bluuebunny/crossref_metadata_2025_split huggingface dataset:
Revisiting tolerance to ocean acidification: insights from a new framework combining physiological and molecular tipping points of Pacific oyster
Authors: Lutier Mathieu , Poi Carole Di , Gazeau Frédéric , Appolis Alexis , Le Luyer Jérémy , Pernet Fabrice 
Published: September 2021

AbstractStudies on the impact of ocean acidification on marine organisms involve exposing organisms to future acidification scenarios as projected for open ocean, which has limited relevance for coastal calcifiers. Characterization of reaction norms across a range of pH and identification of tipping points beyond which detrimental effects are observed has been limited and focus on only a few macro-physiological traits. Here we filled this knowledge gap by developing a framework to analyze the broad macro-physiological and molecular responses over a wide pH range of juvenile Pacific oyster, a model species for which the tolerance threshold to acidification remains unknown. We identify low tipping points for physiological traits at pH 7.3-6.9 that coincide with a major reshuffling in membrane lipids and transcriptome. In contrast, shell parameters exhibit effects with pH drop well before tipping points, likely impacting animal fitness. These findings were made possible by the development of an innovative methodology to synthesize and identify the main patterns of variations in large -omic datasets, fit them to pH and identify molecular tipping-points. We propose the application of our framework broadly to the assessment of effects of global change on other organisms.
Discoidin domain receptor regulates ensheathment, survival, and caliber of peripheral axons
Authors: Corty Megan M. , Lassetter Alexandria P. , Hill Jo Q. , Sheehan Amy E. , Aicher Sue A. , Freeman Marc R. 
Published: September 2021

AbstractInvertebrate axons and small caliber axons in mammalian peripheral nerves are unmyelinated but still ensheathed by glia. How this type of ensheathment is controlled and its roles in supporting neuronal function remain unclear. Here we use Drosophila wrapping glia, which ensheathe peripheral axons to study the function and development of non-myelinating ensheathment. We developed a new SplitGal4 intersectional driver to target wrapping glia for genetic ablation and found that loss of wrapping glia severely impaired larval locomotor behavior. We performed an in vivo RNAi screen in Drosophila to identify glial genes required for axon ensheathment during development and identified the conserved receptor tyrosine kinase Discoidin domain receptor (Ddr). In larval peripheral nerves, loss of Ddr resulted in severely reduced ensheathment of axons. We found a strong dominant genetic interaction between Ddr and the fly type XV/XVIII collagen Multiplexin (Mp), suggesting Ddr functions a collagen receptor to drive wrapping of axons during development. Surprisingly, despite severe impairment of ensheathment, the residual wrapping in Ddr mutants was sufficient to support basic circuit function during larval stages. In adult nerves, loss of Ddr from glia decreased long-term survival of sensory neurons and significantly reduced axon caliber in an identifiable neuron without overtly affecting ensheathment. Our data establish a crucial role for non-myelinating glia in peripheral nerve development and function across the lifespan, and identify Ddr as a key regulator of axon-glia interactions during ensheathment and nerve growth.
Differential Network Analysis of Longitudinal Gene Expression in Response to Perturbations
Authors: Xue Shuyue , Rogers Lavida R.K. , Zheng Minzhang , He Jin , Piermarocchi Carlo , Mias George I. 
Published: September 2021

AbstractUnderstanding changes in gene expression under the effects of a perturbation is a key goal of systems biology. A powerful approach to address this goal uses gene networks and describes the perturbation’s effects as a rewiring of each gene’s connections. This approach is known as differential network (DN) analysis. Here, we used DNs to analyze RNA-sequencing time series datasets, focusing on expression changes: (i) In the saliva of a human subject after vaccination with a pneumococcal vaccine (PPSV23), and (ii) in B cells treatedex vivowith a monoclonal antibody drug (Rituximab). Using network community detection, we revealed the collective behavior of clusters of genes, and detected communities of genes based on their longitudinal behavior, and corresponding pathway activations. We identified biological pathways consistent with the mechanism of action of the vaccine and with Rituximab’s targets. The approach may be useful in drug development by providing an effective analysis of expressing changes in response to a drug.
Chicken Auditory Supporting Cells Express Interferon Response Genes during Regeneration towards Nascent Sensory Hair CellsIn Vivo
Authors: Janesick Amanda , Scheibinger Mirko , Benkafadar Nesrine , Kirti Sakin , Heller Stefan 
Published: September 2021

