Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice

C57BL/6 mice genetically deficient in interleukin 15 (IL-15(-/-) mice) were generated by gene targeting. IL-15(-/-) mice displayed marked reductions in numbers of thymic and peripheral natural killer (NK) T cells, memory phenotype CD8+ T cells, and distinct subpopulations of intestinal intraepithelial lymphocytes (IELs). The reduction but not absence of these populations in IL-15(-/-) mice likely reflects an important role for IL-15 for expansion and/or survival of these cells. IL-15(-/-) mice lacked NK cells, as assessed by both immunophenotyping and functional criteria, indicating an obligate role for IL-15 in the development and functional maturation of NK cells. Specific defects associated with IL-15 deficiency were reversed by in vivo administration of exogenous IL-15. Despite their immunological defects, IL-15(-/-) mice remained healthy when maintained under specific pathogen-free conditions. However, IL-l5(-/-) mice are likely to have compromised host defense responses to various pathogens, as they were unable to mount a protective response to challenge with vaccinia virus. These data reveal critical roles for IL-15 in the development of specific lymphoid lineages. Moreover, the ability to rescue lymphoid defects in IL-15(-/-) mice by IL-15 administration represents a powerful means by which to further elucidate the biological roles of this cytokine

Inhibition of Dihydrotestosterone Synthesis in Prostate Cancer by Combined Frontdoor and Backdoor Pathway Blockade

Androgen deprivation therapy (ADT) is palliative and prostate cancer (CaP) recurs as lethal castration-recurrent/resistant CaP (CRPC). One mechanism that provides CaP resistance to ADT is primary backdoor androgen metabolism, which uses up to four 3α-oxidoreductases to convert 5α-androstane-3α,17β-diol (DIOL) to dihydrotestosterone (DHT). The goal was to determine whether inhibition of 3α-oxidoreductase activity decreased conversion of DIOL to DHT. Protein sequence analysis showed that the four 3α-oxidoreductases have identical catalytic amino acid residues. Mass spectrometry data showed combined treatment using catalytically inactive 3α-oxidoreductase mutants and the 5α-reductase inhibitor, dutasteride, decreased DHT levels in CaP cells better than dutasteride alone. Combined blockade of frontdoor and backdoor pathways of DHT synthesis provides a therapeutic strategy to inhibit CRPC development and growth

Fungal Origins of the Bicyclo[2.2.2]diazaoctane Ring System of Prenylated Indole Alkaloids

Over eight different families of natural products, consisting of nearly seventy secondary metabolites, which contain the bicyclo[2.2.2]diazaoctane ring system, have been isolated from various Aspergillus, Penicillium, and Malbranchea species. Since 1968, these secondary metabolites have been the focus of numerous biogenetic, synthetic, taxonomic, and biological studies, and, as such, have made a lasting impact across multiple scientific disciplines. This review covers the isolation, biosynthesis, and biological activity of these unique secondary metabolites containing the bridging bicyclo[2.2.2]diazaoctane ring system. Furthermore, the diverse fungal origin of these natural products is closely examined and, in many cases, updated to reflect the currently accepted fungal taxonomy

Sonic boom and drag evaluation of supersonic jet concepts

This paper evaluates three different class supersonic airliners (Concorde, Cranfield E-5, and NASA QueSST X-plane) in a multidisciplinary design analysis optimization (MDAO) environment in terms of their sonic boom intensities and aerodynamic performance. The aerodynamic analysis and sonic boom prediction methods are key to this research. The panel method PANAIR is integrated to perform automated aerodynamic analysis. The drag coefficient is corrected by the Harris wave drag formula and form factor method. For sonic boom prediction, the near-field pressure is predicted through the Whitham F-function method. The F-function is decomposed to the F-function due to volume and the F-function due to lift to see their individual effect on sonic boom. The near-field signature propagates in a stratified windy atmosphere using the waveform parameter method. The aerodynamic results are compared with experimental data and the sonic boom prediction results are validated by the NASA PCBoom program. Through the evaluation, we find a direct link between the wave drag and the first derivative of the volume distribution. The sonic boom intensity is influenced by the lift distribution and the volume change rate. The study helps to study the feasibility of low-boom and low-drag supersonic airliners

