Σάββατο, 2 Σεπτεμβρίου 2017

KinFin: Software for Taxon-Aware Analysis of Clustered Protein Sequences

The field of comparative genomics is concerned with the study of similarities and differences between the information encoded in the genomes of organisms. A common approach is to define gene families by clustering protein sequences based on sequence similarity, and analyse protein cluster presence and absence in different species groups as a guide to biology. Due to the high dimensionality of these data, downstream analysis of protein clusters inferred from large numbers of species, or species with many genes, is non-trivial, and few solutions exist for transparent, reproducible and customisable analyses. We present KinFin, a streamlined software solution capable of integrating data from common file formats and delivering aggregative annotation of protein clusters. KinFin delivers analyses based on systematic taxonomy of the species analysed, or on user-defined groupings of taxa, for example sets based on attributes such as life history traits, organismal phenotypes, or competing phylogenetic hypotheses. Results are reported through graphical and detailed text output files. We illustrate the utility of the KinFin pipeline by addressing questions regarding the biology of filarial nematodes, which include parasites of veterinary and medical importance. We resolve the phylogenetic relationships between the species and explore functional annotation of proteins in clusters in key lineages and between custom taxon sets, identifying gene families of interest. KinFin can easily be integrated into existing comparative genomic workflows and promotes transparent and reproducible analysis of clustered protein data.



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Over-Expression of miRNA-9 Generates Muscle Hypercontraction Through Translational Repression of the Troponin-T in Drosophila Indirect Flight Muscles

miRNAs are small non-coding endogenous RNAs, typically 21-23 nucleotides long, that regulate gene expression, usually post-transcriptionally by binding to the 3'-UTR of target mRNA, thus blocking translation. The expression of several miRNAs is significantly altered during cardiac hypertrophy, myocardial ischemia, fibrosis, heart failure and other cardiac myopathies. Recent studies have implicated miR-9 in myocardial hypertrophy. However a detailed mechanism remains obscure. In this study, we have addressed the roles of miR-9 in muscle development and function using the genetically tractable model system, the indirect flight muscles (IFMs) of Drosophila melanogaster. Bioinformatics analysis identified 135 potential miR-9a targets, of which 27 genes were associated with Drosophila muscle development. Troponin-T (TnT) was identified as major structural gene target of miR-9a. We show that flies over-expressing miR-9a in the IFMs have abnormal wing position and are flightless. These flies also exhibit loss of muscle integrity and sarcomeric organization causing an abnormal muscle condition known as "hypercontraction". Additionally, miR-9a over-expression resulted in the reduction of TnT protein levels while transcript levels were unaffected. Furthermore, muscle abnormalities associated with miR-9a over-expression were completely rescued by over-expression of TnT transgenes which lacked the miR-9a binding site. These findings indicate that miR-9a interacts with the 3'-UTR of the TnT mRNA and down-regulates the TnT protein levels by translational repression. The reduction in TnT levels leads to a cooperative down-regulation of other thin filament structural proteins. Our findings have implications for understanding the cellular pathophysiology of cardiomyopathies associated with miR-9 over-expression.



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Long-term effects of tDCS on fatigue, mood and cognition in multiple sclerosis

Fatigue is frequently reported by multiple sclerosis (MS) patients and remains one of their most debilitating and difficult to manage symptoms. It constitutes a great challenge to MS caregivers especially in face of the modest efficacy and numerous side effects of available medications. Apart from fatigue, cognitive and psychiatric manifestations could affect around 65% and 95% of MS patients, respectively (Chalah and Ayache, 2017).

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The Medial Plantar Sensory Response: A Sensitive Marker of Acute Inflammatory Demyelinating Polyneuropathy

Acute Inflammatory Demyelinating Polyneuropathy (AIDP) is an acute neuropathy characterized by ascending motor weakness that is often heralded by sensory symptoms. Diagnosis is confirmed by nerve conduction studies (NCS) that demonstrate the presence of widespread demyelination changes in motor nerves (Hadden et al., 1998). Sensory nerve involvement is early and often follows a typical pattern, the sural sparing pattern (Al-Shekhlee et al., 2007). This pattern is widely accepted as a specific marker of AIDP and is particularly useful when motor changes are not yet apparent (Hiew et al., 2016).

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Prefrontal cortical responses in children with prenatal alcohol-related neurodevelopmental impairment: A functional near-infrared spectroscopy study

Fetal Alcohol Spectrum Disorders (FASDS) is a term that refers to a cluster of physical and neurobehavioral abnormalities, including facial dysmorphology, growth retardation, and disruption to brain development, that have been investigated for over four decades in human and animal model studies of prenatal alcohol exposure (PAE) (Riley et al., 2011). Although public health awareness and prevention efforts have increased as a result of these findings, recent estimates of the prevalence of Fetal Alcohol Syndrome (FAS), the most severe FASD condition, have ranged from .6 to .9 percent of live births with the full range of FASDs estimated to fall between 2.4 to 4.8 percent (May et al., 2014).

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Electrophysiological correlates of performance monitoring in binge drinking: Impaired error-related but preserved feedback processing

Binge drinking is an alcohol consumption pattern characterized by alternations between intense alcohol intakes and abstinence periods (Courtney and Polich, 2009). Despite the lack of consensus regarding its definition, this habit is now widespread in young people in Western countries (e.g., Kanny et al., 2013). As a matter of fact, binge drinking is no longer considered as a recreational and occasional alcohol consumption activity, but rather as a risky behavior with major cognitive consequences (e.g., in memory or attentional processes; Hartley et al., 2004; Heffernan and O'Neill, 2012).

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A pitfall in magnetic stimulation for measuring central motor conduction time

An interesting electrophysiological study of patients with Hirayama disease using magnetic stimulation is published in the current issue of Clinical Neurophysiology. Zheng et al. (2017) measured two types of central motor conduction time (CMCT) in patients with Hirayama disease: one is CMCT using the F-wave technique (CMCTF) and another is CMCT using magnetic motor root stimulation (CMCTM) (Rossini et al. 2015). The authors compared CMCTF and CMCTM, and they showed that CMCTM was abnormally prolonged compared with CMCTF.

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S195 Physiological properties of the seizure onset zone and brain connectivity: Insights gained from callosotomy procedures

Rapidly propagating frontal lobe seizures that are difficult to lateralize may do so after corpus callosotomy. We performed callosotomy using laser interstitial thermal therapy (LITT) in three patients who were undergoing stereoelectroencephalography (SEEG) and examined both the electrocorticogram electrophysiology and neuroimaging connectivity measures.

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The path to colour discrimination is S-shaped: behaviour determines the interpretation of colour models

Abstract

Most of our current understanding on colour discrimination by animal observers is built on models. These typically set strict limits on the capacity of an animal to discriminate between colour stimuli imposed by physiological characteristics of the visual system and different assumptions about the underlying mechanisms of colour processing by the brain. Such physiologically driven models were not designed to accommodate sigmoidal-type discrimination functions as those observed in recent behavioural experiments. Unfortunately, many of the fundamental assumptions on which commonly used colour models are based have been tested against empirical data for very few species and many colour vision studies solely rely on physiological measurements of these species for predicting colour discrimination processes. Here, we test the assumption of a universal principle of colour discrimination only mediated by physiological parameters using behavioural data from four closely related hymenopteran species, considering two frequently used models. Results indicate that there is not a unique function describing colour discrimination by closely related bee species, and that this process is independent of specific model assumptions; in fact, different models produce comparable results for specific test species if calibrated against behavioural data.



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Epigenetic regulation of epithelial to mesenchymal transition by the Lysine-specific demethylase LSD1/KDM1A

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Susanna Ambrosio, Carmen D. Saccà, Barbara Majello
The Lysine-specific demethylase 1, KDM1A/LSD1, plays a central role in the regulation of Pol II transcription through the removal of the activation mark (mono- and dimethyl lysine 4 of histone H3). LSD1 is often deregulated in human cancers, and it is frequently overexpressed in human solid cancers and leukemia. LSD1 regulates the epithelial mesenchymal transition (EMT) in epithelial cells, i.e., the ability to transition into mesenchymal cells, to lose homotypic adhesion and to acquire migratory capacity. From its initial discovery as a component of the Snail complex, multiple studies highlighted the causative role of LSD1 in cell invasiveness and EMT, describing its direct involvement in different molecular processes through the interaction with specific partners. Here we present an overview of the role of LSD1 in the EMT process, summarizing recent findings on its emerging functions in cell migration and invasion in cancer.



