bluuebunny/crossref_metadata_2025 huggingface dataset:
Defective excitatory/inhibitory synaptic balance and increased neuron apoptosis in a zebrafish model of Dravet syndrome
Authors: Brenet Alexandre , Hassan-Abdi Rahma , Somkhit Julie , Yanicostas Constantin , Soussi-Yanicostas Nadia
Published: September 2019

Dravet syndrome is a type of severe childhood epilepsy that responds poorly to current anti-epileptic drugs. In recent years, zebrafish disease models with Scn1Lab sodium channel deficiency have been generated to seek novel anti-epileptic drug candidates, some of which are currently undergoing clinical trials. However, the spectrum of neuronal deficits observed following Scn1Lab depletion in zebrafish larvae has not yet been fully explored. To fill this gap and gain a better understanding of the mechanisms underlying neuron hyperexcitation in Scn1Lab-depleted larvae, we analyzed neuron activity in vivo using combined local field potential recording and transient calcium uptake imaging, studied the distribution of excitatory and inhibitory synapses and neurons as well as investigated neuron apoptosis. We found that Scn1Lab-depleted larvae displayed recurrent epileptiform seizure events, associating massive synchronous calcium uptakes and ictal-like local field potential bursts. Scn1Lab-depletion also caused a dramatic shift in the neuronal and synaptic balance toward excitation and increased neuronal death. Our results thus provide in vivo evidence suggesting that Scn1Lab loss of function causes neuron hyperexcitation as the result of disturbed synaptic balance and increased neuronal apoptosis.
miRNA858b Inhibits Proanthocyanidin Accumulation by Repression ofDkMYB19andDkMYB20in Persimmon
Authors: Yang Sichao , Zhang Meng , Xu Liqing , Luo Zhengrong , Zhang Qinglin
Published: September 2019

Persimmon proanthocyanidin (PA) biosynthetic had been reported to be regulated by several transcription factors, but the miRNAs function involved in this process was poorly understood. We identified a miRNA858b that putatively targeted two R2R3-MYB transcription factors,DkMYB19/DkMYB20. Transcript accumulation ofDkMYB19/DkMYB20and miRNA858b showed contrasting divergent expression patterns during fruit development. DkMYB19/DkMYB20 were confirmed to be localized in the nucleus. The interaction between miRNA858b andDkMYB19/DkMYB20were experimentally validated by 5’ RNA ligase-mediated RACE and LUC enzyme activity detection. Overexpression of miRNA858b led to the down-regulation ofDkMYB19/DkMYB20which reduced the accumulation of PA, whereas the reduced miRNA858b activity that up-regulated theDkMYB19/DkMYB20resulted in high levels of PA in STTM858b transient expression in leavesin vivo. Similarly, the transient transformation of miRNA858b in fruit wafersin vitroalso reduced the accumulation of PA by repressing theDkMYB19/DkMYB20, while the up-regulation ofDkMYB19/DkMYB20enhanced the accumulation of PA in STTM858b orDkMYB19/DkMYB20transient transformation in fruit wafers. PA content decreased after overexpression of miRNA858b inArabidopsiswild type andDkMYB19/DkMYB20in persimmon leaf callus consisted with the above results. These findings suggested that miRNA858b repressed the expression ofDkMYB19/DkMYB20which contribute to PA accumulation in persimmon.
Hepatic JNK-mediated bile acid homeostasis regulates liver cancer through PPARα
Authors: Manieri Elisa , Esteban-Lafuente Laura , Rodríguez María Elena , Leiva-Vega Luis , Chen Chaobo , Cubero Francisco Javier , Barrett Tamera , Cavanagh-Kyros Julie , Seruggia Davide , Monte Maria J. , Marin Jose J.G. , Davis Roger J. , Mora Alfonso , Sabio Guadalupe
Published: September 2019

cJun NH2-terminal kinase (JNK) inhibition has been suggested as a potential treatment for insulin resistance and steatosis through activation of the transcription factor PPARα. However, the long-term consequences have not been evaluated. We found that hepatic JNK deficiency alters bile acid and cholesterol metabolism, resulting in hepatic expression of FGF15 and activation of ERK in cholangiocytes, which ultimately promotes their proliferation. Genetic inactivation of PPARα identifies PPARα hyperactivation as the molecular mechanism for these deleterious effects. Our analysis indicates that hepatic PPARα activation is oncogenic: PPARα deficiency protects mice against carcinogen-induced hepatocellular carcinoma under high fat diet (HFD) condition. These surprising results urge the re-consideration of using JNK inhibitors or PPAR agonists for the treatment of metabolic syndrome.
Admixture-enabled selection for rapid adaptive evolution in the Americas
Authors: Norris Emily T. , Rishishwar Lavanya , Chande Aroon T. , Conley Andrew B. , Ye Kaixiong , Valderrama-Aguirre Augusto , King Jordan I.
Published: September 2019

Background

Admixture occurs when previously isolated populations come together and exchange genetic material. We hypothesized that admixture can enable rapid adaptive evolution in human populations by introducing novel genetic variants (haplotypes) at intermediate frequencies, and we tested this hypothesis via the analysis of whole genome sequences sampled from admixed Latin American populations in Colombia, Mexico, Peru, and Puerto Rico.

