bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic age provides insight into tissue origin in endometriosis
Authors: Leap Katie , Yotova Iveta , Horvath Steve , Martinez-Agosto Julian A 
Published: October 2019

AbstractBackgroundEndometriosis is a common reproductive disease with a heterogeneous presentation. Classification attempts have thus far not offered insight into its cause or its symptoms. Endometriosis may result from the migration of shed endometrium to the peritoneal cavity. However, there are cases reported in girls without uteruses and men. While a non-retrograde menstruation origin of ectopic tissue is certain in these cases, we propose using DNA methylation age (DNAm age) to distinguish between retrograde and non-retrograde etiologies.MethodsUsing publicly available DNA methylation data and Horvath’s pan-tissue epigenetic clock, we compared DNAm age and epigenetic age acceleration (EAA) of ectopic lesions to eutopic endometrium of diseased and control endometrium. We examined EAA in cancer metastasis and teratomas to control for migration and developmental origin.ResultsDisease status does not change DNAm age of eutopic endometrium, but the effect of ectopic status was profound: −16.88 years (p = 4.82 × 10−7). There were no differences between EAA of primary/metastatic tumor pairs, suggesting that the observed effect is not due to migration. Immature or mature teratoma compartments decreased DNAm age by 9.44 and 7.40 years respectively, suggesting that developmental state correlates with DNAm age.ConclusionsEctopic endometriotic tissue exhibits decelerated DNAm age, similar to that observed in teratomas composed of multipotent tissue. The migration process does not change DNAm age and eutopic endometrium is concordant with chronological age regardless of disease status. We conclude that DNAm age of ectopic lesions can classify endometriosis into distinct subtypes that may be clinically relevant.
GPU-accelerated mesh-based Monte Carlo photon transport simulations
Authors: Fang Qianqian , Yan Shijie 
Published: October 2019

AbstractThe mesh-based Monte Carlo (MMC) algorithm is increasingly used as the gold-standard for developing new biophotonics modeling techniques in 3-D complex tissues, including both diffusion-based and various Monte Carlo (MC) based methods. Compared to multi-layered and voxel-based MCs, MMC can utilize tetrahedral meshes to gain improved anatomical accuracy, but also results in higher computational and memory demands. Previous attempts of accelerating MMC using graphics processing units (GPUs) have yielded limited performance improvement and are not publicly available. Here we report a highly efficient MMC – MMCL – using the OpenCL heterogeneous computing framework, and demonstrate a speedup ratio up to 420× compared to state-of-the-art single-threaded CPU simulations. The MMCL simulator supports almost all advanced features found in our widely disseminated MMC software, such as support for a dozen of complex source forms, wide-field detectors, boundary reflection, photon replay and storing a rich set of detected photon information. Furthermore, this tool supports a wide range of GPUs/CPUs across vendors and is freely available with full source codes and benchmark suites at http://mcx.space/#mmc.
Disrupted remapping of place cells and grid cells in knock-in model of Alzheimer’s disease
Authors: Jun Heechul , Soma Shogo , Saito Takashi , Saido Takaomi C , Igarashi Kei M 
Published: October 2019

AbstractPatients with Alzheimer’s disease (AD) frequently suffer from spatial memory impairment and wandering behavior, but brain circuits causing such symptoms remain largely unclear. In healthy brains, spatially-tuned hippocampal place cells and entorhinal grid cells represent distinct spike patterns in different environments, a circuit function called “remapping” that underlies pattern separation of spatial memory. We investigated whether knock-in expression of mutated amyloid precursor protein deteriorates the remapping of place cells and grid cells. We found that the remapping of CA1 place cells was disrupted although their spatial tuning was only mildly diminished. Grid cells in the medial entorhinal cortex (MEC) were impaired, sending severely disrupted remapping signals to the hippocampus. Furthermore, fast gamma oscillations were disrupted in both CA1 and MEC, resulting in impaired fast gamma coupling in the MEC→CA1 circuit. These results point to the link between grid cell impairment and remapping disruption as a circuit mechanism causing spatial memory impairment in AD.
Epigenetic Effects of Assisted Reproductive Technology in Human Offspring
Authors: Chen Wei , Peng Yong , Ma Xinyi , Kong Siming , Tang Shuangyan , Wei Yuan , Zhao Yangyu , Zhang Wenxin , Wang Yang , Yan Liying , Qiao Jie 
Published: October 2019