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CELF1 preferentially binds to exon-intron boundary and regulates alternative splicing in HeLa cells

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Heng Xia, Dong Chen, Qijia Wu, Gang Wu, Yanhong Zhou, Yi Zhang, Libin Zhang
The current RIP-seq approach has been developed for the identification of genome-wide interaction between RNA binding protein (RBP) and the bound RNA transcripts, but still rarely for identifying its binding sites. In this study, we performed RIP-seq experiments in HeLa cells using a monoclonal antibody against CELF1. Mapping of the RIP-seq reads showed a biased distribution at the 3′UTR and intronic regions. A total of 15,285 and 1384 CELF1-specific sense and antisense peaks were identified using the ABLIRC software tool. Our bioinformatics analyses revealed that 5′ and 3′ splice site motifs and GU-rich motifs were highly enriched in the CELF1-bound peaks. Furthermore, transcriptome analyses revealed that alternative splicing was globally regulated by CELF1 in HeLa cells. For example, the inclusion of exon 16 of LMO7 gene, a marker gene of breast cancer, is positively regulated by CELF1. Taken together, we have shown that RIP-seq data can be used to decipher RBP binding sites and reveal an unexpected landscape of the genome-wide CELF1-RNA interactions in HeLa cells. In addition, we found that CELF1 globally regulates the alternative splicing by binding the exon-intron boundary in HeLa cells, which will deepen our understanding of the regulatory roles of CELF1 in the pre-mRNA splicing process.



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Integrin linked kinase regulates the transcription of AQP2 by NFATC3

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Marco Hatem-Vaquero, Mercedes Griera, Wieslawa Giermakowska, Alicia Luengo, Laura Calleros, Laura V. Gonzalez Bosc, Diego Rodríguez-Puyol, Manuel Rodríguez-Puyol, Sergio De Frutos
Two processes are associated with progressive loss of renal function: 1) decreased aquaporin-2 (AQP2) expression and urinary concentrating capacity (Nephrogenic Diabetes Insipidus, NDI); and 2) changes in extracellular matrix (ECM) composition, e.g. increased collagen I (Col I) deposition, characteristic of tubule-interstitial fibrosis. AQP2 expression is regulated by both the ECM-to-intracellular scaffold protein integrin-linked kinase (ILK) by NFATc/AP1 and other transcription factors. In the present work, we used in vivo and in vitro approaches to examine ILK participation in NFATc3/AP-1-mediated increases in AQP2 gene expression. Both NFATc3 knock-out mice and ILK conditional-knockdown mice (cKD-ILK) display symptoms of NDI (polyuria and reduced AQP2 expression). NFATc3 is upregulated in the renal medulla tubular cells of cKD-ILK mice but with reduced nuclear localization. Inner medullary collecting duct mIMCD3 cells were subjected to ILK depletion and transfected with reporter plasmids. Pharmacological activators or inhibitors determined the effect of ILK activity on NFATc/AP-1-dependent increases in transcription of AQP2. Finally, mIMCD3 cultured on Col I showed reduced activity of the ILK/GSK3β/NFATc/AQP2 axis, suggesting this pathway is a potential target for therapeutic treatment of NDI.



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BRG1 and SMARCAL1 transcriptionally co-regulate DROSHA, DGCR8 and DICER in response to doxorubicin-induced DNA damage

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Ketki Patne, Radhakrishnan Rakesh, Vijendra Arya, Upasana Bedi Chanana, Ramesh Sethy, Pynskhem Bok Swer, Rohini Muthuswami
Recent investigations have emphasized the role of miRNA biogenesis proteins in the synthesis of non-coding RNA when double-strand DNA breaks are induced by ionizing radiations. However, the role of these non-coding RNA and their regulation in response to doxorubicin-induced DNA damage is not known.In this paper, BRG1 and SMARCAL1, members of the ATP-dependent chromatin remodelling family, are shown to co-regulate the transcription of DROSHA, DGCR8, and DICER in response to double-strand DNA breaks induced by doxorubicin. Both BRG1 and SMARCAL1 are needed for the upregulation of the three miRNA biogenesis genes as absence of BRG1 results in downregulation of DGCR8 and DICER while absence of SMARCAL1 results in downregulation of DROSHA. These two proteins act in coordination to upregulate expression of DROSHA, DGCR8, and DICER when cells are treated with doxorubicin. This transcriptional regulation of the miRNA biogenesis proteins is needed for the formation of 53BP1 foci as downregulation of either BRG1 or SMARCAL1 reduced the number of 53BP1 foci in DNA damaged cells. The foci formation was restored when the downregulated cells were treated with ncRNA purified from doxorubicin treated HeLa cells.From the results obtained, we conclude that the regulation of miRNA biogenesis proteins by SMARCAL1 and BRG1 is needed for the formation of non-coding RNA and thus, 53BP1 foci in response to doxorubicin-induced DNA damage.



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Selective regulation of biological processes by vitamin D based on the spatio-temporal cistrome of its receptor

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Antonio Neme, Sabine Seuter, Carsten Carlberg
The transcription factor vitamin D receptor (VDR) is the exclusive nuclear target of the biologically active form of vitamin D (1,25(OH)2D3). In THP-1 human monocytes we obtained a highly accurate VDR cistrome after 2 and 24h ligand stimulation comprising >11,600 genomic loci, 78% of which were detected exclusively after 24h. In contrast, a group of 510 persistent VDR sites occurred at all conditions and some 2100 VDR loci were only transiently occupied. Machine learning and statistical analysis as well as a comparison with the re-analyzed B cell VDR cistrome indicated a subgroup of 339 highly conserved persistent VDR sites that were suited best for describing vitamin D-triggered gene regulatory scenarios. The 1,25(OH)2D3-dependent transcriptome of THP-1 cells comprised 587 genes, 311 of which were primary targets with main functions in the immune system. More than 97% of the latter genes were located within 1,25(OH)2D3-modulated topologically associated domains (TADs). The number of persistent and transient VDR sites was found to be the main discriminator for sorting these TADs into five classes carrying vitamin D target genes involved in distinct biological processes. In conclusion, specific regulation of biological processes by vitamin D depends on differences in time-dependent VDR binding.



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Title Page/Sections Editors

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9





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ZNF509S1 downregulates PUMA by inhibiting p53K382 acetylation and p53-DNA binding

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Bu-Nam Jeon, Jae-Hyeon Yoon, Dohyun Han, Min-Kyeong Kim, Youngsoo Kim, Seo-Hyun Choi, Jiyang Song, Kyung-Sup Kim, Kunhong Kim, Man-Wook Hur
Expression of the POK family protein ZNF509L, and -its S1 isoform, is induced by p53 upon exposure to genotoxic stress. Due to alternative splicing of the ZNF509 primary transcript, ZNF509S1 lacks the 6 zinc-fingers and C-terminus of ZNF509L, resulting in only one zinc-finger. ZNF509L and -S1 inhibit cell proliferation by activating p21/CDKN1A and RB transcription, respectively. When cells are exposed to severe DNA damage, p53 activates PUMA (p53-upregulated modulator of apoptosis) transcription. Interestingly, apoptosis due to transcriptional activation of PUMA by p53 is attenuated by ZNF509S1. Thus we investigated the molecular mechanism(s) underlying the transcriptional attenuation and anti-apoptotic effects of ZNF509S1. We show that ZNF509S1 modulation of p53 activity is important in PUMA gene transcription by modulating post-translational modification of p53 by p300. ZNF509S1 directly interacts with p53 and inhibits p300-mediated acetylation of p53 lysine K382, with deacetylation of p53 K382 leading to decreased DNA binding at the p53 response element 1 of the PUMA promoter. ZNF509S1 may play a role not only in cell cycle arrest, by activating RB expression, but also in rescuing cells from apoptotic death by repressing PUMA expression in cells exposed to severe DNA damage.



