Unexpected posthemorrhagic hydrocephalus in patients treated with rFVIIa.
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Aged↗
Biomedical subjects
S Subramaniam
Publications and source records attributed to S Subramaniam.
Extracellular signal-regulated kinase as an inducer of non-apoptotic neuronal death.
Extracellular signal-regulated kinase (ERK) is a versatile protein kinase, which has been implicated in signaling numerous biological functions ranging from embryonic development to memory formation. Recent reports, including ours, indicate that ERK plays a central role in promoting neuronal degeneration in various neuronal systems including neurodegenerative diseases. Mechanisms involved in ERK-induced neuronal degeneration are beginning to emerge. In this review, we summarize evidence suggesting ERK to be a predominant inducer of a non-apoptotic mode of neuronal death. Further, we discuss the mechanisms and the putative molecular inter-players associated with ERK-mediated neuronal death.
Animals↗
Objective decomposition of the stress tensor in granular flows.
A model for the stress tensor in granular flows [Volfson, Tsimring, and Aranson, Phys. Rev. Lett. 90, 254301 (2003)] is correctly generalized to an objective form that is independent of the coordinate system. The objective representation correctly models the isotropic and anisotropic parts of the stress tensor, whereas the original model for stress tensor components is dependent on the coordinate system. This general objective form of the model also relaxes the assumption in the original model that the principal axes of the granular stress tensor be coaxial with that of the "fluid" stress tensor. This generalization expands the applicability of the model to a wider class of granular flows. The objective representation is also useful in analyzing other models based on additive decomposition of the stress tensor in granular flows.
Journal Article↗
Reduced-order modelling of biochemical networks: application to the GTPase-cycle signalling module.
Biochemical systems embed complex networks and hence development and analysis of their detailed models pose a challenge for computation. Coarse-grained biochemical models, called reduced-order models (ROMs), consisting of essential biochemical mechanisms are more useful for computational analysis and for studying important features of a biochemical network. The authors present a novel method to model-reduction by identifying potentially important parameters using multidimensional sensitivity analysis. A ROM is generated for the GTPase-cycle module of m1 muscarinic acetylcholine receptor, Gq, and regulator of G-protein signalling 4 (a GTPase-activating protein or GAP) starting from a detailed model of 48 reactions. The resulting ROM has only 17 reactions. The ROM suggested that complexes of G-protein coupled receptor (GPCR) and GAP--which were proposed in the detailed model as a hypothesis--are required to fit the experimental data. Models previously published in the literature are also simulated and compared with the ROM. Through this comparison, a minimal ROM, that also requires complexes of GPCR and GAP, with just 15 parameters is generated. The proposed reduced-order modelling methodology is scalable to larger networks and provides a general framework for the reduction of models of biochemical systems.
Algorithms↗
A concise review of the basic biology and pharmacology of local analgesia.
Local analgesics are the most commonly used group drugs in dental practice. However, due to their frequent use and high margin of safety, often dental practitioners neglect to properly understand the biology and pharmacology of these drugs. This article reviews the basic concepts of pain, pain pathways, the mode of action of local analgesics and factors which affect their usage. Specific details and properties of some currently available solutions are also outlined. A greater understanding of the biology and pharmacology of local anaesthetics will ultimately lead to safer and more effective use in everyday clinical practice.
Analgesia↗
Histoplasmosis of the larynx.
Primary histoplasmosis of the larynx is not a common disease. Most cases of laryngeal histoplasmosis results from hematogenous spread of disseminated histoplasmosis usually originating from pulmonary infection by Histoplasma capsulatum. We report a 52-year-old male chronic smoker who had prolonged hoarseness and was initially diagnosed with laryngeal carcinoma. However, biopsy of the laryngeal mucosa confirmed the diagnosis of histoplasmosis. There were no signs of pulmonary or systemic involvement. Treatment with intravenous amphotericin B was given for a week and oral ketaconazole was given for a month with complete resolution of symptoms.
Diagnosis, Differential↗
Sterilisation of Lucilia cuprina Wiedemann maggots used in therapy of intractable wounds.
Three new techniques of sterilising maggots of Lucilia cuprina for the purpose of debriding intractable wounds were studied. These techniques were utilisation of ultra-violet C (UVC) and maggot sterilisation with disinfectants. The status of sterility was checked on nutrient agar and blood agar and confirmed with staining. The indicators for the effectiveness of the methods were sterility and survival rate of the eggs or larvae. Egg sterilisation with UVC had the lowest hatching rate (16+/-0.00%) while egg sterilisation with disinfectants showed high hatching rate (36.67+/-4.41%) but low maggot survival rate (31.67+/-1.67%). Sterilisation of the maggots was the most suitable, since the survival rate was the highest (88.67+/-0.88%). Complete sterility was achieved in all cases, except that Proteus mirabilis was consistently found. However, the presence of this microorganism was considered beneficial.