AbstractThe births of more than 8 million infants have been enabled globally through assisted reproductive technologies (ARTs), including conventional in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) with either fresh embryo transfer (ET) or frozen embryo transfer (FET). However, the potential for elevated risks of ART-related disorders persists in adult life, and the underlying epigenetic mechanisms are largely uncharacterized. Here, we recruited 100 nuclear families and profiled the DNA methylomes, genome-wide histone modifications and transcriptomes to clarify the inherent extra risks attributable to specific ART procedures. We discovered that IVF-ET seemed to introduce less disturbance into the infant epigenome than IVF-FET or ICSI-ET did. Furthermore, we noted approximately half of the DNA methylomic changes in ART-conceived offspring could be explained by parental background biases. Through removal of the parental effect, we confirmed that ARTper sewould introduce minor DNA methylation changes locally. More importantly, we found that ART-induced epigenomic alterations were highly enriched in the processes which might contribute to increased incidence of preeclampsia during pregnancy and metabolic syndrome in offspring. Overall, our study provides an epigenetic basis for the potential long-term health risks in ART-conceived offspring that reinforces the need to review all methods of human ART.
Human periventricular nodular heterotopia shows several interictal epileptic patterns, associated with hyperexcitability of neuronal firing
Authors: Frazzini Valerio , Whitmarsh Stephen , Lehongre Katia , Yger Pierre , Lemarechal Jean-Didier , Matching Bertrand , Adam Claude , Hasboun Dominique , Lambrecq Virginie , Navarro Vincent 
Published: October 2019

AbstractPeriventricular nodular heterotopia (PNH) is a malformation of cortical development that frequently causes drug-resistant epilepsy. The epileptogenicity of ectopic neurons in PNH as well as their role in generating interictal and ictal activity is still a matter of debate. We report the firstin vivomicroelectrode recording of heterotopic neurons in humans. Highly consistent interictal patterns (IPs) were identified within the nodules: 1) Periodic Discharges PLUS Fast activity (PD+F), Sporadic discharges PLUS Fast activity (SD+F), and 3) epileptic spikes (ES). Neuronal firing rates were significantly modulated during all IPs, suggesting that multiple IPs were generated by the same local neuronal populations. Furthermore, firing rates closely followed IP morphologies. Among the different IPs, SD+FA pattern was found only in the three nodules that were actively involved in seizure generation, but was never observed in the nodule that did not take part in ictal discharges. On the contrary, PD+F and ES were identified in all nodules. Units that were modulated during the IPs were also found to participate in seizures, increasing their firing rate at seizure onset and maintaining an elevated rate during the seizures. Together, nodules in PNH are highly epileptogenic, and show several IPs that provide promising pathognomonic signatures of PNH. Furthermore, our results show that PNH nodules may well initiate seizures.HighlightsFirstin vivomicroelectrode description of local epileptic activities in human PNHRecordings revealed multiple microscopic epileptic interictal patternsFiring rates ofalldetected units were significantly modulated duringallinterictal patternsSeizures recruited the same units that are involved in interictal activity
Desmosomal coupling in apoptotic cell extrusion
Authors: Thomas Minnah , Ladoux Benoit , Toyama Yusuke 
Published: October 2019

