A Question of Triumph: Effectively Measuring the Success of Intelligence against Terrorism

As intelligence programs continue to be expanded in order to combat the growing threat of terrorism seen around the globe, many critics have questioned whether the success of intelligence against terrorism can be effectively measured. Through the implementation of the United States PATRIOT Act and the mass data collection programs which it created, intelligence programs have gained access to the private interactions and intentions of government officials, civilians, and businesses, foreign and domestic, while terror acts continue to occur on a, seemingly, daily basis. This article seeks to show how the success of intelligence against terrorism can, in fact, be effectively measured when examined in regard to the various aspects of terrorism it seeks to prevent; while acknowledging the continued existence of terrorist groups as a whole. It becomes clear, through the examination of the post-9/11 terror plots, attacks, and bolstered counterstrategies against them, that success of intelligence against terrorism can be effectively measured and is clearly evident

The Role of the 5-hydroxytrptamine 1F Receptor in Mitochondrial Biogenesis and Acute Kidney Injury

Mitochondrial dysfunction exacerbates cellular injury, impairs energy-dependent repair, and leads to kidney damage and failure following acute kidney injury (AKI). Mitochondrial dysfunction and impaired mitochondrial biogenesis correlate with decreased in peroxisome proliferator-activated receptor coactivator 1-α (PGC-1α), the reported master regulator of mitochondrial biogenesis, and its downstream targets following I/R-induced AKI. Furthermore, recovery of renal function and tubular injury is accelerated following pharmacological induction of mitochondrial biogenesis following I/R-induced AKI. These results suggest that recovery of mitochondrial number and function may be an effective therapeutic strategy in restoring renal function following AKI. We recently made the novel observation that agonists of 5-HT1F receptor induce mitochondrial biogenesis in vitro and in vivo. Specifically, following I/R-induced AKI, the 5-HT1F receptor selective agonist LY344864 enhanced the recovery of mitochondrial DNA (mtDNA) copy number and renal function, as indicated by decreased blood urea nitrogen (BUN). These findings demonstrate that 5-HT1F receptor stimulation promotes recovery from AKI and activates mitochondrial biogenesis pathways. The goal of the first aim was to determine the signaling pathways involved in mediating renal proximal tubule 5-HT1F receptor-induced mitochondrial biogenesis. Using pharmacological approaches, we identified Gβγ heterodimer-dependent activation of Akt/eNOS/cGMP/PKG/PGC-1α and inhibition of c-raf/ERK/FOXO3a pathways as the mechanism responsible for 5-HT1F receptor-induced mitochondrial biogenesis. We also identified Akt as the link between these stimulatory and inhibitory pathways, and that the stimulatory pathway is required for mitochondrial biogenesis. Elucidation of this pathway may facilitate the development of novel therapeutic approaches to enhance mitochondrial biogenesis for the treatment of diseases characterized by mitochondrial dysfunction. We then examined the role of the 5-HT1F receptor in renal mitochondrial homeostasis and biogenesis under physiological conditions. To complete this aim, we utilized young (10 weeks) and aged (26 weeks) 5-HT1F receptor knockout (KO) mice. In young 5-HT1F receptor KO mice, we observed increased expression of mtDNA copy number as well as of genes involved in renal mitochondrial biogenesis, oxidative phosphorylation, fission and autophagy compared to wild-type (WT) controls. Aged 5-HT1F receptor KO mice also exhibit increases in renal PGC-1α mRNA expression and mtDNA copy number. Interestingly, we detected a tissue-specific difference in renal cortical mitochondrial homeostasis compared to that of the heart. Specifically, cardiac left ventricular mitochondrial homeostasis markers were initially decreased in the absence of the 5-HT1F receptor KO mice compared to WT mice. However, as the mice aged, these markers returned to WT control levels and this rescue was associated with increased PGC-1α mRNA expression. To determine the potential mechanism responsible for tissue-specific differences in mitochondrial homeostasis markers and the compensatory effect displayed in the renal cortex of the 5-HT1F receptor KO mice, we assessed the gene expression of other 5-HT1 and 5-HT2 receptors. Interestingly, in the heart and kidney of 5-HT1F receptor KO mice, there is a tissue-dependent difference in the gene expression of 5-HT2A and 5-HT2B receptors, both of which have been linked to mitochondria. Further work may lead to the identification of compensatory mechanisms that are activated in the absence of the 5-HT1F receptor. Our final study tested the role of the 5-HT1F receptor in renal mitochondrial biogenesis in AKI and in the recovery of mitochondrial and renal function following I/R-induced AKI. The absence of the 5-HT1F receptor increased tubular injury as measured by KIM-1 and neutrophil gelatinase-associated lipocalin (NGAL) at 24 hr following I/R-induced AKI. Additionally, the 5-HT1F receptor KO mice exhibited reduced renal recovery at 144 hr following I/R-induced AKI as measured by serum creatinine and BUN levels. Impaired renal function and tubular injury recovery was also associated with a persistent suppression in mitochondrial biogenesis as evidenced by reduced PGC-1α and respiratory chain protein expression at 144 hr following renal I/R injury. Injured 5-HT1Freceptor KO mice also displayed sustained depletion in ATP generation and elevated oxidative protein damage at 144 hr. In summary, this study reveals that the 5-HT1F receptor 1) regulates mitochondrial biogenesis and homeostasis under physiological conditions in a tissue-dependent manner, 2) is renal protective in the setting of I/R-induced AKI and 3) promotes the recovery of mitochondrial homeostasis and renal function following I/R injury

