bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic inactivation of oncogenic brachyury (TBXT) by H3K27 histone demethylase controls chordoma cell survival
Authors: Cottone Lucia , Hookway Edward S , Cribbs Adam , Wells Graham , Lombard Patrick , Ligammari Lorena , Tumber Anthony , Tirabosco Roberto , Amary Fernanda , Szommer Tamas , Johannson Catrine , Brennan Paul E , Pillay Nischalan , Oppermann Udo , Flanagan Adrienne M 
Published: October 2018

AbstractThe expression of the transcription factorbrachyury(TBXT) is normally restricted to embryonic development and its silencing after mesoderm development is epigenetically regulated. In chordoma, a rare tumour of notochordal differentiation, TBXT acts as a putative oncogene, and we hypothesised that its expression could be controlled through epigenetic inhibition. Screening of five chordoma cell lines revealed that only inhibitors of the histone 3 lysine 27 demethylases KDM6A (UTX) and KDM6B (Jmjd3) reduceTBXTexpression and lead to cell death, findings validated in primary patient-derived culture systems. Pharmacological inhibition of KDM6 demethylases leads to genome-wide increases in repressive H3K27me3 marks, accompanied by significantly reduced TBXT expression, an effect that is phenocopied by the dual genetic inactivation ofKDM6A/Busing CRISPR/Cas9. Transcriptional profiles in response to a novel KDM6A/B inhibitor, KDOBA67, revealed downregulation of critical genes and transcription factor networks for chordoma survival pathways, whereas upregulated pathways were dominated by stress, cell cycle and pro-apoptotic response pathways.This study supports previous data showing that the function of TBXT is essential for maintaining notochord cell fate and function and provides further evidence that TBXT is an oncogenic driver in chordoma. Moreover, the data suggest that TBXT can potentially be targeted therapeutically by modulating epigenetic control mechanisms such as H3K27 demethylases.
Pacific geoduck (Panopea generosa) resilience to natural pH variation
Authors: Spencer Laura H. , Horwith Micah , Lowe Alexander T. , Venkataraman Yaamini R. , Timmins-Schiffman Emma , Nunn Brook L. , Roberts Steven B. 
Published: October 2018

AbstractPacific geoduck aquaculture is a growing industry, however, little is known about how geoduck respond to varying environmental conditions, or how the industry will fare under projected climate conditions. To understand how geoduck production may be impacted by low pH associated with ocean acidification, multi-faceted environmental heterogeneity needs to be included to understand species and community responses. In this study, eelgrass habitats and environmental heterogeneity across four estuarine bays were leveraged to examine low pH effects on geoduck under different natural regimes, using targeted proteomics to assess physiology. Juvenile geoduck were deployed in eelgrass and adjacent unvegetated habitats for 30 days while pH, temperature, dissolved oxygen, and salinity were monitored. Across the four bays, pH was lower in unvegetated habitats compared to eelgrass habitats. However this did not impact geoduck growth, survival, or proteomic abundance patterns in gill tissue. Temperature and dissolved oxygen differences across all locations corresponded to differences in growth and targeted protein abundance patterns. Specifically, three protein abundance levels (trifunctional-enzyme β-subunit, puromycin-sensitive aminopeptidase, and heat shock protein 90-α) and shell growth positively correlated with dissolved oxygen variability and inversely correlated with mean temperature. These results demonstrate that geoduck may be resilient to low pH in a natural setting, but other abiotic factors (i.e. temperature, dissolved oxygen variability) may have a greater influence on geoduck physiology. In addition this study contributes to the understanding of how eelgrass patches influences water chemistry.
In vivo cerebral microdialysis validation of the acute central glutamate response in a translational rat model of concussion combining force and rotation
Authors: Massé Ian , Moquin Luc , Provost Chloé , Guay Samuel , Gratton Alain , De Beaumont Louis 
Published: October 2018

