Flavor constraints on electroweak ALP couplings

We explore the signals of axion-like particles (ALPs) in flavor-changing neutral current (FCNC) processes. The most general effective linear Lagrangian for ALP couplings to the electroweak bosonic sector is considered, and its contribution to FCNC decays is computed up to one-loop order. The interplay between the different couplings opens new territory for experimental exploration, as analyzed here in the ALP mass range $0<m_a \lesssim 5$ GeV. When kinematically allowed, $K\to \pi \nu \bar{\nu}$ decays provide the most stringent constraints for channels with invisible final states, while $B$-meson decays are more constraining for visible decay channels, such as displaced vertices in $B\to K^{(\ast)} \mu^+ \mu^-$ data. The complementarity with collider constraints is discussed as well.Comment: 12 pages, 6 figure

Germ line Methylation Patterns Determine the Distribution of Recombination Events in the Dog Genome

The positive-regulatory domain containing nine gene, PRDM9, which strongly associates with the location of recombination events in several vertebrates, is inferred to be inactive in the dog genome. Here, we address several questions regarding the control of recombination and its influence on genome evolution in dogs. First, we address whether the association between CpG islands (CGIs) and recombination hotspots is generated by lack of methylation, GC-biased gene conversion (gBGC), or both. Using a genome-wide dog single nucleotide polymorphism data set and comparisons of the dog genome with related species, we show that recombination-associated CGIs have low CpG mutation rates, and that CpG mutation rate is negatively correlated with recombination rate genome wide, indicating that nonmethylation attracts the recombination machinery. We next use a neighbor-dependent model of nucleotide substitution to disentangle the effects of CpG mutability and gBGC and analyze the effects that loss of PRDM9 has on these rates. We infer that methylation patterns have been stable during canid genome evolution, but that dog CGIs have experienced a drastic increase in substitution rate due to gBGC, consistent with increased levels of recombination in these regions. We also show that gBGC is likely to have generated many new CGIs in the dog genome, but these mostly occur away from genes, whereas the number of CGIs in gene promoter regions has not increased greatly in recent evolutionary history. Recombination has a major impact on the distribution of CGIs that are detected in the dog genome due to the interaction between methylation and gBGC. The results indicate that germline methylation patterns are the main determinant of recombination rates in the absence of PRDM9

C/EBPα mediates the growth inhibitory effect of progestins on breast cancer cells

Steroid hormones are key gene regulators in breast cancer cells. While estrogens stimulate cell proliferation, progestins activate a single cell cycle followed by proliferation arrest. Here, we use biochemical and genome‐wide approaches to show that progestins achieve this effect via a functional crosstalk with C/EBPα. Using ChIP‐seq, we identify around 1,000 sites where C/EBPα binding precedes and helps binding of progesterone receptor (PR) in response to hormone. These regions exhibit epigenetic marks of active enhancers, and C/EBPα maintains an open chromatin conformation that facilitates loading of ligand‐activated PR. Prior to hormone exposure, C/EBPα favors promoter–enhancer contacts that assure hormonal regulation of key genes involved in cell proliferation by facilitating binding of RAD21, YY1, and the Mediator complex. Knockdown of C/EBPα disrupts enhancer–promoter contacts and decreases the presence of these architectural proteins, highlighting its key role in 3D chromatin looping. Thus, C/EBPα fulfills a previously unknown function as a potential growth modulator in hormone‐dependent breast cancer.The experimental work was supported by grants from the Departament d'Innovació Universitat i Empresa (DIUiE), and the Spanish Ministry of Economy and Competitiveness (SAF2016‐75006P), “Centro de Excelencia Severo Ochoa 2013‐2017”, SEV‐2012‐0208 and ERC Synergy Grant “4DGenome” nr: 609989

Mobile ad hoc network testbed using mobile robot technology

MANET (Mobile Ad Hoc Network) researchers have shown increased interest in using mobile robot technology for their testbed platforms. Thus, the main motivation of this paper is to review various robot-based MANET testbeds that have been developed in previously reported research. Additionally, suggestions to heighten mobility mechanisms by using mobile robots to be more practical, easy and inexpensive are also included in this paper, as we unveils ToMRobot, a low-cost MANET robot created from an ordinary remote control car that is capable of performing a real system MANET testbed with the addition of only a few low-cost electronic components. Despite greatly reduced costs, the ToMRobot does not sacrifice any of the necessary MANET basic structures and will still be easily customizable and upgradeable through the use of open hardware technology like Cubieboard2 and Arduino, as its robot controller. This paper will also include guidelines to enable technically limited MANET researchers to design and develop the ToMRobot. It is hoped that this paper achieves its two pronged objectives namely (i) to facilitate other MANET researchers by providing them with a source of reference that eases their decision making for selecting the best and most suitable MANET mobile robots for real mobility in their MANET testbeds (ii) to provide MANET researchers with a prospect of building their own MANET robots that can be applied in their own MANET testbed in the future

