Augmentation of Staphylococcal α-Toxin Signaling by the Epidermal Platelet-Activating Factor Receptor

Staphylococcal α-toxin is a cytolytic toxin secreted by many strains of Staphylococcus aureus that has proinflammatory and cytotoxic effects on human keratinocytes. α-toxin exerts its effects by forming a transmembrane pore that behaves like an ionophore for ions such as calcium. Because cellular membrane disruption with resultant intracellular calcium mobilization is a potent stimulus for the synthesis for the lipid mediator platelet-activating factor, the ability of α-toxin to induce platelet-activating factor production was assessed, and whether the epidermal platelet-activating factor receptor could augment toxin-induced signaling in epithelial cells examined. Treatment of the human keratinocyte-derived cell line HaCaT with α-toxin resulted in significant levels of platelet-activating factor, which were approximately 50% of the levels induced by calcium ionophore A23187. α-toxin also stimulated arachidonic acid release in HaCaT keratinocytes. Pretreatment of HaCaT cells with platelet-activating factor receptor antagonists, or overexpression of the platelet-activating factor metabolizing enzyme acetylhydrolase II blunted α-toxin-induced arachidonic acid release by approximately one-third, suggesting a role for toxin-produced platelet-activating factor in this process. Finally, retroviral-mediated expression of the platelet-activating factor receptor into the platelet-activating factor receptor-negative epithelial cell line KB resulted in an augmentation of α-toxin-mediated intracellular calcium mobilization and arachidonic acid release. These studies suggest that α-toxin-mediated signaling can be augmented via the epidermal platelet-activating factor receptor

Maximum Likelihood Estimation of Search Costs

In a recent paper Hong and Shum (forthcoming) present a structural methodology to estimate search cost distributions. We extend their approach to the case of oligopoly and present a maximum likelihood estimate of the search cost distribution. We apply our method to a data set of online prices for different computer memory chips. The estimates of the search cost distribution suggest that consumers have either quite high or quite low search costs so they either search for all prices in the market or for at most three prices. According to Kolmogorov-Smirnov goodness-of-fit tests, we cannot reject the null hypothesis that the observed prices are generated by the mode

Low dose chloroquine decreases insulin resistance in human metabolic syndrome but does not reduce carotid intima-media thickness

Background: Metabolic syndrome, an obesity-related condition associated with insulin resistance and low-grade inflammation, leads to diabetes, cardiovascular diseases, cancer, osteoarthritis, and other disorders. Optimal therapy is unknown. The antimalarial drug chloroquine activates the kinase ataxia telangiectasia mutated (ATM), improves metabolic syndrome and reduces atherosclerosis in mice. To translate this observation to humans, we conducted two clinical trials of chloroquine in people with the metabolic syndrome. Methods: Eligibility included adults with at least 3 criteria of metabolic syndrome but who did not have diabetes. Subjects were studied in the setting of a single academic health center. The specific hypothesis: chloroquine improves insulin sensitivity and decreases atherosclerosis. In Trial 1, the intervention was chloroquine dose escalations in 3-week intervals followed by hyperinsulinemic euglycemic clamps. Trial 2 was a parallel design randomized clinical trial, and the intervention was chloroquine, 80 mg/day, or placebo for 1 year. The primary outcomes were clamp determined-insulin sensitivity for Trial 1, and carotid intima-media thickness (CIMT) for Trial 2. For Trial 2, subjects were allocated based on a randomization sequence using a protocol in blocks of 8. Participants, care givers, and those assessing outcomes were blinded to group assignment. Results: For Trial 1, 25 patients were studied. Chloroquine increased hepatic insulin sensitivity without affecting glucose disposal, and improved serum lipids. For Trial 2, 116 patients were randomized, 59 to chloroquine (56 analyzed) and 57 to placebo (51 analyzed). Chloroquine had no effect on CIMT or carotid contrast enhancement by MRI, a pre-specified secondary outcome. The pre-specified secondary outcomes of blood pressure, lipids, and activation of JNK (a stress kinase implicated in diabetes and atherosclerosis) were decreased by chloroquine. Adverse events were similar between groups. Conclusions: These findings suggest that low dose chloroquine, which improves the metabolic syndrome through ATM-dependent mechanisms in mice, modestly improves components of the metabolic syndrome in humans but is unlikely to be clinically useful in this setting

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

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Imperial versus local perceptions of Indian textiles