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Identification of new TSGA10 transcript variants in human testis with conserved regulatory RNA elements in 5'untranslated region and distinct expression in breast cancer

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Pouya Salehipour, Mahsa Nematzadeh, Maryam Beigom Mobasheri, Mandana Afsharpad, Kamran Mansouri, Mohammad Hossein Modarressi
Testis specific gene antigen 10 (TSGA10) is a cancer testis antigen involved in the process of spermatogenesis. TSGA10 could also play an important role in the inhibition of angiogenesis by preventing nuclear localization of HIF-1α. Although it has been shown that TSGA10 messenger RNA (mRNA) is mainly expressed in testis and some tumors, the transcription pattern and regulatory mechanisms of this gene remain largely unknown. Here, we report that human TSGA10 comprises at least 22 exons and generates four different transcript variants. It was identified that using two distinct promoters and splicing of exons 4 and 7 produced these transcript variants, which have the same coding sequence, but the sequence of 5'untanslated region (5'UTR) is different between them. This is significant because conserved regulatory RNA elements like upstream open reading frame (uORF) and putative internal ribosome entry site (IRES) were found in this region which have different combinations in each transcript variant and it may influence translational efficiency of them in normal or unusual environmental conditions like hypoxia. To indicate the transcription pattern of TSGA10 in breast cancer, expression of identified transcript variants was analyzed in 62 breast cancer samples. We found that TSGA10 tends to express variants with shorter 5'UTR and fewer uORF elements in breast cancer tissues. Our study demonstrates for the first time the expression of different TSGA10 transcript variants in testis and breast cancer tissues and provides a first clue to a role of TSGA10 5'UTR in regulation of translation in unusual environmental conditions like hypoxia.



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Co-regulation of microRNAs and transcription factors in cardiomyocyte specific differentiation of murine embryonic stem cells: An aspect from transcriptome analysis

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Lin Gan, Bernd Denecke
The differentiation process of embryonic stem cells is a comprehensive process regulated by a variety of factors in response to stimulus. Studies of this process can be focused on cell biology as well as on molecular biology level. In this paper we identified the co-regulation of molecular regulators and their interactions during cardiomyocyte specific differentiation of mouse embryonic stem cells based on parallel genome wide transcriptome analyses of mRNA and microRNA. Differentially expressed mRNAs and microRNAs were identified according to their expression profiles. Subsequently, a primary network was generated by using our genome wide profiling data, predicted sequence target information of transcription factors and microRNAs from various sources, validated microRNA target information, as well as tissue specific transcription factor binding information. Considering only validated microRNA target information and tissue specific transcription factor binding information secondary regulatory networks were extracted from the primary network to identify basic regulatory elements. Eight types of 3-node patterns were identified in this network. Novel regulatory modules, like Meis1 - Gata6 and miR-21/24 - Zic3, were discovered with high plausibility by this procedure without complicated and time-consuming experimental processes.

Graphical abstract

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Histone demethylase PHF8 regulates hypoxia signaling through HIF1α and H3K4me3

Publication date: September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 9
Author(s): Peterson Kariuki Maina, Peng Shao, Xiongfei Jia, Qi Liu, Shaikamjad Umesalma, Maximo Marin, Donald Long, Samantha Concepción-Román, Hank Heng Qi
Hypoxia through transcription factor HIF1α plays a critical role in cancer development. In prostate cancer, HIF1α interplays with androgen receptor (AR) to contribute to the progression of this disease to its lethal form—castration-resistant prostate cancer (CRPC). Hypoxia upregulates several epigenetic factors including histone demethylase KDM3A which is a critical co-factor of HIF1α. However, how histone demethylases regulate hypoxia signaling is not fully understood. Here, we report that histone demethylase PHF8 plays an essential role in hypoxia signaling. Knockdown or knockout of PHF8 by RNAi or CRISPR-Cas9 system reduced the activation of HIF1α and the induction of HIF1α target genes including KDM3A. Mechanistically, PHF8 regulates hypoxia inducible genes mainly through sustaining the level of trimethylated histone 3 lysine 4 (H3K4me3), an active mark in transcriptional regulation. The positive role of PHF8 in hypoxia signaling extended to hypoxia-induced neuroendocrine differentiation (NED), wherein PHF8 cooperates with KDM3A to regulate the expression of NED genes. Moreover, we discovered that the role of PHF8 in hypoxia signaling is associated with the presence of full-length AR in CRPC cells. Collectively, our study identified PHF8 as a novel epigenetic factor in hypoxia signaling, and the underlying regulatory mechanisms likely apply to general cancer development involving HIF1α. Therefore, targeting PHF8 can potentially be a novel therapeutic strategy in cancer therapy.



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Regulation and evolution of the interaction of the seed B3 transcription factors with NF-Y subunits

Publication date: Available online 1 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): C. Boulard, A. Fatihi, L. Lepiniec, B. Dubreucq
The LAFL genes (LEC2, ABI3, FUS3, LEC1) encode transcription factors that regulate different aspects of seed development, from early to late embryogenesis and accumulation of storage compounds. These transcription factors form a complex network, with members able to interact with various other players to control the switch between embryo development and seed maturation and, at a later stage in the plant life cycle, between the mature seed and germination.In this review, we first summarize our current understanding of the role of each member in the network in the light of recent advances regarding their regulation and structure/function relationships. In a second part, we discuss new insights concerning the evolution of the LAFL genes to address the more specific question of the conservation of LEAFY COTYLEDONS 2 in both dicots and monocots and the putative origin of the network. Last we examine the current major limitations to current knowledge and future prospects to improve our understanding of this regulatory network.



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Transcriptional and epigenetic analyses of the DMD locus reveal novel cis‑acting DNA elements that govern muscle dystrophin expression

Publication date: Available online 1 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Samuele Gherardi, Matteo Bovolenta, Chiara Passarelli, Maria Sofia Falzarano, Paolo Pigini, Chiara Scotton, Marcella Neri, Annarita Armaroli, Hana Osman, Rita Selvatici, Francesca Gualandi, Alessandra Recchia, Marina Mora, Pia Bernasconi, Lorenzo Maggi, Lucia Morandi, Alessandra Ferlini, Giovanni Perini
The dystrophin gene (DMD) is the largest gene in the human genome, mapping on the Xp21 chromosome locus. It spans 2.2Mb and accounts for approximately 0,1% of the entire human genome. Mutations in this gene cause Duchenne and Becker Muscular Dystrophy, X-linked Dilated Cardiomyopathy, and other milder muscle phenotypes. Beside the remarkable number of reports describing dystrophin gene expression and the pathogenic consequences of the gene mutations in dystrophinopathies, the full scenario of the DMD transcription dynamics remains however, poorly understood. Considering that the full transcription of the DMD gene requires about 16h, we have investigated the activity of RNA Polymerase II along the entire DMD locus within the context of specific chromatin modifications using a variety of chromatin-based techniques.Our results unveil a surprisingly powerful processivity of the RNA polymerase II along the entire 2.2Mb of the DMD locus with just one site of pausing around intron 52. We also discovered epigenetic marks highlighting the existence of four novel cis‑DNA elements, two of which, located within intron 34 and exon 45, appear to govern the architecture of the DMD chromatin with implications on the expression levels of the muscle dystrophin mRNA.Overall, our findings provide a global view on how the entire DMD locus is dynamically transcribed by the RNA pol II and shed light on the mechanisms involved in dystrophin gene expression control, which can positively impact on the optimization of the novel ongoing therapeutic strategies for dystrophinopathies.