Higher-order chromatin organization defines Progesterone Receptor and PAX2 binding to regulate estradiol-primed endometrial cancer gene expression

Estrogen (E2) and Progesterone (Pg), via their specific receptors (ER and PR respectively), are major determinants in the development and progression of endometrial malignancies. Here, we have studied how E2 and the synthetic progestin R5020 affect genomic functions in Ishikawa endometrial cancer cells. Using ChIPseq in cells exposed to the corresponding hormones, we identified cell specific binding sites for ER (ERbs) and PR (PRbs), which mostly correspond to independent sites but both adjacent to sites bound by PAX2. Analysis of long-range interactions by Hi-C showed enrichment of regions co-bound by PR and PAX2 inside TADs that contain differentially progestin-regulated genes. These regions, which we call “progestin control regions” (PgCRs), exhibit an open chromatin state prior to the exposure to the hormone. Our observations suggest that endometrial response to progestins in differentiated endometrial tumor cells results in part from binding of PR together with partner transcription factors to PgCRs, compartmentalizing hormone-independent open chromatin.Fil: la Greca, Alejandro Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Bellora, Nicolás. Comision Nacional de Energia Atomica. Gerencia de Area de Aplicaciones de la Tecnologia Nuclear. Instituto de Tecnologias Nucleares Para la Salud.; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte. Instituto de Investigaciones en Biodiversidad y Medioambiente. Universidad Nacional del Comahue. Centro Regional Universidad Bariloche. Instituto de Investigaciones en Biodiversidad y Medioambiente; ArgentinaFil: Le Dily, Francois. Centro de Regulación Genómica; España. Universitat Pompeu Fabra; EspañaFil: Jara, Rodrigo Agustin. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Quilez Oliete, Javier. Centro de Regulación Genómica; EspañaFil: Villanueva, José Luis. Centro de Regulación Genómica; EspañaFil: Vidal, Enrique. Centro de Regulación Genómica; EspañaFil: Merino, Gabriela Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Fresno Rodríguez, Cristóbal. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Tarifa Reischle, Inti Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Vallejo, Griselda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Vicent, Guillermo P.. Centro de Regulación Genómica; EspañaFil: Fernandez, Elmer Andres. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Beato, Miguel. Centro de Regulación Genómica; España. Universitat Pompeu Fabra; EspañaFil: Saragueta, Patricia Esther. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Development of a framework for genotyping bovine-derived Cryptosporidium parvum, using a multilocus fragment typing tool

Background: There is a need for an integrated genotyping approach for C. parvum; no sufficiently discriminatory scheme to date has been fully validated or widely adopted by veterinary or public health researchers. Multilocus fragment typing (MLFT) can provide good differentiation and is relatively quick and cheap to perform. A MLFT tool was assessed in terms of its typeability, specificity, precision (repeatability and reproducibility), accuracy and ability to genotypically discriminate bovine-derived Cryptosporidium parvum. Methods: With the aim of working towards a consensus, six markers were selected for inclusion based on their successful application in previous studies: MM5, MM18, MM19, TP14, MS1 and MS9. Alleles were assigned according to the fragment sizes of repeat regions amplified, as determined by capillary electrophoresis. In addition, a region of the GP60 gene was amplified and sequenced to determine gp60 subtype and this was added to the allelic profiles of the 6 markers to determine the multilocus genotype (MLG). The MLFT tool was applied to 140 C. parvum samples collected in two cross-sectional studies of UK calves, conducted in Cheshire in 2004 (principally dairy animals) and Aberdeenshire/Caithness in 2011 (beef animals). Results: Typeability was 84 %. The primers did not amplify tested non-parvum species frequently detected in cattle. In terms of repeatability, within- and between-run fragment sizes showed little variability. Between laboratories, fragment sizes differed but allele calling was reproducible. The MLFT had good discriminatory ability (Simpson’s Index of Diversity, SID, was 0.92), compared to gp60 sequencing alone (SID 0.44). Some markers were more informative than others, with MS1 and MS9 proving monoallelic in tested samples. Conclusions: Further inter-laboratory trials are now warranted with the inclusion of human-derived C. parvum samples, allowing progress towards an integrated, standardised typing scheme to enable source attribution and to determine the role of livestock in future outbreaks of human C. parvum

