bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of fracture healing by the transient accumulation of senescent cells
Authors: Saul Dominik , Monroe David G. , Rowsey Jennifer L. , Kosinsky Robyn L. , Vos Stephanie J. , Doolittle Madison L. , Farr Joshua N. , Khosla Sundeep 
Published: May 2021

AbstractSenescent cells have detrimental effects across tissues with aging but may have beneficial effects on tissue repair, specifically on skin wound healing. However, the potential role of senescent cells in fracture healing has not been defined. Here, we performed anin silicoanalysis of public mRNAseq data and found that senescence and senescence-associated secretory phenotype (SASP) markers increased during fracture healing. We next directly established that the expression of senescence biomarkers increased markedly during murine fracture healing. We also identified a subset of cells in the fracture callus that displayed hallmarks of senescence, including distension of satellite heterochromatin and telomeric DNA damage. Then, using a genetic mouse model (p16LUC) containing apl6Ink4a-dnven luciferase reporter, we demonstrated transientin vivosenescent cell accumulation during callus formation. Finally, we intermittently treated young adult mice following fracture with drugs that selectively eliminate senescent cells (“senolytics”, Dasatinib plus Quercetin), and showed that this regimen both decreased senescence and SASP markers in the fracture callus and significantly accelerated the time course of fracture healing. Our findings thus demonstrate that senescent cells accumulate transiently in the murine fracture callus and, in contrast to the skin, their clearance does not impair but rather may improve fracture healing.
PaReBrick: PArallel REarrangements and BReakpoints identification toolkit
Authors: Zabelkin Alexey , Yakovleva Yulia , Bochkareva Olga , Alexeev Nikita 
Published: May 2021

AbstractMotivationHigh plasticity of bacterial genomes is provided by numerous mechanisms including horizontal gene transfer and recombination via numerous flanking repeats. Genome rearrangements such as inversions, deletions, insertions, and duplications may independently occur in different strains, providing parallel adaptation. Specifically, such rearrangements might be responsible for multi-virulence, antibiotic resistance, and antigenic variation. However, identification of such events requires laborious manual inspection and verification of phyletic pattern consistency.ResultsHere we define the term “parallel rearrangements” as events that occur independently in phylogenetically distant bacterial strains and present a formalization of the problem of parallel rearrangements calling. We implement an algorithmic solution for the identification of parallel rearrangements in bacterial population, as a tool PaReBrick. The tool takes synteny blocks and a phylogenetic tree as input and outputs rearrangement events. The tool tests each rearrangement for consistency with a tree, and sorts the events by their parallelism score and provides diagrams of the neighbors for each block of interest, allowing the detection of horizontally transferred blocks or their extra copies and the inversions in which copied blocks are involved. We proved PaReBrick’s efficiency and accuracy and showed its potential to detect genome rearrangements responsible for pathogenicity and adaptation in bacterial genomes.AvailabilityPaReBrick is written in Python and is available on GitHub
Light-weight Electrophysiology Hardware and Software Platform for Cloud-Based Neural Recording Experiments
Authors: Voitiuk Kateryna , Geng Jinghui , Keefe Matthew G. , Parks David F. , Sanso Sebastian E. , Hawthorne Nico , Freeman Daniel B. , Mostajo-Radji Mohammed A. , Nowakowski Tomasz J. , Salama Sofie R. , Teodorescu Mircea , Haussler David 
Published: May 2021

AbstractObjectiveNeural activity represents a functional readout of neurons that is increasingly important to monitor in a wide range of experiments. Extracellular recordings have emerged as a powerful technique for measuring neural activity because these methods do not lead to the destruction or degradation of the cells being measured. Current approaches to electrophysiology have a low throughput of experiments due to manual supervision and expensive equipment. This bottleneck limits broader inferences that can be achieved with numerous long-term recorded samples.ApproachWe developed Piphys, an inexpensive open source neurophysiological recording platform that consists of both hardware and software. It is easily accessed and controlled via a standard web interface through Internet of Things (IoT) protocols.Main ResultsWe used a Raspberry Pi as the primary processing device and Intan bioamplifier. We designed a hardware expansion circuit board and software to enable voltage sampling and user interaction. This standalone system was validated with primary human neurons, showing reliability in collecting real-time neural activity.SignificanceThe hardware modules and cloud software allow for remote control of neural recording experiments as well as horizontal scalability, enabling long-term observations of development, organization, and neural activity at scale.
Garcinia kola and garcinoic acid suppress SARS-CoV-2 spike glycoprotein S1-induced hyper-inflammation in human PBMCs through inhibition of NF-κB activation
Authors: Olajide Olumayokun A , Iwuanyanwu Victoria U , Lepiarz-Raba Izabela , Al-Hindawi Alaa A , Aderogba Mutalib A , Sharp Hazel L , Nash Robert J 
Published: May 2021

