Salience and Asymmetric Judgments of Physical Distance

Previous research has shown that distance estimates made from memory are often asymmetric. Specifically, when A is a prominent location (a land-mark) and B is not, people tend to recall a longer distance from A to B than from B to A. Results of two experiments showed that asymmetric judgments of distance are not restricted to judgments made from memory but occur also for judgments made when all relevant visual cues are still present. Furthermore, results indicated that situational salience is sufficient to produce asymmetric judgments and that distinctiveness (such as in the case of architectural landmarks) is not necessary.

Hindsight bias in gustatory judgments

Being in hindsight, people tend to overestimate what they had known in foresight. This phenomenon has been studied for a wide variety of knowledge domains (e.g., episodes with uncertain outcomes, or solutions to almanac questions). As a result of these studies, hindsight bias turned out to be a robust phenomenon. In this paper, we present two experiments that successfully extended the domain of hindsight bias to gustatory judgments. Participants tasted different food items and were asked to estimate the quantity of a certain ingredient, for example, the residual sugar in a white wine. Judgments in both experiments were systematically biased towards previously presented low or high values that were labeled as the true quantities. Thus, hindsight bias can be considered a phenomenon that extends well beyond the judgment domains studied so far.

Metamorphosis of human lumbar vertebrae induced by VEPTR growth modulation and stress shielding

INTRODUCTION Distraction-based spinal growth modulation by growing rods or vertical expandable prosthetic titanium ribs (VEPTRs) is the mainstay of instrumented operative strategies to correct early onset spinal deformities. In order to objectify the benefits, it has become common sense to measure the gain in spine height by assessing T1-S1 distance on anteroposterior (AP) radiographs. However, by ignoring growth changes on vertebral levels and by limiting measurement to one plane, valuable data is missed regarding the three-dimensional (3D) effects of growth modulation. This information might be interesting when it comes to final fusion or, even more so, when the protective growing implants are removed and the spine re-exposed to physiologic forces at the end of growth. METHODS The goal of this retrospective radiographic study was to assess the growth modulating impact of year-long, distraction-based VEPTR treatment on the morphology of single vertebral bodies. We digitally measured lumbar vertebral body height (VBH) and upper endplate depth (VBD) at the time of the index procedure and at follow-up in nine patients with rib-to-ileum constructs (G1) spanning an anatomically normal lumbar spine. Nine patients with congenital thoracic scoliosis and VEPTR rib-to-rib constructs, but uninstrumented lumbar spines, served as controls (G2). All had undergone more than eight half-yearly VEPTR expansions. A Wilcoxon signed-rank test was used for statistical comparison of initial and follow-up VBH, VBD and height/depth (H/D) ratio (significance level 0.05). RESULTS The average age was 7.1 years (G1) and 5.2 year (G2, p > 0.05) at initial surgery; the average overall follow-up time was 5.5 years (p = 1). In both groups, VBH increased significantly without a significant intergroup difference. Group 1 did not show significant growth in depth, whereas VBD increased significantly in the control group. As a consequence, the H/D ratio increased significantly in group 1 whereas it remained unchanged in group 2. The growth rate for height in mm/year was 1.4 (group 1) and 1.1 (group 2, p = 0.45), and for depth, it was -0.3 and 1.1 (p < 0.05), respectively. CONCLUSIONS VEPTR growth modulating treatment alters the geometry of vertebral bodies by increasing the H/D ratio. We hypothesize that the implant-related deprivation from axial loads (stress-shielding) impairs anteroposterior growth. The biomechanical consequence of such slender vertebrae when exposed to unprotected loads in case of definitive VEPTR removal at the end of growth is uncertain.

A heteromeric potassium channel involved in the modulation of the plasma membrane potential is essential for the survival of African trypanosomes.

Discovery of novel drug targets may lead to improved treatment of trypanosomiasis. We characterize here 2 gene products of Trypanosoma brucei that are essential for the growth of bloodstream form (BSF) parasites, as shown by RNA interference (RNAi)-mediated down-regulation of the individual mRNAs. The primary sequences of the 2 proteins--protein encoded by gene Tb927.1.4450 (TbK1) and protein encoded by gene Tb927.9.4820 (TbK2)--indicate that both belong to the family of putative, Ca(2+)-activated potassium channels. The proteins were expressed in Xenopus laevis oocytes and their functions investigated by use of electrophysiological techniques. Only combined expression of TbK1 and TbK2 results in the formation of sizeable currents, indicating that these proteins probably assemble into a heteromeric ion channel. The current mediated by this channel shows little time and voltage dependence and displays a permeability ratio of K(+)/Na(+) of >20. The known potassium channel blocker barium inhibits this channel with a half-maximal inhibitory concentration (IC50) of 98 ± 15 μM. The membrane potential of trypanosomes was measured with a fluorescent dye. Individual RNAi-mediated down-regulation of TbK1 or TbK2 eliminates a potassium conductance in the plasma membrane of BSF. Thus, this heteromeric potassium channel is involved in the modulation of the plasma membrane potential and represents a novel drug target in T. brucei.

