bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum
Authors: Bevan-Jones W Richard , Cope Thomas E , Jones P Simon , Passamonti Luca , Hong Young T , Fryer Tim D , Arnold Robert , Coles Jonathan P , Aigbirhio Franklin I , Larner Andrew J , Patterson Karalyn , O’Brien John T , Rowe James B 
Published: January 2019

AbstractThe clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation may be common across the disease spectrum. We investigated how neuroinflammation relates to the aggregation of Tau and TDP-43 in frontotemporal dementia, and to the heterogeneity of clinical disease. We used positron emission tomographyin vivowith (a) [11C]PK-11195, a marker of activated microglia and a proxy index of neuroinflammation, and (b) [18F]AV-1451, a radioligand with increased binding to pathologically affected regions in tauopathies and diseases associated with TDP-43 protein aggregation, and which is used as a surrogate marker of non-β-amyloid protein aggregation. We assessed 31 patients with frontotemporal dementia (10 with behavioural variant frontotemporal dementia, 11 with the semantic variant of primary progressive aphasia and 10 with the non-fluent variant of primary progressive aphasia), 28 of whom underwent both [18F]AV-1451 and [11C]PK-11195 PET, and matched controls (14 for [18F]AV-1451 and 15 for [11C]PK-11195). We used univariate region-of-interest analyses, and multivariate analysis of the distribution of binding that explicitly control for individual differences in ligand affinity for TDP-43 and different Tau isoforms. We found differences between patients and controls in frontotemporal regions for both neuroinflammation and protein aggregation, and a strong positive correlation between these two processes in all disease groups. Despite this regional co-localisation, the multivariate distribution of [11C]PK-11195 binding related better to clinical heterogeneity than did the distribution of [18F]AV-1451: distinct spatial modes of neuroinflammation were associated with different frontotemporal dementia syndromes and supported accurate group classification of participants. Thesein vivofindings indicate a close association between neuroinflammation and protein aggregation in frontotemporal dementia. The inflammatory component may be important in shaping the clinical and neuropathological patterns of the diverse clinical syndromes of frontotemporal dementia.
A dynamic control of human telomerase holoenzyme
Authors: Sayed Mohammed E. , Cheng Ao , Yadav Gaya , Ludlow Andrew T. , Shay Jerry W. , Wright Woodring E. , Jiang Qiu-Xing 
Published: January 2019

ABSTRACTHuman telomerase functions in maintaining genome stability by adding telomeric repeats to the termini of linear chromosomes. Past studies have revealed profound insights into telomerase functions. However, low abundance of functional telomerase and difficulty in quantifying its activity leave partially characterized its thermodynamic and kinetic properties. Using a newly developed method to count individual extension products, we demonstrate that human telomerase holoenzymes contain fast- and slow-acting catalytic sites. Surprisingly, both active sites become inactive after two consecutive rounds of catalysis. The fast active sites turn off ~40-fold quicker than the slow ones and exhibit higher affinity to substrates. In dimeric enzymes, the two sites work in tandem with the faster site functioning before the slower one. In monomeric enzymes, the active sites also perform single-run catalysis. Interestingly, the inactive enzymes can be reactivated by intracellular telomerase-activating factors (iTAFs) available in multiple cell types. Together, the single-run catalysis and the iTAF-triggered reactivation serve as a novel control circuit to ensure that the telomerase holoenzymes are dynamically controlled to match their number of active sites with the number of telomeres they extend. Such exquisite kinetic control of telomerase activity is expected to play important roles in cell division and ageing.
Local inhibition of PRC2 activity by H3.3K27M drives DNA replication defects through misregulation of the JNK pathway
Authors: Delaney Kamila , Strobino Maude , Wenda Joanna M. , Pankowski Andrzej , Steiner Florian A. 
Published: January 2019