SUMMARYThe mechanical coupling of epithelia enables coordination of tissue functions and collective tissue movements during different developmental and physiological processes. This coupling is ensured by cell-cell junctions, including adherens junctions (AJs) and desmosomal junctions (DJs) [1, 2]. During apoptosis, or programmed cell death, a dead cell is expelled from the tissue by coordinated processes between the dying cell and its neighbors. Apoptotic cell extrusion is driven by actomyosin cable formation and its contraction, and lamellipodial crawling of the neighboring cells (Fig. S1A-A’’, Movie S1) [3–6]. Throughout cell extrusion, the mechanical coupling of epithelia needs to be maintained in order to preserve tissue homeostasis [3]. Although much is known about the regulation of AJs in apoptotic cell extrusion [6–9], the role and dynamics of DJs during this process remains poorly understood. Here, we show that DJs stay intact throughout and are crucial for apoptotic cell extrusion. Pre-existing DJs between the apoptotic cell and neighboring non-dying cells remain intact even during the formation of de novo DJs between non-dying cells, suggesting that the neighboring cells possess two DJs in the middle of apoptotic cell extrusion. We further found that an actomyosin cable formed in the vicinity of DJs upon apoptosis, and subsequently deviated from DJs during its constriction. Interestingly, the departure of the actomyosin cable from DJs coincided with the timing when DJs lost their straightness, suggesting a release of junctional tension at DJs, and a mechanical coupling between DJs and actomyosin contractility. The depletion of desmoplakin, which links desmosomes and intermediate filaments, resulted in defective apical contraction and an inability to form de novo DJs, leading to a failure of apoptotic cell extrusion. Our study provides a framework to explain how desmosomes play pivotal roles in maintaining epithelial sheet integrity during apoptotic cell extrusion.
Meniscal and ligament modifications in spontaneous and post-traumatic mouse models of osteoarthritis
Authors: Ramos-Mucci Lorenzo , Javaheri Behzad , van ‘t Hof Rob , Bou-Gharios George , Pitsillides Andrew A , Comerford Eithne , Poulet Blandine 
Published: October 2019

AbstractOsteoarthritis (OA) is a whole joint disease that affects all joint tissues, with changes in the articular cartilage (AC), subchondral bone and synovium. Pathologies in menisci and ligaments, however, are rarely analysed, although both are known to play vital roles in the mechanical stability of the joint. The aim of our study was to describe the pathological changes in menisci and ligament during disease development in murine spontaneous and post-traumatic surgically-induced OA and to quantify tissue mineralisation in the joint space using µCT imaging during OA progression.Knees of Str/ort mice (spontaneous OA model; 26-40wks) and C57CBA F1 mice following destabilisation of medial meniscus (DMM) surgery (post-traumatic OA model; 8wks after DMM), were used to assess histological meniscal and ligament pathologies. Joint space mineralised tissue volume was quantified by µCT.Meniscal pathological changes in Str/ort mouse knees were associated with articular cartilage lesion severity. These meniscal changes included ossification, hyperplasia, cell hypertrophy, collagen type II deposition and SOX9 expression in the fibrous region near the attachment to the knee joint capsule. Anterior cruciate ligaments exhibited extracellular matrix changes and chondrogenesis particularly at the tibial attachment site, and ossification was seen in collateral ligaments. Similar changes were confirmed in the post-traumatic DMM model. µCT analysis showed increased joint space mineralised tissue volume with OA progression in both the post-traumatic and spontaneous OA models.Modifications in meniscal and ligament mineralisation and chondrogenesis are seen with overt AC degeneration in murine OA. Although the aetiology and the consequences of such changes remain unknown, they will influence stability and load transmission of the joint and may therefore contribute to OA progression. In addition, these changes may have important roles in movement restriction and pain, which represent major human clinical symptoms of OA. Description of such soft tissue changes, in addition to AC degradation, should be an important aspect of future studies in mouse models in order to furnish a more complete understanding of OA pathogenesis.Summary statementThis manuscript describes histological changes in mouse knee joints in two models of osteoarthritis and correlates joint space mineralised tissue volume measured by µCT with disease severity.
Blood and Tissue Biomarker Analysis in Dogs with Osteosarcoma Treated with Palliative Radiation and Intra-Tumoral Autologous Natural Killer Cell Transfer
Authors: Judge Sean J. , Yanagisawa Mio , Sturgill Ian R. , Bateni Sarah B. , Gingrich Alicia A. , Foltz Jennifer A. , Lee Dean A. , Modiano Jaime F. , Monjazeb Arta M. , Culp William T. N. , Rebhun Robert B. , Murphy William J. , Kent Michael S. , Canter Robert J. 
Published: October 2019

