Coupling the topological defect phase to the extrinsic curvature in nematic shells.

In two dimensional nematics, topological defects are point like singularities with both a charge and a phase. We study the topological defects within curved nematic textures on the surface of a cylinder. This allows us to isolate the effect of extrinsic curvature on the structure of the topological defect. By minimizing the energy associated with distortions in the nematic director around the core of a defect, we show that the phase of the topological defect is coupled to the orientation of the cylinder. This coupling depends on the relative energetic cost associated with splay, bend and twist distortions of the nematic director. We identify a bistability in the phase of the defects when twist deformations dominate. Finally, we show a similar effect for integer charge topological defects.

Lost in Time: Temporal Monitoring Elicits Clinical Decrements in Sustained Attention Post-Stroke.

OBJECTIVES: Mental fatigue, 'brain fog', and difficulties maintaining engagement are commonly reported issues in a range of neurological and psychiatric conditions. Traditional sustained attention tasks commonly measure this capacity as the ability to detect target stimuli based on sensory features in the auditory or visual domains. However, with this approach, discrete target stimuli may exogenously capture attention to aid detection, thereby masking deficits in the ability to endogenously sustain attention over time. METHODS: To address this, we developed the Continuous Temporal Expectancy Task (CTET) where individuals continuously monitor a stream of patterned stimuli alternating at a fixed temporal interval (690 ms) and detect an infrequently occurring target stimulus defined by a prolonged temporal duration (1020 ms or longer). As such, sensory properties of target and non-target stimuli are perceptually identical and differ only in temporal duration. Using the CTET, we assessed stroke survivors with unilateral right hemisphere damage (N = 14), a cohort in which sustained attention deficits have been extensively reported. RESULTS: Stroke survivors had overall lower target detection accuracy compared with neurologically healthy age-matched older controls (N = 18). Critically, stroke survivors performance was characterised by significantly steeper within-block performance decrements, which occurred within short temporal windows (˜3 ½ min), and were restored by the break periods between blocks. CONCLUSIONS: These findings suggest that continuous temporal monitoring taxes sustained attention processes to capture clinical deficits in this capacity over time, and outline a precise measure of the endogenous processes hypothesised to underpin sustained attention deficits following right hemisphere stroke.

Orientational Correlations in Active and Passive Nematic Defects.

We investigate the emergence of orientational order among +1/2 disclinations in active nematic liquid crystals. Using a combination of theoretical and experimental methods, we show that +1/2 disclinations have short-range antiferromagnetic alignment, as a consequence of the elastic torques originating from their polar structure. The presence of intermediate -1/2 disclinations, however, turns this interaction from antialigning to aligning at scales that are smaller than the typical distance between like-sign defects. No long-range orientational order is observed. Strikingly, these effects are insensitive to material properties and qualitatively similar to what is found for defects in passive nematic liquid crystals.

Properties of twisted topological defects in 2D nematic liquid crystals.

Topological defects are one of the most conspicuous features of liquid crystals. In two dimensional nematics, they have been shown to behave effectively as particles with both charge and orientation, which dictate their interactions. Here, we study "twisted" defects that have a radially dependent orientation. We find that twist can be partially relaxed through the creation and annihilation of defect pairs. By solving the equations for defect motion and calculating the forces on defects, we identify four distinct elements that govern the relative relaxational motion of interacting topological defects, namely attraction, repulsion, co-rotation and co-translation. The interaction of these effects can lead to intricate defect trajectories, which can be controlled by setting relevant timescales.

Activity Driven Orientational Order in Active Nematic Liquid Crystals on an Anisotropic Substrate.

We investigate the effect of an anisotropic substrate on the turbulent dynamics of a simulated two-dimensional active nematic. This is introduced as an anisotropic friction and an effective anisotropic viscosity, with the orientation of the anisotropy being defined by the substrate. In this system, we observe the emergence of global nematic order of topological defects that is controlled by the degree of anisotropy in the viscosity and the magnitude of the active stress. No global defect alignment is seen in passive liquid crystals with anisotropic viscosity or friction confirming that ordering is driven by the active stress. We then closely examine the active flow generated by a single defect to show that the net kinetic energy of the flow is dependent on the orientation of the defect relative to the substrate, resulting in a torque on the defect to align it with the anisotropy in the substrate.

Geometrical Control of Active Turbulence in Curved Topographies.

