A Midbrain Circuit that Mediates Headache Aversiveness in Rats.

Migraines are a major health burden, but treatment is limited because of inadequate understanding of neural mechanisms underlying headache. Imaging studies of migraine patients demonstrate changes in both pain-modulatory circuits and reward-processing regions, but whether these changes contribute to the experience of headache is unknown. Here, we demonstrate a direct connection between the ventrolateral periaqueductal gray (vlPAG) and the ventral tegmental area (VTA) that contributes to headache aversiveness in rats. Many VTA neurons receive monosynaptic input from the vlPAG, and cranial nociceptive input increases Fos expression in VTA-projecting vlPAG neurons. Activation of PAG inputs to the VTA induces avoidance behavior, while inactivation of these projections induces a place preference only in animals with headache. This work identifies a distinct pathway that mediates cranial nociceptive aversiveness

Reliability in the Identification of Midbrain Dopamine Neurons

Brain regions typically contain intermixed subpopulations of neurons with different connectivity and neurotransmitters. This complicates identification of neuronal phenotypes in electrophysiological experiments without using direct detection of unique molecular markers. A prime example of this difficulty is the identification of dopamine (DA) neurons in the midbrain ventral tegmental area (VTA). Although immunocytochemistry (ICC) against tyrosine hydroxylase (TH) is widely used to identify DA neurons, a high false negative rate for TH ICC following ex vivo electrophysiology experiments was recently reported, calling into question the validity of comparing DA and non-DA VTA neurons based on post-hoc ICC. However, in whole cell recordings from randomly selected rat VTA neurons we have found that TH labeling is consistently detected in ∼55% of neurons even after long recording durations (range: 2.5–150 min). This is consistent with our prior anatomical finding that 55% of VTA neurons are TH(+). To directly estimate a false negative rate for our ICC method we recorded VTA neurons from mice in which EGFP production is driven by the TH promoter. All 12 EGFP(+) neurons recorded with a K-gluconate internal solution (as used in our rat recordings) were strongly labeled by TH ICC (recording duration 16.6±1.8 min). However, using recording electrodes with an internal solution with high Cl− concentration reduced the intensity of TH co-labeling, in some cases to background (recording duration 16.7±0.9 min; n = 10). Thus TH is a highly reliable molecular marker for DA neurons in VTA patch clamp recordings provided compatible microelectrode solutions are used

The random release of phosphate controls the dynamic instability of microtubules

A simple stochastic model which describes microtubule dynamics and explicitly takes into account the relevant biochemical processes is presented. The model incorporates binding and unbinding of monomers and random phosphate release inside the polymer. It is shown that this theoretical approach provides a microscopic picture of the dynamic instability phenomena of microtubules. The cap size, the concentration dependence of the catastrophe times and the delay before observing catastrophes following a dilution can be quantitatively predicted by this approach in a direct and simple way. Furthermore, the model can be solved analytically to a large extend, thus offering a valuable starting point for more refined studies of microtubules dynamics.Comment: 26 pages, 8 figure

Regulating the automobile

Division of Policy Research and Analysis. National Science Foundatio

Searching for the Kuhnian moment : the Black-Scholes-Merton formula and the evolution of modern finance theory

The Black-Scholes-Merton formula has been put to widespread use by options traders because it provides a means of calculating the theoretically 'correct' price of stock options. Traders can therefore see whether the market price of stock options undervalues or overvalues them compared with their hypothetical Black-Scholes-Merton price, before choosing to buy or sell options accordingly. As a consequence of this close relationship between options pricing theory and options pricing practice, a strong performativity loop was activated, whereby market prices quickly converged on the hypothetical Black-Scholes-Merton prices following the dissemination of the formula. The theory has therefore had significant real-world effects, but how should we characterize the initial instinct to derive the theory from a philosophy of science perspective? The two books under review suggest that a Kuhnian reading of the advancement of scientific knowledge might well be the most appropriate. But, on closer inspection, it becomes clear that the publication of the Black-Scholes-Merton formula should not be seen as a Kuhnian moment with paradigm-shaping attributes. It is shown that, at most, the formula acts as an important exemplar which, via its use in the training of options pricing theorists and options pricing practitioners, reinforces the entrenchment of finance theory within the orthodox economics worldview

