Publications by authors named "Ali Mortazavi"

90 Publications

Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer's disease-like pathology.

Nat Commun 2021 04 23;12(1):2421. Epub 2021 Apr 23.

Department of Developmental and Cell Biology, University of California, Irvine, CA, USA.

The majority of Alzheimer's disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aβ under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aβ sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression. In addition, when exon 14 encoding the Aβ sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAβ expression, rescues cognition and reduces the formation of PAS granules.
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http://dx.doi.org/10.1038/s41467-021-22624-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065162PMC
April 2021

An Infection-Tolerant Mammalian Reservoir for Several Zoonotic Agents Broadly Counters the Inflammatory Effects of Endotoxin.

mBio 2021 04 13;12(2). Epub 2021 Apr 13.

Department of Microbiology & Molecular Genetics, School of Medicine, University of California Irvine, Irvine, California, USA

Animals that are competent reservoirs of zoonotic pathogens commonly suffer little morbidity from the infections. To investigate mechanisms of this tolerance of infection, we used single-dose lipopolysaccharide (LPS) as an experimental model of inflammation and compared the responses of two rodents: , the white-footed deermouse and reservoir for the agents of Lyme disease and other zoonoses, and the house mouse Four hours after injection with LPS or saline, blood, spleen, and liver samples were collected and subjected to transcriptome sequencing (RNA-seq), metabolomics, and specific reverse transcriptase quantitative PCR (RT-qPCR). Differential expression analysis was at the gene, pathway, and network levels. LPS-treated deermice showed signs of sickness similar to those of exposed mice and had similar increases in corticosterone levels and expression of interleukin 6 (IL-6), tumor necrosis factor, IL-1β, and C-reactive protein. By network analysis, the response to LPS was characterized as cytokine associated, while the response was dominated by neutrophil activity terms. In addition, dichotomies in the expression levels of arginase 1 and nitric oxide synthase 2 and of IL-10 and IL-12 were consistent with type M1 macrophage responses in mice and type M2 responses in deermice. Analysis of metabolites in plasma and RNA in organs revealed species differences in tryptophan metabolism. Two genes in particular signified the different phenotypes of deermice and mice: the Slpi and Ibsp genes. Key RNA-seq findings for were replicated in older animals, in a systemic bacterial infection, and with cultivated fibroblasts. The findings indicate that possesses several adaptive traits to moderate inflammation in its balancing of infection resistance and tolerance. Animals that are natural carriers of pathogens that cause human diseases commonly manifest little or no sickness as a consequence of infection. Examples include the deermouse, , which is a reservoir for Lyme disease and several other disease agents in North America, and some types of bats, which are carriers of viruses with pathogenicity for humans. Mechanisms of this phenomenon of infection tolerance and entailed trade-off costs are poorly understood. Using a single injection of lipopolysaccharide (LPS) endotoxin as a proxy for infection, we found that deermice differed from the mouse () in responses to LPS in several diverse pathways, including innate immunity, oxidative stress, and metabolism. Features distinguishing the deermice cumulatively would moderate downstream ill effects of LPS. Insights gained from the model in the laboratory have implications for studying infection tolerance in other important reservoir species, including bats and other types of wildlife.
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http://dx.doi.org/10.1128/mBio.00588-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092257PMC
April 2021

Physicochemical properties and enzymatic activity of wheat germ extract microencapsulated with spray and freeze drying.

Food Sci Nutr 2021 Feb 8;9(2):1192-1201. Epub 2021 Jan 8.

Department of Food Science and Technology Faculty of Industrial and Mechanical Engineering Qazvin Branch Islamic Azad University Qazvin Iran.

Wheat germ is produced as a by-product during wheat milling operations and is a relatively inexpensive protein source that, in spite of its exclusive nutritional properties, is mostly used for animal feed formulation and has limited use in the food industry. In this study, wheat germ extract (WGE) was microencapsulated by spray and freeze drying and with different ratios of maltodextrin to whey protein concentrate (M-W) as the coating material and then physicochemical properties of the microcapsules were evaluated. Results showed decreased moisture content and increased solubility, lipase activity, acid phosphatase activity, and both lipase and acid phosphatase microencapsulation efficiency with increasing M-W ratios in both drying methods. The M-W ratios had no significant effects on the DPPH free radical scavenging activity in both methods. With increasing M-W ratios, particle size decreased and bulk density increased in the spray drying method, while particle size increased and bulk density decreased in the freeze drying method. Spray drying elevated solubility, DPPH free radical scavenging activity, lipase activity, acid phosphatase activity, and both lipase and acid phosphatase microencapsulation efficiency, in comparison with the freeze drying method.
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http://dx.doi.org/10.1002/fsn3.2104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866571PMC
February 2021

Relationship of DUX4 and target gene expression in FSHD myocytes.

Hum Mutat 2021 Apr 4;42(4):421-433. Epub 2021 Feb 4.

Department of Biological Chemistry, School of Medicine, University of California, Irvine, California, USA.