How Biology Became Social and What It Means for Social Theory

In this paper I first offer a systematic outline of a series of conceptual novelties in the life-sciences that have favoured, over the last three decades, the emergence of a more social view of biology. I focus in particular on three areas of investigation: (1) technical changes in evolutionary literature that have provoked a rethinking of the possibility of altruism, morality and prosocial behaviours in evolution; (2) changes in neuroscience, from an understanding of the brain as an isolated data processor to the ultrasocial and multiply connected social brain of contemporary neuroscience; and (3) changes in molecular biology, from the view of the gene as an autonomous master of development to the ‘reactive genome’ of the new emerging field of molecular epigenetics. In the second section I reflect on the possible implications for the social sciences of this novel biosocial terrain and argue that the postgenomic language of extended epigenetic inheritance and blurring of the nature/nurture boundaries will be as provocative for neo-Darwinism as it is for the social sciences as we have known them. Signs of a new biosocial language are emerging in several social-science disciplines and this may represent an exciting theoretical novelty for twenty-first social theory

Ideological cultures and media discourses on scientific knowledge: re-reading news on climate change

Focusing on the representation of climate change in the British “quality press,” this article argues that the discursive (re)construction of scientific claims in the media is strongly entangled with ideological standpoints. Understood here as a set of ideas and values that legitimate a program of action vis-à-vis a given social and political order, ideology works as a powerful selection device in deciding what is scientific news, i.e. what the relevant “facts” are, and who are the authorized “agents of definition” of science matters. The representation of scientific knowledge has important implications for evaluating political programs and assessing the responsibility of both governments and the public in addressing climate change

Understanding and Integrating Local Perceptions of Trees and Forests into Incentives for Sustainable Landscape Management

We examine five forested landscapes in Africa (Cameroon, Madagascar, and Tanzania) and Asia (Indonesia and Laos) at different stages of landscape change. In all five areas, forest cover (outside of protected areas) continues to decrease despite local people’s recognition of the importance of forest products and services. After forest conversion, agroforestry systems and fallows provide multiple functions and valued products, and retain significant biodiversity. But there are indications that such land use is transitory, with gradual simplification and loss of complex agroforests and fallows as land use becomes increasingly individualistic and profit driven. In Indonesia and Tanzania, farmers favor monocultures (rubber and oil palm, and sugarcane, respectively) for their high financial returns, with these systems replacing existing complex agroforests. In the study sites in Madagascar and Laos, investments in agroforests and new crops remain rare, despite government attempts to eradicate swidden systems and their multifunctional fallows. We discuss approaches to assessing local values related to landscape cover and associated goods and services. We highlight discrepancies between individual and collective responses in characterizing land use tendencies, and discuss the effects of accessibility on land management. We conclude that a combination of social, economic, and spatially explicit assessment methods is necessary to inform land use planning. Furthermore, any efforts to modify current trends will require clear incentives, such as through carbon finance. We speculate on the nature of such incentive schemes and the possibility of rewarding the provision of ecosystem services at a landscape scale and in a socially equitable manner

Alopecia in a Viable Phospholipase C Delta 1 and Phospholipase C Delta 3 Double Mutant

BACKGROUND: Inositol 1,4,5trisphosphate (IP(3)) and diacylglycerol (DAG) are important intracellular signalling molecules in various tissues. They are generated by the phospholipase C family of enzymes, of which phospholipase C delta (PLCD) forms one class. Studies with functional inactivation of Plcd isozyme encoding genes in mice have revealed that loss of both Plcd1 and Plcd3 causes early embryonic death. Inactivation of Plcd1 alone causes loss of hair (alopecia), whereas inactivation of Plcd3 alone has no apparent phenotypic effect. To investigate a possible synergy of Plcd1 and Plcd3 in postnatal mice, novel mutations of these genes compatible with life after birth need to be found. METHODOLOGY/PRINCIPAL FINDINGS: We characterise a novel mouse mutant with a spontaneously arisen mutation in Plcd3 (Plcd3(mNab)) that resulted from the insertion of an intracisternal A particle (IAP) into intron 2 of the Plcd3 gene. This mutation leads to the predominant expression of a truncated PLCD3 protein lacking the N-terminal PH domain. C3H mice that carry one or two mutant Plcd3(mNab) alleles are phenotypically normal. However, the presence of one Plcd3(mNab) allele exacerbates the alopecia caused by the loss of functional Plcd1 in Del(9)olt1Pas mutant mice with respect to the number of hair follicles affected and the body region involved. Mice double homozygous for both the Del(9)olt1Pas and the Plcd3(mNab) mutations survive for several weeks and exhibit total alopecia associated with fragile hair shafts showing altered expression of some structural genes and shortened phases of proliferation in hair follicle matrix cells. CONCLUSIONS/SIGNIFICANCE: The Plcd3(mNab) mutation is a novel hypomorphic mutation of Plcd3. Our investigations suggest that Plcd1 and Plcd3 have synergistic effects on the murine hair follicle in specific regions of the body surface