AbstractConcussions/mild traumatic brain injury (mTBI) represent a major public health concern due to persistent behavioral and neurological effects. The mechanisms by which concussions lead to such effects are partly attributable to an hyperacute indiscriminate glutamate release. Cerebral microdialysis studies in rodents reported a peak of extracellular glutamate 10 minutes after injury. Microdialysis has the advantage of being one of the few techniques allowing the quantification of neurotransmitters in vivo and at different time points following injury. In addition to the clear advantages afforded by microdialysis, the Wayne State weight-drop model induces an impact on the skull of a subject unrestrained by the fall of a weight. The latter model allows rapid acceleration and deceleration of the head and torso, an essential feature in human craniocerebral trauma and a factor that is missing from many existing animal concussion models. In the present study, we applied the Wayne State procedure and microdialysis to document, in awake rats, the acute changes in extracellular hippocampal glutamate and GABA levels resulting from concussive trauma. We studied the dorsal CA1 hippocampal region as it contains a high density of glutamatergic terminal and receptors, thus making it vulnerable to excitotoxic insult. Using HPLC, dialysate levels of hippocampal glutamate and GABA were measured in adult male Sprague-Dawley rats in 10 min increments for 60 min prior to, during and for 90 min following concussive trauma induced by the Wayne State weight-drop procedure. Sham control animals were treated in the same manner but without receiving the concussive trauma procedure. Our results show that concussive trauma is followed, within 10 min, by a robust, transient 3-fold increase in hippocampal glutamate levels; such changes were not seen in controls. In contrast, GABA levels were unaffected by the concussive trauma procedure. The findings derived from the approach used here are generally consistent with those of previous other studies. They also provide a crucial in vivo validation of the Wayne State procedure as a model with promising translational potential for pre-clinical studies on early therapeutic responses to concussion.
Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance
Authors: Cirelli Kimberly M. , Carnathan Diane G. , Nogal Bartek , Rodriguez Oscar L. , Martin Jacob T. , Upadhyay Amit A. , Enemuo Chiamaka A. , Gebru Etse H. , Choe Yury , Viviano Federico , Nakao Catherine , Pauthner Matthias , Reiss Samantha , Cottrell Christopher A. , Bastidas Raiza , Gibson William , Wolabaugh Amber N. , Melo Mariane B. , Cosette Benjamin , Kuman Venkatesh , Patel Nirav , Tokatlian Talar , Menis Sergey , Kulp Daniel W. , Burton Dennis R. , Murrell Ben , Bosinger Steven E. , Schief William R. , Ward Andrew B. , Watson Corey T. , Silvestri Guido , Irvine Darrell J. , Crotty Shane 
Published: October 2018

SUMMARYThe observation that humans can produce broadly neutralizing antibodies (bnAbs) against HIV-1 has generated enthusiasm about the potential for a bnAb vaccine against HIV-1. Conventional immunization strategies will likely be insufficient for the development of a bnAb HIV vaccine and vaccines to other difficult pathogens, due to the significant immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. Using longitudinal lymph node fine needle aspirates, we found that two independent methods of slow delivery immunization of rhesus macaques (RM) resulted in larger GCs, more robust and sustained GC Tfh cell responses, and GC B cells with improved Env-binding, which correlated with the development of ~20 to 30-fold higher titers of tier 2 HIV-1 nAbs. Using a new RM genomic immunoglobulin loci reference sequence, we identified differential IgV gene usage between slow delivery immunized and conventional bolus immunized animals. The most immunodominant IgV gene used by conventionally immunized animals was associated with many GC B cell lineages. Ab mapping of those GC B cell specificities demonstrated targeting of an immunodominant non-neutralizing trimer base epitope, while that response was muted in slow delivery immunized animals. Thus, alternative immunization strategies appear to enhance nAb development by altering GCs and modulating immunodominance of non-neutralizing epitopes.
Molecular mechanisms of gating in the calcium-activated chloride channel bestrophin
Authors: Miller Alexandria N. , Vaisey George , Long Stephen B. 
Published: October 2018

AbstractBestrophin (BEST1–4 in humans) channels are ligand gated chloride (Cl−) channels that are activated by calcium (Ca2+). Mutations in BEST1 cause retinal degenerative diseases. Partly because these channels have no sequence or structural similarity to other ion channels, the molecular mechanisms underlying gating are unknown. Here, we present a series of cryo-electron microscopy (cryo-EM) structures of chicken BEST1, determined at 3.1 Å resolution or better, that represent the principal gating states of the channel. Unlike other channels, opening of the pore is due to the repositioning of tethered pore-lining helices within a surrounding protein shell that dramatically widens a “neck” of the pore through a concertina of amino acid rearrangements within the protein core. The neck serves as both the activation and the inactivation gate. The binding of Ca2+ to a cytosolic domain instigates pore opening and the structures reveal that, unlike voltage-gated Na+ and K+ channels, similar molecular rearrangements are responsible for inactivation and deactivation. A single aperture within the 95 Å-long opened pore separates the cytosol from the extracellular milieu and controls anion permeability. The studies define the basis for Ca2+-activated Cl− channel function and reveal a new molecular paradigm for gating in ligand-gated ion channels.
A numerical study into the longitudinal dynamic stability of the tailless aircraft
Authors: Kwiek Agnieszka 
Published: October 2018

Purpose
The purpose of this research is a study into a mathematical approach of a tailless aircraft dynamic stability analysis. This research is focused on investigation of influence of elevons (elevator) on stability derivatives and consequently on the aircraft longitudinal dynamic stability. The main research question is to determine whether this impact should be taken into account on the conceptual and preliminary stage of the analysis of the longitudinal dynamic stability.

