Spatially explicit analysis reveals complex human genetic gradients in the Iberian Peninsula

The Iberian Peninsula is a well-delimited geographic region with a rich and complex human history. However, the causes of its genetic structure and past migratory dynamics are not yet fully understood. In order to shed light on them, here we evaluated the gene flow and genetic structure throughout the Iberian Peninsula with spatially explicit modelling applied to a georeferenced genetic dataset composed of genome-wide SNPs from 746 individuals belonging to 17 different regions of the Peninsula. We found contrasting patterns of genetic structure throughout Iberia. In particular, we identified strong patterns of genetic differentiation caused by relevant barriers to gene flow in northern regions and, on the other hand, a large genetic similarity in central and southern regions. In addition, our results showed a preferential north to south migratory dynamics and suggest a sex-biased dispersal in Mediterranean and southern regions. The estimated genetic patterns did not fit with the geographical relief of the Iberian landscape and they rather seem to follow political and linguistic territorial boundaries.IPATIMUP integrates the i3S Research Unit, which is partially supported by FCT in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274). J.P. and A.M.L. are funded by the Portuguese Government through the FCT fellowship SFRH/BD/97200/2013 and the research contract IF/01262/2014, respectively. M.A. was supported by the “Ramón y Cajal” grant RYC-2015-18241 from the Spanish Government. D.C. was supported by the Spanish grant CGL2016-75389-P (AEI, MINEICO/FEDER, UE), and “Unidad María de Maeztu” funded by the MINECO (MDM-2014-0370)

Population genetic data for 17 Y STR markers from Benghazi (East Libya)

The seventeen Y-STR loci included in the AmpF‘STR1 YfilerTM PCR Amplification kit (DYS19, DYS389I,DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385a/b, DYS438, DYS439, DYS437, DYS448, DYS458,DYS456, DYS635, and Y-GATA-H4) were used to type a sample population of 238 males from eastern Libya (Benghazi region). Of 238 observed haplotypes, 214 were unique (90%) and 24 (10%) were found more than once. The 17 loci gave a discriminating power of 0.999. DYS458 showed the highest diversity as a single-locus marker (0.73). Allelic frequencies and gene diversities for each Y-STR locus were determined. The high haplotype diversity and discrimination capacity (0.996) demonstrate the utility of these loci for human identification in forensic applications. Comparative analysis with Y-STR datasets of relevant populations and submission of the haplotypes to the Y-STR Haplotype Reference Database (YHRD) was undertaken

Three novel mutations in the CFTR gene identified in Galician patients

AbstractWe report three novel CFTR missense mutations detected in Spanish patients from Galicia (North West of Spain). In the first case, a patient homozygous for a novel S1045Y mutation died due to pulmonary problems. In the other two cases, both heterozygous for novel mutations combined with the F508del mutation, clinical symptoms were different depending on the mutation, detected as M595I and A107V

The Holocene volcanism at El Hierro: insights from petrology and geochemistry

The Holocene volcanism at El Hierro consists of basaltic monogenetic volcanic fields associated with o the three rift systems present in this island. In this work we report preliminary petrological and geochemical data of Holocene lava flows belonging to the WNW-striking rift. Sampling was focused in three zones: Orchilla, Verodal-Sabinosa, and Tanganasoga. Petrography of the studied lavas shows that they are homogeneous. All samples are porphyritic with macrocrysts of clinopyroxene and olivine immersed in a groundmass formed by microcrysts of plagioclase, Fe-Ti oxides and clinopyroxene. Clinopyroxenes are diopsides, olivines have forsterite contents ranging from 74 to 84 % and anorthite in plagioclase varies from 66 to 76% (labradorite). Whole-rock geochemical results evidence that all magmas are basic in composition, ranging from picrobasalts to phonotephrites. Major, trace elements and isotope suppor fractional crystallization as the main process of magma evolution. However, petrography and chemistry of clinopyroxene cores agree with a xenocrystic nature of some of them. We suggest that these clinopyroxene cores crystallized from a genetically related magma and subsequently were entrapped o cannibalized by the basic rising magmas

Period Concatenation Underlies Interactions between Gamma and Beta Rhythms in Neocortex

