bluuebunny/crossref_metadata_2025 huggingface dataset:
The DNA Methylome of Inflammatory Bowel Disease (IBD) reflects intrinsic and extrinsic factors in intestinal epithelial cells
Authors: Agliata Iolanda , Fernandez-Jimenez Nora , Goldsmith Chloe , Marie Julien C. , Bilbao Jose Ramon , Dante Robert , Hernandez-Vargas Hector
Published: March 2019

Abnormal DNA methylation has been described in human inflammatory conditions of the gastrointestinal tract, such as inflammatory bowel disease (IBD). As other complex diseases, IBD results from the balance between genetic predisposition and environmental exposures. As such, DNA methylation may be placed as an effector of both, genetic susceptibility variants and/or environmental signals such as cytokine exposure. We attempted to discern between these two non-excluding possibilities by performing a meta-analysis of DNA methylation data in intestinal epithelial cells of IBD and control samples. We identified abnormal DNA methylation at different levels: deviation from mean methylation signals at site and region levels, and differential variability. A fraction of such changes are associated with genetic polymorphisms linked to IBD susceptibility. In addition, by comparing with another intestinal inflammatory condition (i.e. celiac disease) we propose that aberrant DNA methylation can also be the result of unspecific processes such as chronic inflammation. Our characterization suggests that IBD methylomes combine intrinsic and extrinsic responses in intestinal epithelial cells, and could point to knowledge-based biomarkers of IBD detection and progression.

Graphical Abstract

Conceptual representation of the study. Using a meta-analysis strategy we identified differentially methylated positions or regions (DMP/DMR) in IBD. Our assumption is that gene expression changes (IBD phenotype) take place downstream of DNA methylation. In turn, abnormal DNA methylation can be explained by a direct effect of inflammatory cytokines (“signaling”) and/or the result of a genetic polymorphism (SNP). SNP-DMP associations are called methylation quantitative trait loci (mQTL).
Zebrafish (Danio rerio) behavioral laterality predicts increased short-term avoidance memory but not stress-reactivity responses
Authors: Fontana Barbara D. , Cleal Madeleine , Clay James M. , Parker Matthew O.
Published: March 2019

Once considered a uniquely human attribute, behavioral laterality has proven to be ubiquitous among non□human animals, being frequently associated with different neurophenotypes in rodents and fish species. Zebrafish (Danio rerio) are a versatile vertebrate model system that has been widely used in translational neuropsychiatric research due their highly conserved genetic homology, well characterized physiological and extensive behavioral repertoire. Although the spontaneous left- and right-bias responses and associated behavioral domains (e.g. stress reactivity, aggression and learning) have previously been observed in other teleost species, no information regarding how spontaneous motor left-right bias responses of zebrafish predicts other behavioral domains has been described. Thus, we aimed to investigate the existence and incidence of natural left-right bias of adult zebrafish in the Y-maze test and explore any relationship of biasedness on the performance of different behavioral domains. This included learning about threat-cues in the fear conditioning test and locomotion and anxiety-related behavior in the novel tank diving test. In conclusion, we showed for the first time that zebrafish exhibit a natural manifestation of motor behavioral lateralization which can influence aversive learning responses. Although laterality did not change locomotion or anxiety-related behaviors, we found that biased animals had an altered exploration pattern in the Y-maze, making them easily discernable from their unbiased counterparts, and increased learning associated to fear cues.
A stimuli-responsive, pentapeptide, nanofiber hydrogel for tissue engineering
Authors: Tang James D. , Mura Cameron , Lampe Kyle J.
Published: March 2019

Short peptides are uniquely versatile building blocks for self-assembly. Supramolecular peptide assemblies can be used to construct functional hydrogel biomaterials—an attractive approach for neural tissue engineering. Here, we report a new class of short, five-residue peptides that form hydrogels with nanofiber structures. Using rheology and spectroscopy, we describe how sequence variations, pH, and peptide concentration alter the mechanical properties of our pentapeptide hydrogels. We find that this class of seven unmodified peptides forms robust hydrogels from 0.2–20 kPa at low weight percent (less than 3 wt. %) in cell culture media, and undergoes shear-thinning and rapid self-healing. The peptides self-assemble into long fibrils with sequence-dependent fibrillar morphologies. These fibrils exhibit a unique twisted ribbon shape, as visualized by TEM and Cryo-EM imaging, with diameters in the low tens of nanometers and periodicities similar to amyloid fibrils. Experimental gelation behavior corroborates our molecular dynamics simulations, which demonstrate peptide assembly behavior, an increase in β-sheet content, and patterns of variation in solvent accessibility. Our Rapidly Assembling Pentapeptides for Injectable Delivery (RAPID) hydrogels are syringe-injectable and support cytocompatible encapsulation of oligodendrocyte progenitor cells (OPCs), as well as their proliferation and three-dimensional process extension. Furthermore, RAPID gels protect OPCs from mechanical membrane disruption and acute loss of viability when ejected from a syringe needle, highlighting the protective capability of the hydrogel as potential cell carriers for trans-plantation therapies. The tunable mechanical and structural properties of these supramolecular assemblies are shown to be permissive to cell expansion and remodeling, making this hydrogel system suitable as an injectable material for cell delivery and tissue engineering applications.
Developmental Recovery of Impaired Multisensory Processing in Autism and the Cost of Switching Sensory Modality
Authors: Crosse Michael J. , Foxe John J. , Molholm Sophie
Published: March 2019