We investigate the turbulent dynamics of a two-dimensional active nematic liquid crystal constrained to a curved surface. Using a combination of hydrodynamic and particle-based simulations, we demonstrate that the fundamental structural features of the fluid, such as the topological charge density, the defect number density, the nematic order parameter, and defect creation and annihilation rates, are approximately linear functions of the substrate Gaussian curvature, which then acts as a control parameter for the chaotic flow. Our theoretical predictions are then compared with experiments on microtubule-kinesin suspensions confined on toroidal droplets, finding excellent qualitative agreement.

Influenza as a trigger for cardiovascular disease: An investigation of serotype, subtype and geographic location.

BACKGROUND: Seasonal peaks of influenza and cardiovascular disease tend to coincide. Many excess deaths may be triggered by influenza, and the severity of this effect may vary with the virulence of the circulating influenza strain and host susceptibility. We aimed to explore the association between hospital admissions for influenza and/or pneumonia (IP) and acute myocardial infarction (AMI) or ischaemic heart disease (IHD) in Queensland, Australia, taking into account temporal and spatial variation of influenza virus type and subtype in 2007, 2008 and 2009. METHODS: This ecological study at Statistical Subdivision level (SSD, n=38) used linked patient-level data. For each study year, Standardized Morbidity Ratios (SMRs) were calculated for hospital admissions with diagnoses of IP, AMI and IHD. We investigated the associations between IP and AMI or IHD using spatial autoregressive modelling, adjusting for socio-demographic factors. RESULTS: Spatial autocorrelation was detected in SMRs, possibly reflecting underlying social and behavioural risk factors, but consistent with infectious disease spread. SMRs for IP were consistently predictive of SMRs for AMI and IHD when adjusted for socioeconomic status, population density and per cent Indigenous population (coefficient: 0.707, 95% confidence interval (CI): 0.318 - 1.096; 0.553, 0.222 - 0.884; 0.598, 0.307 - 0.888 and 1.017, 0.711 - 1.323; 0.650, 0.342 - 0.958; 1.031, 0.827 - 1.236) in 2007, 2008 and 2009, respectively. CONCLUSIONS: This ecological study provides further evidence that severe respiratory infections may trigger the onset of cardiovascular events, implicating the influenza virus as a contributing factor.

Entrance and propagation pattern of high-frequency electrical currents in biological tissues as applied to fractional skin rejuvenation using penetrating electrodes.

BACKGROUND: Fractional resurfacing of the skin using radiofrequency devices has been used for collagen remodeling and rejuvenation. OBJECTIVES: To determine how radiofrequency current enters and propagates through tissue, and the pattern of the resulting effect. MATERIALS AND METHODS: An electrosurgical device with a 0.4 MHz frequency output was used as the source of radiofrequency current. Current was applied via a metallic needle introduced into a large piece of cow liver, with different amounts of energy delivered at multiple points. Cross-sections of the liver were then studied for tissue effect. RESULTS: Thermal coagulation of tissue started from the tip of the electrode. With higher energy, a rim of coagulated tissue formed around the entire length of the needle. This rim of coagulated tissue was thicker around the tip of the electrode. CONCLUSION: Radiofrequency currents have a tendency to move toward the center of the bulk of tissue. When an electrode of a fractional radiofrequency device enters the skin, maximum heating effect will be around the tip of the electrode in the dermis. This phenomenon can preserve epidermis from injury during dermal heating, reducing post-procedural skin surface side effects seen with many skin rejuvenation procedures.

Action of BTN1, the yeast orthologue of the gene mutated in Batten disease.

Neuronal ceroid-lipofuscinoses (NCL) are autosomal recessive disorders that form the most common group of progressive neurodegenerative diseases in children, with an incidence as high as 1 in 12,500 live births, and with approximately 440,000 carriers in the United States. Disease progression is characterized by a decline in mental abilities, increased severity of untreatable seizures, blindness, loss of motor skills and premature death. The CLN3 gene, which is responsible for Batten disease, has been positionally cloned. The yeast gene, denoted BTN1, encodes a non-essential protein that is 39% identical and 59% similar to human CLN3. Strains lacking Btn1p, btn1-delta, are resistant to D-(-)-threo-2-amino-1-[p-nitrophenyl]-1,3-propanediol (ANP) in a pH-dependent manner. This phenotype was complemented by expression of human CLN3, demonstrating that yeast Btn1p and human CLN3 share the same function. Here, we report that btn1-delta yeast strains have an abnormally acidic vacuolar pH in the early phases of growth. Furthermore, DNA microarray analysis of BTN1 and btn1-delta strains revealed differential expression of two genes, with at least one, HSP30, involved in pH control. Because Btn1p is located in the vacuole, we suggest that Batten disease is caused by a defect in vacuolar (lysosomal) pH control. Our findings draw parallels between fundamental biological processes in yeast and previously observed characteristics of neurodegeneration in humans.