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DNA methyltransferase homologue TRDMT1 in Plasmodium falciparum specifically methylates endogenous aspartic acid tRNA

Publication date: Available online 26 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Gayathri Govindaraju, C.A. Jabeena, Devadathan Valiyamangalath Sethumadhavan, Nivethika Rajaram, Arumugam Rajavelu
In eukaryotes, cytosine methylation regulates diverse biological processes such as gene expression, development and maintenance of genomic integrity. However, cytosine methylation and its functions in pathogenic apicomplexan protozoans remain enigmatic. To address this, here we investigated the presence of cytosine methylation in the nucleic acids of the protozoan Plasmodium falciparum. Interestingly, P. falciparum has TRDMT1, a conserved homologue of DNA methyltransferase DNMT2. However, we found that TRDMT1 did not methylate DNA, in vitro. We demonstrate that TRDMT1 methylates cytosine in the endogenous aspartic acid tRNA of P. falciparum. Through RNA bisulfite sequencing, we mapped the position of 5-methyl cytosine in aspartic acid tRNA and found methylation only at C38 position. P. falciparum proteome has significantly higher aspartic acid content and a higher proportion of proteins with poly aspartic acid repeats than other apicomplexan pathogenic protozoans. Proteins with such repeats are functionally important, with significant roles in host-pathogen interactions. Therefore, TRDMT1 mediated C38 methylation of aspartic acid tRNA might play a critical role by translational regulation of important proteins and modulate the pathogenicity of the malarial parasite.



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Variable cardiac α-actin (Actc1) expression in early adult skeletal muscle correlates with promoter methylation

Publication date: Available online 26 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Jordan K. Boutilier, Rhonda L. Taylor, Ramesh Ram, Elyshia McNamara, Quang Nguyen, Hayley Goullee, David Chandler, Munish Mehta, Lois Balmer, Nigel G. Laing, Grant Morahan, Kristen J. Nowak
Different genes encode the a-actin isoforms that are predominantly expressed in heart and muscle. Mutations in the skeletal muscle α-actin gene (ACTA1) cause muscle diseases that are mostly lethal in the early postnatal period. We previously demonstrated that the disease phenotype of ACTA1 mouse models could be rescued by transgenic over-expression of cardiac α-actin (ACTC1). ACTC1 is the predominant striated α-actin isoform in the heart but is also expressed in developing skeletal muscle. To develop a translatable therapy, we investigated the genetic regulation of Actc1 expression. Using strains from The Collaborative Cross (CC) genetic resource, we found that Actc1 varies in expression by up to 24-fold in skeletal muscle. We defined significant expression quantitative trait loci (eQTL) associated with early adult Actc1 expression in soleus and heart. eQTL in both heart and soleus mapped to the Actc1 locus and replicate an eQTL mapped for Actc1 in BXD heart and quadriceps. We built on this previous work by analysing genes within the eQTL peak regions to prioritise likely candidates for modifying Actc1 expression. Additionally we interrogated the CC founder haplotype contributions to enable prioritisation of genetic variants for functional analyses. Methylation around the Actc1 transcriptional start site in early adult skeletal muscle negatively correlated with Actc1 expression in a strain-dependent manner, while other marks of regulatory potential (histone modification and chromatin accessibility) were unaltered. This study provides novel insights into the complex genetic regulation of Actc1 expression in early adult skeletal muscles.Author SummaryMutations in the skeletal muscle actin gene (ACTA1) cause a severe muscle disease that is usually fatal within the first year of life. Some patients with mutations in the ACTA1 gene do not have any ACTA1 protein present in their skeletal muscles. We have previously shown that some of these patients retain expression of the foetal isoform of the gene, cardiac actin (ACTC1). Further, patients who have ACTC1 expressed in their skeletal muscles have increased longevity and improved muscle function, suggesting that upregulation of ACTC1 may be a viable therapy for ACTA1 disease patients. Thus, we have investigated the mechanisms regulating expression of Actc1 in a genetically diverse population of different mouse strains with the aim of identifying the regulatory controls that cause the gene to be switched off. We identified a number of sequence variants present in Actc1 regulatory regions and show that increased promoter methylation is inversely correlated with Actc1 expression. We also show that expression of ACTC1 in humans is likely to be influenced by non-coding sequence variation in regulatory regions upstream and downstream of the gene. Our findings build on previous work and identify regulatory regions of the genome that can now be investigated further.



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Radiation induced transcriptional and post-transcriptional regulation of the hsa-miR-23a~27a~24-2 cluster suppresses apoptosis by stabilizing XIAP

Publication date: Available online 26 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Theresa Heider, Lisa Mutschelknaus, Vanja Radulović, Klaudia Winkler, Julia Kimmel, Nataša Anastasov, Michael J. Atkinson, Simone Moertl
The non-coding transcriptome, in particular microRNAs (miRNA), influences cellular survival after irradiation. However, the underlying mechanisms of radiation-induced miRNA expression changes and consequently target expression changes are poorly understood.In this study, we show that ionizing radiation decreases expression of the miR-23a~27a~24-2 cluster through transcriptional regulation by promoter methylation and at the post-transcriptional level by reduced processing through AGO-phosphorylation. Furthermore, we demonstrate that all three mature cluster miRNAs reduce apoptosis by increasing expression of the common target protein XIAP.These findings link a temporal succession of transcriptional and post-transcriptional regulatory mechanisms of the miR~23a~24-2~27a cluster, enabling a dynamic stress response and assuring cellular survival after radiation exposure.

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KSRP suppresses cell invasion and metastasis through miR-23a-mediated EGR3 mRNA degradation in non-small cell lung cancer

Publication date: Available online 25 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Ming-Hsien Chien, Wei-Jiunn Lee, Yi-Chieh Yang, Yin-Lin Li, Bo-Rong Chen, Tsu-Yao Cheng, Pei-Wen Yang, Ming-Yang Wang, Yi-Hua Jan, Yen-Kuang Lin, Jang-Ming Lee, Michael Hsiao, Jin-Shing Chen, Kuo-Tai Hua
KH-type splicing regulatory protein (KSRP) is a single-strand RNA binding protein which regulates mRNA stability either by binding to AU-rich elements (AREs) of mRNA 3'UTR or by facilitating miRNA biogenesis to target mRNA. Unlike its well-characterized function at the molecular level in maintaining RNA homeostasis, the role of KSRP in cancer progression remains largely unknown. Here we investigate the role of KSRP in non-small cell lung cancer (NSCLC). We first examined KSRP expression by immunohistochemistry in a cohort containing 196 NSCLC patients and observed a strong positive correlation between KSRP expression and survival of NSCLC patients. Multivariate analysis further identified KSRP as an independent prognostic factor. Manipulating KSRP expression significantly affected in vitro cell mobility and in vivo metastatic ability of NSCLC cells. Microarray analysis identified an ARE-containing gene, EGR3, as a downstream effector of KSRP in NSCLC. Interestingly, we found that KSRP decreased EGR3 mRNA stability in an ARE-independent manner. By screening KSRP-regulated miRNAs in NSCLC cells, we further found that miR-23a directly binds to EGR3 3'UTR, reducing EGR3 expression and thereby inhibiting NSCLC cell mobility. Our findings implicate a targetable KSRP/miR-23a/EGR3 signaling axis in advanced tumor phenotypes.



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HIF-1α coordinates epigenetic activation of SIAH1 in hepatocytes in response to nutritional stress

Publication date: Available online 24 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Zhiwen Fan, Zilong Li, Yuyu Yang, Shuai Liu, Junli Guo, Yong Xu
Hypoxia inducible factor 1 alpha (HIF-1α) regulates a diverse range of pathophysiological processes. It has been demonstrated previously that HIF-1α plays a role in the pathogenesis of steatosis mediating the effects of excessive nutritional insults. In the present study we investigated the role of HIF-1α in trans‑activating the seven in absentia homolog 1 (SIAH1) gene and the underlying mechanism. We report that in response to nutritional stress, SIAH1 expression was up-regulated in the liver in mice and in cultured hepatocytes. In the meantime, HIF-1α started to occupy the SIAH1 promoter. Depletion of HIF-1α with siRNA or inhibition of HIF-1α with chetomin abrogated the induction of SIAH1 expression. HIF-1α knockdown or inhibition paralleled epigenetic alterations surrounding the SIAH1 promoter characterized by the loss of acetylated histone H3 and trimethylated H3K4 as well as the acquisition of dimethylated H3K9. Further analyses revealed that HIF-1α interacted with and recruited the histone demethylase KDM3A to the SIAH1 promoter to activate transcription. HIF-1α also mediated the crosstalk between KDM3A and p300. Depletion of KDM3A coincided with the loss of SIAH1 induction and the accumulation of dimethylated H3K9 surrounding the SIAH1 promoter. Interestingly, KDM3A expression was also up-regulated by nutritional stress in a HIF-1α dependent manner. Together, our data uncover a novel epigenetic pathway that may contribute to the regulation of SIAH1 expression and the pathogenesis of steatosis.



