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Sensitivity analysis plays an important part in the validation of a sensor layout for the identification of the dynamic response of a system. Although sensitivity analysis has been implemented for this purpose in several civil engineering structures, there are still uncertainties in the case of more complex, nonlinear systems, such as guyed masts, where small changes in mass or stiffness can result in large variations of the general dynamic behavior. This paper describes the influence of antenna masses and initial guy tension variation in the total number and position of sensors required to assess the dynamic response of tall guyed mast telecommunication towers. For the study, the computational models of four different guyed masts were generated and a sensor layout was obtained for each model using a sensitivity analysis. Then, the proposed sensor layouts were verified for different initial guy tensions and total antenna mass of the system, by means of the Modal Assurance Criterion. The principal finding is that initial guy tension presents the highest influence on the variation of correspondence values between mode shapes, with modifications of these values in up to [Formula: see text]. This finding suggests that a preliminary sensor layout based on information provided by a computational model or structural drawings of a guyed mast may be rendered inefficient if there is variation in guy tension due to construction errors or relaxation of cables.

The signal transducer and activator of transcription (STAT) are transcription factors that work via JAK/STAT pathway regulating the expression of genes involved in cell survival, proliferation, differentiation, development, immune response, and, among other essential biological functions, hematopoiesis. JAK/STAT signaling is strictly regulated under normal physiological conditions. However, a large group of diverse diseases has been associated to an aberrant regulation of STAT factors. Erroneous modulation of the pathway leads to constitutive STAT activation, thereby driving proliferation, inflammation, and an uncontrolled immune response. Deregulated STAT5 activation has been found in the development of many hematopoietic tumors, including chronic and acute leukemias, polycythemia vera, and lymphoma. Mutations in the kinases that phosphorylate STAT5, and/or overexpression of the upstream receptor-associated tyrosine kinases have been suggested as the main drivers of constitutive STAT5 activation. Hyper-activated STAT5 leads to the aberrant expression of its target genes including antiapoptotic, proliferative, and pro-inflammatory genes, favouring tumorigenesis. In this review, we intent to discuss the biology of JAK/STAT pathway, with particular focus on STAT5 and its crucial role in the development and progression of hematologic malignancies. Furthermore, we provide a synopsis of potential therapeutic strategies based on STAT5 activity inhibition that may represent an excellent opportunity for drug development in oncohematology.

Naphthoquinones are among the most active natural products obtained from plants and microorganisms. Naphthoquinones exert their biological activities through pleiotropic mechanisms that include reactivity against cell nucleophiles, generation of reactive oxygen species (ROS), and inhibition of proteins. Here, we report a mechanistic antiproliferative study performed in the yeast Saccharomyces cerevisiae for several derivatives of three important natural naphthoquinones: lawsone, juglone, and β-lapachone. We have found that (i) the free hydroxyl group of lawsone and juglone modulates toxicity; (ii) lawsone and juglone derivatives differ in their mechanisms of action, with ROS generation being more important for the former; and (iii) a subset of derivatives possess the capability to disrupt mitochondrial function, with β-lapachones being the most potent compounds in this respect. In addition, we have cross-compared yeast results with antibacterial and antitumor activities. We discuss the relationship between the mechanistic findings, the antiproliferative activities, and the physicochemical properties of the naphthoquinones.

A series of 34 1,2,3-triazole-naphthoquinone conjugates were synthesized via copper-catalyzed cycloaddition (CuAAC). They were evaluated for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum and against three different tumor cell lines (SKBr-3, MCF-7, HEL). The most active antimalarial compounds showed a low antiproliferative activity. Simplified analogues were also obtained and some structure&ndash, activity relationships were outlined. The best activity was obtained by compounds 3s and 3j, having IC50 of 0.8 and 1.2 &mu, M, respectively. Molecular dockings were also carried on Plasmodium falciparum enzyme dihydroorotate dehydrogenase (PfDHODH) in order to rationalize the results.

This paper focuses on the study of bone alterations in fumier deposits from an experimental point of view. Fumiers are characteristic of livestock enclosures in the Mediterranean area used from the Neolithic to the Bronze Age. They originate from the process of burning livestock dung piles to reduce the volume of dung accumulation and to rid these spaces of parasites. Therefore, diverse taphonomic processes take part in the formation of these types of deposits, making it difficult to interpret them, despite numerous multidisciplinary studies. This work specifically focuses on bone burning alterations. Two experiments were set up consisting of bone burning in dung piles. Sheep and goat dung was used with different matrix, texture and humidity features. The sample was made up of defleshed fresh, boiled and dry bone fragments from small and medium-sized species. As seen in previous experiments, the burning time and temperature in the two experiments varied due to these different dung features. The resulting bone sample was analyzed using taphonomic methods. Bone alterations essentially depend on the time and intensity of the dung burning. Bone condition is a secondary determining factor. The color degrees were high and coherent with the degree of dung alteration. Cortical damage was more abundant in fresh and boiled bones than in dry bones. No meaningful differences were identified with regard to bones burned in hearth combustions.

