Explore the vast range of titles available.

\"In this penetrating history of the Defense Department's most secret, most powerful, and most controversial military science R&D agency, Annie Jacobsen draws on inside sources, exclusive interviews, private documents, and declassified memos to paint a picture of \"the Pentagon's brain\" from its Cold War inception in 1958 to the present. This is the essential book on DARPA--a compelling narrative about the clandestine intersection of science and the American military and the often jaw-dropping, futuristic, and frightening results\"--Back cover.

The skill of model estimations is examined in reproducing the trajectory of tropical cyclones (TCs) Thane (2011) and Nilam (2012) by comparing the results of a global model (Global Forecast System; GFS) to a regional model (Weather Research and Forecasting—Advanced Research WRF; WRF-ARW). The spatial resolution of the global model (25 km) is chosen similar to the horizontal grid spacing (27 km) of the regional model for a fair comparison over the Bay of Bengal (BOB) region. The objective is to set the basis for future studies that analyze the physical reasons why a particular simulation performs better in the BOB than others in terms of reproducing trajectory. Collectively, 408 h and 288 h of the run of each model are used in this paper for analyzing the TCs Thane and Nilam, respectively. The wind vector plots at 850 hPa, pressure at mean sea level (PMSL), and rainfall are also used for enhancing the analysis. The results show that GFS simulations significantly improve the trajectory of both TCs as compared to WRF with a crucial 13.9%, 24%, and 31.6% (Thane: 6.3%, 21.4%, 31%, and Nilam: 26.6%, 29.2%, 32.9%) reduction in forecast error for a 24-h, 48-h, and 72-h forecast, respectively. By and large, the GFS simulations improve the TCs’ trajectory forecast results by reducing more than one-fourth (26.5%; 30.3% in TC Nilam and 24% in TC Thane) of the forecast error as compared to the WRF data. Moreover, the maximum one-third (31.6%) to a minimum of 13.9% of the trajectory forecast error is reduced in the overall 72-h and 24-h GFS simulations, respectively, in comparison to the WRF simulations. Typically, both models provide less forecast error in the case of TC Nilam in comparison to TC Thane, which is also partially contributed by the anti-clockwise recurvature taken by the TC Thane, again GFS shows better agreement relative to the observations. 795.4 km and 40.2 km are the maximum and minimum forecast errors, which are provided by the 72-h and 24-h WRF simulation on 27 and 30 December 2011, respectively, making the forecast error range 22.9% broader (755.2 km) for WRF simulations over GFS (614.3 km). The paper creates a significant base for future work for assessing model simulation data against topography, in-land water bodies, ocean, and upper-air observations. These future analyses can enhance the understanding of how these models represent the distribution of those variables. Also, it will be utilized to fathom the physical reasons behind the enhanced performance of GFS over WRF in the BOB in terms of reproducing trajectory, although the current situation indicates the possible dominance of the global environmental processes and the BOB ocean water over the regional topographical effects. Historically, the regions around BOB have been known long for huge human and economic losses during the TCs. The extremely heavy population in these regions is considered the central cause behind it. Through a 49-year data analysis in the North Indian Ocean (NIO), this paper also shows a significant enhancement in the strength of TCs, especially during the recent 14-year (2007–2020), which further enhances the crucial need to examine the performance of models to capture the location of TCs for mitigating their impact on human lives in these TC-prone regions.

The history of the Defense Advanced Research Projects Agency, the Pentagon agency that has quietly shaped war and technology for nearly sixty years. Founded in 1958 in response to the launch of Sputnik, the agency's original mission was to create \"the unimagined weapons of the future.\" Over the decades, DARPA has been responsible for countless inventions and technologies that extend well beyond the military. Sharon Weinberger gives us a riveting account of DARPA's successes and failures, its remarkable innovations, and its wild-eyed schemes. We see how the threat of nuclear Armageddon sparked investment in computer networking, leading to the Internet, as well as to a proposal to power a missile-destroying particle beam by draining the Great Lakes. We learn how DARPA was responsible during the Vietnam War for both Agent Orange and the development of the world's first armed drones, and how after 9/11 the agency sparked a national controversy over surveillance with its data-mining research. And we see how DARPA's success with self-driving cars was followed by disappointing contributions to the Afghanistan and Iraq wars. Weinberger has interviewed more than one hundred former Pentagon officials and scientists involved in DARPA's projects -- many of whom have never spoken publicly about their work with the agency -- and pored over countless declassified records from archives around the country, documents obtained under the Freedom of Information Act, and exclusive materials provided by sources.

