bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of PKM1/2 levels by steric blocking morpholinos alters the metabolic and pluripotent state of murine pluripotent stem cells
Authors: Dierolf Joshua G. , Hunter Hailey L.M. , Watson Andrew J. , Betts Dean H. 
Published: November 2021

AbstractCellular metabolism plays both an active and passive role in embryonic development, pluripotency, and cell-fate decisions. However, little is known regarding the role of metabolism in regulating the recently described “formative” pluripotent state. The pluripotent developmental continuum features a metabolic switch from a bivalent metabolism (both glycolysis and oxidative phosphorylation) in naïve cells, to predominantly glycolysis in primed cells. We investigated the role of pyruvate kinase muscle isoforms (PKM1/2) in naïve, formative, and primed mouse embryonic stem cells through modulation of PKM1/2 mRNA transcripts using steric blocking morpholinos that downregulate PKM2 and upregulate PKM1. We have examined these effects in naïve, formative, and primed cells by quantifying the effects of PKM1/2 modulation on pluripotent and metabolic transcripts and by measuring shifts in the population frequencies of cells expressing naïve and primed cell surface markers by flow cytometry. Our results demonstrate that modulating PKM1 and PKM2 levels alters the transition from the naïve state into a primed pluripotent state by enhancing the proportion of the affected cells seen in the “formative” state. Therefore, we conclude that PKM1/2 actively contributes to mechanisms that oversee early stem pluripotency and their progression towards a primed pluripotent state.
PerSVade: Personalized Structural Variation detection in your species of interest
Authors: Schikora-Tamarit Miquel Àngel , Gabaldón Toni 
Published: November 2021

ABSTRACTStructural variants (SVs) like translocations, deletions, and other rearrangements underlie genetic and phenotypic variation. SVs are often overlooked due to difficult detection from short-read sequencing. Most algorithms yield low recall on humans, but the performance in other organisms is unclear. Similarly, despite remarkable differences across species’ genomes, most approaches use parameters optimized for humans. To overcome this and enable species-tailored approaches, we developed perSVade (personalized Structural Variation Detection), a pipeline that identifies SVs in a way that is optimized for any input sample. Starting from short reads, perSVade uses simulations on the reference genome to choose the best SV calling parameters. The output includes the optimally-called SVs and the accuracy, useful to assess the confidence in the results. In addition, perSVade can call small variants and copy-number variations. In summary, perSVade automatically identifies several types of genomic variation from short reads using sample-optimized parameters. We validated that perSVade increases the SV calling accuracy on simulated variants for six diverse eukaryotes, and on datasets of validated human variants. Importantly, we found no universal set of “optimal” parameters, which underscores the need for species-specific parameter optimization. PerSVade will improve our understanding about the role of SVs in non-human organisms.
Competition for endothelial cell polarity drives vascular morphogenesis
Authors: Barbacena Pedro , Dominguez-Cejudo Maria , Fonseca Catarina G. , Gómez-González Manuel , Faure Laura M. , Zarkada Georgia , Pena Andreia A. , Pezzarossa Anna , Ramalho Daniela , Giarratano Ylenia , Ouarné Marie , Barata David , Fortunato Isabela , Misiková Lenka H. , Mauldin Ian , Carvalho Yulia , Trepat Xavier , Roca-Cusachs Pere , Eichmann Anne , Bernabeu Miguel O. , Franco Cláudio A. 
Published: November 2021

AbstractBlood vessel formation generates unique vascular patterns in each individual. The principles governing the apparent stochasticity of this process remain to be elucidated. Using mathematical methods, we find that the transition between two fundamental vascular morphogenetic programs – sprouting angiogenesis and vascular remodeling – is established by a shift on collective front-rear polarity of endothelial cells. We demonstrate that the competition between biochemical (VEGFA) and mechanical (blood flow-induced shear stress) cues controls this collective polarity shift. Shear stress increases tension at focal adhesions overriding VEGFA-driven collective polarization, which relies on tension at adherens junctions. We propose that vascular morphogenetic cues compete to regulate individual cell polarity and migration through tension shifts that translates into tissue-level emergent behaviors, ultimately leading to uniquely organized vascular patterns.
An alternatively spliced TREM2 isoform lacking the ligand binding domain is expressed in human brain
Authors: Shaw Benjamin C. , Snider Henry C. , Turner Andrew K. , Zajac Diana J. , Simpson James F. , Estus Steven 
Published: November 2021