Facioscapulohumeral dystrophy (FSHD) is associated with the upregulation of the DUX4 transcription factor and its target genes. However, low-frequency DUX4 upregulation in patient myocytes is difficult to detect and examining the relationship and dynamics of DUX4 and target gene expression has been challenging. Using RNAScope in situ hybridization with highly specific probes, we detect the endogenous DUX4 and target gene transcripts in situ in patient skeletal myotubes during 13-day differentiation in vitro. We found that the endogenous DUX4 transcripts primarily localize as foci in one or two nuclei as compared with the accumulation of the recombinant DUX4 transcripts in the cytoplasm. We also found the continuous increase of DUX4 and target gene-positive myotubes after Day 3, arguing against its expected immediate cytotoxicity. Interestingly, DUX4 and target gene expression become discordant later in differentiation with the increase of DUX4-positive/target gene-negative as well as DUX4-negative/target gene-positive myotubes. Depletion of DUX4-activated transcription factors, DUXA and LEUTX, specifically repressed a DUX4-target gene, KDM4E, later in differentiation, suggesting that after the initial activation by DUX4, target genes themselves contribute to the maintenance of downstream gene expression. Together, the study provides important new insights into the dynamics of the DUX4 transcriptional network in FSHD patient myocytes.
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http://dx.doi.org/10.1002/humu.24171DOI Listing
April 2021

Transcatheter aortic valve replacement after chest radiation: A propensity-matched analysis.

Int J Cardiol 2021 Apr 24;329:50-55. Epub 2020 Dec 24.

Division of Cardiology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Department of Cardiology, Texas Heart Institute, Houston, TX, USA. Electronic address:

Background: Chest radiation therapy (CRT) for malignant thoracic neoplasms is associated with development of valvular heart disease years later. As previous radiation exposure can complicate surgical treatment, transcatheter aortic valve replacement (TAVR) has emerged as an alternative. However, outcomes data are lacking for TAVR patients with a history of CRT.

Methods: We conducted a retrospective study of all patients who underwent a TAVR procedure at a single institution between September 2012 and November 2018. Among 1341 total patients, 50 had previous CRT. These were propensity-matched in a 1:2 ratio to 100 patients without history of CRT. Thirty-day adverse events were analyzed with generalized estimating equation models. Overall mortality was analyzed with stratified Cox regression modelling.

Results: Median clinical follow-up was 24 months (interquartile range [IQR], 12-44 months). There was no difference between CRT and non-CRT patients in overall mortality (hazard ratio [HR] 0.84 [0.37-1.90], P = 0.67), 30-day mortality (HR 3.1 [0.49-20.03], P = 0.23), or 30-day readmission rate (HR 1.0 [0.43-2.31], P = 1). There were no differences in the rates of most adverse events, but patients with CRT history had higher rates of postprocedural respiratory failure (HR 3.63 [1.32-10.02], P = 0.01) and permanent pacemaker implantation (HR 2.84 [1.15-7.01], P = 0.02).

Conclusions: For patients with aortic valve stenosis and previous CRT, TAVR is safe and effective, with outcomes similar to those in the general aortic stenosis population. Patients with history of CRT are more likely to have postprocedural respiratory failure and to require permanent pacemaker implantation.
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http://dx.doi.org/10.1016/j.ijcard.2020.12.054DOI Listing
April 2021

Unexpected Transcriptional Programs Contribute to Hippocampal Memory Deficits and Neuronal Stunting after Early-Life Adversity.

Cell Rep 2020 12;33(11):108511

Department of Pediatrics, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Anatomy/Neurobiology, University of California, Irvine, Irvine, CA 92697-4475, USA; Department of Neurology, University of California, Irvine, Irvine, CA 92697-4475, USA. Electronic address:

Early-life adversity (ELA) is associated with lifelong memory deficits, yet the responsible mechanisms remain unclear. We impose ELA by rearing rat pups in simulated poverty, assess hippocampal memory, and probe changes in gene expression, their transcriptional regulation, and the consequent changes in hippocampal neuronal structure. ELA rats have poor hippocampal memory and stunted hippocampal pyramidal neurons associated with ~140 differentially expressed genes. Upstream regulators of the altered genes include glucocorticoid receptor and, unexpectedly, the transcription factor neuron-restrictive silencer factor (NRSF/REST). NRSF contributes critically to the memory deficits because blocking its function transiently following ELA rescues spatial memory and restores the dendritic arborization of hippocampal pyramidal neurons in ELA rats. Blocking NRSF function in vitro augments dendritic complexity of developing hippocampal neurons, suggesting that NRSF represses genes involved in neuronal maturation. These findings establish important, surprising contributions of NRSF to ELA-induced transcriptional programming that disrupts hippocampal maturation and memory function.
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http://dx.doi.org/10.1016/j.celrep.2020.108511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817243PMC
December 2020

Model organism development and evaluation for late-onset Alzheimer's disease: MODEL-AD.

Alzheimers Dement (N Y) 2020 23;6(1):e12110. Epub 2020 Nov 23.

Indiana University School of Medicine Indianapolis Indiana USA.