AbstractThe avian hearing organ is the basilar papilla that, in sharp contrast to the mammalian cochlea, can regenerate sensory hair cells and thereby recover from complete deafness within weeks. The mechanisms that trigger, sustain, and terminate the regenerative responsein vivoare largely unknown. Here, we profile the changes in gene expression in the chicken basilar papilla after aminoglycoside antibiotic-induced hair cell loss using RNA-sequencing. The most prominent changes in gene expression were linked to the upregulation of interferon response genes which occurred in supporting cells, confirmed by single-cell RNA-sequencing andin situhybridization. We determined that the JAK/STAT signaling pathway is essential for the interferon gene response in supporting cells, set in motion by hair cell loss. Four days after ototoxic damage, we identified newly regenerated, nascent auditory hair cells that express genes linked to termination of the interferon response. These cells are incipient modified neurons that represent a population of hair cellsen routetowards obtaining their location-specific and fully functional cell identity. The robust, transient expression of immune-related genes in supporting cells suggests a potential functional involvement of JAK/STAT signaling and interferon in sensory hair cell regeneration.
A Comparative Genome-wide Transcriptome Analysis of Glucocorticoid Responder and Non-Responder Primary Human Trabecular Meshwork Cells
Authors: Kathirvel Kandasamy , Haribalaganesh Ravinarayanan , Krishnadas Ramasamy , Muthukkaruppan Veerappan , Willoughby Colin E. , Bharanidharan Devarajan , Senthilkumari Srinivasan 
Published: September 2021

AbstractThe genome-wide gene expression analysis of primary human trabecular meshwork (HTM) cells with known glucocorticoid (GC) responsiveness was not reported earlier. Therefore, the purpose of this study was to investigate genes and pathways involved in the GC responsiveness in human trabecular meshwork (HTM) cells using RNA sequencing. A perfusion cultured human anterior segment ex vivo model was utilized to identify the induction of GC-induced ocular hypertension in one eye of a paired eyes after dexamethasone treatment based on the maximum intraocular pressure response and in the contralateral eye, HTM cells were isolated to classify GC-responder and non-responder cells. Some previously reported and unique genes and their associated pathways were identified in HTM cells in response to dexamethasone treatment versus vehicle control and more significantly in GC-responder and non-responder cells. This study will open up the possibility of identifying suitable molecular targets which have the potential to treat GC-induced ocular hypertension/glaucoma.
Monoclonal antibodies therapy for Covid-19 - Experiences at a regional hospital
Authors: Pannier Judith , Nass Norbert , Behre Gerhard 
Published: September 2021

AbstractApplying monoclonal antibodies against Covid-19 is a promising treatment option for avoiding severe outcomes. However, real life data, especially in regional hospitals are still scarce. We here report on our first results with this therapy in a retrospective, observational study. Indeed, compared to a risk-factor matched reference group, hospitalisation time was reduced but survival rate and kinetics of SARS-CoV-2 RT-PCR results remained apparently unaffected.
Pervasive Downward Bias in Estimates of Liability Scale Heritability in GWAS Meta-Analysis: A Simple Solution
Authors: Grotzinger Andrew D. , de la Fuente Javier , Nivard Michel G. , Tucker-Drob Elliot M. 
Published: September 2021

AbstractSNP heritability is a fundamental quantity in the genetic analysis of complex traits. For binary phenotypes, in which the continuous distribution of risk in the population is unobserved, observed-scale heritabilities must be transformed to the more interpretable liability-scale. We demonstrate here that the field standard approach for performing the liability conversion can downwardly bias estimates by as much as ∼20% in simulation and ∼30% in real data. These attenuated estimates stem from the standard approach failing to appropriately account for varying levels of ascertainment across the cohorts comprising the meta-analysis. We formally derive a simple procedure for incorporating cohort-specific ascertainment based on the summation of effective sample sizes across the contributing cohorts, and confirm via simulation that it produces unbiased estimates of liability-scale heritability.
Impact of the COVID-19 pandemic on treatment patterns for US patients with metastatic solid cancer
Authors: Parikh Ravi B. , Takvorian Samuel U. , Vader Daniel , Wileyto E. Paul , Clark Amy S. , Lee Daniel J. , Goyal Gaurav , Rocque Gabrielle B. , Dotan Efrat , Geynisman Daniel M. , Phull Pooja , Spiess Philippe E. , Kim Roger Y. , Davidoff Amy J. , Gross Cary P. , Neparidze Natalia , Miksad Rebecca A. , Calip Gregory S. , Hearn Caleb M. , Ferrell Will , Shulman Lawrence N. , Mamtani Ronac , Hubbard Rebecca A. ,   for the PRACTICE Investigators
Published: September 2021

