The 5-HT1F receptor agonist lasmiditan as a potential treatment of migraine attacks: a review of two placebo-controlled phase II trials

Lasmiditan is a novel selective 5-HT1F receptor agonist. It is both scientifically and clinically relevant to review whether a 5-HT1F receptor agonist is effective in the acute treatment of migraine. Two RCTs in the phase II development of lasmiditan was reviewed. In the intravenous placebo-controlled RCT, lasmiditan doses of 2.5–45 mg were used, and there was a linear association between headache relief (HR) rates and dose levels (P < 0.02). For lasmiditan 20 mg, HR was 64 % and for placebo it was 45 % (NS). In the oral placebo-controlled RCT, lasmiditan doses of 50, 100, 200 and 400 mg were used. For HR, all doses of lasmiditan were superior to placebo (P < 0.05). For lasmiditan 400 mg, HR was 64 % and it was 25 % for placebo. Adverse events (AEs) emerging from the treatment were reported by 22 % of the patients receiving placebo and by 65, 73, 87 and 87 % of patients receiving 50, 100, 200 and 400 mg, respectively. The majority of AEs after lasmiditan 100 and 400 mg were moderate or severe. For the understanding of migraine pathophysiology, it is very important to note that a selective 5-HT1F receptor agonist like lasmiditan is effective in the acute treatment of migraine. Thus, migraine can be treated with a drug that has no vasoconstrictor ability. While lasmiditan most likely is effective in the treatment of migraine attacks it had, unfortunately, a high incidence of CNS related AEs in the oral RCT. If confirmed in larger studies in phase III, this might adversely limit the use of this highly specific non-vascular acute treatment of migraine. Larger studies including the parameters of patients’ preferences are necessary to accurately position this new treatment principle in relation to the triptans

Non-Perturbative Renormalization Group for Simple Fluids

We present a new non perturbative renormalization group for classical simple fluids. The theory is built in the Grand Canonical ensemble and in the framework of two equivalent scalar field theories as well. The exact mapping between the three renormalization flows is established rigorously. In the Grand Canonical ensemble the theory may be seen as an extension of the Hierarchical Reference Theory (L. Reatto and A. Parola, \textit{Adv. Phys.}, \textbf{44}, 211 (1995)) but however does not suffer from its shortcomings at subcritical temperatures. In the framework of a new canonical field theory of liquid state developed in that aim our construction identifies with the effective average action approach developed recently (J. Berges, N. Tetradis, and C. Wetterich, \textit{Phys. Rep.}, \textbf{363} (2002))

Bacterial Chemotaxis in an Optical Trap

An optical trapping technique is implemented to investigate the chemotactic behavior of a marine bacterial strain Vibrio alginolyticus. The technique takes the advantage that the bacterium has only a single polar flagellum, which can rotate either in the counter-clock-wise or clock-wise direction. The two rotation states of the motor can be readily and instantaneously resolved in the optical trap, allowing the flagellar motor switching rate to be measured under different chemical stimulations. In this paper the focus will be on the bacterial response to an impulsive change of chemoattractant serine. Despite different propulsion apparati and motility patterns, cells of V. alginolyticus apparently use a similar response as Escherichia coli to regulate their chemotactic behavior. Specifically, we found that the switching rate of the bacterial motor exhibits a biphasic behavior, showing a fast initial response followed by a slow relaxation to the steady-state switching rate . The measured can be mimicked by a model that has been recently proposed for chemotaxis in E. coli. The similarity in the response to the brief chemical stimulation in these two different bacteria is striking, suggesting that the biphasic response may be evolutionarily conserved. This study also demonstrated that optical tweezers can be a useful tool for chemotaxis studies and should be applicable to other polarly flagellated bacteria

A Comparison of Ultrasonics and Radiography for Weld Inspection

Since the 1940’s, the accepted inspection method for structural welds in the U.S. Navy has been radiography (RT). This technique has been accepted as an inspection method for welds since the 1940’s. A major advantage of radiography compared to other inspection techniques is the availability of objective quality evidence, the radiograph, as a permanent record of the inspection. Radiography has gained precedence as the inspection method to prescribe for these welds because this permanent record is perceived to evince all discontinuities and facilitates auditing. This technique and the criteria used to accept or reject discontinuities have generally proved adequate although technical limitations and cost disadvantages have been encountered

Wnt4 and LAP2alpha as pacemakers of Thymic Epithelial Senescence

Age-associated thymic involution has considerable physiological impact by inhibiting de novo T-cell selection. This impaired T-cell production leads to weakened immune responses. Yet the molecular mechanisms of thymic stromal adipose involution are not clear. Age-related alterations also occur in the murine thymus providing an excellent model system. In the present work structural and molecular changes of the murine thymic stroma were investigated during aging. We show that thymic epithelial senescence correlates with significant destruction of epithelial network followed by adipose involution. We also show in purified thymic epithelial cells the age-related down-regulation of Wnt4 (and subsequently FoxN1), and the prominent increase in LAP2α expression. These senescence-related changes of gene expression are strikingly similar to those observed during mesenchymal to pre-adipocyte differentiation of fibroblast cells suggesting similar molecular background in epithelial cells. For molecular level proof-of-principle stable LAP2α and Wnt4-over-expressing thymic epithelial cell lines were established. LAP2α over-expression provoked a surge of PPARγ expression, a transcription factor expressed in pre-adipocytes. In contrast, additional Wnt4 decreased the mRNA level of ADRP, a target gene of PPARγ. Murine embryonic thymic lobes have also been transfected with LAP2α- or Wnt4-encoding lentiviral vectors. As expected LAP2α over-expression increased, while additional Wnt4 secretion suppressed PPARγ expression. Based on these pioneer experiments we propose that decreased Wnt activity and increased LAP2α expression provide the molecular basis during thymic senescence. We suggest that these molecular changes trigger thymic epithelial senescence accompanied by adipose involution. This process may either occur directly where epithelium can trans-differentiate into pre-adipocytes; or indirectly where first epithelial to mesenchymal transition (EMT) occurs followed by subsequent pre-adipocyte differentiation. The latter version fits better with literature data and is supported by the observed histological and molecular level changes

