SC83288 is a clinical development candidate for the treatment of severe malaria

Severe malaria is a life-threatening complication of an infection with the protozoan parasite Plasmodium falciparum, which requires immediate treatment. Safety and efficacy concerns with currently used drugs accentuate the need for new chemotherapeutic options against severe malaria. Here we describe a medicinal chemistry program starting from amicarbalide that led to two compounds with optimized pharmacological and antiparasitic properties. SC81458 and the clinical development candidate, SC83288, are fast-acting compounds that can cure a P. falciparum infection in a humanized NOD/SCID mouse model system. Detailed preclinical pharmacokinetic and toxicological studies reveal no observable drawbacks. Ultra-deep sequencing of resistant parasites identifies the sarco/endoplasmic reticulum Ca(2+) transporting PfATP6 as a putative determinant of resistance to SC81458 and SC83288. Features, such as fast parasite killing, good safety margin, a potentially novel mode of action and a distinct chemotype support the clinical development of SC83288, as an intravenous application for the treatment of severe malaria

Incorporation of lippia citriodora microwave extract into total-green biogelatin-phospholipid vesicles to improve its antioxidant activity

Phytochemicals from Lippia citriodora leaves were extracted by applying an innovative technology based on the use of microwaves, which represents an alternative method to extract bioactive substances. The obtained extract was incorporated into phospholipid vesicles in order to promote the antioxidant effect of the bioactive molecules present in L. citriodora extract. The extract was analyzed by High Performance Liquid Chromatography coupled to Time-Of-Flight mass spectrometer by electrospray (HPLC-ESI-TOF-MS) and different phytochemicals were detected and quantified. The whole extract was incorporated in liposomes, glycerosomes (liposomes modified with glycerol) and propylene glycol-containing vesicles (PG-PEVs). Moreover, a biopolymer obtained from fish by-product, that is Thunnus albacares skin, was added to improve the bioactivity of the formulations. The in vitro biocompatibility and the antioxidant efficacy of the extract in solution or loaded in the vesicles were tested in primary mouse embryonic fibroblasts (3T3). The results showed the superior bioactivity of the vesicle formulations over the aqueous solution of the extract, which points to an interesting strategy for the treatment of skin disorders

The clustering of galaxies in the completed SDSS-III Baryon Oscillation Spectroscopic Survey: Angular clustering tomography and its cosmological implications

We investigate the cosmological implications of studying galaxy clustering using a tomographic approach applied to the final BOSS DR12 galaxy sample, including both auto- and cross-correlation functions between redshift shells. We model the signal of the full shape of the angular correlation function, $\omega(\theta)$, in redshift bins using state-of-the-art modelling of non-linearities, bias and redshift-space distortions. We present results on the redshift evolution of the linear bias of BOSS galaxies, which cannot be obtained with traditional methods for galaxy-clustering analysis. We also obtain constraints on cosmological parameters, combining this tomographic analysis with measurements of the cosmic microwave background (CMB) and type Ia supernova (SNIa). We explore a number of cosmological models, including the standard $\Lambda$CDM model and its most interesting extensions, such as deviations from w_\rm{DE} = -1, non-minimal neutrino masses, spatial curvature and deviations from general relativity using the growth-index $\gamma$ parametrisation. These results are, in general, comparable to the most precise present-day constraints on cosmological parameters, and show very good agreement with the standard model. In particular, combining CMB, $\omega(\theta)$ and SNIa, we find a value of w_\rm{DE} consistent with $-1$ to a precision better than 5\% when it is assumed to be constant in time, and better than 6\% when we also allow for a spatially-curved Universe.Comment: 21 pages, 18 figures, accepted for publication MNRAS. The data used in this analysis is publicly available at https://sdss3.org/science/boss_publications.ph

Spatial and temporal patterns of Holocene precipitation change in the Iberian Peninsula