AbstractSymptoms and complications associated with severe SARS-CoV-2 infection such as acute respiratory distress syndrome (ARDS) and organ damage have been linked to SARS-CoV-2 spike glycoprotein S1-induced increased production of pro-inflammatory cytokines by immune cells. In this study, the effects of an extract of Garcinia kola seeds and garcinoic acid were investigated in SARS-CoV-2 spike glycoprotein S1-stimulated human PBMCs. Results of ELISA experiments revealed that Garcinia kola extract (6.25, 12.5 and 25 μg/mL) and garcinoic acid (1.25, 2.5 and 5 μM) significantly reduced SARS-CoV-2 spike glycoprotein S1-induced increased secretion of TNFα, IL-6, IL-1β and IL-8 in PBMCs. In-cell western assays showed that pre-treatment with Garcinia kola extract and garcinoic acid reduced elevated expressions of both phospho-p65 and phospho-κBα proteins, as well as NF-κB DNA binding capacity and NF-κB-driven luciferase expression following stimulation of PBMCs with spike glycoprotein S1. Furthermore, pre-treatment of PBMCs with Garcinia kola extract prior to stimulation with SARS-CoV-2 spike glycoprotein S1 resulted in reduced damage to adjacent A549 lung epithelial cells. Gas Chromatography-Mass Spectrometry (GCMS) and HPLC-PDA confirmed the presence of garcinoic acid in the Garcinia kola extract used in this study. These results suggest that the seed of Garcinia kola and garcinoic acid are natural products which may possess pharmacological/therapeutic benefits in reducing cytokine storm during the late stage of severe SARS-CoV-2 and other coronavirus infections.
A concurrent canonical and modified miRNAome pan-cancer study on TCGA and TARGET cohorts leads to an enhanced resolution in cancer
Authors: Distefano Rosario , Tomasello Luisa , Vinciguerra Gian Luca Rampioni , Gasparini Pierluigi , Xiang Yujia , Bagnoli Marina , Marceca Gioacchino Paolo , Fadda Paolo , Laganà Alessandro , Acunzo Mario , Ma Qin , Nigita Giovanni , Croce Carlo M. 
Published: May 2021

ABSTRACTMiRNA Epitranscriptomics has placed a new layer of complexity in the cancer field. Despite the fast-growing interest in miRNA editing and shifted miRNA isoforms, a simultaneous study of both modifications in cancer is still missing. Here, we concurrently profiled multiple miRNA modifications, including A-to-I RNA editing and shifted miRNA isoforms, in >13K adult and pediatric tumor samples across 38 distinct cancer cohorts from The Cancer Genome Atlas and The Therapeutically Applicable Research to Generate Effective Treatments datasets. We investigated the differences among canonical miRNAs and the wider miRNAome in terms of expression, clustering, dysregulation, and prognostic standpoint. The combination of canonical miRNAs/miRNA isoforms boosted the quality of clustering results, outlining unique cohorts’ clinical-pathological features. We described modified miRNAs showing opposite dysregulation with respect to their canonical counterparts in cancer, potentially impacting their targetome and function. The abundance of expressed miRNA isoforms directly impacted the activation/deactivation of critical carcinogenesis pathways. Finally, we experimentally validated unique targeting for a shifted and edited miRNA isoform. Our findings outlined once more the importance of going beyond the well-established paradigm of one-mature-miRNA per miRNA arm to elucidate novel mechanisms related to cancer progression.
Open-Source Thermometer, Temperature Controller, and Light Meter for Use in Animal Facilities and During Experiments
Authors: Andreev Andrey , Vasnarungruengkul Pavee , Wagenaar Daniel A. , Prober David A. 
Published: May 2021

AbstractExperiments with biological samples require precise control of environmental conditions. In our work we use zebrafish (Danio rerio) to understand the neurobiology of sleep, which requires precise control of temperature and lighting. Like many labs, lighting and temperature in the animal facility are centrally controlled in the building. During behavioral experiments and microscopy sessions, we use custom-built heating systems and perform occasional manual checks of conditions. However, without a system to precisely record conditions, gradual changes in temperature can go unnoticed for a long time, and temporary failures may be missed entirely. Here we present the design and characterization of affordable open-source tools to record temperature and light conditions during animal experiments using an Arduino microcontroller or a Raspberry Pi compact computer. The waterproof temperature sensor has high stability over 50 days of recording and is precise to 0.1°C. The Arduino device can be used through a common serial port interface for which we present code in Python and MATLAB. The Raspberry Pi version can be accessed through a web interface, for which we provide an installation guide. We use the device to record and review temperature and lighting conditions in two zebrafish animal facilities. We use our platform to add a water heating system to maintain temperature at 28°C during in vivo light-sheet imaging of larval zebrafish. We show that a change in temperature from 28°C to 32°C affects resting heart rate of the animal, highlighting the importance of maintaining and recording conditions. The protocols presented here do not require advanced engineering, fabrication, or software skills, and provide an approach to accurately record and report experimental conditions.
Comparison of confound adjustment methods in the construction of gene co-expression networks
Authors: Cote A.C. , Young H.E. , Huckins L.M. 
Published: May 2021

