1,721,160 research outputs found
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Can neap-spring tidal cycles modulate biogeochemical fluxes in the abyssal near-seafloor water column?
Get PDFBefore particulate matter that settles as ‘primary flux’ from the interior ocean is deposited into deep-sea sediments it has to traverse the benthic boundary layer (BBL) that is likely to cover almost all parts of the seafloor in the deep seas. Fluid dynamics in the BBL differ vastly from fluid dynamics in the overlying water column and, consequently, have the potential to lead to quantitative and compositional changes between primary and depositional fluxes. Despite this potential and the likely global relevance very little is known about mechanistic and quantitative aspects of the controlling processes. Here, results are presented for a sediment-trap time-series study that was conducted on the Porcupine Abyssal Plain in the abyssal Northeast Atlantic, with traps deployed at 2, 40 and 569 m above bottom (mab). The two bottommost traps were situated within the BBL-affected part of the water column. The time series captured 3 neap and 4 spring tides and the arrival of fresh settling material originating from a surface-ocean bloom. In the trap-collected material, total particulate matter (TPM), particulate inorganic carbon (PIC), biogenic silica (BSi), particulate organic carbon (POC), particulate nitrogen (PN), total hydrolysable amino acids (AA), hexosamines (HA) and lithogenic material (LM) were determined. The biogeochemical results are presented within the context of time series of measured currents (at 15 mab) and turbidity (at 1 mab). The main outcome is evidence for an effect of neap/spring tidal oscillations on particulate-matter dynamics in BBL-affected waters in the deep sea. Based on the frequency-decomposed current measurements and numerical modelling of BBL fluid dynamics, it is concluded that the neap/spring tidal oscillations of particulate-matter dynamics are less likely due to temporally varying total free-stream current speeds and more likely due to temporally and vertically varying turbulence intensities that result from the temporally varying interplay of different rotational flow components (residual, tidal, near-inertial) within the BBL. Using information from previously published empirical and theoretical relations between fluid and biogeochemical dynamics at the scale of individual particle aggregates, a conceptual and semi-quantitative picture of a mechanism was derived that explains how the neap/spring fluid-dynamic oscillations may translate through particle dynamics into neap/spring oscillations of biogeochemical aggregate decomposition (microbially driven organic-matter breakdown, biomineral dissolution). It is predicted that, during transitions from neap into spring tides, increased aggregation in near-seafloor waters and/or reduced deposition of aggregates at the seafloor coincides with reduced biogeochemical particulate-matter decomposition in near-seafloor waters. By contrast, during transitions from spring into neap tides, enhanced biogeochemical particulate-matter decomposition in near-seafloor waters is predicted to coincide with increased deposition of particulate matter at the seafloor. This study suggests that, in addition to current speed, the specifics and subtleties of the interplay of different rotational flow components can be an important control on how the primary flux from the interior ocean is translated into the depositional flux, with potential implications for sedimentary carbon deposition, benthic food supply and possibly even the sedimentary records of environmental change
Physiological regulation of the CDK16/PCTAIRE-1 protein kinase and its proposed role in the brain
No full textCell signalling, mediated to a large extent by protein kinase phosphorylation, plays a vital role in regulation of cellular function. PCTAIRE-1 (also known as cyclin-dependent protein kinase (CDK)16), is a Ser/Thr kinase that has been implicated in many cellular processes, including cell cycle, apoptosis, insulin secretion, spermatogenesis, neurite outgrowth, and vesicle trafficking. Most recently, it has been proposed as a novel X-linked intellectual disability (XLID) gene, where loss-of-function mutations have been found in patients. The precise molecular mechanisms that regulate PCTAIRE-1 remained largely obscure, and only few substrates have been proposed with no clear functional significance and physiological role. To understand the function of PCTAIRE-1, we previously utilised a peptide library screen to determine the consensus phosphorylation motif. We showed that PCTAIRE-1 preferentially phosphorylated peptide motifs that differed from the classical CDK family substrate preference, suggesting a more distinct role for the kinase. Furthermore, we showed that cyclin Y, a novel cyclin, robustly binds and activates PCTAIRE-1 > 100-fold. In this thesis, we have identified two phosphorylation sites on cyclin Y that are essential for binding the well-known adaptor protein 14-3-3, which we propose stabilizes cyclin Y in a favourable PCTAIRE-1-binding conformation. Mutation of these sites to non-phosphorylatable Ser residues abolished PCTAIRE-1 binding and activation. Furthermore, we have cloned human PCTAIRE-1 mutants identified in XLID patients, and confirmed their failure to bind the cyclin Y-14-3-3 activating complex. In order to understand the physiological relevance of PCTAIRE-1 activity, we have utilised a chemical genetics approach that exploits the ability of an engineered PCTAIRE-1 mutant to selectively modify its substrates, allowing them to be uniquely purified. We have identified three PCTAIRE-1 substrates (AAK1, dynamin 1 and synaptojanin 1) in mouse brain that regulate crucial steps of receptor endocytosis, namely receptor binding, vesicle scission and vesicle uncoating, which are all involved in the regulation of neuronal synaptic transmission. Collectively, this thesis work has provided key molecular regulatory mechanisms and potential downstream targets of PCTAIRE-1, which has laid the foundations for future studies of the role that PCTAIRE-1 plays in specific cellular functions and physiological and pathological settings.ISRE
Circadian clock- and feeding-dependent regulation of translation initiation and elongation in the liver
No full textCircadian rhythms allow organisms to anticipate and adapt to periodic environmental changes related to the day-night cycle. These rhythms originate from a genetic network ticking in almost every cell of our body and the coordination between different organs, thus allowing to generate physiological outputs at the right time of the day. In the liver, which is one of the major metabolic organ of the body, gene expression has to be highly regulated by the circadian clock and feeding rhythms to generate such a timely behavior. Indeed, at every step from transcription to post-translational modifications, the circadian clock and metabolism interplay.
