Pain perception in mice lacking the β3 subunit of voltage-activated calcium channels

The importance of voltage-activated calcium channels in pain processing has been suggested by the spinal antinociceptive action of blockers of N- and P/Q-type calcium channels as well as by gene targeting of the α1B subunit (N-type). The accessory β3 subunits of calcium channels are preferentially associated with the α1B subunit in neurones. Here we show that deletion of the β3 subunit by gene targeting affects strongly the pain processing of mutant mice. We pinpoint this defect in the pain-related behavior and ascending pain pathways of the spinal cordin vivo and at the level of calcium channel currents and proteins in single dorsal root ganglion neurones in vitro. The pain induced by chemical inflammation is preferentially damped by deletion of β3 subunits, whereas responses to acute thermal and mechanical harmful stimuli are reduced moderately or not at all, respectively. The defect results in a weak wind-up of spinal cord activity during intense afferent nerve stimulation. The molecular mechanism responsible for the phenotype was traced to low expression of N-type calcium channels (α1B) and functional alterations of calcium channel currents in neurones projecting to the spinal cord.ThisstudywassupportedbygrantsfromtheDeutscheForschungsgemeinschaftandFondsderChemie(toV.F.).Peer reviewe

Highly enantioselective copper(I)-catalyzed conjugate addition of 1,3-diynes to a,b-unsaturated trifluoromethyl ketones