AbstractBackgroundGenetic variants in TREM2 are strongly associated with Alzheimer’s Disease (AD) risk but alternative splicing in TREM2 transcripts has not been comprehensively described.ObjectiveRecognizing that alternative splice variants can result in reduced gene expression and/or altered function, we sought to fully characterize splice variation in TREM2.MethodsHuman blood and anterior cingulate autopsy tissue from 61 donors were used for end-point and quantitative PCR and Western blotting to identify and quantify novel TREM2 isoforms.ResultsIn addition to previously described transcripts lacking exon 3 or exon 4, or retaining part of intron 3, we identified novel isoforms lacking exon 2, along with isoforms lacking multiple exons. Isoforms lacking exon 2 were predominant at approximately 10% of TREM2 mRNA in the brain. Expression of TREM2 and frequency of exon 2 skipping did not differ between AD samples and non-AD controls (p = 0.1268 and p = 0.4909, respectively). Further, these novel splice isoforms were also observed across multiple tissues with similar frequency (range 5.3 – 13.0%). We found that the exon 2 skipped isoform D2-TREM2 is translated to protein and localizes similarly to full-length TREM2 protein, that both proteins are primarily retained in the Golgi complex, and that D2-TREM2 is expressed in AD and non-AD brain.ConclusionSince the TREM2 ligand binding domain is encoded by exon 2, and skipping this exon retains reading frame while conserving localization, we hypothesize that D2-TREM2 acts as an inhibitor of TREM2 and targeting TREM2 splicing may be a novel therapeutic pathway for AD.
Contractile force of transplanted cardiomyocytes contributes to heart function after injury
Authors: Stüdemann Tim , Rössinger Judith , Manthey Christoph , Geertz Birgit , Srikantharajah Rajiven , von Bibra Constantin , Shibamiya Aya , Köhne Maria , Wiehler Antonius , Wiegert J. Simon , Eschenhagen Thomas , Weinberger Florian 
Published: November 2021

AbstractTransplantation of pluripotent stem cell-derived cardiomyocytes represents an innovative therapeutic strategy for heart failure. Studies in small and large animals have demonstrated functional recovery of left ventricular function after cardiomyocyte transplantation1–4, and first clinical studies are currently underway5. Yet, the mechanism of action underlying graft-induced benefit is unknown6. Here we demonstrate that transplanted cardiomyocytes actively contribute to heart function. We transplanted cardiomyocytes with an optogenetic off-on switch in a guinea pig cardiac injury model. Light-induced inhibition of engrafted cardiomyocyte contractility resulted in a rapid decrease of left ventricular function that was fully reversible with the offset of photostimulation. Hence, our optogenetic approach demonstrated that transplanted cardiomyocytes actively participate in heart function, supporting the hypothesis that the delivery of new force-generating myocardium can serve as a regenerative therapeutic strategy.
Fecal microbiota transplantation derived from Alzheimer’s disease mice worsens brain trauma outcomes in wild-type controls
Authors: Soriano Sirena , Curry Kristen , Wang Qi , Chow Elsbeth , Treangen Todd , Villapol Sonia 
Published: November 2021

AbstractTraumatic brain injury (TBI) causes neuroinflammation and neurodegeneration, both which increase the risk and accelerate the progression of Alzheimer’s disease (AD). The gut microbiome is an essential modulator of the immune system, impacting in the brain. AD has been related with reduced diversity and alterations in the community composition of the gut microbiota. This study aimed to determine whether the gut microbiota from AD mice exacerbates neurological deficits after TBI in control mice. We prepared fecal microbiota transplants from 18-24 months old 3xTg-AD (FMT-AD) and from healthy controls (FMT-young) mice. FMTs were administered orally to young control C57BL/6 (wild-type, WT) mice after they underwent controlled cortical impact (CCI) injury, as a model of TBI. Then, we characterized the microbiota composition of the fecal samples by full-length 16S rRNA gene sequencing analysis. We collected the blood, brain, and gut tissues for protein and immunohistochemical analysis. Our results showed that FMT-AD administration stimulates a higher relative abundance of the genus Muribaculum and a decrease in Lactobacillus johnsonii compared to FMT-young in WT mice. Furthermore, WT mice exhibited larger lesion, increased activated microglia/macrophages, and reduced motor recovery after FMT-AD compared to FMT-young one day after TBI. In summary, we observed gut microbiota from AD mice to have a detrimental effect and aggravate the neuroinflammatory response and neurological outcomes after TBI in young WT mice.
Identification of biological processes and signaling pathways in the stretched nucleus pulposus cells
Authors: Zhang Min , Wang Jing , Gu Hanming 
Published: November 2021