The effects of changing climate on faunal depth distributions determine winners and losers

Changing climate is predicted to impact all depths of the global oceans, yet projections of range shifts in marine faunal distributions in response to changing climate seldom evaluate potential shifts in depth distribution. Marine ectotherms’ thermal tolerance is limited by their ability to maintain aerobic metabolism (oxygen- and capacity-limited tolerance), and is functionally associated with their hypoxia tolerance. Shallow-water (<200 m depth) marine invertebrates and fishes demonstrate limited tolerance of increasing hydrostatic pressure (pressure exerted by the overlying mass of water), and hyperbaric (increased pressure) tolerance is proposed to depend on the ability to maintain aerobic metabolism, too. Here, we report significant correlation between the hypoxia thresholds and the hyperbaric thresholds of taxonomic groups of shallow-water fauna, suggesting that pressure tolerance is indeed oxygen-limited. Consequently, it appears that the combined effects of temperature, pressure, and oxygen concentration constrain the fundamental ecological niches (FENs) of marine invertebrates and fishes. Including depth in a conceptual model of oxygen- and capacity-limited FENs’ responses to ocean warming and deoxygenation confirms previous predictions made based solely on consideration of the latitudinal effects of ocean warming (e.g. Cheung et al., 2009), that polar taxa are most vulnerable to the effects of climate change, with Arctic fauna experiencing the greatest FEN contraction. In contrast, the inclusion of depth in the conceptual model reveals for the first time that temperate fauna as well as tropical fauna may experience substantial FEN expansion with ocean warming and deoxygenation, rather than FEN maintenance or contraction suggested by solely considering latitudinal range shifts

Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation

The mechanisms by which mutant huntingtin (mHTT) leads to neuronal cell death in Huntington’s disease (HD) are not fully understood. To gain new molecular insights, we used single nuclear RNA sequencing (snRNA-seq) and translating ribosome affinity purification (TRAP) to conduct transcriptomic analyses of caudate/putamen (striatal) cell type-specific gene expression changes in human HD and mouse models of HD. In striatal spiny projection neurons, the most vulnerable cell type in HD, we observe a release of mitochondrial RNA (mtRNA) (a potent mitochondrial-derived innate immunogen) and a concomitant upregulation of innate immune signaling in spiny projection neurons. Further, we observe that the released mtRNAs can directly bind to the innate immune sensor protein kinase R (PKR). We highlight the importance of studying cell type-specific gene expression dysregulation in HD pathogenesis and reveal that the activation of innate immune signaling in the most vulnerable HD neurons provides a novel framework to understand the basis of mHTT toxicity and raises new therapeutic opportunities

Perturbations in the carbon budget of the tropics

The carbon budget of the tropics has been perturbed as a result of human influences. Here, we attempt to construct a ‘bottom-up’ analysis of the biological components of the budget as they are affected by human activities. There are major uncertainties in the extent and carbon content of different vegetation types, the rates of land-use change and forest degradation, but recent developments in satellite remote sensing have gone far towards reducing these uncertainties. Stocks of carbon as biomass in tropical forests and woodlands add up to 271 ± 16 Pg with an even greater quantity of carbon as soil organic matter. Carbon loss from deforestation, degradation, harvesting and peat fires is estimated as 2.01 ± 1.1 Pg annum(−1); while carbon gain from forest and woodland growth is 1.85 ± 0.09 Pg annum(−1). We conclude that tropical lands are on average a small carbon source to the atmosphere, a result that is consistent with the ‘top-down’ result from measurements in the atmosphere. If they were to be conserved, they would be a substantial carbon sink. Release of carbon as carbon dioxide from fossil fuel burning in the tropics is 0.74 Pg annum(−1) or 0.57 MgC person(−1) annum(−1), much lower than the corresponding figures from developed regions of the world

Macaque models of human infectious disease.

