bluuebunny/crossref_metadata_2025_split huggingface dataset:
Co-circulation and misdiagnosis led to underestimation of the 2015-2017 Zika epidemic in the Americas
Authors: Oidtman Rachel J. , España Guido , Perkins T. Alex 
Published: October 2019

AbstractDuring the 2015-2017 Zika epidemic, dengue and chikungunya – two other viral diseases with the same vector as Zika – were also in circulation. Clinical presentation of these diseases can vary from person to person in terms of symptoms and severity, making it difficult to differentially diagnose them. Under these circumstances, it is possible that numerous cases of Zika could have been misdiagnosed as dengue or chikungunya, or vice versa. Given the importance of surveillance data for informing epidemiological analyses, our aim was to quantify the potential extent of misdiagnosis during this epidemic. Using basic principles of probability and empirical estimates of diagnostic sensitivity and specificity, we generated revised estimates of Zika incidence that accounted for the accuracy of diagnoses made on the basis of clinical presentation with or without molecular confirmation. Applying this method to weekly incidence data from 43 countries throughout Latin America and the Caribbean, we estimated that 1,062,821 (95% CrI: 1,014,428-1,104,794) Zika cases occurred during this epidemic, which is 56.4% (95% CrI: 49.3-62.6%) more than the 679,743 cases diagnosed as Zika. Our results imply that misdiagnosis was more common in countries with proportionally higher incidence of dengue and chikungunya, such as Brazil.
Comprehensive molecular characterization of pediatric treatment-induced high-grade glioma: A distinct entity despite disparate etiologies with defining molecular characteristics and potential therapeutic targets
Authors: DeSisto John , Lucas John T. , Xu Ke , Donson Andrew , Lin Tong , Sanford Bridget , Wu Gang , Tran Quynh T. , Hedges Dale , Hsu Chih-Yang , Armstrong Gregory T. , Arnold Michael , Bhatia Smita , Flannery Patrick , Lemma Rakeb , Hardie Lakotah , Schüller Ulrich , Hoffman Lindsey M. , Dorris Kathleen , Levy Jean Mulcahy , Hankinson Todd C. , Handler Michael , Liu Arthur , Foreman Nicholas , Vibhakar Rajeev , Jones Kenneth , Allen Sariah , Zhang Jinghui , Baker Suzanne J. , Merchant Thomas E. , Orr Brent A. , Green Adam L. 
Published: October 2019

AbstractTreatment-induced high-grade gliomas (TIHGGs) are an incurable late complication of cranial radiation therapy or combined radiation/chemotherapy used to treat pediatric cancer. We assembled a cohort of 33 TIHGGs from multiple institutions. The primary antecedent malignancies were medulloblastoma, acute lymphoblastic leukemia, astrocytoma, and ependymoma. We performed methylation profiling, RNA-seq, and genomic sequencing (whole-genome or whole-exome) on TIHGG samples. Methylation profiling revealed that TIHGGs cluster primarily with the pediatric receptor tyrosine kinase I subtype (26/31 samples). Common TIHGG copy-number alterations include Chromosome (Ch.) 1p loss/1q gain, Ch. 4 loss, Ch. 6q loss, and Ch. 13 and Ch. 14 loss; focal alterations include PDGFRA and CDK4 gain and loss of CDKN2A and BCOR. Relative to de novo pediatric high-grade glioma (pHGG), BCOR loss (p=0.004) and CDKN2A loss (p=0.005) were significantly increased. Transcriptomic analysis identified two distinct TIHGG subgroups, one with a lesser mutation burden (0.12 mut/Mb), Ch. 1p loss/1q gain (5/6 samples), and stem cell characteristics, and one with a greater mutation burden (1.08 mut/Mb, p<0.0002), depletion of DNA repair pathways, and inflammatory characteristics. We observed increased chromothripsis in TIHGG versus pHGG (67% vs. 31%, p=0.036), which was associated with extrachromosomal circular DNA-mediated amplification of PDGFRA and CDK4. In vitro drug screening in one primary, patient-derived TIHGG cell line from each expression subgroup identified microtubule inhibitors/stabilizers, DNA-damaging agents, MEK inhibition, and, in the inflammatory subgroup, proteasome inhibitors as potentially effective therapies. This study provides a comprehensive molecular profile of TIHGG, including mechanistic insights to TIHGG oncogenesis, and identifies potentially effective therapeutic modalities for further investigation.
Head motion during fMRI tasks is reduced in children and adults if participants take breaks
Authors: Meissner Tobias W. , Walbrin Jon , Nordt Marisa , Koldewyn Kami , Weigelt Sarah 
Published: October 2019

