bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interactions between cardiac activity and conscious somatosensory perception
Authors: Motyka Paweł , Grund Martin , Forschack Norman , Al Esra , Villringer Arno , Gaebler Michael 
Published: January 2019

AbstractFluctuations in the heart’s activity can modulate the access of external stimuli to consciousness. The link between perceptual awareness and cardiac signals has been investigated mainly in the visual and auditory domain. We here investigated whether the phase of the cardiac cycle and the pre-stimulus heart rate influence conscious somatosensory perception. We also tested how conscious detection of somatosensory stimuli affects the heart rate. Electrocardiograms (ECG) of 33 healthy volunteers were recorded while applying near-threshold electrical pulses at a fixed intensity to the left index finger. Conscious detection was not uniformly distributed across the cardiac cycle but significantly higher in diastole than in systole. We found no evidence that the heart rate before a stimulus influenced its detection but hits (correctly detected somatosensory stimuli) led to a more pronounced cardiac deceleration than misses. Our findings demonstrate interactions between cardiac activity and conscious somatosensory perception, which highlights the importance of internal bodily states for sensory processing beyond the auditory and visual domain.Impact StatementIt is highly debated to what extent cardiac activity modulates the access of external stimuli to consciousness. The evidence is inconsistent across sensory modalities and previous research focused at specific intervals within the cardiac cycle. Here, we examined the perception of near-threshold electrical pulses across the entire cardiac cycle. Our results show that conscious somatosensory perception is enhanced during the late phase of the cardiac cycle (at diastole) and associated with a more pronounced cardiac deceleration (as compared to non-detected stimuli). This strengthens the evidence that the physiological state of the body influences how we perceive the world.
Dedifferentiation orchestrated through remodeling of the chromatin landscape defines PSEN1 mutation-induced Alzheimer’s Disease
Authors: Caldwell Andrew B. , Liu Qing , Schroth Gary P. , Tanzi Rudolph E. , Galasko Douglas R. , Yuan Shauna H. , Wagner Steven L. , Subramaniam Shankar 
Published: January 2019

AbstractEarly-Onset Familial Alzheimer’s Disease (EOFAD) is a dominantly inherited neurodegenerative disorder elicited by mutations in the PSEN1, PSEN2, and APP genes1. Hallmark pathological changes and symptoms observed, namely the accumulation of misfolded Amyloid-β (Aβ) in plaques and Tau aggregates in neurofibrillary tangles associated with memory loss and cognitive decline, are understood to be temporally accelerated manifestations of the more common sporadic Late-Onset Alzheimer’s Disease. The complete penetrance of EOFAD-causing mutations has allowed for experimental models which have proven integral to the overall understanding of AD2. However, the failure of pathology-targeting therapeutic development suggests that the formation of plaques and tangles may be symptomatic and not describe the etiology of the disease3,4. Here, we use an integrative, multi-omics approach and systems-level analysis in hiPSC-derived neurons to generate a mechanistic disease model for EOFAD. Using patient-specific cells from donors harboring mutations in PSEN1 differentiated into neurons, we characterize the disease-related gene expression and chromatin accessibility changes by RNA- Seq, ATAC-Seq, and histone methylation ChIP-Seq. We show that the defining disease-causing mechanism of EOFAD is dedifferentiation, primarily through the REST-mediated repression of neuronal lineage specification gene programs and the activation of non-specific germ layer precursor gene programs concomitant with modifications in chromatin accessibility. These gene signature profiles and changes in chromatin topology illustrate that EOFAD neurons traverse the chromatin landscape from an ectodermal origin to a mixed germ lineage state. Further, a reanalysis of existing transcriptomic data from PSEN1 patient brain samples demonstrates that the mechanisms identified in our experimental system recapitulate EOFAD in the human brain. Our results comprise a disease model which describes the mechanisms culminating in dedifferentiation that precede amyloid and tau pathology formation and engender neurodegeneration.
Consecutive signaling pathways are activated in progression of Duchenne muscular dystrophy inC. elegans
Authors: Hrach Heather C , Steber Hannah S , Newbern Jason , Rawls Alan , Mangone Marco 
Published: January 2019