BCR-ABL1-STAT5 is an oncogenic signaling pathway in human chronic myelogenous leukemia (CML) and it represents a valid target for anti-CML drug design. Resistance to direct BCR-ABL1 inhibitors is a common clinical issue, so STAT5 inhibition has become an interesting alternative target. In this study, the effects of NPQ-C6, a novel naphtoquinone-coumarin conjugate, were evaluated on human CML-derived K562 cells. Live-Cell Imaging analysis revealed that NPQ-C6 inhibited 2D (IC50AUC = 1.4 ± 0.6 μM) growth of CML cells. NPQ-C6 increased sub-G1 and reduced G0/G1 cell cycle phases in a dose- and time-dependent manner. This effect on cell cycle was related to increased levels of apoptotic nuclei, cleavage of caspase-3, -9, and PARP and annexin V-positive cells. NPQ-C6 increased γH2AX, a double-strand DNA break marker. NPQ-C6 showed a wide range of modulatory effects on cell signaling through an early increased phosphorylation of JNK, P38-MAPK and AKT, and decreased phosphorylation of ERK1/2, BCR-ABL1, and STAT5. NPQ-C6 inhibited expression of c-MYC and PYM-1, two target gene products of BCR-ABL1/STAT5 signaling pathway. Cytokine-induced activation of STAT5/STAT3-dependent transcriptional and DNA binding activities were also inhibited by NPQ-C6. Notably, NPQ-C6 maintained its activity on BCR-ABL1/STAT5/c-MYC/PIM-1 oncogenic pathway in imatinib-resistant cells. Molecular modeling suggested BCR-ABL1 and JAK2 proteins as NPQ-C6 targets. In summary, our data show a novel multikinase modulator that might be therapeutically effective in BCR-ABL1-STAT5-related malignancies.

Human Chronic Myelogenous Leukemia (CML) is a hematological stem cell disorder which is associated with activation of Bcr-Abl-Stat5 oncogenic pathway. Direct Bcr-Abl inhibitors are initially successful for the treatment of CML but over time many patients develop drug resistance. In the present study, the effects of CM363, a novel naphthoquinone (NPQ) derivative, were evaluated on human CML-derived K562 cells. CM363 revealed an effective cell growth inhibition (IC50 = 0.7 ± 0.5 μM) by inducing cancer cells to undergo cell cycle arrest and apoptosis. CM363 caused a dose- and time-dependent reduction of cells in G0/G1 and G2/M phases. This cell cycle arrest was associated with increased levels of cyclin E, pChk1 and pChk2 whereas CM363 downregulated cyclin B, cyclin D3, p27, pRB, Wee1, and BUBR1. CM363 increased the double-strand DNA break marker γH2AX. CM363 caused a time-dependent increase of annexin V-positive cells, DNA fragmentation and increased number of apoptotic nuclei. CM363 triggered the mitochondrial apoptotic pathway as reflected by a release of cytochrome C from mitochondria and induction of the cleavage of caspase-3 and -9, and PARP. CM363 showed multikinase modulatory effects through an early increased JNK phosphorylation followed by inhibition of pY-Bcrl-Abl and pY-Stat5. CM363 worked synergistically with imatinib to inhibit cell viability and maintained its activity in imatinib-resistant cells. Finally, CM363 (10 mg/Kg) suppressed the growth of K562 xenograft tumors in athymic mice. In summary, CM363 is a novel multikinase modulator that offers advantages to circumvent imanitib resistance and might be therapeutically effective in Bcrl-Abl-Stat5 related malignancies.