Precipitation is a key climate parameter of vegetation and ecosystems in the Iberian Peninsula. Here, we use a regional pollen-climate calibration model and fossil pollen data from eight sites from the Atlantic coast to southern Spain to provide quantitative reconstructions of annual precipitation trends and excursions and their regional patterns for the last 11 700 years. The Early Holocene (11 700 to 11 000 cal. a BP) was characterized by high precipitation values followed by a slowly declining trend until about 9000 cal. a BP in the south and about 8000 cal. a BP in the north. From 8000 to 6000 cal. a BP the reconstructed precipitation values are the highest in most records, especially in those located in the Mediterranean climatic region in the southern part of the peninsula, with maximum values nearly 100% higher than the modern reconstructed values. The results suggest a declining precipitation during the Late Holocene in the south, with a positive excursion at around 2500 cal. a BP, while in the north precipitation remained high until 500 cal. a BP. However, the Late Holocene climate reconstructions in the Iberian Peninsula are biased by intensifying human impact on vegetation. The statistical time series analyses using SiZer technique do not indicate any statistically significant high-frequency drought events in the region. In general, our results suggest regional differences in the precipitation patterns between the northern and southern parts of the peninsula, with a more distinct Middle Holocene period of high humidity in the south.Peer reviewe

Spatial and temporal patterns of Holocene precipitation change in the Iberian Peninsula

Precipitation is a key climate parameter of vegetation and ecosystems in the Iberian Peninsula. Here, we use a regional pollen-climate calibration model and fossil pollen data from eight sites from the Atlantic coast to southern Spain to provide quantitative reconstructions of annual precipitation trends and excursions and their regional patterns for the last 11 700 years. The Early Holocene (11 700 to 11 000 cal. a BP) was characterized by high precipitation values followed by a slowly declining trend until about 9000 cal. a BP in the south and about 8000 cal. a BP in the north. From 8000 to 6000 cal. a BP the reconstructed precipitation values are the highest in most records, especially in those located in the Mediterranean climatic region in the southern part of the peninsula, with maximum values nearly 100% higher than the modern reconstructed values. The results suggest a declining precipitation during the Late Holocene in the south, with a positive excursion at around 2500 cal. a BP, while in the north precipitation remained high until 500 cal. a BP. However, the Late Holocene climate reconstructions in the Iberian Peninsula are biased by intensifying human impact on vegetation. The statistical time series analyses using SiZer technique do not indicate any statistically significant high-frequency drought events in the region. In general, our results suggest regional differences in the precipitation patterns between the northern and southern parts of the peninsula, with a more distinct Middle Holocene period of high humidity in the south.Peer reviewe

Identification of Importin 8 (IPO8) as the most accurate reference gene for the clinicopathological analysis of lung specimens

<p>Abstract</p> <p>Background</p> <p>The accurate normalization of differentially expressed genes in lung cancer is essential for the identification of novel therapeutic targets and biomarkers by real time RT-PCR and microarrays. Although classical "housekeeping" genes, such as GAPDH, HPRT1, and beta-actin have been widely used in the past, their accuracy as reference genes for lung tissues has not been proven.</p> <p>Results</p> <p>We have conducted a thorough analysis of a panel of 16 candidate reference genes for lung specimens and lung cell lines. Gene expression was measured by quantitative real time RT-PCR and expression stability was analyzed with the softwares <it>GeNorm </it>and <it>NormFinder</it>, mean of |ΔCt| (= |Ct Normal-Ct tumor|) ± SEM, and correlation coefficients among genes. Systematic comparison between candidates led us to the identification of a subset of suitable reference genes for clinical samples: IPO8, ACTB, POLR2A, 18S, and PPIA. Further analysis showed that IPO8 had a very low mean of |ΔCt| (0.70 ± 0.09), with no statistically significant differences between normal and malignant samples and with excellent expression stability.</p> <p>Conclusion</p> <p>Our data show that IPO8 is the most accurate reference gene for clinical lung specimens. In addition, we demonstrate that the commonly used genes GAPDH and HPRT1 are inappropriate to normalize data derived from lung biopsies, although they are suitable as reference genes for lung cell lines. We thus propose IPO8 as a novel reference gene for lung cancer samples.</p