Alzheimer's disease (AD) is a major cause of dementia, disability, and death in the elderly. Despite recent advances in our understanding of the basic biological mechanisms underlying AD, we do not know how to prevent it, nor do we have an approved disease-modifying intervention. Both are essential to slow or stop the growth in dementia prevalence. While our current animal models of AD have provided novel insights into AD disease mechanisms, thus far, they have not been successfully used to predict the effectiveness of therapies that have moved into AD clinical trials. The Model Organism Development and Evaluation for Late-onset Alzheimer's Disease (MODEL-AD; www.model-ad.org) Consortium was established to maximize human datasets to identify putative variants, genes, and biomarkers for AD; to generate, characterize, and validate the next generation of mouse models of AD; and to develop a preclinical testing pipeline. MODEL-AD is a collaboration among Indiana University (IU); The Jackson Laboratory (JAX); University of Pittsburgh School of Medicine (Pitt); Sage BioNetworks (Sage); and the University of California, Irvine (UCI) that will generate new AD modeling processes and pipelines, data resources, research results, standardized protocols, and models that will be shared through JAX's and Sage's proven dissemination pipelines with the National Institute on Aging-supported AD Centers, academic and medical research centers, research institutions, and the pharmaceutical industry worldwide.
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http://dx.doi.org/10.1002/trc2.12110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683958PMC
November 2020

Slug regulates the Dll4-Notch-VEGFR2 axis to control endothelial cell activation and angiogenesis.

Nat Commun 2020 10 26;11(1):5400. Epub 2020 Oct 26.

The Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, 92697, USA.

Slug (SNAI2), a member of the well-conserved Snail family of transcription factors, has multiple developmental roles, including in epithelial-to-mesenchymal transition (EMT). Here, we show that Slug is critical for the pathological angiogenesis needed to sustain tumor growth, and transiently necessary for normal developmental angiogenesis. We find that Slug upregulation in angiogenic endothelial cells (EC) regulates an EMT-like suite of target genes, and suppresses Dll4-Notch signaling thereby promoting VEGFR2 expression. Both EC-specific Slug re-expression and reduced Notch signaling, either by γ-secretase inhibition or loss of Dll4, rescue retinal angiogenesis in SlugKO mice. Conversely, inhibition of VEGF signaling prevents excessive angiogenic sprouting of Slug overexpressing EC. Finally, endothelial Slug (but not Snail) is activated by the pro-angiogenic factor SDF1α via its canonical receptor CXCR4 and the MAP kinase ERK5. Altogether, our data support a critical role for Slug in determining the angiogenic response during development and disease.
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http://dx.doi.org/10.1038/s41467-020-18633-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588439PMC
October 2020

Swan: a library for the analysis and visualization of long-read transcriptomes.

Bioinformatics 2020 Sep 29. Epub 2020 Sep 29.

Department of Developmental and Cell Biology, UC Irvine, Irvine CA.

Motivation: Long-read RNA-sequencing technologies such as PacBio and Oxford Nanopore have discovered an explosion of new transcript isoforms that are difficult to visually analyze using currently available tools. We introduce the Swan Python library, which is designed to analyze and visualize transcript models.

Results: Swan finds 4,909 differentially expressed transcripts between cell lines HepG2 and HFFc6, including 279 that are differentially expressed even though the parent gene is not. Additionally, Swan discovers 285 reproducible exon skipping and 47 intron retention events not recorded in the GENCODE v29 annotation.

Availability: The Swan library for Python 3 is available on PyPi at https://pypi.org/project/swan-vis/ and on GitHub at https://github.com/mortazavilab/swan_vis.
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http://dx.doi.org/10.1093/bioinformatics/btaa836DOI Listing
September 2020

A Revised Adaptation of the Smart-Seq2 Protocol for Single-Nematode RNA-Seq.

Methods Mol Biol 2021 ;2170:79-99

Department of Nematology, University of California, Riverside, CA, USA.

The advancement of transcriptomic studies in plant parasitic nematodes will greatly benefit from the development of single-nematode RNA-seq methods. Since many plant parasitic nematodes are obligate parasites, it is often difficult to efficiently obtain sufficient amounts of nematodes for transcriptomic studies. Here we have adapted SMART-Seq2 for single-nematode RNA-seq requiring only an individual nematode for a sample replicate. This protocol provides a detailed step-by-step procedure of the RNA-seq workflow starting from lysis of the nematode to quantification of transcripts using a user-friendly online platform.
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http://dx.doi.org/10.1007/978-1-0716-0743-5_6DOI Listing
March 2021

Expanded encyclopaedias of DNA elements in the human and mouse genomes.

Nature 2020 07 29;583(7818):699-710. Epub 2020 Jul 29.

Department of Biological Science, Florida State University, Tallahassee, FL, USA.

The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE and Roadmap Epigenomics data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.
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http://dx.doi.org/10.1038/s41586-020-2493-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410828PMC
July 2020

Occupancy maps of 208 chromatin-associated proteins in one human cell type.

Nature 2020 07 29;583(7818):720-728. Epub 2020 Jul 29.

HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.