Self-supported telecommunication towers are very important structures in the infrastructure of countries. These structures are highly sensitive to the dynamic effects of wind loads. Several self-supported telecommunication towers have collapsed in Cuba during the last decades due to strong hurricane winds, causing important economic and social losses. The aim of this work is to compare the structural response of a self-supported tower in terms of internal forces and displacements by static equivalent and full dynamic time history methods, taking into account hurricane wind conditions. The static equivalent method used in this paper was Gust Response Factor with the formulation proposed in Eurocode EC 3: Part 3-1. Time history analysis was performed using generated simulated wind data obtained through Montecarlo’s technique and the turbulent component of the velocity was obtained by the formula presented by Shinozuka and Jan. Turbulence parameters, such as power spectral density function, integral scale and turbulence variance were assumed in accordance with the international literature on structural monitoring subjected to hurricane action. A 60m high lattice tower having a square in-plane cross-section was studied. Forces on members and displacements on the tower were found to be 20–25% higher when applying the static equivalent method, as compared to time history method.

This paper discusses the influence of asymmetrical anchors on guyed mast behavior under wind loads. Anchor asymmetry is due to variations on anchor levels in guyed mast placed at the top of hills. Six FEM models were developed with different guy anchor asymmetries. The mast was modeled as a three dimensional structure formed by pinned members (braced and horizontal members) and continuous members (columns). Cables were modeled with catenary formulation. Non-linear analysis under extreme wind loads was performed to calculate internal force on the guyed mast components. Comparison between members force on each model was made to assess structural behavior. Relative increments in internal forces in asymmetric models in relation to symmetric models were observed in all members. Results of this investigation show that asymmetry on anchor levels of guyed mast can produce a significant increase in internal forces of masts members, hence disregard of anchors asymmetry at guyed mast design can conduce to important errors.

A set of 5-ethynylarylnaphthalimides was synthesized by Sonogashira cross-coupling reactions and evaluated for antiproliferative and antitopoisomerase II in vitro activities. Furthermore docking studies of these molecules as DNA-intercalators were carried out and the in vivo DNA-damaging activity was also determined with the model organism Saccharomyces cerevisiae. From the obtained results three naphthalimides 6, 13 and 14 showed strong topoisomerase II inhibitory activity. These three molecules also presented good docking scores as DNA-intercalators using a self-complementary oligodeoxynucleotide d(ATGCAT)2 as a model, and compounds 13 and 14 were among the most cytotoxic in the in vivo DNA-damaging activity.

Human Chronic Myelogenous Leukemia (CML) is a hematological stem cell disorder which is associated with activation of Bcr-Abl-Stat5 oncogenic pathway. Direct Bcr-Abl inhibitors are initially successful for the treatment of CML but over time many patients develop drug resistance. In the present study, the effects of CM363, a novel naphthoquinone (NPQ) derivative, were evaluated on human CML-derived K562 cells. CM363 revealed an effective cell growth inhibition (IC50 = 0.7 ± 0.5 μM) by inducing cancer cells to undergo cell cycle arrest and apoptosis. CM363 caused a dose- and time-dependent reduction of cells in G0/G1 and G2/M phases. This cell cycle arrest was associated with increased levels of cyclin E, pChk1 and pChk2 whereas CM363 downregulated cyclin B, cyclin D3, p27, pRB, Wee1, and BUBR1. CM363 increased the double-strand DNA break marker γH2AX. CM363 caused a timedependent increase of annexin V-positive cells, DNA fragmentation and increased number of apoptotic nuclei. CM363 triggered the mitochondrial apoptotic pathway as reflected by a release of cytochrome C from mitochondria and induction of the cleavage of caspase-3 and -9, and PARP. CM363 showed multikinase modulatory effects through an early increased JNK phosphorylation followed by inhibition of pY-Bcrl-Abl and pY-Stat5. CM363 worked synergistically with imatinib to inhibit cell viability and maintained its activity in imatinib-resistant cells. Finally, CM363 (10 mg/Kg) suppressed the growth of K562 xenograft tumors in athymic mice. In summary, CM363 is a novel multikinase modulator that offers advantages to circumvent imanitib resistance and might be therapeutically effective in Bcrl-Abl- Stat5 related malignancies., This research has been supported by the Spanish Ministry of Science and Innovation (SAF2009-13296) and MINECO (SAF2012-37344, SAF2014-53526R, and SAF2015-65113-C2-2-R) with the co-funding of European Regional Development Fund (ERDF). This Project has been also supported by Centro Atlántico del Medicamento S.A. (CEAMED; www.ceamedsa.com) and Alfredo Martín-Reyes Foundation (Arehucas)-Canary Islands Foundation for Cancer Research (FICIC).