[EN] The conjugate diynylation of a,b-unsaturated trifluoromethyl ketones is carried out in the presence of a low catalytic load (2.5 mol%) of a copper(I)–MeOBIPHEP complex, triethylamine and a terminal 1,3-diyne. Pre-metalation of the terminal 1,3-diyne with stoichiometric or higher amounts of dialkylzinc reagent is not required. The corresponding internal diynes bearing a propargylic stereogenic center are obtained with good yields and excellent enantioselectivities.Financial support from the Ministerio de Economia y Competitividad (MINECO-Gobierno de Espana) and FEDER (EU) (CTQ2013-47494-P) and from Generalitat Valenciana (ISIC2012/001) is gratefully acknowledged. A.S.-M. thanks the MINECO for a predoctoral grant (FPI program). Access to NMR and MS facilities from the Servei Central de Suport a la Investigacio Experimental (SCSIE)-UV is also acknowledged.Sanz-Marco, A.; Blay, G.; Muñoz Roca, MDC.; Pedro, J. (2015). Highly enantioselective copper(I)-catalyzed conjugate addition of 1,3-diynes to a,b-unsaturated trifluoromethyl ketones. Chemical Communications. (51):8958-8961. https://doi.org/10.1039/C5CC01676BS8958896151Shi Shun, A. L. K., & Tykwinski, R. R. (2006). Synthesis of Naturally Occurring Polyynes. Angewandte Chemie International Edition, 45(7), 1034-1057. doi:10.1002/anie.200502071Modern Acetylene Chemistry, ed. P. J. Stang and F. Diederich, VCH, Weinheim, 1995Sindhu, K. S., & Anilkumar, G. (2014). Recent advances and applications of Glaser coupling employing greener protocols. RSC Adv., 4(53), 27867-27887. doi:10.1039/c4ra02416hJung, H.-J., Min, B.-S., Park, J.-Y., Kim, Y.-H., Lee, H.-K., & Bae, K.-H. (2002). Gymnasterkoreaynes A−F, Cytotoxic Polyacetylenes fromGymnasterkoraiensis. Journal of Natural Products, 65(6), 897-901. doi:10.1021/np0104018Mayer, S. F., Steinreiber, A., Orru, R. V. A., & Faber, K. (2002). Chemoenzymatic Asymmetric Total Syntheses of Antitumor Agents (3R,9R,10R)- and (3S,9R,10R)-Panaxytriol and (R)- and (S)-Falcarinol fromPanaxginsengUsing an Enantioconvergent Enzyme-Triggered Cascade Reaction. The Journal of Organic Chemistry, 67(26), 9115-9121. doi:10.1021/jo020073wSatoh, Y., Satoh, M., Isobe, K., Mohri, K., Yoshida, Y., & Fujimoto, Y. (2007). Studies on Panax Acetylenes: Absolute Structure of a New Panax Acetylene, and Inhibitory Effects of Related Acetylenes on the Growth of L-1210 Cells. CHEMICAL & PHARMACEUTICAL BULLETIN, 55(4), 561-564. doi:10.1248/cpb.55.561McLaughlin, N. P., Butler, E., Evans, P., Brunton, N. P., Koidis, A., & Rai, D. K. (2010). A short synthesis of (+) and (−)-falcarinol. Tetrahedron, 66(51), 9681-9687. doi:10.1016/j.tet.2010.10.049Shin, D., Yang, J.-E., Lee, S. B., & Nho, C. W. (2010). SAR studies of gymnasterkoreayne derivatives with cancer chemopreventive activities. 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Hydro-amination/-amidation of 1,3-diynes with indoles/azoles/amides under modified Ullmann conditions: stereo- and regio-selective synthesis of N-alkenynes via N–H bond activation. Tetrahedron Letters, 52(44), 5752-5757. doi:10.1016/j.tetlet.2011.08.079Cho, E. J., Kim, M., & Lee, D. (2006). Reactivity and Selectivity of 1,3-Diyn-6-enes in Electrophilic Transition Metal-Catalyzed Reactions. Organic Letters, 8(23), 5413-5416. doi:10.1021/ol062335cTrost, B. M., & Weiss, A. H. (2009). The Enantioselective Addition of Alkyne Nucleophiles to Carbonyl Groups. Advanced Synthesis & Catalysis, 351(7-8), 963-983. doi:10.1002/adsc.200800776Blay, G., Monleon, A., & Pedro, J. (2009). Recent Developments in Asymmetric Alkynylation of Imines. Current Organic Chemistry, 13(15), 1498-1539. doi:10.2174/138527209789177734Knöpfel, T. F., Zarotti, P., Ichikawa, T., & Carreira, E. M. (2005). Catalytic, Enantioselective, Conjugate Alkyne Addition. Journal of the American Chemical Society, 127(27), 9682-9683. doi:10.1021/ja052411rYazaki, R., Kumagai, N., & Shibasaki, M. (2010). Direct Catalytic Asymmetric Conjugate Addition of Terminal Alkynes to α,β-Unsaturated Thioamides. Journal of the American Chemical Society, 132(30), 10275-10277. doi:10.1021/ja105141xYazaki, R., Kumagai, N., & Shibasaki, M. (2011). Enantioselective Synthesis of a GPR40 Agonist AMG 837 via Catalytic Asymmetric Conjugate Addition of Terminal Alkyne to α,β-Unsaturated Thioamide. Organic Letters, 13(5), 952-955. doi:10.1021/ol102998wSanz-Marco, A., García-Ortiz, A., Blay, G., & Pedro, J. R. (2014). Catalytic asymmetric conjugate addition of terminal alkynes to β-trifluoromethyl α,β-enones. Chem. Commun., 50(18), 2275-2278. doi:10.1039/c3cc48508kSanz-Marco, A., García-Ortiz, A., Blay, G., Fernández, I., & Pedro, J. R. (2013). Highly Enantioselective Copper(I)-Catalyzed Conjugate Addition of Terminal Alkynes to 1,1-Difluoro-1-(phenylsulfonyl)-3-en-2-ones: New Ester/Amide Surrogates in Asymmetric Catalysis. Chemistry - A European Journal, 20(3), 668-672. doi:10.1002/chem.201303920Nishimura, T., Guo, X.