AbstractLow back pain is mostly caused by disc degeneration, which is due to the alterations in the osmotic pressure of nucleus pulposus cells. However, the knowledge about the mechanism and therapies for disc degeneration is not fully understood. Here, our objective is to identify significantly changed genes and biological processes in the stretched nucleus pulposus cells. The GSE175710 dataset was originally produced by using the Illumina HiSeq 4000 (Rattus norvegicus). The KEGG and GO analyses indicated that “MAPK signaling”, “TNF signaling”, “IL17 signaling”, and the “NF-κB signaling pathway” are mostly affected in the stretched nucleus pulposus cells. Moreover, we identified several genes according to the PPI network such as Mmp9, Cxcl12, Col1a1, and Col3a1 in the stretched nucleus pulposus cells. Thus, our study provides further insights into the study of disc deterioration.
Quasi-universal scaling in mouse-brain neuronal activity stems from edge-of-instability critical dynamics
Authors: Morales Guillermo B. , Di Santo Serena , Muñoz Miguel A. 
Published: November 2021

AbstractThe brain is in a state of perpetual reverberant neural activity, even in the absence of specific tasks or stimuli. Shedding light on the origin and functional significance of such a dynamical state is essential to understanding how the brain transmits, processes, and stores information. An inspiring, albeit controversial, conjecture proposes that some statistical characteristics of empirically observed neuronal activity can be understood by assuming that brain networks operate in a dynamical regime near the edge of a phase transition. Moreover, the resulting critical behavior, with its concomitant scale invariance, is assumed to carry crucial functional advantages. Here, we present a data-driven analysis based on simultaneous high-throughput recordings of the activity of thousands of individual neurons in various regions of the mouse brain. To analyze these data, we synergistically combine cutting-edge methods for the study of brain activity (such as a phenomenological renormalization group approach and techniques that infer the general dynamical state of a neural population), while designing complementary tools. This strategy allows us to uncover strong signatures of scale invariance that is ”quasi-universal” across brain regions and reveal that all these areas operate, to a greater or lesser extent, near the edge of instability. Furthermore, this framework allows us to distinguish between quasi-universal background activity and non-universal input-related activity. Taken together, this study provides strong evidence that brain networks actually operate in a critical regime which, among other functional advantages, provides them with a scale-invariant substrate of activity covariances that can sustain optimal input representations.
Long-term potentiation at pyramidal cell to somatostatin interneuron synapses controls hippocampal network plasticity and memory
Authors: Asgarihafshejani Azam , Honoré Ève , Michon François-Xavier , Laplante Isabel , Lacaille Jean-Claude 
Published: November 2021

SUMMARYHippocampal somatostatin (SOM) cells are dendrite-projecting inhibitory interneurons. CA1 SOM cells receive major excitatory inputs from pyramidal cells (PC-SOM synapses) which show mGluR1a- and mTORC1-mediated long-term potentiation (LTP). PC-SOM synapse LTP contributes to CA1 network metaplasticity and memory consolidation, but whether it is sufficient to regulate these processes remains unknown. Here we used optogenetic stimulation of CA1 pyramidal cells and whole cell recordings in slices to show that optogenetic theta burst stimulation (TBSopto) produces LTP at PC-SOM synapses. At the network level, we found that TBSopto differentially regulates metaplasticity of pyramidal cell inputs: enhancing LTP at Schaffer collateral synapses and depressing LTP at temporo-ammonic synapses. At the behavioral level, we uncovered that in vivo TBSopto regulates learning-induced LTP at PC-SOM synapses, as well as contextual fear memory. Thus, LTP of PC-SOM synapses is a long-term feedback mechanism controlling pyramidal cell synaptic plasticity, sufficient to regulate memory consolidation.
Seed bio-priming with phosphate solubilizing bacteria strains to improve rice (Oryza sativa L. var. FARO 44) growth under ferruginous ultisol conditions
Authors: Ibrahim Musa Saheed , Ikhajiagbe Beckley 
Published: November 2021

