One-Pot Phosphate-Mediated Synthesis of Novel 1,3,5-Trisubstituted Pyridinium Salts: A New Family of S. aureus Inhibitors

Polysubstituted pyridinium salts are valuable pharmacophores found in many biologically active molecules. Their synthesis typically involves the use of multistep procedures or harsh reaction conditions. Here, we report water-based phosphate mediated reaction conditions that promote the condensation of arylacetaldehydes with amines to give 1,3,5-pyridinium salts. The reaction, carried out at pH 6, provides conditions suitable for the use of less stable aldehydes and amines in this Chichibabin pyridine condensation. The evaluation of selected 1,3,5-trisubstituted pyridinium salts highlighted that they can inhibit the growth of S. aureus in the low μg/mL range. The synthetic accessibility of these compounds and preliminary growth inhibition data may pave the way towards the discovery of new anti-bacterials based on the 1,3,5-trisubstituted pyridinium scaffold

Age of the Laschamp excursion determined by U-Th dating of a speleothem geomagnetic record from North America

The Laschamp geomagnetic excursion was the first short-lived polarity event recognized and described in the paleomagnetic record, and to date remains the most studied geomagnetic event of its kind. In addition to its geophysical significance, the Laschamp is an important global geochronologic marker. The Laschamp excursion occurred around the time of the demise of Homo neanderthalensis, in conjunction with high-amplitude, rapid climatic oscillations leading into the Last Glacial Maximum, and coeval with a major supervolcano eruption in the Mediterranean. Thus, precise determination of the timing and duration of the Laschamp excursion would help in elucidating major scientific questions situated at the intersection of geology, paleoclimatology, and anthropology. Here we present a North American speleothem geomagnetic record of the Laschamp excursion that is directly dated using a combination of high-precision 230Th dates and annual layer counting using confocal microscopy. We have determined a maximum excursion duration that spans the interval 42,250-39,700 yr BP, and an age of 41,100 ± 350 yr BP for the main phase of the excursion, during which the virtual geomagnetic pole was situated at the southernmost latitude in the record. Our chronology provides the first age bracketing of the Laschamp excursion using radioisotopic dating, and improves on previous age determinations based on 40Ar/39Ar dating of lava flows, and orbitally-tuned sedimentary and ice-core records.This project was funded by NSF-EAR grant 1316385, a University of Minnesota McKnight Land Grant Professorship to JMF, and ERC grant 320750. Confocal microscopy was performed at the University of Minnesota Imaging Centers. We are grateful to John Geissman, Brad Singer, and James Channell for their constructive reviews. This is Institute for Rock Magnetism contribution 1506.This is the author accepted manuscript. The final version is available from the Geological Society of America via http://dx.doi.org/10.1130/G37490.

'I'm not X, I just want Y': formulating 'wants' in interaction

This article provides a conversation analytic description of a two-part structure, ‘I don’t want X, I want/just want Y’. Drawing on a corpus of recordings of family mealtimes and television documentary data, I show how speakers use the structure in two recurrent environments. First, speakers may use the structure to reject a proposal regarding their actions made by an interlocutor. Second, speakers may deliver the structure following a co-interactant’s formulation of their actions or motivations. Both uses decrease the likelihood of challenge in third-turn position. When responding to multi-unit turns speakers routinely deal with the last item first. The value of ‘I want Y’ is to formulate an alternative sense of agency which undermines the preceding turn and shifts the trajectory of the ongoing sequence. The article contributes to work in discursive psychology as I show how speakers may formulate their ‘wants’ in the service of sequentially unfolding social interaction

High motor variability in DYT1 dystonia is associated with impaired visuomotor adaptation.

For the healthy motor control system, an essential regulatory role is maintaining the equilibrium between keeping unwanted motor variability in check whilst allowing informative elements of motor variability. Kinematic studies in children with generalised dystonia (due to mixed aetiologies) show that movements are characterised by increased motor variability. In this study, the mechanisms by which high motor variability may influence movement generation in dystonia were investigated. Reaching movements in the symptomatic arm of 10 patients with DYT1 dystonia and 12 age-matched controls were captured using a robotic manipulandum and features of motor variability were extracted. Given that task-relevant variability and sensorimotor adaptation are related in health, markers of variability were then examined for any co-variance with performance indicators during an error-based learning visuomotor adaptation task. First, we confirmed that motor variability on a trial-by-trial basis was selectively increased in the homogenous and prototypical dystonic disorder DYT1 dystonia. Second, high baseline variability predicted poor performance in the subsequent visuomotor adaptation task offering insight into the rules which appear to govern dystonic motor control. The potential mechanisms behind increased motor variability and its corresponding implications for the rehabilitation of patients with DYT1 dystonia are highlighted

Natural organic matter in sedimentary basins and its relation to arsenic in anoxic ground water: the example of West Bengal and its worldwide implications

