InThe New Masters of Capital, Timothy J. Sinclair examines a key aspect of the global economy-the rating agencies. In the global economy, trust is formalized in the daily operations of such firms as ...Moody's and Standard & Poor's, which continuously monitor the financial health of bond-issuers ranging from private corporations to local and national governments. Their judgments affect unimaginably large sums, approximately $30 trillion in outstanding debt issues, according to a recent Moody's estimate. The difference between an AA and a BB rating may cost millions of dollars in interest payments or determine if a corporation or government can even issue bonds.
Without bond rating agencies, there would be no standard means to compare risks in the global economy, and international investment would be problematic. Most observers assume that the agencies are neutral and scientific, and that they interpret their role in narrowly economic terms. But these agencies, by their nature, wield extraordinary power and exert massive influence over public policy. Sinclair offers a highly accessible account of these institutions, their origins, and the rating processes they use to judge creditworthiness. Illustrated with a wide range of cases, this book offers a fresh assessment of the role of an often-overlooked institution in the dynamics of modern global capitalism.
Migraine is a disabling primary headache disorder that directly affects more than one billion people worldwide. Despite its widespread prevalence, migraine remains under-diagnosed and under-treated. ...To support clinical decision-making, we convened a European panel of experts to develop a ten-step approach to the diagnosis and management of migraine. Each step was established by expert consensus and supported by a review of current literature, and the Consensus Statement is endorsed by the European Headache Federation and the European Academy of Neurology. In this Consensus Statement, we introduce typical clinical features, diagnostic criteria and differential diagnoses of migraine. We then emphasize the value of patient centricity and patient education to ensure treatment adherence and satisfaction with care provision. Further, we outline best practices for acute and preventive treatment of migraine in various patient populations, including adults, children and adolescents, pregnant and breastfeeding women, and older people. In addition, we provide recommendations for evaluating treatment response and managing treatment failure. Lastly, we discuss the management of complications and comorbidities as well as the importance of planning long-term follow-up.
To the Brink of Destruction
exposes how America's rating agencies helped generate the
global financial crisis of 2007 and beyond, surviving and thriving
in the aftermath. Despite widespread scrutiny, ...rating agencies
continued to operate on the same business model and wield
extraordinary power, exerting extensive influence over public
policy.
Timothy J. Sinclair brings the shadowy corners of this story to
life by examining congressional testimony, showing how the wheels
of accountability turned-and ultimately failed-during the crisis.
He asks how and why the agencies risked their lucrative franchise
by aligning so closely with a process of financial innovation that
came undone during the crisis. What he finds is that key
institutions, including the agencies, changed from being judges to
being advocates years before the crisis, eliminating a vital safety
valve meant to hinder financial excess.
Sinclair's well-researched investigation offers a clear,
accessible explanation of structured finance and how it works.
To the Brink of Destruction avoids tired accusations,
instead providing novel insight into the role rating agencies
played in the worst crisis of modern global capitalism.
Estrogens play a key role in sexual differentiation of both the gonads and external traits in birds. The production of estrogen occurs via a well-characterised steroidogenic pathway, which is a ...multi-step process involving several enzymes, including cytochrome P450 aromatase. In chicken embryos, the aromatase gene (CYP19A1) is expressed female-specifically from the time of gonadal sex differentiation. To further explore the role of aromatase in sex determination, we ectopically delivered this enzyme using the retroviral vector RCASBP in ovo. Aromatase overexpression in male chicken embryos induced gonadal sex-reversal characterised by an enlargement of the left gonad and development of ovarian structures such as a thickened outer cortex and medulla with lacunae. In addition, the expression of key male gonad developmental genes (DMRT1, SOX9 and Anti-Müllerian hormone (AMH)) was suppressed, and the distribution of germ cells in sex-reversed males followed the female pattern. The detection of SCP3 protein in late stage sex-reversed male embryonic gonads indicated that these genetically male germ cells had entered meiosis, a process that normally only occurs in female embryonic germ cells. This work shows for the first time that the addition of aromatase into a developing male embryo is sufficient to direct ovarian development, suggesting that male gonads have the complete capacity to develop as ovaries if provided with aromatase.