Occupation-Related Differences in the Prevalence of Metabolic Syndrome

OBJECTIVE—To investigate the prevalence of metabolic syndrome in the Spanish working population and determine how the prevalence varies according to occupation and sex

Fisheries and Oceanography off Galicia, NW Spain: Mesoscale Spatial and Temporal Changes in Physical Processes and Resultant Patterns of Biological Productivity

The Galician shelf off NW Spain (43N degrees 9W degrees) exhibits mesoscale spatial and temporal changes in biological productivity associated with upwelling. Spatial heterogeneity results from local geomorphic and land-sea interactions superimposed on the large scale atmospheric processes that produce upwelling. Wind-induced upwelling events, commonly of short (i.e., week) duration, are more common in the summer than in the winter. A Series of cruises, including some time series sampling, and satellite imagery analysis showed that surface upwelling was more common and persistent on the northern coast compared with the western coast off the coastal embayments, the Rias Bajas. Nearshore off the rias, coastal runoff, which is greater in the rainy winter/spring versus the dry summer, affected upwelling. In early summer, upwelling less often reaches the surface because of increased water column stratification associated with lower surface salinities and thus upwelling is not detected by satellite imagery. Conversely, in late summer, upwelling more often reaches the surface because coastal runoff is reduced during the dry summer months and the water column tends to be less stratified. Plankton biomass and rate processes along the Galician shelf reflected both ambient hydrographic conditions as well as prior history of upwelling or downwelling. Phytoplankton and bacterioplankton were in greatest abundance during upwelling conditions (June through August); in contrast, both zooplankton and fish larvae exhibited highest abundances in March, when there were upwelling conditions prior to our cruise. Spatial differences in the duration and frequency of upwelling events, in combination with advection of water masses, are critical to the patterns of water column productivity and sardine fisheries production off the Galician coast. More persistent upwelling at this NW corner of the Iberian peninsula Supports large sardine fisheries because zooplankton and larval fish populations have time to respond to the higher primary production. Farther down the western Galician coast, the episodic upwelling and resultant intermittent primary production does not support a stable food supply needed to support fisheries. Times series sampling revealed mean response times of bacteria, phytoplankton, and zooplankton to be on the order of a day, days, and weeks, respectively. Sardines showed no spawning response in the relatively short time series sampling. The observed distributional patterns of fish eggs and larvae showed some offshore transport of fish larvae that were spawned inshore during upwelling periods and aggregation of larvae in a convergence zone northwest of Cabo Villano

Promoter hypomethylation of the LINE-1 retrotransposable elements activates sense/antisense transcription and marks the progression of chronic myeloid leukemia

Aberrant genome-wide hypomethylation is thought to be related to tumorigenesis by promoting genomic instability. Since DNA methylation is considered an important mechanism for the silencingof retroelements, hypomethylation in human tumors may lead to their reactivation. However, the role of DNA hypomethylation in chronic myeloid leukemia (CML) remains to be elucidated. In this study, the methylation status of the LINE-1 (L1) retrotransposon promoter was analysed in CML samples from the chronicphase (CP, n¼140) and the blast crisis (BC, n¼47). L1 hypomethylation was significantly more frequent in BC (74.5%) than in CP (38%) (Po0.0001). Furthermore, L1 hypomethylation led to activation of both ORF1 sense transcription (Po0.0001) and c-MET gene antisense transcription (Po0.0001), and was significantly associated with high levels of BCR–ABL (P¼0.02) and DNMT3b4 (P¼0.001) transcripts. Interestingly, in CP-CML, extensive L1 hypomethylation was associated with poorer prognosis in terms of cytogenetic response to interferon (P¼0.004) or imatinib (P¼0.034) and progression-free survival (P¼0.005). The above results strongly suggest that activation of both sense and antisense transcriptions by aberrant promoter hypomethylation of the L1 elements plays a role in the progression and clinical behavior of the CML