Results

Our screen for admixture-enabled selection relies on the identification of loci that contain more or less ancestry from a given source population than would be expected given the genome-wide ancestry frequencies. We employed a combined evidence approach to evaluate levels of ancestry enrichment at (1) single loci across multiple populations and (2) multiple loci that function together to encode polygenic traits. We found cross-population signals of African ancestry enrichment at the major histocompatibility locus on chromosome 6, consistent with admixture-enabled selection for enhanced adaptive immune response. Several of the human leukocyte antigen genes at this locus (HLA-A,HLA-DRB51andHLA-DRB5) showed independent evidence of positive selection prior to admixture, based on extended haplotype homozygosity in African populations. A number of traits related to inflammation, blood metabolites, and both the innate and adaptive immune system showed evidence of admixture-enabled polygenic selection in Latin American populations.

Conclusions

The results reported here, considered together with the ubiquity of admixture in human evolution, suggest that admixture serves as a fundamental mechanism that drives rapid adaptive evolution in human populations.
Systematic assessment of regulatory effects of human disease variants in pluripotent cells
Authors: Bonder Marc Jan , Smail Craig , Gloudemans Michael J. , Frésard Laure , Jakubosky David , D’Antonio Matteo , Li Xin , Ferraro Nicole M. , Carcamo-Orive Ivan , Mirauta Bogdan , Seaton Daniel D. , Cai Na , Horta Danilo ,   HipSci Consortium,   iPSCORE Consortium,   GENESiPS Consortium,   PhLiPS Consortium, Smith Erin N. , Frazer Kelly A. , Montgomery Stephen B. , Stegle Oliver
Published: September 2019

Identifying regulatory genetic effects in pluripotent cells provides important insights into disease variants with potentially transient or developmental origins. Combining existing and newly-generated data, we characterized 1,367 iPSC lines from 948 unique donors, collectively analyzed within the “Integrated iPSC QTL” (i2QTL) Consortium. The sample size of our study allowed us to derive the most comprehensive map of quantitative trait loci (QTL) in pluripotent human cells to date. We mapped the effects of nearby common genetic variants on five expression phenotypes, identifying cis-QTL at gene-, exon-level and transcript-, splicing-, alternative polyadenylation-ratio (APA) for a total of 18,556 genes. For gene-level, we further quantified the effects of rare and singleton variants, and the effect of distal variants that act in trans (trans-eQTL), which we replicated in independent samples. Our data are a valuable community resource, uncovering novel regulatory effects that have not previously been described in differentiated cells and tissues. Building on this regulatory map, we functionally explore GWAS signals for over 4,336 trait loci, finding evidence for colocalization with common and rare iPSC QTL for traits such as height and BMI, and diseases, such as cancer and coronary artery disease.
X chromosome inactivation in the human placenta is patchy and distinct from adult tissues
Authors: Phung Tanya N. , Olney Kimberly C. , Silasi Michelle , Perley Lauren , O’Bryan Jane , Kliman Harvey J. , Wilson Melissa A.
Published: September 2019

One of the X chromosomes in genetic females is silenced by a process called X chromosome inactivation (XCI). Variation in XCI across the placenta may contribute to observed sex differences and variability in pregnancy outcomes. However, XCI has predominantly been studied in human adult tissues. Here we sequenced and analyzed DNA and RNA from two locations from 30 full-term pregnancies. Implementing an allele specific approach to examine XCI, we report evidence that XCI in the human placenta is patchy, with large patches of either silenced maternal or paternal X chromosomes. Further, using similar measurements, we show that this is in contrast to adult tissues, which generally exhibit mosaic X-inactivation, where bulk samples exhibit both maternal and paternal X chromosome expression. Further, by comparing skewed samples in placenta and adult tissues, we identify genes that are uniquely silenced or expressed in the placenta compared to adult tissues highlighting the need for tissue-specific maps of XCI.
Prevalent pH Controls the Capacity of Galdieria Maxima to Use Ammonia and Nitrate as a Nitrogen Source
Authors: Iovinella M. , Carbone DA. , Cioppa D. , Davis S.J. , Innangi M. , Esposito S. , Ciniglia C.
Published: September 2019

Galdieria maxima is a polyextremophilic alga capable of diverse metabolic processes. Ammonia is widely used in culture media typical of laboratory growth. Recent reports that this species can grow on wastes promote the concept that G. maxima might have biotechnological utility. Accordingly, there is a need to know the range of pH levels that can support G. maxima growth in a given nitrogen source. Here, we examined the combined effect of pH and nitrate/ammonium source on the growth and long-term response of the photochemical process to a pH gradient in different G. maxima strains. All were able to use differing nitrogen sources, despite both the growth rate and photochemical activity were significantly affected by the combination with the pH. All strains acidified the NH4+-medium (pH<3); only G. maxima IPPAS P507 showed reduced capacity in lowering the pH from 6.5. pH was a limiting factor in nitrate uptake at pH≥6.5; noteworthy, at pH 5 on nitrate G. maxima ACUF551 showed a good growth performance, despite the alkalization of the medium.
A new role of the Mus81 nuclease for replication completion after fork restart
Authors: Pardo Benjamin , Moriel-Carretero María , Vicat Thibaud , Aguilera Andrés , Pasero Philippe
Published: September 2019