Transcription factors are DNA-binding proteins that have key roles in gene regulation. Genome-wide occupancy maps of transcriptional regulators are important for understanding gene regulation and its effects on diverse biological processes. However, only a minority of the more than 1,600 transcription factors encoded in the human genome has been assayed. Here we present, as part of the ENCODE (Encyclopedia of DNA Elements) project, data and analyses from chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) experiments using the human HepG2 cell line for 208 chromatin-associated proteins (CAPs). These comprise 171 transcription factors and 37 transcriptional cofactors and chromatin regulator proteins, and represent nearly one-quarter of CAPs expressed in HepG2 cells. The binding profiles of these CAPs form major groups associated predominantly with promoters or enhancers, or with both. We confirm and expand the current catalogue of DNA sequence motifs for transcription factors, and describe motifs that correspond to other transcription factors that are co-enriched with the primary ChIP target. For example, FOX family motifs are enriched in ChIP-seq peaks of 37 other CAPs. We show that motif content and occupancy patterns can distinguish between promoters and enhancers. This catalogue reveals high-occupancy target regions at which many CAPs associate, although each contains motifs for only a minority of the numerous associated transcription factors. These analyses provide a more complete overview of the gene regulatory networks that define this cell type, and demonstrate the usefulness of the large-scale production efforts of the ENCODE Consortium.
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http://dx.doi.org/10.1038/s41586-020-2023-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398277PMC
July 2020

Single-nucleus RNA-seq identifies divergent populations of FSHD2 myotube nuclei.

PLoS Genet 2020 05 4;16(5):e1008754. Epub 2020 May 4.

Department of Developmental and Cell Biology, University of California Irvine, Irvine, California, United States of America.

FSHD is characterized by the misexpression of DUX4 in skeletal muscle. Although DUX4 upregulation is thought to be the pathogenic cause of FSHD, DUX4 is lowly expressed in patient samples, and analysis of the consequences of DUX4 expression has largely relied on artificial overexpression. To better understand the native expression profile of DUX4 and its targets, we performed bulk RNA-seq on a 6-day differentiation time-course in primary FSHD2 patient myoblasts. We identify a set of 54 genes upregulated in FSHD2 cells, termed FSHD-induced genes. Using single-cell and single-nucleus RNA-seq on myoblasts and differentiated myotubes, respectively, we captured, for the first time, DUX4 expressed at the single-nucleus level in a native state. We identified two populations of FSHD myotube nuclei based on low or high enrichment of DUX4 and FSHD-induced genes ("FSHD-Lo" and "FSHD Hi", respectively). FSHD-Hi myotube nuclei coexpress multiple DUX4 target genes including DUXA, LEUTX and ZSCAN4, and also upregulate cell cycle-related genes with significant enrichment of E2F target genes and p53 signaling activation. We found more FSHD-Hi nuclei than DUX4-positive nuclei, and confirmed with in situ RNA/protein detection that DUX4 transcribed in only one or two nuclei is sufficient for DUX4 protein to activate target genes across multiple nuclei within the same myotube. DUXA (the DUX4 paralog) is more widely expressed than DUX4, and depletion of DUXA suppressed the expression of LEUTX and ZSCAN4 in late, but not early, differentiation. The results suggest that the DUXA can take over the role of DUX4 to maintain target gene expression. These results provide a possible explanation as to why it is easier to detect DUX4 target genes than DUX4 itself in patient cells and raise the possibility of a self-sustaining network of gene dysregulation triggered by the limited DUX4 expression.
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http://dx.doi.org/10.1371/journal.pgen.1008754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224571PMC
May 2020

Molecular evolution and expression of opsin genes in Hydra vulgaris.

BMC Genomics 2019 Dec 17;20(1):992. Epub 2019 Dec 17.

Department of Developmental and Cell Biology, University of California, Irvine, CA, 92697, USA.

Background: The evolution of opsin genes is of great interest because it can provide insight into the evolution of light detection and vision. An interesting group in which to study opsins is Cnidaria because it is a basal phylum sister to Bilateria with much visual diversity within the phylum. Hydra vulgaris (H. vulgaris) is a cnidarian with a plethora of genomic resources to characterize the opsin gene family. This eyeless cnidarian has a behavioral reaction to light, but it remains unknown which of its many opsins functions in light detection. Here, we used phylogenetics and RNA-seq to investigate the molecular evolution of opsin genes and their expression in H. vulgaris. We explored where opsin genes are located relative to each other in an improved genome assembly and where they belong in a cnidarian opsin phylogenetic tree. In addition, we used RNA-seq data from different tissues of the H. vulgaris adult body and different time points during regeneration and budding stages to gain insight into their potential functions.

Results: We identified 45 opsin genes in H. vulgaris, many of which were located near each other suggesting evolution by tandem duplications. Our phylogenetic tree of cnidarian opsin genes supported previous claims that they are evolving by lineage-specific duplications. We identified two H. vulgaris genes (HvOpA1 and HvOpB1) that fall outside of the two commonly determined Hydra groups; these genes possibly have a function in nematocytes and mucous gland cells respectively. We also found opsin genes that have similar expression patterns to phototransduction genes in H. vulgaris. We propose a H. vulgaris phototransduction cascade that has components of both ciliary and rhabdomeric cascades.

Conclusions: This extensive study provides an in-depth look at the molecular evolution and expression of H. vulgaris opsin genes. The expression data that we have quantified can be used as a springboard for additional studies looking into the specific function of opsin genes in this species. Our phylogeny and expression data are valuable to investigations of opsin gene evolution and cnidarian biology.
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http://dx.doi.org/10.1186/s12864-019-6349-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918707PMC
December 2019

[Calcitonin as an analgesic agent: review of mechanisms of action and clinical applications].