The human impact on the environment in the Holocene has usually been characterized on the basis of palaeobotanical records, but attempts to distinguish the anthropogenic impact from natural events in landscape evolution have been the subject of much debate in recent years. The aim of this paper is to analyse small-mammal diversity and the presence of synanthropic species, whose small size makes them more sensitive to any changes in their environment that may occur. This study has allowed us to characterize palaeoclimatic and palaeoenvironmental changes, recording small changes whether resulting from a human influence or otherwise. Our object of study is El Mirador cave, which has a sequence with a well-documented human occupation extending from 7200 to 3000 cal. BP. The study has led us to differentiate two phases. In one phase, we can see small changes in diversity related to climatic oscillations from ca. 7200 to 6800 cal. BP, while in the second phase, lasting from ca. 6800 to 3000 cal. BP, the changes in diversity and in the assemblage of synanthropic species are associated with human economic strategies. Moreover, we distinguish which kinds of economic activity (crop and livestock farming) have influenced these changes, because some small-mammal species are influenced, positively or negatively, by environmental changes based on crop farming and animal husbandry. All this information is contrasted with other archaeological proxies, such as the large-mammal and palaeobotanical assemblages from El Mirador cave. Furthermore, this integrative analysis has made it possible to identify the existence of altered environments more generally throughout the Iberian Peninsula from ca. 6000 cal. BP. It additionally confirms the theory of low human occupation intensity in the northern Meseta and in high mountainous areas during the early Neolithic.

In this paper we present an experimental study of bone modifications caused by human chewing during consumption. Traditionally, tooth marks have been attributed to non-human actors. However, ethnoarchaeological as well as previous experimental work has shown that humans can make many modifications during chewing. Our results suggest that the range of damage is as extensive as that most likely to be produced by carnivores. This damage includes furrowing, scooping-out, crenulated and saw-toothed edges, longitudinal cracking, crushing, peeling and tooth marks. In this paper we present a description of the types of damage observed in the experimental sample. Some of this damage shows parallels between the experimental modifications and archaeological assemblages from Pleistocene and Holocene deposits at the Sierra de Atapuerca sites (Burgos, Spain). The repetition of morphologies allowed us to attribute some of the damage to tooth marks made by human chewing.

The communication lattice towers must be designed to resist wind forces and support antennas under heavy working conditions. In the past few years, a number of communication lattice towers have collapsed in Cuba as a consequence of strong winds. Antennas modify the wind flow around their tower and act as a screen against wind loads and transmit strong efforts to its members. The aim of this chapter is to assess the effect of antenna locations on some structural parameters of the tower by means of physical and numerical experiments with computational applications. A physical experiment in a wind tunnel was conducted in order to obtain the drag coefficients of a tower holding dish antennas. Finite element method models of the tower with the implementation of SAP2000 code were generated to obtain forces and displacements on the members, and natural periods of the structure. The numerical experiment consisted of a 23 factorial experiment, where the independent variables were horizontal position, vertical position, and number of dishes on the tower. The results show that the vertical position of dish antennas has the greatest influence on the structural behavior of their supporting tower.

En este trabajo se investiga el comportamiento estructural de una torre atirantada considerando el efecto dinámico de la carga de viento por dos métodos alternativos. La torre fue analizada bajo carga de viento extrema de acuerdo a la normativa cubana de viento. Los resultados se obtuvieron por medio del análisis no lineal geométrico de la estructura. Se realiza el análisis comparativo entre las fuerzas interiores obtenidas en los elementos del fuste, en anclajes y cables, según los dos métodos simplificados basados en modelos deformacionales diferentes. This research deals with the structural behavior of a guyed mast considering the dynamic effect of wind loads. Wind loads are calculated according Cuban code requirements for wind action on structures. The guyed mast is analyzed applying two alternative simplified methods. Structure is analyzed through a non linear geometric analysis. Internal forces in mast members, guys and anchors obtained as a result of the application of the two simplified methods are compared and discussed.

Seven new triterpenoids (1-7) and 36 known compounds were isolated from the root bark of Maytenus retusa. Their structures were determined by 1D and 2D spectroscopic studies. Several compounds were evaluated for their cytotoxicity against the human tumor cell lines HL-60 and MCF-7. Some of them were cytotoxic, with IC(50) values ranging between 0.2 and 4.7 μM.

A set of derivatives encompassing structural modifications on the privileged phenalenone scaffold were assessed for their antiparasitic activities against the most clinically relevant forms of trypanosomiasis and leishmaniasis. Several compounds exhibited leishmanicidal effects at levels comparable or better than the reference drug pentamidine, while the parent phenalenone was shown to have a level of activity against Trypanosoma cruzi comparable to the marketed drug benznidazole.