853 research outputs found

    A Phase 2 study of cisplatin analog CI-973 in the treatment of patients with refractory, advanced ovarian cancer

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    Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71591/1/j.1525-1438.1996.06040257.x.pd

    Positive expectations predict improved mental-health outcomes linked to psychedelic microdosing

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    Psychedelic microdosing describes the ingestion of near-threshold perceptible doses of classic psychedelic substances. Anecdotal reports and observational studies suggest that microdosing may promote positive mood and well-being, but recent placebo-controlled studies failed to fnd compelling evidence for this. The present study collected web-based mental health and related data using a prospective (before, during and after) design. Individuals planning a weekly microdosing regimen completed surveys at strategic timepoints, spanning a core four-week test period. Eightyone participants completed the primary study endpoint. Results revealed increased self-reported psychological well-being, emotional stability and reductions in state anxiety and depressive symptoms at the four-week primary endpoint, plus increases in psychological resilience, social connectedness, agreeableness, nature relatedness and aspects of psychological fexibility. However, positive expectancy scores at baseline predicted subsequent improvements in well-being, suggestive of a signifcant placebo response. This study highlights a role for positive expectancy in predicting positive outcomes following psychedelic microdosing and cautions against zealous inferences on its putative therapeutic value

    A study of inter-individual variability in the Phase II metabolism of xenobiotics in human skin

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    YesUnderstanding skin metabolism is key to improve in vitro to in vivo extrapolations used to inform risk assessments of topically applied products. However, published literature is scarce and usually covers a limited and non-representative number of donors. We developed a protocol to handle and store ex vivo skin samples post-surgery and prepare skin S9 fractions to measure the metabolic activity of Phase II enzymes. Preincubation of an excess of cofactors at 37 °C for fifteen minutes in the S9 before introduction of the testing probe, greatly increased the stability of the enzymes. Using this standardised assay, the rates of sulphation (SULT) and glucuronidation (UGT) of 7-hydroxycoumarin, methylation (COMT) of dopamine and N-acetylation (NAT) of procainamide were measured in the ng/mg protein/h (converted to ng/cm2/h) range in eighty-seven individuals. Glutathione conjugation (GST) of 1-chloro-2,4-dinitrobenzene was assessed in a smaller pool of fifty donors; the metabolic rate was much faster and measured over six minutes using a different methodology to express rates in μg/mg protein/min (converted to μg/cm2/min). A comprehensive statistical analysis of these results was carried out, separating donors by age, gender and metabolic rate measured

    An RNA interference-based screen of transcription factor genes identifies pathways necessary for sensory regeneration in the avian inner ear

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    Sensory hair cells of the inner ear are the mechano-electric transducers of sound and head motion. In mammals, damage to sensory hair cells leads to hearing or balance deficits. Non-mammalian vertebrates such as birds can regenerate hair cells after injury. In a previous study, we characterized transcription factor gene expression during chicken hair cell regeneration. In those studies, a laser micro-beam or ototoxic antibiotics were used to damage the sensory epithelia (SE). The current study focused on 27 genes that were up-regulated in regenerating SE compared to untreated SE in the previous study. Those genes were knocked down by siRNA, to determine their requirement for supporting cell proliferation and to measure resulting changes in the larger network of gene expression. We identified 11 genes necessary for proliferation and also identified novel interactive relationships between many of them. Defined components of the WNT, PAX and AP1 pathways were shown to be required for supporting cell proliferation. These pathways intersect on WNT4, which is also necessary for proliferation. Among the required genes, the CCAAT enhancer binding protein, CEBPG, acts downstream of Jun Kinase and JUND in the AP1 pathway. The WNT co-receptor LRP5 acts downstream of CEBPG as does the transcription factor BTAF1. Both of these genes are also necessary for supporting cell proliferation. This is the first large scale screen of its type and suggests an important intersection between the AP1 pathway, the PAX pathway and WNT signaling in the regulation of supporting cell proliferation during inner ear hair cell regeneration

    Fossils, fish and tropical forests: prehistoric human adaptations on the island frontiers of Oceania

