Review on investigations of antisense oligonucleotides with the use of mass spectrometry

Publication date: 1 January 2018
Source:Talanta, Volume 176
Author(s): Sylwia Studzińska
Antisense oligonucleotides have been investigated as potential drugs for years. They inhibit target gene or protein expression. The present review summarizes their modifications, modes of action, and applications of liquid chromatography coupled with mass spectrometry for qualitative and quantitative analysis of these compounds. The most recent reports on a given topic were given prominence, while some early studies were reviewed in order to provide a theoretical background. The present review covers the issues of using ion-exchange chromatography, ion-pair reversed-phase high performance liquid chromatography and hydrophilic interaction chromatography for the separation of antisense oligonucleotides. The application of mass spectrometry was described with regard to the ionization type used for the determination of these potential therapeutics. Moreover, the current approaches and applications of mass spectrometry for quantitative analysis of antisense oligonucleotides and their metabolites as well as their impurities during in vitro and in vivo studies were discussed. Finally, certain conclusions and perspectives on the determination of therapeutic oligonucleotides in various samples were briefly described.

Graphical abstract

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Noninvasive penetration of 5 nm hyaluronic acid molecules across the epidermal barrier (in vitro) and its interaction with human skin cells

Abstract

Objective

Hyaluronic acid represents one of the major components of the extracellular environment. The main challenge remains in the ability to deliver these molecules noninvasively across the skin barrier, which can be overcome by the reduction in size to an extent that allows these molecules to pass across the skin barrier.

The aim of this study was to measure the penetration and bioavailability of low molecular weight hyaluronic acid to cross an epidermal barrier model.

Methods

Determining the quantity of hyaluronic acid in the test solutions was carried with method of photocolorimetry analysis. Investigation of the interaction of cells with LMWHA was studied with a confocal microscope.

Results

The study showed that LMWHA is able to cross the epidermis. Most effective penetration level is during the first 6 hours reaching 75%, and then the concentration started to decline and reached the equilibrium state within the following 2 hours. Confocal laser microscopy demonstrated different distribution and behavior of these molecules among the keratinocytes and fibroblasts.

Conclusion

Reducing the size of hyaluronic acid to 5 nm enhance their transport across the epidermal layer. The concentration of hyaluronic acid molecules was higher on the fibroblast surface in comparison to their extracellular environment.

http://ift.tt/2vRJWr6

Neurophysiologically-informed markers of individual variability and pharmacological manipulation of human cortical gamma

Publication date: 1 November 2017
Source:NeuroImage, Volume 161
Author(s): A.D. Shaw, R.J. Moran, S.D. Muthukumaraswamy, J. Brealy, D.E. Linden, K.J. Friston, K.D. Singh
The ability to quantify synaptic function at the level of cortical microcircuits from non-invasive data would be enormously useful in the study of neuronal processing in humans and the pathophysiology that attends many neuropsychiatric disorders. Here, we provide proof of principle that one can estimate inter-and intra-laminar interactions among specific neuronal populations using induced gamma responses in the visual cortex of human subjects – using dynamic causal modelling based upon the canonical microcircuit (CMC; a simplistic model of a cortical column). Using variability in induced (spectral) responses over a large cohort of normal subjects, we find that the predominant determinants of gamma responses rest on recurrent and intrinsic connections between superficial pyramidal cells and inhibitory interneurons. Furthermore, variations in beta responses were mediated by inter-subject differences in the intrinsic connections between deep pyramidal cells and inhibitory interneurons. Interestingly, we also show that increasing the self-inhibition of superficial pyramidal cells suppresses the amplitude of gamma activity, while increasing its peak frequency. This systematic and nonlinear relationship was only disclosed by modelling the causes of induced responses. Crucially, we were able to validate this form of neurophysiological phenotyping by showing a selective effect of the GABA re-uptake inhibitor tiagabine on the rate constants of inhibitory interneurons. Remarkably, we were able to recover the pharmacodynamics of this effect over the course of several hours on a per subject basis. These findings speak to the possibility of measuring population specific synaptic function – and its response to pharmacological intervention – to provide subject-specific biomarkers of mesoscopic neuronal processes using non-invasive data. Finally, our results demonstrate that, using the CMC as a proxy, the synaptic mechanisms that underlie the gain control of neuronal message passing within and between different levels of cortical hierarchies may now be amenable to quantitative study using non-invasive (MEG) procedures.