Children with autism spectrum disorder (ASD) are often impaired in their ability to cope with and process multisensory information, which may contribute to some of the social and communicative deficits that are prevalent in this population. Amelioration of such deficits in adolescence has been observed for ecologically-relevant stimuli such as speech. However, it is not yet known if this recovery generalizes to the processing of nonsocial stimuli such as more basic beeps and flashes, typically used in cognitive neuroscience research. We hypothesize that engagement of different neural processes and lack of environmental exposure to such artificial stimuli leads to protracted developmental trajectories in both neurotypical (NT) individuals and individuals with ASD, thus delaying the age at which we observe this “catch up”. Here, we test this hypothesis using a bisensory detection task by measuring human response times to randomly presented auditory, visual and audiovisual stimuli. By measuring the behavioral gain afforded by an audiovisual signal, we show that the multisensory deficit previously reported in children with ASD recovers in adulthood by the mid-twenties. In addition, we examine the effects of switching between sensory modalities and show that teenagers with ASD incur less of a behavioral cost than their NT peers. Computational modelling reveals that multisensory information interacts according to different rules in children and adults, and that sensory evidence is weighted differently too. In ASD, weighting of sensory information and allocation of attention during multisensory processing differs to that of NT individuals. Based on our findings, we propose a theoretical framework of multisensory development in NT and ASD individuals.
Structural basis of the differential binding of engineered knottins 2.5F and 2.5D to integrins αVβ3 and α5β1
Authors: Van Agthoven Johannes F. , Shams Hengameh , Cochran Frank V. , Alonso José L. , Kintzing James R. , Garakani Kiavash , Xiong Jian-Ping , Mofrad Mohammad R. K. , Cochran Jennifer R. , Arnaout M. Amin
Published: March 2019

Integrins αVβ3 and α5β1 play critical roles in tumor survival, invasion, metastasis, and angiogenesis and are validated targets for cancer therapy and molecular imaging. Increasing evidence suggests that targeting both integrins simultaneously with antagonists is more effective in cancer therapy because of concerns about resistance and paradoxical promotion of tumor growth with use of agents highly selective for a single integrin. Engineered Arg-Gly-Asp (RGD)-containing 3.5 kDa cysteine-knot proteins (knottins 2.5F and 2.5D) are attractive drug candidates due to their exceptional structural stability and high affinity binding to certain integrins. 2.5F binds both αVβ3 and α5β1, whereas 2.5D is αVβ3-selective. To elucidate the structural basis of integrin selection, we determined the structures of 2.5F and 2.5D both as apo-proteins and in complex with αVβ3. These data, combined with MD simulations and mutational studies, revealed a critical role of two αVβ3-specific residues in the vicinity of the metal ion dependent adhesion site (MIDAS) in promoting an αVβ3-induced fit of 2.5D. In contrast, conformational selection accounted for the specificity of 2.5F to both integrins. These data provide new insights into the structural basis of integrin-ligand binding specificity, and could help in development of integrin-targeted therapeutics.
Body-map proto-organization in newborn macaques
Authors: Arcaro Michael J. , Schade Peter F. , Livingstone Margaret S.
Published: March 2019

Topographic sensory maps are a prominent feature of the adult primate brain. Here, we asked whether topographic representations of the environment are fundamental to early development. Using fMRI, we find that the newborn somato-motor system, spanning frontoparietal cortex and subcortex, comprises multiple topographic body representations. The organization of these large-scale body maps was indistinguishable from those in adults and already exhibited features stereotypical of adult maps. Finer-scale differentiation of individual fingers increased over the first two years, suggesting that topographic representations are refined during early development. Last, we found that somato-motor representations were unchanged in two visually impaired monkeys who relied entirely on touch for interacting with their environment, demonstrating that massive shifts in early sensory experience in an otherwise anatomically intact brain are not sufficient for driving cross-modal plasticity. We propose that a topographic scaffolding is present at birth that both directs and constrains experience-driven modifications throughout sensory systems.
TGF-β family ligands exhibit distinct signaling dynamics that are driven by receptor localization
Authors: Miller Daniel S. J. , Schmierer Bernhard , Hill Caroline S.
Published: March 2019

Growth factor-induced signal transduction pathways are tightly regulated at multiple points intracellularly, but how cells monitor levels of extracellular ligand and translate this information into appropriate downstream responses remains unclear. Understanding signaling dynamics is thus a key challenge in determining how cells respond to external cues. Here, we demonstrate that different TGF-β family ligands, namely Activin A and BMP4, signal with distinct dynamics, which differ profoundly from those of TGF-β itself. The distinct signaling dynamics are driven by differences in the localization and internalization of receptors for each ligand, which in turn determine the capability of cells to monitor levels of extracellular ligand. Using mathematical modeling, we demonstrate that the distinct receptor behaviors and signaling dynamics observed may be primarily driven by differences in ligand-receptor affinity. Furthermore, our results provide a clear rationale for the different mechanisms of pathway regulation foundin vivofor each of these growth factors.
Replay as wavefronts and theta sequences as bump oscillations in a grid cell attractor network
Authors: Kang Louis , DeWeese Michael R.
Published: March 2019

