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A new method for the reproducible generation of polymorphs: two forms of sulindac with very different solubilities
Polymorphism of drugs has been the subject of intense interest in the pharmaceutical industry for over forty years. Although identical in chemical composition, polymorphs differ in bioavailability, solubility, dissolution rate, chemical and physical stability, melting point, colour, filterability, density, flow properties, and many other properties. The difference in solubility is particularly important for pharmaceuticals, as it can affect drug efficacy, bioavailability and safety. Despite significant investment in processes to find all the possible polymorphs of active pharmaceutical ingredients (APIs), new polymorphs can suddenly appear without warning. Polymorphs tend to convert spontaneously from less stable to more stable forms, and, therefore, it is best to discover and characterize the stable form as early as possible. Ideally the most stable polymorph will be found while the drug candidate is still in the discovery process, so that this is the form used for subsequent testing. The most stable polymorph will be the least soluble and solubility may be a limiting factor in the efficacy of the API. Despite the huge importance of polymorphism in the properties of materials, however, there is no method that can produce all the stable polymorphs of a compound, or even one that can provide confidence that the most stable polymorph has been obtained. Here we describe a new method, `potentiometric cycling for polymorph creation (PC)2', which is able to generate the most stable polymorph in aqueous solution. This new method has been applied to sulindac, a non-steroidal anti-inflammatory drug, which also shows promise in anticancer treatment, producing two polymorphs of this API, including a new more stable one. By adjusting the conditions, this method is able to produce either polymorph exclusively.</jats:p
PNAS plus: plasmodium falciparum responds to amino acid starvation by entering into a hibernatory state
The human malaria parasite Plasmodium falciparum is auxotrophic for most amino acids. Its amino acid needs are met largely through the degradation of host erythrocyte hemoglobin; however the parasite must acquire isoleucine exogenously, because this amino acid is not present in adult human hemoglobin. We report that when isoleucine is withdrawn from the culture medium of intraerythrocytic P. falciparum, the parasite slows its metabolism and progresses through its developmental cycle at a reduced rate. Isoleucine-starved parasites remain viable for 72 h and resume rapid growth upon resupplementation. Protein degradation during starvation is important for maintenance of this hibernatory state. Microarray analysis of starved parasites revealed a 60% decrease in the rate of progression through the normal transcriptional program but no other apparent stress response. Plasmodium parasites do not possess a TOR nutrient-sensing pathway and have only a rudimentary amino acid starvation-sensing eukaryotic initiation factor 2α (eIF2α) stress response. Isoleucine deprivation results in GCN2-mediated phosphorylation of eIF2α, but kinase-knockout clones still are able to hibernate and recover, indicating that this pathway does not directly promote survival during isoleucine starvation. We conclude that P. falciparum, in the absence of canonical eukaryotic nutrient stress-response pathways, can cope with an inconsistent bloodstream amino acid supply by hibernating and waiting for more nutrient to be provided
A role for fast rhythmic bursting neurons in cortical gamma oscillations in vitro
Basic cellular and network mechanisms underlying gamma frequency oscillations (30–80 Hz) have been well characterized in the hippocampus and associated structures. In these regions, gamma rhythms are seen as an emergent property of networks of principal cells and fast-spiking interneurons. In contrast, in the neocortex a number of elegant studies have shown that specific types of principal neuron exist that are capable of generating powerful gamma frequency outputs on the basis of their intrinsic conductances alone. These fast rhythmic bursting (FRB) neurons (sometimes referred to as "chattering" cells) are activated by sensory stimuli and generate multiple action potentials per gamma period. Here, we demonstrate that FRB neurons may function by providing a large-scale input to an axon plexus consisting of gap-junctionally connected axons from both FRB neurons and their anatomically similar counterparts regular spiking neurons. The resulting network gamma oscillation shares all of the properties of gamma oscillations generated in the hippocampus but with the additional critical dependence on multiple spiking in FRB cells
Stimulus - response curves of a neuronal model for noisy subthreshold oscillations and related spike generation
We investigate the stimulus-dependent tuning properties of a noisy ionic
conductance model for intrinsic subthreshold oscillations in membrane potential