Alcohols↗
Variance-modeled posterior inference of microarray data: detecting gene-expression changes in 3T3-L1 adipocytes.
MOTIVATION: Microarrays are becoming an increasingly common tool for observing changes in gene expression over a large cross section of the genome. This experimental tool is particularly valuable for understanding the genome-wide changes in gene transcription in response to thiazolidinedione (TZD) treatment. The TZD class of drugs is known to improve insulin-sensitivity in diabetic patients, and is clinically used in treatment regimens. In cells, TZDs bind to and activate the transcriptional activity of peroxisome proliferator-activated receptor gamma (PPAR-gamma). Large-scale array analyses will provide some insight into the mechanisms of TZD-mediated insulin sensitization. Unfortunately, a theoretical basis for analyzing array data has not kept pace with the rapid adoption of this tool. The methods that are commonly used, particularly the fold-change approach and the standard t-test, either lack statistical rigor or resort to generalized statistical models that do not accurately estimate variability at low replicate numbers. RESULTS: We introduce a statistical framework that models the dependence of measurement variance on the level of gene expression in the context of a Bayesian hierarchical model. We compare several methods of parameter estimation and subsequently apply these to determine a set of genes in 3T3-L1 adipocytes that are differentially regulated in response to TZD treatment. When the number of experimental replicates is low (n = 2-3), this approach appears to qualitatively preserve an equivalent degree of specificity, while vastly improving sensitivity over other comparable methods. In addition, the statistical framework developed here can be readily applied to understand the implicit assumptions made in traditional fold-change approaches to array analysis.
3T3-L1 Cells↗
Direct visualization of receptor arrays in frozen-hydrated sections and plunge-frozen specimens of E. coli engineered to overproduce the chemotaxis receptor Tsr.
We have recently reported electron tomographic studies of sections obtained from chemically fixed E. coli cells overproducing the 60-kDa chemotaxis receptor Tsr. Membrane extracts from these cells prepared in the presence of Tween-80 display hexagonally close-packed microcrystalline assemblies of Tsr, with a repeating unit large enough to accommodate six Tsr molecules arranged as trimers of receptor dimers. Here, we report the direct visualization of the Tsr receptor clusters in (i) vitrified cell suspensions of cells overproducing Tsr, prepared by rapid plunge-freezing, and (ii) frozen-hydrated sections obtained from cells frozen under high pressure. The frozen-hydrated sections were generated by sectioning at -150 degrees C using a diamond knife with a 25 degrees knife angle, with nominal thicknesses ranging from 20 to 60 nm. There is excellent correspondence between the spatial arrangement of receptors in thin frozen-hydrated sections and the arrangements found in negatively stained membrane extracts and plunge-frozen cells, highlighting the potential of using frozen-hydrated sections for the study of macromolecular assemblies within cells under near-native conditions.
Bacterial Proteins↗
Late cytomegalovirus infection after oral ganciclovir prophylaxis in renal transplant recipients.
The purpose of this study was to retrospectively review our experience with a consecutive group of 41 renal transplant recipients (R) who received a kidney from a cytomegalovirus (CMV) seropositive donor (D(+)) and had 3 months of prophylaxis with oral ganciclovir. Patients were prospectively monitored clinically and with determinations of CMV antigenemia for at least 6 months. Patients were followed for a mean period of 247+/-16 days. CMV antigenemia developed in 51% of patients (53% D(+)R(-), 47% D(+)R(+)) after the transplant, but in no case was antigenemia seen during the period of oral ganciclovir therapy. Antigenemia developed at a median of 167 days post transplant (range 99-522 days) and peak antigen counts ranged from <1-3940, and tended to be higher in D(+)R(-) recipients. Infection was symptomatic in 67% of the antigenemic patients and symptoms tended to be more marked in the D(+)/R(-) than in the D(+)/R(+) group. All symptomatic patients were treated with intravenous ganciclovir (21 days) followed by 9 weeks of oral ganciclovir and responded with resolution of symptoms and antigenemia. No evidence of tissue-invasive disease was seen. Recurrence of antigenemia was observed exclusively in the D(+)R(-) group, occurred with less severe manifestations of CMV infection, and invariably responded to retreatment with ganciclovir. Our results suggest that oral ganciclovir prophylaxis is effective in preventing CMV infection during the 3-month period of prophylaxis, that a 3-month period of prophylaxis appears to be sufficient for D(+)R(+) recipients, but a longer period of oral ganciclovir prophylaxis may be needed in D(+)R(-) recipients. Clinicians caring for renal transplant recipients should be vigilant to the possibility of late CMV infection, especially in D(+)R(-) recipients.
Administration, Oral↗
Eagle's syndrome.