Grid cells fire in sequences that represent rapid trajectories in space. During locomotion, theta sequences encode sweeps in position starting slightly behind the animal and ending ahead of it. During quiescence and slow wave sleep, bouts of synchronized activity represent long trajectories called replays, which are well-established in place cells and have been recently reported in grid cells. Theta sequences and replay are hypothesized to facilitate many cognitive functions, but their underlying mechanisms are unknown. A leading mechanism proposed for grid cell formation is the continuous attractor network. We demonstrate that this established architecture naturally produces theta sequences and replay as distinct consequences of modulating external input. Driving inhibitory interneurons at the theta frequency causes attractor bumps to oscillate in speed and size, which gives rise to theta sequences and phase precession, respectively. Decreasing input drive to all neurons produces traveling wavefronts of activity that are decoded as replays.
Supercharged Assembly: A Broad-Spectrum Mechanism of Action for Drugs that Undermine Controlled HIV-1 Viral Capsid Formation
Authors: Pak Alexander J. , Grime John M. A. , Yu Alvin , Voth Gregory A.
Published: March 2019

The early and late stages of human immunodeficiency virus (HIV) replication are orchestrated by the capsid (CA) protein, which self-assembles into a conical protein shell during viral maturation. Small molecule drugs known as capsid inhibitors (CIs) impede the highly-regulated activity of CA. Intriguingly, a few CIs, such as PF-3450074 (PF74) and GS-CA1, exhibit effects at multiple stages of the viral lifecycle at effective concentrations in the pM to nM regimes, while the majority of CIs target a single stage of the viral lifecycle and are effective at nM to µM concentrations. In this work, we use coarse-grained (CG) molecular dynamics simulations to elucidate the molecular mechanisms that enable CIs to have such curious broad-spectrum activity. Our quantitatively analyzed findings show that CIs can have a profound impact on the hierarchical self-assembly of CA by perturbing the population of small CA oligomers. The self-assembly process is accelerated by the emergence of alternative assembly pathways that favor the rapid incorporation of CA pentamers, and leads to increased structural pleomorphism of mature capsids. Two relevant phenotypes are observed: (1) eccentric capsid formation that may fail to encase the viral genome and (2) rapid disassembly of the capsid, which express at late and early stages of infection, respectively. Finally, our study emphasizes the importance of adopting a dynamical perspective on inhibitory mechanisms and provides a basis for the design of future therapeutics that are effective at low stoichiometric ratios of drug to protein.
Avant-garde: An automated data-driven DIA data curation tool
Authors: Jacome Alvaro Sebastian Vaca , Peckner Ryan , Shulman Nicholas , Krug Karsten , DeRuff Katherine C. , Officer Adam , MacLean Brendan , MacCoss Michael J. , Carr Steven A. , Jaffe Jacob D.
Published: March 2019

Data-Independent Acquisition (DIA) is a technique that promises to comprehensively detect and quantify all peptides above an instrument’s limit of detection. Several software tools to analyze DIA data have been developed in recent years. However, several challenges still remain, like confidently identifying peptides, defining integration boundaries, dealing with interference for selected transitions, and scoring and filtering of peptide signals in order to control false discovery rates. In practice, a visual inspection of the signals is still required, which is impractical with large datasets. Avant-garde is a new tool to refine DIA (and PRM) by removing interfered transitions, adjusting integration boundaries and scoring peaks to control the FDR. Unlike other tools where MS runs are scored independently from each other, Avant-garde uses a novel data-driven scoring strategy. DIA signals are refined by learning from the data itself, using all measurements in all samples together to achieve the best optimization. We evaluated the performances of Avant-garde with a calibrated sample using spiked-in standards in a complex background, a phospho-enriched dataset (Abelin et al, 2016), and two complex hybrid proteome samples for benchmarking DIA software tools. The results clearly showed that Avant-garde is capable of improving the selectivity, accuracy, and reproducibility of the quantification results in very complex biological matrices. We have further shown that it can evaluate the suitability of a peak to be used for quantification reaching the same levels of selectivity, accuracy, and reproducibility obtained with manual validation.
Syndecan-1 facilitates breast cancer metastasis to the brain
Authors: Sayyad Megan R. , Puchalapalli Madhavi , Vergara Natasha G. , Wangensteen Sierra Mosticone , Moore Melvin , Mu Liang , Edwards Chevaunne , Anderson Aubree , Kall Stefanie , Sullivan Megan , Dozmorov Mikhail , Singh Jaime , Idowu Michael O. , Koblinski Jennifer E.
Published: March 2019

Purpose

Although survival rates for patients with localized breast cancer have increased, patients with metastatic breast cancer still have poor prognosis. Understanding key factors involved in promoting breast cancer metastasis is imperative for better treatments. In this study, we investigated the role of syndecan-1 (Sdc1) in breast cancer metastasis.

Methods

To assess the role of Sdc1 in breast cancer metastasis, we silenced Sdc1 expression in the triple-negative breast cancer human MDA-MB-231 cell line and overexpressed it in the mouse mammary carcinoma 4T1 cell line. Intracardiac injections were performed in an experimental mouse metastasis model using both cell lines. In vitro transwell blood-brain barrier (BBB) and brain section adhesion assays were utilized to specifically investigate how Sdc1 promotes brain metastasis. A cytokine array was performed to evaluate differences in the breast cancer cell secretome when Sdc1 was silenced.

Results

Silencing expression of Sdc1 in breast cancer cells significantly reduced metastasis to the brain. Conversely, overexpression of Sdc1 increased metastasis to the brain. We found that the reduction in brain metastases with Sdc1 knockdown was likely due to reduced breast cancer cell migration across the BBB and adhesion to the perivascular regions of the brain. However, there was no change in attachment to brain endothelial cells or astrocytes. Loss of Sdc1 also led to changes in breast cancer cell-secreted cytokines, which may influence the BBB.

