bluuebunny/crossref_metadata_2025 huggingface dataset:
Galvanic current activates the NLRP3 inflammasome to promote type I collagen production in tendon
Authors: Peñín-Franch Alejandro , Antonio García-Vidal José , Martínez Carlos Manuel , Escolar-Reina Pilar , I.Gómez Ana , Minaya-Muñoz Francisco , Valera-Garrido Fermín , Medina-Mirapeix Francesc , Pelegrín Pablo
Published: September 2021

The NLRP3 inflammasome coordinates inflammation in response to different pathogen- and damage-associated molecular patterns, being implicated in different infectious, chronic inflammatory, metabolic and degenerative diseases. In chronic tendinopathies lesions, different non-resolving mechanisms produce a degenerative condition that impairs tissue healing, complicating their clinical management. Percutaneous needle electrolysis consist in the application of a galvanic current and is emerging as a novel treatment for tendinopathies. Here we found that galvanic current activates the NLRP3 inflammasome and the induction of an inflammatory response promoting a collagen-mediated regeneration of the tendon. This study establish the molecular mechanism of percutaneous electrolysis for the treatment of chronic lesions and the beneficial effects of an induced inflammasome-related response.
Seeing the Forest for the trees: Assessing genetic offset predictions with Gradient Forest
Authors: Láruson Áki Jarl , Fitzpatrick Matthew C. , Keller Stephen R. , Haller Benjamin C. , Lotterhos Katie E.
Published: September 2021

Gradient Forest (GF) is increasingly being used to forecast climate change impacts, but remains mostly untested for this purpose. We explore its robustness to assumption violations, and relationship to measures of fitness, using SLiM simulations with explicit genome architecture and a spatial metapopulation. We evaluate measures of GF offset in: (1) a neutral model with no environmental adaptation; (2) a monogenic “population genetic” model with a single environmentally adapted locus; and (3) a polygenic “quantitative genetic” model with two adaptive traits, each adapting to a different environment. Although we found GF Offset to be broadly correlated with fitness offsets under both single locus and polygenic architectures. It could also be confounded by neutral demography, genomic architecture, and the nature of the adaptive environment. GF Offset is a promising tool, but it is important to understand its limitations and underlying assumptions, especially when used in the context of forecasting maladaptation.
Minimum complexity drives regulatory logic in Boolean models of living systems
Authors: Subbaroyan Ajay , Martin Olivier C. , Samal Areejit
Published: September 2021

The properties of random Boolean networks as models of gene regulation have been investigated extensively by the statistical physics community. In the past two decades, there has been a dramatic increase in the reconstruction and analysis of Boolean models of biological networks. In such models, neither network topology nor Boolean functions (or logical update rules) should be expected to be random. In this contribution, we focus on biologically meaningful types of Boolean functions, and perform a systematic study of their preponderance in gene regulatory networks. By applying the k[P] classification based on number of inputs k and bias P of functions, we find that most Boolean functions astonishingly have odd bias in a reference biological dataset of 2687 functions compiled from published models. Subsequently, we are able to explain this observation along with the enrichment of read-once functions (RoFs) and its subset, nested canalyzing functions (NCFs), in the reference dataset in terms of two complexity measures: Boolean complexity based on string lengths in formal logic which is yet unexplored in the biological context, and the average sensitivity. Minimizing the Boolean complexity naturally sifts out a subset of odd-biased Boolean functions which happen to be the RoFs. Finally, we provide an analytical proof that NCFs minimize not only the Boolean complexity, but also the average sensitivity in their k[P] set.
LOICA: Logical Operators for Integrated Cell Algorithms
Authors: Vidal Gonzalo , Vidal-Céspedes Carlos , Rudge Timothy James
Published: September 2021

1

Mathematical and computational modeling is essential to genetic design automation and for the synthetic biology design-build-test-learn cycle. The construction and analysis of models is enabled by abstraction based on a hierarchy of components, devices, and systems that can be used to compose genetic circuits. These abstract elements must be parameterized from data derived from relevant experiments, and these experiments related to the part composition of the abstract components of the circuits measured. Here we present LOICA (Logical Operators for Integrated Cell Algorithms), a Python package for modeling and characterizing genetic circuits based on a simple object-oriented design abstraction. LOICA uses classes to represent different biological and experimental components, which generate models through their interactions. High-level designs are linked to their part composition via SynBioHub. Furthermore, LOICA communicates with Flapjack, a data management and analysis tool, to link to experimental data, enabling abstracted elements to characterize themselves.
Controlling fibroblast fibrinolytic activity allows for the bio-engineering of stable connective tissue equivalents
Authors: Boucard Elea , Coulon Flora , Vidal Luciano , Hascoët Jean-Yves , Mota Carlos Domingues , Halary Franck
Published: September 2021