Design/methodology/approach
Aerodynamic coefficients and longitudinal stability derivatives were computed by Panukl (panel methods). The analysis of the dynamic stability of the tailless aircraft was made by the Matlab code and SDSA package.

Findings
The main result of the research is a comparison of the dynamic stability of the tailless aircraft for different approaches, with and without the impact of elevator deflection on the trim drag and stability derivatives.

Research limitations/implications
This paper presents research that mostly should be considered on the preliminary stage of aircraft design and dynamic stability analysis. The impact of elevons deflection on the aircraft moment of inertia has been omitted.

Practical implications
The results of this research will be useful for the further design of small tailless unmanned aerial vehicles (UAVs).

Originality/value
This research reveals that in case of the analysis of small tailless UAVs, the impact of elevons deflection on stability derivatives is bigger than the impact of a Mach number. This impact should be taken into consideration, especially for a phugoid mode.
Aerodynamic and flight dynamic interaction in spin
Authors: Marcinkiewicz Ewa , Goraj Zdobyslaw Jan , Figat Marcin 
Published: October 2018

PurposeThe purpose of this paper is to describe an integrated approach to spin analysis based on 6-DOF (degrees of freedom) fully nonlinear equations of motion and a three-dimensional multigrid Euler method used to specify a flow model. Another purpose of this study is to investigate military trainer performance during a developed phase of a deliberately executed spin, and to predict an aircraft tendency while entering a spin and its response to control surface deflections needed for recovery.Design/methodology/approachTo assess spin properties, the calculations of aerodynamic characteristics were performed through an angle-of-attack range of −30 degrees to +50 degrees and a sideslip-angle range of −30 degrees to +30 degrees. Then, dynamic equations of motion of a rigid aircraft together with aerodynamic loads being premised on stability derivatives concept were numerically integrated. Finally, the examination of light turboprop dynamic behaviour in post-stalling conditions was carried out.FindingsThe computational method used to evaluate spin was positively verified by comparing it with the experimental outcome. Moreover, the Euler code-based approach to lay down aerodynamics could be considered as reliable to provide high angles-of-attack characteristics. Conclusions incorporate the results of a comparative analysis focusing especially on comprehensive assessment of output data quality in relation to flight tests.Originality/valueThe conducted calculations take into account aerodynamic and flight dynamic interaction of an aerobatic-category turboprop in spin conditions. A number of manoeuvres considering different aircraft configurations were simulated. The computational outcomes were subsequently compared to the results of in-flight tests and the collected data were thoroughly analysed to draw final conclusions.
A new fuel-balanced formation keeping reference trajectories planning method
Authors: Wang Jihe , Zhang Dexin , Chen GuoZhong , Shao Xiaowei 
Published: October 2018

Purpose
The purpose of this paper is to propose a new fuel-balanced formation keeping reference trajectories planning method based on selecting the virtual reference center(VRC) in a fuel-balanced sense in terms of relative eccentricity and inclination vectors (E/I vectors).

Design/methodology/approach
By using the geometrical intuitive relative E/I vectors theory, the fuel-balanced VRC selection problem is reformulated as the geometrical problem to find the optimal point to equalize the distances between the VRC and the points determined by the relative E/I vectors of satellites in relative E/I vectors plane, which is solved by nonlinear programming method.

Findings
Numerical simulations demonstrate that the new proposed fuel-balanced formation keeping strategy is valid, and the new method achieves better fuel-balanced performance than the traditional method, which keeps formation with respect to geometrical formation center.

Research limitations/implications
The new fuel-balanced formation keeping reference trajectories planning method is valid for formation flying mission whose member satellite is in circular or near circular orbit in J2 perturbed orbit environment.

Practical implications
The new fuel-balanced formation keeping reference trajectories planning method can be used to solve formation flying keeping problem, which involves multiple satellites in the formation.

Originality/value
The fuel-balanced reference trajectories planning problem is reformulated as a geometrical problem, which can provide insightful way to understand the dynamic nature of the fuel-balanced reference trajectories planning issue.
Designing flow chart for aircraft type training in aviation training process management
Authors: Yazgan Ebru , Kucuk Yilmaz Ayşe 
Published: October 2018

Purpose
Training management has critical in developing of civil aviation sector in Turkey. It requires using serious corporate sources for this reason is directly topic of aviation management and strategy.it is also about process management. According to this view, this paper aims to become a guidance to management training for maintenance or training organisations in the aviation sector wishing to obtain the authorisation, given national civil aviation authority (Directorate General of Civil Aviation), of providing type rating trainings that cover the types of aeroplanes including Beech 90 Series, Socata TB Series and Cessna/Reims-Cessna 172/F172 Series.