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    Oceania is a key region for studying human dispersals, adaptations and interactions with other hominin populations. Although archaeological evidence now reveals occupation of the region by approximately 65–45 000 years ago, its human fossil record, which has the best potential to provide direct insights into ecological adaptations and population relationships, has remained much more elusive. Here, we apply radiocarbon dating and stable isotope approaches to the earliest human remains so far excavated on the islands of Near and Remote Oceania to explore the chronology and diets of the first preserved human individuals to step across these Pacific frontiers. We demonstrate that the oldest human (or indeed hominin) fossil outside of the mainland New Guinea-Aru area dates to approximately 11 800 years ago. Furthermore, although these early sea-faring populations have been associated with a specialized coastal adaptation, we show that Late Pleistocene–Holocene humans living on islands in the Bismarck Archipelago and in Vanuatu display a persistent reliance on interior tropical forest resources. We argue that local tropical habitats, rather than purely coasts or, later, arriving domesticates, should be emphasized in discussions of human diets and cultural practices from the onset of our species' arrival in this part of the world.1. Introduction 2. Background (a) Human colonization of near and remote Oceania (b) Stable isotope analysis and past human adaptations in the tropics 3. Methods (a) Radiocarbon dating (b) Stable isotope analysis (c) Phytolith analysis of dental calculus 4. Results (a) Radiocarbon dating and Bayesian modelling (b) Stable isotope analysis (c) Phytolith analysis of dental calculus 5. Discussion and conclusio

    Resolving the ancestry of Austronesian-speaking populations

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    There are two very different interpretations of the prehistory of Island Southeast Asia (ISEA), with genetic evidence invoked in support of both. The “out-of-Taiwan” model proposes a major Late Holocene expansion of Neolithic Austronesian speakers from Taiwan. An alternative, proposing that Late Glacial/postglacial sea-level rises triggered largely autochthonous dispersals, accounts for some otherwise enigmatic genetic patterns, but fails to explain the Austronesian language dispersal. Combining mitochondrial DNA (mtDNA), Y-chromosome and genome-wide data, we performed the most comprehensive analysis of the region to date, obtaining highly consistent results across all three systems and allowing us to reconcile the models. We infer a primarily common ancestry for Taiwan/ISEA populations established before the Neolithic, but also detected clear signals of two minor Late Holocene migrations, probably representing Neolithic input from both Mainland Southeast Asia and South China, via Taiwan. This latter may therefore have mediated the Austronesian language dispersal, implying small-scale migration and language shift rather than large-scale expansion

    Landesque capital as an alternative to food storage in Melanesia: Irrigated taro terraces in New Georgia, Solomon Islands

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    In the Pacific islands, subsistence diversity made possible continuous production of food while welldeveloped exchange networks redistributed these foodstuffs as well as items within the prestige economy. All these were aspects of the ‘storage structures’ that enabled social and nutritional value to be saved, accumulated and later mobilised. In addition, there were investments in the land, landesque capital, which secured future food surpluses and so provided an alternative to food storage, in a region where the staple foods were mostly perishable, yams excepted, and food preservation was difficult. Landesque capital included such long-term improvements to productivity as terraces, mounds, irrigation channels, drainage ditches, soil structural changes and tree planting. These investments provided an effective alternative to food storage and made possible surplus production for exchange purposes. As an example, in the New Georgia group of the western Solomon Islands irrigated terraces, termed ruta, were constructed for growing the root crop taro (Colocasia esculenta). Surplus taro from ruta enabled inland groups to participate in regional exchange networks and so obtain the shell valuables that were produced by coastal groups. In this paper, we reconstruct how this exchange system worked in New Georgia using ethno-archaeological evidence, we chart its prehistoric rise and post-colonial fall, and we outline the factors that constrained its long-term expansion.Our gratitude for support during earlier fieldwork in the New Georgia group has already been expressed in previous publications. The 2014 project was supported by the Smuts Fund and Foreign Travel Fund, University of Cambridge, and by St John’s College, Cambridge.This is the accepted manuscript. The final version is available from Maney at http://dx.doi.org/10.1179/1749631414Y.000000004
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