INTERMOLECULAR NON-COVALENT INTERACTIONS REVEALED BY BROADBAND ROTATIONAL SPECTROSCOPY

Non-covalent interactions play a key role in chemistry, physics and biology, being responsible for the three-dimensional structure of proteins, the physical properties of condensed phases, and the outcome of molecular recognition processes, to cite just a few examples. In this talk we will focus on intermolecular non-covalent interactions and present our results on several complexes investigated by chirped pulsed Fourier transform microwave spectroscopy and computational methods. A range of clusters, involving odorants, aromatic hydrocarbons, alcohols and water will be reviewed. The interplay between primary and secondary hydrogen bonds and/or dispersion forces will be discussed, as well as the performance of several theoretical methods in view of the experimental data

Restoration of microRNA-214 expression reduces growth of myeloma cells through positive regulation of P53 and inhibition of DNA replication

This is an open-access paper.-- et al.MicroRNA have been demonstrated to be deregulated in multiple myeloma. We have previously reported that miR-214 is down-regulated in multiple myeloma compared to in normal plasma cells. The functional role of miR- 214 in myeloma pathogenesis was explored by transfecting myeloma cell lines with synthetic microRNA followed by gene expression profiling. Putative miR-214 targets were validated by luciferase reporter assay. Ectopic expression of miR-214 reduced cell growth and induced apoptosis of myeloma cells. In order to identify the potential direct target genes of miR-214 which could be involved in the biological pathways regulated by this microRNA, gene expression profiling of the H929 myeloma cell line transfected with precursor miR-214 was carried out. Functional analysis revealed significant enrichment for DNA replication, cell cycle phase and DNA binding. miR- 214 directly down-regulated the expression of PSMD10, which encodes the oncoprotein gankyrin, and ASF1B, a histone chaperone required for DNA replication, by binding to their 3'-untranslated regions. In addition, gankyrin inhibition induced an increase of P53mRNA levels and subsequent up-regulation of CDKN1A (p21Waf1/Cip1) and BAX transcripts, which are direct transcriptional targets of p53. In conclusion, MiR-214 functions as a tumor suppressor in myeloma by positive regulation of p53 and inhibition of DNA replication.This work was partially supported by the Spanish FIS (PI080568 and PS0901897), the >Gerencia Regional de Salud, Junta de Castilla y León> (GRS202/A08 and GRS 702/A/11), and the Spanish Myeloma Network Program (RD06/0020/0006). MES is supported by the Ministerio de Sanidad y Consumo (CA08/00212).Peer Reviewe

Biochemical Profile and Antioxidant Properties of Propolis from Northern Spain

[EN] The antioxidant, anti-inflammatory, and antimicrobial characteristics of propolis, a bioactive compound collected from hives, have prompted its use in the food sector in recent times. This study investigated the physicochemical characteristics, phenolic profile, and antioxidant capacity of 31 propolis extracts collected from Northern Spain. The physicochemical composition (resins, waxes, ashes mineral content, and heavy metals) was within the allowable regulatory limits. The analysis of bioactive compounds enabled the identification of 51 constituents: flavonoids (apigenin, catechin, chrysin, quercetin, and pinocembrin) and phenolic acids (caffeic, ferulic, and coumaric). The mean value of total polyphenols was 42.72 ± 13.19 Pinocembrin–Galangin Equivalents/100 g, whereas a range between 1.64 ± 0.04 and 4.95 ± 0.36 Quercetin Equivalents (QE) g/100 g was found for total flavonoids content. The determination of bioactivities revealed significant antioxidant capacity using DPPH (1114.28 ± 10.39 µM Trolox Equivalents and 3487.61 ± 318.66 µM Vitamin C Equivalents). Resin content in propolis samples was positively and significantly correlated with both polyphenols (rho = 0.365; p = 0.043) and flavonoid composition (rho = 0.615; p = 0.000) as well as the antioxidant capacity TEAC DPPH (rho = 0.415; p = 0.020). A multiple regression analysis modeled the correlation between resin composition, flavonoids, and TEAC DPPH values, yielding a significant regression equation (R2 = 0.618; F (2,28) = 22.629; p < 0.000; d = 2.299). Therefore, evaluating physicochemical parameters and biological activities provides a promising framework for predicting propolis’ quality and antioxidant properties, thus suggesting its potential as a functional and bioactive compound for the food industry.S

The microwave spectrum, ab initio analysis, and structure of the fluorobenzene–hydrogen chloride complex

The fluorobenzene–hydrogen chloride π-hydrogen-bonded complex has been studied by high resolution microwave spectroscopy and ab initio calculations. Rotational spectra of the C6H5F–H35Cl,C6H5F–H35Cl, C6H5F–H37Cl,C6H5F–H37Cl, and C6D5F–H35ClC6D5F–H35Cl isotopomers were assigned using pulsed molecular beam techniques in a Fourier-transform microwave spectrometer. The spectra are consistent with a structure of the complex in which the HCl is above the fluorobenzene ring near the ring center, similar to the benzene–HCl prototype dimer. An analysis of the inertial data and the chlorine quadrupole coupling tensor results in two mathematically possible locations for the HCl subunit with respect to the fluorobenzene arising from sign ambiguities in interpreting the spectral constants. One structure has the HCl nearly perpendicular to the aromatic ring; the other has the HCl pointing toward the fluorine end of the ring. Spectral intensities for the μaμa and μbμb transitions favor the former configuration. Ab initio calculations (MP2/6-311++G(2df,2pd)+BSSE corrections) indicate that the position of the HCl is driven by electrostatic interactions with the π electrons of the benzene ring. HCl is shifted by 0.16 Å from the center of the ring toward the para-C atom, where the π density is significantly higher. In the equilibrium form, HCl is tilted by δ=14° from perpendicular to the ring with the hydrogen end toward the para-C atom. The H atom can perform an internal rotation or at least a half-circular libration (barriers smaller than 100 cm−1). An average δ value of 0.7° is estimated in reasonable agreement with the derived vibrationally averaged value of 3.8°. The complex binding energy ΔEΔE calculated at the CCSD(T)/6-311++G(2df,2pd)+CP(BSSE) level of theory is 2.8 kcal/mol, suggesting a lower ΔEΔE value for benzene–HCl than previously reported. Fluorobenzene–HCl possesses some charge transfer character; however, just 5.5 melectron are transferred from the benzene ring to HCl. In view of this, π–H bonding in fluorobenzene–HCl is predominantly electrostatic rather than covalent in character contrary to claims made in connection with benzene–HCl. © 2003 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/71342/2/JCPSA6-118-20-9278-1.pd

Transcriptome analysis reveals molecular profiles associated with evolving steps of monoclonal gammopathies

This is an open-access paper.-- et al.A multistep model has been proposed of disease progression starting in monoclonal gammopathy of undetermined significance continuing through multiple myeloma, sometimes with an intermediate entity called smoldering myeloma, and ending in extramedullary disease. To gain further insights into the role of the transcriptome deregulation in the transition from a normal plasma cell to a clonal plasma cell, and from an indolent clonal plasma cell to a malignant plasma cell, we performed gene expression profiling in 20 patients with monoclonal gammopathy of undetermined significance, 33 with high-risk smoldering myeloma and 41 with multiple myeloma. The analysis showed that 126 genes were differentially expressed in monoclonal gammopathy of undetermined significance, smoldering myeloma and multiple myeloma as compared to normal plasma cell. Interestingly, 17 and 9 out of the 126 significant differentially expressed genes were small nucleolar RNA molecules and zinc finger proteins. Several proapoptotic genes (AKT1 and AKT2) were down-regulated and antiapoptotic genes (APAF1 and BCL2L1) were up-regulated in multiple myeloma, both symptomatic and asymptomatic, compared to monoclonal gammopathy of undetermined significance. When we looked for those genes progressively modulated through the evolving stages of monoclonal gammopathies, eight snoRNA showed a progressive increase while APAF1, VCAN and MEGF9 exhibited a progressive downregulation. In conclusion, our data show that although monoclonal gammopathy of undetermined significance, smoldering myeloma and multiple myeloma are not clearly distinguishable groups according to their gene expression profiling, several signaling pathways and genes were significantly deregulated at different steps of the transformation process.This study was partially supported by Spanish FIS (PI080568, PS09/01450 and PS0901897), “Gerencia Regional de Salud, Junta de Castilla y León” (GRS 702/A/11) grant, and the Spanish Myeloma Network Program (RD06/0020/0006, RD12/0036/0058 and RD12/0036/0046).Peer Reviewe