A Prospective Study of Leukocyte Telomere Length and Risk of Type 2 Diabetes in Postmenopausal Women

Telomere length (TL) has been implicated in the pathogenesis of age-related disorders. However, there are no prospective studies directly investigating the role of TL and relevant genes in diabetes development. In the multiethnic Women’s Health Initiative, we identified 1,675 incident diabetes case participants in 6 years of follow-up and 2,382 control participants matched by age, ethnicity, clinical center, time of blood draw, and follow-up duration. Leukocyte TL at baseline was measured using quantitative PCR, and Mendelian randomization analysis was conducted to test whether TL is causally associated with diabetes risk. After adjustment for matching and known diabetes risk factors, odds ratios per 1-kilobase increment were 1.00 (95% CI 0.90–1.11) in whites, 0.95 (0.85–1.06) in blacks, 0.96 (0.79–1.17) in Hispanics, and 0.88 (0.70–1.10) in Asians. Of the 80 single nucleotide polymorphisms (SNPs) in nine genes involved in telomere regulation, 14 SNPs were predictive of TL, but none were significantly associated with diabetes risk. Using ethnicity-specific SNPs as randomization instruments, we observed no statistically significant association between TL and diabetes risk (P = 0.52). Although leukocyte TL was weakly associated with diabetes risk, this association was not independent of known risk factors. These prospective findings indicate limited clinical utility of TL in diabetes risk stratification among postmenopausal women