Macaques have served as models for more than 70 human infectious diseases of diverse etiologies, including a multitude of agents-bacteria, viruses, fungi, parasites, prions. The remarkable diversity of human infectious diseases that have been modeled in the macaque includes global, childhood, and tropical diseases as well as newly emergent, sexually transmitted, oncogenic, degenerative neurologic, potential bioterrorism, and miscellaneous other diseases. Historically, macaques played a major role in establishing the etiology of yellow fever, polio, and prion diseases. With rare exceptions (Chagas disease, bartonellosis), all of the infectious diseases in this review are of Old World origin. Perhaps most surprising is the large number of tropical (16), newly emergent (7), and bioterrorism diseases (9) that have been modeled in macaques. Many of these human diseases (e.g., AIDS, hepatitis E, bartonellosis) are a consequence of zoonotic infection. However, infectious agents of certain diseases, including measles and tuberculosis, can sometimes go both ways, and thus several human pathogens are threats to nonhuman primates including macaques. Through experimental studies in macaques, researchers have gained insight into pathogenic mechanisms and novel treatment and vaccine approaches for many human infectious diseases, most notably acquired immunodeficiency syndrome (AIDS), which is caused by infection with human immunodeficiency virus (HIV). Other infectious agents for which macaques have been a uniquely valuable resource for biomedical research, and particularly vaccinology, include influenza virus, paramyxoviruses, flaviviruses, arenaviruses, hepatitis E virus, papillomavirus, smallpox virus, Mycobacteria, Bacillus anthracis, Helicobacter pylori, Yersinia pestis, and Plasmodium species. This review summarizes the extensive past and present research on macaque models of human infectious disease

Quantifying garnet-melt trace element partitioning using lattice-strain theory: New crystal-chemical and thermodynamic constraints

Many geochemical models of major igneous differentiation events on the Earth, the Moon, and Mars invoke the presence of garnet or its high-pressure majoritic equivalent as a residual phase, based on its ability to fractionate critical trace element pairs (Lu/Hf, U/Th, heavy REE/light REE). As a result, quantitative descriptions of mid-ocean ridge and hot spot magmatism, and lunar, martian, and terrestrial magma oceans require knowledge of garnet-melt partition coefficients over a wide range of conditions. In this contribution, we present new crystal-chemical and thermodynamic constraints on the partitioning of rare earth elements (REE), Y and Sc between garnet and anhydrous silicate melt as a function of pressure (P), temperature (T), and composition (X). Our approach is based on the interpretation of experimentally determined values of partition coefficients D using lattice-strain theory. In this and a companion paper (Draper and van Westrenen this issue) we derive new predictive equations for the ideal ionic radius of the dodecahedral garnet X-site,

Group B Streptococcus vaccine development: present status and future considerations, with emphasis on perspectives for low and middle income countries.

Globally, group B Streptococcus (GBS) remains the leading cause of sepsis and meningitis in young infants, with its greatest burden in the first 90 days of life. Intrapartum antibiotic prophylaxis (IAP) for women at risk of transmitting GBS to their newborns has been effective in reducing, but not eliminating, the young infant GBS disease burden in many high income countries. However, identification of women at risk and administration of IAP is very difficult in many low and middle income country (LMIC) settings, and is not possible for home deliveries. Immunization of pregnant women with a GBS vaccine represents an alternate pathway to protecting newborns from GBS disease, through the transplacental antibody transfer to the fetus in utero. This approach to prevent GBS disease in young infants is currently under development, and is approaching late stage clinical evaluation. This manuscript includes a review of the natural history of the disease, global disease burden estimates, diagnosis and existing control options in different settings, the biological rationale for a vaccine including previous supportive studies, analysis of current candidates in development, possible correlates of protection and current status of immunogenicity assays. Future potential vaccine development pathways to licensure and use in LMICs, trial design and implementation options are discussed, with the objective to provide a basis for reflection, rather than recommendations

Seismic anisotropy of the Archean crust in the Minnesota River Valley, Superior Province

The Minnesota River Valley (MRV) subprovince is a well-exposed example of late Archean lithosphere. Its high-grade gneisses display a subhorizontal layering, most likely extending down to the crust-mantle boundary. The strong linear fabric of the gneisses results from high-temperature plastic flow during collage-related contraction. Seismic anisotropies measured up to 1 GPa in the laboratory, and seismic anisotropies calculated through forward-modeling indicate ΔVP ~5-6% and ΔVS ~3%. The MRV crust exhibits a strong macroscopic layering and foliation, and relatively strong seismic anisotropies at the hand specimen scale. Yet the horizontal attitude of these structures precludes any substantial contribution of the MRV crust to shear wave splitting for vertically propagating shear waves such as SKS. The origin of the regionally low seismic anisotropy must lie in the upper mantle. A horizontally layered mantle underneath the United States interior could provide an explanation for the observed low SWS. Key Points The Archean crust of the Minnesota River Valley is strongly anisotropic The horizontally layered crust of the MRV cannot split vertical shear waves The cause of low SWS in the MRV must be in the uppermost mantle ©2014. American Geophysical Union. All Rights Reserved

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead