Unexpected N-C bond fission of fused N-alkylbenzimidazolium salts. A new approach to pyrido[1,2-a]- or pyridazino[1,6-a]benzimidazoles

The reaction of N-carboxymethylpyrido[1,2-a]- and pyridazino[1,6-a]benzimidazolium salts with thionyl chloride resulted in an N-C bond fission, yielding the corresponding pyrido[1,2-a]- and pyridazino[1,6-a]benzimidazoles. A similar dealkylation process was observed when analogous N-propargylic derivatives were treated with Cu (II) acetate.Universidad de Alcal

An experimental approach to the study of Iron Age combustion structures in northeastern Iberia: the TRANSCOMB Project

We are presenting the first results of an experimental project carried out in the Iberian Citadel of Calafell (Calafell, Tarragona, Spain), a reconstructed Iron Age site that is also a field of experimental archaeology. The aim of this experimentation is to investigate the efficiency of fire installations as well as the range of domestic activities they would have been built for, the fuels employed, and the management of natural resources related to them.This research is integrated within the framework of the TRANSCOMB (Transdisciplinary and experimental study of combustion structures in the western Mediterranean during Protohistory) project, funded by the Spanish Ministry of Science. Experimentation works have been performed on present-day replicas of archaeological combustion structures, more precisely six hearths of different types and one oven, located both indoors and outdoors. Various fuel-types (wood, grasses, palm leaves and animal dung) have been used, according to the available archaeobotanical records. Variables such as increased heating and time have been measured, in order to determine whether variations occur, depending on the fuels used, the type of structure, its location or weather conditions. Liquid boiling and meat cooking tests have also been performed. After use, these structures have been sampled for diverse analyses(anthracology, phytoliths and other calcitic microfossils, FTIR, micromorphology, chemical analysis of hearths surfaces), in order to compare the results of the same analyses performed in archaeological Iron Age combustion structures

Multiple cancer pathways regulate telomere protection

Telomeres are considered as universal anti-cancer targets, as telomere maintenance is essential to sustain indefinite cancer growth. Mutations in telomerase, the enzyme that maintains telomeres, are among the most frequently found in cancer. In addition, mutations in components of the telomere protective complex, or shelterin, are also found in familial and sporadic cancers. Most efforts to target telomeres have focused in telomerase inhibition; however, recent studies suggest that direct targeting of the shelterin complex could represent a more effective strategy. In particular, we recently showed that genetic deletion of the TRF1 essential shelterin protein impairs tumor growth in aggressive lung cancer and glioblastoma (GBM) mouse models by direct induction of telomere damage independently of telomere length. Here, we screen for TRF1 inhibitory drugs using a collection of FDA-approved drugs and drugs in clinical trials, which cover the majority of pathways included in the Reactome database. Among other targets, we find that inhibition of several kinases of the Ras pathway, including ERK and MEK, recapitulates the effects of Trf1 genetic deletion, including induction of telomeric DNA damage, telomere fragility, and inhibition of cancer stemness. We further show that both bRAF and ERK2 kinases phosphorylate TRF1 in vitro and that these modifications are essential for TRF1 location to telomeres in vivo Finally, we use these new TRF1 regulatory pathways as the basis to discover novel drug combinations based on TRF1 inhibition, with the goal of effectively blocking potential resistance to individual drugs in patient-derived glioblastoma xenograft models.We thank the Confocal Microscopy, Protein Engineering, Mass Spectrometry,Comparative Pathology, and Mouse Facility Units at CNIO. MAB laboratory is funded by SAF 2013-45111-R from MINECO,Fundación Botín and Banco Santander, Worldwide Cancer Research 16-1177. LB is a fellow of the La Caixa-Severo Ochoa International PhD Programme.S

Funcionamiento del sistema nervioso autónomo y estado de salud en la fibromialgia

Presently it is proposed that an alteration of autonomic nervous system (ANS) functioning may be involved in the chronicity of fibromyalgia (FM) symptoms. The aim of this study is to compare ANS activity by assessing the heart rate variability (HRV) between women with FM and healthy ones, and analyze its relationship with different dimensions of perceived health. The results confirm that women with FM have a more diminished parasympathetic, hormonal and thermoregulatory activity than healthy women at rest; and the existing relationship of ANS imbalance (analyzed with HRV) with the most common FM symptoms, while its relationship with perceived health needs more development.En la actualidad se plantea que una alteración en el funcionamiento del sistema nervioso autónomo (SNA) podría está implicada en la cronificación de la sintomatología que presenta la Fibromialgia. El objetivo de este estudio es comparar el funcionamiento del SNA mediante la evaluación de la Variabilidad de la Frecuencia Cardiaca (VFC) entre mujeres con Fibromialgia y sanas, y analizar su relación con distintas dimensiones del estado de salud percibido. Los resultados confirman que las mujeres con FM presentan una actividad parasimpática, hormonal y termorreguladora más disminuida que las mujeres sanas en situación de reposo; y  la relación del desequilibrio del SNA (mediante el análisis de la VFC) con los síntomas más frecuentes en la FM, mientras que su relación con el estado de salud percibido queda pendiente de desarrollo

Anti-tumor effects of PIM/PI3K/mTOR triple kinase inhibitor IBL-302 in neuroblastoma

The PI3K pathway is a major driver of cancer progression. However, clinical resistance to PI3K inhibition is common. IBL-302 is a novel highly specific triple PIM, PI3K, and mTOR inhibitor. Screening IBL-302 in over 700 cell lines representing 47 tumor types identified neuroblastoma as a strong candidate for PIM/PI3K/mTOR inhibition. IBL-302 was more effective than single PI3K inhibition in vitro, and IBL-302 treatment of neuroblastoma patient-derived xenograft (PDX) cells induced apoptosis, differentiated tumor cells, and decreased N-Myc protein levels. IBL-302 further enhanced the effect of the common cytotoxic chemotherapies cisplatin, doxorubicin, and etoposide. Global genome, proteome, and phospho-proteome analyses identified crucial biological processes, including cell motility and apoptosis, targeted by IBL-302 treatment. While IBL-302 treatment alone reduced tumor growth in vivo, combination therapy with low-dose cisplatin inhibited neuroblastoma PDX growth. Complementing conventional chemotherapy treatment with PIM/PI3K/mTOR inhibition has the potential to improve clinical outcomes and reduce severe late effects in children with high-risk neuroblastoma.This work was supported by funding from the Swedish Cancer Society (to SM, DB), the Swedish Research Council (to DB), the Swedish Childhood Cancer Fund (to SM, KvS, DB), Region Skåne and the research funds of Skåne University Hospital (to DB), the Mary Bevé Foundation (to SM, KvS, DB), Magnus Bergvalls stiftelse (to SM, DB), the Thelma Zoéga Foundation (to SM), Hans von Kantzow Foundation (to SM), Crafoord Foundation (to DB), Åke Wiberg Foundation (to DB), Jeanssons Stiftelser (to DB), Ollie och Elof Ericssons stiftelser (to DB), Berth von Kantzows stiftelse (to DB), the Royal Physiographic Society of Lund (to SM, DB), and the Spanish Ministry of Health and Social Policy (ADE 08 / 90038 ) and the Spanish Ministry of Science and Innovation (CIT- 090000 - 2008 - 14 ) (to JP, SMa, CBA). We would like to thank the Local MS Support at Medical Faculty, Lund University. The authors would like to acknowledge support of the National Genomics Infrastructure (NGI)/Uppsala Genome Center and UPPMAX for providing assistance in massive parallel sequencing and computational infrastructure. Work performed at NGI/Uppsala Genome Center has been funded by RFI/VR and Science for Life Laboratory, SwedenS

Modulation of telomere protection by the PI3K/AKT pathway

Telomeres and the insulin/PI3K pathway are considered hallmarks of aging and cancer. Here, we describe a role for PI3K/AKT in the regulation of TRF1, an essential component of the shelterin complex. PI3K and AKT chemical inhibitors reduce TRF1 telomeric foci and lead to increased telomeric DNA damage and fragility. We identify the PI3Kα isoform as responsible for this TRF1 inhibition. TRF1 is phosphorylated at different residues by AKT and these modifications regulate TRF1 protein stability and TRF1 binding to telomeric DNA in vitro and are important for in vivo TRF1 telomere location and cell viability. Patient-derived breast cancer PDX mouse models that effectively respond to a PI3Kα specific inhibitor, BYL719, show decreased TRF1 levels and increased DNA damage. These findings functionally connect two of the major pathways for cancer and aging, telomeres and the PI3K pathway, and pinpoint PI3K and AKT as novel targets for chemical modulation of telomere protection.We are indebted to D. Megias for microscopy analysis, to D. Calvo for protein purification as well as to J. Muñoz and F. García for LC/MS/MS analysis. The research was funded by project SAF2013-45111-R of Societal Changes Program of the Spanish Ministry of Economics and Competitiveness (MINECO) co-financed through the European Fund of Regional Development (FEDER), Fundación Botín, Banco Santander (Santander Universities Global Division) and Worldwide Cancer Research (WCR 16-1177).S

Critical Elements in Supergene Phosphates: The Example of the Weathering Profile at the Gavà Neolithic Mines, Catalonia, Spain

The essential role of Critical Elements (CE) in 21st century economy has led to an increasing demand of these metals and promotes the exploration of non-conventional deposits such as weathering profiles. The present work is focused on the study of a weathering profile located at the Archaeological Park of the Gavà Neolithic Mines, Barcelona, Catalonia, Spain. In the Gavà deposit, acid and oxidising meteoric fluids generated intense weathering during the early Pleistocene, affecting series of Llandoverian black shales and associated syn-sedimentary phosphates. The circulation of these acid fluids at deeper levels of the profile generated supergene vein-like mineralisations comprised of secondary phosphates (e.g., variscite, perhamite, crandallite, phosphosiderite) and sulphates (e.g., jarosite, alunite). This supergene mineralisation is significantly enriched in certain CE (e.g., Ga, Sc, REE, In, Co and Sb) that were mobilised from host rock components and later hosted in the crystal lattice of supergene minerals. Weathering processes and corresponding supergene enrichment of CE at the Gavà deposit could be used as an example to determine exploration guidelines of CE in weathering profiles and associated supergene phosphates worldwide

Highly N2-Selective Activated Carbon-Supported Pt-In Catalysts for the Reduction of Nitrites in Water

The catalytic reduction of nitrites over Pt-In catalysts supported on activated carbon has been studied in a semi-batch reactor, at room temperature and atmospheric pressure, and using hydrogen as the reducing agent. The influence of the indium content on the activity and selectivity was evaluated. Monometallic Pt catalysts are very active for nitrite reduction, but the addition of up to 1 wt% of indium significantly increases the nitrogen selectivity from 0 to 96%. The decrease in the accessible noble metal surface area reduces the amount of hydrogen available at the catalyst surface, this favoring the combination of nitrogen-containing intermediate molecules to promote the formation of N2 instead of being deeply hydrogenated into NH4+. Several activated carbon-supported Pt-In catalysts, activated under different calcination and reduction temperatures, have been also evaluated in nitrite reduction. The catalyst calcined and reduced at 400°C showed the best performance considering both the activity and the selectivity to nitrogen. This enhanced selectivity is ascribed to the formation of Pt-In alloy. The electronic properties of Pt change upon alloy formation, as it is demonstrated by XPS.This work was financially supported by Base-UIDB/50020/2020 and Programmatic-UIDP/50020/2020 Funding of LSRE-LCM, funded by natiunal funds through FCT/MCTES (PIDDAC). Financial support from Ministerio de Ciencia e Innovación (Spain, Project PID 2019-108453GB-C21 and PID 2020-116998RB-I00) is gratefully acknowledged