The 1851 Crystal Palace exhibition in London brought together arts and crafts from around the world particularly those produced in the British empire. The great popularity of the exhibition documented how much people in Britain delighted in seeing the huge diversity of artistic expression from around the world. The following decades witnessed similar exhibitions in various European cities as well as contained the growth and development of museums. While Indian textiles had long fascinated people in Britain and had been eagerly purchased, museum holdings in both India and Britain of these distinctive fabrics have remained minimal. British collecting activities and resulting museum collections of textiles from India thus present an excellent example of global perspectives between an imperial power, Great Britain, and India, a colony within the vast British Empire. Given the great diversity and artistic expression of Indian textiles it is strange museums overwhelmingly confine their displays to an extremely limited variety of textile types. Magnificent as these works are, they do not represent the depth and variety of Indian textile artistic expression. Most unfortunately both British as well as Indian museum collections of Indian textiles never evolved from the time of their original collecting activities and thus rigidly preserve a tradition or canon of a century and a half ago based on the concerns and interests of a handful of collectors and museum officials. Take the case of embroidery in India. Recognized as one of the finest artistic expressions of numerous communities, embroidery has long been largely ignored in both British as well as Indian museums. Three examples point out this non-inclusion of distinctive embroidery in museums. First, the small but influential Parsi community initially rose to prominence building ships for the East India Company. Subsequently the Parsis engaged in trade and successfully competed with the British in the cotton and opium trade to China. While in China the Parsis observed distinctive embroidery techniques that so impressed them they brought Chinese embroiderers to India to teach their distinctive techniques to Indians. The transition from Chinese to Indian embroiderers within this tradition resulted in motifs and expressions suitably adapted to Indian cultural aesthetics and sensibilities. Embroidered works produced in China, for instance, contained pagodas, a motif that disappeared in works produced in India

Queen Alexandra’s 1902 Coronation Gown

Queen Victoria\u27s wearing black mourning clothes for 40 of the 63 years of her reign prompted much discussion between fashion-setting Prince Edward and Princess Alexandra about what should the new queen wear for her coronation, the first state occasion in which they, as king and queen, could define taste and fashion for what was to become the Edwardian era. With such a long interval of time since the last coronation there were no strong expressions of traditional attire for such a ritual occasion which prompted the new king and queen to think expansively about the roles and functions the coronation attire would project to the world. In 1901 Lady Curzon, wife of the Viceroy of India, returned to England from India and at a social event met the new queen. Lady Curzon wore a dress made from Indian cloth that so impressed Alexandra that she requested Lady Curzon upon her return to India to make her coronation gown as well as three additional dresses. The gown, embroidered with gold, magnificently portrayed the pomp and grandeur of a coronation as well as vividly demonstrated the extraordinary textiles India produced. Queen Alexandra\u27s use of Indian fabric in her gown however markedly contrasted with the attire worn by British women in India who steadfastly used British cloth for their gowns and dresses. This paper analyzes Queen Alexandra\u27s coronation gown, British power, imperialism, and the textile traditions of India from which its fabric came

Challenging Tradition in Religious Textiles: The Mata Ni Pachedi of India

A community of block printers and dyers in the Indian state of Gujarat has concentrated upon producing religious textiles for nomadic groups. These unique textiles, known as Mata Ni Pachedi, fulfill the need for a religious representation/environment for groups who have no permanent settlement and thus need to construct temporary shrines for their religious ceremonies. The brilliant red, white, and black cloths portray events from the Mother Goddess tradition. Her depiction as the central and by far the largest representation, as well as the Hindu God Ganesh, distinctively identifies these religious cloths. Since the cloths need to be dried in the sun to set their colors after they are block printed and painted, work on them traditionally was done, literally, on the sidewalks of Ahmedabad, the largest city in Gujarat. Joan Erikson in 1968 published “Mata Ni Pachedi” on these religious textiles as part of work she undertook at the National Institute of Design in Ahmedabad. In 1984 Katherine F. Hacker and Krista Jensen Turnbull included Mata Ni Pachedi in the exhibition “Courtyard, Bazaar, Temple: Traditions of Textile Expression in India” they organized at the Costume and Textile Study Center of the University of Washington. Western knowledge of this distinctive folk religious textile seemed established. Yet Beverly Gordon’s 2011 Textiles: the whole story: uses, meanings, significance on pages 260-1 contains two illustrations showing that the iconography and colors of Mata Ni Pachedi have been completely and totally transformed. The distinctive red, white, and black palette has been enriched by additional colors, the folk depictions of the life of the Goddess have been completely changed, a completely new religious/artistic sensibility has evolved. This paper investigates the earlier tradition and its contemporary re-incarnation