-X., Uchiyama, N., Katoh, T., & Hayashi, T. (2008). Steric Tuning of Silylacetylenes and Chiral Phosphine Ligands for Rhodium-Catalyzed Asymmetric Conjugate Alkynylation of Enones. Journal of the American Chemical Society, 130(5), 1576-1577. doi:10.1021/ja710540sNishimura, T., Sawano, T., & Hayashi, T. (2009). Asymmetric Synthesis of β-Alkynyl Aldehydes by Rhodium-Catalyzed Conjugate Alkynylation. Angewandte Chemie International Edition, 48(43), 8057-8059. doi:10.1002/anie.200904486Fillion, E., & Zorzitto, A. K. (2009). Enantioselective Rhodium-Catalyzed Conjugate Alkynylation of 5-Benzylidene Meldrum’s Acids with TMS-acetylene. Journal of the American Chemical Society, 131(41), 14608-14609. doi:10.1021/ja905336pBlay, G., Cardona, L., Pedro, J. R., & Sanz-Marco, A. (2012). Enantioselective Zinc-Mediated Conjugate Addition of Terminal Alkynes to Enones. Chemistry - A European Journal, 18(41), 12966-12969. doi:10.1002/chem.201201765Blay, G., Muñoz, M. C., Pedro, J. R., & Sanz-Marco, A. (2013). Enantioselective Synthesis of 4-Substituted Dihydrocoumarins through a Zinc Bis(hydroxyamide)-Catalyzed Conjugate Addition of Terminal Alkynes. Advanced Synthesis & Catalysis, 355(6), 1071-1076. doi:10.1002/adsc.201201120Cui, S., Walker, S. D., Woo, J. C. S., Borths, C. J., Mukherjee, H., Chen, M. J., & Faul, M. M. (2010). Practical Asymmetric Conjugate Alkynylation of Meldrum’s Acid-Derived Acceptors: Access to Chiral β-Alkynyl Acids. Journal of the American Chemical Society, 132(2), 436-437. doi:10.1021/ja909105sKwak, Y.-S., & Corey, E. J. (2004). Catalytic Enantioselective Conjugate Addition of Trimethylsilylacetylene to 2-Cyclohexen-1-one. Organic Letters, 6(19), 3385-3388. doi:10.1021/ol048623vLarionov, O. V., & Corey, E. J. (2010). Ni(II)-Catalyzed Enantioselective Conjugate Addition of Acetylenes to α,β-Enones. Organic Letters, 12(2), 300-302. doi:10.1021/ol902643wReber, S., Knöpfel, T. F., & Carreira, E. M. (2003). Enantioselective total synthesis of (R)-strongylodiols A and B. Tetrahedron, 59(35), 6813-6817. doi:10.1016/s0040-4020(03)00905-0Trost, B. M., Chan, V. S., & Yamamoto, D. (2010). Enantioselective ProPhenol-Catalyzed Addition of 1,3-Diynes to Aldehydes to Generate Synthetically Versatile Building Blocks and Diyne Natural Products. Journal of the American Chemical Society, 132(14), 5186-5192. doi:10.1021/ja910656bTurlington, M., Du, Y., Ostrum, S. G., Santosh, V., Wren, K., Lin, T., … Pu, L. (2011). From Highly Enantioselective Catalytic Reaction of 1,3-Diynes with Aldehydes to Facile Asymmetric Synthesis of Polycyclic Compounds. Journal of the American Chemical Society, 133(30), 11780-11794. doi:10.1021/ja204289qGraham, E. R., & Tykwinski, R. R. (2011). Chiral Propargyl Alcohols via the Enantioselective Addition of Terminal Di- and Triynes to Aldehydes. The Journal of Organic Chemistry, 76(16), 6574-6583. doi:10.1021/jo2008719Zheng, B., Li, S.-N., Mao, J.-Y., Wang, B., Bian, Q.-H., Liu, S.-Z., … Wang, M. (2012). Highly Enantioselective Addition of 1,3-Diynes to Aldehydes Catalyzed by a Zinc-Amino Alcohol Complex. Chemistry - A European Journal, 18(30), 9208-9211. doi:10.1002/chem.201200728Liu, T.-L., Ma, H., Zhang, F.-G., Zheng, Y., Nie, J., & Ma, J.-A. (2011). Catalytic enantioselective addition of terminal 1,3-diynes to aromatic ketones: facile access to chiral nonracemic tertiary alcohols. Chemical Communications, 47(48), 12873. doi:10.1039/c1cc15968bLiu, T.-L., Zhang, H.-X., Zheng, Y., Yao, Q., & Ma, J.-A. (2012). Catalytic enantioselective addition of terminal 1,3-diynes to N-sulfonyl aldimines: access to chiral diynylated carbinamines. Chemical Communications, 48(100), 12234. doi:10.1039/c2cc37290hZhang, F.-G., Ma, H., Zheng, Y., & Ma, J.-A. (2012). Zinc-mediated enantioselective addition of terminal 1,3-diynes to N-arylimines of trifluoropyruvates. Tetrahedron, 68(37), 7663-7669. doi:10.1016/j.tet.2012.05.086Zhang, F.-G., Ma, H., Nie, J., Zheng, Y., Gao, Q., & Ma, J.-A. (2012). Enantioselective Diynylation of Cyclic N-Acyl Ketimines: Access to Chiral Trifluoromethylated Tertiary Carbinamines. Advanced Synthesis & Catalysis, 354(8), 1422-1428. doi:10.1002/adsc.201100926Nie, J., Guo, H.-C., Cahard, D., & Ma, J.-A. (2011). Asymmetric Construction of Stereogenic Carbon Centers Featuring a Trifluoromethyl Group from Prochiral Trifluoromethylated Substrates. Chemical Reviews, 111(2), 455-529. doi:10.1021/cr100166aCahard, D., Xu, X., Couve-Bonnaire, S., & Pannecoucke, X. (2010). Fluorine & chirality: how to create a nonracemic stereogenic carbon–fluorine centre? Chem. Soc. Rev., 39(2), 558-568. doi:10.1039/b909566gKirk, K. L. (2008). Fluorination in Medicinal Chemistry: Methods, Strategies, and Recent Developments. Organic Process Research & Development, 12(2), 305-321. doi:10.1021/op700134jMa, J.-A., & Cahard, D. (2008). Update 1 of: Asymmetric Fluorination, Trifluoromethylation, and Perfluoroalkylation Reactions. Chemical Reviews, 108(9), PR1-PR43. doi:10.1021/cr800221vPurser, S., Moore, P. R., Swallow, S., & Gouverneur, V. (2008). Fluorine in medicinal chemistry. Chem. Soc. Rev., 37(2), 320-330. doi:10.1039/b610213cMorrill, L. C., Smith, S. M., Slawin, A. M. Z., & Smith, A. D. (2014). Isothiourea-Mediated Asymmetric Functionalization of 3-Alkenoic Acids. 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ChemCatChem, 6(2), 580-591. doi:10.1002/cctc.20130087