AbstractHead motion remains a challenging confound in functional magnetic resonance imaging (fMRI) studies of both children and adults. Most pediatric neuroimaging labs have developed experience-based, child-friendly standards concerning e.g. the maximum length of a session or the time between mock scanner training and actual scanning. However, it is unclear which factors of child-friendly neuroimaging approaches are effective in reducing head motion. Here, we investigate three main factors including (i) time lag of mock scanner training to the actual scan, (ii) prior scan time, and (iii) task engagement in a dataset of 77 children (aged 6-13) and 64 adults (aged 18-35) using a multilevel modeling approach. In children, distributing fMRI data acquisition across multiple same-day sessions reduces head motion. In adults, motion is reduced after inside-scanner breaks. Despite these positive effects of splitting up data acquisition, motion increases over the course of a study as well as over the course of a run in both children and adults. Our results suggest that splitting up fMRI data acquisition is an effective tool to reduce head motion in general. At the same time, different ways of splitting up data acquisition benefit children and adults.HighlightsIn children, fMRI data acquisition split into multiple sessions reduces head motionIn adults, fMRI data acquisition split by inside-scanner breaks reduces head motionIn both children and adults, motion increases over the duration of a studyIn both children and adults, motion increases over the duration of a run
Two Receptor-Like Kinases Required For Arabidopsis Endodermal Root Organisation Shape The Rhizosphere Microbiome
Authors: Durr Julius , Reyt Guilhem , Spaepen Stijn , Hilton Sally , Meehan Cathal , Qi Wu , Kamiya Takehiro , Flis Paulina , Dickinson Hugh G. , Feher Attila , Bending Gary D. , Schulze-Lefert Paul , Salt David , Gutierrez-Marcos Jose 
Published: October 2019

AbstractThe Casparian Strip (CS) constitutes a physical diffusion barrier to water and nutrients in plant roots, and is formed by the polar deposition of lignin polymer in the endodermis. This precise pattern of lignin deposition is thought to be mediated by the scaffolding activity of membrane-bound Casparian Strip domain proteins (CASPs). However, we show that endodermis-specific receptor-like kinase 1 (ERK1) and ROP Binding Kinase1 (RBK1) are also involved in this intricate process, with the former playing an essential role both in the localization of CASP1 and in lignin deposition. We further characterised ERK1 and determined its subcellular localisation in the cytoplasm and nucleus of the endodermis, as well as provide evidence for its involvement in a signalling pathway together with the circadian clock regulator, Time for Coffee (TIC). We also show that disruption to CS organisation and increased suberisation in the endodermis due to loss of function of eitherERK1orTICcollectively leads to an altered root microbiome composition. Thus, our work reveals additional players in the complex cascade of signalling events operating in the root endodermis to establish both the CS diffusion barrier and the microbial composition of the rhizosphere.
Male genital lobe morphology affects the chance to copulate inDrosophila pachea
Authors: Lefèvre Bénédicte M. , Catté Diane , Courtier-Orgogozo Virginie , Lang Michael 
Published: October 2019

AbstractIntroductionMale genitalia are thought to ensure transfer of sperm through direct physical contact with female during copulation. However, little attention has been given to their pre-copulatory role with respect to sexual selection and sexual conflict. Males of the fruitflyDrosophila pacheahave a pair of asymmetric external genital lobes, which are primary sexual structures and stabilize the copulatory complex of female and male genitalia. We wondered if genital lobes inD. pacheamay have a role before or at the onset of copulation, before genitalia contacts are made.ResultsWe tested this hypothesis with aD. pacheastock where males have variable lobe lengths. In 92 mate competition trials with a single female and two males, females preferentially engaged into a first copulation with males that had a longer left lobe and that displayed increased courtship vigor. In 53 additional trials with both males having partially amputated left lobes of different lengths, we observed a weaker and non-significant effect of left lobe length on copulation success. Courtship durations significantly increased with female age and when two males courted the female simultaneously, compared to trials with only one courting male. In addition, lobe length did not affect sperm transfer once copulation was established.ConclusionLeft lobe length affects the chance of a male to engage into copulation. The morphology of this primary sexual trait may affect reproductive success by mediating courtship signals or by facilitating the establishment of genital contacts at the onset of copulation.
Targeting AKT elicits tumor suppressive functions of FOXO transcription factors and GSK3 kinase in Multiple Myeloma
Authors: Bloedjes Timon A. , de Wilde Guus , Maas Chiel , Eldering Eric E. , Bende Richard J. , van Noesel Carel J.M. , Pals Steven T. , Spaargaren Marcel , Guikema Jeroen E.J. 
Published: October 2019