Conclusions

Taken together, our study demonstrates a role for Sdc1 in promoting breast cancer metastasis to the brain. These findings suggest that Sdc1 supports breast cancer cell migration across the BBB through regulation of cytokines, which may modulate the BBB. Further elucidating this mechanism will allow for the development of therapeutic strategies to combat brain metastasis.
Trait convergence in photosynthetic nutrient‐use efficiency along a 2‐million year dune chronosequence in a global biodiversity hotspot
Authors: Guilherme Pereira Caio , Hayes Patrick E. , O’Sullivan Odhran S. , Weerasinghe Lasantha K. , Clode Peta L. , Atkin Owen K. , Lambers Hans
Published: March 2019

The Jurien Bay dune chronosequence in south‐western Australia’s biodiversity hotspot comprises sites differing in nutrient availability, with phosphorus (P) availability declining strongly with increasing soil age. We have explored the exceptionally high photosynthetic P‐use efficiency (PPUE) of Proteaceae in this region, triggering the question what the PPUE of co‐occurring species in other families might be along the Jurien Bay chronosequence.

We explored how traits associated with PPUE, photosynthetic nitrogen (N)‐use efficiency (PNUE) and leaf respiration might converge along the chronosequence, and whether Proteaceae and non‐Proteaceae species differ in leaf traits associated with nutrient use.

Seven to 10 species were sampled at three sites differing in nutrient availability (ranging from N‐ to P‐limited). Measurements of leaf light‐saturated photosynthesis and dark respiration were integrated with measurements of total N and P concentration in both mature and senesced leaves, and leaf mass per unit area (LMA).

Contrary to what is known for other chronosequences, rates of photosynthesis and respiration did not decrease with increasing soil age and LMA along the Jurien Bay chronosequence. However, they increased when expressed per unit leaf P. Both N and P were used much more efficiently for photosynthesis on nutrient‐poor sites, in both Proteaceae and non‐Proteaceae species. Proteaceae had the fastest rate of photosynthesis per unit leaf P, followed by species that preferentially allocate P to mesophyll cells, rather than epidermal cells.

Synthesis. Our results show that with declining soil P availability, photosynthetic P‐use efficiency of all investigated species from different families increased. Plants growing on the oldest, most nutrient‐impoverished soils exhibited similar rates of CO2 exchange as plants growing on more nutrient‐rich younger soils, and extraordinarily high photosynthetic P‐use efficiency. This indicates convergence in leaf traits related to photosynthetic nutrient use on severely P‐impoverished sites.
Genetic variation in the constitutive defensive metabolome and its inducibility are geographically structured and largely determined by demographic processes in maritime pine
Authors: López‐Goldar Xosé , Villari Caterina , Bonello Pierluigi , Borg‐Karlson Anna Karin , Grivet Delphine , Sampedro Luis , Zas Rafael
Published: March 2019

Interspecific phenotypic variation in plant secondary metabolites (PSM) is often explained by biotic and abiotic factors. However, patterns of variation within species do not clearly fit the theoretical predictions. Exploring how genetics, environment and demographic processes shape such variation among and within populations is crucial for understanding evolution of PSM, particularly in long‐lived plants such as forest trees.

Here, we quantified genetic variation in PSM among and within populations, and explored drivers of local adaptation by studying the role of climate as a source of population differentiation in PSM of maritime pine. Constitutive profile and concentrations of 63 PSM and their herbivory‐associated inducibility were determined in the bark of 130 clonally replicated genotypes with known familial structure from 10 populations covering the distribution range of the species. We compared neutral and quantitative population genetic differentiation of PSM (FST and QST). Also, we accounted for population genetic structure and kinship among individuals when exploring climate–trait relationships.

We found large population differentiation and additive genetic variation in constitutive PSM. Many PSM were inducible, although very low genetic variation was observed with respect to their inducibility. QST–FST comparisons suggest that differentiation of most diterpenes, monoterpenes, and phenolics can be explained by neutral demographic processes. Spatially heterogeneous selection across populations leading to local adaptation was only found for total constitutive sesquiterpenes and a few individual PSM. After accounting for population genetic structure, only the constitutive concentration of two sesquiterpenes showing signs of diversifying selection was predicted by climate, with decreasing concentrations along a growth‐prone climatic gradient.

Synthesis. Evolutionary patterns of plant secondary metabolites depended on their chemical nature, with neutral differentiation governing most plant secondary metabolites. Evidence of local adaptation was only found for total constitutive sesquiterpenes and a few individual plant secondary metabolites. The low genetic variation in the inducibility of plant secondary metabolites suggests a conserved model of defensive induction in this species. Since population differentiation linked to past demographic history could lead to false positives of adaptive differentiation signals, accounting for the genetic relatedness among populations is required to infer the environmental determinants of intraspecific genetic variation in putatively adaptive traits such as plant defences.
The Network of Law Reviews: Citation Cartels, Scientific Communities, and Journal Rankings
Authors: Perez Oren , Bar‐Ilan Judit , Cohen Reuven , Schreiber Nir
Published: March 2019