In tissue engineering, cell origin is important to ensure outcome quality. However, the impact of the cell type chosen for seeding in a biocompatible matrix has been less investigated. Here, we investigated the capacity of primary and immortalized fibroblasts of distinct origins to degrade a gelatin/alginate/fibrin (GAF)-based biomaterial. We further established that fibrin was targeted by degradative fibroblasts through the secretion of fibrinolytic matrix-metalloproteinases (MMPs) and urokinase, two types of serine protease. Finally, we demonstrated that besides aprotinin, specific targeting of fibrinolytic MMPs and urokinase led to cell-laden GAF stability for at least several days. These results support the use of specific strategies to tune fibrin-based biomaterials degradation over time. It emphasizes the need to choose the right cell type and further bring targeted solutions to avoid the degradation of fibrin-containing hydrogels or bioinks.
The genes controlling normal function of citrate and spermine secretion is lost in aggressive prostate cancer and prostate model systems
Authors: Rye Morten Beck , Krossa Sebastian , Hall Martina , van Mourik Casper , Bathen Tone F. , Drabløs Finn , Tessem May-Britt , Bertilsson Helena
Published: September 2021

Background

Secretion of the metabolites citrate and spermine into prostate lumen is a unique hallmark for normal prostate epithelial cells. However, the identity of the genes controlling citrate and spermine secretion remains mostly unknown despite their obvious relevance for progression to aggressive prostate cancer.

Materials & Methods

In this study, we have correlated simultaneous measurement of citrate/spermine and transcriptomics data. We have refined these gene correlations in 12 prostate cancer cohorts containing 2915 tissue samples to create a novel gene signature of 150 genes connected with citrate and spermine secretion. We further explored the signature in public data, interrogating over 18 000 samples from various tissues and model systems, including 3826 samples from prostate and prostate cancer.

Results

In prostate cancer, the expression of this gene signature is gradually lost in tissue from normal epithelial cells through PIN, low grade (Gleason <= 7), high grade cancer (Gleason >= 8) and metastatic lesions. The accuracy of the signature is validated by its unique enrichment in prostate compared to other tissues, and its strong enrichment in epithelial tissue compartments compared to stroma. Several zinc-binding proteins that are not previously investigated in the prostate are present in the gene signature, suggesting new mechanisms for controlling zinc homeostasis in citrate/spermine secretion. However, the absence of the gene signature in all common prostate normal and cancer cell-lines, as well as prostate organoids, underlines the challenge to study the role of these genes during prostate cancer progression in model systems.

Conclusions

A large collection of transcriptomics data integrated with metabolomics identifies the genes related to citrate and spermine secretion in the prostate, and show that the expression of these genes gradually decreases on the path towards aggressive prostate cancer. In addition, the study questions the relevance of currently available model systems to study metabolism in prostate cancer development.
High permeability of the CSF flow in the juvenile mouse brain by brain-wide DCE-MRI
Authors: Wada Yayoi , Imai Hirohiko , Yamawaki Yuki , Parvez Md Sorwer Alam , Matsui Sae , Ohtsuki Gen
Published: September 2021