Control of Mycobacterium tuberculosis growth by activated natural killer cells.

We characterized the underlying mechanisms by which glutathione (GSH)-enhanced natural killer (NK) cells inhibit the growth of Mycobacterium tuberculosis (M. tb) inside human monocytes. We observed that in healthy individuals, treatment of NK cells with N-acetyl cysteine (NAC), a GSH prodrug in conjunction with cytokines such as interleukin (IL)-2 + IL-12, resulted in enhanced expression of NK cytotoxic ligands (FasL and CD40L) with concomitant stasis in the intracellular growth of M. tb. Neutralization of FasL and CD40L in IL-2 + IL-12 + NAC-treated NK cells resulted in abrogation in the growth inhibition of M. tb inside monocytes. Importantly, we observed that the levels of GSH are decreased significantly in NK cells derived from individuals with HIV infection compared to healthy subjects, and this decrease correlated with a several-fold increase in the growth of M. tb inside monocytes. This study describes a novel innate defence mechanism adopted by NK cells to control M. tb infection.

Electronic medical record reduces HIV medication refill response time and emergency refills in a Latino community clinic.

In May 2006, our community clinic, serving mainly indigent HIV+ Latinos, initiated an electronic medical record (EMR) system that transmitted refill requests and responses between the pharmacy's software to and from the EMR. Prior to this time, refill requests had been perceived as delayed at times due to system problems and pharmacies had responded by issuing emergency refills of antiretrovirals to prevent possible medication resistance and morbidity as may result from missed doses. The EMR service appeared to reduce response time and errors. HealthMatics EMR and the Internet service SureScripts, in cooperation with two MOMS pharmacies, were utilized. We compared the following data from before EMR initiation and after 10 months of use: number of emergency refills/28 days, response times of the clinic to refill requests and opinions of the pharmacists. The average refill response time decreased from 1.57 to 1.04 days (P < 0.004) from 2006 (n = 115) to 2007 (n = 217). Variance decreased from 3.53 to 1.73, respectively, between two same 28-day periods. Before EMR, one pharmacy felt the response times were worse than other clinics, but both perceived general improvement with EMR. The numbers of emergency refills per period were 88 and <1 respectively. In conclusion, with the utilization of EMR for medication refill requests, (1) there was a statistically significant decrease in emergency refill utilization, (2) there was a statistically significant improvement in the response time to a refill request, and (3) pharmacists perceived improvement in response times.

Altered arginine metabolism in the central nervous system (CNS) of the Cln3-/- mouse model of juvenile Batten disease.

BACKGROUND: Juvenile neuronal ceroid lipofuscinoses (JNCL) or juvenile Batten disease is a recessively inherited childhood neurodegenerative disorder resulting from a mutation in CLN3, which encodes a putative lysosomal protein of unknown function. AIM: Recent evidence suggests that a disruption in CLN3 function results in altered regulation of arginine transport into lysosomes, and may influence intracellular arginine levels. We sought to investigate the possible consequences of arginine dysregulation in the brain of the Cln3(-/-) mouse model of JNCL. METHODS: Using a combination of enzyme assays, metabolite profiling, quantitative reverse-transcription polymerase chain reaction and Western blotting, we analysed the activities and expression of enzymes involved in arginine metabolism in the cerebral cortex and cerebellum of Cln3(-/-) mice over several developmental time points. RESULTS: We report subtle, but significant changes in the activities of enzymes involved in the citrulline-NO recycling pathway, and altered regulation of neuronal nitric oxide synthase in the cortex and cerebellum of Cln3(-/-) mice. In addition, a significant decrease in arginine transport into cerebellar granule cells was observed, despite an apparent upregulation of the cationic amino acid transporter-1 transporter at the cell surface. Our results provide further evidence that CLN3 function and arginine homeostasis are intricately related, and that cellular mechanisms may act to compensate for the loss of this protein. CONCLUSIONS: This and other studies indicate that CLN3 dysfunction in JNCL may result in multiple disturbances in metabolism that together contribute to the pathophysiological processes underlying this disease.