Research evaluation is increasingly influenced by quantitative data. We focus on the influential Web of Science Journal Citation Reports (JCR) ranking of law journals and critically assess its methodology. In particular, we consider the existence and impact of a tacit citation cartel between US law reviews. A study of 45 US student‐edited (SE) and 45 peer‐reviewed (PR) journals included in the category of Law in the JCR revealed that PR and SE journals are more inclined to cite members of their own class and that this phenomenon is more pronounced in SE generalist journals, reflecting tacit cartelistic behavior generated by deeply entrenched institutional practices. Because US SE journals produce more citations than PR journals, the fact that their citations are directed almost exclusively to SE journals elevates their scores and distorts the journals' ranking and can consequently undermine the flow and creation of ideas. We discuss policy measures that can counter the adverse effects of this situation.
Lessons learnt from anonymized review of cases of peripartum hysterectomy by international experts: A qualitative pilot study
Authors: Jónasdóttir Eva , Aabakke Anna J. M. , Colmorn Lotte B. , Jakobsson Maija , Äyräs Outi , Baghestan Elham , Svanvik Teresia , van den Akker Thomas , Bloemenkamp Kitty , van Roosmalen Jos , Krebs Lone , Knight Marian , Langhoff‐Roos Jens ,   on behalf of the Nordic Obstetric Surveillance System and the International Network of Obstetric Survey Systems
Published: March 2019

Severe obstetric complications are not extensively studied and individual cases are used too little and inappropriately in quality improvement activities, due to limited numbers and prioritization of quantitative research. Nordic and European experts performed a qualitative pilot study using anonymized cases of peripartum hysterectomy. It was feasible to anonymize narratives and we learned lessons in the form of themes for improved clinical care and future research. Therefore, we plan a Nordic anonymized review of the care of women who have undergone peripartum hysterectomy based on narratives. The qualitative outcomes of clinically relevant themes for quality improvement and research will add value to the quantitative analyses from the Nordic medical birth registries. In the longer term, we believe that qualitative audits should be an essential part of the process of continuing improvement in maternity care.
Teaching a history of “race” and anti‐racist action in an academic classroom
Authors: Hinton Mark , Ono‐George Meleisa
Published: March 2019

In this paper, we critically reflect on the challenges and successes in designing and co‐teaching an interdisciplinary module on the history of “race” and racism and its legacies within British communities today. We do so by returning to the two key questions that shaped the intended learning outcomes, namely: How can we employ an anti‐racist pedagogy within a university classroom that challenges teachers and students to reflect on “race” in their lives and within their communities? Is it possible for the history of “race” and racism to be taught in a way that is academically rigorous and transformative for the students and teachers? Through sharing how the authors addressed these questions, the paper contributes to longstanding, and more recent, efforts within the social sciences and humanities to address racism through learning, teaching and activism.
Effects of woody species encroachment and fire on vegetation and the soil seed bank in dry grasslands of Transylvania
Authors: Görzen Eugen , Borisova Karina , Fenesi Annamária , Ruprecht Eszter , Donath Tobias W.
Published: March 2019

Questions

(a) In which ways do woody species encroachment and fire affect vegetation and seed bank composition, structure and diversity in Transylvanian dry grassland; (b) do native and non‐native woody species differ with respect to their impact on grassland community composition and structure; (c) is burning useful to control woody species encroachment; and (d) can soil seed banks contribute to the restoration of grasslands in Transylvania?

Location

Transylvania, Romania.

Methods

We collected data on vegetation and seed bank composition in 4 m2plots in 16 shrub‐encroached grasslands and adjacent open grassland. Data were analyzed with regard to the impact of woody species encroachment (native vs non‐native) and fire on grassland vegetation and the seed bank usingNMDSandLMEmodels combined withANOVAand Tukey contrast tests.

Results

Encroachment was accompanied by a decrease in plant species diversity and altered microclimatic conditions. There was a lack of sufficient evidence for a difference in effect size between native and non‐native woody species on tested vegetation or seed bank parameters. While the effects of fire on vegetation were weak compared to encroachment, burning failed to reduce the cover of woody species sustainably. Grassland vegetation and the seed bank differed significantly in species composition and diversity, indicating a limited potential for restoration from the seed bank alone.

Conclusions

To halt secondary succession in Transylvanian grassland sustainably, we suggest the establishment of a post‐fire management regime including the cutting of woody species and/or re‐introduction of grazing and mowing. Grassland restoration from the seed bank may be supported by the introduction of species from surrounding intact grassland.
Why do women fast during breast cancer chemotherapy? A qualitative study of the patient experience
Authors: Mas Sébastien , Le Bonniec Alice , Cousson‐Gélie Florence
Published: March 2019

Background

Why do patients practice fasting? The effects of fasting before treatment with chemotherapy for cancer in humans are currently unknown. However, there is an apparent enthusiasm for fasting among cancer patients. This qualitative study provides data on the motivations to fast and the experience of fasting among a population of women with breast cancer.

Method

Sixteen semi‐structured interviews were conducted, and two researchers independently performed a thematic analysis. To ensure the internal validity of the study, patients had the possibility to rate their agreement with the study results through a satisfaction questionnaire.

Results

Six main themes were identified in this study: main reasons to fast, alternative authorities to the oncologist, adapting the fast to social and lifestyle constraints, fasting effects felt during chemotherapy, barriers and facilitators of fasting during chemotherapy, and seeking for a more integrative medicine. Patients’ primary motivation to fast was to lower the negative side effects of chemotherapy. Fasting was also reported as a coping strategy to give them a greater sense of control over their treatment and to reduce their anxiety.

