secCl is a cys-loop ion channel necessary for the chloride conductance that mediates hormone-induced fluid secretion in Drosophila

Organisms use circulating diuretic hormones to control water balance (osmolarity), thereby avoiding dehydration and managing excretion of waste products. The hormones act through G-protein-coupled receptors to activate second messenger systems that in turn control the permeability of secretory epithelia to ions like chloride. In insects, the chloride channel mediating the effects of diuretic hormones was unknown. Surprisingly, we find a pentameric, cys-loop chloride channel, a type of channel normally associated with neurotransmission, mediating hormone-induced transepithelial chloride conductance. This discovery is important because: 1) it describes an unexpected role for pentameric receptors in the membrane permeability of secretory epithelial cells, and 2) it suggests that neurotransmitter-gated ion channels may have evolved from channels involved in secretion

Solid-Phase Synthesis of Amine/Carboxyl Substituted Prolines and Proline Homologues: Scope and Limitations

A solid-phase procedure is used to synthesize racemic peptidomimetics based on the fundamental peptide unit. The peptidomimetics are constructed around proline or proline homologues variably substituted at the amine and carbonyl sites. The procedure expands the diversity of substituted peptidomimetic molecules available to the Distributed Drug Discovery (D3) project. Using a BAL-based solid-phase synthetic sequence the proline or proline homologue subunit is both constructed and incorporated into the peptidomimetic by an α-alkylation, hydrolysis and intramolecular cyclization sequence. Further transformations on solid-phase provide access to a variety of piperazine derivatives representing a class of molecules known to exhibit central nervous system activity. The procedure works well with proline cores, but with larger six- and seven-membered ring homologues the nature of the carboxylic acid acylating the cyclic amine can lead to side reactions and result in poor overall yields

Elimination of TFA-Mediated Cleavage in Distributed Drug Discovery

Distributed Drug Discovery (D3) is a multi-disciplinary approach to the discovery of new drugs, which target neglected diseases or conditions common to developing-world countries. As part of a continuing effort to improve D3 methodology, two approaches for eliminating the final step TFA-mediated resin cleavage are proposed for investigation. Cleavage under basic conditions (saponification) and mild acid conditions (dilute HCl/hexafluoroisopropanol or dilute HCl/trifluoroethanol) represent improvements in safety and convenience to the undergraduate student researcher. Previous studies have shown that saponification provides yields comparable to the traditional TFA cleavage but recovery is not as convenient. Further improvements in the saponification workup will be evaluated by analyzing the effectiveness of simple trituration with acetone compared to use of a strong anion-exchange resin or drying reagents to isolate the free acid from the salt. Different trituration procedural modifications have been made and are being tested. Results have shown that in the presence of methanol, esterification will occur when the acid is liberated from the salt using HCl. To counter this problem, the samples are first evaporated to remove methanol and then the pH is adjusted with HCl. It was shown that using acetic acid did not result in pH levels low enough to guarantee complete protonation of the carboxylate. Through the use of a Bill-Board, an apparatus that holds six reaction vessels, several procedural modifications can be carried out simultaneously. Analysis is conducted by liquid chromatography coupled with a mass spectrometer and with nuclear magnetic resonance spectroscopy. Further studies will be carried out to assess the efficiency and practicality of using mild acidic conditions for cleavage using HCl/hexafluoroisopropanol or dilute HCl/trifluoroethanol. Both saponification and mild acid cleavage would represent improvements in safety and convenience to the undergraduate student researcher

Cutibacterium (formerly Propionibacterium) acnes clavicular infection.

Cutibacterium (formerly Propionibacterium) acnes13, 16 is a slow growing, gram-positive bacteria that is naturally found in higher concentrations as skin flora on the chest and back, as well as in other areas with greater numbers of hair follicles.25, 37 Most of the reported cases of C. acnes shoulder girdle infection follow arthroplasty surgery,18, 20, 26, 27, 32, 35 which then often requires debridement, administration of intravenous antibiotics, and surgical revision of the implanted device.12, 15, 21, 28-30 In a recent study, 56% of 193 shoulder revisions had a positive culture, 70% of which grew C. acnes.30 Despite the relatively common presumed association of C. acnes humeral osteomyelitis with prosthetic infection, infection of the scapula or clavicle secondary to C. acnes is rare.4, 23, 36 Osteomyelitis of the clavicle involving any organism is also an uncommon event that can arise spontaneously via presumed hematogenous spread, or secondary to open fractures or internal fixation.6, 33 The most commonly found organism in clavicular osteomyelitis is Staphylococcus aureus.9 We here report two cases of clavicular infection secondary to C. acnes that were not associated with implants

First evidence of cryptotephra in palaeoenvironmental records associated with Norse occupation sites in Greenland

The Norse/Viking occupation of Greenland is part of a dispersal of communities across the North Atlantic coincident with the supposed Medieval Warm Period of the late 1st millennium AD. The abandonment of the Greenland settlements has been linked to climatic deterioration in the Little Ice Age as well as other possible explanations. There are significant dating uncertainties over the time of European abandonment of Greenland and the potential influence of climatic deterioration. Dating issues largely revolve around radiocarbon chronologies for Norse settlements and associated mire sequences close to settlement sites. Here we show the potential for moving this situation forward by a combination of palynological, radiocarbon and cryptotephra analyses of environmental records close to three ‘iconic’ Norse sites in the former Eastern Settlement of Greenland – Herjolfsnes, Hvalsey and Garðar (the modern Igaliku). While much work remains to be undertaken, our results show that palynological evidence can provide a useful marker for both the onset and end of Norse occupation in the region, while the radiocarbon chronologies for these sequences remain difficult. Significantly, we here demonstrate the potential for cryptotephra to become a useful tool in resolving the chronology of Norse occupation, when coupled with palynology. For the first time, we show that cryptotephra are present within palaeoenvironmental sequences located within or close to Norse settlement ruin-groups, with tephra horizons detected at all three sites. While shard concentrations were small at Herjolfsnes, concentrations sufficient for geochemical analyses were detected at Igaliku and Hvalsey. WDS-EPMA analyses of these tephra indicate that, unlike the predominantly Icelandic tephra sources reported in the Greenland ice core records, the tephra associated with the Norse sites correlate more closely with volcanic centres in the Aleutians and Cascades. Recent investigations of cryptotephra dispersal from North American centres, along with our new findings, point to the potential for cryptotephra to facilitate hypothesis testing, providing a key chronological tool for refining the timing of Norse activities in Greenland (e.g. abandonment) and of environmental contexts and drivers (e.g. climate forcing)