Translation of a behavioral weight loss intervention for mid‐life, low‐income women in local health departments

Objective: To translate a behavioral weight loss intervention for mid-life, low-income women in real world settings. Design and Methods: In this pragmatic clinical trial, we randomly selected six North Carolina county health departments and trained their current staff to deliver a 16-session evidence-based behavioral weight loss intervention (special intervention, SI). SI weight loss outcomes were compared to a delayed intervention (DI) control group. Results: Of 432 women expressing interest, 189 completed baseline measures and were randomized within health departments to SI (N = 126) or DI (N = 63). At baseline, average age was 51 years, 53% were African American, mean weight was 100 kg, and BMI averaged 37 kg/m(2). A total of 96 (76%) SI and 55 (87%) DI participants returned for 5-month follow-up measures. The crude weight change was -3.1 kg in the SI and -0.4 kg in the DI group, for a difference of 2.8 kg (95% CI 1.4 to 4.1, p = 0.0001). Diet quality and physical activity improved significantly more in the SI group, and estimated intervention costs were $327 per participant. Conclusion: This pragmatic short‐term weight loss intervention targeted to low‐income mid‐life women yielded meaningful weight loss when translated to the county health department setting.Keywords: US, Primary care, Risk factors, Obesity, Management, Adults, Physical activity, Rural communities, Clinical trial, Randomized tria