Rev Bras Anestesiol 2019 Nov - Dec;69(6):594-604. Epub 2019 Dec 3.

Tabriz University of Medical Sciences, Department of Oral and Maxillofacial Surgery, Tabriz, Irã. Electronic address:

Background And Objectives: Calcitonin is a polypeptide hormone regulating the metabolism calcium in the body. For many years calcitonin has been used to maintain and improve bone mineral density and to reduce the fracture rate. Many studies showed that calcitonin had analgesic role in several painful circumstances. This pain-ameliorating effect is irrelevant to its osteoclastic inhibitory effect and mechanisms like altering Na+ channel and serotonin receptor expression or hypothesis including the endorphin-mediated mechanism were used to explain this effect. In this study we performed a thorough review on the role of calcitonin as an analgesic agent in different scenarios and investigated the fact that calcitonin can be a feasible medication to relieve pain.

Method: Many studies focused on the analgesic effect of calcitonin in several painful circumstances, including acute pains related to vertebral fractures, metastasis, migraine and reflex sympathetic dystrophy as well as neuropathic pains related to spinal injuries or diabetes, and phantom pain. Also, calcitonin was showed to be a useful additive to local anesthesia in the case of controlling postoperative pain or trigeminal neuralgia more effectively. However we faced some contradictory data for conditions like lumbar canal stenosis, complex regional pain syndrome, phantom pain and malignancies.

Conclusion: This study showed that calcitonin could be helpful analgesic agent in different painful situations. Calcitonin can be considered an eligible treatment for acute pains related to vertebral fractures and a feasible alternative for the treatment of the acute and chronic neuropathic pains where other medications might fail.
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http://dx.doi.org/10.1016/j.bjan.2019.08.004DOI Listing
July 2020

Building gene regulatory networks from scATAC-seq and scRNA-seq using Linked Self Organizing Maps.

PLoS Comput Biol 2019 11 4;15(11):e1006555. Epub 2019 Nov 4.

Developmental and Cell Biology, University of California Irvine, Irvine, California, United States of America.

Rapid advances in single-cell assays have outpaced methods for analysis of those data types. Different single-cell assays show extensive variation in sensitivity and signal to noise levels. In particular, scATAC-seq generates extremely sparse and noisy datasets. Existing methods developed to analyze this data require cells amenable to pseudo-time analysis or require datasets with drastically different cell-types. We describe a novel approach using self-organizing maps (SOM) to link scATAC-seq regions with scRNA-seq genes that overcomes these challenges and can generate draft regulatory networks. Our SOMatic package generates chromatin and gene expression SOMs separately and combines them using a linking function. We applied SOMatic on a mouse pre-B cell differentiation time-course using controlled Ikaros over-expression to recover gene ontology enrichments, identify motifs in genomic regions showing similar single-cell profiles, and generate a gene regulatory network that both recovers known interactions and predicts new Ikaros targets during the differentiation process. The ability of linked SOMs to detect emergent properties from multiple types of highly-dimensional genomic data with very different signal properties opens new avenues for integrative analysis of heterogeneous data.
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http://dx.doi.org/10.1371/journal.pcbi.1006555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855564PMC
November 2019

STATegra, a comprehensive multi-omics dataset of B-cell differentiation in mouse.

Sci Data 2019 10 31;6(1):256. Epub 2019 Oct 31.

Microbiology and Cell Science Department, Institute for Food and Agricultural Research, Genetics Institute, University of Florida, Gainesville, Florida, USA.

Multi-omics approaches use a diversity of high-throughput technologies to profile the different molecular layers of living cells. Ideally, the integration of this information should result in comprehensive systems models of cellular physiology and regulation. However, most multi-omics projects still include a limited number of molecular assays and there have been very few multi-omic studies that evaluate dynamic processes such as cellular growth, development and adaptation. Hence, we lack formal analysis methods and comprehensive multi-omics datasets that can be leveraged to develop true multi-layered models for dynamic cellular systems. Here we present the STATegra multi-omics dataset that combines measurements from up to 10 different omics technologies applied to the same biological system, namely the well-studied mouse pre-B-cell differentiation. STATegra includes high-throughput measurements of chromatin structure, gene expression, proteomics and metabolomics, and it is complemented with single-cell data. To our knowledge, the STATegra collection is the most diverse multi-omics dataset describing a dynamic biological system.
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http://dx.doi.org/10.1038/s41597-019-0202-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823427PMC
October 2019

Dynamics of microRNA expression during mouse prenatal development.

Genome Res 2019 11 23;29(11):1900-1909. Epub 2019 Oct 23.

Department of Developmental and Cell Biology, University of California Irvine, Irvine, California 92697, USA.