In this context, we quantified transcription, mRNA accumulation and translation in liver from wild-type and clock-deficient mice fed ad libitum or only during the night period. RNA-Sequencing and ribosome profiling combined with mathematical modeling were used to assess rhythmic regulation along the gene expression process. Transcription was found to be the main driver of temporal mRNA accumulation and its subsequent translation. We observed a diurnal translation efficiency in genes with 5'-Terminal Oligo Pyrimidine tract (5'-TOP) sequences or with Translation Initiator of Short 5'-UTR (TISU) motifs. Remarkably, the rhythmic translation efficiency was mainly driven by feeding cues although clock-deficiency slightly affected the amplitude and phase of the oscillations.
In a subsequent work, we emphasized the above analysis of translation regulation with a focus on the ribosome elongation process. A statistical model and bioinformatics pipeline were developed to infer codon dwell times from ribosome profiling data. The method has the particularity of integrating pairs of codons between the sites of the ribosome and to fit every sequencing read on an individual basis. We validated our approach on a yeast dataset and then studied extensively the mouse liver translation elongation landscape. A large dynamic range between the fastest and longest codons was uncovered in the ribosome A and P sites with strong synergic interaction of pairs of codons clustering by amino acids. In order to challenge our system, we performed drug free ribosome profiling, modified to reduce library biases, in liver of mice fed ad libitum or starved. Unexpectedly, codon dwell times were conserved between the two conditions despite a gene expression landscape reflecting low energy state of the mice and subsequent amino acid shortage.
Finally, to understand how the ribosome elongation velocity is regulated by (aminoacyl)-tRNA levels, we adapted and modified a published DNA hybridization-based tRNA profiling method in liver of mice fed ad libitum or starved. While the quantified tRNAs abundance showed a large dynamic range and specific isoacceptors patterns, no differences in (aminoacyl)-tRNAs were found between the two feeding conditions. Nevertheless, tRNAs for isoleucine, asparagine, aspartate and arginine exhibited a relative low loading state compared to other tRNA in both conditions. Altogether, correlation between codon usage, codon dwell times and tRNA abundances provided insights of how translation elongation is regulated in mammals. Together, this thesis aimed to dissect the mechanisms regulating gene expression by the interplay of the circadian clock and metabolism, as well as understand how translation elongation is regulated in mammals.UPNA
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
AMP-activated protein kinase : strategies for activation and downstream target identification
No full textAMP-activated protein kinase (AMPK) is an evolutionally conserved key sensor of cellular energy status. Under conditions of cellular energy stress, AMPK is activated and will switch off anabolic processes that consume ATP, while activating catabolic processes that will generate ATP in order to restore energy balance. AMPK has been proposed as a drug target to treat metabolic disorders, and selective AMPK activators are being developed with the prospect of therapeutic application. In light of this, it is important to understand the molecular and physiological effects of AMPK activation in different cells/tissues. The aim of this thesis is to further our understanding of AMPK downstream actions through identification and characterization of novel AMPK substrates. In the studies encompassed in this thesis, we have investigated the effect of a dual treatment with two small molecule drugs on cellular AMPK activity and downstream action, and we have employed this pharmacological dual activation strategy to identify novel substrates of AMPK using two affinity proteomics-based approaches. We found that co-treatment of primary hepatocytes with two small molecule AMPK activators targeting distinct allosteric sites was able to robustly activate cellular AMPK. This treatment with submaximal dose of AICAR (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside) and low dose (1 ΌM) of A769662 produced a synergistic effect on AMPKα Thr172 phosphorylation and associated catalytic activity. Furthermore, the activation of AMPK activity by the co-treatment resulted in a more pronounced inhibition of lipogenesis in primary hepatocytes compared to single compound treatment. We further established two methodologies to identify AMPK targets based on: (1) immunoprecipitation with an antibody recognizing the optimal AMPK phosphorylation motif, and (2) ectopical expression of genetically engineered AMPK allowing specific labelling of direct phosphorylation targets. Using these two approaches, we identified putative AMPK substrates involved in a variety of cellular processes in mouse primary hepatocytes, such as mitochondrial dynamics and glycogen metabolism. We further identified Ser129 and Ser146 on mitochondrial fission factor (MFF), Ser902 on GTPase-activating protein and VPS9 domain-containing protein 1 (Gapex-5) and Ser175 on starch-binding domain-containing protein 1 (STBD1) as AMPK target phosphorylation sites, and further characterized them with respect to their AMPK-dependent regulation by small molecule activators, establishing them as genuine novel AMPK substrates. This work provides novel insights into the molecular mechanisms of AMPK downstream action in hepatocytes, and subsequent studies are starting to elucidate the physiological role of these regulatory events, although further work is still required. Additionally, the methodologies we and others have developed will allow further investigation of AMPK downstream effectors in a cell- and tissue-dependent manner. This will advance our understanding of the effects of AMPK activation by physiological and pathological stimuli, as well as in the context of pharmacological activation of AMPK for the treatment of metabolic disorders
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
- …