ABSTRACTBackgroundThe COVID-19 pandemic has led to delays in patients seeking care for life-threatening conditions; however, its impact on treatment patterns for patients with metastatic cancer is unknown. We assessed the COVID-19 pandemic’s impact on time to treatment initiation (TTI) and treatment selection for patients newly diagnosed with metastatic solid cancer.MethodsWe used an electronic health record-derived longitudinal database curated via technology-enabled abstraction to identify 14,136 US patients newly diagnosed with de novo or recurrent metastatic solid cancer between January 1 and July 31 in 2019 or 2020. Patients received care at ∼280 predominantly community-based oncology practices. Controlled interrupted time series analyses assessed the impact of the COVID-19 pandemic period (April-July 2020) on TTI, defined as the number of days from metastatic diagnosis to receipt of first-line systemic therapy, and use of myelosuppressive therapy.ResultsThe adjusted probability of treatment within 30 days of diagnosis [95% confidence interval] was similar across periods: January-March 2019 41.7% [32.2%, 51.1%]; April-July 2019 42.6% [32.4%, 52.7%]; January-March 2020 44.5% [30.4%, 58.6%]; April-July 2020 46.8% [34.6%, 59.0%]; adjusted percentage-point difference-in-differences 1.4% [-2.7%, 5.5%]. Among 5,962 patients who received first-line systemic therapy, there was no association between the pandemic period and use of myelosuppressive therapy (adjusted percentage-point difference-in-differences 1.6% [-2.6%, 5.8%]). There was no meaningful effect modification by cancer type, race, or age.ConclusionsDespite known pandemic-related delays in surveillance and diagnosis, the COVID-19 pandemic did not impact time to treatment initiation or treatment selection for patients with metastatic solid cancers.
Leveraging genomic diversity for discovery in an EHR-linked biobank: the UCLA ATLAS Community Health Initiative
Authors: Johnson Ruth , Ding Yi , Venkateswaran Vidhya , Bhattacharya Arjun , Chiu Alec , Schwarz Tommer , Freund Malika , Zhan Lingyu , Burch Kathryn S. , Caggiano Christa , Hill Brian , Rakocz Nadav , Balliu Brunilda , Sul Jae Hoon , Zaitlen Noah , Arboleda Valerie A. , Halperin Eran , Sankararaman Sriram , Butte Manish J. ,   UCLA Precision Health Data Discovery Repository Working Group,   UCLA Precision Health ATLAS Working Group, Lajonchere Clara , Geschwind Daniel H. , Pasaniuc Bogdan 
Published: September 2021

AbstractLarge medical centers located in urban areas such as Los Angeles care for a diverse patient population and offer the potential to study the interplay between genomic ancestry and social determinants of health within a single medical system. Here, we introduce the UCLA ATLAS Community Health Initiative – a biobank of genomic data linked with de-identified electronic health records (EHRs) of UCLA Health patients. We leverage the unique genomic diversity of the patient population in ATLAS to explore the interplay between self-reported race/ethnicity and genetic ancestry within a disease context using phenotypes extracted from the EHR. First, we identify an extensive amount of continental and subcontinental genomic diversity within the ATLAS data that is consistent with the global diversity of Los Angeles; this includes clusters of ATLAS individuals corresponding to individuals with Korean, Japanese, Filipino, and Middle Eastern genomic ancestries. Most importantly, we find that common diseases and traits stratify across genomic ancestry clusters, thus suggesting their utility in understanding disease biology across diverse individuals. Next, we showcase the power of genetic data linked with EHR to perform ancestry-specific genome and phenome-wide scans to identify genetic factors for a variety of EHR-derived phenotypes (phecodes). For example, we find ancestry-specific associations for liver disease, and link the genetic variants with neurological and neoplastic phenotypes primarily within individuals of admixed ancestries. Overall, our results underscore the utility of studying the genomes of diverse individuals through biobank-scale genotyping efforts linked with EHR-based phenotyping.
Comparison of breeding strategies for the creation of a synthetic pig line
Authors: Ganteil Audrey , Pook Torsten , Rodriguez-Ramilo Silvia T. , Ligonesche Bruno , Larzul Catherine 
Published: September 2021