ABSTRACTBackground:Duchenne muscular dystrophy (DMD) is a lethal, X-linked disease characterized by progressive muscle degeneration. The condition is driven by nonsense and missense mutations in the dystrophin gene, but the resulting changes in muscle-specific gene expression that take place in dystrophin’s absence remain uncharacterized, as they are potentially obscured by the chronic inflammation elicited by muscle damage in humans.C. eleganspossess a mild inflammatory response that allows for the characterization of the transcriptome rearrangements affecting disease progression independently of inflammation.Results:In effort to better understand these dynamics we have isolated and sequenced body muscle-specific transcriptomes fromC. eleganslacking functional dystrophin at distinct stages of disease progression. We have identified two consecutively altered gene networks, which are also disrupted in the dystrophin deficientmdxmouse model. We found an upregulation of genes involved in mitochondrial function early in disease progression, and an upregulation of genes related to muscle fibre repair in later stages. This suggests that dystrophin may have a signaling role early in development, and its absence may activate compensatory mechanisms that counteract muscle degradation caused by loss of dystrophin. We have also developed a temperature-based screening method for synthetic paralysis that can be used to rapidly identify genetic partners of dystrophin.Conclusions:Our results allow for the comprehensive identification of transcriptome rearrangements that potentially serve as independent drivers of disease progression and may in turn allow for the identification of new therapeutic targets for the treatment of DMD.One Sentence Summary:A tissue specific transcriptome analysis of dystrophin deficient muscle inC. elegansreveals that dystrophin has distinct, dynamic signaling roles in early and late stage progression of Duchenne muscular dystrophy.
Comparative ChIP-seq (Comp-ChIP-seq): a practical guideline for experimental design and a novel computational methodology
Authors: Blanco Enrique , Croce Luciano Di , Aranda Sergi 
Published: January 2019

ABSTRACTChromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) is a pivotal technique for understanding the functionality of the chromatin-bound factors and for mapping the functional elements of the genome. In order to evaluate cell- and disease-specific changes in the interacting strength of chromatin targets, ChIP-seq signal across multiple conditions must undergo robust normalization. However, this is not possible using the standard ChIP-seq scheme, which lacks a reference for the control of biological and experimental variabilities. While several studies have recently proposed different solutions to circumvent this problem, substantial technical and analytical differences among methodologies could hamper the experimental reproducibility. Here we provide a practical binary decision-making process to experimentally implement a normalizing method for comparative ChIP-seq across different samples. In addition, we evaluate side-by-side the current computational approaches for normalizing using a reference internal genome. Finally, we propose a local regression strategy to accurately normalize ChIP-seq data in a genome-wide manner. Overall, our proposed experimental and computational standard for comparative ChIP-seq (Comp-ChIP-seq) will increase experimental reproducibility, thereby reducing this major confounding factor in interpreting ChIP-seq results.
Thioridazine as an Anticancer Therapeutic: Interplay with the Isoprenoid Biosynthetic Pathway
Authors: Weissenrieder Jillian S. , Reed Jessie L. , Neighbors Jeffrey D. , Hohl Raymond J. 
Published: January 2019

AbstractGlioblastoma multiforme is a form of cancer with poor survival prognosis and few treatment options. The cerebrovascular barrier complicates the delivery of chemotherapeutic agents and contributes to poor treatment response in patients with this disease. Recently, dopamine D2 receptor antagonizing compounds, including the FDA-approved phenothiazine, thioridazine, were identified as potential anticancer therapeutics, but their mechanism of action is as yet poorly understood. We investigated the hypothesis that the cytotoxicity of thioridazine may be tied to disruption of lipid metabolism, specifically the synthesis of isoprenoids and cholesterol by the isoprenoid biosynthetic pathway. We show that, while pathway inhibitors lovastatin and zoledronate can sensitize U87MG and U251MG cells to thioridazine treatment, the addition of pathway intermediates cannot prevent thioridazine’s cytotoxic effects. Treatment with methyl-schweinfurthin G, which is known to disrupt lipid trafficking, is able to sensitize these cell lines as well, suggesting that cholesterol availability or localization may be involved in these effects. However, all measured effects were of very small, biologically insignificant magnitude and thus findings are of limited utility.
Defining tissue- and disease-associated macrophages using a transcriptome-based classification model
Authors: Chen Hung-Jen , Li Yim Andrew Y.F. , Griffith Guillermo R. , de Jonge Wouter J. , Mannens Marcel M.A.M. , Ferrero Enrico , Henneman Peter , de Winther Menno P.J. 
Published: January 2019