ABSTRACTThe phosphatidylinositide-3 kinases (PI3K) and the downstream mediator AKT drive survival and proliferation of multiple myeloma (MM) cells and several AKT inhibitors are currently being tested in clinical trials for MM patients. AKT inhibition has pleiotropic effects, and the key aspects that determine therapeutic efficacy are not fully clear. Therefore, we investigated the antimyeloma mechanism(s) of AKT inhibition. Among the various downstream AKT targets are Forkhead box O (FOXO) transcription factors, and we demonstrate that they are crucial for changes in gene expression upon AKT inhibition. Based on gene expression profiling we defined an AKT-induced FOXO-dependent gene set that has prognostic significance in a large cohort of MM patients, where low FOXO activity correlates with inferior survival. We show that cell cycle exit and cell death of MM cells after AKT inhibition required FOXO. In addition, glycogen synthase kinase 3 (GSK3), a negatively regulated AKT substrate, proved to be pivotal to induce cell death and to inhibit cell cycle progression after AKT inhibition. Finally, we demonstrate that FOXO and GSK3 induced cell death by increasing the turnover of the myeloid cell leukemia 1 (MCL1) protein. In concordance, the AKT inhibitor MK2206 greatly sensitized MM cells for the MCL1 inhibitor S63845. Thus, our results indicate that FOXO and GSK3 are crucial mediators of the antimyeloma effects of AKT inhibition, and suggest combination therapies that may have therapeutic potential in MM.KEYPOINTSFOXO transcription factors and the GSK3 kinase are pivotal tumor suppressors downstream of AKT inhibition in MM cells.FOXO and GSK3 activation after AKT inhibition leads to a decrease in MCL1 levels in MM cells resulting in cell death.
Sensory substitution reveals a manipulation bias
Authors: Zai AT , Cavé-Lopez S , Rolland M , Giret N , Hahnloser RHR 
Published: October 2019

AbstractSensory substitution is a promising therapeutic approach for replacing a missing or diseased sensory organ by translating inaccessible information into another sensory modality. What aspects of substitution are important such that subjects accept an artificial sense and that it benefits their voluntary action repertoire? To obtain an evolutionary perspective on affective valence implied in sensory substitution, we introduce an animal model of deaf songbirds. As a substitute of auditory feedback, we provide binary visual feedback. Deaf birds respond appetitively to song-contingent visual stimuli, they skillfully adapt their songs to increase the rate of visual stimuli, showing that auditory feedback is not required for making targeted changes to a vocal repertoire. We find that visually instructed song learning is basal-ganglia dependent. Because hearing birds respond aversively to the same visual stimuli, sensory substitution reveals a bias for actions that elicit feedback to meet animals’ manipulation drive, which has implications beyond rehabilitation.
Use of a counterselectable transposon to create markerless knockouts from a 18,432-clone orderedM. bovisBCG mutant resource
Authors: Borgers Katlyn , Vandewalle Kristof , Van Hecke Annelies , Michielsen Gitte , Plets Evelyn , van Schie Loes , Vanmarcke Sandrine , Schindfessel Laurent , Festjens Nele , Callewaert Nico 
Published: October 2019