Drug-tubulin interactions interrogated by transient absorption spectroscopy

[EN] Colchicine (COL) is a bioactive molecule with antitumor properties. When COL binds to tubulin (TU), it inhibits microtubule assembly dynamics. We have investigated COL-TU interactions using laser flash photolysis (LFP) technique and performing fully flexible molecular dynamics simulations. Excitation of COL at 355 nm in aqueous medium did not lead to any transient absorption spectrum. By contrast, in the presence of TU a transient peaking at lambda(max) ca. 420 nm was registered and assigned as triplet excited COL complexed with TU ((COL)-C-3*@TU). In aerated medium, the lifetime was tau ca. 160 mu s and the quantum yield was 0.138. Likewise, when the bicyclic COL analog MTC was submitted to LFP in the presence of TU, (MTC)-M-3@TU* was detected with a lifetime of ca. 62 ms and a quantum yield of 0.296, Aqueous solutions of MTC did not produce any signal in the microsecond timescale. The triplet energy of MTC was obtained by means of emission measurements and found to be ca. 200 kJ mol(-1), a value that matches with that previously reported for COL (188 kJ mol(-1)). Molecular dynamic simulations, both with the ground and triplet excited state, reveal a strong interaction between COL and TU to give stabilized complexes with restricted mobility inside the protein binding site. These results demonstrate that LFP is a useful methodology to study the binding of COL derivatives to TU and open a new way to evaluate the interactions of non-fluorescent anticancer drugs with this protein.Financial support from the Spanish Government (grants CTQ2010-19909; BFU2011-23416 and SEV 2012-0267), the Generalitat Valenciana (Prometeo II/2013/005) and Comunidad de Madrid (S2010/BMD-2353) is gratefully acknowledged. G.S. thanks ASIC-UPV for computing time.Bosca Mayans, F.; Sastre Navarro, GI.; Andreu, JM.; Jornet, D.; Tormos Faus, RE.; Miranda Alonso, MÁ. (2015). 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A., Jourdain, I., Lachkar, S., Sobel, A., & Knossow, M. (2004). Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature, 428(6979), 198-202. doi:10.1038/nature02393Cormier, A., Marchand, M., Ravelli, R. B. G., Knossow, M., & Gigant, B. (2008). Structural insight into the inhibition of tubulin by vinca domain peptide ligands. EMBO reports, 9(11), 1101-1106. doi:10.1038/embor.2008.171Prota, A. E., Bargsten, K., Diaz, J. F., Marsh, M., Cuevas, C., Liniger, M., … Steinmetz, M. O. (2014). A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs. Proceedings of the National Academy of Sciences, 111(38), 13817-13821. doi:10.1073/pnas.1408124111Prota, A. E., Bargsten, K., Zurwerra, D., Field, J. J., Díaz, J. F., Altmann, K.-H., & Steinmetz, M. O. (2013). Molecular Mechanism of Action of Microtubule-Stabilizing Anticancer Agents. Science, 339(6119), 587-590. doi:10.1126/science.1230582Prota, A. E., Bargsten, K., Northcote, P. T., Marsh, M., Altmann, K.-H., Miller, J. H., … Steinmetz, M. O. (2014). Structural Basis of Microtubule Stabilization by Laulimalide and Peloruside A. Angewandte Chemie International Edition, 53(6), 1621-1625. doi:10.1002/anie.201307749Brossi, A., Yeh, H. J. C., Chrzanowska, M., Wolff, J., Hamel, E., Lin, C. M., … Silverton, J. (1988). Colchicine and its analogues: Recent findings. Medicinal Research Reviews, 8(1), 77-94. doi:10.1002/med.2610080105Imazio, M., Trinchero, R., & Adler, Y. (2008). Colchicine for the treatment of pericarditis. Future Cardiology, 4(6), 599-607. doi:10.2217/14796678.4.6.599Fakih, M., Replogle, T., Lehr, J. E., Pienta, K. J., & Yagoda, A. (1995). Inhibition of prostate cancer growth by estramustine and colchicine. The Prostate, 26(6), 310-315. doi:10.1002/pros.2990260606Lee, R. M., & Gewirtz, D. A. (2008). Colchicine site inhibitors of microtubule integrity as vascular disrupting agents. 