Phenotypic, genomic and functional characterization reveals no differences between CD138++ and CD138low subpopulations in multiple myeloma cell lines

This is an open-access article distributed under the terms of the Creative Commons Attribution License.Despite recent advances in the treatment of multiple myeloma (MM), it remains an incurable disease potentially due to the presence of resistant myeloma cancer stem cells (MM-CSC). Although the presence of clonogenic cells in MM was described three decades ago, the phenotype of MM-CSC is still controversial, especially with respect to the expression of syndecan-1 (CD138). Here, we demonstrate the presence of two subpopulations - CD138++ (95-99%) and CD138low (1-5%) - in eight MM cell lines. To find out possible stem-cell-like features, we have phenotypically, genomic and functionally characterized the two subpopulations. Our results show that the minor CD138low subpopulation is morphologically identical to the CD138++ fraction and does not represent a more immature B-cell compartment (with lack of CD19, CD20 and CD27 expression). Moreover, both subpopulations have similar gene expression and genomic profiles. Importantly, both CD138++ and CD138low subpopulations have similar sensitivity to bortezomib, melphalan and doxorubicin. Finally, serial engraftment in CB17-SCID mice shows that CD138++ as well as CD138low cells have self-renewal potential and they are phenotypically interconvertible. Overall, our results differ from previously published data in MM cell lines which attribute a B-cell phenotype to MM-CSC. Future characterization of clonal plasma cell subpopulations in MM patients' samples will guarantee the discovery of more reliable markers able to discriminate true clonogenic myeloma cells.This work was supported by the Cooperative Research Thematic Network (RTICs; RD06/0020/0006), the “Junta de Castilla y León. Consejería de Sanidad” (GRS 391/B/09), the “Ministerio de Ciencia e Innovación” (PS09/01897), the “Fundación Memoria D. Samuel Solórzano Barruso” (FS/2-2010) and Asociación Española Contra el Cáncer (AECC)(GCB120981SAN).Peer Reviewe

Role of atrial tissue remodeling on rotor dynamics an in vitro study

The objective of this article is to present an in vitro model of atrial cardiac tissue that could serve to study the mechanisms of remodeling related to atrial fibrillation (AF). We analyze the modification on gene expression and modifications on rotor dynamics following tissue remodeling. Atrial murine cells (HL-1 myocytes) were maintained in culture after the spontaneous initiation of AF and analyzed at two time points: 3.1 +/- 1.3 and 9.7 +/- 0.5 days after AF initiation. The degree of electrophysiological remodeling (i.e., relative gene expression of key ion channels) and structural inhomogeneity was compared between early and late cell culture times both in nonfibrillating and fibrillating cell cultures. In addition, the electrophysiological characteristics of in vitro fibrillation [e.g., density of phase singularities (PS/cm2), dominant frequency, and rotor meandering] analyzed by means of optical mapping were compared with the degree of electrophysiological remodeling. Fibrillating cell cultures showed a differential ion channel gene expression associated with atrial tissue remodeling (i.e., decreased SCN5A, CACN1C, KCND3, and GJA1 and increased KCNJ2) not present in nonfibrillating cell cultures. Also, fibrillatory complexity was increased in late- vs. early stage cultures (1.12 +/- 0.14 vs. 0.43 +/- 0.19 PS/cm(2), P < 0.01), which was associated with changes in the electrical reentrant patterns (i.e., decrease in rotor tip meandering and increase in wavefront curvature). HL-1 cells can reproduce AF features such as electrophysiological remodeling and an increased complexity of the electrophysiological behavior associated with the fibrillation time that resembles those occurring in patients with chronic AF.This work was supported in part by grants from the Spanish Ministry of Science and Innovation (PLE2009-0152), the Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain: PI13-01882, PI13-00903, and TEC2013-50391-EXP), and the Red de Investigacion Cardiovacular (RIC) from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain).Climent, A.; Guillem Sánchez, MS.; Fuentes, L.; Lee, P.; Bollensdorff, C.; Fernandez-Santos, M.; Suarez-Sancho, S.... (2015). Role of atrial tissue remodeling on rotor dynamics an in vitro study. AJP - Heart and Circulatory Physiology. 309(11):H1964-H1973. doi:10.1152/ajpheart.00055.2015SH1964H197330911Allessie, M. (2002). 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H., Cappato, R., Brugada, J., Camm, A. J., Chen, S.-A., … Wilber, D. (2012). 2012 HRS/EHRA/ECAS Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation: Recommendations for Patient Selection, Procedural Techniques, Patient Management and Follow-up, Definitions, Endpoints, and Research Trial Design. Heart Rhythm, 9(4), 632-696.e21. doi:10.1016/j.hrthm.2011.12.016Claycomb, W. C., Lanson, N. A., Stallworth, B. S., Egeland, D. B., Delcarpio, J. B., Bahinski, A., & Izzo, N. J. (1998). HL-1 cells: A cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte. Proceedings of the National Academy of Sciences, 95(6), 2979-2984. doi:10.1073/pnas.95.6.2979Filgueiras-Rama, D., Price, N. F., Martins, R. P., Yamazaki, M., Avula, U. M. R., Kaur, K., … Berenfeld, O. (2012). Long-Term Frequency Gradients During Persistent Atrial Fibrillation in Sheep Are Associated With Stable Sources in the Left Atrium. Circulation: Arrhythmia and Electrophysiology, 5(6), 1160-1167. doi:10.1161/circep.111.969519Haïssaguerre, M., Jaïs, P., Shah, D. C., Takahashi, A., Hocini, M., Quiniou, G., … Clémenty, J. (1998). Spontaneous Initiation of Atrial Fibrillation by Ectopic Beats Originating in the Pulmonary Veins. New England Journal of Medicine, 339(10), 659-666. doi:10.1056/nejm199809033391003Haralick, R. M., Shanmugam, K., & Dinstein, I. (1973). Textural Features for Image Classification. IEEE Transactions on Systems, Man, and Cybernetics, SMC-3(6), 610-621. doi:10.1109/tsmc.1973.4309314Jalife, J. (2010). Deja vu in the theories of atrial fibrillation dynamics. Cardiovascular Research, 89(4), 766-775. doi:10.1093/cvr/cvq364Koivumäki, J. T., Seemann, G., Maleckar, M. M., & Tavi, P. (2014). In Silico Screening of the Key Cellular Remodeling Targets in Chronic Atrial Fibrillation. 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High-resolution copy number analysis of paired normal-tumor samples from diffuse large B cell lymphoma