The neocortex generates rhythmic electrical activity over a frequency range covering many decades. Specific cognitive and motor states are associated with oscillations in discrete frequency bands within this range, but it is not known whether interactions and transitions between distinct frequencies are of functional importance. When coexpressed rhythms have frequencies that differ by a factor of two or more interactions can be seen in terms of phase synchronization. Larger frequency differences can result in interactions in the form of nesting of faster frequencies within slower ones by a process of amplitude modulation. It is not known how coexpressed rhythms, whose frequencies differ by less than a factor of two may interact. Here we show that two frequencies (gamma – 40 Hz and beta2 – 25 Hz), coexpressed in superficial and deep cortical laminae with low temporal interaction, can combine to generate a third frequency (beta1 – 15 Hz) showing strong temporal interaction. The process occurs via period concatenation, with basic rhythm-generating microcircuits underlying gamma and beta2 rhythms forming the building blocks of the beta1 rhythm by a process of addition. The mean ratio of adjacent frequency components was a constant – approximately the golden mean – which served to both minimize temporal interactions, and permit multiple transitions, between frequencies. The resulting temporal landscape may provide a framework for multiplexing – parallel information processing on multiple temporal scales

Evaluation of the dual mTOR / PI3K inhibitors Gedatolisib (PF-05212384) and PF-04691502 against ovarian cancer xenograft models

We are grateful to Wyeth/Pfizer (ONC-EU-150) and to the Scottish Funding Council (SRDG HR07005) for support of this study.This study investigated the antitumour effects of two dual mTOR/PI3K inhibitors, gedatolisib (WYE-129587/PKI-587/PF-05212384) and PF-04691502 against a panel of six human patient derived ovarian cancer xenograft models. Both dual mTOR/PI3K inhibitors demonstrated antitumour activity against all xenografts tested. The compounds produced tumour stasis during the treatment period and upon cessation of treatment, tumours re-grew. In several models, there was an initial rapid reduction of tumour volume over the first week of treatment before tumour stasis. No toxicity was observed during treatment. Biomarker studies were conducted in two xenograft models; phospho-S6 (Ser235/236) expression (as a readout of mTOR activity) was reduced over the treatment period in the responding xenograft but expression increased to control (no treatment) levels on cessation of treatment. Phospho-AKT (Ser473) expression (as a readout of PI3K) was inhibited by both drugs but less markedly so than phospho-S6 expression. Initial tumour volume reduction on treatment and regrowth rate after treatment cessation was associated with phospho-S6/total S6 expression ratio. Both drugs produced apoptosis but minimally influenced markers of proliferation (Ki67, phospho-histone H3). These results indicate that mTOR/PI3K inhibition can produce broad spectrum tumour growth stasis in ovarian cancer xenograft models during continuous chronic treatment and this is associated with apoptosis.Publisher PDFPeer reviewe

Floating stones off El Hierro, Canary Islands: xenoliths of pre-island sedimentary origin in the early products of the October 2011 eruption

The eruption that started off the south coast of El Hierro, Canary Islands, in October 2011 has emitted intriguing eruption products found floating in the sea. These specimens appeared as floating volcanic "bombs" that have in the meantime been termed "restingolites" (after the close-by village of La Restinga) and exhibit cores of white and porous pumice-like material. Currently the nature and origin of these "floating stones" is vigorously debated among researchers, with important implications for the interpretation of the hazard potential of the ongoing eruption. The "restingolites" have been proposed to be either (i) juvenile high-silica magma (e.g. rhyolite), (ii) remelted magmatic material (trachyte), (iii) altered volcanic rock, or (iv) reheated hyaloclastites or zeolite from the submarine slopes of El Hierro. Here, we provide evidence that supports yet a different conclusion. We have collected and analysed the structure and composition of samples and compared the results to previous work on similar rocks found in the archipelago. Based on their high silica content, the lack of igneous trace element signatures, and the presence of remnant quartz crystals, jasper fragments and carbonate relicts, we conclude that "restingolites" are in fact xenoliths from pre-island sedimentary rocks that were picked up and heated by the ascending magma causing them to partially melt and vesiculate. They hence represent messengers from depth that help us to understand the interaction between ascending magma and crustal lithologies in the Canary Islands as well as in similar Atlantic islands that rest on sediment/covered ocean crust (e.g. Cape Verdes, Azores). The occurrence of these "restingolites" does therefore not indicate the presence of an explosive high-silica magma that is involved in the ongoing eruption