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Audio-visual synchrony and spatial attention enhance processing of dynamic visual stimulation independently and in parallel: A frequency-tagging study

Publication date: 1 November 2017
Source:NeuroImage, Volume 161
Author(s): Amra Covic, Christian Keitel, Emanuele Porcu, Erich Schröger, Matthias M. Müller
The neural processing of a visual stimulus can be facilitated by attending to its position or by a co-occurring auditory tone. Using frequency-tagging, we investigated whether facilitation by spatial attention and audio-visual synchrony rely on similar neural processes. Participants attended to one of two flickering Gabor patches (14.17 and 17 Hz) located in opposite lower visual fields. Gabor patches further "pulsed" (i.e. showed smooth spatial frequency variations) at distinct rates (3.14 and 3.63 Hz). Frequency-modulating an auditory stimulus at the pulse-rate of one of the visual stimuli established audio-visual synchrony. Flicker and pulsed stimulation elicited stimulus-locked rhythmic electrophysiological brain responses that allowed tracking the neural processing of simultaneously presented Gabor patches. These steady-state responses (SSRs) were quantified in the spectral domain to examine visual stimulus processing under conditions of synchronous vs. asynchronous tone presentation and when respective stimulus positions were attended vs. unattended. Strikingly, unique patterns of effects on pulse- and flicker driven SSRs indicated that spatial attention and audiovisual synchrony facilitated early visual processing in parallel and via different cortical processes. We found attention effects to resemble the classical top-down gain effect facilitating both, flicker and pulse-driven SSRs. Audio-visual synchrony, in turn, only amplified synchrony-producing stimulus aspects (i.e. pulse-driven SSRs) possibly highlighting the role of temporally co-occurring sights and sounds in bottom-up multisensory integration.



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Parsing the neural signatures of reduced error detection in older age

Publication date: 1 November 2017
Source:NeuroImage, Volume 161
Author(s): Siobhán Harty, Peter R. Murphy, Ian H. Robertson, Redmond G. O'Connell
Recent work has demonstrated that explicit error detection relies on a neural evidence accumulation process that can be traced in the human electroencephalogram (EEG). Here, we sought to establish the impact of natural aging on this process by recording EEG from young (18–35 years) and older adults (65–88 years) during the performance of a Go/No-Go paradigm in which participants were required to overtly signal their errors. Despite performing the task with equivalent accuracy, older adults reported substantially fewer errors, and the timing of their reports were both slower and more variable. These behavioral differences were linked to three key neurophysiological changes reflecting distinct parameters of the error detection decision process: a reduction in medial frontal delta/theta (2–7 Hz) activity, indicating diminished top-down input to the decision process; a slower rate of evidence accumulation as indexed by the rate of rise of a centro-parietal signal, known as the error positivity; and a higher motor execution threshold as indexed by lateralized beta-band (16–30 Hz) activity. Our data provide novel insight into how the natural aging process affects the neural underpinnings of error detection.



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An adaptive, individualized fMRI delay discounting procedure to increase flexibility and optimize scanner time