AbstractMacrophages are heterogeneous multifunctional leukocytes which are regulated in a tissue-and disease-specific context. Many different studies have been published using in vitro macrophage models to study disease. Here, we aggregated public expression data to define consensus expression profiles for eight commonly-used in vitro macrophage models. Altogether, we observed well-known but also novel markers for different macrophage subtypes. Using these data we subsequently built the classifier macIDR, capable of distinguishing macrophage subsets with high accuracy (>0.95). This classifier was subsequently applied to transcriptional profiles of tissue-isolated and disease-associated macrophages to specifically define macrophage characteristics in vivo. Classification of these in vivo macrophages showed that alveolar macrophages displayed high resemblance to interleukin-10 activated macrophages, whereas macrophages from patients with chronic obstructive pulmonary disease patients displayed a drop in interferon-γ signature. Adipose tissue-derived macrophages were classified as unstimulated macrophages, but resembled LPS-activated macrophages more in diabetic-obese patients. Finally, rheumatoid arthritic synovial macrophages showed characteristics of both interleukin-10 or interferon-γ signatures. Altogether, our results suggest that macIDR is capable of identifying macrophage-specific changes as a result of tissue-and disease-specific stimuli and thereby can be used to better define and model populations of macrophages that contribute to disease.
Reallocation to lateral and early-emerging axial roots allows maize (Zea mays L.) with reduced nodal root number to more efficiently forage for nitrate
Authors: Guo Haichao , York Larry M. 
Published: January 2019

ABSTRACTPrevious simulations indicated reduced nodal root number (NRN) was promising for maize (Zea maysL.) breeding, and were partially confirmed using variation in NRN among inbreds. However, the exact mechanism was unknown, therefore manipulative experiments were conducted in hydroponics and tall solid-media mesocosms with treatments involving no nodal root excision (0% NRE) or excising either 33% or 67% of the nodal roots (NR) as they emerged under high or low levels of nitrogen (N). Reduced NRN was hypothesized to increase elongation of all remaining root classes, increase N acquisition under low N, and increase shoot mass. In both experiments, plants with 67% NRE had 12% and 19% less root fraction of total biomass, 61% and 91% greater lateral-to-axial root length ratio regardless of N levels; and 61% and 182% greater biomass of embryonic roots under low N, compared to 0% NRE for hydroponics and mesocosms studies, respectively. In hydroponics, regardless of NRE level, specific root respiration under high N was 2.6 times of low N, and was greatest at depth. Under low N in mesocosms, plants with 67% NRE had 52% greater shoot biomass, 450% greater root length at depth, and 232% greater deep-injected15N content in the shoot relative to 0% NRE, however biomass in hydroponics did not differ based on NRE. These results reveal the mechanism by which plants with fewer nodal roots increase N capture and shoot mass by reallocation of biomass to lateral, embryonic, and first whorl nodal roots that increases foraging efficiency in solid media.SummaryReallocating root biomass from nodal roots to lateral and early-emerging axial roots allows grasses to capture more nitrogen under limiting conditions, including by increasing foraging at depth.
Single-molecule long-read sequencing reveals the chromatin basis of gene expression
Authors: Wang Yunhao , Wang Anqi , Liu Zujun , Thurman Andrew , Powers Linda S. , Zou Meng , Hefel Adam , Li Yunyi , Zabner Joseph , Au Kin Fai 
Published: January 2019