The vasculature system with a lymphatic function in the brain is manifested as meningeal lymphatic vessels and the glymphatic system, which drain waste products from cerebrospinal fluid (CSF) and produce interstitial fluid. Invasion of stimulated immune cells or inflammatory cytokines during the maturation is regarded as a sign of the disruption of brain functions through excessive immune stresses. However, it is unclear when the lymphatic system is functionally completed and in which parts of the organ the brain immunity is privileged (i.e., the blood-brain barrier is fully established). Here, we visualized the whole-head signal of gadolinium (Gd) contrast agents in mouse brains to investigate the CSF flow from the signals of Gd-contrast agents using magnetic resonance imaging (MRI) in the course of developmental stages. We found higher Gd-signals in the olfactory bulbs, prefrontal cortex, parietal surface regions of the neocortex along with dorsal meningeal lymphatic vessels, ventral midbrain, and a part of cerebellum, as well as in the basal brain regions, at the immature stage of postnatal (P) 4 weeks, compared to the P8-12 weeks. Our results suggest that the barrier of the vasculature system in mouse brains is still permeable until P1-month and small molecules can leak into the parenchyma.
PharmacoDB 2.0 : Improving scalability and transparency ofin vitropharmacogenomics analysis
Authors: Feizi Nikta , Nair Sisira Kadambat , Smirnov Petr , Beri Gangesh , Eeles Christopher , Esfahani Parinaz Nasr , Nakano Minoru , Tkachuk Denis , Mammoliti Anthony , Gorobets Evgeniya , Mer Arvind Singh , Lin Eva , Yu Yihong , Martin Scott , Hafner Marc , Haibe-Kains Benjamin
Published: September 2021

Cancer pharmacogenomics studies provide valuable insights into disease progression and associations between genomic features and drug response. PharmacoDB integrates multiple cancer pharmacogenomics datasets profiling approved and investigational drugs across cell lines from diverse tissue types. The web-application enables users to efficiently navigate across datasets, view and compare drug dose-response data for a specific drug-cell line pair. In the new version of PharmacoDB (version 2.0,https://pharmacodb.ca/), we present: (i) new datasets such as NCI-60, the Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) dataset, as well as updated data from the Genomics of Drug Sensitivity in Cancer (GDSC) and the Genentech Cell Line Screening Initiative (gCSI); (ii) implementation of FAIR data pipelines using ORCESTRA and PharmacoDI; (iii) enhancements to drug response analysis such as tissue distribution of dose-response metrics and biomarker analysis; (iv) improved connectivity to drug and cell line databases in the community. The web interface has been rewritten using a modern technology stack to ensure scalability and standardization to accommodate growing pharmacogenomics datasets. PharmacoDB 2.0 is a valuable tool for mining pharmacogenomics datasets, comparing and assessing drug response phenotypes of cancer models.

HIGHLIGHTS

PharmacoDB 2.0 includes new and updated large pharmacogenomic datasets. The data processing for PharmacoDB is made fully reproducible through the use of the ORCESTRA platform and automated data ingestion pipelines

The new release contains enriched annotations for drugs and cell lines via connectivity to external databases, as well as new analytical methods for tissue-specific and pan-cancer biomarker discovery

The new version of PharmacoDB incorporates a scalable and reproducible framework that can accelerate the implementation of analytical pipelines including machine learning/AI for biomarker discovery in the future
A waveform-independent measure of recurrent neural activity
Authors: Weber Immo , Oehrn Carina R.
Published: September 2021

Rhythmic neural activity, so called oscillations, play a key role for neural information transmission, processing and storage. Neural oscillations in distinct frequency bands are central to physiological brain function and alterations thereof have been associated with several neurological and psychiatric disorders. The most common methods to analyse neural oscillations, e.g. short-term Fourier transform or wavelet analysis, assume that measured neural activity is composed of a series of symmetric prototypical waveforms, e.g. sinusoids. However, usually the models generating the signal, including waveform shapes of experimentally measured neural activity are unknown. Decomposing asymmetric waveforms of nonlinear origin using these classic methods may result in spurious harmonics visible in the estimated frequency spectra. Here, we introduce a new method for capturing rhythmic brain activity based on recurrences of similar states in phase-space. This method allows for a time-resolved estimation of amplitude fluctuations of recurrent activity irrespective of or specific to waveform-shapes. The algorithm is derived from the well-established field of recurrence analysis, which has rarely been adopted in neuroscience. In this paper, we show its advantages and limitations in comparison to short-time Fourier transform and wavelet convolution using periodic signals of different waveform shapes. Further, we demonstrate its application using experimental data, i.e. intracranial electrophysiological recordings from the human motor cortex of one epilepsy patient.
On the effect of inheritance of microbes in commensal microbiomes
Authors: Zapién-Campos Román , Bansept Florence , Sieber Michael , Traulsen Arne
Published: September 2021

Background

Our current view of nature depicts a world where macroorganisms dwell in a landscape full of microbes. Some of these microbes not only transit but establish themselves in or on hosts. Although hosts might be occupied by microbes for most of their lives, a microbe-free stage during their prenatal development seems to be the rule for many hosts. The questions of who the first colonizers of a newborn host are and to what extent these are obtained from the parents follow naturally.