Copy number analysis can be useful for assessing prognosis in diffuse large B cell lymphoma (DLBCL). We analyzed copy number data from tumor samples of 60 patients diagnosed with DLBCL de novo and their matched normal samples. We detected 63 recurrent copy number alterations (CNAs), including 33 gains, 30 losses, and nine recurrent acquired copy number neutral loss of heterozygosity (CNN-LOH). Interestingly, 20 % of cases acquired CNN-LOH of 6p21 locus, which involves the HLA region. In normal cells, there were no CNAs but we observed CNN-LOH involving some key lymphoma regions such as 6p21 and 9p24.1 (5 %) and 17p13.1 (2.5 %) in DLBCL patients. Furthermore, a model with some specific CNA was able to predict the subtype of DLBCL, 1p36.32 and 10q23.31 losses being restricted to germinal center B cell-like (GCB) DLBCL. In contrast, 8p23.3 losses and 11q24.3 gains were strongly associated with the non-GCB subtype. A poor prognosis was associated with biallelic inactivation of TP53 or 18p11.32 losses, while prognosis was better in cases carrying 11q24.3 gains. In summary, CNA abnormalities identify specific DLBCL groups, and we describe CNN-LOH in germline cells from DLBCL patients that are associated with genes that probably play a key role in DLBCL development.This work was supported by research funding from the Health Council of Castilla y León (GRS265/A/08), the Health Research Program (PS09/01382), and the Red Temática de Investigación Cooperativa en Cáncer (RTICC) grant RD12/0036 (groups 0069, 0029, 0036, 0058, and 0060) included in the National Plan I+D+I supported by the Instituto Carlos III and the Fondo Europeo de Desarrollo Regional (FEDER), the Spanish Ministry of Economy and Competitiveness, and the European Regional Development Fund (ERDF) 'Una manera de hacer Europa' (Innocampus; CEI-2010-1-0010). ES was supported by CM10/00078-Río Hortega, an ISCIII contract, FEHH grant 2013–2014 and JR14/00025-Juan Rodés, an ISCIII contract. IS was supported by the Subprograma Juan de la Cierva (JCI-2011-10232) and a Miguel Servet contract (CP13/00159).Peer Reviewe