MicroRNAs (miRNAs) play a critical role as posttranscriptional regulators of gene expression. The ENCODE Project profiled the expression of miRNAs in an extensive set of organs during a time-course of mouse embryonic development and captured the expression dynamics of 785 miRNAs. We found distinct organ-specific and developmental stage-specific miRNA expression clusters, with an overall pattern of increasing organ-specific expression as embryonic development proceeds. Comparative analysis of conserved miRNAs in mouse and human revealed stronger clustering of expression patterns by organ type rather than by species. An analysis of messenger RNA expression clusters compared with miRNA expression clusters identifies the potential role of specific miRNA expression clusters in suppressing the expression of mRNAs specific to other developmental programs in the organ in which these miRNAs are expressed during embryonic development. Our results provide the most comprehensive time-course of miRNA expression as part of an integrated ENCODE reference data set for mouse embryonic development.
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http://dx.doi.org/10.1101/gr.248997.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836743PMC
November 2019

Comparison of analgesic effects of intravenous and intranasal ketorolac in patients with mandibular fracture-A Randomized Clinical Trial.

J Clin Exp Dent 2019 Sep 1;11(9):e768-e775. Epub 2019 Sep 1.

Postgraduate Student, Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran.

Background: Similarity of pharmacokinetics of intranasal ketorolac to the intravenous form and other advantages have promoted its application. This study compared the analgesic effects of intravenous and intranasal ketorolac in patients undergoing mandibular fracture surgery.

Material And Methods: In this clinical trial study, Sixty-four patients with unilateral mandibular fracture were divided randomly into two groups. In group 1, 30 mg of intravenous (IV) ketorolac was injected every 8 hours and in group 2, intranasal (IN) ketorolac spray was used as a 100-µL puff in each nostril (31.5 mg) every 6 hours. After each patient regained consciousness, pain intensity was measured based on visual analogue scale for 48 hours. Finally, the total dose of the opioid analgesic agent (pethidine) and the time for the first request for an analgesic agent were recorded for each patient, and their means were compared in each group with proper statistical tests.

Results: Mean pain intensity of patients at baseline was significantly higher than that at other intervals and then, it decreased significantly (<0.001). Furthermore, 2, 4, 6 and 8 hours after surgery, mean pain intensity in the IN group was significantly lower than that in the IV group (<0.05). In the IN group, dose of antinociceptive medicine was slightly higher and the time to request it was shorter than the other group, but it was not statistically significant ( >0.05).

Conclusions: Application of intranasal ketorolac spray decreased pain after mandibular fracture surgery, especially at 8-hour interval after surgery, decreasing the need for opioids. Ketorolac, intranasal, intravenous, mandibular fracture.
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http://dx.doi.org/10.4317/jced.55753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797447PMC
September 2019

Intra-individual changes in methylome profiles: an epigenetic 'scar' of early-life adversity?

Neuropsychopharmacology 2020 01;45(1):218

Departments of Pediatrics, Anatomy/Neurobiology, Neurology, University of California-Irvine, Irvine, CA, 92697-4475, USA.

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http://dx.doi.org/10.1038/s41386-019-0496-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879488PMC
January 2020

The genome of , natural host for Lyme disease and other emerging infections.

Sci Adv 2019 07 24;5(7):eaaw6441. Epub 2019 Jul 24.

Departments of Microbiology and Molecular Genetics and Medicine, University of California, Irvine, Irvine, CA, USA.

The rodent is the natural reservoir of several tick-borne infections, including Lyme disease. To expand the knowledge base for this key species in life cycles of several pathogens, we assembled and scaffolded the genome. The resulting assembly was 2.45 Gb in total length, with 24 chromosome-length scaffolds harboring 97% of predicted genes. RNA sequencing following infection of with , a Lyme disease agent, shows that, unlike blood, the skin is actively responding to the infection after several weeks. has a high level of segregating nucleotide variation, suggesting that natural resistance alleles to Crispr gene targeting constructs are likely segregating in wild populations. The reference genome will allow for experiments aimed at elucidating the mechanisms by which this widely distributed rodent serves as natural reservoir for several infectious diseases of public health importance, potentially enabling intervention strategies.
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http://dx.doi.org/10.1126/sciadv.aaw6441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656541PMC
July 2019

Use of Fish Oil Nanoencapsulated with Gum Arabic Carrier in Low Fat Probiotic Fermented Milk.

Food Sci Anim Resour 2019 Apr 30;39(2):309-323. Epub 2019 Apr 30.

Department of Biotechnology and Plant Breeding, College of Agricultural Sciences and Food Industries, Science and Research Branch, Islamic Azad University, Tehran, Iran.

Fish oil consists of omega-3 fatty acids which play an important role in human health. Its susceptibility to oxidation causes considerable degradation during the processing and storage of food products. Accordingly, encapsulation of this ingredient through freeze drying was studied with the aim of protecting it against environmental conditions. Gum arabic (GA) was used as the wall material for fish oil nanoencapsulation where tween 80 was applied as the emulsifier. A water-in-oil (W/O) emulsion was prepared by sonication, containing 6% fish oil dispersed in aqueous solutions including 20% and 25% total wall material. The emulsion was sonicated at 24 kHz for 120 s. The emulsion was then freeze-dried and the nanocapsules were incorporated into probiotic fermented milk, with the effects of nanocapsules examined on the milk. The results showed that the nanoparticles encapsulated with 25% gum arabic and 4% emulsifier had the highest encapsulation efficiency (EE) (87.17%) and the lowest surface oil (31.66 mg/100 kg). Using nanoencapsulated fish oil in fermented milk significantly (p<0.05) increased the viability of as well as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) contents. The fermented milk sample containing fish oil nanoencapsulated with 25% wall material and 4% emulsifier yielded the greatest probiotic bacterial count (8.41 Log CFU/mL) and the lowest peroxide value (0.57 mEq/kg). Moreover, this sample had the highest EPA and DHA contents. Utilizing this nanoencapsulated fish oil did not adversely affect fermented milk overall acceptance. Therefore, it can be used for fortification of low fat probiotic fermented milk.
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http://dx.doi.org/10.5851/kosfa.2019.e25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533394PMC
April 2019