Positive modulation of synaptic and extrasynaptic GABAA receptors by an antagonist of the high affinity benzodiazepine binding site.

GABAA receptors are the major inhibitory neurotransmitter receptors in the brain and are the target for many clinically important drugs such as the benzodiazepines. Benzodiazepines act at the high-affinity binding site at the α+/γ- subunit interface. Previously, an additional low affinity binding site for diazepam located in the transmembrane (TM) domain has been described. The compound SJM-3 was recently identified in a prospective screening of ligands for the benzodiazepine binding site and investigated for its site of action. We determined the binding properties of SJM-3 at GABAA receptors recombinantly expressed in HEK-cells using radioactive ligand binding assays. Impact on function was assessed in Xenopus laevis oocytes with electrophysiological experiments using the two-electrode voltage clamp method. SJM-3 was shown to act as an antagonist at the α+/γ- site. At the same time it strongly potentiated GABA currents via the binding site for diazepam in the transmembrane domain. Mutation of a residue in M2 of the α subunit strongly reduced receptor modulation by SJM-3 and a homologous mutation in the β subunit abolished potentiation. SJM-3 acts as a more efficient modulator than diazepam at the site in the trans-membrane domain. In contrast to low concentrations of benzodiazepines, SJM-3 modulates both synaptic and extrasynaptic receptors. A detailed exploration of the membrane site may provide the basis for the design and identification of subtype-selective modulatory drugs.

Functional sites involved in modulation of the GABAA receptor channel by the intravenous anesthetics propofol, etomidate and pentobarbital.

GABAA receptors are the major inhibitory neurotransmitter receptors in the brain and are the target for many clinically important drugs. Among the many modulatory compounds are also the intravenous anesthetics propofol and etomidate, and barbiturates. The mechanism of receptor modulation by these compounds is of mayor relevance. The site of action of these compounds has been located to subunit interfaces in the intra-membrane region of the receptor. In α1β2γ2 GABAA receptors there are five such interfaces, two β+/α- and one each of α+/β-, α+/γ- and γ+/β- subunit interfaces. We have used reporter mutations located in the second trans-membrane region in different subunits to probe the effects of changes at these subunit interfaces on modulation by propofol, etomidate and pentobarbital. We provide evidence for the fact that each of these compounds either modulates through a different set of subunit interfaces or through the same set of subunit interfaces to a different degree. As a GABAA receptor pentamer harbors two β+/α- subunit interfaces, we used concatenated receptors to dissect the contribution of individual interfaces and show that only one of these interfaces is important for receptor modulation by etomidate.

The modulation of reading strategies by language opacity in early bilinguals: an eye movement study

Converging evidences from eye movement experiments indicate that linguistic contexts influence reading strategies. However, the question of whether different linguistic contexts modulate eye movements during reading in the same bilingual individuals remains unresolved. We examined reading strategies in a transparent (German) and an opaque (French) language of early, highly proficient French–German bilinguals: participants read aloud isolated French and German words and pseudo-words while the First Fixation Location (FFL), its duration and latency were measured. Since transparent linguistic contexts and pseudo-words would favour a direct grapheme/phoneme conversion, the reading strategy should be more local for German than for French words (FFL closer to the beginning) and no difference is expected in pseudo-words’ FFL between contexts. Our results confirm these hypotheses, providing the first evidence that the same individuals engage different reading strategy depending on language opacity, suggesting that a given brain process can be modulated by a given context.

Neutrophils: Between host defence, immune modulation, and tissue injury.

Neutrophils, the most abundant human immune cells, are rapidly recruited to sites of infection, where they fulfill their life-saving antimicrobial functions. While traditionally regarded as short-lived phagocytes, recent findings on long-term survival, neutrophil extracellular trap (NET) formation, heterogeneity and plasticity, suppressive functions, and tissue injury have expanded our understanding of their diverse role in infection and inflammation. This review summarises our current understanding of neutrophils in host-pathogen interactions and disease involvement, illustrating the versatility and plasticity of the neutrophil, moving between host defence, immune modulation, and tissue damage.