AbstractThe research investigated the possibility of phosphate solubilizing bacteria (PSB) with plant growth-promoting (PGP) capabilities to improve growth properties of rice plant under ferruginous ultisol (FU) condition through bio-priming strategy. The PSB with PGP properties used in this research were Bacillus cereus strain GGBSU-1, Proteus mirabilis strain TL14-1 and Klebsiella variicola strain AUH-KAM-9 that were previously isolated and characterized following the 16S rRNA gene sequencing. Biosafety analysis of the PSB isolates was conducted using blood agar. The rice seeds were then bio-primed with the PSBs at 3, 12 and 24 hours priming durations and then sown in a composite FU soil sample. Differences in germination bioassay involving SEM, morphology, physiology and biomass parameters were investigated for 15 weeks after bio-priming. The composite FU soil used in the study had high pH, low bioavailable phosphorus, low water holding capacity and high iron levels which has led to a low growth properties of rice seeds without bio-priming in FU soil. Germination parameters was better in seeds bio-primed with the PSBs, especially at 12h priming duration as against seeds without priming. SEM showed more bacterial colonization in the PSB bio-primed seeds. Seed bio-priming of rice seed with Bacillus cereus strain GGBSU-1, Proteus mirabilis strain TL14-1 and Klebsiella variicola strain AUH-KAM-9 under FU soil condition significantly improved seed microbiome, rhizocolonization and soil nutrient properties, thereby enhancing growth properties of the rice plant. This suggest the ability of PSB to solubilize and mineralize soil phosphate and improve its availability and soil property for optimum plant usage in phosphate stressed and iron toxic soils.
Comparison of neuromuscular junction dynamics following ischemic and aged skeletal muscle
Authors: Aliya Berna , Mohiuddin Mahir , Choi Jeongmoon J. , Jeong Gunjae , Kang Innie , Castels Hannah , Jones Cade , Jang Young C. 
Published: November 2021

AbstractBoth aging and neuromuscular diseases lead to significant changes in the morphology and functionality of the neuromuscular synapse. Skeletal muscles display a remarkable regenerative capacity, however, are still susceptible to diseases of aging and peripheral nerve perturbations. In this study, we assessed how neuromuscular synapses differ in aged and injured skeletal muscle using an improved neuromuscular junction (NMJ) staining and imaging method. We found that both aged and ischemic skeletal muscle display Wallerian degeneration of the presynaptic motor axons and fragmentation of postsynaptic acetylcholine receptors (AChRs). Quantifiable measurements of various metrics of the NMJs provide a more concrete idea of the dynamics that are occurring in the muscle microenvironment. We questioned whether neuronal degradation precedes myofiber atrophy or vice versa. Previously, it was shown that a cellular crosstalk exists among the motor neurons, myofibers, vasculature, and mitochondria within the muscle microdomain. It is apparent that lack of blood flow to motor neurons in ischemic skeletal muscle disrupts the structure of NMJs, however it is unclear if the aging condition experiences similar dynamics. We demonstrated that both aged and ischemic skeletal muscle demonstrate similar patterns of degeneration, characterized by a smaller percentage overlap of presynaptic and postsynaptic sides, greater fragmentation of AChRs, and a smaller area of AChR clusters. Together, these results reveal high resolution, precise parallels between the aged and ischemic NMJs.Impact StatementThe goal of this study was to assess changes in presynaptic motor neurons and postsynaptic acetylcholine receptors following an ischemic injury model and compare this with an aging model. This was accomplished by characterizing key components of NMJ morphology, including overlap and size of the receptors. There is currently limited research investigating the cellular communication between skeletal muscle fibers and motor neurons. Additionally, there is limited work comparing neuromuscular remodeling in aged and young models. With the substantial prevalence of neuromuscular disorders, especially in the aging population, it is essential to understand nerve-muscle interactions in order to promote increased mobility and improved quality of life in both injury and aging models.
Ribonucleotide Reductase Regulatory Subunit M2 as a Driver of Glioblastoma TMZ-Resistance through Modulation of dNTP Production
Authors: Perrault Ella N , Shireman Jack M , Ali Eunus S , Preddy Isabelle , Lin Peiyu , Park Cheol , Tomes Luke , Zolp Andrew J , Budhiraja Shreya , Baisiwala Shivani , James C. David , Ben-Sahra Issam , Pott Sebastian , Basu Anindita , Ahmed Atique U 
Published: November 2021