AbstractMutant resources are essential to improve our understanding of the biology of slow-growing mycobacteria, which include the causative agents of tuberculosis in various species, including humans. The generation of deletion mutants in slow-growing mycobacteria in a gene-by-gene approach in order to make genome-wide ordered mutant resources is still a laborious and costly approach; despite the recent development of improved methods. On the other hand, transposon mutagenesis in combination with Cartesian Pooling-Coordinate Sequencing allows the creation of large archivedMycobacteriumtransposon insertion libraries. However, such mutants contain selection marker genes with a risk of polar gene effects, which is undesired both for research and for use of these mutants as live attenuated vaccines. In this paper, a derivative of the Himar1 transposon is described, which allows the generation of clean, markerless knockouts from archived transposon libraries. By incorporatingFRTsites for FlpE/FRT-mediated recombination andI-SceIsites for ISceIM-based transposon removal, we enable two thoroughly experimentally validated possibilities to create unmarked mutants from such marked transposon mutants. TheFRTapproach is highly efficient but leaves anFRTscar in the genome, whereas theI-SceImediated approach can create mutants without any heterologous DNA in the genome. The combined use of CP-CSeq and this optimized transposon was applied in the BCG Danish 1331 vaccine strain (WHO reference 07/270), creating the largest ordered, characterized resource of mutants in a member of theM. tbcomplex (18,432 clones, mutating 83% of the non-essentialM. tbhomologues), from which clean knockouts can be generated.ImportanceWhile speeding up research for many fields of biology (e.g. yeast, plant, andC. elegans), genome-wide ordered mutant collections are still elusive in mycobacterial research. We developed methods to generate such resources in a time- and cost-effective manner, and developed a newly engineered transposon from which unmarked mutants can be efficiently generated. Our library in the WHO reference vaccine strain ofM. bovisBCG Danish targets 83% of all non-essential genes and was made publicly available via the BCCM/ITM Mycobacteria Collection. This resource will speed upMycobacteriumresearch (e.g. drug resistance research, vaccine development) and paves the way to similar genome-wide mutant collections in other strains of theM. tbcomplex. The stretch to a full collection of mutants in all non-essential genes is now much shorter, with just 17% remaining genes to be targeted using gene-by-gene approaches, for which highly effective methods have recently also been described.
Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis
Authors: Bolte Ashley C. , Hurt Mariah E. , Smirnov Igor , Kovacs Michael A. , McKee Celia A. , Natale Nick , Ennerfelt Hannah E. , Frost Elizabeth L. , Lammert Catherine E. , Kipnis Jonathan , Lukens John R. 
Published: October 2019

ABSTRACTTraumatic brain injury (TBI) has emerged as a leading cause of death and disability. Despite being a growing medical issue, the biological factors that promote central nervous system (CNS) pathology and neurological dysfunction following TBI remain poorly characterized. Recently, the meningeal lymphatic system was identified as a critical mediator of drainage from the CNS. In comparison to other peripheral organs, our understanding of how defects in lymphatic drainage from the CNS contribute to disease is limited. It is still unknown how TBI impacts meningeal lymphatic function and whether disruptions in this drainage pathway are involved in driving TBI pathogenesis. Here we demonstrate that even mild forms of brain trauma cause severe deficits in meningeal lymphatic drainage that can last out to at least two weeks post-injury. To investigate a mechanism behind impaired lymphatic function in TBI, we examined how increased intracranial pressure (ICP) influences the meningeal lymphatics, as increased ICP commonly occurs in TBI. We demonstrate that increased ICP is capable of provoking meningeal lymphatic dysfunction. Moreover, we show that pre-existing lymphatic dysfunction mediated by targeted photoablation before TBI leads to increased neuroinflammation and cognitive deficits. These findings provide new insights into both the causes and consequences of meningeal lymphatic dysfunction in TBI and suggest that therapeutics targeting the meningeal lymphatic system may offer strategies to treat TBI.
Kia kaua te reo e rite ki te moa, ka ngaro: Do not let the language suffer the same fate as the moa
Authors: Barrett-Walker Tessa , Plank Michael J. , Ka’ai-Mahuta Rachael , Hikuroa Daniel , James Alex 
Published: October 2019

AbstractMore than a third of the world’s languages are currently classified as endangered and more than half are expected to go extinct by 2100. Strategies aimed at revitalising endangered languages have been implemented in numerous countries, with varying degrees of success. Here, we develop a new model regarding language transmission by dividing the population into defined proficiency categories and dynamically quantifying transition rates between categories. The model can predict changes in proficiency levels over time and, ultimately, whether a given endangered language is on a long-term trajectory towards extinction or recovery. We calibrate the model using data from Wales and show that the model predicts that the Welsh language will thrive in the long term. We then apply the model to te reo Māori, the Indigenous language of New Zealand, as a case study. Initial conditions for this model are estimated using New Zealand census data. We modify the model to describe a country, such as New Zealand, where the endangered language is associated with a particular subpopulation representing the Indigenous People. We conclude that, with current learning rates, te reo Māori is on a pathway towards extinction, but identify strategies that could help restore it to an upward trajectory.
A missense variant impairing TRMT1 function in tRNA modification is linked to intellectual disability
Authors: Zhang Kejia , Lentini Jenna M , Prevost Christopher T , Hashem Mais O , Alkuraya Fowzan S , Fu Dragony 
Published: October 2019