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Correlation between desiccation stress response and epigenetic modifications of genes in Drosophila melanogaster: An example of environment-epigenome interaction

Publication date: Available online 8 August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Vineeta Sharma, Surbhi Kohli, Vani Brahmachari
Animals from different phyla including arthropods tolerate water stress to different extent. This tolerance is accompanied by biochemical changes which in turn are due to transcriptional alteration. The changes in transcription can be an indirect effect on some of the genes, ensuing from the effect of stress on the regulators of transcription including epigenetic regulators. Within this paradigm, we investigated the correlation between stress response and epigenetic modification underlying gene expression modulation during desiccation stress in Canton-S. We report altered resistance of flies in desiccation stress for heterozygote mutants of PcG and TrxG members. Pc/+ mutant shows lower survival, while ash1/+ mutants show higher survival under desiccation stress as compared to Canton-S. We detect expression alteration in stress related genes as well the genes of the Polycomb and trithorax complex in Canton-S subjected to desiccation stress. Concomitant with this, there is an altered enrichment of H3K27me3 and H3K4me3 at the upstream regions of the stress responsive genes. The enrichment of activating mark, H3K4me3, is higher in non-stress condition while H3K27me3, the repressive mark, is more pronounced under stress condition, which in turn, can be correlated with the binding of Pc and Ash1. Our results show that desiccation stress induces dynamic switching in expression and enrichment of PcG and TrxG in the upstream region of genes, which correlates with histone modifications. We provide evidence that epigenetic modulation could be one of the mechanisms to adapt to the desiccation stress in Drosophila. Thus, our study proposes the interaction of epigenome and environmental factors.

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Title Page/Sections Editors

Publication date: August 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, Volume 1860, Issue 8





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Enrichment of putatively damaging rare variants in the DYX2 locus and the reading-related genes CCDC136 and FLNC

Abstract

Eleven loci with prior evidence for association with reading and language phenotypes were sequenced in 96 unrelated subjects with significant impairment in reading performance drawn from the Colorado Learning Disability Research Center collection. Out of 148 total individual missense variants identified, the chromosome 7 genes CCDC136 and FLNC contained 19. In addition, a region corresponding to the well-known DYX2 locus for RD contained 74 missense variants. Both allele sets were filtered for a minor allele frequency ≤0.01 and high Polyphen-2 scores. To determine if observations of these alleles are occurring more frequently in our cases than expected by chance in aggregate, counts from our sample were compared to the number of observations in the European subset of the 1000 Genomes Project using Fisher's exact test. Significant P values were achieved for both CCDC136/FLNC (P = 0.0098) and the DYX2 locus (P = 0.012). Taken together, this evidence further supports the influence of these regions on reading performance. These results also support the influence of rare variants in reading disability.



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3D geometric morphometrics of thorax variation and allometry in Hominoidea

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Publication date: December 2017
Source:Journal of Human Evolution, Volume 113
Author(s): Markus Bastir, Daniel García-Martínez, Scott A. Williams, Wolfgang Recheis, Isabel Torres-Sánchez, Francisco García Río, Motoharu Oishi, Naomichi Ogihara
Ever since the seminal papers of Keith and Schultz, hominoid primate ribcages have been described as either "funnel-" or "barrel-shaped." Following this dichotomic typology, it is currently held that Homo sapiens and hylobatids (gibbons and siamangs) share a barrel-shaped ribcage and that they are more similar to each other than to the funnel-shaped thoraces of great apes (Gorilla, Pan, and Pongo). Other researchers hypothesized that thoracic width and the invagination of the thoracic spine into the thorax are related to allometry. However, analyses that take into account the complex three-dimensional (3D) shape of the ribcage are lacking. Here, we address hypotheses about thorax shape and evolution using 3D morphometrics of thoraces in anatomical connection obtained by computed tomography scans of 23 hominoid cadavers and 10 humans and examining thorax compartments composed of seven ribs (1–7 thorax) and of 11 ribs (1–11 thorax). In the 1–7 thorax analyses, the human thorax is uniquely flat because of torsion of the upper and central ribs, differing from all non-human hominoids including hylobatids. In the 1–11 thorax analyses, humans are markedly different from African great apes, with hylobatids and orangutans intermediate. In full shape space analyses, affinities between orangutans and humans on the one hand and between hylobatids and African great apes on the other are evident. Therefore, we reject the hypothesis that humans and hylobatids bear any special affinities in overall 3D thorax shape to each other. We find that larger thoraces are wider and flatter, with a more invaginated spine, supporting the allometric hypothesis. Hominoid thorax variation shows complex interactions between allometry, rib curves, torsion, and declination, and the morphology of the costo-vertebral joint and the thoracic vertebral column. When considering functional specializations alongside phylogenetic relationships, an overly simplistic dichotomy between funnel-shaped and barrel-shaped thoraces is not supported.



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Early evolutionary diversification of mandible morphology in the New World monkeys (Primate, Platyrrhini)

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Publication date: December 2017
Source:Journal of Human Evolution, Volume 113
Author(s): Guido Rocatti, Leandro Aristide, Alfred L. Rosenberger, S. Ivan Perez
New World monkeys (order Primates) are an example of a major mammalian evolutionary radiation in the Americas, with a contentious fossil record. There is evidence of an early platyrrhine occupation of this continent by the Eocene–Oligocene transition, evolving in isolation from the Old World primates from then on, and developing extensive morphological and size variation. Previous studies postulated that the platyrrhine clade arose as a local version of the Simpsonian ecospace model, with an early phase involving a rapid increase in morphological and ecological diversity driven by selection and ecological opportunity, followed by a diversification rate that slowed due to niche-filling. Under this model, variation in extant platyrrhines, in particular anatomical complexes, may resemble patterns seen among middle–late Miocene (10–14 Ma) platyrrhines as a result of evolutionary stasis. Here we examine the mandible in this regard, which may be informative about the dietary and phylogenetic history of the New World monkeys. Specifically, we test the hypothesis that the Simpsonian ecospace model applies to the platyrrhine mandible through a geometric morphometric analysis of digital images of the jaws of extant and extinct species, and we compare these results to those obtained using a phylogenetic comparative approach based on extant species. The results show a marked phylogenetic structure in the mandibular morphology of platyrrhines. Principal component analyses highlight the morphological diversity among modern forms, and reveal a similar range of variation for the clade when fossil specimens are included. Disparity-Through-Time analysis shows that most of the shape variation between platyrrhines originated early in their evolution (between 20 and 15 Ma). Our results converge with previous studies of body mass, cranial shape, the brain and the basicranium to show that platyrrhine evolution might have been shaped by an early increase in morphological variation followed by a decelerated rate of diversification and evolutionary stasis.



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Relationship between foramen magnum position and locomotion in extant and extinct hominoids

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Publication date: December 2017
Source:Journal of Human Evolution, Volume 113
Author(s): Dimitri Neaux, Thibaut Bienvenu, Franck Guy, Guillaume Daver, Gabriele Sansalone, Justin A. Ledogar, Todd C. Rae, Stephen Wroe, Michel Brunet
From the Miocene Sahelanthropus tchadensis to Pleistocene Homo sapiens, hominins are characterized by a derived anterior position of the foramen magnum relative to basicranial structures. It has been previously suggested that the anterior position of the foramen magnum in hominins is related to bipedal locomotor behavior. Yet, the functional relationship between foramen magnum position and bipedal locomotion remains unclear. Recent studies, using ratios based on cranial linear measurements, have found a link between the anterior position of the foramen magnum and bipedalism in several mammalian clades: marsupials, rodents, and primates. In the present study, we compute these ratios in a sample including a more comprehensive dataset of extant hominoids and fossil hominins. First, we verify if the values of ratios can distinguish extant humans from apes. Then, we test whether extinct hominins can be distinguished from non-bipedal extant hominoids. Finally, we assess if the studied ratios are effective predictors of bipedal behavior by testing if they mainly relate to variation in foramen magnum position rather than changes in other cranial structures. Our results confirm that the ratios discriminate between extant bipeds and non-bipeds. However, the only ratio clearly discriminating between fossil hominins and other extant apes is that which only includes basicranial structures. We show that a large proportion of the interspecific variation in the other ratios relates to changes in facial, rather than basicranial, structures. In this context, we advocate the use of measurements based only on basicranial structures when assessing the relationship between foramen magnum position and bipedalism in future studies.



