Bone mineral as a drug-seeking moiety and a waste dump

Bone is a dynamic tissue with a quarter of the trabecular and a fifth of the cortical bone being replaced continuously each year in a complex process that continues throughout an individual’s lifetime. Bone has an important role in homeostasis of minerals with non-stoichiometric hydroxyapatite bone mineral forming the inorganic phase of bone. Due to its crystal structure and chemistry, hydroxyapatite (HA) and related apatites have a remarkable ability to bind molecules. This review article describes the accretion of trace elements in bone mineral giving a historical perspective. Implanted HA particles of synthetic origin have proved to be an efficient recruiting moiety for systemically circulating drugs which can locally biomodulate the material and lead to a therapeutic effect. Bone mineral and apatite however also act as a waste dump for trace elements and drugs, which significantly affects the environment and human health

Casein Kinase 1 Proteomics Reveal Prohibitin 2 Function in Molecular Clock

Throughout the day, clock proteins synchronize changes in animal physiology (e.g., wakefulness and appetite) with external cues (e.g., daylight and food). In vertebrates, both casein kinase 1 delta and epsilon (CK1δ and CK1ε) regulate these circadian changes by phosphorylating other core clock proteins. In addition, CK1 can regulate circadian-dependent transcription in a non-catalytic manner, however, the mechanism is unknown. Furthermore, the extent of functional redundancy between these closely related kinases is debated. To further advance knowledge about CK1δ and CK1ε mechanisms of action in the biological clock, we first carried out proteomic analysis of both kinases in human cells. Next, we tested interesting candidates in a cell-based circadian readout which resulted in the discovery of PROHIBITIN 2 (PHB2) as a modulator of period length. Decreasing the expression of PHB2 increases circadian-driven transcription, thus revealing PHB2 acts as an inhibitor in the molecular clock. While stable binding of PHB2 to either kinase was not detected, knocking down CK1ε expression increases PHB2 protein levels and, unexpectedly, knocking down CK1δ decreases PHB2 transcript levels. Thus, isolating CK1 protein complexes led to the identification of PHB2 as an inhibitor of circadian transcription. Furthermore, we show that CK1δ and CK1ε differentially regulate the expression of PHB2

Irony Detection in Twitter: The Role of Affective Content

© ACM 2016. This is the author's version of the work. It is posted here for your personal use. Not for redistribution. The definitive Version of Record was published in ACM Transactions on Internet Technology, Vol. 16. http://dx.doi.org/10.1145/2930663.[EN] Irony has been proven to be pervasive in social media, posing a challenge to sentiment analysis systems. It is a creative linguistic phenomenon where affect-related aspects play a key role. In this work, we address the problem of detecting irony in tweets, casting it as a classification problem. We propose a novel model that explores the use of affective features based on a wide range of lexical resources available for English, reflecting different facets of affect. Classification experiments over different corpora show that affective information helps in distinguishing among ironic and nonironic tweets. Our model outperforms the state of the art in almost all cases.The National Council for Science and Technology (CONACyT Mexico) has funded the research work of Delia Irazu Hernandez Farias (Grant No. 218109/313683 CVU-369616). The work of Viviana Patti was partially carried out at the Universitat Politecnica de Valencia within the framework of a fellowship of the University of Turin cofunded by Fondazione CRT (World Wide Style Program 2). The work of Paolo Rosso has been partially funded by the SomEMBED TIN2015-71147-C2-1-P MINECO research project and by the Generalitat Valenciana under the grant ALMAMATER (PrometeoII/2014/030).Hernandez-Farias, DI.; Patti, V.; Rosso, P. (2016). Irony Detection in Twitter: The Role of Affective Content. ACM Transactions on Internet Technology. 16(3):19:1-19:24. https://doi.org/10.1145/2930663S19:119:24163Rob Abbott, Marilyn Walker, Pranav Anand, Jean E. Fox Tree, Robeson Bowmani, and Joseph King. 2011. 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Guidelines for Genome-Scale Analysis of Biological Rhythms