Mineralocorticoid and glucocorticoid receptor activities distinguished by nonreceptor factors at a composite response element.

Mineralocorticoid and glucocorticoid hormones elicit distinct physiologic responses, yet the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) bind to and activate transcription similarly from a consensus simple hormone response element (HRE). The activities of GR and MR at plfG, a 25-base pair composite response element to which both the steroid receptors and transcription factor AP1 can bind, are analyzed here. Under conditions in which GR represses AP1-stimulated transcription from plfG, MR was inactive. With the use of MR-GR chimeras, a segment of the NH2-terminal region of GR (amino acids 105 to 440) was shown to be required for this repression. Thus, the distinct physiologic effects mediated by MR and GR may be determined by differential interactions of nonreceptor factors with specific receptor domains at composite response elements.

Gibberellins: a phytohormonal basis for heterosis in maize.

Four commercially important maize parental inbreds and their 12 F(1) hybrids were studied to investigate the role of the phytohormone gibberellin (GA) in the regulation of heterosis (hybrid vigor). All hybrids grew faster than any inbred. In contrast, all inbreds showed a greater promotion of shoot growth after the exogenous application of GA(3). Concentrations of endogenous GA(1), the biological effector for shoot growth in maize, and GA(19), a precursor of GA(1), were measured in apical meristematic shoot cylinders for three of the inbreds and their hybrids by gas chromatography-mass spectrometry with selected ion monitoring; deuterated GAs were used as quantitative internal standards. In 34 of 36 comparisons, hybrids contained higher concentrations of endogenous GAs than their parental inbreds. Preferential growth acceleration of the inbreds by exogenous GA(3) indicates that a deficiency of endogenous GA limits the growth of the inbreds and is thus a cause of inbreeding depression. Conversely, the increased endogenous concentration of GA in the hybrids could provide a phytohormonal basis for heterosis for shoot growth.

Cellular geometry controls the efficiency of motile sperm aggregates.

Sperm that swim collectively to the fertilization site have been observed across several vertebrate and invertebrate species, with groups ranging in size from sperm pairs to massive aggregates containing hundreds of cells. Although the molecular mechanisms that regulate sperm-sperm adhesion are still unclear, aggregation can enhance sperm motility and thus offer a fertilization advantage. Here, we report a thorough computational investigation on the role of cellular geometry in the performance of sperm aggregates. The sperm head is modelled as a persistent random walker characterized by a non-trivial three-dimensional shape and equipped with an adhesive region where cell-cell binding occurs. By considering both, a simple parametric head shape and a computer reconstruction of a real head shape based on morphometric data, we demonstrate that the geometry of the head and the structure of the adhesive region crucially affects both the stability and motility of the aggregates. Our analysis further suggests that the apical hook commonly found in the sperm of muroid rodents might serve to shield portions of the adhesive region and promote efficient alignment of the velocities of the interacting cells.

Expression of rat renal Na/H antiporter mRNA levels in response to respiratory and metabolic acidosis.

The mammalian proximal tubule is an important mediator of the renal adaptive response to systemic acidosis. In chronic metabolic and respiratory acidosis the bicarbonate reabsorptive (or proton secretory) capacity is increased. This increase is mediated, at least in part, by an increase in Vmax of the luminal Na/H antiporter. To determine whether this adaptation involves increased mRNA expression, Na/H antiporter mRNA levels were measured by Northern analysis in renal cortex of rats with metabolic (6 mmol/kg body wt NH4Cl for 2 or 5 d) and respiratory (10% CO2/air balanced for 2 or 5 d) acidosis and of normal, pair-fed rats. Na/H antiporter mRNA levels were unchanged after 2 d of both metabolic and respiratory acidosis. After 5 d, however, Na/H antiporter mRNA expression was increased 1.76 +/- 0.12-fold in response to metabolic acidosis (P less than 0.005, n = 8), but was not different from normal in response to respiratory acidosis: 1.1 +/- 0.2 (NS, n = 8). Thus, the renal adaptive response to metabolic acidosis involves increased cortical Na/H antiporter mRNA levels. In contrast, the enhanced proximal tubule Na/H antiporter activity and bicarbonate reabsorption in respiratory acidosis seem to involve mechanisms other than increased Na/H antiporter gene expression.