AbstractCreating a new synthetic line by crossbreeding means complementary traits from pure breeds can be combined in the new population. Although diversity is generated during the crossbreeding stage, in this study, we analyze diversity management before selection starts. Using genomic and phenotypic data from animals belonging to the first generation (G0) of a new line, different simulations were run to evaluate diversity management during the first generations of a new line and to test the effects of starting selection at two alternative times, G3 and G4. Genetic diversity was characterized by allele frequency, inbreeding coefficients based on genomic and pedigree data, and expected heterozygosity. Breeding values were extracted at each generation to evaluate differences in starting selection at G3 or G4. All simulations were run for ten generations. A scenario with genomic data to manage diversity during the first generations of a new line was compared with a random and a selection scenario. As expected, loss of diversity was higher in the selection scenario, while the scenario with diversity control preserved diversity. We also combined the diversity management strategy with different selection scenarios involving different degrees of diversity control. Our simulation results show that a diversity management strategy combining genomic data with selection starting at G4 and a moderate degree of diversity control generates genetic progress and preserves diversity.
Automated 3D reconstruction of the fetal thorax in the standard atlas space from motion-corrupted MRI stacks for 21-36 weeks GA range
Authors: Uus Alena , Grigorescu Irina , van Poppel Milou P.M. , Steinweg Johannes K. , Roberts Thomas A. , Rutherford Mary A. , Hajnal Joseph V. , Lloyd David F.A. , Pushparajah Kuberan , Deprez Maria 
Published: September 2021

ABSTRACTSlice-to-volume registration (SVR) methods allow reconstruction of high-resolution 3D images from multiple motion-corrupted stacks. SVR-based pipelines have been increasingly used for motion correction for T2-weighted fetal MRI since they allow more informed and detailed diagnosis of brain and body anomalies including congenital heart defects (Lloyd et al., 2019). Recently, fully automated rigid SVR reconstruction of the fetal brain in the atlas space was achieved in (Salehi et al., 2019) that used convolutional neural networks (CNNs) for segmentation and pose estimation. However, these CNN-based methods have not yet been applied to the fetal trunk region. Meanwhile, the existing rigid and deformable SVR (DSVR) solutions (Uus et al., 2020) for the fetal trunk region are limited by the requirement of manual input as well the narrow capture range of the classical gradient descent based registration methods that cannot resolve severe fetal motion frequently occurring at the early gestational age (GA). Furthermore, in our experience, the conventional 2D slice-wise CNN-based brain masking solutions are reportedly prone to errors that require manual corrections when applied on a wide range of acquisition protocols or abnormal cases in clinical setting.In this work, we propose a fully automated pipeline for reconstruction of the fetal thorax region for 21-36 weeks GA range T2-weighted MRI datasets. It includes 3D CNN-based intra-uterine localisation of the fetal trunk and landmark-guided pose estimation steps that allow automated DSVR reconstruction in the standard radiological space irrespective of the fetal trunk position or the regional stack coverage. The additional step for generation of the common template space and rejection of outliers provides the means for automated exclusion of stacks affected by low image quality or extreme motion. The pipeline was evaluated on a series of experiments including fetal MRI datasets and simulated rotation motion. Furthermore, we performed a qualitative assessment of the image reconstruction quality in terms of the definition of vascular structures on 100 early (median 23.14 weeks) and late (median 31.79 weeks) GA group MRI datasets covering 21 to 36 weeks GA range.
Identification of active modules in interaction networks using node2vec network embedding
Authors: Pasquier Claude , Guerlais Vincent , Pallez Denis , Rapetti-Mauss Raphaël , Soriani Olivier 
Published: September 2021