Genome biology approaches have made enormous contributions to our understanding of biological rhythms, particularly in identifying outputs of the clock, including RNAs, proteins, and metabolites, whose abundance oscillates throughout the day. These methods hold significant promise for future discovery, particularly when combined with computational modeling. However, genome-scale experiments are costly and laborious, yielding “big data” that are conceptually and statistically difficult to analyze. There is no obvious consensus regarding design or analysis. Here we discuss the relevant technical considerations to generate reproducible, statistically sound, and broadly useful genome-scale data. Rather than suggest a set of rigid rules, we aim to codify principles by which investigators, reviewers, and readers of the primary literature can evaluate the suitability of different experimental designs for measuring different aspects of biological rhythms. We introduce CircaInSilico, a web-based application for generating synthetic genome biology data to benchmark statistical methods for studying biological rhythms. Finally, we discuss several unmet analytical needs, including applications to clinical medicine, and suggest productive avenues to address them

Alternating hemiplegia of childhood: Retrospective genetic study and genotype-phenotype correlations in 187 subjects from the US AHCF registry

Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clustered in exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K (26%) and 11 had G937R (8%) mutations. Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies

Guidelines for Genome-Scale Analysis of Biological Rhythms

Genome biology approaches have made enormous contributions to our understanding of biological rhythms, particularly in identifying outputs of the clock, including RNAs, proteins, and metabolites, whose abundance oscillates throughout the day. These methods hold significant promise for future discovery, particularly when combined with computational modeling. However, genome-scale experiments are costly and laborious, yielding ‘big data’ that is conceptually and statistically difficult to analyze. There is no obvious consensus regarding design or analysis. Here we discuss the relevant technical considerations to generate reproducible, statistically sound, and broadly useful genome scale data. Rather than suggest a set of rigid rules, we aim to codify principles by which investigators, reviewers, and readers of the primary literature can evaluate the suitability of different experimental designs for measuring different aspects of biological rhythms. We introduce CircaInSilico, a web-based application for generating synthetic genome biology data to benchmark statistical methods for studying biological rhythms. Finally, we discuss several unmet analytical needs, including applications to clinical medicine, and suggest productive avenues to address them

Chemical evolution of the continental crust from a data-driven inversion of terrigenous sediment compositions

The nature of emerged continents through time is highly debated. Several studies relying on trace element data concluded that the Archaean crust was predominantly mafic, while Ti isotope systematics point to an Archaean crust that was predominantly felsic. Here, we resolve the inconsistency between these two approaches by applying a novel statistical method to a compilation of published elemental concentrations in terrigenous sediments (the OrTeS database). We use a filter based on the Local Outlier Factor to reject sediment samples that have been affected by alteration processes or mineral fractionation during transport. The nature of the emerged continents is calculated using an inverse mixing model based on a Markov Chain Monte Carlo algorithm. A procedure is presented to automatically select elemental ratios that are best suited for constraining the sediment provenance. We find that for all systems that accurately reconstruct the modern-day composition of the continents, a continuous >50% felsic contribution is required to explain the composition of fine-grained terrigenous sediments starting from 3.5 billion years ago. This finding is consistent with an early onset of plate tectonics. We estimate the geothermal gradient in the Archaean upper continental crust by tracking the reconstructed concentrations of the radiogenic heat-producing elements K, U, and Th through time. Radioactive heat production in the bulk continental crust was 50% higher in the Archaean compared to the present, resulting in a continental geothermal gradient that was about 40% higher

Episodic Neurological Channelopathies

Inherited episodic neurological disorders are often due to mutations in ion channels or their interacting proteins, termed channelopathies. There are a wide variety of such disorders, from those causing paralysis, to extreme pain, to ataxia. A common theme in these is alteration of action potential properties or synaptic transmission and a resulting increased propensity of the resulting tissue to enter into or stay in an altered excitability state. Manifestations of these disorders are triggered by an array of precipitants, all of which stress the particular affected tissue in some way and aid in propelling its activity into an aberrant state. Study of these disorders has aided in the understanding of disease risk factors and elucidated the cause of clinically related sporadic disorders. The findings from study of these disorders will aid in the diagnosis and efficient targeted treatment of affected patients