Hybrid Assembly of the Genome of the Entomopathogenic Nematode Identifies the X-Chromosome.

G3 (Bethesda) 2019 08 8;9(8):2687-2697. Epub 2019 Aug 8.

Department of Developmental and Cell Biology, University of California, Irvine, CA 92697,

Entomopathogenic nematodes from the genus are lethal insect parasites that quickly kill their insect hosts with the help of their symbiotic bacteria. is one of the most studied entomopathogens due to its broad lethality to diverse insect species and its effective commercial use as a biological control agent for insect pests, as well as a genetic model for studying parasitism, pathogenesis, and symbiosis. In this study, we used long-reads from the Pacific Biosciences platform and BioNano Genomics Irys system to assemble the most complete genome of the ALL strain to date, comprising 84.5 Mb in 16 scaffolds, with an N50 of 7.36 Mb. The largest scaffold, with 20.9 Mb, was identified as chromosome X based on sex-specific genome sequencing. The high level of contiguity allowed us to characterize gene density, repeat content, and GC content. RNA-seq data from 17 developmental stages, spanning from embryo to adult, were used to predict 30,957 gene models. Using this improved genome, we performed a macrosyntenic analysis to and and found chromosome X to be primarily orthologous to ' and ' chromosome II and IV. We also investigated the expansion of protein families and gene expression differences between adult male and female stage nematodes. This new genome and more accurate set of annotations provide a foundation for additional comparative genomic and gene expression studies within the clade and across the Nematoda phylum.
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http://dx.doi.org/10.1534/g3.119.400180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686942PMC
August 2019

A core set of venom proteins is released by entomopathogenic nematodes in the genus Steinernema.

PLoS Pathog 2019 05 1;15(5):e1007626. Epub 2019 May 1.

Department of Nematology, University of California, Riverside, California, United States of America.

Parasitic helminths release molecular effectors into their hosts and these effectors can directly damage host tissue and modulate host immunity. Excreted/secreted proteins (ESPs) are one category of parasite molecular effectors that are critical to their success within the host. However, most studies of nematode ESPs rely on in vitro stimulation or culture conditions to collect the ESPs, operating under the assumption that in vitro conditions mimic actual in vivo infection. This assumption is rarely if ever validated. Entomopathogenic nematodes (EPNs) are lethal parasites of insects that produce and release toxins into their insect hosts and are a powerful model parasite system. We compared transcriptional profiles of individual Steinernema feltiae nematodes at different time points of activation under in vitro and in vivo conditions and found that some but not all time points during in vitro parasite activation have similar transcriptional profiles with nematodes from in vivo infections. These findings highlight the importance of experimental validation of ESP collection conditions. Additionally, we found that a suite of genes in the neuropeptide pathway were downregulated as nematodes activated and infection progressed in vivo, suggesting that these genes are involved in host-seeking behavior and are less important during active infection. We then characterized the ESPs of activated S. feltiae infective juveniles (IJs) using mass spectrometry and identified 266 proteins that are released by these nematodes. In comparing these ESPs with those previously identified in activated S. carpocapsae IJs, we identified a core set of 52 proteins that are conserved and present in the ESPs of activated IJs of both species. These core venom proteins include both tissue-damaging and immune-modulating proteins, suggesting that the ESPs of these parasites include both a core set of effectors as well as a specialized set, more adapted to the particular hosts they infect.
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http://dx.doi.org/10.1371/journal.ppat.1007626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513111PMC
May 2019

miR-128 Restriction of LINE-1 (L1) Retrotransposition Is Dependent on Targeting hnRNPA1 mRNA.

Int J Mol Sci 2019 Apr 21;20(8). Epub 2019 Apr 21.

Department of Molecular Biology and Biochemistry, Francisco J. AyalaSchool of Biological Sciences, University of California, Irvine, CA 92697, USA.

