic focus; however, increasing evidence suggests that targeting abnormal tau phosphorylation could be beneficial. Tau is phosphorylated by several protein kinases and this is balanced by dephosphorylation by protein phosphatases. Phosphorylation at specific sites can influence the physiological functions of tau, including its role in binding to and stabilizing the neuronal cytoskeleton. aberrant phosphorylation of tau could render it susceptible to potentially pathogenic alterations, including conformational changes, proteolytic cleavage and aggregation. While strategies that reduce tau phosphorylation in transgenic models of disease have been promising, our understanding of the mechanisms through which tau becomes abnormally phosphorylated in disease is lacking.