Impediments to DNA replication threaten genome stability. The homologous recombination (HR) pathway is involved in the restart of blocked replication forks. Here, we used a new method to study at the molecular level the restart of replication in response to DNA topoisomerase I poisoning by camptothecin (CPT). We show that HR-mediated restart at the global genomic level occurs by a BIR-like mechanism that requires Rad52, Rad51 and Pol32. The Mus81 endonuclease, previously proposed to cleave blocked forks, is not required for replication restart in S phase but appears to be essential to resolve fork-associated recombination intermediates in G2/M as a step necessary to complete replication. We confirmed our results using an independent system that allowed us to conclude that this mechanism is independent of the accumulation of DNA supercoiling and DNA-protein crosslinks normally caused by CPT. Thus, we describe here a specific function for Mus81 in the processing of HR-restarted forks required to complete DNA replication.
Genome-wide dysregulation of histone acetylation in the Parkinson’s disease brain
Authors: Toker Lilah , Tran Gia T , Sundaresan Janani , Tysnes Ole-Bjørn , Alves Guido , Haugarvoll Kristoffer , Nido Gonzalo S , Dölle Christian , Tzoulis Charalampos
Published: September 2019

Parkinson disease (PD) is a complex neurodegenerative disorder of largely unknown etiology. While several genetic risk factors have been identified, the involvement of epigenetics in the pathophysiology of PD is mostly unaccounted for. We conducted a histone acetylome-wide association study in PD, using brain tissue from two independent cohorts of cases and controls. Immunoblotting revealed increased acetylation at several histone sites in PD, with the most prominent change observed for H3K27, a marker of active promoters and enhancers. Chromatin immunoprecipitation sequencing (ChIP-seq) further indicated that H3K27 hyperacetylation in the PD brain is a genome-wide phenomenon, with a strong predilection for genes implicated in the disease, includingSNCA, PARK7, PRKNandMAPT. Integration of the ChIP-seq with transcriptomic data revealed that the correlation between promoter H3K27 acetylation and gene expression is attenuated in PD patients, suggesting that H3K27 acetylation may be decoupled from transcription in the PD brain. Our findings strongly suggest that dysregulation of histone acetylation plays an important role in the pathophysiology of PD and identify novel epigenetic signatures associated with the disease.
Functionally overlapping variants control TB susceptibility in Collaborative Cross mice
Authors: Smith Clare M. , Proulx Megan K. , Lai Rocky , Kiritsy Michael C. , Bell Timothy A , Hock Pablo , Pardo-Manuel de Villena Fernando , Ferris Martin T. , Baker Richard E. , Behar Samuel M. , Sassetti Christopher M.
Published: September 2019

Host genetics plays an important role in determining the outcome ofMycobacterium tuberculosis(Mtb) infection. We previously found that Collaborative Cross mouse strains differ in their susceptibility to Mtb, and that the CC042/GeniUnc (CC042) strain suffered from a rapidly progressive disease and failed to produce the protective cytokine, IFNγ, in the lung. Here, we used parallel genetic and immunological approaches to investigate the basis of CC042 susceptibility. Using a population derived from a CC001/Unc (CC001) × CC042 intercross, we mapped four QTL underlying Tuberculosis ImmunoPhenotypes (Tip1-4). These included 2 major effect QTL on Chromosome 7 (Tip1andTip2) that were associated with bacterial burden.Tip2, along withTip3(Chromosome 15) andTip4(Chromosome 16) also correlated with IFNγproduction following infection, whereasTip1appeared to control an IFNγ-independent mechanism of bacterial control. Further immunological characterization revealed that CC042 animals recruited relatively few antigen-specific T cells to the lung and these T cells failed to express the Integrin alpha L (αL; i.e., CD11a), which contributes to T cell activation and migration. These defects could be explained by a CC042 private variant in theItgalgene, which encodes CD11a, and is found within theTip2interval. This 15bp deletion leads to aberrant mRNA splicing and is predicted to result in a truncated protein product. TheItgalCC042genotype was associated with all measured disease traits, indicating that this variant is a major determinant of susceptibility in CC042. The combined effect of functionally distinctTipvariants likely explains the profound susceptibility of CC042 and highlights the multigenic nature of TB control in the Collaborative Cross.

Importance statement

The variable outcome ofMycobacterium tuberculosisinfection observed natural populations is difficult to model in genetically homogenous small animal models. The newly-developed Collaborative Cross (CC) represents a reproducible panel of genetically-diverse mice that display a broad range of phenotypic responses to infection. We explored the genetic basis of this variation, focusing on a CC line that is highly susceptible toM. tuberculosisinfection. This study identified multiple quantitative trait loci associated with bacterial control and cytokine production, including one that is caused by a novel loss-of-function mutation in theItgalgene that is necessary for T cell recruitment to the infected lung. These studies verify the multigenic control of mycobacterial disease in the CC panel, identify genetic loci controlling diverse aspects of pathogenesis, and highlight the utility of the CC resource.
A phased, diploid assembly of the Cascade hop (Humulus lupulus) genome reveals patterns of selection and haplotype variation
Authors: Padgitt-Cobb Lillian K. , Kingan Sarah B. , Wells Jackson , Elser Justin , Kronmiller Brent , Moore Daniel , Concepcion Gregory , Peluso Paul , Rank David , Jaiswal Pankaj , Henning John , Hendrix David A.
Published: September 2019