In order to investigate the mechanism of As release to anoxic ground water in alluvial aquifers, the authors sampled ground waters from 3 piezometer nests, 79 shallow (80 m) wells, in an area 750 m by 450 m, just north of Barasat, near Kolkata (Calcutta), in southern West Bengal. High concentrations of As (200-1180 mug L-1) are accompanied by high concentrations of Fe (3-13.7 mgL(-1)) and PO4 (1-6.5 mg L-1). Ground water that is rich in Mn (1-5.3 mg L-1) contains <50 mug L-1 of As. The composition of shallow ground water varies at the 100-m scale laterally and the metre-scale vertically, with vertical gradients in As concentration reaching 200 mug L-1 m(-1). The As is supplied by reductive dissolution of FeOOH and release of the sorbed As to solution. The process is driven by natural organic matter in peaty strata both within the aquifer sands and in the overlying confining unit. In well waters, thermotolerant coliforms, a proxy for faecal contamination, are not present in high numbers (<10 cfu/100 ml in 85% of wells) showing that faecally-derived organic matter does not enter the aquifer, does not drive reduction of FeOOH, and so does not release As to ground water.Arsenic concentrations are high (much greater than50 mug L-1) where reduction of FeOOH is complete and its entire load of sorbed As is released to solution, at which point the aquifer sediments become grey in colour as FeOOH vanishes. Where reduction is incomplete, the sediments are brown in colour and resorption of As to residual FeOOH keeps As concentrations below 10 mug L-1 in the presence of dissolved Fe. Sorbed As released by reduction of Mn oxides does not increase As in ground water because the As resorbs to FeOOH. High concentrations of As are common in alluvial aquifers of the Bengal Basin arise because Himalayan erosion supplies immature sediments, with low surface-loadings of FeOOH on mineral grains, to a depositional environment that is rich in organic mater so that complete reduction of FeOOH is common. (C) 2004 Published by Elsevier Ltd

High-frequency peripheral vibration decreases completion time on a number of motor tasks.

A recent theoretical account of motor control proposes that modulation of afferent information plays a role in affecting how readily we can move. Increasing the estimate of uncertainty surrounding the afferent input is a necessary step in being able to move. It has been proposed that an inability to modulate the gain of this sensory information underlies the cardinal symptoms of Parkinson's disease (PD). We aimed to test this theory by modulating the uncertainty of the proprioceptive signal using high-frequency peripheral vibration, to determine the subsequent effect on motor performance. We investigated if this peripheral stimulus might modulate oscillatory activity over the sensorimotor cortex in order to understand the mechanism by which peripheral vibration can change motor performance. We found that 80 Hz peripheral vibration applied to the right wrist of a total of 54 healthy human participants reproducibly improved performance across four separate randomised experiments on a number of motor control tasks (nine-hole peg task, box and block test, reaction time task and finger tapping). Improved performance on all motor tasks (except the amplitude of finger tapping) was also seen for a sample of 18PD patients ON medication. EEG data investigating the effect of vibration on oscillatory activity revealed a significant decrease in beta power (15-30 Hz) over the contralateral sensorimotor cortex at the onset and offset of 80 Hz vibration. This finding is consistent with a novel theoretical account of motor initiation, namely that modulating uncertainty of the proprioceptive afferent signal improves motor performance potentially by gating the incoming sensory signal and allowing for top-down proprioceptive predictions

Wilson Loops in N=2 Super-Yang-Mills from Matrix Model

We compute the expectation value of the circular Wilson loop in N=2 supersymmetric Yang-Mills theory with N_f=2N hypermultiplets. Our results indicate that the string tension in the dual string theory scales as the logarithm of the 't Hooft coupling.Comment: 37 pages, 9 figures; v2: Numerical factors corrected, simple derivation of Wilson loop and discussion of continuation to complex lambda added; v3: instanton partition function re-analyzed in order to take into account a contribution of the hypermultiplet

Anomalous diffusion in polymers: long-time behaviour

We study the Dirichlet boundary value problem for viscoelastic diffusion in polymers. We show that its weak solutions generate a dissipative semiflow. We construct the minimal trajectory attractor and the global attractor for this problem.Comment: 13 page

Trial protocol OPPTIMUM : does progesterone prophylaxis for the prevention of preterm labour improve outcome?

Background Preterm birth is a global problem, with a prevalence of 8 to 12% depending on location. Several large trials and systematic reviews have shown progestogens to be effective in preventing or delaying preterm birth in selected high risk women with a singleton pregnancy (including those with a short cervix or previous preterm birth). Although an improvement in short term neonatal outcomes has been shown in some trials these have not consistently been confirmed in meta-analyses. Additionally data on longer term outcomes is limited to a single trial where no difference in outcomes was demonstrated at four years of age of the child, despite those in the “progesterone” group having a lower incidence of preterm birth. Methods/Design The OPPTIMUM study is a double blind randomized placebo controlled trial to determine whether progesterone prophylaxis to prevent preterm birth has long term neonatal or infant benefit. Specifically it will study whether, in women with singleton pregnancy and at high risk of preterm labour, prophylactic vaginal natural progesterone, 200 mg daily from 22 – 34 weeks gestation, compared to placebo, improves obstetric outcome by lengthening pregnancy thus reducing the incidence of preterm delivery (before 34 weeks), improves neonatal outcome by reducing a composite of death and major morbidity, and leads to improved childhood cognitive and neurosensory outcomes at two years of age. Recruitment began in 2009 and is scheduled to close in Spring 2013. As of May 2012, over 800 women had been randomized in 60 sites. Discussion OPPTIMUM will provide further evidence on the effectiveness of vaginal progesterone for prevention of preterm birth and improvement of neonatal outcomes in selected groups of women with singleton pregnancy at high risk of preterm birth. Additionally it will determine whether any reduction in the incidence of preterm birth is accompanied by improved childhood outcome