AbstractAdjustment for confounding sources of expression variation is an important preprocessing step in large gene expression studies, but the effect of confound adjustment on co-expression network analysis has not been well-characterized. Here, we demonstrate that the choice of confound adjustment method can have a considerable effect on the architecture of the resulting co-expression network. We compare standard and alternative confound adjustment methods and provide recommendations for their use in the construction of gene co-expression networks from bulk tissue RNA-seq datasets.
Converting Muscle-mimetic Biomaterials to Cartilage-like Materials
Authors: Fu Linglan , Li Lan , Xue Bin , Jin Jing , Cao Yi , Jiang Qing , Li Hongbin 
Published: May 2021

SummaryLoad-bearing tissues, such as muscle and cartilage, exhibit mechanical properties that often combine high elasticity, high toughness and fast recovery, despite their different stiffness (∼100 kPa for muscles and one to several MPa for cartilage).1-7 The advance in protein engineering and protein mechanics has made it possible to engineer protein-based biomaterials to mimic soft load-bearing tissues, such as muscles.8-10 However, it is challenging to engineer protein biomaterials to achieve the mechanical properties exhibited by stiff tissues, such as articular cartilage,6,11 or to develop stiff synthetic extracellular matrices for cartilage stem/progenitor cell differentiation12. By employing physical entanglements13 of protein chains and force-induced protein unfolding,14,15 here we report the engineering of a highly tough and stiff protein hydrogel to mimic articular cartilage. By crosslinking an engineered artificial elastomeric protein from its unfolded state, we introduced chain entanglement into the hydrogel network. Upon renaturation, the entangled protein chain network and forced protein unfolding entailed this single network protein hydrogel with superb mechanical properties in both tensile and compression tests, showing a Young’s modulus of ∼0.7 MPa and toughness of 250 kJ/m3 in tensile testing; and ∼1.7 MPa in compressive modulus and toughness of 3.2 MJ/m3. The energy dissipation in both tensile and compression tests is reversible and the hydrogel can recovery its mechanical properties rapidly. Moreover, this hydrogel can withstand a compression stress of >60 MPa without failure, amongst the highest compressive strength achieved by a hydrogel. These properties are comparable to those of articular cartilage, making this protein hydrogel a novel cartilage-mimetic biomaterial. Our study opened up a new potential avenue towards engineering protein hydrogel-based substitute for articular cartilage, and may also help develop protein biomaterials with superb mechanical properties for applications in soft actuators and robotics.
A Model for Self-Organization of Sensorimotor Function: The Spinal Monosynaptic Loop
Authors: Enander Jonas M.D. , Jones Adam M. , Kirkland Matthieu , Hurless Jordan , Jörntell Henrik , Loeb Gerald E. 
Published: May 2021

AbstractRecent spinal cord literature abounds with descriptions of genetic preprogramming and the molecular control of circuit formation. In this paper we explore to what extent circuit formation based on learning rather than preprogramming could explain some prominent aspects of the spinal cord connectivity patterns observed in animals. To test this we developed an artificial organism with a basic musculoskeletal system and proprioceptive sensors, connected to a neural network. We adjusted the initially randomized gains in the neural network according to a Hebbian plasticity rule while exercising the model system with spontaneous muscle activity patterns similar to those observed during early fetal development. The resulting connection matrices support functional self-organization of the mature pattern of Ia to motoneuron connectivity in the spinal circuitry. More coordinated muscle activity patterns such as observed later during neonatal locomotion impaired projection selectivity. These findings imply a generic functionality of a musculoskeletal system to imprint important aspects of its mechanical dynamics onto a neural network, without specific preprogramming other than setting a critical period for the formation and maturation of this general pattern of connectivity. Such functionality would facilitate the successful evolution of new species with altered musculoskeletal anatomy and it may help to explain patterns of connectivity and associated reflexes that appear during abnormal development.
Haplotype-aware inference of human chromosome abnormalities
Authors: Ariad Daniel , Yan Stephanie M. , Victor Andrea R. , Barnes Frank L. , Zouves Christo G. , Viotti Manuel , McCoy Rajiv C. 
Published: May 2021