ABSTRACTGenome-wide chromatin accessibility and nucleosome occupancy profiles have been widely investigated, while the long-range dynamics remains poorly studied at the single-cell level. Here we present a new experimental approach MeSMLR-seq (methyltransferase treatment followed by single-molecule long-read sequencing) for long-range mapping of nucleosomes and chromatin accessibility at single DNA molecules, and thus achieve comprehensive-coverage characterization of the corresponding heterogeneity. We applied MeSMLR-seq to haploid yeast, where single DNA molecules represent single cells, and thus we could investigate the combinatorics of many (up to 356) nucleosomes at long range in single cells. We illustrated the differential organization principles of nucleosomes surrounding transcription start site for silently- and actively-transcribed genes, at the single-cell level and in the long-range scale. The heterogeneous patterns of chromatin statuses spanning multiple genes were phased. Together with single-cell RNA-seq data, we quantitatively revealed how chromatin accessibility correlated with gene transcription positively in a highly-heterogeneous scenario. Moreover, we quantified the openness of promoters and investigated the coupled chromatin changes of adjacent genes at single DNA molecules during transcription reprogramming.
Accumulation of Rare Coding Variants in Genes Implicated in Risk of Human Cleft Lip with or without Cleft Palate
Authors: Marini Nicholas J. , Asrani Kripa , Yang Wei , Rine Jasper , Shaw Gary M 
Published: January 2019

ABSTRACTCleft lip with/without cleft palate (CLP) is a common craniofacial malformation with complex etiologies, reflecting both genetic and environmental factors. Most of the suspected genetic risk for CLP has yet to be identified. To further classify risk loci and estimate the contribution of rare variants, we sequenced the exons in 49 candidate genes in 323 CLP cases and 211 non-malformed controls. Our findings indicated that rare, protein-altering variants displayed markedly higher burdens in CLP cases at relevant loci. First, putative loss-of-function mutations (nonsense, frameshift) were significantly enriched among cases: 13 of 323 cases (~4%) harbored such alleles within these 49 genes, versus one such change in controls (p= 0.01). Second, in gene-level analyses, the burden of rare alleles showed greater case-association for several genes previously implicated in cleft risk. For example,BHMTdisplayed a 10-fold increase in protein-altering variants in CLP cases (p= 0.03), including multiple case occurrences of a rare frameshift mutation (K400fs). Other loci with greater rare, coding allele burdens in cases were in signaling pathways relevant to craniofacial development (WNT9B,BMP4,BMPR1B) as well as the methionine cycle (MTRR). We conclude that rare coding variants may confer risk for isolated CLP.
Multi-omic analysis of CIC’s functional networks reveals novel interaction partners and a potential role in mitotic fidelity
Authors: Takemon Yuka , LeBlanc Véronique G. , Song Jungeun , Chan Susanna Y. , Lee Stephen Dongsoo , Trinh Diane L. , Ahmad Shiekh Tanveer , Brothers William R. , Corbett Richard D. , Gagliardi Alessia , Moradian Annie , Cairncross J Gregory , Yip Stephen , Aparicio Samuel A.J.R. , Chan Jennifer A. , Hughes Christopher S. , Morin Gregg B. , Gorski Sharon M. , Chittaranjan Suganthi , Marra Marco A. 
Published: January 2019