AbstractSubstitution of lysine 27 with methionine in histone H3.3 is a recently discovered driver mutation of pediatric high-grade gliomas. Mutant tumor cells show decreased levels and altered distribution of H3K27me3. How these chromatin changes are established genome-wide and lead to tumorigenesis only in specific tissues remains unclear. Here we show that H3.3K27M-mediated alterations in H3K27me3 distribution result in ectopic DNA replication and cell cycle progression of germ cells inCaenorhabditis elegans. By genetically inducing changes in the H3.3 distribution, we demonstrate that both H3.3K27M oncohistone incorporation and pre-existing H3K27me3 act locally and antagonistically on Polycomb Repressive Complex 2 (PRC2) in a concentration-dependent manner, explaining the observed H3K27me3 distribution in mutant cells. The altered heterochromatin patterns lead to extensive misregulation of gene expression. Through unbiased genetic screening, we found that inhibiting JNK pathway components, which are overexpressed in H3.3K27M cells, suppresses the ectopic DNA replication and cell cycle progression without rescuing the altered H3K27me3 distribution. Moreover, we show that JNK inhibition suppresses the replicative fate in human tumor-derived H3.3K27M cells, thus establishingC. elegansas a powerful model for the identification of potential drug targets for treatment of H3.3K27M tumors.
Regionally Diffuse Muscle Pain-Hypersensitivity in Humans During Acute Muscle Pain
Authors: Dunn J. S. , Nagi S. S. , Mahns D. A. 
Published: January 2019

AbstractBackgroundWe have previously shown that an intramuscular infusion of 5% hypertonic saline (HS) produces a painful response to normally innocuous stimuli applied to overlying and adjacent skin regions. In the current study, we explored whether a similar interaction could be observed between adjacent, contralateral and remote muscles. Indeed, widespread muscle pain-hypersensitivity is a hallmark of chronic pain conditions such as fibromyalgia.Methods5% HS was infused into the flexor carpi ulnaris (FCU) muscle to develop a stable baseline pain (n=30). In separate experiments, each of the three test locations (n=10 per site), the adjacent abductor digiti minimi (ADM), contralateral FCU and contralateral tibialis anterior (TA) (part 1-3, respectively), 50μL of 0.9% normal saline (NS) was infused (in triplicate) prior to, during and following HS-induced muscle pain.ResultsUnder control conditions (no background pain), the infusion of NS was imperceptible by all subjects. In the presence of HS-induced background pain (FCU), in part 1 the NS co-infusion into ADM increased overall pain by 17%. This was replicated in the contralateral FCU (part 2) with a 12% pain increase, and in the TA (part 3) with a 15% pain increase in response to the NS co-infusions. Notably, over 80% of subjects perceived the NS-induced increase in pain at the HS-infusion location (FCU) rather than the NS-infusion location (adjacent, contralateral and remote).ConclusionsIntramuscular infusion of HS results in pain-hypersensitivity to sub-perceptual stimulation of muscle afferents in a somatotopically unrestricted manner, indicating the involvement of a central (likely supra-spinal) mechanism.SignificanceThis work provides evidence for a regionally diffuse type of pain hypersensitivity, manifesting as a painful response to normally sub-perceptual stimulation in the context of acute experimentally induced muscle pain. This phenomenon may provide parallels to clinically relevant painful conditions and neuropathies.
Enabling MHC-mismatched hematopoietic stem cell transplants and organ graft tolerance without chemotherapy or radiation
Authors: George Benson M. , Kao Kevin S. , Chen Angela , Le Alan C. , Chhabra Akanksha , Burnett Cassandra , Loh Kyle M. , Shizuru Judith A. , Weissman Irving L. 
Published: January 2019