AbstractExtra or missing chromosomes—a phenomenon termed aneuploidy—frequently arises during human meiosis and embryonic mitosis and is the leading cause of pregnancy loss, including in the context ofin vitrofertilization (IVF). While meiotic aneuploidies affect all cells and are deleterious, mitotic errors generate mosaicism, which may be compatible with healthy live birth. Large-scale abnormalities such as triploidy and haploidy also contribute to adverse pregnancy outcomes, but remain hidden from standard sequencing-based approaches to preimplantation genetic testing (PGT-A). The ability to reliably distinguish meiotic and mitotic aneuploidies, as well as abnormalities in genome-wide ploidy may thus prove valuable for enhancing IVF outcomes. Here, we describe a statistical method for distinguishing these forms of aneuploidy based on analysis of low-coverage whole-genome sequencing data, which is the current standard in the field. Our approach overcomes the sparse nature of the data by leveraging allele frequencies and linkage disequilibrium (LD) measured in a population reference panel. The method, which we term LD-informed PGT-A (LD-PGTA), retains high accuracy down to coverage as low as 0.05× and at higher coverage can also distinguish between meiosis I and meiosis II errors based on signatures spanning the centromeres. LD-PGTA provides fundamental insight into the origins of human chromosome abnormalities, as well as a practical tool with the potential to improve genetic testing during IVF.Significance StatementWhole chromosome gains and losses—termed aneuploidies—are the leading cause of human pregnancy loss and congenital disorders. Recent work has demonstrated that in addition to harmful meiotic aneuploidies, mitotic aneuploidies (which lead to mosaic embryos harboring cells with different numbers of chromosomes) may also be common in preimplantation embryos but potentially compatible with healthy birth. Here we developed and tested a method for distinguishing these forms of aneuploidy using genetic testing data from 8154 IVF embryos. We re-classified embryos based on signatures of meiotic and mitotic error, while also revealing lethal forms of chromosome abnormality that were hidden to existing approaches. Our method complements standard protocols for preimplantation and prenatal genetic testing, while offering insight into the biology of early development.
CeAid: A smartphone application for logging and plotting C. elegans assays
Authors: Sohrabi Salman , Moore Rebecca S. , Murphy Coleen T. 
Published: May 2021

AbstractC. elegans is used as a model organism to study a wide range of topics in molecular and cellular biology. Conventional C. elegans assays often require a large sample size with frequent manipulations, rendering them labor-intensive. Automated high-throughput workflows may not be always the best solution to reduce benchwork labor, as they may introduce more complexity. Thus, most assays are carried out manually, where logging and digitizing experimental data can be as time-consuming as picking and scoring worms. Here we report the development of CeAid, C. elegansApplication for inputting data, which significantly expedites the data entry process, utilizing swiping gestures and a voice recognition algorithm for logging data using a standard smartphone or Android device. This modular platform can also be adapted for a wide range of assays where recording data is laborious, even beyond worm research.
A small molecule, ACAi-028, with anti-HIV-1 activity targets a novel hydrophobic pocket on HIV-1 capsid
Authors: Chia Travis , Nakamura Tomofumi , Amano Masayuki , Takamune Nobutoki , Matsuoka Masao , Nakata Hirotomo 
Published: May 2021

AbstractThe human immunodeficiency virus type 1 (HIV-1) capsid (CA) is an essential viral component of HIV-1 infection, and an attractive therapeutic target for antivirals. We report that a small molecule, ACAi-028, inhibits HIV-1 replication by targeting a hydrophobic pocket in the N-terminal domain of CA (CA-NTD). ACAi-028 is one of more than 40 candidate anti-HIV-1 compounds identified by in silico screening and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Our binding model showed that ACAi-028 interacts with the Q13, S16, and T19 amino acid residues, via hydrogen bonds, in the targeting pocket of CA-NTD. Using recombinant fusion methods, TZM-bl, time-of-addition, and colorimetric reverse transcriptase (RT) assays, the compound was found to exert anti-HIV-1 activity in the early stage between a reverse transcriptase inhibitor, azidothymidine (AZT), and an integrase inhibitor, raltegravir (RAL), without any effect on RT activity, suggesting that this compound may affect HIV-1 core disassembly (uncoating). Moreover, electrospray ionization mass spectrometry (ESI-MS) also showed that the compound binds directly and non-covalently to the CA monomer. CA multimerization and thermal stability assays showed that ACAi-028 decreased CA multimerization and thermal stability via S16 or T19 residues.ImportanceThese results indicate that ACAi-028 is a novel CA inhibitor that binds to the novel hydrophobic pocket of CA-NTD. This study demonstrates that a compound targeting the new hydrophobic pocket is a promising anti-HIV-1 inhibitor. The findings presented here may offer the development of a novel class of anti-viral agents that can be used, providing HIV-1 patients with more options for Anti-retroviral therapy (ART) treatment. Despite many years of successful pharmaceutical developments in the area of anti-retroviral therapy, the prevalence of drug-resistant mutations in HIV-1, necessitates the continued development of novel agents, such as ACAi-028.