Publication date: 1 November 2017
Source:NeuroImage, Volume 161
Author(s): Mikhail N. Koffarnus, Harshawardhan U. Deshpande, Jonathan M. Lisinski, Anders Eklund, Warren K. Bickel, Stephen M. LaConte
Research on the rate at which people discount the value of future rewards has become increasingly prevalent as discount rate has been shown to be associated with many unhealthy patterns of behavior such as drug abuse, gambling, and overeating. fMRI research points to a fronto-parietal-limbic pathway that is active during decisions between smaller amounts of money now and larger amounts available after a delay. Researchers in this area have used different variants of delay discounting tasks and reported various contrasts between choice trials of different types from these tasks. For instance, researchers have compared 1) choices of delayed monetary amounts to choices of the immediate monetary amounts, 2) 'hard' choices made near one's point of indifference to 'easy' choices that require little thought, and 3) trials where an immediate choice is available versus trials where one is unavailable, regardless of actual eventual choice. These differences in procedure and analysis make comparison of results across studies difficult. In the present experiment, we designed a delay discounting task with the intended capability of being able to construct contrasts of all three comparisons listed above while optimizing scanning time to reduce costs and avoid participant fatigue. This was accomplished with an algorithm that customized the choice trials presented to each participant with the goal of equalizing choice trials of each type. We compared this task, which we refer to here as the individualized discounting task (IDT), to two other delay discounting tasks previously reported in the literature (McClure et al., 2004; Amlung et al., 2014) in 18 participants. Results show that the IDT can examine each of the three contrasts mentioned above, while yielding a similar degree of activation as the reference tasks. This suggests that this new task could be used in delay discounting fMRI studies to allow researchers to more easily compare their results to a majority of previous research while minimizing scanning duration.



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Cortical representation of persistent visual stimuli

Publication date: 1 November 2017
Source:NeuroImage, Volume 161
Author(s): Edden M. Gerber, Tal Golan, Robert T. Knight, Leon Y. Deouell
Research into visual neural activity has focused almost exclusively on onset- or change-driven responses and little is known about how information is encoded in the brain during sustained periods of visual perception. We used intracranial recordings in humans to determine the degree to which the presence of a visual stimulus is persistently encoded by neural activity. The correspondence between stimulus duration and neural response duration was strongest in early visual cortex and gradually diminished along the visual hierarchy, such that is was weakest in inferior-temporal category-selective regions. A similar posterior-anterior gradient was found within inferior temporal face-selective regions, with posterior but not anterior sites showing persistent face-selective activity. The results suggest that regions that appear uniform in terms of their category selectivity are dissociated by how they temporally represent a stimulus in support of ongoing visual perception, and delineate a large-scale organizing principle of the ventral visual stream.



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Real-time motion analytics during brain MRI improve data quality and reduce costs

Publication date: 1 November 2017
Source:NeuroImage, Volume 161
Author(s): Nico U.F. Dosenbach, Jonathan M. Koller, Eric A. Earl, Oscar Miranda-Dominguez, Rachel L. Klein, Andrew N. Van, Abraham Z. Snyder, Bonnie J. Nagel, Joel T. Nigg, Annie L. Nguyen, Victoria Wesevich, Deanna J. Greene, Damien A. Fair
Head motion systematically distorts clinical and research MRI data. Motion artifacts have biased findings from many structural and functional brain MRI studies. An effective way to remove motion artifacts is to exclude MRI data frames affected by head motion. However, such post-hoc frame censoring can lead to data loss rates of 50% or more in our pediatric patient cohorts. Hence, many scanner operators collect additional 'buffer data', an expensive practice that, by itself, does not guarantee sufficient high-quality MRI data for a given participant. Therefore, we developed an easy-to-setup, easy-to-use Framewise Integrated Real-time MRI Monitoring (FIRMM) software suite that provides scanner operators with head motion analytics in real-time, allowing them to scan each subject until the desired amount of low-movement data has been collected. Our analyses show that using FIRMM to identify the ideal scan time for each person can reduce total brain MRI scan times and associated costs by 50% or more.