A common motif within the negative regulatory regions of multiple factors inhibits their transcriptional synergy.

DNA regulatory elements frequently harbor multiple recognition sites for several transcriptional activators. The response mounted from such compound response elements is often more pronounced than the simple sum of effects observed at single binding sites. The determinants of such transcriptional synergy and its control, however, are poorly understood. Through a genetic approach, we have uncovered a novel protein motif that limits the transcriptional synergy of multiple DNA-binding regulators. Disruption of these conserved synergy control motifs (SC motifs) selectively increases activity at compound, but not single, response elements. Although isolated SC motifs do not regulate transcription when tethered to DNA, their transfer to an activator lacking them is sufficient to impose limits on synergy. Mechanistic analysis of the two SC motifs found in the glucocorticoid receptor N-terminal region reveals that they function irrespective of the arrangement of the receptor binding sites or their distance from the transcription start site. Proper function, however, requires the receptor's ligand-binding domain and an engaged dimer interface. Notably, the motifs are not functional in yeast and do not alter the effect of p160 coactivators, suggesting that they require other nonconserved components to operate. Many activators across multiple classes harbor seemingly unrelated negative regulatory regions. The presence of SC motifs within them, however, suggests a common function and identifies SC motifs as critical elements of a general mechanism to modulate higher-order interactions among transcriptional regulators.

Distinct glucocorticoid receptor transcriptional regulatory surfaces mediate the cytotoxic and cytostatic effects of glucocorticoids.

Glucocorticoids act through the glucocorticoid receptor (GR), which can function as a transcriptional activator or repressor, to elicit cytostatic and cytotoxic effects in a variety of cells. The molecular mechanisms regulating these events and the target genes affected by the activated receptor remain largely undefined. Using cultured human osteosarcoma cells as a model for the GR antiproliferative effect, we demonstrate that in U20S cells, GR activation leads to irreversible growth inhibition, apoptosis, and repression of Bcl2. This cytotoxic effect is mediated by GR's transcriptional repression function, since transactivation-deficient mutants and ligands still bring about apoptosis and Bcl2 down-regulation. In contrast, the antiproliferative effect of GR in SAOS2 cells is reversible, does not result in apoptosis or repression of Bcl2, and is a function of the receptor's ability to stimulate transcription. Thus, the cytotoxic versus cytostatic outcome of glucocorticoid treatment is cell context dependent. Interestingly, the cytostatic effect of glucocorticoids in SAOS2 cells involves multiple GR activation surfaces. GR mutants and ligands that disrupt individual transcriptional activation functions (activation function 1 [AF-1] and AF-2) or receptor dimerization fail to fully inhibit cellular proliferation and, remarkably, discriminate between the targets of GR's cytostatic action, the cyclin-dependent kinase inhibitors p21(Cip1) and p27(Kip1). Induction of p21(Cip1) is agonist dependent and requires AF-2 but not AF-1 or GR dimerization. In contrast, induction of p27(Kip1) is agonist independent, does not require AF-2 or AF-1, but depends on GR dimerization. Our findings indicate that multiple GR transcriptional regulatory mechanisms that employ distinct receptor surfaces are used to evoke either the cytostatic or cytotoxic response to glucocorticoids.

Microbial metabolism directly affects trace gases in (sub) polar snowpacks.

Concentrations of trace gases trapped in ice are considered to develop uniquely from direct snow/atmosphere interactions at the time of contact. This assumption relies upon limited or no biological, chemical or physical transformations occurring during transition from snow to firn to ice; a process that can take decades to complete. Here, we present the first evidence of environmental alteration due to in situ microbial metabolism of trace gases (methyl halides and dimethyl sulfide) in polar snow. We collected evidence for ongoing microbial metabolism from an Arctic and an Antarctic location during different years. Methyl iodide production in the snowpack decreased significantly after exposure to enhanced UV radiation. Our results also show large variations in the production and consumption of other methyl halides, including methyl bromide and methyl chloride, used in climate interpretations. These results suggest that this long-neglected microbial activity could constitute a potential source of error in climate history interpretations, by introducing a so far unappreciated source of bias in the quantification of atmospheric-derived trace gases trapped within the polar ice caps.