ABSTRACTGlioblastoma (GBM) remains one of the most resistant and fatal forms of cancer. Previous studies have examined primary and recurrent GBM tumors, but it is difficult to study tumor evolution during therapy where resistance develops. To investigate this, we performed an in vivo single-cell RNA sequencing screen in a patient-derived xenograft (PDX) model. Primary GBM was modeled by mice treated with DMSO control, recurrent GBM was modeled by mice treated with temozolomide (TMZ), and during therapy GBM was modeled by mice euthanized after two of five TMZ treatments. Our analysis revealed the cellular population present during therapy to be distinct from primary and recurrent GBM. We found the Ribonucleotide Reductase gene family to exhibit a unique signature in our data due to an observed subunit switch to favor RRM2 during therapy. GBM cells were shown to rely on RRM2 during therapy causing RRM2-knockdown (KD) cells to be TMZ-sensitive. Using targeted metabolomics, we found RRM2-KDs to produce less dGTP and dCTP than control cells in response to TMZ (p<0.0001). Supplementing RRM2-KDs with deoxycytidine and deoxyguanosine rescued TMZ-sensitivity, suggesting an RRM2-driven mechanism of chemoresistance, established by regulating the production of these nucleotides. In vivo, tumor-bearing mice treated with the RRM2-inhibitor, Triapine, in combination with TMZ, survived longer than mice treated with TMZ alone (p<0.01), indicating promising clinical opportunities in targeting RRM2. Our data present a novel understanding of RRM2 activity, and its alteration during therapeutic stress as response to TMZ-induced DNA damage.
Prevalence and correlates of phenazine resistance in culturable bacteria from a dryland wheat field
Authors: Perry Elena K. , Newman Dianne K. 
Published: November 2021

AbstractPhenazines are a class of bacterially-produced redox-active natural antibiotics that have demonstrated potential as a sustainable alternative to traditional pesticides for the biocontrol of fungal crop diseases. However, the prevalence of bacterial resistance to agriculturally-relevant phenazines is poorly understood, limiting both the understanding of how these molecules might shape rhizosphere bacterial communities and the ability to perform risk assessment for off-target effects. Here, we describe profiles of susceptibility to the antifungal agent phenazine-1-carboxylic acid (PCA) across more than 100 bacterial strains isolated from a wheat field where PCA producers are indigenous and abundant. We find that Gram-positive bacteria are typically more sensitive to PCA than Gram-negative bacteria, but that there is also significant variability in susceptibility both within and across phyla. Phenazine-resistant strains are more likely to be isolated from the wheat rhizosphere, where PCA producers are also more abundant, compared to bulk soil. Furthermore, PCA toxicity is pH-dependent for most susceptible strains and broadly correlates with PCA reduction rates, suggesting that uptake and redox-cycling are important determinants of phenazine toxicity. Our results shed light on which classes of bacteria are most likely to be susceptible to phenazine toxicity in acidic or neutral soils. In addition, the taxonomic and phenotypic diversity of our strain collection represents a valuable resource for future studies on the role of natural antibiotics in shaping wheat rhizosphere communities.ImportanceMicrobial communities contribute to crop health in important ways. For example, phenazine metabolites are a class of redox-active molecules made by diverse soil bacteria that underpin the biocontrol of wheat and other crops. Their physiological functions are nuanced: in some contexts they are toxic, in others, beneficial. While much is known about phenazine production and the effect of phenazines on producing strains, our ability to predict how phenazines might shape the composition of environmental microbial communities is poorly constrained; that phenazine prevalence in the rhizosphere is predicted to increase in arid soils as the climate changes provides an impetus for further study. As a step towards gaining a predictive understanding of phenazine-linked microbial ecology, we document the effects of phenazines on diverse bacteria that were co-isolated from a wheat rhizosphere and identify conditions and phenotypes that correlate with how a strain will respond to phenazines.