SummaryHematopoietic stem cell (HSC) transplantation can replace diseased blood systems with a healthy one, thereby treating or curing genetic blood and immune disorders including autoimmune diseases and immunodeficiencies. However, toxic chemotherapy or radiation is necessary to ablate an animal’s existing blood system prior to HSC transplantation, leading to significant morbidity. To accomplish safer blood-system replacement we developed a combination of six monoclonal antibodies to safely and specifically deplete the HSCs, T cells and NK cells of immune-competent mice. Remarkably, immunologically-foreign (allogeneic) HSCs mismatched at half or all the MHC genes could engraft these antibody-treated mice, generating donor blood systems that stably co-existed with host blood cells. These chimeric immune systems were immunologically tolerant to heart tissue from the HSC donor, providing a safe platform for HSC transplantation as a means to solid organ transplantation. The ability to transplant MHC-mismatched HSCs without chemotherapy or radiation has significant ramifications for regenerative medicine.
Accelerated loss of hypoxia response in zebrafish with familial Alzheimer’s disease-like mutation of Presenilin 1
Authors: Newman Morgan , Nik Hani Moussavi , Sutherland Greg T. , Hin Nhi , Kim Woojin S. , Halliday Glenda M. , Jayadev Suman , Smith Carole , Laird Angela , Lucas Caitlin , Kittipassorn Thaksaon , Peet Dan J. , Lardelli Michael 
Published: January 2019

AbstractAgeing is the major risk factor for Alzheimer’s disease (AD), a condition involving brain hypoxia. The majority of early onset familial AD (EOfAD) cases involve dominant mutations in the gene PSEN1. PSEN1 null mutations do not cause EOfAD. We exploited putative hypomorphic and EOfAD-like mutations in the zebrafish psen1 gene to explore the effects of age and genotype on brain responses to acute hypoxia. Both mutations accelerate age-dependent changes in hypoxia-sensitive gene expression supporting that ageing is necessary, but insufficient, for AD occurrence. Curiously, the responses to acute hypoxia become inverted in extremely aged fish. This is associated with an apparent inability to upregulate glycolysis. Wild type PSEN1 allele expression is reduced in post-mortem brains of human EOfAD mutation carriers (and extremely aged fish), possibly contributing to EOfAD pathogenesis. We also observed that age-dependent loss of HIF1 stabilisation under hypoxia is a phenomenon conserved across vertebrate classes.
Caveolae and scaffold detection from single molecule localization microscopy data using deep learning
Authors: Khater Ismail M. , Aroca-Ouellette Stephane T. , Meng Fanrui , Nabi Ivan Robert , Hamarneh Ghassan 
Published: January 2019

AbstractCaveolae are plasma membrane invaginations whose formation requires caveolin-1 (Cav1), the adaptor protein polymerase I, and the transcript release factor (PTRF or CAVIN1). Caveolae have an important role in cell functioning, signaling, and disease. In the absence of CAVIN1/PTRF, Cav1 forms non-caveolar membrane domains called scaffolds. In this work, we train machine learning models to automatically distinguish between caveolae and scaffolds from single molecule localization microscopy (SMLM) data. We apply machine learning algorithms to discriminate biological structures from SMLM data. Our work is the first that is leveraging machine learning approaches (including deep learning models) to automatically identifying biological structures from SMLM data. In particular, we develop and compare three binary classification methods to identify whether or not a given 3D cluster of Cav1 proteins is a caveolae. The first uses a random forest classifier applied to 28 hand-crafted/designed features, the second uses a convolutional neural net (CNN) applied to a projection of the point clouds onto three planes, and the third uses a PointNet model, a recent development that can directly take point clouds as its input. We validate our methods on a dataset of super-resolution microscopy images of PC3 prostate cancer cells labeled for Cav1. Specifically, we have images from two cell populations: 10 PC3 and 10 CAVIN1/PTRF-transfected PC3 cells (PC3-PTRF cells) that form caveolae. We obtained a balanced set of 1714 different cellular structures. Our results show that both the random forest on hand-designed features and the deep learning approach achieve high accuracy in distinguishing the intrinsic features of the caveolae and non-caveolae biological structures. More specifically, both random forest and deep CNN classifiers achieve classification accuracy reaching 94% on our test set, while the PointNet model only reached 83% accuracy. We also discuss the pros and cons of the different approaches.
The response of genes and pathways of immunological system induced by irradiation
Authors: Ribeiro F. M. , Silveira D. A. , Simão E. M. , Mattos V. L. D. , Góes E. G. 
Published: January 2019