Expanding the genetic spectrum of TUBB1-related thrombocytopenia

β1-Tubulin plays a major role in proplatelet formation and platelet shape maintenance, and pathogenic variants in TUBB1 lead to thrombocytopenia and platelet anisocytosis (TUBB1-RT). To date, the reported number of pedigrees with TUBB1-RT and of rare TUBB1 variants with experimental demonstration of pathogenicity is limited. Here, we report 9 unrelated families presenting with thrombocytopenia carrying 6 β1-tubulin variants, p.Cys12LeufsTer12, p.Thr107Pro, p.Gln423*, p.Arg359Trp, p.Gly109Glu, and p.Gly269Asp, the last of which novel. Segregation studies showed incomplete penetrance of these variants for platelet traits. Indeed, most carriers showed macrothrombocytopenia, some only increased platelet size, and a minority had no abnormalities. Moreover, only homozygous carriers of the p.Gly109Glu variant displayed macrothrombocytopenia, highlighting the importance of allele burden in the phenotypic expression of TUBB1-RT. The p.Arg359Trp, p.Gly269Asp, and p.Gly109Glu variants deranged β1-tubulin incorporation into the microtubular marginal ring in platelets but had a negligible effect on platelet activation, secretion, or spreading, suggesting that β1-tubulin is dispensable for these processes. Transfection of TUBB1 missense variants in CHO cells altered β1-tubulin incorporation into the microtubular network. In addition, TUBB1 variants markedly impaired proplatelet formation from peripheral blood CD34+ cell-derived megakaryocytes. Our study, using in vitro modeling, molecular characterization, and clinical investigations provides a deeper insight into the pathogenicity of rare TUBB1 variants. These novel data expand the genetic spectrum of TUBB1-RT and highlight a remarkable heterogeneity in its clinical presentation, indicating that allelic burden or combination with other genetic or environmental factors modulate the phenotypic impact of rare TUBB1 variants.This work was partially supported by grants from Instituto de Salud Carlos III (ISCIII) and Feder (PI17/01311, PI17/01966, PI20/00926 and CB15/00055), Fundacion Séneca (19873/ GERM/15), Gerencia Regional de Salud (GRS 2061A/19 and 1647/A/17), Fundacion Mutua Madrile´ña (AP172142019), and ~ Sociedad Espanola de Trombosis y Hemostasia (Premio L ~ opez Borrasca 2019 and Ayuda a Grupos de Trabajo en Patologıa Hemorragica). The authors’ research on inherited platelet disorders is conducted in accordance with the aims of the Functional and Molecular Characterization of Patients with Inherited Platelet Disorders Project, from Grupo Espanol de Alteraciones Plaqueta- ~ rias Congenitas, which is supported by the Spanish Society of Thrombosis and Haemostasis. V.P.-B. has a predoctoral contract from CIBERER. L.B. was supported by a fellowship from Fondazione Umberto Veronesi. M.E.d.l.M.-B. holds a postdoctoral fellowship from the University of Murcia. A.M.-Q. holds a predoctoral grant from the Junta de Castilla y Leon

Changes in bread consumption and 4-year changes in adiposity in Spanish subjects at high cardiovascular risk

The effects of bread consumption change over time on anthropometric measures have been scarcely studied. We analysed 2213 participants at high risk for CVD from the PREvención con DIeta MEDiterránea (PREDIMED) trial to assess the association between changes in the consumption of bread and weight and waist circumference gain over time. Dietary habits were assessed with validated FFQ at baseline and repeatedly every year during 4 years of follow-up. Using multivariate models to adjust for covariates, long-term weight and waist circumference changes according to quartiles of change in energy-adjusted white and whole-grain bread consumption were calculated. The present results showed that over 4 years, participants in the highest quartile of change in white bread intake gained 0·76 kg more than those in the lowest quartile (P for trend = 0·003) and 1·28 cm more than those in the lowest quartile (P for trend 2 kg) and gaining waist circumference (>2 cm) during follow-up was not associated with increase in bread consumption, but participants in the highest quartile of changes in white bread intake had a reduction of 33 % in the odds of losing weight (>2 kg) and a reduction of 36 % in the odds of losing waist circumference (>2 cm). The present results suggest that reducing white bread, but not whole-grain bread consumption, within a Mediterranean-style food pattern setting is associated with lower gains in weight and abdominal fat