AbstractThe identification of condition-specific gene sets from transcriptomic experiments is important to reveal regulatory and signaling mechanisms associated with a given cellular response. Statistical approaches using only expression data allow the identification of genes whose expression is most altered between different conditions. However, a phenotype is rarely a direct consequence of the activity of a single gene, but rather reflects the interplay of several genes to carry out certain molecular processes. Many methods have been proposed to analyze the activity of genes in light of our knowledge of their molecular interactions. However, existing methods have many limitations that make them of limited use to biologists: they detect modules that are too large, too small, or they require the users to specify a priori the size of the modules they are looking for.We propose AMINE (Active Module Identification through Network Embedding), an efficient method for the identification of active modules. Experiments carried out on artificial data sets show that the results obtained are more reliable than many available methods. Moreover, the size of the modules to be identified is not a fixed parameter of the method and does not need to be specified; rather, it adjusts according to the size of the modules to be found. The applications carried out on real datasets show that the method enables to find important genes already highlighted by approaches solely based on gene variations, but also to identify new groups of genes of high interest. In addition, AMINE method can be used as a web service on your own data (http://amine.i3s.unice.fr).
Engineered neuron-targeting, placental mesenchymal stromal cell-derived extracellular vesicles for in utero treatment of myelomeningocele
Authors: Zhang Xinke , Chen Hongyuan , Gao Kewa , He Siqi , Ma Zhao , Liu Ruiwu , Hao Dake , Wang Yan , Kumar Priyadarsini , Ramasubramanian Lalithasri , Pivetti Christopher D , Li Yuanpei , Guo Fuzheng , Wang Fengshan , Carney Randy , Farmer Diana L , Wang Aijun 
Published: September 2021

ABSTRACTThis study investigated the feasibility and efficiency of neuron-targeting hybrid placental mesenchymal stromal cell-derived extracellular vesicles (PMSC-EVs), engineered by membrane fusion with Targeted Axonal Import (TAxI) peptide modified, TrkB agonist 7,8-DHF-loaded liposomes for treatment of myelomeningocele (MMC) via intra-amniotic cavity administration. The prepared TAxI modified liposomes with 7,8-DHF were used to fuse with PMSC-EVs. Different fusion approaches were investigated and freeze-thaw-extrude method was found to be the optimal. The engineered PMSC-EVs had a uniform particle size and efficiently loaded 7,8-DHF. It also had typical markers of native EVs. Freeze-thaw-extrude process did not change the release profile of 7,8-DHF from engineered EVs compared to TAxI modified, 7,8-DHF loaded liposomes. The engineered EVs could elicit TrkB phosphorylation depending on the incorporation of 7,8-DHF while native EVs did not. The engineered EVs increased neurite outgrowth of apoptotic cortical neurons induced by staurosporine, suggesting that they exhibited neuroprotective function. In a rodent model of MMC, neuron-targeting, engineered EVs became an active targeting delivery system to MMC defect sites. Pups treated with engineered EVs had the lowest density of apoptotic cells and displayed a therapeutic outcome. The study suggests the potential use of engineered hybrid, active neuron-targeting EVs for the in utero treatment of MMC.
NMDAr Blocking by MK801 Alters Hippocampal and Prefrontal Cortex Oscillations and Impairs Spatial Working Memory in Mice
Authors: Abad-Perez P. , Molina-Payá F.J. , Martínez-Otero L. , Borrell V. , Redondo R.L. , Brotons-Mas J.R. 
Published: September 2021

AbstractAbnormal NMDAr function has been linked to rhythmopathies, psychosis, and cognitive dysfunction in schizophrenia (SCZ). Here, we investigate the role of NMDAr hypofunction in pathological oscillations and behavior. We implanted mice with tetrodes in the dorsal hippocampus and medial prefrontal cortex (mPFC), administered the NMDAr antagonist MK801, and recorded oscillations during spontaneous exploration in an open field and in the y-maze spatial working memory test. Our results show that NMDAr blockade increased locomotor activity, impaired spatial working memory, and disrupted the correlation between oscillations and speed of movement, which is crucial for internal representations of distance. In the hippocampus, MK801 increased gamma oscillations and disrupted theta/gamma coupling. In the mPFC, MK801 increased the power of theta and gamma, generated high-frequency oscillations (HFO 155-185 Hz), and disrupted theta/gamma coupling. The performance of mice in the spatial working memory version of the y-maze was strongly correlated with CA1-PFC theta/ low gamma co-modulation. Thus, theta/gamma mediated by NMDAr function might be essential to explaining several of SCZ’s cognitive symptoms and might be crucial to explaining hippocampal-PFC interaction.Significance StatementNMDAr hypofunction might be the basis of cognitive symptoms and oscillopathies found in SCZ. In this work, we aimed to understand this link further. We found that NMDAr hypofunction altered theta/gamma co-modulation in the hippocampus and the PFC, explaining spatial working memory deficits.