Sex in birds is chromosomally based, as in mammals, but the sex chromosomes are different and the mechanism of avian sex determination has been a long-standing mystery. In the chicken and all other ...birds, the homogametic sex is male (ZZ) and the heterogametic sex is female (ZW). Two hypotheses have been proposed for the mechanism of avian sex determination. The W (female) chromosome may carry a dominant-acting ovary determinant. Alternatively, the dosage of a Z-linked gene may mediate sex determination, two doses being required for male development (ZZ). A strong candidate avian sex-determinant under the dosage hypothesis is the conserved Z-linked gene, DMRT1 (doublesex and mab-3-related transcription factor 1). Here we used RNA interference (RNAi) to knock down DMRT1 in early chicken embryos. Reduction of DMRT1 protein expression in ovo leads to feminization of the embryonic gonads in genetically male (ZZ) embryos. Affected males show partial sex reversal, characterized by feminization of the gonads. The feminized left gonad shows female-like histology, disorganized testis cords and a decline in the testicular marker, SOX9. The ovarian marker, aromatase, is ectopically activated. The feminized right gonad shows a more variable loss of DMRT1 and ectopic aromatase activation, suggesting differential sensitivity to DMRT1 between left and right gonads. Germ cells also show a female pattern of distribution in the feminized male gonads. These results indicate that DMRT1 is required for testis determination in the chicken. Our data support the Z dosage hypothesis for avian sex determination.
The nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) is a proposed therapy for age‐related disease, whereby it is assumed that NMN is incorporated into NAD+ ...through the canonical recycling pathway. During oral delivery, NMN is exposed to the gut microbiome, which could modify the NAD+ metabolome through enzyme activities not present in the mammalian host. We show that orally delivered NMN can undergo deamidation and incorporation in mammalian tissue via the de novo pathway, which is reduced in animals treated with antibiotics to ablate the gut microbiome. Antibiotics increased the availability of NAD+ metabolites, suggesting the microbiome could be in competition with the host for dietary NAD+ precursors. These findings highlight new interactions between NMN and the gut microbiome.
Exogenous treatment with the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) is presumed to elevate NAD+ levels through its direct incorporation via the canonical NAD+ recycling pathway. Here, metabolic tracing of strategically designed NMN isotopologues in vivo reveals that the gut microbiome mediates NMN deamidation and uptake into the NAD+ metabolome via the de novo pathway.
Estrogens play a key role in sexual differentiation of both the gonads and external traits in birds. The production of estrogen occurs via a well-characterized steroidogenic pathway, which is a ...multistep process involving several enzymes, including cytochrome P450 aromatase. In chicken embryos, the aromatase gene (CYP19A1) is expressed female-specifically from the time of gonadal sex differentiation. Ectopic overexpression of aromatase in male chicken embryos induces gonadal sex reversal, and male embryos treated with estradiol become feminized; however, this is not permanent. To test whether a continuous supply of estrogen in adult chickens could induce stable male to female sex reversal, 2 transgenic male chickens overexpressing aromatase were generated using the Tol2/transposase system. These birds had robust ectopic aromatase expression, which resulted in the production of high serum levels of estradiol. Transgenic males had female-like wattle and comb growth and feathering, but they retained male weights, displayed leg spurs, and developed testes. Despite the small sample size, this data strongly suggests that high levels of circulating estrogen are insufficient to maintain a female gonadal phenotype in adult birds. Previous observations of gynandromorph birds and embryos with mixed sex chimeric gonads have highlighted the role of cell autonomous sex identity in chickens. This might imply that in the study described here, direct genetic effects of the male chromosomes largely prevailed over the hormonal profile of the aromatase transgenic birds. This data therefore support the emerging view of at least partial cell autonomous sex development in birds. However, a larger study will confirm this intriguing observation.