Clinical implications

Results from the study suggest that, if discouraged from fasting, patients may turn to complementary health care practitioners for support. Medical professionals may thus not know of patients’ fasting practice. Health psychologists could play a key role fostering the dialogue between different health professionals and the patient. They could also help to meet patients’ needs during cancer treatment to reduce treatment anxiety.

Statement of contribution

What is already known on this subject?

Fasting diet in cancer treatment has become an important topic since Raffaghello et al. published their study on mice in 2008. While the (positive) effects of fasting in humans remain to be proven, there has been a significant enthusiasm for this practice among patients in the last few years. However, patients’ motivations to fast remain unclear to the scientific community and clinicians.

What does this study add?

This study is the first to investigate patients’ motivations to fast and patients’ experience of fasting in a cancer population.

Patients’ primary motivation to fast was to lower the side effects of chemotherapy.

Fasting acts as an active coping strategy that helps to reduce anxiety.

Unsupported patients may turn to complementary health care practitioners.
The effectiveness of short‐format refutational fact‐checks
Authors: Ecker Ullrich K. H. , O'Reilly Ziggy , Reid Jesse S. , Chang Ee Pin
Published: March 2019

Fact‐checking has become an important feature of the modern media landscape. However, it is unclear what the most effective format of fact‐checks is. Some have argued that simple retractions that repeat a false claim and tag it as false may backfire because they boost the claim's familiarity. More detailed refutations may provide a more promising approach, but may not be feasible under the severe space constraints associated with social‐media communication. In two experiments, we tested whether (1) simple ‘false‐tag’ retractions can indeed be ineffective or harmful; and (2) short‐format (140‐character) refutations are more effective than simple retractions. Regarding (1), simple retractions reduced belief in false claims, and we found no evidence for a familiarity‐driven backfire effect. Regarding (2), short‐format refutations were found to be more effective than simple retractions after a 1‐week delay but not a one‐day delay. At both delays, however, they were associated with reduced misinformation‐congruent reasoning.
Still a matter of dialogue: A response to Potter's, Augoustinos's, and Jovchelovitch's commentaries
Authors: Batel Susana , Castro Paula
Published: March 2019

In their insightful and challenging commentaries, Potter, Augoustinos, and Jovchelovitch interestingly contributed to the debate we sought to promote. They allowed us to further reflect on our proposal of bringing together some strands of theory of social representations and discursive psychology for forging a stronger social psychology, that is, one more prepared to understand social change by better comprehending how meaning is constructed and transformed in discourse and communication. Through the present commentary, we attempt to better clarify this proposal in dialogue with their observations.
A transcriptomic signature of tertiary Gleason 5 predicts worse clinicopathological outcome
Authors: Martini Alberto , Wang Joanna , Brown Nicholas M. , Cumarasamy Shivaram , Sfakianos John P. , Rastinehad Ardeshir R. , Haines Kenneth G. , Wiklund Nils Peter , Nair Sujit S. , Tewari Ashutosh K.
Published: March 2019

Objective

To investigate the genomic features of tertiary pattern 5 (TP5) on radical prostatectomy specimens in an effort to explain the poor clinical outcomes associated with this disease subtype.

Patients and methods

Data from 159 men with Gleason Grade Group (GGG) 3 or 4 were considered. All patients had Decipher diagnostic testing with transcript profiles and single‐channel array normalisation (SCAN)‐normalised expression of coding genes.

The relationship between Decipher and TP5 was investigated by linear and binary logistic regressions. A differential transcriptomic analysis between patients with and without TP5 was performed. The prognostic role of these genes on progression‐free survival (PFS) and overall survival (OS) was evaluated using The Cancer Genome Atlas.

Results

In all, 52/159 (33%) patients had GGG 3–4 with TP5 disease. TP5 was associated with a higher Decipher score (β 0.07, 95% confidence interval [CI] 0.02–0.13; P = 0.04) and higher likelihood of falling within the intermediate‐ or high‐risk categories (odds ratio 3.34, 95% CI 1.34–8.35; P = 0.01). Analysis of microarray data revealed an 18‐gene signature that was differentially expressed in patients with TP5; 13 genes were over‐ and five under‐expressed in the TP5 cohort.

The overexpression of cyclin dependent kinase inhibitor 2B (CDKN2B), polo‐like kinase 1 (PLK1), or cell division cycle 20 (CDC20) was associated with worse PFS. The group harbouring overexpression of at least one gene had a 5‐year PFS rate of 50% vs 74% in the group without overexpression (P < 0.001).

Conclusions

Our studies have elucidated unique genomic features of TP5, whilst confirming previous clinical findings that patients harbouring TP5 tend to have worse prognosis. This is the first RNA‐based study to investigate the molecular diversity of TP5 and the first correlating CDKN2B to poorer prognosis in patients with prostate cancer.
Late Quaternary glacial history of Khentey Mountains, Central Mongolia
Authors: Khandsuren Purevmaa , Seong Yeong Bae , Oh Jeong Sik , Rhee Hyun Hee , Sandag Khadbaatar , Yu Byung Yong
Published: March 2019