AbstractCICencodes a transcriptional repressor and MAPK signalling effector that is inactivated by loss-of-function mutations in several cancer types, consistent with a role as a tumour suppressor. Here, we used bioinformatic, genomic, and proteomic approaches to investigate CIC’s interaction networks. We observed both previously identified and novel candidate interactions between CIC and SWI/SNF complex members, and also observed novel interactions between CIC and cell cycle regulators and RNA processing factors. We found that CIC loss is associated with an increased frequency of mitotic defects in human cell lines and anin vivomouse model and with dysregulated expression of mitotic regulators. We also observed aberrant splicing in CIC-deficient cell lines predominantly at 3’ and 5’ untranslated regions of genes, including genes involved in MAPK signalling, DNA repair, and cell cycle regulation. Our study thus characterises the complexity of CIC’s functional network and describes the effect of its loss on cell cycle regulation, mitotic integrity, and transcriptional splicing, thereby expanding our understanding of CIC’s potential roles in cancers. In addition, our work exemplifies how multi-omic, network-based analyses can be used to uncover novel insights into the interconnected functions of pleiotropic genes/proteins across cellular contexts.Simple summaryCapicua (CIC) is a gene that is frequently mutated in several cancer types, including stomach cancers and certain subtypes of brain tumours and sarcomas. CIC, the protein encoded by theCICgene, has been shown to play a multitude of roles in both normal and cancer cell functions; however, most studies exploring these roles focus on a single aspect of CIC function and may therefore overlook complex interconnected activities in which CIC is involved. In this study, we have used multiple complementary approaches to obtain a broader view of CIC’s complex functional networks. We observed novel interactions (genetic or physical) between CIC and genes/proteins involved in various aspects of cellular function, including regulation of cell division and processing of RNA molecules. Altogether, our work characterises the complexity of CIC’s functional network and expands our understanding of its potential roles in cancer.
A sensory ecological perspective on mate sampling strategies: simulation models and an empirical test
Authors: Nandi Diptarup , Suswaram Megha , Balakrishnan Rohini 
Published: January 2019

AbstractLong-range communication signals play a central role in mate search and mate choice across a wide range of taxa. Among the different aspects of mate choice, the strategy an individual employ to search for potential mates (mate sampling) has been less explored despite its significance. Although analytical models of mate sampling have demonstrated significant differences in individual fitness returns for different sampling strategies, these models have rarely incorporated relevant information on the ecology of signalers and sensory physiology of receivers, both of which can profoundly influence which sampling strategy is optimal. In this study, we used simulation models to compare the costs and benefits of different female mate sampling strategies in an acoustically communicating field cricket (Plebeiogryllus guttiventris) by incorporating information on relative spacing of callers in natural choruses, their signal intensity and the effect of signal intensity on female phonotaxis behaviour. Mating with the louder caller that the female first approaches emerged as the optimal strategy, thus reflecting the importance of physiological mechanisms of sound signal localization (passive attraction) over active sampling. When tested empirically in the field, female behaviour was consistent with passive attraction.
The influence of object-colour knowledge on emerging object representations in the brain
Authors: Teichmann Lina , Quek Genevieve L. , Robinson Amanda K. , Grootswagers Tijl , Carlson Thomas A. , Rich Anina N. 
Published: January 2019

AbstractThe ability to rapidly and accurately recognise complex objects is a crucial function of the human visual system. To recognise an object, we need to bind incoming visual features such as colour and form together into cohesive neural representations and integrate these with our pre-existing knowledge about the world. For some objects, typical colour is a central feature for recognition; for example, a banana is typically yellow. Here, we applied multivariate pattern analysis on time-resolved neuroimaging (magnetoencephalography) data to examine how object-colour knowledge affects emerging object representations over time. Our results from 20 participants (11 female) show that the typicality of object-colour combinations influences object representations, although not at the initial stages of object and colour processing. We find evidence that colour decoding peaks later for atypical object-colour combinations in comparison to typical object-colour combinations, illustrating the interplay between processing incoming object features and stored object-knowledge. Taken together, these results provide new insights into the integration of incoming visual information with existing conceptual object knowledge.Significance StatementTo recognise objects, we have to be able to bind object features such as colour and shape into one coherent representation and compare it to stored object knowledge. The magnetoencephalography data presented here provide novel insights about the integration of incoming visual information with our knowledge about the world. Using colour as a model to understand the interaction between seeing and knowing, we show that there is a unique pattern of brain activity for congruently coloured objects (e.g., a yellow banana) relative to incongruently coloured objects (e.g., a red banana). This effect of object-colour knowledge only occurs after single object features are processed, demonstrating that conceptual knowledge is accessed relatively late in the visual processing hierarchy.