AbstractBackgroundWe have previously reported radiation-induced sensitization of canine osteosarcoma (OSA) to natural killer (NK) therapy, including results from a first-in-dog clinical trial. Here, we report correlative analyses of blood and tissue specimens for signals of immune activation in trial subjects.MethodsAmong 10 dogs treated with palliative radiotherapy (RT) and intra-tumoral adoptive NK transfer, we performed ELISA on serum cytokines, flow cytometry for immune phenotype of PBMCs, and PCR on tumor tissue for immune-related gene expression. We then queried The Cancer Genome Atlas (TCGA) to evaluate the association of cytotoxic/immune-related gene expression with human sarcoma survival.ResultsUpdated survival analysis revealed five 6-month survivors, including one dog who lived 17.9 months. Using feeder line co-culture for NK expansion, we observed maximal activation of dog NK cells on day 17 – 19 post isolation with near 100% expression of granzyme B and NKp46 and high cytotoxic function in the injected NK product. Among dogs on trial, we observed a trend for higher baseline serum IL-6 to predict worse lung metastasis-free and overall survival (P=0.08). PCR analysis revealed low absolute gene expression of CD3, CD8, and NKG2D in untreated OSA. Among treated dogs, there was marked heterogeneity in the expression of immune-related genes pre- and post-treatment, but increases in CD3 and CD8 gene expression were higher among dogs that lived > 6 months compared to those who did not. Analysis of the TCGA confirmed significant differences in survival among human sarcoma patients with high and low expression of genes associated with greater immune activation and cytotoxicity (CD3e, CD8a, IFN-γ, perforin, and CD122/IL-2 receptor beta).ConclusionsUpdated results from a first-in-dog clinical trial of palliative RT and autologous NK cell immunotherapy for OSA illustrate the translational relevance of companion dogs for novel cancer therapies. Similar to human studies, analyses of immune markers from canine serum, PBMCs, and tumor tissue are feasible and provide insight into potential biomarkers of response and resistance.
Target Of Rapamycin pathway in the white-rot fungus Phanerochaete chrysosporium
Authors: Vuong Nguyen Duy , Thomas Roret , Antonio Fernandez-Gonzalez , Annegret Kohler , Mélanie Morel-Rouhier , Eric Gelhaye , Rodnay Sormani 
Published: October 2019

AbstractThe Target Of Rapamycin (TOR) signaling pathway is known to regulate growth in response to nutrient availability and stress in eukaryotic cells. In the present study, we have investigated the TOR pathway in the white-rot fungus Phanerochaete chrysosporium. Inhibition of TOR activity by rapamycin affects conidia germination and hyphal growth highlighting the conserved mechanism of susceptibility to rapamycin. Interestingly, the secreted protein content is also affected by the rapamycin treatment. Finally, homologs of the components of TOR pathway can be identified in P. chrysosporium. Altogether, those results indicate that the TOR pathway of P. chrysosporium plays a central role in this fungus.
USMPep: Universal Sequence Models for Major Histocompatibility Complex Binding Affinity Prediction
Authors: Vielhaben Johanna , Wenzel Markus , Samek Wojciech , Strodthoff Nils 
Published: October 2019

AbstractBackgroundImmunotherapy is a promising route towards personalized cancer treatment. A key algorithmic challenge in this process is to decide if a given peptide (neoepitope) binds with the major histocompatibility complex (MHC). This is an active area of research and there are many MHC binding prediction algorithms that can predict the MHC binding affinity for a given peptide to a high degree of accuracy. However, most of the state-of-the-art approaches make use of complicated training and model selection procedures, are restricted to peptides of a certain length and/or rely on heuristics.ResultsWe put forward USMPep, a simple recurrent neural network that reaches state-of-the-art approaches on MHC class I binding prediction with a single, generic architecture and even a single set of hyperparameters both on IEDB benchmark datasets and on the very recent HPV dataset. Moreover, the algorithm is competitive for a single model trained from scratch, while ensembling multiple regressors and language model pretraining can still slightly improve the performance. The direct application of the approach to MHC class II binding prediction shows a solid performance despite of limited training data.ConclusionsWe demonstrate that competitive performance in MHC binding affinity prediction can be reached with a standard architecture and training procedure without relying on any heuristics.
The latitudinal gradient in hand-wing-index: global patterns and predictors of wing morphology in birds
Authors: Sheard Catherine , Neate-Clegg Montague H. C. , Alioravainen Nico , Jones Samuel E. I. , Vincent Claire , MacGregor Hannah E. A. , Bregman Tom P. , Claramunt Santiago , Tobias Joseph A. 
Published: October 2019