In the 21st century, the US government has passed a series of laws and regulations on energy, strengthening the domestic supply of energy and reducing its dependence on international energy supply. The US government uses legal instruments and fiscal and taxation levers to promote energy conservation. It vigorously develops renewable energy, researches on substitute energy, and invests on clean energy such as natural gas and nuclear energy, to create a diversified energy landscape. It has a profound impact on global new energy and its industries, international energy supply, and the world's environmental protection industry.

Large-eddy simulation (LES) within a weather research and forecasting (WRF) model coupled with an active scalar transport equation was used to simulate Atmospheric Boundary Layer conditions during the Mosquito fire, the largest wildland fire in California during September 2022. The simulations were conducted with realistic boundary conditions derived from the National Oceanic and Atmospheric Administration (NOAA) High Resolution Rapid Refresh (HRRR) model, with the aim of better understanding the two-way coupling between the ABL and plume dynamics. The terrain was extremely inhomogeneous, and the topography varied significantly within the numerical domain. Initially, LES of the smoke-free ABL was conducted on nested domains, and detailed ABL data were gathered from 8 to 9 September 2022. LES simulations were validated using four Automated Surface Observing System (ASOS) stations and NOAA meteorological (MET) observations, as well as NOAA met Twin Otter measurements, and the desired accuracy was established. The smoke plume was then released into the ABL at noon on 9 September 2022, and the plume simulations were conducted for a period of one hour following the release. During this period, the ABL transitioned from convective to buoyancy-shear-driven regimes. Late-night and early-morning conditions are influenced by the complex topography and low-level jet, whereas buoyancy and shear control the ABL dynamics during the morning and afternoon hours. The plume vertical transport is influenced by the ABL depth and the size of the vertical turbulence structures during that time, whereas the wind conditions and turbulent kinetic energy within the ABL dictate the horizontal transport scales of the plume. In addition, the results demonstrate that the plume modifies the microclimate along its path.

Macroautophagy (commonly referred to as autophagy) is an evolutionarily conserved catabolic process that degrades cytosolic components by sequestering them into double- membrane autophagic vesicles (AVs), which are subsequently broken down by lysosomes. The physiological and medical significance of autophagy is widely acknowledged, but we still lack important knowledge on the mechanism governing autophagy in response tissue specific needs. In this talk, I will discuss emerging pathways that regulate cargo selection in autophagy in response to various metabolic, developmental, and disease-related stimuli. Special attention will be given to new mechanisms controlling the degradation of the endoplasmic reticulum and ribosomes through autophagy. These findings challenge the long-standing view that starvation-induced autophagy is a bulk, non-selective process.

Mitochondria are organelles not only involved in cellular respiration but also in several other pathways important for cell life and death. They are not isolated within the cells but are closely interconnected with other organelles, among which the Endoplasmic Reticulum (ER). Defective ER-mitochondria crosstalk and ER stress impacts on several cellular functions as well as on important intracellular pathways that promote the cancer development. Modulation of ER-mitochondria contacts have a role in cancer development and resistance to pharmacological therapy by impacting on cellular bioenergetics and metabolism. More recently, we showed that a reduction of mitochondria-ER contacts sites, by downregulation of tethers, can tune cancer cells intracellular signaling (e.g. Wnt signaling) both in vitro and in vivo, ultimately impacting on cancer cells proliferation. In addition, we have demonstrated that organelle contacts are mutually regulated in response to metabolism rewiring and to various diet and nutrients availability so affecting cancer formation/progression and cancer cells sensitivity to drugs. These findings reveal that affecting mitochondria-ER tethering may be beneficial against cancer by altering the cellular signaling, and in turn sensitizing tumor cells to chemotherapeutic treatment.