Insects in the field are exposed to multiple bouts of cold, and there is increasing evidence that the fitness consequences of repeated cold exposure differ from the impacts of a single cold exposure. ...We tested the hypothesis that different kinds of cold exposure (in this case, single short, prolonged and repeated cold exposure) would result in differential gene expression. We exposed 3 day old adult female wild-type Drosophila melanogaster (Diptera: Drosophilidae) to -0.5°C for a single 2 h exposure, a single 10 h exposure, or five 2 h exposures on consecutive days, and extracted RNA after 6 h of recovery. Global gene expression was quantified using an oligonucleotide microarray and validated with real-time PCR using different biological replicates. We identified 76 genes upregulated in response to multiple cold exposure, 69 in response to prolonged cold exposure and 20 genes upregulated in response to a single short cold exposure, with a small amount of overlap between treatments. Three genes--Turandot A, Hephaestus and CG11374--were upregulated in response to all three cold exposure treatments. Key functional groups upregulated include genes associated with muscle structure and function, the immune response, stress response, carbohydrate metabolism and egg production. We conclude that cold exposure has wide-ranging effects on gene expression in D. melanogaster and that increased duration or frequency of cold exposure has impacts different to those of a single short cold exposure. This has important implications for extrapolating laboratory studies of insect overwintering that are based on only a single cold exposure.
Moody's and Standard & Poor's, the major American credit rating agencies, were expected to outcompete and overwhelm the local agencies in Japan during the 1990s. The local Japanese rating agencies ...were widely understood to be compromised by their links to government and banks. Why have the influences of the American agencies in Japan diminished, while the local Japanese agencies survived? We emphasise the concept of 'systemic support' as a solution to this puzzle. Our broadened definition of systemic support incorporates dominant elites' support and protection of subordinates in exchange for loyalty and obedience. We argue Japanese society's anti-liberal, anti-free market norms (epitomised by systemic support) are a form of counter-hegemony, and this has resisted American financial hegemony and prevented capitalist dominance from severing long-term social relations (including management-labour alliances). Credit rating in Japan is an ideational battlefield between the market liberalisation and anti-free market camps within the Japanese elite. The American agencies' market friendly, short-term profit-seeking mental framework clashes with the continuing attachment to systemic support in Japan. Similar conflicts can be witnessed in other constrained market economies in Asia and Europe, where corporate bailouts often occur, and local agencies compete against the American majors.
The primary role of Anti-Müllerian hormone (AMH) during mammalian development is the regression of Müllerian ducts in males. This highly conserved function is retained in birds and is supported by ...the high levels of AMH expression in developing testes. Mammalian AMH expression is regulated by a combination of transcription factors, the most important being Sry-type high-mobility-group box transcription factor-9 (SOX9). In the chicken embryo, however, AMH mRNA expression precedes that of SOX9, leading to the view that AMH may play a more central role in avian testicular development. To define its role in chicken gonadal development, AMH was overexpressed using the RCASBP viral vector. AMH caused the gonads of both sexes to develop as small and undeveloped structures at both embryonic and adult stages. Molecular analysis revealed that although female gonads developed testis-like cords, gonads lacked Sertoli cells and were incapable of steroidogenesis. A similar gonadal phenotype was also observed in males, with a complete loss of both Sertoli cells, disrupted SOX9 expression and gonadal steroidogenesis. At sexual maturity both sexes showed a female external phenotype but retained sexually dimorphic body weights that matched their genetic sexes. These data suggest that AMH does not operate as an early testis activator in the chicken but can affect downstream events, such as sex steroid hormone production. In addition, this study provides a unique opportunity to assess chicken sexual development in an environment of sex hormone deficiency, demonstrating the importance of both hormonal signaling and direct cell autonomous factors for somatic sex identity in birds.
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