Eagle's syndrome is an uncommon condition resulting from an elongated styloid process, which causes cervico facial pain, tinnitus and otalgia. A 48-year-old female presented to the clinic with bilateral upper neck pain radiating to the ears with tinnitus for almost one-year duration. Examination of the oral cavity revealed atrophic tonsils and palpable bony projection deep in the tonsillar fossa. Plain lateral neck X-ray and CT scan confirmed the presence of bilateral elongated styloid processes, which were subsequently resected surgically through an oropharyngeal approach. The patient was asymptomatic at follow up at 2 years.
Earache↗
Proton translocation by bacteriorhodopsin in the absence of substantial conformational changes.
Unlike wild-type bacteriorhodopsin (BR), the BR triple mutant D96G/F171C/F219L has been shown to undergo only minor structural rearrangements during its photocycle. Nonetheless, the mutant is capable of transporting protons at a rate of 125(+/-40) H+/BR per minute under light-saturating conditions. Light adaptation of the triple mutant's retinal proceeds in a pH-dependent manner up to a maximum of 63% all-trans. These two findings imply that the transport activity of the triple mutant comprises 66% of the wild-type activity. Time-resolved spectroscopy reveals that the identity and sequence of intermediates in the photocycle of the triple mutant in the all-trans configuration correspond to that of wild-type BR. The only differences relate to a slower rise and decay of the M and O intermediates, and a significant spectral contribution from a 13-cis component. No indication for accumulation of the N intermediate is found under a variety of conditions that normally favor the formation of this species in wild-type BR. The Fourier transform infrared (FTIR) spectrum of the M intermediate in the triple mutant resembles that of wild type. Minor changes in the amide I region during the photocycle suggest that only small movements of the protein backbone occur. Electron microscopy reveals large differences in conformation between the unilluminated state of the mutant protein and wild-type but no light-induced changes in time-resolved measurements. Evidently, proton transport by the triple mutant does not require the major conformational rearrangements that occur on the same time-scale with wild-type. Thus, we conclude that large conformational changes observed in the photocycle of the wild-type and many BR mutants are not a prerequisite for the change in accessibility of the Schiff base nitrogen atom that must occur during vectorial catalysis to allow proton transport.
Archaea↗
Projection structure and molecular architecture of OxlT, a bacterial membrane transporter.
The major facilitator superfamily (MFS) represents the largest collection of evolutionarily related members within the class of membrane 'carrier' proteins. OxlT, a representative example of the MFS, is an oxalate-transporting membrane protein in Oxalobacter formigenes. From an electron crystallographic analysis of two-dimensional crystals of OxlT, we have determined the projection structure of this membrane transporter. The projection map at 6 A resolution indicates the presence of 12 transmembrane helices in each monomer of OxlT, with one set of six helices related to the other set by an approximate internal two-fold axis. The projection map reveals the existence of a central cavity, which we propose to be part of the pathway of oxalate transport. By combining information from the projection map with related biochemical data, we present probable models for the architectural arrangement of transmembrane helices in this protein superfamily.
Amino Acid Sequence↗
Differential changes in synaptic terminal protein expression between nucleus accumbens core and shell in the amphetamine-sensitized rat.
Repeated, intermittent administration of psychostimulant drugs such as D-amphetamine (AMPH) produces a state of behavioral sensitization to the drug that can last up to weeks to months. The molecular basis of this enhanced sensitivity to AMPH is poorly understood; however, adaptive changes in the mesocorticolimbic dopamine system has been postulated to be of primary importance. In the present investigation we used Western blotting to examine the expression of candidate presynaptic proteins involved in regulating neurotransmitter release and synaptic plasticity. Specifically, syntaxin 1, synaptophysin and synapsin I protein levels were examined in the nucleus accumbens (Nacc) and ventral tegmental area (VTA) of Sprague-Dawley rats following AMPH-sensitization. Animals received five repeated administrations of AMPH (1.5 mg/kg, i.p. on alternate days) followed by 14 days of withdrawal. Levels of syntaxin 1 and synaptophysin were found to be significantly reduced in the Nacc core of sensitized animals compared to saline-treated and untreated controls. However, syntaxin 1 expression was significantly increased in the Nacc shell subregion of sensitized animals. No significant difference in the level of synapsin I was noted in any of the brain regions. Further, expression of none of the synaptic proteins was significantly altered in the VTA of sensitized animals. Given the importance of syntaxin and synaptophysin in learning and memory processes and in the regulation of neurotransmitter release, changes in these proteins suggest their involvement in the associative learning aspects of sensitization and differential neurotransmitter release in the Nacc subregions.
Amphetamine-Related Disorders↗
Automated data collection with a Tecnai 12 electron microscope: applications for molecular imaging by cryomicroscopy.