Graphical abstract

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Identification of preliminary core outcome domains for communication about childhood vaccination: An online Delphi survey

Publication date: Available online 20 August 2017
Source:Vaccine
Author(s): Jessica Kaufman, Rebecca Ryan, Simon Lewin, Xavier Bosch-Capblanch, Claire Glenton, Julie Cliff, Angela Oyo-Ita, Artur Manuel Muloliwa, Afiong Oku, Heather Ames, Gabriel Rada, Yuri Cartier, Sophie Hill
BackgroundCommunication interventions for childhood vaccination are promising strategies to address vaccine hesitancy, but current research is limited by the outcomes measured. Most studies measure only vaccination-related outcomes, with minimal consideration of vaccine hesitancy-relevant intermediate outcomes. This impedes understanding of which interventions or elements are effective.It is also unknown which outcomes are important to the range of stakeholders affected by vaccine hesitancy. Outcome selection shapes the evidence base, informing future interventions and trials, and should reflect stakeholder priorities.Therefore, our aim was to identify which outcome domains (i.e. broad outcome categories) are most important to different stakeholders, identifying preliminary core outcome domains to inform evaluation of three common vaccination communication types: (i) communication to inform or educate, (ii) remind or recall, and (iii) enhance community ownership.MethodsWe conducted a two-stage online Delphi survey, involving four stakeholder groups: parents or community members, healthcare providers, researchers, and government or non-governmental organisation representatives. Participants rated the importance of eight outcome domains for each of the three communication types. They also rated specific outcomes within one domain ("attitudes or beliefs") and provided feedback about the survey.ResultsCollectively, stakeholder groups prioritised outcome domains differently when considering the effects of different communication types. For communication that aims to (i) inform or educate, the most important outcome domain is "knowledge or understanding"; for (ii) reminder communication, "vaccination status and behaviours"; and for (iii) community engagement communication, "community participation". All stakeholder groups rated most outcome domains as very important or critical. The highest rated specific outcome within the "attitudes or beliefs" domain was "trust".ConclusionThis Delphi survey expands the field of core outcomes research and identifies preliminary core outcome domains for measuring the effects of communication about childhood vaccination. The findings support the argument that vaccination communication is not a single homogenous intervention – it has a range of purposes, and vaccination communication evaluators should select outcomes accordingly.



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Dual use issues in research – A subject of increasing concern?

Publication date: Available online 20 August 2017
Source:Vaccine
Author(s): Trevor W. Drew, Uwe Ulex Mueller-Doblies
Dual use is defined as the application of materials, knowledge or technologies for military or terrorist purposes, as well as for good. In biological science, it is considered to be a growing threat as the genetics of pathogenicity traits and toxins are becoming on one hand elucidated in a detail that was not anticipated 20years ago and on the other hand technological advances in genetic engineering and synthetic biology are continually enabling easier access to these technologies. On a theoretical and policy level, much has happened over the past decade, but translating these policies and concepts to operational level awareness and robust processes requires more attention. Where the research is conducted, scientists have to make ethical judgements and account for their data sharing and publication policies. How can we ensure the requirement for dual use review is taken on board, but is not skewing research detrimentally and imposing a disproportionate burden?



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Scholar : Journal of Natural History, Volume 51, Issue 29-30, August 2017 is now available online on Taylor & Francis Online