Mongolian glaciers have been the subject of relatively little research, resulting in less geochronological constraint than other parts of Central Asia. The Khentey Mountains (latitude 47–51°N, longitude 105–112°E) are a typical landlocked mountain range exhibiting clear geomorphic evidence of late Quaternary glaciation. Yet, compared to western parts of Mongolia such as the Mongolian Altay, Gobi Altay, Khangay, and Khovsgol, glacial history of the Khentey Mountains is poorly understood. To address this, and permit comparison of the Khentey glacier–climate record with other alpine regions in Mongolia, we performed geomorphological mapping and cosmogenic10Be surface‐exposure dating in two glaciated regions of the Khentey Mountains: Yestii and Khagiin Khar. Specifically, we measured10Be in 34 samples collected from five moraine sequences, which, together with morphostratigraphy, correspond to four main glacial stages: (i) The My1terminal moraine sequence for Yestii (21.0±4.9 ka) and the Mk1moraine for Khagiin Khar (19.6±2.6 ka), both of which represent the Last Glacial Maximum; (ii) the Lateglacial Mk2moraine, dated to 16.0±3.5 ka; (iii) the Mk3moraine, dated to either 17.6±7.0 ka (Lateglacial) or 12.1±1.1 ka (Younger Dryas); and (iv) the currently undated Mk4moraine (~2200 m a.s.l.), to which we assign a Holocene age. Our results suggest that the timing of maximum glacier extent in Mongolia was regionally variable. In the Khentey Mountains, maximum glaciation occurred during Marine Isotope Stage (MIS) 2, whereas the maximum occurred duringMIS3 in Khangay and Khovsgol and duringMIS4 in the Altay. TheMIS2 glacial maximum in the Khentey Mountains coincided with the global sea level minimum during the Last Glacial Maximum, and was followed by at least three glacial re‐advances during the Lateglacial to possibly the Holocene.
Hypoxia modulates protein phosphatase 2A through HIF‐1α dependent and independent mechanisms in human aortic smooth muscle cells and ventricular cardiomyocytes
Authors: Elgenaidi Ismail Suliman , Spiers James Paul
Published: March 2019

Background and Purpose

Although protein phosphatases regulate multiple cellular functions, their modulation under hypoxia remains unclear. We investigated expression of the protein phosphatase system under normoxic/hypoxic conditions and the mechanism by which hypoxia alters protein phosphatase 2A (PP2A) activity.

Experimental Approach

Human cardiovascular cells were cultured in cell type specific media under normoxic or hypoxic conditions (1% O2). Effects on mRNA expression, phosphatase activity, post‐translational modification, and involvement of hypoxia inducible factor 1α (HIF‐1α) were assessed using RT‐PCR, immunoblotting, an activity assay, and siRNA silencing.

Key Results

All components of the protein phosphatase system studied were expressed in each cell line. Hypoxia attenuated mRNA expression of the transcripts in a cell line‐ and time‐dependent manner. In human aortic smooth muscle cells (HASMC) and AC16 cells, hypoxia decreased PP2Ac activity and mRNA expression without altering PP2Ac abundance. Hypoxia increased demethylated PP2Ac (DPP2Ac) and phosphatase methylesterase 1 (PME‐1) abundance but decreased leucine carboxyl methyltransferase 1 (LCMT‐1) abundance. HIF‐1α siRNA prevented the hypoxia‐mediated decrease in phosphatase activity and expression of the catalytic subunit of protein phosphatase 2A (PPP2CA), independently of altering pPP2Ac, DPP2Ac, LCMT‐1, or PME‐1 abundance.

Conclusion and Implications

Cardiovascular cells express multiple components of the PP2A system. In HASMC and AC16 cells, hypoxia inhibits PP2A activity through HIF‐1α‐dependent and ‐independent mechanisms, with the latter being consistent with altered PP2A holoenzyme assembly. This indicates a complex inhibitory effect of hypoxia on the PP2A system, and highlights PP2A as a therapeutic target for diseases associated with dysregulated protein phosphorylation.
Cyclic nucleotide signalling compartmentation by PDEs in cultured vascular smooth muscle cells
Authors: Zhang Liang , Bouadjel Kaouter , Manoury Boris , Vandecasteele Grégoire , Fischmeister Rodolphe , Leblais Véronique
Published: March 2019

Background and Purpose

Up‐regulation of phosphodiesterases (PDEs) is associated with several vascular diseases, and better understanding of the roles of each PDE isoform in controlling subcellular pools of cyclic nucleotides in vascular cells is needed. We investigated the respective role of PDE1, PDE5, and PDE9 in controlling intracellular cAMP and/or cGMP concentrations ([cAMP]i, [cGMP]i) in cultured rat aortic smooth muscle cells (RASMCs).

Experimental Approach

We used selective inhibitors of PDE1 (PF‐04471141), PDE5 (sildenafil), and PDE9 (PF‐04447943) to measure cAMP‐ and cGMP‐PDE activities with a radioenzymatic assay, in RASMC extracts. Real‐time [cAMP]i and [cGMP]i were recorded by Förster resonance energy transfer‐imaging in single living cells, and cell proliferation was assessed in FBS‐stimulated cells.

Key Results

PDE1, PDE5, and PDE9 represented the major cGMP‐hydrolyzing activity in RASMCs. Basal PDE1 exerted a functional role in degrading in situ the cGMP produced in response to activation of particulate GC by C‐type natriuretic peptide. In high intracellular Ca2+ concentrations, PDE1 also regulated the NO/soluble GC‐dependent cGMP response, as well as the β‐adrenoceptor‐mediated cAMP response. PDE5 exerted a major role in degrading cGMP produced by NO and the natriuretic peptides. PDE9 only regulated the NO‐induced [cGMP]i increase. All three PDEs contributed differently to regulate cell proliferation under basal conditions and upon cGMP‐elevating stimuli.