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Dietary traits of the ungulates from the HWK EE site at Olduvai Gorge (Tanzania): Diachronic changes and seasonality

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Publication date: Available online 2 September 2017
Source:Journal of Human Evolution
Author(s): Florent Rivals, Kevin T. Uno, Faysal Bibi, Michael C. Pante, Jackson Njau, Ignacio de la Torre
The Oldowan site HWK EE (Olduvai Gorge, Tanzania) has yielded a large fossil and stone tool assemblage at the transition from Lower to Middle Bed II, ∼1.7 Ma. Integrated tooth wear and stable isotope analyses were performed on the three most abundant ungulate taxa from HWK EE, namely Alcelaphini, cf. Antidorcas recki (Antilopini) and Equus oldowayensis (Equini), to infer dietary traits in each taxon. Some paleodietary changes were observed for cf. A. recki and E. oldowayensis based on tooth wear at the transition from the Lemuta to the Lower Augitic Sandstone (LAS) interval within the HWK EE sequence. Stable carbon and oxygen isotope data show no significant changes in bulk diet or hydroclimate between the Lemuta and LAS intervals. The combined tooth wear and stable isotope data suggest similar paleoecological conditions across the two HWK EE intervals, but that differences in vegetation consumed among ungulates may have resulted in changes in dietary niches. Integrating tooth wear and stable isotope analyses permits the characterization of ungulate diets and habitats at HWK EE where C4 dominated and minor mixed C3 and C4 habitats were present. Our results provide a better understanding of the paleoenvironmental conditions of the Lemuta and LAS intervals. The LAS assemblage was mostly accumulated during relatively dry periods at Olduvai Gorge when grasses were not as readily available and grazing animals may have been more nutritionally-stressed than during the formation of the Lemuta assemblage. This helps to contextualize variations in hominin and carnivore feeding behavior observed from the faunal assemblages produced during the two main occupations of the site.



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Investigating hominin carnivory in the Okote Member of Koobi Fora, Kenya with an actualistic model of carcass consumption and traces of butchery on the elbow

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Publication date: Available online 1 September 2017
Source:Journal of Human Evolution
Author(s): Stephen R. Merritt
Previous zooarchaeological analysis at Koobi Fora indicates that Okote Member hominins were the primary agents of bone assemblage formation, gained early access to large and small mammal flesh, and consumed both high- and low-ranked carcass parts. The discovery of additional butchered specimens prompted the re-analysis presented here of three large and well-preserved zooarchaeological assemblages from the Okote member, GaJi14, FwJj14N and FwJj14S, to revisit paleoecological hypotheses about tool-assisted carnivory. Cow and goat limb butchery documenting the skeletal location of cut marks created by skinning, defleshing, and disarticulation was used to build an actualistic model to infer hominin consumption of distinct carcass resources. Archaeological specimens were assigned to early (defleshing limbs), middle (defleshing ribs, viscera, vertebrae, and head) and late (metapodial tendon removal, element disarticulation, long bone fragmentation) carcass consumption stages, and the incidence of these butchery behaviors was examined for specimens and minimum number of element and individual aggregates. Elbow specimens, where traces of defleshing, disarticulation, and percussion co-occur, offer a sequential view of carcass consumption behaviors that is free from fragmentation bias. Classification trees populated with actualistic data were used to identify defleshing and disarticulation cut mark clusters on archaeological elbow portions by their location, cut mark count, median length, and median cross-sectional width. Actualistically-informed configurational analysis offers high-resolution behavioral reconstruction of the butchered sub-assemblage and should be integrated with assemblage-scale zooarchaeological methods. These experiments highlight the bias for detecting butchery traces of early carcass access, because defleshing cut marks are abundant and introduced to dense midshaft portions, whereas disarticulation cut marks are rare and occur on epiphyseal portions, which are often deleted by density-mediated destruction. Butchery trace interpretation across multiple analytical scales confirms a flexible carnivorous paleoecological role for Okote hominins that included primary and secondary access to carcass resources from large and small mammals.



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Recent advances in assays for the fragile X-related disorders

Abstract

The fragile X-related disorders are a group of three clinical conditions resulting from the instability of a CGG-repeat tract at the 5′ end of the FMR1 transcript. Fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI) are disorders seen in carriers of FMR1 alleles with 55–200 repeats. Female carriers of these premutation (PM) alleles are also at risk of having a child who has an FMR1 allele with >200 repeats. Most of these full mutation (FM) alleles are epigenetically silenced resulting in a deficit of the FMR1 gene product, FMRP. This results in fragile X Syndrome (FXS), the most common heritable cause of intellectual disability and autism. The diagnosis and study of these disorders is challenging, in part because the detection of alleles with large repeat numbers has, until recently, been either time-consuming or unreliable. This problem is compounded by the mosaicism for repeat length and/or DNA methylation that is frequently seen in PM and FM carriers. Furthermore, since AGG interruptions in the repeat tract affect the risk that a FM allele will be maternally transmitted, the ability to accurately detect these interruptions in female PM carriers is an additional challenge that must be met. This review will discuss some of the pros and cons of some recently described assays for these disorders, including those that detect FMRP levels directly, as well as emerging technologies that promise to improve the diagnosis of these conditions and to be useful in both basic and translational research settings.



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Uptake of Plutonium-238 into Solanum tuberosum L. (potato plants) in presence of complexing agent EDTA

Publication date: November 2017
Source:Journal of Environmental Radioactivity, Volumes 178–179
Author(s): Frank Tawussi, Dharmendra K. Gupta, Elena L. Mühr-Ebert, Stephanie Schneider, Stefan Bister, Clemens Walther
Bioavailability and plant uptake of radionuclides depend on various factors. Transfer into different plant parts depends on chemical and physical processes, which need to be known for realistic ingestion dose modelling when these plants are used for food. Within the scope of the present work, the plutonium uptake by potato plants (Solanum tuberosum L.) was investigated in hydroponic solution of low concentration [Pu] = 10−9 mol L−1. Particular attention was paid to the speciation of radionuclides in the solution which was modelled by the speciation code PHREEQC. The speciation, the solubility and therefore the plant availability of radionuclides mainly depend on the pH value and the redox potential of the solution. During the contamination period, the redox potential did not change significantly. In contrast, the pH value showed characteristic changes depending on exudates excreted by the plants. Plant roots took up high amounts of plutonium (37%–50% of the added total amount). In addition to the uptake into the roots, the radionuclides can also adsorb to the exterior root surface. The solution-to-plant transfer factor showed values between 0.03 and 0.80 (Bq kg−1/ Bq L−1) for the potato tubers. By addition of the complexing agent EDTA (10−4 mol L-1), the plutonium uptake from solution increased by 58% in tubers and by 155% in shoots/leaves. The results showed that excreted substances by plants affect bioavailability of radionuclides at low concentration, on the one hand. On the other hand, the uptake of plutonium by roots and the accumulation in different plant parts can lead to non-negligible ingestion doses, even at low concentration. We are aware of the limited transferability of data obtained in hydroponic solutions to plants growing in soil. However, the aim of this study is twofold: First we want to investigate the influence of Pu speciation on plant uptake in a rather well defined system which can be modelled using available thermodynamic data. Second, techniques developed here shall be applied to the investigation of plants growing in soil in the future. The present work contributes to the basic understanding how plant induced effects on nutrient solution influence bioavailability of radionuclides and fosters the need for more detailed investigations of the complex uptake and accumulation processes of radionuclides into plants.

Graphical abstract

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From mechanisms to therapy: RNA processing’s impact on human genetics



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Functional assessment of genetic variants located in the promoter of SHP1 (NR0B2).