Hop (Humulus lupulus L. var Lupulus) is a diploid, dioecious plant with a history of cultivation spanning more than one thousand years. Hop cones are valued for their use in brewing, and around the world, hop has been used in traditional medicine to treat a variety of ailments. Efforts to determine how biochemical pathways responsible for desirable traits are regulated have been challenged by the large, repetitive, and heterozygous genome of hop. We present the first report of a haplotype-phased assembly of a large plant genome. Our assembly and annotation of the Cascade cultivar genome is the most extensive to date. PacBio long-read sequences from hop were assembled with FALCON and phased with FALCON-Unzip. Using the diploid assembly to assess haplotype variation, we discovered genes under positive selection enriched for stress-response, growth, and flowering functions. Comparative analysis of haplotypes provides insight into large-scale structural variation and the selective pressures that have driven hop evolution. Previous studies estimated repeat content at around 60%. With improved resolution of long terminal retrotransposons (LTRs) due to long-read sequencing, we found that hop is nearly 78% repetitive. Our quantification of repeat content provides context for the size of the hop genome, and supports the hypothesis of whole genome duplication (WGD), rather than expansion due to LTRs. With our more complete assembly, we have identified a homolog of cannabidiolic acid synthase (CBDAS) that is expressed in multiple tissues. The approaches we developed to analyze a phased, diploid assembly serve to deepen our understanding of the genomic landscape of hop and may have broader applicability to the study of other large, complex genomes.
Evolution of NLR resistance genes with non-canonical N-terminal domains in wild tomato species
Authors: Seong Kyungyong , Seo Eunyoung , Li Meng , Staskawicz Brian
Published: September 2019

Background

Nucleotide-binding and leucine-rich repeat immune receptors (NLRs) are an important component of plant immunity that provides resistance against diverse pathogens. NLRs often exist as large gene families, the members of which display diverse multi-domain architectures (MDAs) and evolve through various mechanisms of duplications and selections.

Results

We conducted resistance gene enrichment sequencing (RenSeq) with single-molecule real time (SMRT) sequencing of PacBio for 18 accessions in Solanaceae including 15 wild tomatoes. We demonstrate what was previously known as Solanaceae Domain (SD) not only is more diverse in structure and function but also far anciently originated from the most recent common ancestor (MRCA) between Asterids and Amaranthaceae. In tomato, NLRs with the extended N-terminus displayed distinct patterns of evolution based on phylogenetic clades by proliferation, continuous elongation and domain losses.

Conclusions

Our study provides high quality gene models of NLRs that can serve as resources for future studies for crop engineering and elucidates greater evolutionary dynamics of the extended NLRs than previously assumed.
Impact of economic crises on offspring health and the developmental origins of health and disease concept
Authors: Sdona Emmanouela , Briana Despina D. , Malamitsi‐Puchner Ariadne
Published: September 2019

There is emerging evidence that economic crises may impact long‐term health. Furthermore, adversity experienced by women and their offspring might be transmitted to next generations. The Developmental Origins of Health and Disease (DOHaD) approach emphasises the importance of early life events for the state of health and risk for disease later in life. In this review, we discuss current evidence on the possible impact of economic crises on offspring health through the DOHaD framework and highlight the importance of critical periods of development for future disease risk. Therefore, successful interventions should prioritise strategies that address early life risk factors.
Post‐socialist infrastructuring
Authors: Tuvikene Tauri , Sgibnev Wladimir , Zupan Daniela , Jovanović Deana , Neugebauer Carola S.
Published: September 2019

Infrastructures from different time periods, installed for different purposes in often discordant political and economic systems, function alongside one another in contemporary cities. While infrastructures attracted a great deal of attention in geographical research, the “East” of Europe has still largely been left out, as the studies mostly focused on the global North and the global South. This paper, thus, takes on two challenges by intersecting an infrastructural lens with the re‐conceptualisation of post‐socialism. First, following calls from comparative urbanism and the postcolonial turn in urban studies and geography to work beyond usual suspects, the paper expands the territorial scope of infrastructure research. Second, the paper takes the critical edge of the aforementioned calls by offering new ways of attending to infrastructures through relations to the (socialist) past. Taking a threefold approach of expanding, learning, and challenging from a more‐than‐North/South perspective, this paper analyses post‐socialist infrastructuring by highlighting inequalities, such as the introduction of individual measuring of heat, using green spaces as boosterist urban governing, and turning transport to a consumer good. Instead of centralising the present or the “Western” best practice, the paper investigates to what extent it is possible to take elements of the (socialist) past and develop them into forward‐looking measures. The paper shows the need to incorporate questions of social justice and equity – perspectives which were more central for infrastructural provision under socialism – into the ways in which infrastructures are planned, made, and used today.
A “landscapes of power” framework for historical political ecology: The production of cultural hegemony in Araucanía‐Wallmapu
Authors: Escalona Ulloa Miguel , Barton Jonathan R.
Published: September 2019