Conclusions and Implications

Our data emphasize the distinct roles of PDE1, PDE5, and PDE9 in local regulation of [cAMP]i and [cGMP]i, in vascular smooth muscle cells, strengthening the concept of PDEs as key actors in the subcellular compartmentation of cyclic nucleotides.
Identification of the Raf kinase inhibitor TAK‐632 and its analogues as potent inhibitors of necroptosis by targeting RIPK1 and RIPK3
Authors: Chen Xiaofei , Zhuang Chunlin , Ren Yibin , Zhang Hao , Qin Xia , Hu Longmiao , Fu Jing , Miao Zhenyuan , Chai Yifeng , Liu Zheng‐gang , Zhang Haibing , Cai Zhenyu , Wang Hong‐yang
Published: March 2019

Background and Purpose

Necroptosis is a form of programmed, caspase‐independent, cell death, mediated by receptor‐interacting protein kinases, RIPK1 and RIPK3, and the mixed lineage kinase domain‐like (MLKL). Necroptosis contributes to the pathophysiology of various inflammatory, infectious, and degenerative diseases. Thus, identification of low MW inhibitors for necroptosis has broad therapeutic relevance. Here, we identified that the pan‐Raf inhibitor TAK‐632 was also an inhibitor of necroptosis. We have further generated a more selective, highly potent analogue of TAK‐632 by targeting RIPK1 and RIPK3.

Experimental Approach

Cell viability was measured by MTT, propidium staining, or CellTiter‐Glo luminescent assays. Effects of TAK‐632 on necroptosis signalling pathways were investigated by western blotting, immunoprecipitation, and in vitro kinase assays. Downstream targets of TAK‐632 were identified by a drug affinity responsive target stability assay and a pull‐down assay with biotinylated TAK‐632. A mouse model of TNF‐α‐induced systemic inflammatory response syndrome (SIRS) was further used to explore the role of TAK‐632 in protecting against necroptosis‐associated inflammation in vivo.

Key Results

TAK‐632 protected against necroptosis in human and mouse cells but did not protect cells from apoptosis. TAK‐632 directly bound with RIPK1 and RIPK3 to inhibit kinase activities of both enzymes. In vivo, TAK‐632 alleviated TNF‐induced SIRS. Furthermore, we performed a structure–activity relationship analysis of TAK‐632 analogues and generated SZM594, a highly potent inhibitor of RIPK1/3.

Conclusions and Implications

TAK‐632 is an inhibitor of necroptosis and represents a new lead compound in the development of highly potent inhibitors of RIPK1 and RIPK3.
Squamous cell carcinoma antigen 1 is associated to poor prognosis in esophageal cancer through immune surveillance impairment and reduced chemosensitivity
Authors: Turato Cristian , Scarpa Melania , Kotsafti Andromachi , Cappon Andrea , Quarta Santina , Biasiolo Alessandra , Cavallin Francesco , Trevellin Elisabetta , Guzzardo Vincenza , Fassan Matteo , Chiarion‐Sileni Vanna , Castoro Carlo , Rugge Massimo , Vettor Roberto , Scarpa Marco , Pontisso Patrizia
Published: March 2019

Squamous cell carcinoma antigen‐1 (SCCA1) overexpression is associated with poor prognosis and chemoresistance in several tumor types, however, the underlying mechanisms remain elusive. Here, we report SCCA1 in relation to the immune and peritumoral adipose tissue microenvironment in early and advanced esophageal adenocarcinoma (EAC). In our series of patients with EAC, free SCCA1 serum levels were associated with significantly worse overall survival, and SCCA1‐IgM serum levels showed a trend to a worse overall survival. Serum SCCA1 and intratumoral SCCA1 were inversely correlated with immune activation markers. In agreement with these findings, SCCA1 induced the expression of the immune checkpoint molecule programmed death ligand‐1 on monocytes and a direct correlation of these 2 molecules was observed in sequential tumor sections. Furthermore, SCCA1 mRNA expression within the tumor was inversely correlated with stem cell marker expression both within the tumor and in the peritumoral adipose tissue. In vitro, in EAC cell lines treated with different chemotherapeutic drugs, cell viability was significantly modified by SCCA1 presence, as cells overexpressing SCCA1 were significantly more resistant to cell death. In conclusion, poor prognosis in EAC overexpressing SCCA1 is due to reduced tumor chemosensitivity as well as intratumoral immunity impairment, likely induced by this molecule.
Classroom Popularity Hierarchy Predicts Prosocial and Aggressive Popularity Norms Across the School Year
Authors: Laninga‐Wijnen Lydia , Harakeh Zeena , Garandeau Claire F. , Dijkstra Jan K. , Veenstra René , Vollebergh Wilma A. M.
Published: March 2019

This study examined the coevolution of prosocial and aggressive popularity norms with popularity hierarchy (asymmetries in students’ popularity). Cross‐lagged‐panel analyses were conducted on 2,843 secondary school students (Nclassrooms = 120; Mage = 13.18; 51.3% girls). Popularity hierarchy predicted relative change in popularity norms over time, but not vice versa. Specifically, classrooms with few highly popular and many unpopular students increased in aggressive popularity norms at the beginning of the school year and decreased in prosocial popularity norms at the end of the year. Also, strong within‐classroom asymmetries in popularity predicted relatively higher aggressive popularity norms. These findings may indicate that hierarchical contexts elicit competition for popularity, with high aggression and low prosocial behavior being seen as valuable tools to achieve popularity.