Small heterodimer partner 1 (SHP1, NR0B2) is a member of the superfamily of nuclear receptors (NRs). Even if this orphan receptor, unlike other NRs, lacks the DNA-binding domain, it is capable of regulating transcription by repressing the activity of other NRs by direct protein-protein interaction. Accordingly, SHP1 is part of negative feedback loops of the transcriptional regulation of genes involved in drug metabolism and various metabolic pathways including bile acid and glucose homeostasis. Although it is known that several interacting partners of SHP1 also modulate its expression, there is little information about genetic variability of this regulatory mechanism. Our study aimed to identify genetic variants in the NR0B2 promoter region and to determine their impact on NR0B2 transcription. For this, DNA samples originating from 119 participants of the population-based cohort Study of Health in Pomerania were analyzed by Sanger sequencing revealing four genetic variants: NR0B2:c.-594T>C (rs71636795), NR0B2:c.-414G>C (newly identified), NR0B2:c.-423C>T (rs78182695), and NR0B2:c.-224delCTGA (rs145613139) localized in the 5' untranslated region of NR0B2. The impact of these variants on transactivation of the NR0B2 promoter by NRs known to be regulators of SHP1 expression (hepatocyte nuclear factor 4[alpha], liver receptor homolog-1, and farnesoid X receptor) was assessed in a cell-based reporter gene assay, showing that transactivation by hepatocyte nuclear factor 4[alpha] and liver receptor homolog-1 was significantly decreased in the presence of the genetic variant NR0B2:c.-594T>C, even though this effect was cell specific. However, SHP1 mRNA expression in a small collection of human kidney samples was not affected by these genetic variants. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Hyperthermia-induced Neural Alterations Impair Proprioception and Balance.

Purpose: Hyperthermia has been shown to affect both central and peripheral nervous systems. However, the consequences of these alterations on the proprioceptive mechanisms underlying human movement control remain unclear. The aim of this study was to investigate the effect of passive hyperthermia on various measures of proprioception and balance, two key components of injury prevention and movement efficiency. Methods: Following a familiarization session, 14 volunteers (8 males, 6 females) completed 2 experimental sessions in temperate (CON, 24[degrees]C) and hot (HOT, 44-50[degrees]C) conditions, in a counterbalanced order. Participants were tested for neural function (electrically evoked M-wave and H-reflex, Soleus), active movement discrimination (5 positions, 50 trials, dorsiflexion), dynamic balance (Star Excursion Balance Test, 3 directions) and static balance (single leg stance). Results: Both rectal (39.0+/-0.3 vs. 36.9+/-0.6[degrees]C) and mean skin (37.9+/-1.0 vs. 32.0+/-2.7[degrees]C) temperatures were significantly higher in HOT than CON (p0.05) amplitudes; increased the mean error for active movement discrimination (0.58+/-0.13 vs. 0.50+/-0.11 degrees, +17%, p

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Interval Walking Training and Nutritional Intake to Increase Plasma Volume in Elderly.

Purpose: Aerobic training-induced plasma volume (PV) expansion improves thermoregulation, and carbohydrate (CHO) + whey protein supplementation enhanced the effects in older people; however, these were suggested by studies on gym-based cycling training but not on home-based interval walking training (IWT). Moreover, long-term walking training effects on PV remain unknown. Methods: Seventeen male and 10 female subjects (~69 yr), having performed IWT for >=24 months before the study, were used. After pre-intervention measurement (PRE) of PV, plasma albumin content (Albcont), fasting glucose concentration ([Glc]f), and HbA1c, the subjects were randomly divided into two groups: CHO and Pro-CHO, either consuming CHO (22.5 g) alone or CHO (15 g) + whey protein (10 g), respectively, during additional 5-month IWT from May to November, 2009. After the additional IWT, we measured the same variables again (post-intervention measurement, POST). Results: The baseline PV and Albcont were significantly correlated with the number of IWT days for the 12 months preceding PRE (r=0.716, P0.74), with significant differences in the changes between groups (P=0.020, P=0.041, and P=0.018 respectively). Conclusion: PV was proportional to the number of IWT days for 12 months and a CHO + whey protein supplementation during the 5-month IWT prevented PV reduction for the period of no supplementation, which might be partially linked with blood glucose control mechanisms. (C) 2017 American College of Sports Medicine

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Intervertebral Disc Degeneration in a Percutaneous Mouse Tail Injury Model.

Objectives: Intervertebral disc (IVD) degenerates progressively with age and after injuries. In this study, we aimed to characterize early molecular events underlying disc degeneration using a mouse tail IVD injury model. Design: We have established a transcutaneous minimally invasive approach to induce mouse tail IVD injury under fluoroscopic guidance. Morphological and molecular changes in the injured IVDs are compared with the baseline features of adjacent intact levels. Results: After needle puncture, tail IVDs exhibited time-dependent histological changes. The aggrecan neoepitope VDIPEN was evident from 2 days to 4 wks after injury. A disintegrin and metalloproteinase domain-containing protein 8 (adam8) is a surface protease known to cleave fibronectin in the IVD. Gene expression of adam8 was elevated at all time points after injury, whereas the increase of C-X-C motif chemokine ligand (cxcl)-1 gene expression was statistically significant at 2 days and 2 wks after injury. Type 1 collagen gene expression decreased initially at day 2 but increased at 2 wks after injury, whereas no significant change in type 2 collagen gene expression was observed. The extracellular matrix gene expression pattern is consistent with fibrocartilage formation after injury. Conclusions: Mouse tail IVDs degenerate after needle puncture, as demonstrated by histological changes and aggrecan degradation. The minimally invasive tail IVD injury model should prove useful to investigators studying mechanisms of IVD degeneration and repair. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Validating the Physiologic Model HumMod as a Substitute for Clinical Trials Involving Acute Normovolemic Hemodilution.

BACKGROUND: Blood conservation strategies and transfusion guidelines remain a heavily debated clinical topic. Previous investigational trials have shown that acute isovolemic hemodilution does not limit adequate oxygen delivery; however, a true critical hemoglobin level has never been investigated or defined due to safety concerns for human volunteers. Validated physiologic modeling may be useful to investigate hemodilution at critical hemoglobin levels without the ethical or safety hazards of clinical trials. Our hypothesis is that HumMod, an integrative physiological model, can replicate the cardiovascular and metabolic findings of previous clinical studies of acute isovolemic hemodilution and use coronary blood flow and coronary oxygen delivery in extreme hemodilution to predict a safety threshold. METHODS: By varying cardiovascular and sizing parameters, unique individuals were generated to simulate a population using HumMod, an integrative mathematical model of human physiology. Hemodilution was performed by simultaneously hemorrhaging 500 mL aliquots of blood while infusing equal volumes of hetastarch, 5% albumin balanced salt solution, or triple volumes of lactated Ringer's solution over 10 minutes. Five hemodilution protocols reported over 3 studies were directly replicated with HumMod to compare and validate essential cardiovascular and metabolic responses to hemodilution in moderately healthy, awake adults. Cardiovascular parameters, mental status, arterial and mixed venous oxygen content, and oxyhemoglobin saturation were recorded after the removal of each aliquot. The outputs of this simulation were considered independent variables and were stratified by hemoglobin concentration at the time of measurement to assess hemoglobin as an independent predictor of hemodynamic and metabolic behavior. RESULTS: The published reports exhibited discrepancies: Weiskopf saw increased heart rate and cardiac index, while Jones and Ickx saw no change in these variables. In HumMod, arterial pressure was maintained during moderate hemodilution due to decreases in peripheral resistance opposing increases in cardiac index. HumMod showed preserved ventilation through moderate hemodilution, compensated for by an increased oxygen extraction similar to the studies of Jones and Ickx. The simulation results qualitatively followed the clinical studies, but there were statistical differences. In more extreme hemodilution, HumMod had a lesser increase in cardiac index, which led to deficiencies in oxygen delivery and low venous saturation. In the simulations, coronary blood flow and oxygen delivery increase up to a critical hemoglobin threshold of 55-75 g/L in HumMod. In this range, coronary blood flow and oxygen delivery fell, leading to cardiac injury. The allowable amount of hemodilution before reaching the critical point is most closely correlated with nonmuscle mass (r = 0.69) and resting cardiac output (r = 0.67). CONCLUSIONS: There were significant statistical differences in the model population and the clinical populations, but overall, the model responses lay within the clinical findings. This suggests our model is an effective replication of hemodilution in conscious, healthy adults. A critical hemoglobin range of 5.5-7.5 g/L was predicted and found to be highly correlated with nonmuscle mass and resting cardiac output. (C) 2017 International Anesthesia Research Society

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The Effect of Head Position on the Cross-sectional Area of the Subclavian Vein.