Results

We have developed a mathematical model to study the effect of the transfer of microbes from parents to offspring. Even without selection, we observe that microbial inheritance is particularly effective in modifying the microbiome of hosts with a short lifespan or limited colonization from the environment, for example by favouring the acquisition of rare microbes.

Conclusion

By modelling the inheritance of commensal microbes to newborns, our results suggest that, in an eco-evolutionary context, the impact of microbial inheritance is of particular importance for some specific life histories.
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

Studies 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

Invertebrate 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

Understanding 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

The 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

The 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

Applying 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

SNP 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

Background

The 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.

Methods

We 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.

Results

The 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.

Conclusions

Despite 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

Large 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

Creating 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

Slice-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

The 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

This 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

Abnormal 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 Statement

NMDAr 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.
Labeling fibrin fibers with microparticle sized beads alter single fibrin fiber lysis, external clot lysis, and produce large fibrin aggregates upon lysis
Authors: Helms Christine Carlisle , Rimi Najnin
Published: September 2021

Background

Fluorescent beads are often used as a tool for visualizing fibrin fibers and can mimic the size of microparticles in the blood. Studies showed microparticles alter the appearance and behavior of whole blood clot systems.

Objectives

Here we investigate the effect of beads on fibrin fiber lysis and extensibility to enhance understanding of this common research technique and as a biomimetic system for fibrin-microparticle interaction.

Methods

We used fluorescence microscopy, atomic force microscopy (AFM), and scanning electron microscopy (SEM) to quantify changes in lysis, extensibility, and clot structure of fibrin fibers and clots in the presence and absence of beads.

Results and Conclusions

Fibrin clot structure and lysis were altered in the presence of beads. Fibrin clots formed with beads had a higher fiber density, smaller fibers, and smaller pores. The rate of lysis for clots was reduced when beads were present. Lysis of bead-labeled individual fibers showed that beads, at concentrations similar to those reported for microparticles in the blood, cause a subset of fibers to resist lysis. In the absence of beads, all fibers lyse. These results demonstrate that beads alter fiber lysis through both a change in fibrin clot structure as well as changes to individual fiber lysis behavior. Additionally, the lysis of clots with beads produced large fibrin aggregates. This data encourages researchers to use careful consideration when labeling fibrin fibers with fluorescent beads and suggests that particles binding fibrin(ogen) in the bloodstream may be an underappreciated mechanism increasing the risk of thrombosis.
Dominant negative effects ofSCN5Amissense variants
Authors: O’Neill Matthew J. , Muhammad Ayesha , Li Bian , Wada Yuko , Hall Lynn , Solus Joseph F. , Short Laura , Roden Dan M. , Glazer Andrew M.
Published: September 2021

Introduction

Up to 30% of patients with Brugada Syndrome (BrS) carry loss-of-function (LoF) variants in the cardiac sodium channel geneSCN5A. Recent studies have suggested that theSCN5Aprotein product NaV1.5 can form dimers and exert dominant negative effects.

Methods

We identified 35 LoF variants (<10% peak current compared to wild type (WT)) and 15 partial LoF variants (10-50% peak current compared to WT) that we assessed for dominant negative behavior.SCN5Avariants were studied in HEK293T cells alone or in heterozygous co-expression with WTSCN5Ausing automated patch clamp. To assess clinical risk, we compared the prevalence of dominant negative vs. putative haploinsufficient (frameshift/splice site) variants in a BrS case consortium and the gnomAD population database.

Results

In heterozygous expression with WT, 32/35 LoF variants and 6/15 partial LoF showed reduction to <75% of WT-alone peak INa, demonstrating a dominant negative effect. Carriers of dominant negative LoF missense variants had an enriched disease burden compared to putative haploinsufficient variant carriers (2.7-fold enrichment in BrS cases, p=0.019).