AbstractThe humanTRMT1gene encodes a tRNA methyltransferase enzyme responsible for the formation of the dimethylguanosine (m2,2G) modification in cytoplasmic and mitochondrial tRNAs. Frameshift mutations in theTRMT1gene have been shown to cause autosomal-recessive intellectual disability (ID) in the human population but additional TRMT1 variants remain to be characterized. Moreover, the impact of ID-associated TRMT1 mutations on m2,2G levels in ID-affected patients is unknown. Here, we describe a homozygous missense variant inTRMT1in a patient displaying developmental delay, ID, and epilepsy. The missense variant changes a conserved arginine residue to a cysteine (R323C) within the methyltransferase domain of TRMT1 and is expected to perturb protein folding. Patient cells expressing the TRMT1-R323C variant exhibit a severe deficiency in m2,2G modifications within tRNAs, indicating that the mutation causes loss-of-function. Notably, the TRMT1 R323C mutant retains the ability to bind tRNA but is unable to rescue m2,2G formation in TRMT1-deficient human cells. Our results identify a pathogenic point mutation in TRMT1 that severely perturbs tRNA modification activity, and provide the first demonstration that m2,2G modifications are disrupted in patients with TRMT1-associated ID disorders.
Integrating somatosensory information over time
Authors: Hernández-Pérez Raúl , Rojas-Hortelano Eduardo , de Lafuente Victor 
Published: October 2019

AbstractOur choices are often informed by temporally integrating streams of sensory information. This has been well demonstrated in the visual and auditory domains, but the integration of tactile information over time has been less studied. We designed an active touch task in which subjects explored a spheroid-shaped object to determine its inclination with respect to the horizontal plane (inclined to the left or to the right). In agreement with previous findings, our results show that more errors, and longer decision times, accompany difficult decisions (small inclination angles). To gain insight into the decision-making process, we used a task in which the time available for tactile exploration was varied by the experimenter, in a trial-by-trial basis. The behavioral results were fit with a model of bounded accumulation, and also with an independent-sampling model which assumes no sensory accumulation. The results of model fits favor an accumulation-to-bound mechanism, and suggest that participants integrate the first 600 ms of 1800 ms-long stimuli. This means that the somatosensory system benefits from longer streams of information although it does not make use of all available evidence.HighlightsThe somatosensory system integrates information streams through time.Somatosensory discrimination thresholds decrease with longer stimuli.A bounded accumulation model is favored over independent sampling.Humans accumulate up to 600 ms, out of 1800 ms-long stimuli.
Mutant evolution in spatially structured and fragmented populations
Authors: Wodarz Dominik , Komarova Natalia L 
Published: October 2019

AbstractUnderstanding mutant evolution in spatially structured systems is crucially important for a range of biological systems, including bacterial populations and cancer. While previous work has shown that the mutation load is higher in spatially structured compared to well-mixed systems for neutral mutants in the absence of cell death, we demonstrate a significantly higher degree of complexity, using a comprehensive computational modeling approach that takes into account different mutant fitness, cell death, and different population structures. While an agent-based model assuming nearest neighbor interactions predicts a higher abundance of neutral or advantageous mutants compared to well-mixed systems of the same size, we show that for disadvantageous mutants, results depend on the nature of the disadvantage. In particular, if the disadvantage occurs through higher death rates, as opposed to lower reproduction rates, the result is the opposite, and a lower mutation load occurs in spatial compared to mixed systems. Interestingly, we show that in all cases, the same results are observed in fragmented patch models, where individuals can migrate to randomly chosen patches, thus lacking a strict spatial component. Hence, the results reported for spatial models are the consequence of population fragmentation, and not spatial restrictions per se. We further derive growth laws that characterize the expansion of wild type and mutant populations in different dimensionalities. For example, we find that while disadvantageous mutant abundance scales with the total population size, N, neutral mutants grow faster (as N2for 1D, as N3/2in 2D, and as N4/3in 3D). Advantageous mutants scale with the cube of N in 1D and with the square of N in higher dimensions. These laws are universal (as long as mutants remain a minority) and independent of “microscopic” modeling details.