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The online platform for Taylor & Francis Online content Journal of Natural History, Volume 51, Issue 29-30, August 2017 is now available online on Taylor & Francis Online. This new issue contains the following articles: Original Articles Macroinvertebrate richness is lower in high-elevation lakes vs nearby streams: evidence from Grand Teton National Park, Wyoming Scott Hotaling, Lusha M. Tronstad & James Cody Bish Pages: 1657-1669 | DOI: 10.1080/00222933.2017.1353149 Eight new species of the genus Promalactis (Lepidoptera: Oecophoridae) from Indonesia, with a checklist of the genus Sora Kim , John B. Heppner & Kyu-Tek Park Pages: 1671-1695 | DOI: 10.1080/00222933.2017.1353154 First record of genus Promalactis Meyrick (Lepidoptera: oecophoridae) from Cambodia with five new species Sora Kim , Ram Keshari Duwal , John B. Heppner, Wonhoon Lee, Yang-Seop Bae & Seunghwan Lee Pages: 1697-1712 | DOI: 10.1080/00222933.2017.1355501 Four new species of the genus Trichomyia − subgenus Septemtrichomyia Bravo (Diptera: Psychodidae: Trichomyiinae) from Brazil Maíra Xavier Araújo, Claudiney Biral Dos Santos, Freddy Bravo & Claudio J.B. de Carvalho Pages: 1713-1725 | DOI: 10.1080/00222933.2017.1353148 Life cycles and host–parasitoid relationships of five species of Leucospis wasps in Argentina (Hymenoptera: Leucospidae) Juan Pablo Torretta, Gonzalo A. R. Molina & Daniel A. Aquino Pages: 1727-1742 | DOI: 10.1080/00222933.2017.1353151 The taxonomic identity of Anthidium fasciatellum Friese, 1917 (Hymenoptera: Apoidea: Anthidiini) Max Kasparek Pages: 1743-1757 | DOI: 10.1080/00222933.2017.1353152 A new genus and species of the termitophilous Neotropical Hybosorinae (Coleoptera: Scarabaeoidea: Hybosoridae) associated with Cornitermes (Isoptera: Termitidae) in the Cerrado ecoregion in Brazil Andrey V. Frolov , Federico C. Ocampo , Lilia A. Akhmetova & Fernando Vaz-de-Mello Pages: 1759-1765 | DOI: 10.1080/00222933.2017.1353150 Revision of the Neotropical scarab beetle genus Aegidiellus Paulian (Coleoptera: Scarabaeidae: Orphninae) with description of two new species Andrey V. Frolov , Lilia A. Akhmetova & Fernando Z. Vaz-de-Mello Pages: 1767-1779 | DOI: 10.1080/00222933.2017.1353153 Cladocera and Copepoda of Shokalsky Island: new data from northwest Siberia Anna A. Novichkova & Elena S. Chertoprud Pages: 1781-1793 | DOI: 10.1080/00222933.2017.1355077 To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Globalisation and its effect on pollution in Malaysia: the role of Trans-Pacific Partnership (TPP) agreement

Abstract

The main objective of this study is to investigate the influence of the globalisation (Trans-Pacific Partnership (TPP) agreement in particular) on air pollution in Malaysia. To achieve this goal, the Autoregressive Distributed Lag (ARDL) model, Johansen cointegration test and fully modified ordinary least square (FMOLS) methods are utilised. CO₂ emission is used as an indicator of pollution while GDP per capita and urbanisation serve as its other determinants. In addition, this study uses Malaysia's total trade with 10 TPP members as an indicator of globalisation and analyse its effect on CO₂ emission in Malaysia. The outcome of this research shows that the variables are cointegrated. Additionally, GDP per capita, urbanisation and trade between Malaysia and its 10 TPP partners have a positive impact on CO₂ emissions in general. Based on the outcome of this research, important policy implications are provided for the investigated country.

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Scholar : These new articles for Journal of Natural History are available online

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The online platform for Taylor & Francis Online content New for Journal of Natural History and online now on Taylor & Francis Online: Article Aggressive, omnivorous, invasive: the Erythraean moon crab Matuta victor (Fabricius, 1781) (Crustacea: Decapoda: Matutidae) in the eastern Mediterranean sea Gianna Innocenti , Gianluca Stasolla , Moti Mendelson & Bella S. Galil Pages: 1-10 | DOI: 10.1080/00222933.2017.1363305 To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Scholar : These new articles for Journal of Tourism and Cultural Change are available online

The online platform for Taylor & Francis Online content New for Journal of Tourism and Cultural Change and online now on Taylor & Francis Online: Book Reviews Alternative tourism in Budapest: class, culture and identity in a postsocialist city Emanuela Guano Pages: 1-2 | DOI: 10.1080/14766825.2017.1364001 To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Scholar : These new articles for Asian Journal of Political Science are available online

The online platform for Taylor & Francis Online content New for Asian Journal of Political Science and online now on Taylor & Francis Online: Original Articles Local climate governance and policy innovation in China: a case study of a piloting emission trading scheme in Guangdong province Bo Chen, Wei Shen, Peter Newell & Yao Wang Pages: 1-21 | DOI: 10.1080/02185377.2017.1352524 Find out more about the issues and challenges in Governing Asia. This collection includes free access papers on security challenges, the Abe and Modi administration, reflections on the Chinese Governance and more. Browse today! To update which email alerts you receive, manage your alerts within the My Account area. You can also unsubscribe from this alert with one click. If you need any further help, please contact us at support@tandfonline.com Please do not reply to this email. To ensure that you receive your alerts and information from Taylor & Francis Online, please add "alerts@tandfonline.com" and "info@tandfonline.com" to your safe senders list. Taylor & Francis, an Informa business. Taylor & Francis is a trading name of Informa UK Limited, registered in England under no. 1072954. Registered office: 5 Howick Place, London, SW1P 1WG.