and associated spike generation. On depolarization by an applied current, the
model exhibits subthreshold oscillatory activity with occasional spike
generation when oscillations reach the spike threshold. We consider how the
amount of applied current, the noise intensity, variation of maximum
conductance values and scaling to different temperature ranges alter the
responses of the model with respect to voltage traces, interspike intervals and
their statistics and the mean spike frequency curves. We demonstrate that
subthreshold oscillatory neurons in the presence of noise can sensitively and
also selectively be tuned by stimulus-dependent variation of model parameters.Comment: 19 pages, 7 figure
The Case for Dynamic Models of Learners' Ontologies in Physics
In a series of well-known papers, Chi and Slotta (Chi, 1992; Chi & Slotta,
1993; Chi, Slotta & de Leeuw, 1994; Slotta, Chi & Joram, 1995; Chi, 2005;
Slotta & Chi, 2006) have contended that a reason for students' difficulties in
learning physics is that they think about concepts as things rather than as
processes, and that there is a significant barrier between these two
ontological categories. We contest this view, arguing that expert and novice
reasoning often and productively traverses ontological categories. We cite
examples from everyday, classroom, and professional contexts to illustrate
this. We agree with Chi and Slotta that instruction should attend to learners'
ontologies; but we find these ontologies are better understood as dynamic and
context-dependent, rather than as static constraints. To promote one
ontological description in physics instruction, as suggested by Slotta and Chi,
could undermine novices' access to productive cognitive resources they bring to
their studies and inhibit their transition to the dynamic ontological
flexibility required of experts.Comment: The Journal of the Learning Sciences (In Press
Regional differences in modelled net production and shallow remineralization in the North Atlantic subtropical gyre
© The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Biogeosciences 9 (2012): 2831-2846, doi:10.5194/bg-9-2831-2012.We used 5-yr concomitant data of tracer distribution from the BATS (Bermuda Time-series Study) and ESTOC (European Station for Time-Series in the Ocean, Canary Islands) sites to build a 1-D tracer model conservation including horizontal advection, and then compute net production and shallow remineralization rates for both sites. Our main goal was to verify if differences in these rates are consistent with the lower export rates of particulate organic carbon observed at ESTOC. Net production rates computed below the mixed layer to 110 m from April to December for oxygen, dissolved inorganic carbon and nitrate at BATS (1.34±0.79 mol O2 m−2, −1.73±0.52 mol C m−2 and −125±36 mmol N m−2) were slightly higher for oxygen and carbon compared to ESTOC (1.03±0.62 mol O2 m−2, −1.42±0.30 mol C m−2 and −213±56 mmol N m−2), although the differences were not statistically significant. Shallow remineralization rates between 110 and 250 m computed at ESTOC (−3.9±1.0 mol O2 m−2, 1.53±0.43 mol C m−2 and 38±155 mmol N m−2) were statistically higher for oxygen compared to BATS (−1.81±0.37 mol O2 m−2, 1.52±0.30 mol C m−2 and 147±43 mmol N m−2). The lateral advective flux divergence of tracers, which was more significant at ESTOC, was responsible for the differences in estimated oxygen remineralization rates between both stations. According to these results, the differences in net production and shallow remineralization cannot fully explain the differences in the flux of sinking organic matter observed between both stations, suggesting an additional consumption of non-sinking organic matter at ESTOC.B. Mourino was supported by the
Ramon y Cajal program from the Spanish Minister of Science and
Technology. Funding for this study was provided by the Xunta de
Galicia under the research project VARITROP (09MDS001312PR,
PI B. Mourino) and by the Ministerio de Ciencia e Innovation
MOMAC project (CTM2008-05914/MAR)
Chemical Power for Microscopic Robots in Capillaries
The power available to microscopic robots (nanorobots) that oxidize
bloodstream glucose while aggregated in circumferential rings on capillary
walls is evaluated with a numerical model using axial symmetry and
time-averaged release of oxygen from passing red blood cells. Robots about one
micron in size can produce up to several tens of picowatts, in steady-state, if
they fully use oxygen reaching their surface from the blood plasma. Robots with
pumps and tanks for onboard oxygen storage could collect oxygen to support
burst power demands two to three orders of magnitude larger. We evaluate
effects of oxygen depletion and local heating on surrounding tissue. These
results give the power constraints when robots rely entirely on ambient
available oxygen and identify aspects of the robot design significantly
affecting available power. More generally, our numerical model provides an
approach to evaluating robot design choices for nanomedicine treatments in and
near capillaries.Comment: 28 pages, 7 figure
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