Pharmacological Modulation of Hemodynamics in Adult Zebrafish In Vivo

INTRODUCTION: Hemodynamic parameters in zebrafish receive increasing attention because of their important role in cardiovascular processes such as atherosclerosis, hematopoiesis, sprouting and intussusceptive angiogenesis. To study underlying mechanisms, the precise modulation of parameters like blood flow velocity or shear stress is centrally important. Questions related to blood flow have been addressed in the past in either embryonic or ex vivo-zebrafish models but little information is available for adult animals. Here we describe a pharmacological approach to modulate cardiac and hemodynamic parameters in adult zebrafish in vivo. MATERIALS AND METHODS: Adult zebrafish were paralyzed and orally perfused with salt water. The drugs isoprenaline and sodium nitroprusside were directly applied with the perfusate, thus closely resembling the preferred method for drug delivery in zebrafish, namely within the water. Drug effects on the heart and on blood flow in the submental vein were studied using electrocardiograms, in vivo-microscopy and mathematical flow simulations. RESULTS: Under control conditions, heart rate, blood flow velocity and shear stress varied less than ± 5%. Maximal chronotropic effects of isoprenaline were achieved at a concentration of 50 μmol/L, where it increased the heart rate by 22.6 ± 1.3% (n = 4; p < 0.0001). Blood flow velocity and shear stress in the submental vein were not significantly increased. Sodium nitroprusside at 1 mmol/L did not alter the heart rate but increased blood flow velocity by 110.46 ± 19.64% (p = 0.01) and shear stress by 117.96 ± 23.65% (n = 9; p = 0.03). DISCUSSION: In this study, we demonstrate that cardiac and hemodynamic parameters in adult zebrafish can be efficiently modulated by isoprenaline and sodium nitroprusside. Together with the suitability of the zebrafish for in vivo-microscopy and genetic modifications, the methodology described permits studying biological processes that are dependent on hemodynamic alterations.

No scope for social modulation of steroid levels in a year-round territorial damselfish.

Both latitude and mating system have been proposed to shape relationships between steroid hormone levels and social behavior. Recently it has been postulated that species with long lasting non-seasonal territorial behavior have low androgen responsiveness. Tropical damselfishes are an ideal family to test this proposition because they show a large variety in mating systems. Here we contribute to the comparative dataset by measuring the response in steroid levels after social modulation in the banded sergeant, Abudefduf septemfasciatus, a species with non-seasonal territoriality. In highly territorial and brooding males, we found low androgen and cortisol levels that did not increase after experimental intraspecific simulated territorial intrusions (STI tests). No relationship was found between the variation in steroid hormone levels and territorial responses to naturally occurring territorial intrusions. Although steroid levels were low, male A. septemfasciatus were highly territorial both to STI challenges and to fishes that passed the territory. They often chased intruders for several meters away from the territory. This indicates that during nest defence in a non-seasonal territorial damselfish species, territorial behaviors are shown independent of variation in androgen and cortisol levels.

Redox modulation of STIM-ORAI signaling.

STIM1 and ORAI1 constitute the core machinery of the ubiquitous store-operated calcium entry pathway and loss of function in these proteins is associated with severe immune and muscular disorders. Other isoforms-STIM1L, STIM2, ORAI2 and ORAI3 exhibit varied expression levels in different cell types along with several other interaction partners and thereby play different roles to facilitate, regulate and fine-tune the calcium entry. STIM proteins convey the Ca(2+) store-depletion message to the PM and thereby participate in refilling of the ER by physically interacting with the Ca(2+)-selective ORAI channels at the PM. STIM and ORAI are exposed to oxidative modifications in the ER, the cytosol, and at the cell surface, and redox-mediated alterations in STIM/ORAI coupling might contribute to autoimmune disorders and cancer progression. This review discusses the redox reactivity of cysteine residues in STIM and ORAI isoforms, focusing on the oxidative modifications of STIM and ORAI proteins by which STIM-ORAI signaling can be modulated.

Search for Event Rate Modulation in XENON100 Electronic Recoil Data

We have searched for periodic variations of the electronic recoil event rate in the (2-6) keV energy range recorded between February 2011 and March 2012 with the XENON100 detector, adding up to 224.6 live days in total. Following a detailed study to establish the stability of the detector and its background contributions during this run, we performed an un-binned profile likelihood analysis to identify any periodicity up to 500 days. We find a global significance of less than 1 sigma for all periods suggesting no statistically significant modulation in the data. While the local significance for an annual modulation is 2.8 sigma, the analysis of a multiple-scatter control sample and the phase of the modulation disfavor a dark matter interpretation. The DAMA/LIBRA annual modulation interpreted as a dark matter signature with axial-vector coupling of WIMPs to electrons is excluded at 4.8 sigma.

Frequency modulation of ERK activation dynamics rewires cell fate.

Transient versus sustained ERK MAP kinase (MAPK) activation dynamics induce proliferation versus differentiation in response to epidermal (EGF) or nerve (NGF) growth factors in PC-12 cells. Duration of ERK activation has therefore been proposed to specify cell fate decisions. Using a biosensor to measure ERK activation dynamics in single living cells reveals that sustained EGF/NGF application leads to a heterogeneous mix of transient and sustained ERK activation dynamics in distinct cells of the population, different than the population average. EGF biases toward transient, while NGF biases toward sustained ERK activation responses. In contrast, pulsed growth factor application can repeatedly and homogeneously trigger ERK activity transients across the cell population. These datasets enable mathematical modeling to reveal salient features inherent to the MAPK network. Ultimately, this predicts pulsed growth factor stimulation regimes that can bypass the typical feedback activation to rewire the system toward cell differentiation irrespective of growth factor identity.