In high-resolution biological electron microscopy, the speed of collection of large numbers of high-quality micrographs is a rate-limiting step in the overall process of structure determination. Approaches to speed up data collection can be very useful, especially in "single-molecule" microscopy of large multiprotein and protein-nucleic acid complexes, where many thousands of individual molecular images need to be averaged to determine the three-dimensional structure. Toward this end, we report the development of automated low-dose image acquisition procedures on a Tecnai 12 electron microscope using the scripting functionality available on the microscope computer. At the lowest level of automation, the user is required to select regions of interest that are to be imaged. All subsequent steps of image acquisition are then carried out automatically to record high-resolution images on either film or CCD, at desired defocus values, under conditions that satisfy user-specified limits for drift rates of the specimen stage. At the highest level of automation, determination of the best grid squares and the best regions suitable for imaging are carried out automatically. A medium level of automation is also available in which the user can designate the most promising grid squares manually and leave the process of finding the best holes in those grid squares to the microscope computer. We also show that all steps subsequent to insertion of the specimen in the microscope can be carried out remotely by connecting to the microscope computer via the Internet. Both features are implemented using Windows NT and Web-based tools and provide tools for automated data collection on any Tecnai microscope from any location.
Cryoelectron Microscopy↗
Molecular simulation of dioleoylphosphatidylcholine lipid bilayers at differing levels of hydration.
The structure and dynamics of the lipid and water components of dioleoylphosphatidylcholine bilayers at various levels of hydration were studied using molecular dynamics (MD) simulations. Equilibration of these systems proceeded by use of a hybrid MD and configurational-bias Monte Carlo technique using one atmosphere of pressure normal to the membrane and a set point for the lateral area derived from experimental Bragg spacings, combined with experimentally derived specific volumes for each of the system components. Membrane surface tensions were observed to be of the order of tens of dyn/cm. The transbilayer molecular fragment peak positions at low hydration were found to agree with experimental neutron and x-ray scattering profiles and previously published simulations. For hydration levels of 5.4, 11.4, and 16 waters/lipid, molecular fragment distributions and order parameters for the headgroup, lipid chains, and water were quantified. Spin-lattice relaxation rates and lateral self-diffusion coefficients of water agreed well with results from experimental nuclear magnetic resonance studies. Relaxation rates of the choline segments and chemical shift anisotropies for the phosphate and carbonyls were computed. Headgroup orientation, as measured by the P-N vector, showed enhanced alignment with the membrane surface at low hydration. The sign of the membrane dipole potential reversed at low hydration, with the membrane interior negative relative to the interlamellar region. Calculation of the number of water molecules in the headgroup hydration shell, as a function of hydration level, supports the hypothesis that the break point in the curve of Bragg spacing versus hydration level near 12 waters/lipid, observed experimentally by Hristova and White (1988. Biophys. J. 74:2419-2433), marks the completion of the first hydration shell.
Anisotropy↗
Size tuning in the absence of spatial frequency tuning in object recognition.
How do we attend to objects at a variety of sizes as we view our visual world? Because of an advantage in identification of lowpass over highpass filtered patterns, as well as large over small images, a number of theorists have assumed that size-independent recognition is achieved by spatial frequency (SF) based coarse-to-fine tuning. We found that the advantage of large sizes or low SFs was lost when participants attempted to identify a target object (specified verbally) somewhere in the middle of a sequence of 40 images of objects, each shown for only 72 ms, as long as the target and distractors were the same size or spatial frequency (unfiltered or low or high bandpassed). When targets were of a different size or scale than the distractors, a marked advantage (pop out) was observed for large (unfiltered) and low SF targets against small (unfiltered) and high SF distractors, respectively, and a marked decrement for the complementary conditions. Importantly, this pattern of results for large and small images was unaffected by holding absolute or relative SF content constant over the different sizes and it could not be explained by simple luminance- or contrast-based pattern masking. These results suggest that size/scale tuning in object recognition was accomplished over the first several images (<576 ms) in the sequence and that the size tuning was implemented by a mechanism sensitive to spatial extent rather than to variations in spatial frequency.
Analysis of Variance↗
Early decentration of plate-haptic silicone intraocular lenses.
We report 4 eyes of a consecutive series of 1299 that developed early decentration of a 10.5 mm diameter plate-haptic silicone intraocular lens (IOL) after uneventful phacoemulsification. All eyes had an intact continuous curvilinear capsulorhexis (CCC) with the IOL placed in the capsular bag. After an initial period of good vision, patients noted the onset of glare or monocular diplopia between 1 and 5 weeks after surgery. On examination, there was no significant anterior capsule contraction; however, the edge of the IOL optic was visible in the undilated pupil. There was adhesion between the anterior and posterior capsules at the margin of the CCC that maintained the IOL decentration. Decentration recurred in 1 eye after the IOL was rotated 90 degrees and recentered. Symptoms resolved in 3 eyes after the IOL was removed and replaced with a rigid IOL with a larger diameter optic.
Device Removal↗