AbstractAn organism’s ability to disperse influences many fundamental processes in ecology. However, standardised estimates of dispersal ability are rarely available, and thus the patterns and drivers of broad-scale variation in dispersal ability remain unclear. Here we present a global dataset of avian hand-wing index (HWI), an estimate of wingtip pointedness widely adopted as a proxy for flight efficiency and dispersal in birds. We show that HWI is correlated with geography and ecology across 10,391 (>99 %) bird species, increasing at higher latitudes and in migratory and/or non-territorial species. After controlling for these effects, the strongest predictor of HWI is temperature variability (i.e. seasonality), with secondary effects of diet and habitat type. Our analyses (1) reveal a prominent latitudinal gradient in HWI shaped by ecological and environmental factors, and (2) provide a global index of avian dispersal ability for wider use in community ecology, macroecology, and macroevolution.Statement of authorshipThe study was conceived by CS and JAT. Data collection was led by JAT, SC, and CS, with contributions from CS, MNC, NA, SEIJ, CV, HEAM, TPB, and SC. CS performed the analyses. CS and JAT wrote the manuscript and all authors revised the text.
The transcriptional signature associated with human motile cilia
Authors: Patir Anirudh , Fraser Amy M. , Barnett Mark W. , McTeir Lynn , Rainger Joe , Davey Megan G. , Freeman Tom C. 
Published: October 2019

AbstractCilia are complex microtubule-based organelles implicated in the aetiology of numerous diseases. Accordingly, many cilia-associated proteins have been described, while those distinguishing cilia subtypes are poorly defined. Here, we characterise the gene signature associated with human motile cilia that captures both known and unknown components of this class of cilia. To define the signature, we performed network deconvolution of transcriptomics data derived from tissues possessing motile ciliated cell populations. For each tissue, genes coexpressed with the motile cilia-associated transcriptional factor, FOXJ1, were identified. The consensus across tissues provided a transcriptional signature of 248 genes. For validation, we examined the literature, databases, single cell RNA-Seq data, and the localisation of mRNA and proteins in motile ciliated cells. To validate some of the many poorly characterised genes, we performed new localisation experiments on ARMC3, EFCAB6, FAM183A, MYCBPAP, RIBC2 and VWA3A. In summary, we report a highly validated set of motile cilia-associated genes that helps shape our understanding of these complex cellular organelles.SummaryThis work defines a conserved transcriptional signature associated with human motile cilia, including many genes with little or no previous association with these structures. These genes were compared with existing resources and a number of poorly characterised genes validated.Graphical abstract
Tunable Fibrin-Alginate Interpenetrating Network Hydrogels to Guide Cell Behavior
Authors: Vorwald Charlotte E. , Gonzalez-Fernandez Tomas , Joshee Shreeya , Sikorski Pawel , Leach J. Kent 
Published: October 2019

ABSTRACTHydrogels are effective platforms for use as artificial extracellular matrices, cell carriers, and to present bioactive cues. Two common natural polymers, fibrin and alginate, are broadly used to form hydrogels and have numerous advantages over synthetic materials. Fibrin is a provisional matrix containing native adhesion motifs for cell engagement, yet the interplay between mechanical properties, degradation, and gelation rate is difficult to decouple. Conversely, alginate is highly tunable yet bioinert and requires modification to present necessary adhesion ligands. To address these challenges, we developed a fibrin-alginate interpenetrating network (IPN) hydrogel to combine the desirable adhesion and stimulatory characteristics of fibrin with the tunable mechanical properties of alginate. We tested its efficacy by examining capillary network formation with entrapped co-cultures of mesenchymal stromal cells (MSCs) and endothelial cells (ECs). We manipulated thrombin concentration and alginate crosslinking density independently to modulate the fibrin structure, mesh size, degradation, and biomechanical properties of these constructs. In IPNs of lower stiffness, we observed a significant increase in total cell area (1.72×105 ± 7.9×104 μm2) and circularity (0.56 ± 0.03) compared to cells encapsulated in stiffer IPNs (3.98×104 ± 1.49×104 μm2 and 0.77 ± 0.09, respectively). Fibrinogen content did not influence capillary network formation. However, higher fibrinogen content led to greater retention of these networks confirmed via increased spreading and presence of F-actin at 7 days. This is an elegant platform to decouple cell adhesion and hydrogel bulk stiffness that will be broadly useful for cell instruction and delivery.