Adiposity, Cardiometabolic Risk, and Vitamin D Status: The Framingham Heart Study

OBJECTIVE: Because vitamin D deficiency is associated with a variety of chronic diseases, understanding the characteristics that promote vitamin D deficiency in otherwise healthy adults could have important clinical implications. Few studies relating vitamin D deficiency to obesity have included direct measures of adiposity. Furthermore, the degree to which vitamin D is associated with metabolic traits after adjusting for adiposity measures is unclear. RESEARCH DESIGN AND METHODS: We investigated the relations of serum 25-hydroxyvitamin D (25[OH]D) concentrations with indexes of cardiometabolic risk in 3,890 nondiabetic individuals; 1,882 had subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes measured by multidetector computed tomography (CT). RESULTS: In multivariable-adjusted regression models, 25(OH)D was inversely associated with winter season, waist circumference, and serum insulin (P < 0.005 for all). In models further adjusted for CT measures, 25(OH)D was inversely related to SAT (−1.1 ng/ml per SD increment in SAT, P = 0.016) and VAT (−2.3 ng/ml per SD, P < 0.0001). The association of 25(OH)D with insulin resistance measures became nonsignificant after adjustment for VAT. Higher adiposity volumes were correlated with lower 25(OH)D across different categories of BMI, including in lean individuals (BMI <25 kg/m2). The prevalence of vitamin D deficiency (25[OH]D <20 ng/ml) was threefold higher in those with high SAT and high VAT than in those with low SAT and low VAT (P < 0.0001). CONCLUSIONS: Vitamin D status is strongly associated with variation in subcutaneous and especially visceral adiposity. The mechanisms by which adiposity promotes vitamin D deficiency warrant further study.National Institutes of Health's National Heart, Lung, and Blood Institute (N01-HC-25195, R01-DK-80739): American Heart Associatio

Research shapes policy: but the dynamics are subtle

Major policy initiatives such as the Quality and Outcomes Framework (QOF) in the national contract for UK general practitioners might variably be informed by evidence at their inception, implementation and subsequent evolution. But what evidence gets admitted into these policy debates—and what is left out? Using QOF as an example, this article demonstrates what an analysis of the relationship between policy and the associated research can tell us about the underlying policy assumptions and about the role of evidence in policy debates

Spin measurements for 147Sm+n resonances: Further evidence for non-statistical effects

We have determined the spins J of resonances in the 147Sm(n,gamma) reaction by measuring multiplicities of gamma-ray cascades following neutron capture. Using this technique, we were able to determine J values for all but 14 of the 140 known resonances below En = 1 keV, including 41 firm J assignments for resonances whose spins previously were either unknown or tentative. These new spin assignments, together with previously determined resonance parameters, allowed us to extract separate level spacings and neutron strength functions for J = 3 and 4 resonances. Furthermore, several statistical test of the data indicate that very few resonances of either spin have been missed below En = 700eV. Because a non-statistical effect recently was reported near En = 350 eV from an analysis of 147Sm(n,alpha) data, we divided the data into two regions; 0 < En < 350 eV and 350 < En < 700 eV. Using neutron widths from a previous measurement and published techniques for correcting for missed resonances and for testing whether data are consistent with a Porter-Thomas distribution, we found that the reduced-neutron-width distribution for resonances below 350 eV is consistent with the expected Porter-Thomas distribution. On the other hand, we found that reduced-neutron-width data in the 350 < En < 700 eV region are inconsistent with a Porter-Thomas distribution, but in good agreement with a chi-squared distribution having two or more degrees of freedom. We discuss possible explanations for these observed non-statistical effects and their possible relation to similar effects previously observed in other nuclides.Comment: 40 pages, 13 figures, accepted by Phys. Rev.

A phase 1 trial dose-escalation study of tipifarnib on a week-on, week-off schedule in relapsed, refractory or high-risk myeloid leukemia.

Inhibition of farnesyltransferase (FT) activity has been associated with in vitro and in vivo anti-leukemia activity. We report the results of a phase 1 dose-escalation study of tipifarnib, an oral FT inhibitor, in patients with relapsed, refractory or newly diagnosed (if over age 70) acute myelogenous leukemia (AML), on a week-on, week-off schedule. Forty-four patients were enrolled, two patients were newly diagnosed, and the rest were relapsed or refractory to previous treatment, with a median age of 61 (range 33-79). The maximum tolerated dose was determined to be 1200 mg given orally twice daily (b.i.d.) on this schedule. Cycle 1 dose-limiting toxicities were hepatic and renal. There were three complete remissions seen, two at the 1200 mg b.i.d. dose and one at the 1000 mg b.i.d. dose, with minor responses seen at the 1400 mg b.i.d. dose level. Pharmacokinetic studies performed at doses of 1400 mg b.i.d. showed linear behavior with minimal accumulation between days 1-5. Tipifarnib administered on a week-on, week-off schedule shows activity at higher doses, and represents an option for future clinical trials in AML