Composite Fermion Metals from Dyon Black Holes and S-Duality

We propose that string theory in the background of dyon black holes in four-dimensional anti-de Sitter spacetime is holographic dual to conformally invariant composite Dirac fermion metal. By utilizing S-duality map, we show that thermodynamic and transport properties of the black hole match with those of composite fermion metal, exhibiting Fermi liquid-like. Built upon Dirac-Schwinger-Zwanziger quantization condition, we argue that turning on magnetic charges to electric black hole along the orbit of Gamma(2) subgroup of SL(2,Z) is equivalent to attaching even unit of statistical flux quanta to constituent fermions. Being at metallic point, the statistical magnetic flux is interlocked to the background magnetic field. We find supporting evidences for proposed holographic duality from study of internal energy of black hole and probe bulk fermion motion in black hole background. They show good agreement with ground-state energy of composite fermion metal in Thomas-Fermi approximation and cyclotron motion of a constituent or composite fermion excitation near Fermi-point.Comment: 30 pages, v2. 1 figure added, minor typos corrected; v3. revised version to be published in JHE

Chemotactic response and adaptation dynamics in Escherichia coli

Adaptation of the chemotaxis sensory pathway of the bacterium Escherichia coli is integral for detecting chemicals over a wide range of background concentrations, ultimately allowing cells to swim towards sources of attractant and away from repellents. Its biochemical mechanism based on methylation and demethylation of chemoreceptors has long been known. Despite the importance of adaptation for cell memory and behavior, the dynamics of adaptation are difficult to reconcile with current models of precise adaptation. Here, we follow time courses of signaling in response to concentration step changes of attractant using in vivo fluorescence resonance energy transfer measurements. Specifically, we use a condensed representation of adaptation time courses for efficient evaluation of different adaptation models. To quantitatively explain the data, we finally develop a dynamic model for signaling and adaptation based on the attractant flow in the experiment, signaling by cooperative receptor complexes, and multiple layers of feedback regulation for adaptation. We experimentally confirm the predicted effects of changing the enzyme-expression level and bypassing the negative feedback for demethylation. Our data analysis suggests significant imprecision in adaptation for large additions. Furthermore, our model predicts highly regulated, ultrafast adaptation in response to removal of attractant, which may be useful for fast reorientation of the cell and noise reduction in adaptation.Comment: accepted for publication in PLoS Computational Biology; manuscript (19 pages, 5 figures) and supplementary information; added additional clarification on alternative adaptation models in supplementary informatio

Exogenous dopamine reduces GABA receptor availability in the human brain

Background: While it has recently been shown that dopamine release stimulates conscious self‐monitoring through the generation of gamma oscillations in medial prefrontal/anterior cingulate cortex, and that the GABAergic system is effective in producing such oscillations, interaction of the two transmitter systems has not been demonstrated in humans. We here hypothesize that dopamine challenge stimulates the GABA system directly in the medial prefrontal/anterior cingulate region in the human brain. // Methods: Positron emission tomography (PET) with the GABA receptor α1/α5 subtype ligand [11C] Ro15‐4513 was used to detect changes in GABA receptor availability after clinical oral doses of levodopa in a double blind controlled study. // Results: We here provide the first direct evidence for such coupling in the cerebral cortex, in particular in the medial prefrontal anterior cingulate region, by showing that exogenous dopamine decreases [11C] Ro15‐4513 binding widely in the human brain compatible with a fall in α1 subtype availability in GABA complexes due to increased GABA activity

Predicted Auxiliary Navigation Mechanism of Peritrichously Flagellated Chemotactic Bacteria

Chemotactic movement of Escherichia coli is one of the most thoroughly studied paradigms of simple behavior. Due to significant competitive advantage conferred by chemotaxis and to high evolution rates in bacteria, the chemotaxis system is expected to be strongly optimized. Bacteria follow gradients by performing temporal comparisons of chemoeffector concentrations along their runs, a strategy which is most efficient given their size and swimming speed. Concentration differences are detected by a sensory system and transmitted to modulate rotation of flagellar motors, decreasing the probability of a tumble and reorientation if the perceived concentration change during a run is positive. Such regulation of tumble probability is of itself sufficient to explain chemotactic drift of a population up the gradient, and is commonly assumed to be the only navigation mechanism of chemotactic E. coli. Here we use computer simulations to predict existence of an additional mechanism of gradient navigation in E. coli. Based on the experimentally observed dependence of cell tumbling angle on the number of switching motors, we suggest that not only the tumbling probability but also the degree of reorientation during a tumble depend on the swimming direction along the gradient. Although the difference in mean tumbling angles up and down the gradient predicted by our model is small, it results in a dramatic enhancement of the cellular drift velocity along the gradient. We thus demonstrate a new level of optimization in E. coli chemotaxis, which arises from the switching of several flagellar motors and a resulting fine tuning of tumbling angle. Similar strategy is likely to be used by other peritrichously flagellated bacteria, and indicates yet another level of evolutionary development of bacterial chemotaxis