The region of Araucania, since its incorporation into the Republic of Chile, has been subject to significant territorial transformations. The Chilean State, supported by economic elites, the political class, and intellectuals have all contributed to the discursive positioning of, and the creation of artefacts in, this regional space. These devices for mobilising power have enabled an appropriation of nature – through natural resource exploitation – and an appropriation of land rights through property titles. The occupation of Araucania from the end of the 19th century was achieved principally through the artefacts of larger settlement consolidation, the railway network, and the building of roads. These were designed and imposed from Santiago through political and administrative channels based on an internal colonialism logic. Conflicts with indigenous Mapuche in Wallmapu (the Mapudungun name for their territory) arose as a consequence of asymmetries of power and this appropriation of space, including expulsion from their land, deforestation, increasing poverty due to restricted access to traditional resources, and epistemic violence through specific constructions of development and the subalterning of indigenous “others.” This historical political ecology not only reveals the expanding frontiers of extractivism and processes of accumulation in favour of national political and economic elites, but more importantly shows how the construction of cultural landscapes became a device for exercising power and justifying appropriation in pursuit of modernity, progress, and development. These landscapes of power evolved over time as different demands were placed on this territory: first as a wheat bowl, and second as forestry plantation. A “landscapes of power” framework is presented in order to work through these constructions of landscape, building on phenomenological and dwelling perspectives in order to focus on the role of cultural hegemony and power relations.
The influence of halokinesis on prograding clinoforms: Insights from the Tiddlybanken Basin, Norwegian Barents Sea
Authors: Rojo Luis Alberto , Marín Dora , Cardozo Nestor , Escalona Alejandro , Koyi Hemin
Published: September 2019

Although the trajectory and geometry of clinoforms in different types of basins have been described in many studies, few studies discuss the influence of halokinesis on clinoforms in salt‐related basins. In this study, we analyse the Lower Cretaceous clinoforms in the Tiddlybanken Basin, Norwegian Barents Sea to evaluate the impact of salt mobilization on the geometry and trajectory of clinoforms as well as its implications on sediment partitioning. To accomplish this objective, we use a multidisciplinary approach consisting of seismic and well‐interpretation, 3D structural restoration, and forward stratigraphic modelling. The results show that salt mobilization affects prograding clinoforms by: (a) causing lateral variations in progradation rates, resulting in complex palaeogeography, (b) increasing slope angles, which affect the equilibrium of the clinoform profile and can trigger slope‐readjustment processes and (c) producing lateral and temporal variations in accommodation space, leading to different clinoform trajectories, stacking patterns and reservoir distribution along the basin. Forward stratigraphic modelling shows that in salt‐related basins and other tectonically active basins, the isolated use of conventional methods for clinoform analysis might lead to potential interpretation pitfalls such as misinterpretation of trajectories and overestimation of foreset angles, which can have negative consequences for exploration models.
The Sound of Grasp Affordances: Influence of Grasp‐Related Size of Categorized Objects on Vocalization
Authors: Vainio Lari , Vainio Martti , Lipsanen Jari , Ellis Rob
Published: September 2019

Previous research shows that simultaneously executed grasp and vocalization responses are faster when the precision grip is performed with the vowel [i] and the power grip is performed with the vowel [ɑ]. Research also shows that observing an object that is graspable with a precision or power grip can activate the grip congruent with the object. Given the connection between vowel articulation and grasping, this study explores whether grasp‐related size of observed objects can influence not only grasp responses but also vowel pronunciation. The participants had to categorize small and large objects into natural and manufactured categories by pronouncing the vowel [i] or [ɑ]. As predicted, [i] was produced faster when the object's grasp‐related size was congruent with the precision grip while [ɑ] was produced faster when the size was congruent with the power grip (Experiment 1). The effect was not, however, observed when the participants were presented with large objects that are not typically grasped by the power grip (Experiment 2). This study demonstrates that vowel production is systematically influenced by grasp‐related size of a viewed object, supporting the account that sensory‐motor processes related to grasp planning and representing grasp‐related properties of viewed objects interact with articulation processes. The paper discusses these findings in the context of size–sound symbolism, suggesting that mechanisms that transform size‐grasp affordances into corresponding grasp‐ and articulation‐related motor programs might provide a neural basis for size‐sound phenomena that links small objects with closed‐front vowels and large objects with open‐back vowels.
Prevalence of somatic and germline mutations of Fumarate hydratase in uterine leiomyomas from young patients
Authors: Liu Chengbao , Dillon Jessica , Beavis Anna L , Liu Yuehua , Lombardo Kara , Fader Amanda N , Hung Chien‐Fu , Wu Tzyy‐Choou , Vang Russell , Garcia Jairo E , Xing Deyin
Published: September 2019

Aims

Hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome is caused by germline mutations in the Fumarate hydratase (FH) gene. In young women, the syndrome often presents with symptomatic uterine leiomyomas, leading to myomectomy or hysterectomy. In this study, we aimed to investigate the incidence and mutational profiles of FH‐negative leiomyomas from young patients, thus allowing for early identification and triage of syndromic patients for surveillance.

Methods and results

We evaluated 153 cases of uterine leiomyomas from women aged up to 30 years for loss of FH expression by tissue microarray (TMA)‐based immunohistochemical staining. Mutational analysis of tumours with loss of FH was carried out by polymerase chain reaction (PCR) amplification of 10 exons within the FH gene and subsequent Sanger sequencing. The status of promoter methylation was assessed by bisulphite sequencing. Loss of FH protein expression was detected in seven (4.6%) of 153 tested uterine leiomyomas from young patients. All FH‐negative leiomyomas displayed staghorn vasculature and fibrillary/neurophil‐like cytoplasm. We found that six (86%) of seven FH‐negative tumours detected by immunohistochemistry harboured FH mutations, 50% of which contained germline mutations. In particular, the germline mutational rate in FH gene was 2.0% (three of 153 cases). Bisulphite sequencing analysis failed to detect promoter methylation in any of the seven tumours.

