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Using a complete record of U.S. over-the-counter (OTC) secondary trades in corporate bonds, we estimate average transaction costs as a function of trade size for each bond that traded more than nine times between January 2003 and January 2005. We find that transaction costs decrease significantly with trade size. Highly rated bonds, recently issued bonds, and bonds close to maturity have lower transaction costs than do other bonds. Costs are lower for bonds with transparent trade prices, and they drop when the TRACE system starts to publicly disseminate their prices. The results suggest that public traders benefit significantly from price transparency.

This collection of twelve essays reviews the history of welfare in Britain over the past 150 years. It focuses on the ideas that have shaped the development of British social policy, and on the thinkers who have inspired and also contested the welfare state. It thereby constructs an intellectual history of British welfare since the concept first emerged at the end of the nineteenth century.0The essays divide into four sections. The first considers the transition from laissez-faire to social liberalism from the 1870s, and the enduring impact of late-Victorian philosophical idealism on the development of the welfare state. It focuses on the moral philosophy of T. H. Green and his influence on key figures in the history of British social policy like William Beveridge, R. H. Tawney, and William Temple. The second section is devoted to the concept of 'planning' which was once, in the mid-twentieth century, at the heart of social policy and its implementation, but which has subsequently fallen out of favour. A third section examines the intellectual debate over the welfare state since its creation in the 1940s. Though a consensus seemed to have emerged during the Second World War over the desirability and scope of a welfare state extending 'from the cradle to the grave', libertarian and conservative critiques endured and re-emerged a generation later. A final section examines social policy and its implementation more recently, both at grass roots level in a study of community action in West London in the districts made infamous by the fire at Grenfell Tower in 2017, and at a systemic level where different models of welfare provision are shown to be in uneasy co-existence today.The collection is a tribute to Jose Harris, emeritus professor of history in the University of Oxford and a pioneer of the intellectual history of social policy. Taken together, these essays conduct the reader through the key phases and debates in the history of British welfare.

The absence of ‘shovel-ready’ anti-coronavirus drugs during vaccine development has exceedingly worsened the SARS-CoV-2 pandemic. Furthermore, new vaccine-resistant variants and coronavirus outbreaks may occur in the near future, and we must be ready to face this possibility. However, efficient antiviral drugs are still lacking to this day, due to our poor understanding of the mode of incorporation and mechanism of action of nucleotides analogs that target the coronavirus polymerase to impair its essential activity. Here, we characterize the impact of remdesivir (RDV, the only FDA-approved anti-coronavirus drug) and other nucleotide analogs (NAs) on RNA synthesis by the coronavirus polymerase using a high-throughput, single-molecule, magnetic-tweezers platform. We reveal that the location of the modification in the ribose or in the base dictates the catalytic pathway(s) used for its incorporation. We show that RDV incorporation does not terminate viral RNA synthesis, but leads the polymerase into backtrack as far as 30 nt, which may appear as termination in traditional ensemble assays. SARS-CoV-2 is able to evade the endogenously synthesized product of the viperin antiviral protein, ddhCTP, though the polymerase incorporates this NA well. This experimental paradigm is essential to the discovery and development of therapeutics targeting viral polymerases. To multiply and spread from cell to cell, the virus responsible for COVID-19 (also known as SARS-CoV-2) must first replicate its genetic information. This process involves a ‘polymerase’ protein complex making a faithful copy by assembling a precise sequence of building blocks, or nucleotides. The only drug approved against SARS-CoV-2 by the US Food and Drug Administration (FDA), remdesivir, consists of a nucleotide analog, a molecule whose structure is similar to the actual building blocks needed for replication. If the polymerase recognizes and integrates these analogs into the growing genetic sequence, the replication mechanism is disrupted, and the virus cannot multiply. Most approaches to study this process seem to indicate that remdesivir works by stopping the polymerase and terminating replication altogether. Yet, exactly how remdesivir and other analogs impair the synthesis of new copies of the virus remains uncertain. To explore this question, Seifert, Bera et al. employed an approach called magnetic tweezers which uses a magnetic field to manipulate micro-particles with great precision. Unlike other methods, this technique allows analogs to be integrated under conditions similar to those found in cells, and to be examined at the level of a single molecule. The results show that contrary to previous assumptions, remdesivir does not terminate replication; instead, it causes the polymerase to pause and backtrack (which may appear as termination in other techniques). The same approach was then applied to other nucleotide analogs, some of which were also found to target the SARS-CoV-2 polymerase. However, these analogs are incorporated differently to remdesivir and with less efficiency. They also obstruct the polymerase in distinct ways. Taken together, the results by Seifert, Bera et al. suggest that magnetic tweezers can be a powerful approach to reveal how analogs interfere with replication. This information could be used to improve currently available analogs as well as develop new antiviral drugs that are more effective against SARS-CoV-2. This knowledge will be key at a time when treatments against COVID-19 are still lacking, and may be needed to protect against new variants and future outbreaks.