AbstractCurrent studies have shown that ionizing radiation (IR) could increase the efficiency of radiation therapy by the stimulation of the immune system. This occurs in low-dose radiation as well as doses within hypofractionated range usually used in radiotherapy. However, the elucidation of the mechanisms of immunogenic modulation reported at these doses remain an issue. In this study, we analyzed transcriptome data available in Gene Expression Omnibus (GEO) database related to B cells isolated from whole blood of 95 donors and then irradiated with 10 Gy. The aim of this study is to investigate the regulation of genes and pathways of the immune system considering the B7-CD28/CTLA4 superfamily, CD40-CD40LG molecules, and cytokines expressed by B cells irradiated. The connection between genes and pathways is established by the Reactome database. Relative activity and diversity of pathways were calculated to determine the modulation of the immune system response to irradiation. Analysis of variance (ANOVA) with repeated measures and Bonferroni’s method were used to determine differentially expressed genes. It was observed that IR up-modulates the response of pathways and genes considered in this study, which indicates that 10 Gy can enhance antitumor immune responses.
Triangular mesh generation on free-form surfaces based on bubble dynamics simulation
Authors: Wang Qisheng , Gao Boqing , Wu Hui 
Published: January 2019

Purpose
Modern CAD systems facilitate the creation of any surface geometry imaginable, and complex surfaces for free-form grid shells are often represented by a set of Non-Uniform Rational B-Splines surface patches. But it remains an intractable issue how to generate high-quality grids on complex surfaces efficiently. To solve this issue, an automatic triangular mesh generation method is presented, based on bubble dynamics simulation and a modified Delaunay method.

Design/methodology/approach
A moderate amount of points are first distributed on a given surface. Next, by regarding the points as elastic bubbles with the same size and introducing the forces acting on bubbles, the motion control equations of bubbles are established. The equilibrium state of the bubble system is found by Verlet algorithm. Then, the Voronoi diagram on the surface is obtained by calculating the intersection between the surface and the three-dimensional (3D) Voronoi diagram of the centers of bubbles. Finally, a triangular mesh, Delaunay triangulation on the surface, is determined based on the dual change of the Voronoi diagram.

Findings
This method generates meshes on the surface directly, unlike mapping-based methods, avoiding the mapping distortion. Examples are given to demonstrate the successful execution of this method. The result also illustrates that this method is applicable to various surfaces in high automation level and resultant meshes are highly uniform and well-shaped.

Originality/value
Thus, this method provides the convenience for the geometry design of complex free-form grid structure.
For diversity scholars who have considered activism when scholarship isn’t enough!
Authors: Holmes IV Oscar 
Published: January 2019

Purpose
The paper is the abridged text of the author’s opening keynote address given on June 28, 2017 at the 10th Annual Equality Diversity Inclusion Conference hosted at Brunel University (London, UK). The conference theme was Borders. The paper aims to discuss this issue.

Design/methodology/approach
The address was given orally accompanied with slides that included pictures and quotes of referenced authors and works, websites, memes and various civil rights events. The address interwove personal experiences, published research, social movement strategies and current events and social issues. A brief question and answer period followed the address.

Findings
The address made the case that while scholarship is important, diversity scholars need to do more than publish scholarship but also engage in activism. In fact, the author argued that history has informed us that scholarship has never been enough to produce significant civil rights advancements.

Originality/value
Toward this end, the author provides three action steps that diversity scholars can take to engage in activism that produces results: translate research for the general public; partner with activist groups, and call out respectability politics and false equivalencies.
Diverse perspectives on inclusion
Authors: Singletary Walker Sarah , Ruggs Enrica N. , Botsford Morgan Whitney , W. DeGrassi Sandra 
Published: January 2019

PurposeThe purpose of this paper is to examine the extent to which racioethnicity influences perceptions of inclusion (i.e. information sharing, collective efficacy, satisfaction and relationship conflict) when working in racially heterogeneous groups.Design/methodology/approachIndividuals were placed in groups in order to participate in ethical-decision making tasks.FindingsResults reveal that individuals representing varied racioethnic groups are in general satisfied working in racially heterogeneous groups. However, reports of relationship conflict and information sharing varied as a function of racioethnicity.Originality/valueThe authors discuss possible rationales for differences in how racioethnic groups perceive and experience group processes over time as well as practical implications for social psychology and diversity in teams.
Changes in higher education teachers’ perceptions of curriculum
Authors: Nguyen Thi Van Su , Laws Kevin 
Published: January 2019

Purpose
The purpose of this paper is to examine the degree to which a compulsory induction program for Vietnamese higher education teachers influences participants’ perceptions of curriculum and course design.