Analysis and quantification of bone healing after open wedge high tibial osteotomy

Background: The aim of this study was to analyze radiographic imaging techniques and to quantify bone ossification in the osteotomy gap after high tibial osteotomy. ------ Material and methods: Study phase 1: high tibial osteotomy was performed on six lower extremities of human body donors and experimental X‑rays and computed tomography (CT) scans were applied. Different techniques were evaluated by three specialists for best representation of the osteotomy gap. Study phase 2: optimized radiological techniques were used for follow-up on 12 patients. The radiographs were examined by 3 specialists measuring 10 different parameters. The CT scans were analyzed with semiautomatic computer software for quantification of bone ossification. ----- Results: The osteotomy gap was best represented in 30° of flexion in the knee and 20° internal rotation of the leg. There were significant changes of the medial width over time (p < 0.019) as well as of the length of fused osteotomy, the Schröter score, sclerosis, trabecular structure and zone area measurements. Sclerosis, medial width of the osteotomy and area measurements were detected as reproducible parameters. Bone mineral density was calculated using CT scans, showing a significantly higher value 12 weeks postoperatively (112.5 mg/cm3) than at baseline (54.6 mg/cm3). The ossification of the gap was visualized by color coding. ----- Conclusion: Sclerosis and medial width of the osteotomy gap as well as area measurements were determined as reproducible parameters for evaluation of bone healing. Quantification of bone ossification can be calculated with CT scans using a semiautomatic computer program and should be used for research in bone healing

Enantioselective direct aldol reaction of α-keto esters catalyzed by (Sa)-binam-D-prolinamide under quasi solvent-free conditions

(Sa)-Binam-D-prolinamide (20 mol%), instead of (Sa)-binam-L-prolinamide, in combination with chloroacetic acid (100 mol%) is an efficient organocatalyst for the direct aldol reaction between α-keto esters as electrophiles and alkyl and α-functionalised ketones, under quasi solvent-free conditions, providing access to highly functionalised chiral quaternary γ-keto α-hydroxyesters with up to 92% ee.This research was supported by the Ministerio de Ciencia e Innovación (MICINN: Projects CTQ2007-62771/BQU, CTQ2010-20387, and Consolider Ingenio2010 CSD2007-00006,), FEDER, the Generalitat Valenciana (Project PROMETEO/2009/039), and the EU (ORCA action CM0905). A.B.-C. thanks the Spanish MICINN for a predoctoral fellowship (FPU AP2009-3601)

Chemoenzymatic synthesis of hygromycin aminocyclitol moiety and its C2 epimer

This manuscript describes the enantioselective synthesis of the aminocyclitol moiety of the antibiotic hygromycin A in eight steps and 39 % overall yield from a non-chiral starting material. The sequence made use of an initial enzymatic step to transfer chirality to an aromatic ring and was followed by selective organic chemistry transformations (oxidation, pro-tection, azidation, hydrolysis) of the six-membered ring in order to achieve the target. The approach is also amenable to the synthesis of other related unnatural analogues as exemplified by the synthesis of the C2 epimer of the natural aminocyclitol. All the intermediates were fully characterized, and the absolute stereochemistry assigned by spectrometric methods.Fil: Carrau, Gonzalo. Universidad de la República; UruguayFil: Bellomo Peraza, Ana Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Suescun, Leopoldo. Universidad de la República; UruguayFil: Gonzalez, David. Universidad de la República; Urugua