Gene therapy: Human genome editing in heart disease

Nature Reviews Genetics. doi:10.1038/nrg.2017.69

Author: Gregory B. Lim

http://ift.tt/2fXosUc

Human genetic variation and the gut microbiome in disease

Nature Reviews Genetics. doi:10.1038/nrg.2017.63

Authors: Andrew Brantley Hall, Andrew C. Tolonen & Ramnik J. Xavier

http://ift.tt/2ijzLHi

Tracking MET de-addiction in lung cancer: a road towards the oncogenic target.

Publication date: Available online 20 August 2017
Source:Cancer Treatment Reviews
Author(s): S. Pilotto, L. Carbognin, N. Karachaliou, P.C. Ma, R. Rosell, G. Tortora, E. Bria
The discovery of druggable oncogenic drivers (i.e. EGFR and ALK), along with the introduction of comprehensive tumor genotyping techniques into the daily clinical practice define non-small-cell lung cancer (NSCLC) as a group of heterogeneous diseases, requiring a context-personalized clinico-therapeutical approach. Among the most investigated biomarkers, the MET proto-oncogene has been extensively demonstrated to play a crucial role throughout the lung oncogenesis, unbalancing the proliferation/apoptosis signaling and influencing the epithelial-mesenchymal transition and the invasive phenotype. Nevertheless, although different mechanisms eliciting the aberrant MET-associated oncogenic stimulus have been detected in lung cancer (such as gene amplification, increased gene copy number, mutations and MET/HGF overexpression), to date no clinically impactful results have been achieved with anti-MET tyrosine kinase inhibitors and monoclonal antibodies in the context of an unselected or MET enriched population. Recently, MET exon 14 splicing abnormalities have been identified as a potential oncogenic target in lung cancer, able to drive the activity of MET inhibitors in molecularly selected patients.In this paper, the major advancement and drawbacks of MET history in lung cancer are reviewed, underlying the renewed scientific euphoria related to the recent identification of MET exon 14 splicing variants as an actionable oncogenic target.



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Elizabeth Croll: ASPS Patient of Courage 2016

Summary: Mrs. Elizabeth Croll was selected as an American Society of Plastic Surgeons (ASPS) Patient of Courage in 2016. During a boating accident that occurred within 1 month after graduating from Harvard Business School, she was struck by an oncoming boat and suffered severe facial trauma, resulting in an open skull injury with loss of her right eye. She has since undergone multiple reconstructive surgical procedures beginning in 1997 and continuing up to the month before she was awarded the ASPS Patient of Courage. During this time, she got married, started a family, and continued an ambitious business career. Mrs. Croll is the epitome of an individual who has overcome tragedy to further her career, her community, and access to medical care for indigent children.

http://ift.tt/2vMoZyr

An Unusual Presentation of an Osteoid Osteoma in the Lunate Bone

Summary: An osteoid osteoma is a rare benign tumor of the carpal bones. It is extremely rarely found in the lunate bone in patients above 30 years of age. We present a case report of a 61-year-old man with an osteoid osteoma of the left wrist, which was masked by degenerative carpal bone disease and a comorbidity of an inflammatory bowel disease. The mainstay of imaging including plain radiographs, computed tomography, magnetic resonance imaging, and bone scintigraphy led to the clinical diagnosis of a lunatomalacia. The tumor was removed by coincidence during removal of the diseased lunate bone. Postoperatively, the patient was immediately free of pain and remained free at his 3 months postoperative follow-up.

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