Design/methodology/approach
Aviation training organisations must be managed according to aviation law and regulations. It includes several approval processes about training content. Managers must be organising their resources, and they should get well timely decision made in optimum time. In this study, a flowchart, that is the procedure to follow in accordance with the related aviation regulations, has been developed while taking the opinion of experts and using experience gained from the approval process for the type trainings. This flowchart may gain time to managers in their approval process. It may use as guidance to create optimum flow in their process management.

Findings
The purpose of flowchart developed is to shorten the authorisation processes of the relative institutions by eliminating the challenges caused by the excess and complexity of national or international regulations related to the of authorisation of aircraft type rating training.

Originality/value
It is important to gain authority. But more important is to manage the authority as sustainable way in aviation training. Loosing authority in specific field may effect on both corporate reputation and doing aviation business. Anadolu University manages related risk via scientific project during using their authorisation. The results developed as a result of the expert opinions and the experience gained during the aircraft type training authorisation process will contribute to the literature. When considered from this point of view, it is expected for this study to fill an important gap in the literature. It is highly important for the aviation sector in terms of evaluating and interpreting academically such a process for practice, and also raising awareness or providing awareness for similar practices. It may also useful for process management.
Ensuring a personalised approach
Authors: Sanderson James , Hawdon Nicola 
Published: October 2018

Purpose
The purpose of this paper is to outline how personal health budgets and a universal, integrated model of support, can positively transform the way in which individuals with a learning disability experience their health and support needs.

Design/methodology/approach
The review recognises that Integrated Personal Commissioning, as a policy approach, provides the framework to offer personalised care, and enables people to live an independent, happy, healthy and meaningful life.

Findings
Evidence suggests that a personalised and integrated approach to both health and social care not only offers better outcomes on all levels for the individual, but also benefits the system as a whole.

Originality/value
The study reveals that a personalised care leads to people to have choices and control over decisions that affect in better health and wellbeing outcomes for people.
Mental health services for people with intellectual disability in the United Kingdom
Authors: Perera Bhathika , Courtenay Ken 
Published: October 2018

Purpose
Services for people with intellectual disabilities in the UK have evolved over the years from hospital-based care to more community provision. There are multiple reasons for these changes, however, often it was due to changes in social policy or following a scandal in provision. The paper aims to discuss these issues.

Design/methodology/approach
Providing services to meet the health and social care needs of people with intellectual disabilities is well-established in the four countries of the UK with support from legislation. There are often specialist mental health and social care teams. Dedicated professionals work with people with intellectual disabilities who experience mental health problems with a focus on support in the community. A range of services for children and adults and for offenders exist across the UK that often vary in composition and structure.

Findings
The challenges in providing mental health services for children and adults with intellectual disabilities in the future include recruitment and training of the workforce with the remit of enhancing community support and reduced in-patient care.

Practical implications
This paper helps the reader to understand how ID mental health services are organised in the UK.

Originality/value
This paper gives a summary of the ID mental health services in the UK. Even though there are various papers looking at different aspects of mental health services for people with ID in the UK, this paper brings all that information together to help reader get a better understanding of the mental health services for people with ID.
Understanding the accelerator from resources-based perspective
Authors: Uhm Chul Hyun , Sung Chang Soo , Park Joo Yeon 
Published: October 2018

Purpose
This study aims to explore Accelerators and their practices in sustaining start-ups within their innovative programs for these companies based on the resource-based perspective. Moreover, with an ever-increasing demand for Accelerators amongst start-up companies, this study also demonstrates the importance of Accelerators, as it pertains to new venture creation.

Design/methodology/approach
This research uses an exploratory case study approach to examine a comparative view of leading Accelerator companies in the USA and Korea based on resource support.

Findings
The results of this study show that there are a number of differences between Accelerators of the two countries in terms of the resources they support for early-stage start-ups. The findings also show some similarities. However, in Korea, the Accelerator landscape is limited, where mentorship, resources and investments are not readily accessible, resulting in low success rates for Korean start-up companies. These limitations have had a negative trickle-down effect when providing entrepreneurs with strong access to resources and investors, which highly affects the success rates of early-stage start-ups.

Practical implications
In terms of the resource-based theory, this study contributes to the growth of early start-ups by emphasizing the role of the accelerator and suggesting the extent and impact that entrepreneurs have access to resources and investors.

Originality/value
With significant growth in start-ups around the world, the necessity for start-up funding and mentorship has increased drastically. Start-up companies need various types of assets, systems, knowledge and information to achieve their goals. In Accelerators, start-ups receive all the aforementioned resources while also improving their entrepreneurial skills. Start-up companies have many options in seeking investors who support both tangible and intangible resources to boost growth. While there is a wealth of information on traditional funding methods, there are few studies that shed light on the role of Accelerators from the resource-based point of view.