Design/methodology/approach
This case study uses a qualitative, interpretive approach to data collection. Semi-structured interviews were conducted with 15 program participants before they started the program and immediately after they completed the program. Five program presenters also were interviewed and documents related to the program were analyzed.

Findings
The findings reflect the influence of Biggs’ (2003) constructive alignment approach on participants’ curriculum perceptions, although this approach was not explicitly stated in the program guidelines. Upon the completion of the program, participants realized the importance of their voices in curriculum construction and course design, which was absent from the pre-program findings. However, students’ agency in co-constructing the curriculum and the “being” of curriculum were not perceived.

Research limitations/implications
The paper adds to the growing literature on induction programs and their relation to curriculum perceptions.

Practical implications
The paper provides examples of the changes in participants’ perceptions of curriculum and accentuates, what is neglected in the construction of curriculum.

Originality/value
The paper invites reflection on the design and implementation of curriculum from academic developers, education practitioners and researchers in similar contexts.
Validating a scale for measuring teachers’ expectations about generic competences in higher education
Authors: Serrano Rocio , Macias Washington , Rodriguez Katia , Amor María Isabel 
Published: January 2019

Purpose
The purpose of this paper is to develop and validate a questionnaire to assess the expectations of university teachers about the importance of generic competences in Higher Education Institutions of Ecuador (E-DUC, acronym in Spanish), based on the competences typology from the Tuning Latin America Project.

Design/methodology/approach
A questionnaire with Likert scales was administered to 458 university teachers from seven universities in Ecuador. Exploratory and confirmatory analyzes have been carried out to validate the theoretical model.

Findings
After the validation process, four groups of generic competences were confirmed and the measurement model showed high levels of reliability, as well as content and construct validity.

Research limitations/implications
Since tuning project has an international scope, the research could be replicated in other Latin American countries for comparability purposes regarding teachers’ perceived importance of generic competences in teaching activity. In addition, further research can relate teachers’ expectations with teaching performance and other constructs, based on a broad theoretical framework.

Practical implications
These technical characteristics allow the use of E-DUC as an instrument to measure the expectations of teachers on the general competences that are worked on in higher education in Ecuador. Data about these perceptions are useful for the design of teachers’ training programs, curriculum reforms and other higher education policies.

Originality/value
It is the first research carried out in Ecuador and Latin America in order to validate a scale for measuring the expectations of teachers about the importance of the generic competences proposed in the Tuning Latin America Project.
Available study time and undergraduate student exam performance
Authors: Sansani Shahar , Rahamim Afik 
Published: January 2019

PurposeThe purpose of this paper is to determine whether the number of lecture-free and exam-free days before a final exam affects students’ scores overall and by gender.Design/methodology/approachThe paper exploits scheduling differences in final exams between two groups of students who take identical final exams. The treatment group and the control group have similar exam spacing for one “early exam,” but the treatment group has four additional days between exams for another “later exam,” allowing for a difference-in-differences analysis. A survey of contemporary students is conducted to complement the empirical results.FindingsOverall, there are no statistically significant differences in the grades on the exams between the control group and the group that had four more study days. When examined by gender, the point estimate on females is large in magnitude but statistically insignificant at conventional levels (p-value=0.087).Research limitations/implicationsThe study uses data on undergraduate students studying economics in Israel. More research in other contexts is needed to determine the robustness of the findings.Originality/valueThis is the first paper to study the effect of the number of days students have between final exams on student final exam scores. The results can aid in determining optimal final exam schedules.