Conclusion

Our study showed a relatively high rate of FH germline mutation in FH‐negative uterine leiomyomas from patients aged up to 30 years. While genetic mutations confer protein expression loss, epigenetic regulation of the FH gene appears to be unrelated to this phenotype.
Effect of dopant precursors on the optical properties of rare‐earths doped oxyfluoride glass‐ceramics
Authors: Gorni Giulio , Serrano Aida , Bravo David , Castro German R. , Balda Rolindes , Fernández Joaquín , Durán Alicia , Pascual María J.
Published: September 2019

The crystallization of fluoride nanocrystals (NCs) in chemically and mechanically stable aluminosilicate glasses has shown interesting optical properties even for small crystal fractions (10‐15 wt%). When rare‐earth (RE) ions are used as dopants, crystal‐like features can be reproduced and an increase in the emission and/or energy transfer processes, with respect to the starting glasses, is observed. A crucial point for these materials is the study of the local surrounding of RE ions and their incorporation in the NCs. In fact, the effective concentration in the NCs can be much higher than the nominal concentration, up to one order of magnitude or even higher. The knowledge of RE ions incorporation in the NCs permits choosing proper doping levels to optimize both linear and nonlinear optical properties. In this work, transparent oxyfluoride glass‐ceramics with LaF3 NCs, doped with Nd3+ and Er3+ using oxide and fluoride precursors, were prepared using the melt‐quenching method and controlled crystallization. The local surrounding of the RE ions was studied using X‐ray absorption spectroscopy, electron paramagnetic resonance and photoluminiscence. The results show that most RE ions are already in a fluorine‐rich amorphous environment even in the initial glass. The crystallization process provokes the RE ion redistribution and incorporation in the fluoride NCs. The different RE precursors, used as oxides or fluorides, have an influence on the incorporation of the RE in the NCs and, as a consequence, on the final optical properties.
Loss of insulin‐like growth factor‐1 signaling in astrocytes disrupts glutamate handling
Authors: Prabhu Disha , Khan Sariya M. , Blackburn Katherine , Marshall Jessica P. , Ashpole Nicole M.
Published: September 2019

Insulin‐like Growth Factor‐1 (IGF‐1) has been studied extensively for its ability to promote neuronal growth and excitability. Declining levels of IGF‐1 have been correlated with impaired learning and memory as well as an increased risk of neurodegenerative diseases. While neuronal regulation by IGF‐1 is well understood, the role of IGF‐1 in influencing astrocyte function requires further exploration. Astrocytes regulate many aspects of the brain microenvironment, including controlling glutamate‐glutamine cycling, which ultimately supports neuronal metabolism, neurotransmission, and protection from over stimulation. In this study, we examined whether IGF‐1 acts through its cognate receptor, IGFR, to alter astrocytic glutamate handling. We utilized both small molecule IGFR inhibitors and Cre‐driven genetic approaches to reduce IGFR in vivo and in cultured rodent astrocytes. When IGFR was knocked out of primary astrocytes derived from igfrf/f mice using AAV5‐CMV‐Cre, significant reductions in glutamate uptake were observed. Similarly, inhibition of IGFR with picropodophyllotoxin for 2 h, as well as 24 h, reduced glutamate uptake in vitro. Mechanistically, short‐term inhibition of IGFR resulted in a significant decrease in glutamate transporter availability on the cell surface, as assessed by biotinylation. Long‐term inhibition of IGFR led to significant reductions in mRNA expression of glutamate transport machinery, as assessed with qPCR. Reduced glutamate transporter mRNA was also observed in the brains of astrocyte‐specific IGFR‐deficient mice, three to four months after knock‐out was induced with tamoxifen. Interestingly, long‐term IGF‐1 inhibition also resulted in an increase in adenosine triphosphate‐stimulated glutamate release, though no change in adenosine triphosphate‐stimulated calcium flux was observed nor were any changes in purinergic receptor protein expression. Together, these data suggest that reduced IGF‐1 signaling will favor an accumulation of extrasynaptic glutamate, which may contribute to neurodegeneration in disease states where IGF‐1 levels are low.

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Cover Image for this issue: doi: 10.1111/jnc.14534.
Heterogeneous glutamatergic receptor mRNA expression across phrenic motor neurons in rats
Authors: Rana Sabhya , Sieck Gary C. , Mantilla Carlos B.
Published: September 2019

The diaphragm muscle comprises various types of motor units that are recruited in an orderly fashion governed by the intrinsic electrophysiological properties (membrane capacitance as a function of somal surface area) of phrenic motor neurons (PhMNs). Glutamate is the main excitatory neurotransmitter at PhMNs and acts primarily via fast acting AMPA and N‐methyl‐D‐aspartic acid (NMDA) receptors. Differences in receptor expression may also contribute to motor unit recruitment order. We used single cell, multiplex fluorescence in situ hybridization to determine glutamatergic receptor mRNA expression across PhMNs based on their somal surface area. In adult male and female rats (n = 9) PhMNs were retrogradely labeled for analyses (n = 453 neurons). Differences in the total number and density of mRNA transcripts were evident across PhMNs grouped into tertiles according to somal surface area. A ~ 25% higher density of AMPA (Gria2) and NMDA (Grin1) mRNA expression was evident in PhMNs in the lower tertile compared to the upper tertile. These smaller PhMNs likely comprise type S motor units that are recruited first to accomplish lower force, ventilatory behaviors. In contrast, larger PhMNs with lower volume densities of AMPA and NMDA mRNA expression presumably comprise type FInt and FF motor units that are recruited during higher force, expulsive behaviors. Furthermore, there was a significantly higher cytosolic NMDA mRNA expression in small PhMNs suggesting a more important role for NMDA‐mediated glutamatergic neurotransmission at smaller PhMNs. These results are consistent with the observed order of motor unit recruitment and suggest a role for glutamatergic receptors in support of this orderly recruitment.