Surface-controlled reversal of the selectivity of halogen bonds

Intermolecular halogen bonds are ideally suited for designing new molecular assemblies because of their strong directionality and the possibility of tuning the interactions by using different types of halogens or molecular moieties. Due to these unique properties of the halogen bonds, numerous areas of application have recently been identified and are still emerging. Here, we present an approach for controlling the 2D self-assembly process of organic molecules by adsorption to reactive vs. inert metal surfaces. Therewith, the order of halogen bond strengths that is known from gas phase or liquids can be reversed. Our approach relies on adjusting the molecular charge distribution, i.e., the σ-hole, by molecule-substrate interactions. The polarizability of the halogen and the reactiveness of the metal substrate are serving as control parameters. Our results establish the surface as a control knob for tuning molecular assemblies by reversing the selectivity of bonding sites, which is interesting for future applications

The helicase HAGE prevents interferon-a-induced PML expression in ABCB5+ malignant melanoma-initiating cells by promoting the expression of SOCS1

The tumour suppressor PML (promyelocytic leukaemia protein) regulates several cellular pathways involving cell growth, apoptosis, differentiation and senescence. PML also has an important role in the regulation of stem cell proliferation and differentiation. Here, we show the involvement of the helicase HAGE in the transcriptional repression of PML expression in ABCB5 + malignant melanoma-initiating cells (ABCB5 + MMICs), a population of cancer stem cells which are responsible for melanoma growth, progression and resistance to drug-based therapy. HAGE prevents PML gene expression by inhibiting the activation of the JAK-STAT (janus kinase-signal transducers and activators of transcription) pathway in a mechanism which implicates the suppressor of cytokine signalling 1 (SOCS1). Knockdown of HAGE led to a significant decrease in SOCS1 protein expression, activation of the JAK-STAT signalling cascade and a consequent increase of PML expression. To confirm that the reduction in SOCS1 expression was dependent on the HAGE helicase activity, we showed that SOCS1, effectively silenced by small interfering RNA, could be rescued by re-introduction of HAGE into cells lacking HAGE. Furthermore, we provide a mechanism by which HAGE promotes SOCS1 mRNA unwinding and protein expression in vitro

Overlapping variants in the blood, tissues and cell lines for patients with intracranial meningiomas are predominant in stem cell-related genes

Objective: Bulk tissue genomic analysis of meningiomas identified common somatic mutations, however, it often excluded blood-related variants. In contrast, genomic characterisation of primary cell lines that can provide critical information regarding growth and proliferation, have been rare. In our work, we identified the variants that are present in the blood, tissues and corresponding cell lines that are likely to be predictive, tumorigenic and progressive. Method: Whole-exome sequencing was used to identify variants and distinguish related pathways that exist in 42 blood, tissues and corresponding cell lines (BTCs) samples for patients with intracranial meningiomas. Conventional sequencing was used for the confirmation of variants. Integrative analysis of the gene expression for the corresponding samples was utilised for further interpretations. Results: In total, 926 BTC variants were detected, implicating 845 genes. A pathway analysis of all BTC genes with damaging variants indicated the 'cell morphogenesis involved in differentiation' stem cell-related pathway to be the most frequently affected pathway. Concordantly, five stem cell-related genes, GPRIN2, ALDH3B2, ASPN, THSD7A and SIGLEC6, showed BTC variants in at least five of the patients. Variants that were heterozygous in the blood and homozygous in the tissues or the corresponding cell lines were rare (average: 1.3 +/- 0.3%), and included variants in the RUNX2 and CCDC114 genes. An analysis comparing the variants detected only in tumours with aggressive features indicated a total of 240 BTC genes, implicating the 'homophilic cell adhesion via plasma membrane adhesion molecules' pathway, and identifying the stem cell-related transcription coactivator NCOA3/AIB1/SRC3 as the most frequent BTC gene. Further analysis of the possible impact of the poly-Q mutation present in the NCOA3 gene indicated associated deregulation of 15 genes, including the up-regulation of the stem cell related SEMA3D gene and the angiogenesis related VEGFA gene. Conclusion: Stem cell-related pathways and genes showed high prevalence in the BTC variants, and novel variants in stem cell-related genes were identified for meningioma. These variants can potentially be used as predictive, tumorigenic and progressive biomarkers for meningioma