The majority of the human genome is made of transposable elements, giving rise to interspaced repeats, including Long INterspersed Element-1s (LINE-1s or L1s). L1s are active human transposable elements involved in genomic diversity and evolution; however, they can also contribute to genomic instability and diseases. L1s require host factors to complete their life cycles, whereas the host has evolved numerous mechanisms to restrict L1-induced mutagenesis. Restriction mechanisms in somatic cells include methylation of the L1 promoter, anti-viral factors and RNA-mediated processes such as small RNAs. microRNAs (miRNAs or miRs) are small non-coding RNAs that post-transcriptionally repress multiple target genes often found in the same cellular pathways. We have recently established that miR-128 functions as a novel restriction factor inhibiting L1 mobilization in somatic cells. We have further demonstrated that miR-128 functions through a dual mechanism; by directly targeting L1 RNA for degradation and indirectly by inhibiting a cellular co-factor which L1 is dependent on to transpose to new genomic locations (TNPO1). Here, we add another piece to the puzzle of the enigmatic L1 lifecycle. We show that miR-128 also inhibits another key cellular factor, hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1), by significantly reducing mRNA and protein levels through direct interaction with the coding sequence (CDS) of hnRNPA1 mRNA. In addition, we demonstrate that repression of hnRNPA1 using hnRNPA1-shRNA significantly decreases de novo L1 retro-transposition and that induced hnRNPA1 expression enhances L1 mobilization. Furthermore, we establish that hnRNPA1 is a functional target of miR-128. Finally, we determine that induced hnRNPA1 expression in miR-128-overexpressing cells can partly rescue the miR-128-induced repression of L1's ability to transpose to different genomic locations. Thus, we have identified an additional mechanism by which miR-128 represses L1 retro-transposition and mediates genomic stability.
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http://dx.doi.org/10.3390/ijms20081955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515209PMC
April 2019

Feedforward regulation of Myc coordinates lineage-specific with housekeeping gene expression during B cell progenitor cell differentiation.

PLoS Biol 2019 04 12;17(4):e2006506. Epub 2019 Apr 12.

Unit of Computational Medicine, Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

The differentiation of self-renewing progenitor cells requires not only the regulation of lineage- and developmental stage-specific genes but also the coordinated adaptation of housekeeping functions from a metabolically active, proliferative state toward quiescence. How metabolic and cell-cycle states are coordinated with the regulation of cell type-specific genes is an important question, because dissociation between differentiation, cell cycle, and metabolic states is a hallmark of cancer. Here, we use a model system to systematically identify key transcriptional regulators of Ikaros-dependent B cell-progenitor differentiation. We find that the coordinated regulation of housekeeping functions and tissue-specific gene expression requires a feedforward circuit whereby Ikaros down-regulates the expression of Myc. Our findings show how coordination between differentiation and housekeeping states can be achieved by interconnected regulators. Similar principles likely coordinate differentiation and housekeeping functions during progenitor cell differentiation in other cell lineages.
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http://dx.doi.org/10.1371/journal.pbio.2006506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481923PMC
April 2019

Intra-individual methylomics detects the impact of early-life adversity.

Life Sci Alliance 2019 04 1;2(2). Epub 2019 Apr 1.

Department of Developmental and Cell Biology, University of California, Irvine, CA, USA

Genetic and environmental factors interact during sensitive periods early in life to influence mental health and disease via epigenetic processes such as DNA methylation. However, it is not known if DNA methylation changes outside the brain provide an "epigenetic signature" of early-life experiences. Here, we used a novel intra-individual approach by testing DNA methylation from buccal cells of individual rats before and immediately after exposure to one week of typical or adverse life experience. We find that whereas inter-individual changes in DNA methylation reflect the effect of age, DNA methylation changes within paired DNA samples from the same individual reflect the impact of diverse neonatal experiences. Genes coding for critical cellular metabolic enzymes, ion channels, and receptors were more methylated in pups exposed to the adverse environment, predictive of their repression. In contrast, the adverse experience was associated with less methylation on genes involved in pathways of death and inflammation as well as cell-fate-related transcription factors, indicating their potential up-regulation. Thus, intra-individual methylome signatures indicate large-scale transcription-driven alterations of cellular fate, growth, and function.
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http://dx.doi.org/10.26508/lsa.201800204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445397PMC
April 2019

A limited capacity for microglial repopulation in the adult brain.

Glia 2018 11 28;66(11):2385-2396. Epub 2018 Oct 28.

Department of Neurobiology and Behavior Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California.

Microglia are the resident immune cell of the central nervous system (CNS), and serve to protect and maintain the local brain environment. Microglia are critically dependent on signaling through the colony-stimulating factor 1 receptor (CSF1R); administration of CSF1R inhibitors that cross the blood brain barrier (BBB) lead to the elimination of up to 99% of microglia, depending on CNS exposure and treatment duration. Once microglia are depleted, withdrawal of inhibitor stimulates repopulation of the entire CNS with new cells, conceivably enabling a therapeutic strategy for beneficial renewal of the entire microglial tissue. We have explored the kinetics and limits of this repopulation event and show that the rate of microglial repopulation is proportional to the extent of microglial depletion - greater depletion of microglia results in more rapid repopulation. Using a CSF1R inhibitor formulation that eliminates approximately 99% of microglia within 7 days, we subjected mice to multiple rounds of elimination (7 days' treatment) and repopulation (7 days' recovery) and found that the brain only has the capacity for a single complete repopulation event; subsequent elimination and CSF1R inhibitor withdrawal fail to repopulate the brain. However, if the recovery time between, or after, cycles is extended sufficiently then the brain can ultimately repopulate. These kinetic studies define the opportunities and possible limits of the remarkable renewal capacities of microglia.
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http://dx.doi.org/10.1002/glia.23477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269202PMC
November 2018