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Cover Image for this issue: doi: 10.1111/jnc.14747.
Till death do us part: Transactions between losing one’s spouse and the Big Five personality traits
Authors: Asselmann Eva , Specht Jule
Published: September 2019

Objective

Although losing one's spouse is one of the worst experiences that can occur in life, it has not been resolved yet how this experience relates to personality development.

Method

In the German Socio‐Economic Panel study, information on the death of a spouse was assessed yearly from 1985 to 2017 and personality was measured repeatedly in 2005, 2009, 2013, and 2017 with a short version of the Big Five Inventory. We used multilevel analyses to simultaneously model whether personality differed between individuals who did or did not lose their spouse and whether personality changed prior to and after this experience.

Results

Compared to controls without the event, individuals who lost their spouse at a later point of time were more conscientious (β = .21) and more extraverted (β = .17). They became gradually more extraverted in the three years prior to the event (β = .25), but were less extraverted thereafter (β =−.27). Moreover, they gradually increased in Emotional Stability in the three years after this experience (β = .30). These changes were primarily driven by women and middle‐aged individuals. Men whose spouse died were less open in the first year after the event (β =−.47).

Conclusions

Losing one's spouse relates to changes in Extraversion and Emotional Stability, especially in women and middle‐aged adults.
Could drug burden be associated with severe periodontitis in patients receiving haemodialysis?
Authors: Yeter Hasan H. , Erten Yasemin , Isler Sila C. , Soysal Fatma , Elbeg Sehri , Unsal Berrin
Published: September 2019

Background

Periodontitis increases the risk of cardiovascular disease in the general population by triggering systemic inflammation.

Aim

To investigate the relationship between systemic inflammation and periodontitis, and clarify any association between severe periodontitis and the medications used by patients receiving haemodialysis.

Design

A cross‐sectional study.

Participants

The study was undertaken with 56 patients receiving haemodialysis.

Measurements

Demographic and laboratory data and prescribed drugs regularly used by patients were recorded from hospital records. During the dialysis session, a validated Xerostomia Inventory score was completed. A complete dental/periodontal examination was also undertaken on all patients by the same periodontist.

Results

In the study population, stage I periodontitis was determined in 41%, stage II periodontitis in 17%, stage III periodontitis in 21%, and stage IV periodontitis in 21%. Male gender, hypertension, coronary artery disease, β antagonists, calcium channel blockers, sodium polystyrene sulphonate, teeth brushing less than twice a day and high sensitive C‐reactive protein > 8 mg/l were significantly associated with severe periodontitis.

Conclusion

Drugs, including β antagonists, calcium channel blockers, polystyrene sulphonate, co‐morbid conditions and poor or insufficient oral care could facilitate an increase in the severity of periodontitis in patients receiving haemodialysis. Severe periodontitis also seems to be associated with cardiovascular disease and inflammation in patients with chronic renal disease.
Cluster headache and trigeminal autonomic cephalalgias: Recent advances in diagnosis and management
Authors: Imai Noboru
Published: September 2019

Trigeminal autonomic cephalalgias (TACs) are a group of primary headache disorders characterized by unilateral distribution of trigeminal pain that occurs in association with prominent ipsilateral cranial autonomic features. TACs include cluster headache, paroxysmal hemicrania, short‐lasting unilateral neuralgiform headache attacks, and hemicrania continua. The severity of these disorders has major effects on quality of life. Early diagnosis and appropriate management can thus markedly improve quality of life for the patient. Subcutaneous sumatriptan and pure oxygen inhalation are the most effective abortive therapies for acute cluster headache. Home oxygen therapy (HOT) has been covered by health insurance in Japan since 2018. Several drugs, such as verapamil and prednisolone, are effective in reducing the frequency of attacks in patients with cluster headache. Calcitonin gene‐related peptide monoclonal antibodies and non‐invasive vagus nerve stimulation are new treatments that have proven effective against cluster headache. Patients with paroxysmal hemicrania and hemicrania continua show absolute positive responses to indomethacin. Lamotrigine and several other anticonvulsants are effective in reducing the frequency of attacks in patients with short‐lasting unilateral neuralgiform headache.
Exploring GRHL3 polymorphisms and SNP‐SNP interactions in the risk of non‐syndromic oral clefts in the Brazilian population
Authors: Azevedo Camilla de Marchi Sanches , Machado Renato Assis , Martelli‐Júnior Hercílio , Reis Silvia Regina de Almeida , Persuhn Darlene Camati , Coletta Ricardo D. , Rangel Ana Lúcia Carrinho Ayroza
Published: September 2019

Objective

To investigate the association of single‐nucleotide polymorphisms (SNP) in grainyhead‐like 3 (GRHL3) and to verify its possible interactions with others genes responsible for craniofacial development in the risk of non‐syndromic oral cleft (NSOC).