In 41 healthy volunteers, we investigated the cross-sectional area (CSA) of the subclavian vein (SCV) in the following head positions: neutral and 30[degrees] head rotation toward the contralateral or ipsilateral sides. Significant differences were observed in the CSA of the SCV at 3 different head positions: contralateral 30[degrees] versus neutral, -0.05 cm2 (95% confidence interval, -0.08 to -0.03); contralateral 30[degrees] versus ipsilateral 30[degrees], -0.15 cm2 (-0.19 to -0.12); neutral versus ipsilateral 30[degrees], -0.10 cm2 (-0.13 to -0.07); all Pcorrected

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Transesohageal Echocardiographic-Guided Transapical Neochord Implantation.

No abstract available

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Evaluation of the Augmented Infant Resuscitator: A Monitoring Device for Neonatal Bag-Valve-Mask Resuscitation.

BACKGROUND: Annually, 6 million newborns require bag-valve-mask resuscitation, and providing live feedback has the potential to improve the quality of resuscitation. The Augmented Infant Resuscitator (AIR), a real-time feedback device, has been designed to identify leaks, obstructions, and inappropriate breath rates during bag-valve-mask resuscitation. However, its function has not been evaluated. METHODS: The resistance of the AIR was measured by attaching it between a ventilator and a ventilator tester. To test the device's reliability in training and clinical-use settings, it was placed in-line between a ventilation bag or ventilator and a neonatal manikin and a clinical lung model simulator. The lung model simulator simulated neonates of 3 sizes (2, 4, and 6 kg). Leaks, obstructions, and respiratory rate alterations were introduced. RESULTS: At a flow of 5 L/min, the pressure drop across the AIR was only 0.38 cm H2O, and the device had almost no effect on ventilator breath parameters. During the manikin trials, it was able to detect all leaks and obstructions, correctly displaying an alarm 100% of the time. During the simulated clinical trials, the AIR performed best on the 6-kg neonatal model, followed by the 4-kg model, and finally the 2-kg model. Over all 3 clinical models, the prototype displayed the correct indicator 73.5% of the time, and when doing so, took 1.6 +/- 0.9 seconds. CONCLUSIONS: The AIR is a promising innovation that has the potential to improve neonatal resuscitation. It introduces only marginal resistance and performs well on neonatal manikins, but its firmware should be improved before clinical use. (C) 2017 International Anesthesia Research Society

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Neurologic Injury With Severe Adult Respiratory Distress Syndrome in Patients Undergoing Extracorporeal Membrane Oxygenation: A Single-Center Retrospective Analysis.

This retrospective single-center study investigated the incidence of neurologic injury as determined by autopsy or cerebral imaging in 74 patients undergoing extracorporeal membrane oxygenation (ECMO) for acute respiratory distress syndrome. Seventy-three percent of patients were treated with venovenous and 27% with venoarterial ECMO. ECMO-associated intracerebral hemorrhage was diagnosed in 10.8% of patients. There were no cases of ischemic stroke. Clinical characteristics did not differ between patients with and without neurologic injury. Six-month survival was 13% (Wilson confidence interval, 2%-47%) in patients with severe intracerebral hemorrhage compared to an overall survival rate of 57% (Wilson confidence interval, 45%-67%). (C) 2017 International Anesthesia Research Society

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Women and Leadership in Anesthesiology: Can We "Lean In" Further?.

No abstract available

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Transfusion of Older Red Blood Cells Increases the Risk of Acute Kidney Injury After Orthotopic Liver Transplantation: A Propensity Score Analysis.

BACKGROUND: Acute kidney injury (AKI) is a common and serious complication of orthotopic liver transplantation (OLT). Transfusion of older red blood cells (RBCs) has been implicated in poor outcomes in trauma, cardiac surgery, and critically ill patients. However, whether transfusion of older RBCs plays any role in post-OLT AKI remained unknown. The aim of this study was to investigate the effect of the age of transfused RBCs on post-OLT AKI. METHODS: The clinical data of consecutive adult patients who received donation after cardiac death and underwent OLT from December 2011 to December 2015 were analyzed. These patients were divided into 2 groups: the newer blood group, who received exclusively RBCs that had been stored for

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Pediatric Anesthesiology Fellows' Perception of Quality of Attending Supervision and Medical Errors.

BACKGROUND: Appropriate supervision has been shown to reduce medical errors in anesthesiology residents and other trainees across various specialties. Nonetheless, supervision of pediatric anesthesiology fellows has yet to be evaluated. The main objective of this survey investigation was to evaluate supervision of pediatric anesthesiology fellows in the United States. We hypothesized that there was an indirect association between perceived quality of faculty supervision of pediatric anesthesiology fellow trainees and the frequency of medical errors reported. METHODS: A survey of pediatric fellows from 53 pediatric anesthesiology fellowship programs in the United States was performed. The primary outcome was the frequency of self-reported errors by fellows, and the primary independent variable was supervision scores. Questions also assessed barriers for effective faculty supervision. RESULTS: One hundred seventy-six pediatric anesthesiology fellows were invited to participate, and 104 (59%) responded to the survey. Nine of 103 (9%, 95% confidence interval [CI], 4%-16%) respondents reported performing procedures, on >1 occasion, for which they were not properly trained for. Thirteen of 101 (13%, 95% CI, 7%-21%) reported making >1 mistake with negative consequence to patients, and 23 of 104 (22%, 95% CI, 15%-31%) reported >1 medication error in the last year. There were no differences in median (interquartile range) supervision scores between fellows who reported >1 medication error compared to those reporting 1 mistake with negative patient consequences, 3.3 (3.0-3.7), compared with those who did not report mistakes with negative patient consequences (3.4 [3.3-3.7]; median difference, 0.1; 99% CI, -0.2 to 0.6; P = .35). CONCLUSIONS: We detected a high rate of self-reported medication errors in pediatric anesthesiology fellows in the United States. Interestingly, fellows' perception of quality of faculty supervision was not associated with the frequency of reported errors. The current results with a narrow CI suggest the need to evaluate other potential factors that can be associated with the high frequency of reported errors by pediatric fellows (eg, fatigue, burnout). The identification of factors that lead to medical errors by pediatric anesthesiology fellows should be a main research priority to improve both trainee education and best practices of pediatric anesthesia. (C) 2017 International Anesthesia Research Society

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Comparative expression profiling of AtRAD5B and AtNDL1: Hints towards a role in G protein mediated signaling

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Publication date: Available online 1 September 2017
Source:Gene Expression Patterns
Author(s): Nisha Khatri, Swati Singh, Nasmeen Hakim, Yashwanti Mudgil
Arabidopsis AtRAD5B encodes for a putative helicase of the class SWItch/Sucrose Non-Fermentable (SWI/SNF) ATPases. We identified AtRAD5B as an interactor of N-MYC DOWNREGULATED-LIKE1 (AtNDL1) in a yeast two-hybrid screen. AtNDL1 is a G protein signaling component which regulates auxin transport and gradients together with GTP binding protein beta 1 (AGB1). Auxin gradients are known to recruit SWI/SNF remodeling complexes to the chromatin and regulate expression of genes involved in flower and leaf formation. In current study, a comparative spatial and temporal co-expression/localization analysis of AtNDL1, AGB1 with AtRAD5B was carried out in order to explore the possibility of their coexistence in a common signaling network. Translational fusion (GUS) of AtNDL1 and AtRAD5B in seedlings and reproductive organs revealed that both shared similar expression patterns with the highest expression observed in male reproductive organs. Moreover, they shared similar domains of localization in roots, suggesting their potential functioning together in reproductive and root development processes. This study predicts the existence of a signaling network involving AtNDL1, AGB1 with AtRAD5B.



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