Conclusions

MostSCN5Amissense LoF variants exert a dominant negative effect. Cohort analyses reveal that this class of variant confers an especially high burden of BrS.
How the naked mole-rat resists senescence: a constraints-based theory
Authors: Veloso Felipe A.
Published: September 2021

Here, I present a theory describing how the stabilization of constraints imposed on chromatin dynamics by the naked mole-rat’s histone H1.0 protein—which in terminally differentiated cells constrains the accessibility of the nucleosome core particle for histone-modifying enzymes and chromatin remodeling factors—explains its resistance to both senescence and cancer. Further, this theory predicts that a mutant house mouse displaying such stabilization will be similarly resistant to both senescence and cancer. A proof-of-concept computational analysis is presented and two predictions for the direct testing of the theory are provided. These experiments comprise, as test subjects, mutant naked mole-rats synthesizing a house mouse (Mus musculus)-like histone H1.0, and mutant house mice synthesizing a naked mole-rat-like histone H1.0. The predictions are that the constraints on chromatin dynamics embodied by the respective mutant histone H1.0 proteins will negate the otherwise significant resistance to both senescence and cancer of the naked mole-rats and, conversely, confer such resistance to the house mice. A verification of these predictions will imply that constraints on chromatin dynamics embodied by naked mole-rat-like histone H1.0 proteins may confer significant resistance to both senescence and age-related cancer to otherwise senescence-prone and/or cancer-susceptible multicellular species, including humans.
Structural Mechanics of the Alpha-2-Macroglobulin Transformation
Authors: Arimura Yasuhiro , Funabiki Hironori
Published: September 2021

Alpha-2-Macroglobulin (A2M) is the critical pan-protease inhibitor of the innate immune system. When proteases cleave the A2M bait region, global structural transformation of the A2M tetramer is triggered to entrap the protease. The structural basis behind the cleavage-induced transformation and the protease entrapment remains unclear. Here, we report cryo-EM structures of native- and intermediate-forms of the Xenopus laevis egg A2M homolog (A2Moo or ovomacroglobulin) tetramer at 3.7-4.1 Å and 6.4 Å resolution, respectively. In the native A2Moo tetramer, two pairs of dimers arrange into a cross-like configuration with four 60 Å-wide bait-exposing grooves. Each bait in the native form threads into an aperture formed by three macroglobulin domains (MG2, MG3, MG6). The bait is released from the narrowed aperture in the induced protomer of the intermediate form. We propose that the intact bait region works as a “latch-lock” to block futile A2M transformation until its protease-mediated cleavage.
Bifunctional Peptide that Anneals to Damaged Collagen and Clusters TGF-β Receptors Enhances Wound Healing
Authors: Chattopadhyay Sayani , Teixeira Leandro B. C. , Kiessling Laura L. , McAnulty Jonathan F. , Raines Ronald T.
Published: September 2021

Transforming growth factor-β (TGF-β) plays important roles in wound healing. The activity of TGF-β is initiated upon binding of the growth factor to extracellular domains of its receptors. We sought to facilitate activation by clustering these extracellular domains. To do so, we used a known peptide that binds to TGF-β receptors without diminishing their affinity for TGF-β. We conjugated this peptide to a collagen-mimetic peptide that can anneal to damaged collagen in a wound bed. We find that the conjugate enhances collagen deposition and wound closure in mice in a manner consistent with the clustering of TGF-β receptors. This strategy provides a means to upregulate the TGF-β signaling pathway without adding exogenous TGF-β and could inspire means to treat severe wounds.

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Zebrafish Information Network, the knowledgebase for Danio rerio research
Authors: Bradford Yvonne M. , Van Slyke Ceri E. , Singer Amy , Paddock Holly , Eagle Anne , Fashena David , Howe Douglas G. , Frazer Ken , Martin Ryan , Pich Christian , Ramachandran Sridhar , Ruzicka Leyla , Westerfield Monte
Published: September 2021

The Zebrafish Information Network (ZFIN, zfin.org) is the central repository for zebrafish genetic and genomic data. ZFIN expertly curates, integrates, and displays zebrafish data including genes, alleles, human disease models, gene expression, phenotype, gene function, orthology, morpholino, CRISPR, TALEN, and antibodies. ZFIN makes zebrafish research data Findable, Accessible, Interoperable, and Reusable (FAIR) through nomenclature, curatorial and annotation activities, web interfaces, and data downloads. ZFIN is a founding member of the Alliance of Genome Resources, providing zebrafish data for integration into the cross species platform as well as contributing to model organism data harmonization efforts.