Methods

Applying TaqMan allelic discrimination assays, we evaluated GRHL3 SNPs (rs10903078, rs41268753, and rs4648975) in an ancestry‐structured case–control sample composed of 1,127 Brazilian participants [272 non‐syndromic cleft palate only (NSCPO), 242 non‐syndromic cleft lip only (NSCLO), 319 non‐syndromic cleft lip and palate (NSCLP), and 294 healthy controls]. Additionally, SNP‐SNP interactions of GRHL3 and previously reported variants in FAM49A, FOXE1, NTN1, and VAX1 were verified in non‐syndromic cleft lip with or without cleft palate (NSCL ± P). To eliminate false‐positive associations, Bonferroni correction or 1,000 permutation method was applied.

Results

The multiple logistic regression analysis showed that the CC genotype of rs10903078 (p = .03) and the haplotype C‐C formed by the SNPs rs10903078 and rs41268753 (p = .04) were associated with NSCLO, but the p‐values did not withstand Bonferroni correction. However, SNP‐SNP test revealed significant interactions between GRHL3 SNPs and FAM49A (rs7552), FOXE1 (rs3758249), VAX1 (rs7078160 and rs751231), and NTN1 (rs9891446).

Conclusions

Our results confirm the importance of GRHL3 and its interactions with previously NSOC‐associated genes, including FAM49A, FOXE1, NTN1, and VAX1, in the pathogenesis of NSOC in the Brazilian population.
Perforated trapezoidal artificial reefs can augment the benefits of restoration of an island and its marine ecosystem
Authors: Jayanthi M , Patterson Edward J. K. , Malleshappa H , Gladwin Gnana Asir N , Mathews G , Diraviya Raj K , Bilgi Deepak S. , Ashok Kumar T. K , Sannasiraj S. A
Published: September 2019

The Gulf of Mannar (GoM) is located along the southeast coast of India. It has a chain of 21 low‐lying uninhabited islands extending from Rameswaram to Tuticorin. These islands are endowed with coral reefs, beds of seagrasses, and other associated marine life. Growing human population has led to accelerated coral mining and destructive fishing practices and this has brought about changes in the bio‐geomorphology of the islands, altered the hydrodynamic conditions, and resulted in severe erosion of the islands. The area of Vaan Island had decreased from 20.8 ha in 1969 to 2.33 ha in 2015. While hard measures have proven successful in preventing erosion, ecosystem‐based measures taking into account the resilience of the flora and fauna yield greater and more natural benefits. A total of 10,600 perforated trapezoidal artificial reef (AR) modules were deployed in clusters along two rows on the windward side of Vaan Island. ARs of 1 and 2 m height were placed respectively along contours of 2 and 3 m depth. The shape and arrangement of the ARs dissipated wave energy through the shoaling effect. As a result, a spit appeared and the area increased to 3.15 ha. The ARs also support epibenthic communities, benthic macrofauna, corals, and fishes. The deployment of an ecosystem‐based multipurpose perforated trapezoidal AR model has been successful not only in restoring the sinking island but also in enhancing the species richness, and it can be adopted as a tool in the restoration of islands and their marine ecosystems.
The relationship of volume overload and its control to hypertension in hemodialysis patients
Authors: Flythe Jennifer E. , Bansal Nisha
Published: September 2019

Hypertension is highly prevalent and associated with poor clinical outcomes among individuals receiving maintenance hemodialysis (HD). Volume overload is a key modifiable contributor to hypertension and cardiovascular disease in the HD population. Despite their importance, assessment and treatment of volume overload and hypertension remain major clinical challenges and have substantial implications for both clinical outcomes and patient experiences of care. This review will summarize current data on the diagnosis, epidemiology, pathophysiology, and clinical consequences of hypertension and volume overload in HD patients. We will also identify priorities for future research studies.
Cognitive Science Is and Should Be Pluralistic
Authors: Gentner Dedre
Published: September 2019

Núñez et al (2019) argue (1) that the field of Cognitive Science has failed, in that it has not arrived at a cohesive theory, and (2) that this is contrary to the intentions of the founders. Their survey of publication and citation patterns bears out the lack of a cohesive theory and also provides corroboration for (3) the concern that the field is becoming unbalanced, with psychology overweighted (Gentner, 2010). I will argue against points (1) and (2), but agree with point (3). My central claim is that cognitive science was never meant to have one unified theoretical framework, nor should it have.
Multidisciplinary Flux and Multiple Research Traditions Within Cognitive Science
Authors: Cooper Richard P.
Published: September 2019

Núñez et al. (2019) argue that cognitive science has failed either “to transition to a mature inter‐disciplinary coherent field” (p. 782) or “to generate a successful [Lakatosian] research program” (p. 789). We argue that the former was never the intention of many early researchers within the field, while the latter is an inappropriate criterion by which to judge an entire discipline. However, we concur with Núñez et al. (2019) that the individual disciplinary balance within cognitive science has changed over time. Of particular concern is the fact that the use of computational methods appears to be on the wane.
Events in Early Nervous System Evolution
Authors: Paulin Michael G. , Cahill‐Lane Joseph
Published: September 2019

We propose that neurons and nervous systems evolved among thin, motile, microbe‐eating animals during the Ediacaran period (635–543 million years ago). Spiking neurons evolved from epithelial cells around the margins of Ediacaran microbial mat grazers that initially specialized to detect weak bioelectric fields of nearby animals and to trigger rapid withdrawal movements. According to this scenario, nervous systems are a consequence of two preceding animal innovations, external digestion and motility, which have co‐evolved in concert with nervous systems ever since. We suggest that fundamental characteristics of modern nervous systems can be explained by studying how nervous systems originated during the Ediacaran period, as natural computers for predictive statistical inference given event‐based sense data.