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

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

Collaboration and knowledge exchange between scholars in Britain and the empire, 1830–1914

In recent years there has been a growing interest among historians in the British Empire as a space of knowledge production and circulation. Much of this work assumes that scholarly cooperation and collaboration between individuals and institutions within the Empire had the effect (and often also the aim) of strengthening both imperial ties and the idea of empire. This chapter argues, however, that many examples of scholarly travel, exchange, and collaboration were undertaken with very different goals in mind. In particular, it highlights the continuing importance of an ideal of scientific internationalism, which stressed the benefits of scholarship for the whole of humanity and prioritized the needs and goals of individual academic and scientific disciplines. As the chapter shows, some scholars even went on to develop nuanced critiques of the imperial project while using the very structures of empire to further their own individual, disciplinary and institutional goals

Who Sets the Agenda? Analyzing Key Actors and Dynamics of Economic Diversification in Kazakhstan Throughout 2011–2016

This contribution attempts to answer the key question: Who sets the agenda for economic diversification in the context of Kazakhstan? This question remains critical in current scholarly debates. Although Kazakhstan, a young post-Soviet developing nation, has received fair scholarly attention with regard to the agenda setting stage of the policy cycle, the existing literature has yet failed to (1) empirically establish who actually sets the agenda for a certain policy issue and (2) employ the Internet research methods. This paper seeks to fill these gaps. The literature review of Kazakh-specific agenda setting publications suggests that among the major actors, the government tends to exert predominant influence, though other actors may also play a role, for example, media and academia. This research is driven by Internet penetration rate data and focuses on the period from January 2011 until December 2016. The findings lead to two key conclusions. First, think tanks seem to set the government agenda for economic diversification policy in Kazakhstan. Second, the government, while exhibiting the larger agenda setting magnitude vis-à-vis the other actors, shapes the subsequent debates as measured by the number of relevant references in media, think tanks, and academic publications. This research seeks to contribute to existing agenda setting theories in the Internet era by defining the most important actor(s), specifically in the Kazakh context based on longitudinal dynamics in attention

Comparative Performance of Private and Public Healthcare Systems in Low- and Middle-Income Countries: A Systematic Review

A systematic review conducted by Sanjay Basu and colleagues reevaluates the evidence relating to comparative performance of public versus private sector healthcare delivery in low- and middle-income countries

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

Two Genetic Determinants Acquired Late in Mus Evolution Regulate the Inclusion of Exon 5, which Alters Mouse APOBEC3 Translation Efficiency

Mouse apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like editing complex 3 (mA3), an intracellular antiviral factor, has 2 allelic variations that are linked with different susceptibilities to beta- and gammaretrovirus infections among various mouse strains. In virus-resistant C57BL/6 (B6) mice, mA3 transcripts are more abundant than those in susceptible BALB/c mice both in the spleen and bone marrow. These strains of mice also express mA3 transcripts with different splicing patterns: B6 mice preferentially express exon 5-deficient (Δ5) mA3 mRNA, while BALB/c mice produce exon 5-containing full-length mA3 mRNA as the major transcript. Although the protein product of the Δ5 mRNA exerts stronger antiretroviral activities than the full-length protein, how exon 5 affects mA3 antiviral activity, as well as the genetic mechanisms regulating exon 5 inclusion into the mA3 transcripts, remains largely uncharacterized. Here we show that mA3 exon 5 is indeed a functional element that influences protein synthesis at a post-transcriptional level. We further employed in vitro splicing assays using genomic DNA clones to identify two critical polymorphisms affecting the inclusion of exon 5 into mA3 transcripts: the number of TCCT repeats upstream of exon 5 and the single nucleotide polymorphism within exon 5 located 12 bases upstream of the exon 5/intron 5 boundary. Distribution of the above polymorphisms among different Mus species indicates that the inclusion of exon 5 into mA3 mRNA is a relatively recent event in the evolution of mice. The widespread geographic distribution of this exon 5-including genetic variant suggests that in some Mus populations the cost of maintaining an effective but mutagenic enzyme may outweigh its antiviral function

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