Neuronal cell cycle re-entry is a pathological hallmark of Huntington’s disease (HD) and other neurodegenerative disorders. Calcium-responsive transactivator(CREST) has been found to play a critical role in dendritic development through calcium-dependent transcriptional regulation and to form a functional complex with p300 and p53 to suppress retinoblastoma protein (Rb) phosphorylation and cyclin expression, thereby arresting the cell cycle and promoting neuronal differentiation. Here we demonstrated that mutant huntingtin (mHtt) significantly reduced full-length CREST levels while inducing the production of truncated CREST fragments. This process was blocked by inhibitors of calpain-1 and -2, suggesting calpain involvement. Using mass spectrometry, co-IP, and in vitro pull-down assays, we provided direct evidence that mHtt enhanced the interaction between calpain-2 and CREST, leading to increased CREST cleavage which generated a toxic C-terminal fragment that accumulated abnormally in the nucleus. Furthermore, we designed a TAT peptide targeting the calpain-2 cleavage site of CREST, which effectively prevented CREST degradation and significantly ameliorated mHtt-induced pathological phenotypes in N2a cells, including neuronal death, neurite retraction, and aberrant Rb phosphorylation. Collectively, our findings establish CREST as a specific substrate of calpain-2 and reveal a novel mechanism by which mHtt promotes neuronal cell cycle re-entry and neurotoxicity through calpain-2-mediated CREST degradation. The toxic C-terminal fragment of CREST exhibits distinct pathological properties. Importantly, our study identifies the calpain cleavage site on CREST as a potential therapeutic target for HD intervention. Targeting this site with specific inhibitors or peptide blockers may represent a promising strategy to prevent mHtt-induced neuronal dysfunction and cell death.

HaCaT cells are spontaneously transformed keratinocytes from human epidermis that are useful for studying epithelial homeostasis and related diseases due to their proliferative and differentiating abilities. We analyzed interactions between these cells and pro-inflammatory psoriatic cytokines (TNF-alpha and IL-17A), focusing on cell proliferation and differentiation in term of intercellular junctions, and the cytoskeleton. Additionally, we examined how psoriatic cytokines contribute to susceptibility to ferroptosis, a novel cell death mechanism recently recognised in psoriatic plaques. HaCaT cells were induced to differentiate using 1.8 mM CaCl2. After four days, cells were exposed to a combination (MIX) of interleukins (IL-17A, IL-22, IL-23, and TNF-alpha) for 24 (T24) and 48 (T48) h. Proliferation was assessed through BrdU incorporation assay; ultrastructural morphology was also analyzed. Claudin 1 (CLDN-1), Zonula Occludens 1 (ZO-1), keratin (K) 10, and K14 were evaluated using immunofluorescence and western blot. We also induced ferroptosis for 24 and 48 h with 20uM erastin to evaluate cell susceptibility to MIX by analyzing the concentration of GSH (glutathione, an important antioxidant) and the ratio of GSH/GSSG (reduced glutathione/oxidized glutathione), examining membrane integrity, ATP concentration and cell availability. The biological effect induced by MIX on cell differentiation was evident after 48 h of incubation on all the considered markers. Cell proliferation progressively increased with time, but in T48 MIX-incubated samples, the proliferative activity was reduced (p<0.01). The presence of both MIX and erastin after 48 h affected mitochondrial ultrastructure, suggesting an early involvement of psoriatic cytokines also in ferroptosis mechanisms. Our experimental conditions mimic the early (de)differentiation features of psoriatic keratinocytes, indicating this model can elucidate early cellular and molecular processes during the early pathogenetic phases of psoriatic plaque organization.

. A Generation of Excellencetells the story of one of the country?s most remarkable institutions.