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Biochemical Journal, 327(3), 685-688. doi:10.1042/bj3270685Andreu, J. M., Gorbunopff, M. J., Lee, J. C., & Timasheff, S. N. (1984). Interaction of tubulin with bifunctional colchicine analogs: an equilibrium study. Biochemistry, 23(8), 1742-1752. doi:10.1021/bi00303a025Nguyen, T. L., McGrath, C., Hermone, A. R., Burnett, J. C., Zaharevitz, D. W., Day, B. W., … Gussio, R. (2005). A Common Pharmacophore for a Diverse Set of Colchicine Site Inhibitors Using a Structure-Based Approach. Journal of Medicinal Chemistry, 48(19), 6107-6116. doi:10.1021/jm050502tTorin Huzil, J., Winter, P., Johnson, L., Weis, A. L., Bakos, T., Banerjee, A., … Tuszynski, J. A. (2010). Computational Design and Biological Testing of Highly Cytotoxic Colchicine Ring A Modifications. Chemical Biology & Drug Design, 75(6), 541-550. doi:10.1111/j.1747-0285.2010.00970.xCao, R., Liu, M., Yin, M., Liu, Q., Wang, Y., & Huang, N. (2012). Discovery of Novel Tubulin Inhibitors via Structure-Based Hierarchical Virtual Screening. Journal of Chemical Information and Modeling, 52(10), 2730-2740. doi:10.1021/ci300302cLaing, N., Dahllöf, B., Hartley-Asp, B., Ranganathan, S., & Tew, K. D. (1997). Interaction of Estramustine with Tubulin Isotypes†. Biochemistry, 36(4), 871-878. doi:10.1021/bi961445wGireesh, K. K., Rashid, A., Chakraborti, S., Panda, D., & Manna, T. (2012). CIL-102 binds to tubulin at colchicine binding site and triggers apoptosis in MCF-7 cells by inducing monopolar and multinucleated cells. Biochemical Pharmacology, 84(5), 633-645. doi:10.1016/j.bcp.2012.06.008Gunasekera, N., Xiong, G., Musier-Forsyth, K., & Arriaga, E. (2004). A capillary electrophoretic method for monitoring the presence of α-tubulin in nuclear preparations. Analytical Biochemistry, 330(1), 1-9. doi:10.1016/j.ab.2004.03.059Medrano, F. J., Andreu, J. M., Gorbunoff, M. J., & Timasheff, S. N. (1991). Roles of ring C oxygens in the binding of colchicine to tubulin. Biochemistry, 30(15), 3770-3777. doi:10.1021/bi00229a026Morrison, K. C., & Hergenrother, P. J. (2012). Whole cell microtubule analysis by flow cytometry. Analytical Biochemistry, 420(1), 26-32. doi:10.1016/j.ab.2011.08.020Hastie, S. B., & Rava, R. P. (1989). Analysis of the near-ultraviolet absorption band of colchicine and the effect of tubulin binding. Journal of the American Chemical Society, 111(18), 6993-7001. doi:10.1021/ja00200a015Bhattacharyya, B., Kapoor, S., & Panda, D. (2010). Fluorescence Spectroscopic Methods to Analyze Drug–Tubulin Interactions. Microtubules, in vitro, 301-329. doi:10.1016/s0091-679x(10)95017-6Sardar, P. S., Maity, S. S., Das, L., & Ghosh, S. (2007). Luminescence Studies of Perturbation of Tryptophan Residues of Tubulin in the Complexes of Tubulin with Colchicine and Colchicine Analogues†. Biochemistry, 46(50), 14544-14556. doi:10.1021/bi701412kBhattacharyya, B., & Wolff, J. (1974). Promotion of Fluorescence upon Binding of Colchicine to Tubulin. Proceedings of the National Academy of Sciences, 71(7), 2627-2631. doi:10.1073/pnas.71.7.2627Lhiaubet-Vallet, V., Sarabia, Z., Boscá, F., & Miranda, M. A. (2004). Human Serum Albumin-Mediated Stereodifferentiation in the Triplet State Behavior of (S)- and (R)-Carprofen. Journal of the American Chemical Society, 126(31), 9538-9539. doi:10.1021/ja048518gVayá, I., Lhiaubet-Vallet, V., Jiménez, M. C., & Miranda, M. A. (2014). Photoactive assemblies of organic compounds and biomolecules: drug–protein supramolecular systems. Chem. Soc. Rev., 43(12), 4102-4122. doi:10.1039/c3cs60413fBosca, F., & Tormos, R. (2013). Behavior of Drug Excited States within Macromolecules: Binding of Colchicine and Derivatives to Albumin. The Journal of Physical Chemistry B, 117(25), 7528-7534. doi:10.1021/jp402489jFltzgerald, T. J. (1976). 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The twilight of the Liberal Social Contract? On the Reception of Rawlsian Political Liberalism

This chapter discusses the Rawlsian project of public reason, or public justification-based 'political' liberalism, and its reception. After a brief philosophical rather than philological reconstruction of the project, the chapter revolves around a distinction between idealist and realist responses to it. Focusing on political liberalism’s critical reception illuminates an overarching question: was Rawls’s revival of a contractualist approach to liberal legitimacy a fruitful move for liberalism and/or the social contract tradition? The last section contains a largely negative answer to that question. Nonetheless the chapter's conclusion shows that the research programme of political liberalism provided and continues to provide illuminating insights into the limitations of liberal contractualism, especially under conditions of persistent and radical diversity. The programme is, however, less receptive to challenges to do with the relative decline of the power of modern states

Constitutivism

A brief explanation and overview of constitutivism