أهمية هذه المذكرات، لا تكمن وحسب في كونها تجربة أول صحافي بريطاني حاور المولي عبد الحفيظ بعد جلوسه على العرش بل أنها تسجل تجربة صحافي في المغرب، تحدث عن الوزاراء المغاربة وعلية القوم وأثرياء طنجة وفاس وشحصيات أجنبية عاشت فيها، وتحدث أيضا عن المغاربة مرافقيه الذيت أستأجرهم لكي يسافر من طنجة إلى فاس حتى يتسنى له إنجاز المهمة الصحافية التي جاء من أجلها

Using new econometric methods, we separately estimate average transaction costs for over 167,000 bonds from a 1-year sample of all U.S. municipal bond trades. Municipal bond transaction costs decrease with trade size and do not depend significantly on trade frequency. Also, municipal bond trades are substantially more expensive than similar-sized equity trades. We attribute these results to the lack of bond market price transparency. Additional cross-sectional analyses show that bond trading costs increase with credit risk, instrument complexity, time to maturity, and time since issuance. Investors, and perhaps ultimately issuers, might benefit if issuers issued simpler bonds.

Bile acid receptors have been identified as important targets for the development of new therapeutics to treat various metabolic and inflammatory diseases. The synthesis of new bile acid analogues can help elucidate structure–activity relationships and define compounds that activate these receptors selectively. Towards this, access to large quantities of a chenodeoxycholic acid derivative bearing a C-12 methyl and a C-13 to C-14 double bond provided an interesting scaffold to investigate the chemical manipulation of the C/D ring junction in bile acids. The reactivity of this alkene substrate with various zinc carbenoid species showed that those generated using the Furukawa methodology achieved selective α-cyclopropanation, whereas those generated using the Shi methodology reacted in an unexpected manner giving rise to a rearranged skeleton whereby the C ring has undergone contraction to form a novel spiro–furan ring system. Further derivatization of the cyclopropanated steroid included O-7 oxidation and epimerization to afford new bile acid derivatives for biological evaluation.

BackgroundThe E-cadherin gene (CDH1) is frequently mutated in diffuse gastric cancer and lobular breast cancer, and germline mutations predispose to the cancer syndrome Hereditary Diffuse Gastric Cancer. We are taking a synthetic lethal approach to identify druggable vulnerabilities in CDH1-mutant cancers.MethodsDensity distributions of cell viability data from a genome-wide RNAi screen of isogenic MCF10A and MCF10A-CDH1−/− cells were used to identify protein classes affected by CDH1 mutation. The synthetic lethal relationship between selected protein classes and E-cadherin was characterised by drug sensitivity assays in both the isogenic breast MCF10A cells and CDH1-isogenic gastric NCI-N87. Endocytosis efficiency was quantified using cholera toxin B uptake. Pathway metagene expression of 415 TCGA gastric tumours was statistically correlated with CDH1 expression.ResultsMCF10A-CDH1−/− cells showed significantly altered sensitivity to RNAi inhibition of groups of genes including the PI3K/AKT pathway, GPCRs, ion channels, proteosomal subunit proteins and ubiquitinylation enzymes. Both MCF10A-CDH1−/− and NCI-N87-CDH1−/− cells were more sensitive than wild-type cells to compounds that disrupted plasma membrane composition and trafficking, but showed contrasting sensitivities to inhibitors of actin polymerisation and the chloride channel inhibitor NS3728. The MCF10A-CDH1−/− cell lines showed reduced capacity to endocytose cholera toxin B. Pathway metagene analysis identified 20 Reactome pathways that were potentially synthetic lethal in tumours. Genes involved in GPCR signalling, vesicle transport and the metabolism of PI3K and membrane lipids were strongly represented amongst the candidate synthetic lethal genes.ConclusionsE-cadherin loss leads to disturbances in receptor signalling and plasma membrane trafficking and organisation, creating druggable vulnerabilities.

Parkinson’s Disease is the most common neurodegenerative movement disorder globally, with prevalence increasing. There is an urgent need for new therapeutics which are disease-modifying rather than symptomatic. Mitochondrial dysfunction is a well-documented mechanism in both sporadic and familial Parkinson’s Disease. Furthermore, ursodeoxycholic acid (UDCA) has been identified as a bile acid which leads to increased mitochondrial function in multiple in vitro and in vivo models of Parkinson’s Disease. Here, we describe the synthesis of novel C-nor-D-homo bile acid derivatives and the 12-hydroxy-methylated derivative of lagocholic acid (7) and their biological evaluation in fibroblasts from patients with either sporadic or LRRK2 mutant Parkinson’s Disease. These compounds boost mitochondrial function to a similar level or above that of UDCA in many assays; notable, however, is their ability to boost mitochondrial function to a higher level and at lower concentrations than UDCA specifically in the fibroblasts from LRRK2 patients. Our study indicates that novel bile acid chemistry could lead to the development of more efficacious bile acids which increase mitochondrial function and ultimately cellular health at lower concentrations proving attractive potential novel therapeutics for Parkinson’s Disease.

We discuss Lagrange interpolation on two sets of nodes in two dimensions where the coordinates of the nodes are Chebyshev points having either the same or opposite parity. We use a formula of Xu for Lagrange polynomials to obtain a general interpolation theorem for bivariate polynomials at either set of Chebyshev nodes. An extra term must be added to the interpolation formula to handle all polynomials with the same degree as the Lagrange polynomials. We express this term as a specifically determined linear combination of canonical polynomials that vanish on the set of Chebyshev nodes being considered. As an application we deduce in an elementary way known minimal and near minimal cubature formulas applying to both the even and the odd Chebyshev nodes. Finally, we restrict to triangular subsets of the Chebyshev nodes to show unisolvence and deduce a Lagrange interpolation formula for bivariate symmetric and skew-symmetric polynomials. This result leads to another proof of the interpolation formula.